RNA viruses in trypanosomatid parasites: a historical overview

PubMed Central

Grybchuk, Danyil; Kostygov, Alexei Y; Macedo, Diego H; d’Avila-Levy, Claudia M; Yurchenko, Vyacheslav

2018-01-01

Viruses of trypanosomatids are now being extensively studied because of their diversity and the roles they play in flagellates’ biology. Among the most prominent examples are leishmaniaviruses implicated in pathogenesis of Leishmania parasites. Here, we present a historical overview of this field, starting with early reports of virus-like particles on electron microphotographs, and culminating in detailed molecular descriptions of viruses obtained using modern next generation sequencing-based techniques. Because of their diversity, different life cycle strategies and host specificity, we believe that trypanosomatids are a fertile ground for further explorations to better understand viral evolution, routes of transitions, and molecular mechanisms of adaptation to different hosts. PMID:29513877

RNA viruses in trypanosomatid parasites: a historical overview.

PubMed

Grybchuk, Danyil; Kostygov, Alexei Y; Macedo, Diego H; d'Avila-Levy, Claudia M; Yurchenko, Vyacheslav

2018-02-19

Viruses of trypanosomatids are now being extensively studied because of their diversity and the roles they play in flagellates' biology. Among the most prominent examples are leishmaniaviruses implicated in pathogenesis of Leishmania parasites. Here, we present a historical overview of this field, starting with early reports of virus-like particles on electron microphotographs, and culminating in detailed molecular descriptions of viruses obtained using modern next generation sequencing-based techniques. Because of their diversity, different life cycle strategies and host specificity, we believe that trypanosomatids are a fertile ground for further explorations to better understand viral evolution, routes of transitions, and molecular mechanisms of adaptation to different hosts.

Infrared radiative energy transfer in gaseous systems

NASA Technical Reports Server (NTRS)

Tiwari, Surendra N.

1991-01-01

Analyses and numerical procedures are presented to investigate the radiative interactions in various energy transfer processes in gaseous systems. Both gray and non-gray radiative formulations for absorption and emission by molecular gases are presented. The gray gas formulations are based on the Planck mean absorption coefficient and the non-gray formulations are based on the wide band model correlations for molecular absorption. Various relations for the radiative flux and divergence of radiative flux are developed. These are useful for different flow conditions and physical problems. Specific plans for obtaining extensive results for different cases are presented. The procedure developed was applied to several realistic problems. Results of selected studies are presented.

Molecular heterogeneity at the network level: high-dimensional testing, clustering and a TCGA case study.

PubMed

Städler, Nicolas; Dondelinger, Frank; Hill, Steven M; Akbani, Rehan; Lu, Yiling; Mills, Gordon B; Mukherjee, Sach

2017-09-15

Molecular pathways and networks play a key role in basic and disease biology. An emerging notion is that networks encoding patterns of molecular interplay may themselves differ between contexts, such as cell type, tissue or disease (sub)type. However, while statistical testing of differences in mean expression levels has been extensively studied, testing of network differences remains challenging. Furthermore, since network differences could provide important and biologically interpretable information to identify molecular subgroups, there is a need to consider the unsupervised task of learning subgroups and networks that define them. This is a nontrivial clustering problem, with neither subgroups nor subgroup-specific networks known at the outset. We leverage recent ideas from high-dimensional statistics for testing and clustering in the network biology setting. The methods we describe can be applied directly to most continuous molecular measurements and networks do not need to be specified beforehand. We illustrate the ideas and methods in a case study using protein data from The Cancer Genome Atlas (TCGA). This provides evidence that patterns of interplay between signalling proteins differ significantly between cancer types. Furthermore, we show how the proposed approaches can be used to learn subtypes and the molecular networks that define them. As the Bioconductor package nethet. staedler.n@gmail.com or sach.mukherjee@dzne.de. Supplementary data are available at Bioinformatics online. © The Author(s) 2017. Published by Oxford University Press.

Validation, acceptance, and extension of a predictive model of reproductive toxicity using ToxCast data

EPA Science Inventory

The EPA ToxCast research program uses a high-throughput screening (HTS) approach for predicting the toxicity of large numbers of chemicals. Phase-I tested 309 well-characterized chemicals (mostly pesticides) in over 500 assays of different molecular targets, cellular responses an...

Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron.

PubMed

Xiao, Qingpin; Hu, Xiaohui; Wei, Zhiyi; Tam, Kin Yip

2016-01-01

Cells make use of molecular motors to transport small molecules, macromolecules and cellular organelles to target region to execute biological functions, which is utmost important for polarized cells, such as neurons. In particular, cytoskeleton motors play fundamental roles in neuron polarization, extension, shape and neurotransmission. Cytoskeleton motors comprise of myosin, kinesin and cytoplasmic dynein. F-actin filaments act as myosin track, while kinesin and cytoplasmic dynein move on microtubules. Cytoskeleton motors work together to build a highly polarized and regulated system in neuronal cells via different molecular mechanisms and functional regulations. This review discusses the structures and working mechanisms of the cytoskeleton motors in neurons.

X-ray-induced dissociation of H.sub.2O and formation of an O.sub.2-H.sub.2 alloy at high pressure

DOEpatents

Mao, Ho-kwang [Washington, DC; Mao, Wendy L [Washington, DC

2011-11-29

A novel molecular alloy of O.sub.2 and H.sub.2 and a method of producing such a molecular alloy are provided. When subjected to high pressure and extensive x-radiation, H.sub.2O molecules cleaved, forming O--O and H--H bonds. In the method of the present invention, the O and H framework in ice VII was converted into a molecular alloy of O.sub.2 and H.sub.2. X-ray diffraction, x-ray Raman scattering, and optical Raman spectroscopy demonstrate that this crystalline solid differs from previously known phases.

Hidden diversity within the lizard genus Liolaemus: Genetic vs morphological divergence in the L. rothi complex (Squamata:Liolaeminae).

PubMed

Olave, Melisa; Avila, Luciano J; Sites, Jack W; Morando, Mariana

2017-02-01

Currently, Liolaemus is the second most species-rich reptile genus in the world (257 species), and predictions of its real diversity suggest that it may be the most diverse genus. Originally, Liolaemus species were described as widely distributed and morphologically variable taxa, but extensive sampling in previously unexplored geographic areas, coupled with molecular and more extensive morphological studies, have discovered an unexpectedly high number of previously undetected species. Here, we study the level of molecular vs. morphological divergence within the L. rothi complex, combining a total of 14 loci (2 mitochondrial and 12 nuclear loci) for 97 individuals, as well as morphological data (nine morphometric and 15 color pattern variables), that represent all six described species of the L. rothi complex, plus two candidate species. We use the multi-coalescent species delimitation program iBPP and resolve strong differences in molecular divergence; and each species is inferred as an independent lineage supported by high posterior probabilities. However, morphological differences are not that clear, and our modeling of morphological characters suggests differential selection pressures implying some level of morphological stasis. We discuss the role of natural selection on phenotypic traits, which may be an important factor in "hiding" the real diversity of the genus. Copyright © 2016. Published by Elsevier Inc.

Quantum-SAR Extension of the Spectral-SAR Algorithm. Application to Polyphenolic Anticancer Bioactivity

PubMed Central

Putz, Mihai V.; Putz, Ana-Maria; Lazea, Marius; Ienciu, Luciana; Chiriac, Adrian

2009-01-01

Aiming to assess the role of individual molecular structures in the molecular mechanism of ligand-receptor interaction correlation analysis, the recent Spectral-SAR approach is employed to introduce the Quantum-SAR (QuaSAR) “wave” and “conversion factor” in terms of difference between inter-endpoint inter-molecular activities for a given set of compounds; this may account for inter-conversion (metabolization) of molecular (concentration) effects while indicating the structural (quantum) based influential/detrimental role on bio-/eco- effect in a causal manner rather than by simple inspection of measured values; the introduced QuaSAR method is then illustrated for a study of the activity of a series of flavonoids on breast cancer resistance protein. PMID:19399244

Recombinant proteins incorporating short non-native extensions may display increased aggregation propensity as detected by high resolution NMR spectroscopy

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

Zanzoni, Serena; D'Onofrio, Mariapina; Molinari, Henriette

2012-10-26

Highlights: Black-Right-Pointing-Pointer Bile acid binding proteins from different constructs retain structural integrity. Black-Right-Pointing-Pointer NMR {sup 15}N-T{sub 1} relaxation data of BABPs show differences if LVPR extension is present. Black-Right-Pointing-Pointer Deviations from a {sup 15}N-T{sub 1}/molecular-weight calibration curve indicate aggregation. -- Abstract: The use of a recombinant protein to investigate the function of the native molecule requires that the former be obtained with the same amino acid sequence as the template. However, in many cases few additional residues are artificially introduced for cloning or purification purposes, possibly resulting in altered physico-chemical properties that may escape routine characterization. For example, increased aggregationmore » propensity without visible protein precipitation is hardly detected by most analytical techniques but its investigation may be of great importance for optimizing the yield of recombinant protein production in biotechnological and structural biology applications. In this work we show that bile acid binding proteins incorporating the common C-terminal LeuValProArg extension display different hydrodynamic properties from those of the corresponding molecules without such additional amino acids. The proteins were produced enriched in nitrogen-15 for analysis via heteronuclear NMR spectroscopy. Residue-specific spin relaxation rates were measured and related to rotational tumbling time and molecular size. While the native-like recombinant proteins show spin-relaxation rates in agreement with those expected for monomeric globular proteins of their mass, our data indicate the presence of larger adducts for samples of proteins with very short amino acid extensions. The used approach is proposed as a further screening method for the quality assessment of biotechnological protein products.« less

Polymeric proanthocyanidins from the bark of Hamamelis virginiana.

PubMed

Dauer, A; Rimpler, H; Hensel, A

2003-01-01

Polymeric proanthocyanidins were isolated from the bark of Hamamelis virginiana L. in yields of about 5 %. Fractionation yielded fractions with similar structures but different molecular weights with DP between 17-29 (thiolysis) and 11-20 (GPC). Polymers were composed predominantly of epicatechin and epigallocatechin as chain extension units at ratio of about 1.3:1. Terminal chain units were catechin (approximately 95 %) and gallocatechin (approximately 5 %). All chain extension units were completely galloylated at position O-3, while chain terminating units were not galloylated. Predominant interflavan linkages were 4 --> 8-bonds.

A search for interstellar nitrous oxide

NASA Technical Reports Server (NTRS)

Wilson, W. J.; Snyder, L. E.

1981-01-01

An extensive search for interstellar nitrous oxide (N2O) has been made at two different frequencies, 75.4 and 100.5 GHz, in a number of molecular sources. No N2O signal was detected; however, a number of other spectral lines including two new transitions of methyl formate and several new unidentified lines were measured.

Sequence analysis of a bitter taste receptor gene repertoires in different ruminant species

USDA-ARS?s Scientific Manuscript database

Bitter taste has been extensively studied in mammalian species and is associated with sensitivity to toxins and with food choices that avoid dangerous substances in the diet. At the molecular level, bitter compounds are sensed by bitter taste receptor proteins (T2R) present at the surface of taste r...

Effect of the molecular weight of a neutral polysaccharide on soy protein gelation.

PubMed

Monteiro, Sónia R; Lopes-da-Silva, José A

2017-12-01

The effects of galactomannans with different molecular weights on the heat-induced gelation characteristics of soybean protein were investigated using dynamic small-strain rheometry, under conditions where the proteins carry a net negative charge (pH7). Microstructure of the resulting gels was investigated by confocal laser scanning microscopy. Phase-separated systems were obtained with different morphologies and degree of phase separation, depending on both biopolymer concentrations and polysaccharide molecular weight. In general, a gelling enhancing effect on soy proteins was verified, despite extensive phase-separation processes observed at the higher polysaccharide molecular weight. This effect was demonstrated by an increase of the gelation rate, a decrease in the temperature at the onset of gelation, and an increase of gel stiffness and elastic character, with the length of polysaccharide chains. Overall, the results obtained established that the judicious selection of the galactomannan molecular weight may be used to modify the structure and gelation properties of soy proteins, originating a diversity of rheological characteristics and microstructures that will impact on the design of novel food formulations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Extension of a Kinetic-Theory Approach for Computing Chemical-Reaction Rates to Reactions with Charged Particles

NASA Technical Reports Server (NTRS)

Liechty, Derek S.; Lewis, Mark J.

2010-01-01

Recently introduced molecular-level chemistry models that predict equilibrium and nonequilibrium reaction rates using only kinetic theory and fundamental molecular properties (i.e., no macroscopic reaction rate information) are extended to include reactions involving charged particles and electronic energy levels. The proposed extensions include ionization reactions, exothermic associative ionization reactions, endothermic and exothermic charge exchange reactions, and other exchange reactions involving ionized species. The extensions are shown to agree favorably with the measured Arrhenius rates for near-equilibrium conditions.

Squamous cell carcinoma – similarities and differences among anatomical sites

PubMed Central

Yan, Wusheng; Wistuba, Ignacio I; Emmert-Buck, Michael R; Erickson, Heidi S

2011-01-01

Squamous cell carcinoma (SCC) is an epithelial malignancy involving many anatomical sites and is the most common cancer capable of metastatic spread. Development of early diagnosis methods and novel therapeutics are important for prevention and mortality reduction. In this effort, numerous molecular alterations have been described in SCCs. SCCs share many phenotypic and molecular characteristics, but they have not been extensively compared. This article reviews SCC as a disease, including: epidemiology, pathology, risk factors, molecular characteristics, prognostic markers, targeted therapy, and a new approach to studying SCCs. Through this comparison, several themes are apparent. For example, HPV infection is a common risk factor among the four major SCCs (NMSC, HNSC, ESCC, and NSCLC) and molecular abnormalities in cell-cycle regulation and signal transduction predominate. These data reveal that the molecular insights, new markers, and drug targets discovered in individual SCCs may shed light on this type of cancer as a whole. PMID:21938273

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

Maaloum, M.; Muller, P.; Beker, A-F.

Almost two decades ago, measurements of force versus extension on isolated double-stranded DNA molecules revealed a force plateau. This unusual stretching phenomenon in DNA suggests that the long molecules may be extended from the usual B form into a new conformation. Different models have been proposed to describe the nature of DNA in its stretched form, S-DNA. Using atomic force microscopy combined with a molecular combing method, we identified the structure of {lambda}-phage DNA for different stretching values. We provide strong evidence for the existence of a first-order transition between B form and S form. Beyond a certain extension ofmore » the natural length, DNA molecules adopt a new double-helix conformation characterized by a diameter of 1.2 nm and a helical pitch of18 nm.« less

Neuronal cell fate specification by the molecular convergence of different spatio-temporal cues on a common initiator terminal selector gene

PubMed Central

Stratmann, Johannes

2017-01-01

The extensive genetic regulatory flows underlying specification of different neuronal subtypes are not well understood at the molecular level. The Nplp1 neuropeptide neurons in the developing Drosophila nerve cord belong to two sub-classes; Tv1 and dAp neurons, generated by two distinct progenitors. Nplp1 neurons are specified by spatial cues; the Hox homeotic network and GATA factor grn, and temporal cues; the hb -> Kr -> Pdm -> cas -> grh temporal cascade. These spatio-temporal cues combine into two distinct codes; one for Tv1 and one for dAp neurons that activate a common terminal selector feedforward cascade of col -> ap/eya -> dimm -> Nplp1. Here, we molecularly decode the specification of Nplp1 neurons, and find that the cis-regulatory organization of col functions as an integratory node for the different spatio-temporal combinatorial codes. These findings may provide a logical framework for addressing spatio-temporal control of neuronal sub-type specification in other systems. PMID:28414802

Synthesis and characterization of superparamagnetic iron-oxide nanoparticles (SPIONs) and utilization of SPIONs in X-ray imaging

NASA Astrophysics Data System (ADS)

Justin, C.; Philip, Sheryl Ann; Samrot, Antony V.

2017-10-01

The versatility of superparamagnetic iron-oxide nanoparticles (SPIONs) have been extensively investigated, especially for their applications in therapeutics and diagnostics. Considering their intriguing feature of contrasting agent, in terms of medical applications, it is still in its infancy. Various physicochemical parameters like magnetism, crystallinity, and optical parameters contribute to their better contrasting agent. In this study, SPIONs were synthesized with different concentrations of precursor iron molecular solution in the presence of magnetic field and the optimum concentration of precursor iron molecular solution was determined as 0.133%. SPIONs obtained at optimum concentration were further analyzed by both microscopic and spectroscopic analysis. The difference occurred in the elemental nature of SPIONs as they were synthesized in the magnetic field out of precursor iron molecular solution was analyzed with a specific reference to NMR spectroscopy. SPIONs as contrasting agent against X-ray imaging was also investigated in quail's egg.

Adaptively biased molecular dynamics for free energy calculations

NASA Astrophysics Data System (ADS)

Babin, Volodymyr; Roland, Christopher; Sagui, Celeste

2008-04-01

We present an adaptively biased molecular dynamics (ABMD) method for the computation of the free energy surface of a reaction coordinate using nonequilibrium dynamics. The ABMD method belongs to the general category of umbrella sampling methods with an evolving biasing potential and is inspired by the metadynamics method. The ABMD method has several useful features, including a small number of control parameters and an O(t ) numerical cost with molecular dynamics time t. The ABMD method naturally allows for extensions based on multiple walkers and replica exchange, where different replicas can have different temperatures and/or collective variables. This is beneficial not only in terms of the speed and accuracy of a calculation, but also in terms of the amount of useful information that may be obtained from a given simulation. The workings of the ABMD method are illustrated via a study of the folding of the Ace-GGPGGG-Nme peptide in a gaseous and solvated environment.

Integrating sequence and structural biology with DAS

PubMed Central

Prlić, Andreas; Down, Thomas A; Kulesha, Eugene; Finn, Robert D; Kähäri, Andreas; Hubbard, Tim JP

2007-01-01

Background The Distributed Annotation System (DAS) is a network protocol for exchanging biological data. It is frequently used to share annotations of genomes and protein sequence. Results Here we present several extensions to the current DAS 1.5 protocol. These provide new commands to share alignments, three dimensional molecular structure data, add the possibility for registration and discovery of DAS servers, and provide a convention how to provide different types of data plots. We present examples of web sites and applications that use the new extensions. We operate a public registry of DAS sources, which now includes entries for more than 250 distinct sources. Conclusion Our DAS extensions are essential for the management of the growing number of services and exchange of diverse biological data sets. In addition the extensions allow new types of applications to be developed and scientific questions to be addressed. The registry of DAS sources is available at PMID:17850653

Modeling AFM-induced PEVK extension and the reversible unfolding of Ig/FNIII domains in single and multiple titin molecules.

PubMed Central

Zhang, B; Evans, J S

2001-01-01

Molecular elasticity is associated with a select number of polypeptides and proteins, such as titin, Lustrin A, silk fibroin, and spider silk dragline protein. In the case of titin, the globular (Ig) and non-globular (PEVK) regions act as extensible springs under stretch; however, their unfolding behavior and force extension characteristics are different. Using our time-dependent macroscopic method for simulating AFM-induced titin Ig domain unfolding and refolding, we simulate the extension and relaxation of hypothetical titin chains containing Ig domains and a PEVK region. Two different models are explored: 1) a series-linked WLC expression that treats the PEVK region as a distinct entropic spring, and 2) a summation of N single WLC expressions that simulates the extension and release of a discrete number of parallel titin chains containing constant or variable amounts of PEVK. In addition to these simulations, we also modeled the extension of a hypothetical PEVK domain using a linear Hooke's spring model to account for "enthalpic" contributions to PEVK elasticity. We find that the modified WLC simulations feature chain length compensation, Ig domain unfolding/refolding, and force-extension behavior that more closely approximate AFM, laser tweezer, and immunolocalization experimental data. In addition, our simulations reveal the following: 1) PEVK extension overlaps with the onset of Ig domain unfolding, and 2) variations in PEVK content within a titin chain ensemble lead to elastic diversity within that ensemble. PMID:11159428

Strategic placement of stereogenic centers in molecular materials for second harmonic generation.

PubMed

Gangopadhyay, P; Rao, D Narayana; Agranat, Israel; Radhakrishnan, T P

2002-01-01

Basic aspects of the nonlinear optical phenomenon of second harmonic generation (SHG) and the assembly of molecular materials for SHG are reviewed. Extensive use of chirality as a convenient tool to generate noncentrosymmetricity in molecular lattices, an essential requirement for the development of quadratic nonlinear optical materials, is noted. An overview of our investigations of chiral diaminodicyanoquinodimethanes is presented, which provides insight into a systematic approach to the effective deployment of chirality to achieve optimal molecular orientations for enhanced solid state SHG. Extension of these ideas to the realization of strong SHG in materials based on helical superstructures is outlined.

The different mechanisms of sporophytic self-incompatibility.

PubMed

Hiscock, Simon J; Tabah, David A

2003-06-29

Flowering plants have evolved a multitude of mechanisms to avoid self-fertilization and promote outbreeding. Self-incompatibility (SI) is by far the most common of these, and is found in ca. 60% of flowering plants. SI is a genetically controlled pollen-pistil recognition system that provides a barrier to fertilization by self and self-related pollen in hermaphrodite (usually co-sexual) flowering plants. Two genetically distinct forms of SI can be recognized: gametophytic SI (GSI) and sporophytic SI (SSI), distinguished by how the incompatibility phenotype of the pollen is determined. GSI appears to be the most common mode of SI and can operate through at least three different mechanisms, two of which have been characterized extensively at a molecular level in the Solanaceae and Papaveraceae. Because molecular studies of SSI have been largely confined to species from the Brassicaceae, predominantly Brassica species, it is not yet known whether SSI, like GSI, can operate through different molecular mechanisms. Molecular studies of SSI are now being carried out on Ipomoea trifida (Convolvulaceae) and Senecio squalidus (Asteraceae) and are providing important preliminary data suggesting that SSI in these two families does not share the same molecular mechanism as that of the Brassicaceae. Here, what is currently known about the molecular regulation of SSI in the Brassicaceae is briefly reviewed, and the emerging data on SSI in I. trifida, and more especially in S. squalidus, are discussed.

The Halogen Bond

PubMed Central

2016-01-01

The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. In this fairly extensive review, after a brief history of the interaction, we will provide the reader with a snapshot of where the research on the halogen bond is now, and, perhaps, where it is going. The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design. PMID:26812185

Interpretation of screen factor measurements

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

Lim, T.; Uhl, J.T.; Prud'Homme, R.K.

1983-08-01

Screen viscometer measurements give different information about polymer molecular weight and molecular weight distribution than intrinsic viscosity or relative viscosity measurements. This study shows that conventional screen viscometers measure elongation flow properties of solutions, and that for flexible polymers such as polyacrylamides, a sharp transition in conformation from a coiled to a stretched state is observed, which occurs at a Deborah number of 0.5. Conventional screen viscometers operate just above this critical Deborah number. Evidence for this transition in polymer conformation comes from measurements on a modified screen viscometer, from extensive work by Durst and Interhal on the sudden pressuremore » jumps during flow of polyacrylamide solutions through porous media, and from polymer kinetic theory modeling of molecular deformation in flow. ll references.« less

Exploring molecular networks using MONET ontology.

PubMed

Silva, João Paulo Müller da; Lemke, Ney; Mombach, José Carlos; Souza, José Guilherme Camargo de; Sinigaglia, Marialva; Vieira, Renata

2006-03-31

The description of the complex molecular network responsible for cell behavior requires new tools to integrate large quantities of experimental data in the design of biological information systems. These tools could be used in the characterization of these networks and in the formulation of relevant biological hypotheses. The building of an ontology is a crucial step because it integrates in a coherent framework the concepts necessary to accomplish such a task. We present MONET (molecular network), an extensible ontology and an architecture designed to facilitate the integration of data originating from different public databases in a single- and well-documented relational database, that is compatible with MONET formal definition. We also present an example of an application that can easily be implemented using these tools.

BioFrameNet: A FrameNet Extension to the Domain of Molecular Biology

ERIC Educational Resources Information Center

Dolbey, Andrew Eric

2009-01-01

In this study I introduce BioFrameNet, an extension of the Berkeley FrameNet lexical database to the domain of molecular biology. I examine the syntactic and semantic combinatorial possibilities exhibited in the lexical items used in this domain in order to get a better understanding of the grammatical properties of the language used in scientific…

Dynamics of Poly(methyl methacrylate) and Polystyrene Thin Films on Hydrophobic and Hydrophilic Surfaces

NASA Astrophysics Data System (ADS)

Tsige, Mesfin

While an extensive literature dealing with the structure and dynamics of polymers at surfaces and interfaces exist, there has been a paucity of information regarding the length scale of the influence of the surface on polymer mobility and its dependence on polymer-surface interaction. To address this issue, we have investigated using molecular dynamics simulations the dynamics of PMMA and PS films of similar system sizes on two different surfaces as a function of film thickness, polymer molecular weight, and temperature. The dynamics of the polymer chains in the film on two different surfaces will be discussed in the context of a three-layer model. This work was supported by NSF Grant DMR1410290.

Structural Characterization of the Low-Molecular-Weight Heparin Dalteparin by Combining Different Analytical Strategies.

PubMed

Bisio, Antonella; Urso, Elena; Guerrini, Marco; de Wit, Pauline; Torri, Giangiacomo; Naggi, Annamaria

2017-06-24

A number of low molecular weight heparin (LMWH) products are available for clinical use and although all share a similar mechanism of action, they are classified as distinct drugs because of the different depolymerisation processes of the native heparin resulting in substantial pharmacokinetic and pharmacodynamics differences. While enoxaparin has been extensively investigated, little information is available regarding the LMWH dalteparin. The present study is focused on the detailed structural characterization of Fragmin ® by LC-MS and NMR applied both to the whole drug and to its enzymatic products. For a more in-depth approach, size homogeneous octasaccharide and decasaccharide components together with their fractions endowed with high or no affinity toward antithrombin were also isolated and their structural profiles characterized. The combination of different analytical strategies here described represents a useful tool for the assessment of batch-to-batch structural variability and for comparative evaluation of structural features of biosimilar products.

Functional optical coherence tomography: principles and progress

NASA Astrophysics Data System (ADS)

Kim, Jina; Brown, William; Maher, Jason R.; Levinson, Howard; Wax, Adam

2015-05-01

In the past decade, several functional extensions of optical coherence tomography (OCT) have emerged, and this review highlights key advances in instrumentation, theoretical analysis, signal processing and clinical application of these extensions. We review five principal extensions: Doppler OCT (DOCT), polarization-sensitive OCT (PS-OCT), optical coherence elastography (OCE), spectroscopic OCT (SOCT), and molecular imaging OCT. The former three have been further developed with studies in both ex vivo and in vivo human tissues. This review emphasizes the newer techniques of SOCT and molecular imaging OCT, which show excellent potential for clinical application but have yet to be well reviewed in the literature. SOCT elucidates tissue characteristics, such as oxygenation and carcinogenesis, by detecting wavelength-dependent absorption and scattering of light in tissues. While SOCT measures endogenous biochemical distributions, molecular imaging OCT detects exogenous molecular contrast agents. These newer advances in functional OCT broaden the potential clinical application of OCT by providing novel ways to understand tissue activity that cannot be accomplished by other current imaging methodologies.

Functional Optical Coherence Tomography: Principles and Progress

PubMed Central

Kim, Jina; Brown, William; Maher, Jason R.; Levinson, Howard; Wax, Adam

2015-01-01

In the past decade, several functional extensions of optical coherence tomography (OCT) have emerged, and this review highlights key advances in instrumentation, theoretical analysis, signal processing and clinical application of these extensions. We review five principal extensions: Doppler OCT (DOCT), polarization-sensitive OCT (PS-OCT), optical coherence elastography (OCE), spectroscopic OCT (SOCT), and molecular imaging OCT. The former three have been further developed with studies in both ex vivo and in vivo human tissues. This review emphasizes the newer techniques of SOCT and molecular imaging OCT, which show excellent potential for clinical application but have yet to be well reviewed in the literature. SOCT elucidates tissue characteristics, such as oxygenation and carcinogenesis, by detecting wavelength-dependent absorption and scattering of light in tissues. While SOCT measures endogenous biochemical distributions, molecular imaging OCT detects exogenous molecular contrast agents. These newer advances in functional OCT broaden the potential clinical application of OCT by providing novel ways to understand tissue activity that cannot be accomplished by other current imaging methodologies. PMID:25951836

Long non-coding RNAs as molecular players in plant defense against pathogens.

PubMed

Zaynab, Madiha; Fatima, Mahpara; Abbas, Safdar; Umair, Muhammad; Sharif, Yasir; Raza, Muhammad Ammar

2018-05-31

Long non-coding RNAs (lncRNAs) has significant role in of gene expression and silencing pathways for several biological processes in eukaryotes. lncRNAs has been reported as key player in remodeling chromatin and genome architecture, RNA stabilization and transcription regulation, including enhancer-associated activity. Host lncRNAs are reckoned as compulsory elements of plant defense. In response to pathogen attack, plants protect themselves with the help of lncRNAs -dependent immune systems in which lncRNAs regulate pathogen-associated molecular patterns (PAMPs) and other effectors. Role of lncRNAs in plant microbe interaction has been studied extensively but regulations of several lncRNAs still need extensive research. In this study we discussed and provide as overview the topical advancements and findings relevant to pathogen attack and plant defense mediated by lncRNAs. It is hoped that lncRNAs would be exploited as a mainstream player to achieve food security by tackling different plant diseases. Copyright © 2018. Published by Elsevier Ltd.

Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways

PubMed Central

Simons, Matias; Gloy, Joachim; Ganner, Athina; Bullerkotte, Axel; Bashkurov, Mikhail; Krönig, Corinna; Schermer, Bernhard; Benzing, Thomas; Cabello, Olga A; Jenny, Andreas; Mlodzik, Marek; Polok, Bozena; Driever, Wolfgang; Obara, Tomoko; Walz, Gerd

2013-01-01

Cystic renal diseases are caused by mutations of proteins that share a unique subcellular localization: the primary cilium of tubular epithelial cells1. Mutations of the ciliary protein inversin cause nephronophthisis type II, an autosomal recessive cystic kidney disease characterized by extensive renal cysts, situs inversus and renal failure2. Here we report that inversin acts as a molecular switch between different Wnt signaling cascades. Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation; concomitantly, it is required for convergent extension movements in gastrulating Xenopus laevis embryos and elongation of animal cap explants, both regulated by noncanonical Wnt signaling. In zebrafish, the structurally related switch molecule diversin ameliorates renal cysts caused by the depletion of inversin, implying that an inhibition of canonical Wnt signaling is required for normal renal development. Fluid flow increases inversin levels in ciliated tubular epithelial cells and seems to regulate this crucial switch between Wnt signaling pathways during renal development. PMID:15852005

Calculating the Bending Modulus for Multicomponent Lipid Membranes in Different Thermodynamic Phases

PubMed Central

2013-01-01

We establish a computational approach to extract the bending modulus, KC, for lipid membranes from relatively small-scale molecular simulations. Fluctuations in the splay of individual pairs of lipids faithfully inform on KC in multicomponent membranes over a large range of rigidities in different thermodynamic phases. Predictions are validated by experiments even where the standard spectral analysis-based methods fail. The local nature of this method potentially allows its extension to calculations of KC in protein-laden membranes. PMID:24039553

Information Theory Broadens the Spectrum of Molecular Ecology and Evolution.

PubMed

Sherwin, W B; Chao, A; Jost, L; Smouse, P E

2017-12-01

Information or entropy analysis of diversity is used extensively in community ecology, and has recently been exploited for prediction and analysis in molecular ecology and evolution. Information measures belong to a spectrum (or q profile) of measures whose contrasting properties provide a rich summary of diversity, including allelic richness (q=0), Shannon information (q=1), and heterozygosity (q=2). We present the merits of information measures for describing and forecasting molecular variation within and among groups, comparing forecasts with data, and evaluating underlying processes such as dispersal. Importantly, information measures directly link causal processes and divergence outcomes, have straightforward relationship to allele frequency differences (including monotonicity that q=2 lacks), and show additivity across hierarchical layers such as ecology, behaviour, cellular processes, and nongenetic inheritance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular Structure and Free Energy Landscape for Electron Transport in the Deca-Heme Cytochrome MtrF

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

Breuer, Marian; Zarzycki, Piotr P.; Shi, Liang

2012-12-01

The free energy profile for electron flow through the bacterial deca-heme cytochrome MtrF has been computed using thermodynamic integration and classical molecular dynamics. The extensive calculations on two versions of the structure help validate the method and results, because differences in the profiles can be related to differences in the charged amino acids local to specific heme groups. First estimates of reorganization free energies λ yield a range consistent with expectations for partially solvent exposed cofactors, and reveal an activation energy range surmountable for electron flow. Future work will aim at increasing the accuracy of λ with polarizable force fieldmore » dynamics and quantum chemical energy gap calculations, as well as quantum chemical computation of electronic coupling matrix elements.« less

Molecular properties of the N-terminal extension of the fission yeast kinesin-5, Cut7.

PubMed

Edamatsu, M

2016-02-11

Kinesin-5 plays an essential role in spindle formation and function, and serves as a potential target for anti-cancer drugs. The aim of this study was to elucidate the molecular properties of the N-terminal extension of the Schizosaccharomyces pombe kinesin-5, Cut7. This extension is rich in charged amino acids and predicted to be intrinsically disordered. In S. pombe cells, a Cut7 construct lacking half the N-terminal extension failed to localize along the spindle microtubules and formed a monopolar spindle. However, a construct lacking the entire N-terminal extension exhibited normal localization and formed a typical bipolar spindle. In addition, in vitro analyses revealed that the truncated Cut7 constructs demonstrated similar motile velocities and directionalities as the wild-type motor protein, but the microtubule landing rates were significantly reduced. These findings suggest that the N-terminal extension is not required for normal Cut7 intracellular localization or function, but alters the microtubule-binding properties of this protein in vitro.

Molecular genotyping of ABO blood groups in some population groups from India.

PubMed

Ray, Sabita; Gorakshakar, Ajit C; Vasantha, K; Nadkarni, Anita; Italia, Yazdi; Ghosh, Kanjaksha

2014-01-01

Indian population is characterized by the presence of various castes and tribal groups. Various genetic polymorphisms have been used to differentiate among these groups. Amongst these, the ABO blood group system has been extensively studied. There is no information on molecular genotyping of ABO blood groups from India. Therefore, the main objective of this study was to characterize the common A, B and O alleles by molecular analysis in some Indian population groups. One hundred samples from the mixed population from Mumbai, 101 samples from the Dhodia tribe and 100 samples from the Parsi community were included in this study. Initially, the samples were phenotyped by standard serologic techniques. PCR followed by single strand conformational polymorphsim (SSCP) was used for molecular ABO genotyping. Samples showing atypical SSCP patterns were further analysed by DNA sequencing to characterize rare alleles. Seven common ABO alleles with 19 different genotypes were found in the mixed population. The Dhodias showed 12 different ABO genotypes and the Parsis revealed 15 different ABO genotypes with six common ABO alleles identified in each of them. Two rare alleles were also identified. This study reports the distribution of molecular genotypes of ABO alleles among some population groups from India. Considering the extremely heterogeneous nature of the Indian population, in terms of various genotype markers like blood groups, red cell enzymes, etc., many more ABO alleles are likely to be encountered.

Molecular Dynamics Simulations of the [2Fe-2S] Cluster-Binding Domain of NEET Proteins Reveal Key Molecular Determinants That Induce Their Cluster Transfer/Release.

PubMed

Pesce, Luca; Calandrini, Vania; Marjault, Henri-Baptiste; Lipper, Colin H; Rossetti, Gulia; Mittler, Ron; Jennings, Patricia A; Bauer, Andreas; Nechushtai, Rachel; Carloni, Paolo

2017-11-30

The NEET proteins are a novel family of iron-sulfur proteins characterized by an unusual three cysteine and one histidine coordinated [2Fe-2S] cluster. Aberrant cluster release, facilitated by the breakage of the Fe-N bond, is implicated in a variety of human diseases, including cancer. Here, the molecular dynamics in the multi-microsecond timescale, along with quantum chemical calculations, on two representative members of the family (the human NAF-1 and mitoNEET proteins), show that the loss of the cluster is associated with a dramatic decrease in secondary and tertiary structure. In addition, the calculations provide a mechanism for cluster release and clarify, for the first time, crucial differences existing between the two proteins, which are reflected in the experimentally observed difference in the pH-dependent cluster reactivity. The reliability of our conclusions is established by an extensive comparison with the NMR data of the solution proteins, in part measured in this work.

Visualizing the Role of Molecular Orbitals in Charge Transport through Individual Diarylethene Isomers

PubMed Central

2016-01-01

Diarylethene molecules are prototype molecular switches with their two isomeric forms exhibiting strikingly different conductance, while maintaining similar length. We employed low-temperature scanning tunneling microscopy (STM) to resolve the energy and the spatial extend of the molecular orbitals of the open and closed isomers when lying on a Au(111) surface. We find an intriguing difference in the extension of the respective HOMOs and a peculiar energy splitting of the formerly degenerate LUMO of the open isomer. We then lift the two isomers with the tip of the STM and measure the current through the individual molecules. By a simple analytical model of the transport, we show that the previously determined orbital characteristics are essential ingredients for the complete understanding of the transport properties. We also succeeded in switching the suspended molecules by the current, while switching the ones which are in direct contact to the surface occurs nonlocally with the help of the electric field of the tip. PMID:27775886

Single-molecule analysis of the major glycopolymers of pathogenic and non-pathogenic yeast cells

NASA Astrophysics Data System (ADS)

El-Kirat-Chatel, Sofiane; Beaussart, Audrey; Alsteens, David; Sarazin, Aurore; Jouault, Thierry; Dufrêne, Yves F.

2013-05-01

Most microbes are coated with carbohydrates that show remarkable structural variability and play a crucial role in mediating microbial-host interactions. Understanding the functions of cell wall glycoconjugates requires detailed knowledge of their molecular organization, diversity and heterogeneity. Here we use atomic force microscopy (AFM) with tips bearing specific probes (lectins, antibodies) to analyze the major glycopolymers of pathogenic and non-pathogenic yeast cells at molecular resolution. We show that non-ubiquitous β-1,2-mannans are largely exposed on the surface of native cells from pathogenic Candida albicans and C. glabrata, the former species displaying the highest glycopolymer density and extensions. We also find that chitin, a major component of the inner layer of the yeast cell wall, is much more abundant in C. albicans. These differences in molecular properties, further supported by flow cytometry measurements, may play an important role in strengthening cell wall mechanics and immune interactions. This study demonstrates that single-molecule AFM, combined with immunological and fluorescence methods, is a powerful platform in fungal glycobiology for probing the density, distribution and extension of specific cell wall glycoconjugates. In nanomedicine, we anticipate that this new form of AFM-based nanoglycobiology will contribute to the development of sugar-based drugs, immunotherapeutics, vaccines and diagnostics.

A Computational Framework for 3D Mechanical Modeling of Plant Morphogenesis with Cellular Resolution

PubMed Central

Gilles, Benjamin; Hamant, Olivier; Boudaoud, Arezki; Traas, Jan; Godin, Christophe

2015-01-01

The link between genetic regulation and the definition of form and size during morphogenesis remains largely an open question in both plant and animal biology. This is partially due to the complexity of the process, involving extensive molecular networks, multiple feedbacks between different scales of organization and physical forces operating at multiple levels. Here we present a conceptual and modeling framework aimed at generating an integrated understanding of morphogenesis in plants. This framework is based on the biophysical properties of plant cells, which are under high internal turgor pressure, and are prevented from bursting because of the presence of a rigid cell wall. To control cell growth, the underlying molecular networks must interfere locally with the elastic and/or plastic extensibility of this cell wall. We present a model in the form of a three dimensional (3D) virtual tissue, where growth depends on the local modulation of wall mechanical properties and turgor pressure. The model shows how forces generated by turgor-pressure can act both cell autonomously and non-cell autonomously to drive growth in different directions. We use simulations to explore lateral organ formation at the shoot apical meristem. Although different scenarios lead to similar shape changes, they are not equivalent and lead to different, testable predictions regarding the mechanical and geometrical properties of the growing lateral organs. Using flower development as an example, we further show how a limited number of gene activities can explain the complex shape changes that accompany organ outgrowth. PMID:25569615

Light Vision Color

NASA Astrophysics Data System (ADS)

Valberg, Arne

2005-04-01

Light Vision Color takes a well-balanced, interdisciplinary approach to our most important sensory system. The book successfully combines basics in vision sciences with recent developments from different areas such as neuroscience, biophysics, sensory psychology and philosophy. Originally published in 1998 this edition has been extensively revised and updated to include new chapters on clinical problems and eye diseases, low vision rehabilitation and the basic molecular biology and genetics of colour vision. Takes a broad interdisciplinary approach combining basics in vision sciences with the most recent developments in the area Includes an extensive list of technical terms and explanations to encourage student understanding Successfully brings together the most important areas of the subject in to one volume

Structure and photochromic properties of molybdenum-containing silica gels obtained by molecular-lamination method

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

Belotserkovskaya, N.G.; Dobychin, D.P.; Pak, V.N.

1992-05-10

The structure and physicochemical properties of molybdenum-containing silica gels obtained by molecular lamination have been studied quite extensively. Up to the present, however, no studies have been made of the influence of the pore structure of the original silica gel on the structure and properties of molybdenum-containing silica gels (MSG). The problem is quite important, since molybdenum silicas obtained by molecular lamination may find applications in catalysis and as sensors of UV radiation. In either case, the structure of the support is not a factor to be ignored. Here, the authors are reporting on an investigation of the structure ofmore » MSG materials with different pore structures and their susceptibility to reduction of the Mo(VI) oxide groupings when exposed to UV radiation. 16 refs., 2 figs., 2 tabs.« less

Potential for protein surface shape analysis using spherical harmonics and 3D Zernike descriptors.

PubMed

Venkatraman, Vishwesh; Sael, Lee; Kihara, Daisuke

2009-01-01

With structure databases expanding at a rapid rate, the task at hand is to provide reliable clues to their molecular function and to be able to do so on a large scale. This, however, requires suitable encodings of the molecular structure which are amenable to fast screening. To this end, moment-based representations provide a compact and nonredundant description of molecular shape and other associated properties. In this article, we present an overview of some commonly used representations with specific focus on two schemes namely spherical harmonics and their extension, the 3D Zernike descriptors. Key features and differences of the two are reviewed and selected applications are highlighted. We further discuss recent advances covering aspects of shape and property-based comparison at both global and local levels and demonstrate their applicability through some of our studies.

Efficient molecular dynamics simulations with many-body potentials on graphics processing units

NASA Astrophysics Data System (ADS)

Fan, Zheyong; Chen, Wei; Vierimaa, Ville; Harju, Ari

2017-09-01

Graphics processing units have been extensively used to accelerate classical molecular dynamics simulations. However, there is much less progress on the acceleration of force evaluations for many-body potentials compared to pairwise ones. In the conventional force evaluation algorithm for many-body potentials, the force, virial stress, and heat current for a given atom are accumulated within different loops, which could result in write conflict between different threads in a CUDA kernel. In this work, we provide a new force evaluation algorithm, which is based on an explicit pairwise force expression for many-body potentials derived recently (Fan et al., 2015). In our algorithm, the force, virial stress, and heat current for a given atom can be accumulated within a single thread and is free of write conflicts. We discuss the formulations and algorithms and evaluate their performance. A new open-source code, GPUMD, is developed based on the proposed formulations. For the Tersoff many-body potential, the double precision performance of GPUMD using a Tesla K40 card is equivalent to that of the LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator) molecular dynamics code running with about 100 CPU cores (Intel Xeon CPU X5670 @ 2.93 GHz).

Radiative interactions in transient energy transfer in gaseous systems

NASA Technical Reports Server (NTRS)

Tiwari, S. N.

1985-01-01

Analyses and numerical procedures are presented to investigate the radiative interactions in transient energy transfer processes in gaseous systems. The nongray radiative formulations are based on the wide-band model correlations for molecular absorption. Various relations for the radiative flux are developed; these are useful for different flow conditions and physical problems. Specific plans for obtaining extensive results for different cases are presented. The methods presented in this study can be extended easily to investigate the radiative interactions in realistic flows of hydrogen-air species in the scramjet engine.

Data-Driven Model Reduction and Transfer Operator Approximation

NASA Astrophysics Data System (ADS)

Klus, Stefan; Nüske, Feliks; Koltai, Péter; Wu, Hao; Kevrekidis, Ioannis; Schütte, Christof; Noé, Frank

2018-06-01

In this review paper, we will present different data-driven dimension reduction techniques for dynamical systems that are based on transfer operator theory as well as methods to approximate transfer operators and their eigenvalues, eigenfunctions, and eigenmodes. The goal is to point out similarities and differences between methods developed independently by the dynamical systems, fluid dynamics, and molecular dynamics communities such as time-lagged independent component analysis, dynamic mode decomposition, and their respective generalizations. As a result, extensions and best practices developed for one particular method can be carried over to other related methods.

Molecular, Physicochemical and Rheological Characteristics of Introgressive Triticale/Triticum monococcum ssp. monococcum Lines with Wheat 1D/1A Chromosome Substitution

PubMed Central

Salmanowicz, Bolesław P.; Langner, Monika; Wiśniewska, Halina; Apolinarska, Barbara; Kwiatek, Michał; Błaszczyk, Lidia

2013-01-01

Three sets of hexaploid introgressive triticale lines, with Triticum monococcum ssp. monococcum (cultivated einkorn wheat) genes and a bread wheat chromosome 1D substituted for chromosome 1A, and one set of secondary triticale lines were evaluated for grain and flour physicochemical and dough rheological characteristics in two generations (F7 and F8). Genomic in situ hybridization (GISH) and fluorescence in situ hybridization (FISH) confirmed the 1D/1A chromosome substitution. The presence or absence of einkorn high-molecular-weight (HMW) glutenin subunits and the wheat Glu-D1d locus encoding the 5 + 10 subunits was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary zone electrophoresis, and allele-specific molecular markers. Significant differences were found among physicochemical properties (with the exception of the Hagberg falling number) of all introgressive Triticale/T. monococcum lines and the secondary triticale lines. The wheat 1D/1A chromosome substitution also affected these properties. The results showed that in all introgressive triticale lines, the protein and gluten content, Zeleny sedimentation value, and water absorption capacity, were increased. The rheological parameters estimated using micro-farinograph, reomixer, and Kieffer dough extensibility systems also showed an appreciable increase in dough-mixing properties, maximum resistance to extension (Rmax), and dough extensibility. Introgressive Triticale/T. monococcum lines with 5 + 10 subunits have particularly favorable rheological parameters. The results obtained in this study suggest that the cultivated einkorn genome Am, in the context of hexaploid secondary triticale lines and with a wheat 1D/1A substitution, has the potential to improve gluten polymer interactions and be a valuable genetic resource for triticale quality improvement. PMID:23896593

MDWiZ: a platform for the automated translation of molecular dynamics simulations.

PubMed

Rusu, Victor H; Horta, Vitor A C; Horta, Bruno A C; Lins, Roberto D; Baron, Riccardo

2014-03-01

A variety of popular molecular dynamics (MD) simulation packages were independently developed in the last decades to reach diverse scientific goals. However, such non-coordinated development of software, force fields, and analysis tools for molecular simulations gave rise to an array of software formats and arbitrary conventions for routine preparation and analysis of simulation input and output data. Different formats and/or parameter definitions are used at each stage of the modeling process despite largely contain redundant information between alternative software tools. Such Babel of languages that cannot be easily and univocally translated one into another poses one of the major technical obstacles to the preparation, translation, and comparison of molecular simulation data that users face on a daily basis. Here, we present the MDWiZ platform, a freely accessed online portal designed to aid the fast and reliable preparation and conversion of file formats that allows researchers to reproduce or generate data from MD simulations using different setups, including force fields and models with different underlying potential forms. The general structure of MDWiZ is presented, the features of version 1.0 are detailed, and an extensive validation based on GROMACS to LAMMPS conversion is presented. We believe that MDWiZ will be largely useful to the molecular dynamics community. Such fast format and force field exchange for a given system allows tailoring the chosen system to a given computer platform and/or taking advantage of a specific capabilities offered by different software engines. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Influence of crystal fields on the quasimetallic reflection spectra of crystals: Optical spectra of polymorphs of a squarylium dye

NASA Astrophysics Data System (ADS)

Tristani-Kendra, M.; Eckhardt, C. J.

1984-08-01

The reflection and Kramers-Kronig absorption spectra have been obtained from the monoclinic and triclinic polymorphs of a squarylium dye, 2,4-bis(4-diethylamino-2-hydroxy phenyl) cyclobutadienediylium-1,3-diolate. The extremely different optical responses were found to arise from two molecular singlet transitions of essentially long axis polarization. Successful application of a four oscillator molecular exciton-polariton theory required the use of point charge densities rather than point dipoles in an extension of the theory which employed both interactions between the two singlets as well as a frequency dependent lattice damping. An intermolecular charge transfer transition is also assigned.

Molecular genotyping of ABO blood groups in some population groups from India

PubMed Central

Ray, Sabita; Gorakshakar, Ajit C.; Vasantha, K.; Nadkarni, Anita; Italia, Yazdi; Ghosh, Kanjaksha

2014-01-01

Background & objectives: Indian population is characterized by the presence of various castes and tribal groups. Various genetic polymorphisms have been used to differentiate among these groups. Amongst these, the ABO blood group system has been extensively studied. There is no information on molecular genotyping of ABO blood groups from India. Therefore, the main objective of this study was to characterize the common A, B and O alleles by molecular analysis in some Indian population groups. Methods: One hundred samples from the mixed population from Mumbai, 101 samples from the Dhodia tribe and 100 samples from the Parsi community were included in this study. Initially, the samples were phenotyped by standard serologic techniques. PCR followed by single strand conformational polymorphsim (SSCP) was used for molecular ABO genotyping. Samples showing atypical SSCP patterns were further analysed by DNA sequencing to characterize rare alleles. Results: Seven common ABO alleles with 19 different genotypes were found in the mixed population. The Dhodias showed 12 different ABO genotypes and the Parsis revealed 15 different ABO genotypes with six common ABO alleles identified in each of them. Two rare alleles were also identified. Interpretation & conclusions: This study reports the distribution of molecular genotypes of ABO alleles among some population groups from India. Considering the extremely heterogeneous nature of the Indian population, in terms of various genotype markers like blood groups, red cell enzymes, etc., many more ABO alleles are likely to be encountered. PMID:24604045

Free-energy landscape of the GB1 hairpin in all-atom explicit solvent simulations with different force fields: Similarities and differences.

PubMed

Best, Robert B; Mittal, Jeetain

2011-04-01

Although it is now possible to fold peptides and miniproteins in molecular dynamics simulations, it is well appreciated that force fields are not all transferable to different proteins. Here, we investigate the influence of the protein force field and the solvent model on the folding energy landscape of a prototypical two-state folder, the GB1 hairpin. We use extensive replica-exchange molecular dynamics simulations to characterize the free-energy surface as a function of temperature. Most of these force fields appear similar at a global level, giving a fraction folded at 300 K between 0.2 and 0.8 in all cases, which is a difference in stability of 2.8 kT, and are generally consistent with experimental data at this temperature. The most significant differences appear in the unfolded state, where there are different residual secondary structures which are populated, and the overall dimensions of the unfolded states, which in most of the force fields are too collapsed relative to experimental Förster Resonance Energy Transfer (FRET) data.

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

Sotomayor, Marcos

Hair cell mechanotransduction happens in tens of microseconds, involves forces of a few picoNewtons, and is mediated by nanometer-scale molecular conformational changes. As proteins involved in this process become identified and their high resolution structures become available, multiple tools are being used to explore their “single-molecule responses” to force. Optical tweezers and atomic force microscopy offer exquisite force and extension resolution, but cannot reach the high loading rates expected for high frequency auditory stimuli. Molecular dynamics (MD) simulations can reach these fast time scales, and also provide a unique view of the molecular events underlying protein mechanics, but its predictionsmore » must be experimentally verified. Thus a combination of simulations and experiments might be appropriate to study the molecular mechanics of hearing. Here I review the basics of MD simulations and the different methods used to apply force and study protein mechanics in silico. Simulations of tip link proteins are used to illustrate the advantages and limitations of this method.« less

Molecular diagnostics of Galactic star-formation regions

NASA Astrophysics Data System (ADS)

Loenen, Edo; Baan, Willem; Spaans, Marco

2007-10-01

We propose a sensitive spectral survey of Galactic star-formation regions. Using the broadband correlator at two different frequencies, we expect to detect the (1-0) transition of CO, CN, HNC, HCN, HCO+, and HCO and various of their isotopes lines, as well as the (12-11) and (10-9) transitions of HC3N. The purpose of these observations is to create a consistent (public) database of molecular emission from galactic star-formation regions. The data will be interpreted using extensive physical and chemical modeling of the whole ensemble of lines, in order to get an accurate description of the molecular environment of these regions. In particular, this diagnostic approach will describe the optical depths, the densities, and the radiation fields in the medium and will allow the establishment of dominant temperature gradients. These observations are part of a program to study molecular emission on all scales, going from individual Galactic star-formation regions, through resolved nearby galaxies, to unresolved extra-galactic emission.

A parametric study of surface roughness and bonding mechanisms of aluminum alloys with epoxies: a molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Timilsina, Rajendra; Termaath, Stephanie

The marine environment is highly aggressive towards most materials. However, aluminium-magnesium alloys (Al-Mg, specifically, 5xxx series) have exceptionally long service life in such aggressive marine environments. For instance, an Al-Mg alloy, AA5083, is extensively used in naval structures because of its good mechanical strength, formability, seawater corrosion resistance and weldability. However, bonding mechanisms of these alloys with epoxies in a rough surface environment are not fully understood yet. It requires a rigorous investigation at molecular or atomic levels. We performed a molecular dynamics simulation to study an adherend surface preparation and surface bonding mechanisms of Al-Mg alloy (AA5083) with different epoxies by developing several computer models. Various distributions of surface roughness are introduced in the models and performed molecular dynamics simulations. Formation of a beta phase (Al3Mg2) , microstructures, bonding energies at the interface, bonding strengths and durability are investigated. Office of Naval Research.

Detection of different oxidation states of individual manganese porphyrins during their reaction with oxygen at a solid/liquid interface.

PubMed

den Boer, Duncan; Li, Min; Habets, Thomas; Iavicoli, Patrizia; Rowan, Alan E; Nolte, Roeland J M; Speller, Sylvia; Amabilino, David B; De Feyter, Steven; Elemans, Johannes A A W

2013-07-01

Manganese porphyrins have been extensively investigated as model systems for the natural enzyme cytochrome P450 and as synthetic oxidation catalysts. Here, we report single-molecule studies of the multistep reaction of manganese porphyrins with molecular oxygen at a solid/liquid interface, using a scanning tunnelling microscope (STM) under environmental control. The high lateral resolution of the STM, in combination with its sensitivity to subtle differences in the electronic properties of molecules, allowed the detection of at least four distinct reaction species. Real-space and real-time imaging of reaction dynamics enabled the observation of active sites, immobile on the experimental timescale. Conversions between the different species could be tuned by the composition of the atmosphere (argon, air or oxygen) and the surface bias voltage. By means of extensive comparison of the results to those obtained by analogous solution-based chemistry, we assigned the observed species to the starting compound, reaction intermediates and products.

Nanoscale tailor-made membranes for precise and rapid molecular sieve separation.

PubMed

Wang, Jing; Zhu, Junyong; Zhang, Yatao; Liu, Jindun; Van der Bruggen, Bart

2017-03-02

The precise and rapid separation of different molecules from aqueous, organic solutions and gas mixtures is critical to many technologies in the context of resource-saving and sustainable development. The strength of membrane-based technologies is well recognized and they are extensively applied as cost-effective, highly efficient separation techniques. Currently, empirical-based approaches, lacking an accurate nanoscale control, are used to prepare the most advanced membranes. In contrast, nanoscale control renders the membrane molecular specificity (sub-2 nm) necessary for efficient and rapid molecular separation. Therefore, as a growing trend in membrane technology, the field of nanoscale tailor-made membranes is highlighted in this review. An in-depth analysis of the latest advances in tailor-made membranes for precise and rapid molecule sieving is given, along with an outlook to future perspectives of such membranes. Special attention is paid to the established processing strategies, as well as the application of molecular dynamics (MD) simulation in nanoporous membrane design. This review will provide useful guidelines for future research in the development of nanoscale tailor-made membranes with a precise and rapid molecular sieve separation property.

Structural optimization of mangiferin binding to cancer molecular targets: a guide for synthetic derivatization.

PubMed

Taiwo, Bamigboye J; Olubiyi, Olujide O; van Heerden, Fanie R

2018-03-20

Nigerian medicinal plants have been demonstrated to be veritable source of lead compounds for drug discovery efforts. One such example is mangiferin. Mangiferin was originally isolated from the Nigerian plant Ceiba pentandra (Mombacaceae), after which its structure was elucidated with the aid of spectroscopy. Mangiferin, a xanthone glycoside, has also been reported in certain other plant families including Gentianaceae and Anacardiaceae. In certain other climes and different parts of the world, folkloric and traditional medicine has extensively employed Mangifera indica (another source of mangiferin) in treating different diseases. For many of such cultural uses carefully designed experimental investigations have been conducted confirming mangiferin's efficacies in those different pathologies which have included but not limited to cytotoxic as well as chemopreventive properties in selected cancer cell lines. In this study, computational techniques were employed to profile the interaction of the xanthone glycoside at the atomistic level against nine selected molecular targets with clinical relevance in tumorigenesis. In attempt to investigate the potential of the mangiferin structure as a viable starting point for synthetic exploration of mangiferin-based analogs, extensive structural modifications were performed. By analyzing the resulting structure-energetic pattern, critical points capable of improving mangiferin interaction with the profiled targets were identified. The outcome of this study provides both direction and impetus for synthetic derivitization of the mangiferin molecule into novel optimized inhibitors for anticancer lead development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Generation of Well-Relaxed All-Atom Models of Large Molecular Weight Polymer Melts: A Hybrid Particle-Continuum Approach Based on Particle-Field Molecular Dynamics Simulations.

PubMed

De Nicola, Antonio; Kawakatsu, Toshihiro; Milano, Giuseppe

2014-12-09

A procedure based on Molecular Dynamics (MD) simulations employing soft potentials derived from self-consistent field (SCF) theory (named MD-SCF) able to generate well-relaxed all-atom structures of polymer melts is proposed. All-atom structures having structural correlations indistinguishable from ones obtained by long MD relaxations have been obtained for poly(methyl methacrylate) (PMMA) and poly(ethylene oxide) (PEO) melts. The proposed procedure leads to computational costs mainly related on system size rather than to the chain length. Several advantages of the proposed procedure over current coarse-graining/reverse mapping strategies are apparent. No parametrization is needed to generate relaxed structures of different polymers at different scales or resolutions. There is no need for special algorithms or back-mapping schemes to change the resolution of the models. This characteristic makes the procedure general and its extension to other polymer architectures straightforward. A similar procedure can be easily extended to the generation of all-atom structures of block copolymer melts and polymer nanocomposites.

An N-terminal peptide extension results in efficient expression, but not secretion, of a synthetic horseradish peroxidase gene in transgenic tobacco.

PubMed

Kis, Mihaly; Burbridge, Emma; Brock, Ian W; Heggie, Laura; Dix, Philip J; Kavanagh, Tony A

2004-03-01

Native horseradish (Armoracia rusticana) peroxidase, HRP (EC 1.11.1.7), isoenzyme C is synthesized with N-terminal and C-terminal peptide extensions, believed to be associated with protein targeting. This study aimed to explore the specific functions of these extensions, and to generate transgenic plants with expression patterns suitable for exploring the role of peroxidase in plant development and defence. Transgenic Nicotiana tabacum (tobacco) plants expressing different versions of a synthetic horseradish peroxidase, HRP, isoenzyme C gene were constructed. The gene was engineered to include additional sequences coding for either the natural N-terminal or the C-terminal extension or both. These constructs were placed under the control of a constitutive promoter (CaMV-35S) or the tobacco RUBISCO-SSU light inducible promoter (SSU) and introduced into tobacco using Agrobacterium-mediated transformation. To study the effects of the N- and C-terminal extensions, the localization of recombinant peroxidase was determined using biochemical and molecular techniques. Transgenic tobacco plants can exhibit a ten-fold increase in peroxidase activity compared with wild-type tobacco levels, and the majority of this activity is located in the symplast. The N-terminal extension is essential for the production of high levels of recombinant protein, while the C-terminal extension has little effect. Differences in levels of enzyme activity and recombinant protein are reflected in transcript levels. There is no evidence to support either preferential secretion or vacuolar targeting of recombinant peroxidase in this heterologous expression system. This leads us to question the postulated targeting roles of these peptide extensions. The N-terminal extension is essential for high level expression and appears to influence transcript stability or translational efficiency. Plants have been generated with greatly elevated cytosolic peroxidase activity, and smaller increases in apoplastic activity. These will be valuable for exploring the role of these enzymes in stress amelioration and plant development.

An N‐terminal Peptide Extension Results in Efficient Expression, but not Secretion, of a Synthetic Horseradish Peroxidase Gene in Transgenic Tobacco

PubMed Central

KIS, MIHALY; BURBRIDGE, EMMA; BROCK, IAN W.; HEGGIE, LAURA; DIX, PHILIP J.; KAVANAGH, TONY A.

2004-01-01

• Background and Aims Native horseradish (Armoracia rusticana) peroxidase, HRP (EC 1.11.1.7), isoenzyme C is synthesized with N‐terminal and C‐terminal peptide extensions, believed to be associated with protein targeting. This study aimed to explore the specific functions of these extensions, and to generate transgenic plants with expression patterns suitable for exploring the role of peroxidase in plant development and defence. • Methods Transgenic Nicotiana tabacum (tobacco) plants expressing different versions of a synthetic horseradish peroxidase, HRP, isoenzyme C gene were constructed. The gene was engineered to include additional sequences coding for either the natural N‐terminal or the C‐terminal extension or both. These constructs were placed under the control of a constitutive promoter (CaMV‐35S) or the tobacco RUBISCO‐SSU light inducible promoter (SSU) and introduced into tobacco using Agrobacterium‐mediated transformation. To study the effects of the N‐ and C‐terminal extensions, the localization of recombinant peroxidase was determined using biochemical and molecular techniques. • Key Results Transgenic tobacco plants can exhibit a ten‐fold increase in peroxidase activity compared with wild‐type tobacco levels, and the majority of this activity is located in the symplast. The N‐terminal extension is essential for the production of high levels of recombinant protein, while the C‐terminal extension has little effect. Differences in levels of enzyme activity and recombinant protein are reflected in transcript levels. • Conclusions There is no evidence to support either preferential secretion or vacuolar targeting of recombinant peroxidase in this heterologous expression system. This leads us to question the postulated targeting roles of these peptide extensions. The N‐terminal extension is essential for high level expression and appears to influence transcript stability or translational efficiency. Plants have been generated with greatly elevated cytosolic peroxidase activity, and smaller increases in apoplastic activity. These will be valuable for exploring the role of these enzymes in stress amelioration and plant development. PMID:14749254

Pydna: a simulation and documentation tool for DNA assembly strategies using python.

PubMed

Pereira, Filipa; Azevedo, Flávio; Carvalho, Ângela; Ribeiro, Gabriela F; Budde, Mark W; Johansson, Björn

2015-05-02

Recent advances in synthetic biology have provided tools to efficiently construct complex DNA molecules which are an important part of many molecular biology and biotechnology projects. The planning of such constructs has traditionally been done manually using a DNA sequence editor which becomes error-prone as scale and complexity of the construction increase. A human-readable formal description of cloning and assembly strategies, which also allows for automatic computer simulation and verification, would therefore be a valuable tool. We have developed pydna, an extensible, free and open source Python library for simulating basic molecular biology DNA unit operations such as restriction digestion, ligation, PCR, primer design, Gibson assembly and homologous recombination. A cloning strategy expressed as a pydna script provides a description that is complete, unambiguous and stable. Execution of the script automatically yields the sequence of the final molecule(s) and that of any intermediate constructs. Pydna has been designed to be understandable for biologists with limited programming skills by providing interfaces that are semantically similar to the description of molecular biology unit operations found in literature. Pydna simplifies both the planning and sharing of cloning strategies and is especially useful for complex or combinatorial DNA molecule construction. An important difference compared to existing tools with similar goals is the use of Python instead of a specifically constructed language, providing a simulation environment that is more flexible and extensible by the user.

[Medulloblastoma. Pathology].

PubMed

Siegfried, A; Delisle, M-B

2018-04-24

Medulloblastomas, embryonal neuroepithelial tumors developed in the cerebellum or brain stem, are mainly observed in childhood. The treatment of WHO-Grade IV tumors depends on stratifications that are usually based on postoperative data, histopathological subtype, tumor extension and presence of MYC or NMYC amplifications. Recently, molecular biology studies, based on new technologies (i.e. sequencing, transcriptomic, methylomic) have introduced genetic subtypes integrated into the latest WHO-2016 neuropathological classification. According to this classification, the three genetic groups WNT, SHH, with or without mutated TP53 gene, and non-WNT/non-SHH, comprising subgroups 3 and 4, are recalled in this review. The contribution of immunohistochemistry to define these groups is specified. The four histopathological groups are detailed in comparison to the WHO-2007 classification and the molecular data: classic medulloblastoma, desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, and large cell/anaplastic medulloblastoma. The groups defined on genetic and histopathological grounds are not strictly concordant. Depending on the age of the patients, their correlations are different, as well as their role in the management and prognosis of these tumors. Other embryonal tumors, for which new classifications are in progress and gliomas may be confused with a medulloblastoma and the elements of the differential diagnosis of these entities are discussed. This evolution in classification fully justifies ongoing structuring procedures such as histopathological review (RENOCLIP) and the organization of molecular biology platforms. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Influence of Hydrogen Bonding on the Surface Diffusion of Molecular Glasses: Comparison of Three Triazines

DOE PAGES

Chen, Yinshan; Zhu, Men; Laventure, Audrey; ...

2017-06-26

Surface grating decay measurements have been performed on three closely related molecular glasses to study the effect of intermolecular hydrogen bonds on surface diffusion. The three molecules are derivatives of bis(3,5-dimethyl-phenylamino)-1,3,5-triazine and differ only in the functional group R at the 2-position, with R being C 2H 5, OCH 3, and NHCH 3, and referred to as “Et”, “OMe”, and “NHMe”, respectively. Of the three molecules, NHMe forms more extensive intermolecular hydrogen bonds than Et and OMe and was found to have slower surface diffusion. For Et and OMe, surface diffusion is so fast that it replaces viscous flow asmore » the mechanism of surface grating decay as temperature is lowered. In contrast, no such transition was observed for NHMe under the same conditions, indicating significantly slower surface diffusion. This result is consistent with the previous finding that extensive intermolecular hydrogen bonds slow down surface diffusion in molecular glasses and is attributed to the persistence of hydrogen bonds even in the surface environment. Here, this result is also consistent with the lower stability of the vapor-deposited glass of NHMe relative to those of Et and OMe and supports the view that surface mobility controls the stability of vapor-deposited glasses.« less

Heritability and molecular genetic basis of acoustic startle eye blink and affectively modulated startle response: A genome-wide association study

PubMed Central

VAIDYANATHAN, UMA; MALONE, STEPHEN M.; MILLER, MICHAEL B.; McGUE, MATT; IACONO, WILLIAM G.

2014-01-01

Acoustic startle responses have been studied extensively in relation to individual differences and psychopathology. We examined three indices of the blink response in a picture-viewing paradigm—overall startle magnitude across all picture types, and aversive and pleasant modulation scores—in 3,323 twins and parents. Biometric models and molecular genetic analyses showed that half the variance in overall startle was due to additive genetic effects. No single nucleotide polymorphism was genome-wide significant, but GRIK3 did produce a significant effect when examined as part of a candidate gene set. In contrast, emotion modulation scores showed little evidence of heritability in either biometric or molecular genetic analyses. However, in a genome-wide scan, PARP14 did produce a significant effect for aversive modulation. We conclude that, although overall startle retains potential as an endophenotype, emotion-modulated startle does not. PMID:25387708

Is pigment patterning in fish skin determined by the Turing mechanism?

PubMed

Watanabe, Masakatsu; Kondo, Shigeru

2015-02-01

More than half a century ago, Alan Turing postulated that pigment patterns may arise from a mechanism that could be mathematically modeled based on the diffusion of two substances that interact with each other. Over the past 15 years, the molecular and genetic tools to verify this prediction have become available. Here, we review experimental studies aimed at identifying the mechanism underlying pigment pattern formation in zebrafish. Extensive molecular genetic studies in this model organism have revealed the interactions between the pigment cells that are responsible for the patterns. The mechanism discovered is substantially different from that predicted by the mathematical model, but it retains the property of 'local activation and long-range inhibition', a necessary condition for Turing pattern formation. Although some of the molecular details of pattern formation remain to be elucidated, current evidence confirms that the underlying mechanism is mathematically equivalent to the Turing mechanism. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

PubMed

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

2016-11-10

Accurately prioritizing candidate disease genes is an important and challenging problem. Various network-based methods have been developed to predict potential disease genes by utilizing the disease similarity network and molecular networks such as protein interaction or gene co-expression networks. Although successful, a common limitation of the existing methods is that they assume all diseases share the same molecular network and a single generic molecular network is used to predict candidate genes for all diseases. However, different diseases tend to manifest in different tissues, and the molecular networks in different tissues are usually different. An ideal method should be able to incorporate tissue-specific molecular networks for different diseases. In this paper, we develop a robust and flexible method to integrate tissue-specific molecular networks for disease gene prioritization. Our method allows each disease to have its own tissue-specific network(s). We formulate the problem of candidate gene prioritization as an optimization problem based on network propagation. When there are multiple tissue-specific networks available for a disease, our method can automatically infer the relative importance of each tissue-specific network. Thus it is robust to the noisy and incomplete network data. To solve the optimization problem, we develop fast algorithms which have linear time complexities in the number of nodes in the molecular networks. We also provide rigorous theoretical foundations for our algorithms in terms of their optimality and convergence properties. Extensive experimental results show that our method can significantly improve the accuracy of candidate gene prioritization compared with the state-of-the-art methods. In our experiments, we compare our methods with 7 popular network-based disease gene prioritization algorithms on diseases from Online Mendelian Inheritance in Man (OMIM) database. The experimental results demonstrate that our methods recover true associations more accurately than other methods in terms of AUC values, and the performance differences are significant (with paired t-test p-values less than 0.05). This validates the importance to integrate tissue-specific molecular networks for studying disease gene prioritization and show the superiority of our network models and ranking algorithms toward this purpose. The source code and datasets are available at http://nijingchao.github.io/CRstar/ .

QM/MM Geometry Optimization on Extensive Free-Energy Surfaces for Examination of Enzymatic Reactions and Design of Novel Functional Properties of Proteins.

PubMed

Hayashi, Shigehiko; Uchida, Yoshihiro; Hasegawa, Taisuke; Higashi, Masahiro; Kosugi, Takahiro; Kamiya, Motoshi

2017-05-05

Many remarkable molecular functions of proteins use their characteristic global and slow conformational dynamics through coupling of local chemical states in reaction centers with global conformational changes of proteins. To theoretically examine the functional processes of proteins in atomic detail, a methodology of quantum mechanical/molecular mechanical (QM/MM) free-energy geometry optimization is introduced. In the methodology, a geometry optimization of a local reaction center is performed with a quantum mechanical calculation on a free-energy surface constructed with conformational samples of the surrounding protein environment obtained by a molecular dynamics simulation with a molecular mechanics force field. Geometry optimizations on extensive free-energy surfaces by a QM/MM reweighting free-energy self-consistent field method designed to be variationally consistent and computationally efficient have enabled examinations of the multiscale molecular coupling of local chemical states with global protein conformational changes in functional processes and analysis and design of protein mutants with novel functional properties.

Primitive chain network simulations for entangled DNA solutions

NASA Astrophysics Data System (ADS)

Masubuchi, Yuichi; Furuichi, Kenji; Horio, Kazushi; Uneyama, Takashi; Watanabe, Hiroshi; Ianniruberto, Giovanni; Greco, Francesco; Marrucci, Giuseppe

2009-09-01

Molecular theories for polymer rheology are based on conformational dynamics of the polymeric chain. Hence, measurements directly related to molecular conformations appear more appealing than indirect ones obtained from rheology. In this study, primitive chain network simulations are compared to experimental data of entangled DNA solutions [Teixeira et al., Macromolecules 40, 2461 (2007)]. In addition to rheological comparisons of both linear and nonlinear viscoelasticities, a molecular extension measure obtained by Teixeira et al. through fluorescent microscopy is compared to simulations, in terms of both averages and distributions. The influence of flow on conformational distributions has never been simulated for the case of entangled polymers, and how DNA molecular individualism extends to the entangled regime is not known. The linear viscoelastic response and the viscosity growth curve in the nonlinear regime are found in good agreement with data for various DNA concentrations. Conversely, the molecular extension measure shows significant departures, even under equilibrium conditions. The reason for such discrepancies remains unknown.

QM/MM Geometry Optimization on Extensive Free-Energy Surfaces for Examination of Enzymatic Reactions and Design of Novel Functional Properties of Proteins

NASA Astrophysics Data System (ADS)

Hayashi, Shigehiko; Uchida, Yoshihiro; Hasegawa, Taisuke; Higashi, Masahiro; Kosugi, Takahiro; Kamiya, Motoshi

2017-05-01

Many remarkable molecular functions of proteins use their characteristic global and slow conformational dynamics through coupling of local chemical states in reaction centers with global conformational changes of proteins. To theoretically examine the functional processes of proteins in atomic detail, a methodology of quantum mechanical/molecular mechanical (QM/MM) free-energy geometry optimization is introduced. In the methodology, a geometry optimization of a local reaction center is performed with a quantum mechanical calculation on a free-energy surface constructed with conformational samples of the surrounding protein environment obtained by a molecular dynamics simulation with a molecular mechanics force field. Geometry optimizations on extensive free-energy surfaces by a QM/MM reweighting free-energy self-consistent field method designed to be variationally consistent and computationally efficient have enabled examinations of the multiscale molecular coupling of local chemical states with global protein conformational changes in functional processes and analysis and design of protein mutants with novel functional properties.

Degradation of porous poly(D,L-lactic-co-glycolic acid) films based on water diffusion.

PubMed

Huang, Ying-Ying; Qi, Min; Liu, Hong-Ze; Zhao, Hong; Yang, Da-Zhi

2007-03-15

Poly(D,L-lactic-co-glycolic acid) has been extensively used as a controlled release carrier for drug delivery due to its good biocompatibility, biodegradability, and mechanical strength. Effects of dense and porous film's degradation behavior have been systematically investigated up to 17 weeks in Hank's Simulated Body Fluid at 37 degrees C. The degradation of the films was studied by measuring changes in weight, molecular weight and its distribution, morphology, composition etc.. A special thing was that the differences in water diffusion in dense and porous structure films caused the different degradation behavior. According to the characteristic changes of various properties of films, the degradation process is suggested to be roughly divided into four stages, tentatively named as water absorption stage, dramatic loss of molecular weight or micro-pores formed stage, loss of weight or enlarged-pores formed stage, pores diminished or pores collapse stage.

The new program OPAL for molecular dynamics simulations and energy refinements of biological macromolecules.

PubMed

Luginbühl, P; Güntert, P; Billeter, M; Wüthrich, K

1996-09-01

A new program for molecular dynamics (MD) simulation and energy refinement of biological macromolecules, OPAL, is introduced. Combined with the supporting program TRAJEC for the analysis of MD trajectories, OPAL affords high efficiency and flexibility for work with different force fields, and offers a user-friendly interface and extensive trajectory analysis capabilities. Salient features are computational speeds of up to 1.5 GFlops on vector supercomputers such as the NEC SX-3, ellipsoidal boundaries to reduce the system size for studies in explicit solvents, and natural treatment of the hydrostatic pressure. Practical applications of OPAL are illustrated with MD simulations of pure water, energy minimization of the NMR structure of the mixed disulfide of a mutant E. coli glutaredoxin with glutathione in different solvent models, and MD simulations of a small protein, pheromone Er-2, using either instantaneous or time-averaged NMR restraints, or no restraints.

Microbial production of polyhydroxybutyrate with tailor-made properties: an integrated modelling approach and experimental validation.

PubMed

Penloglou, Giannis; Chatzidoukas, Christos; Kiparissides, Costas

2012-01-01

The microbial production of polyhydroxybutyrate (PHB) is a complex process in which the final quantity and quality of the PHB depend on a large number of process operating variables. Consequently, the design and optimal dynamic operation of a microbial process for the efficient production of PHB with tailor-made molecular properties is an extremely interesting problem. The present study investigates how key process operating variables (i.e., nutritional and aeration conditions) affect the biomass production rate and the PHB accumulation in the cells and its associated molecular weight distribution. A combined metabolic/polymerization/macroscopic modelling approach, relating the process performance and product quality with the process variables, was developed and validated using an extensive series of experiments and measurements. The model predicts the dynamic evolution of the biomass growth, the polymer accumulation, the consumption of carbon and nitrogen sources and the average molecular weights of the PHB in a bioreactor, under batch and fed-batch operating conditions. The proposed integrated model was used for the model-based optimization of the production of PHB with tailor-made molecular properties in Azohydromonas lata bacteria. The process optimization led to a high intracellular PHB accumulation (up to 95% g of PHB per g of DCW) and the production of different grades (i.e., different molecular weight distributions) of PHB. Copyright © 2011 Elsevier Inc. All rights reserved.

The coexistence temperature of hydrogen clathrates: A molecular dynamics study

NASA Astrophysics Data System (ADS)

Luis, D. P.; Romero-Ramirez, I. E.; González-Calderón, A.; López-Lemus, J.

2018-03-01

Extensive molecular dynamics simulations in the equilibrium isobaric-isothermal (NPT) ensemble were developed to determine the coexistence temperatures of the water hydrogen mixture using the direct coexistence method. The water molecules were modeled using the four-site TIP4P/Ice analytical potential, and the hydrogen molecules were described using a three-site potential. The simulations were performed at different pressures (p = 900, 1500, 3000, and 4000 bars). At each pressure, a series of simulations were developed at different temperatures (from 230 to 270 K). Our results followed a line parallel to the experimental coexistence temperatures and underestimated these temperatures by approximately 25 K in the investigated range. The final configurations could or could not contain a fluid phase depending on the pressure, in accordance with the phase diagram. In addition, we explored the dynamics of the H2 molecules through clathrate hydrate cages and observed different behaviors of the H2 molecules in the small cages and the large cages of the sII structure.

Molecular modeling and SPRi investigations of interleukin 6 (IL6) protein and DNA aptamers.

PubMed

Rhinehardt, Kristen L; Vance, Stephen A; Mohan, Ram V; Sandros, Marinella; Srinivas, Goundla

2018-06-01

Interleukin 6 (IL6), an inflammatory response protein has major implications in immune-related inflammatory diseases. Identification of aptamers for the IL6 protein aids in diagnostic, therapeutic, and theranostic applications. Three different DNA aptamers and their interactions with IL6 protein were extensively investigated in a phosphate buffed saline (PBS) solution. Molecular-level modeling through molecular dynamics provided insights of structural, conformational changes and specific binding domains of these protein-aptamer complexes. Multiple simulations reveal consistent binding region for all protein-aptamer complexes. Conformational changes coupled with quantitative analysis of center of mass (COM) distance, radius of gyration (R g ), and number of intermolecular hydrogen bonds in each IL6 protein-aptamer complex was used to determine their binding performance strength and obtain molecular configurations with strong binding. A similarity comparison of the molecular configurations with strong binding from molecular-level modeling concurred with Surface Plasmon Resonance imaging (SPRi) for these three aptamer complexes, thus corroborating molecular modeling analysis findings. Insights from the natural progression of IL6 protein-aptamer binding modeled in this work has identified key features such as the orientation and location of the aptamer in the binding event. These key features are not readily feasible from wet lab experiments and impact the efficacy of the aptamers in diagnostic and theranostic applications.

Atomistic simulation of solid-liquid coexistence for molecular systems: application to triazole and benzene.

PubMed

Eike, David M; Maginn, Edward J

2006-04-28

A method recently developed to rigorously determine solid-liquid equilibrium using a free-energy-based analysis has been extended to analyze multiatom molecular systems. This method is based on using a pseudosupercritical transformation path to reversibly transform between solid and liquid phases. Integration along this path yields the free energy difference at a single state point, which can then be used to determine the free energy difference as a function of temperature and therefore locate the coexistence temperature at a fixed pressure. The primary extension reported here is the introduction of an external potential field capable of inducing center of mass order along with secondary orientational order for molecules. The method is used to calculate the melting point of 1-H-1,2,4-triazole and benzene. Despite the fact that the triazole model gives accurate bulk densities for the liquid and crystal phases, it is found to do a poor job of reproducing the experimental crystal structure and heat of fusion. Consequently, it yields a melting point that is 100 K lower than the experimental value. On the other hand, the benzene model has been parametrized extensively to match a wide range of properties and yields a melting point that is only 20 K lower than the experimental value. Previous work in which a simple "direct heating" method was used actually found that the melting point of the benzene model was 50 K higher than the experimental value. This demonstrates the importance of using proper free energy methods to compute phase behavior. It also shows that the melting point is a very sensitive measure of force field quality that should be considered in parametrization efforts. The method described here provides a relatively simple approach for computing melting points of molecular systems.

Patient-derived organoid models help define personalized management of gastrointestinal cancer. | Office of Cancer Genomics

Cancer.gov

Background: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models.

Extensive molecular analysis suggested the strong genetic heterogeneity of idiopathic chronic pancreatitis.

PubMed

Sofia, Valentina Maria; Da Sacco, Letizia; Surace, Cecilia; Tomaiuolo, Anna Cristina; Genovese, Silvia; Grotta, Simona; Gnazzo, Maria; Petrocchi, Stefano; Ciocca, Laura; Alghisi, Federico; Montemitro, Enza; Martemucci, Luigi; Elce, Ausilia; Lucidi, Vincenzina; Castaldo, Giuseppe; Angioni, Adriano

2016-05-26

Genetic features of Chronic Pancreatitis (CP) have been extensively investigated mainly testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. 80 patients with Idiopathic CP were investigated using Next Generation Sequencing approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen; modifier genes of Cystic Fibrosis phenotype; pancreatic secretion and ion homeostasis; Calcium signalling and zymogen granules exocytosis; autophagy; autoimmune pancreatitis related genes. We detected mutations in 34 out of 70 genes examined; 64/80 patients (80.0%) were positive for mutations in one or more genes, 16/80 patients (20.0%) had no mutations. Mutations in CFTR were detected in 32/80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38/64 patients positive for mutations showed variants in two or more genes (59.3%). Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in chronic pancreatitis and that trans-heterozygosity may predispose to the idiopathic CP phenotype.

Influence of rotational energy barriers to the conformational search of protein loops in molecular dynamics and ranking the conformations.

PubMed

Tappura, K

2001-08-15

An adjustable-barrier dihedral angle potential was added as an extension to a novel, previously presented soft-core potential to study its contribution to the efficacy of the search of the conformational space in molecular dynamics. As opposed to the conventional soft-core potential functions, the leading principle in the design of the new soft-core potential, as well as of its extension, the soft-core and adjustable-barrier dihedral angle (SCADA) potential (referred as the SCADA potential), was to maintain the main equilibrium properties of the original force field. This qualifies the methods for a variety of a priori modeling problems without need for additional restraints typically required with the conventional soft-core potentials. In the present study, the different potential energy functions are applied to the problem of predicting loop conformations in proteins. Comparison of the performance of the soft-core and SCADA potential showed that the main hurdles for the efficient sampling of the conformational space of (loops in) proteins are related to the high-energy barriers caused by the Lennard-Jones and Coulombic energy terms, and not to the rotational barriers, although the conformational search can be further enhanced by lowering the rotational barriers of the dihedral angles. Finally, different evaluation methods were studied and a few promising criteria found to distinguish the near-native loop conformations from the wrong ones.

Structural and functional photoacoustic molecular tomography aided by emerging contrast agents

PubMed Central

Nie, Liming

2015-01-01

Photoacoustic tomography (PAT) can offer structural, functional and molecular contrasts at scalable observation level. By ultrasonically overcoming the strong optical scattering, this imaging technology can reach centimeters penetration depth while retaining high spatial resolution in biological tissue. Recent extensive research has been focused on developing new contrast agents to improve the imaging sensitivity, specificity and efficiency. These emerging materials have substantially accelerated PAT applications in signal sensing, functional imaging, biomarker labeling and therapy monitoring etc. Here, the potentials of different optical probes as PAT contrast agents were elucidated. We first describe the instrumental embodiments and the measured functional parameters, then focus on emerging contrast agent-based PAT applications, and finally discuss the challenges and prospects. PMID:24967718

Chloride Channelopathies of ClC-2

PubMed Central

Bi, Miao Miao; Hong, Sen; Zhou, Hong Yan; Wang, Hong Wei; Wang, Li Na; Zheng, Ya Juan

2014-01-01

Chloride channels (ClCs) have gained worldwide interest because of their molecular diversity, widespread distribution in mammalian tissues and organs, and their link to various human diseases. Nine different ClCs have been molecularly identified and functionally characterized in mammals. ClC-2 is one of nine mammalian members of the ClC family. It possesses unique biophysical characteristics, pharmacological properties, and molecular features that distinguish it from other ClC family members. ClC-2 has wide organ/tissue distribution and is ubiquitously expressed. Published studies consistently point to a high degree of conservation of ClC-2 function and regulation across various species from nematodes to humans over vast evolutionary time spans. ClC-2 has been intensively and extensively studied over the past two decades, leading to the accumulation of a plethora of information to advance our understanding of its pathophysiological functions; however, many controversies still exist. It is necessary to analyze the research findings, and integrate different views to have a better understanding of ClC-2. This review focuses on ClC-2 only, providing an analytical overview of the available literature. Nearly every aspect of ClC-2 is discussed in the review: molecular features, biophysical characteristics, pharmacological properties, cellular function, regulation of expression and function, and channelopathies. PMID:24378849

The molecular composition of ambers

USGS Publications Warehouse

Grimalt, J.O.; Simoneit, B.R.T.; Hatcher, P.G.; Nissenbaum, A.

1988-01-01

Bulk (elemental composition, IR, CP/MAS 13C NMR) and molecular (GC-MS) analyses have been performed on a series of ambers and resins derived from different locations (Dominican Republic, Philippines, Canada, Israel, New Zealand, Chile) having diverse botanical affinities (Araucariaceae, Hymenaea) and variable age (from Holocene to Early Cretaceous). No major differences have been observed from the elemental composition and the spectroscopic data; however, the molecular analyses of the solvent extractable fraction show that a specific mixture of components is present in each sample. These are mainly diterpenoid products that in general are also found abundantly in the higher plants from which the ambers and resins originate. Nevertheless, a direct relationship between major terpenoid constituents in fossil resins and precursor plant materials can only be established for the younger samples. Irrespective of the geographical or botanical origin of the ambers and resins, several common age-dependent molecular transformation trends can be recognized: (1) progressive loss of olefinic bonds (especially those located in exocyclic positions), (2) decrease of functionalized products, and (3) increasing proportion of aromatized components. However, even in the samples of older age (Cretaceous) the degree of aromatization is very low when compared with that of other higher-plant related materials such as fossilized woods or low rank coals. This indicates that maturation must involve essentially olefin polymerization processes instead of extensive aromatization. ?? 1988.

Genes and (Common) Pathways Underlying Drug Addiction

PubMed Central

Li, Chuan-Yun; Mao, Xizeng; Wei, Liping

2008-01-01

Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction. PMID:18179280

Emerging insights into the molecular and cellular basis of glioblastoma

PubMed Central

Dunn, Gavin P.; Rinne, Mikael L.; Wykosky, Jill; Genovese, Giannicola; Quayle, Steven N.; Dunn, Ian F.; Agarwalla, Pankaj K.; Chheda, Milan G.; Campos, Benito; Wang, Alan; Brennan, Cameron; Ligon, Keith L.; Furnari, Frank; Cavenee, Webster K.; Depinho, Ronald A.; Chin, Lynda; Hahn, William C.

2012-01-01

Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that “glioblastoma” represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions. PMID:22508724

FRET detection of lymphocyte function–associated antigen-1 conformational extension

PubMed Central

Chigaev, Alexandre; Smagley, Yelena; Haynes, Mark K.; Ursu, Oleg; Bologa, Cristian G.; Halip, Liliana; Oprea, Tudor; Waller, Anna; Carter, Mark B.; Zhang, Yinan; Wang, Wei; Buranda, Tione; Sklar, Larry A.

2015-01-01

Lymphocyte function–associated antigen 1 (LFA-1, CD11a/CD18, αLβ2-integrin) and its ligands are essential for adhesion between T-cells and antigen-presenting cells, formation of the immunological synapse, and other immune cell interactions. LFA-1 function is regulated through conformational changes that include the modulation of ligand binding affinity and molecular extension. However, the relationship between molecular conformation and function is unclear. Here fluorescence resonance energy transfer (FRET) with new LFA-1–specific fluorescent probes showed that triggering of the pathway used for T-cell activation induced rapid unquenching of the FRET signal consistent with extension of the molecule. Analysis of the FRET quenching at rest revealed an unexpected result that can be interpreted as a previously unknown LFA-1 conformation. PMID:25378583

Application of the phase extension method in virus crystallography.

PubMed

Reddy, Vijay S

2016-01-01

The procedure for phase extension (PX) involves gradually extending the initial phases from low resolution (e.g., ~8Å) to the high-resolution limit of a diffraction data set. Structural redundancy present in the viral capsids that display icosahedral symmetry results in a high degree of non-crystallographic symmetry (NCS), which in turn translates into higher phasing power and is critical for improving and extending phases to higher resolution. Greater completeness of the diffraction data and determination of a molecular replacement solution, which entails accurately identifying the virus particle orientation(s) and position(s), are important for the smooth progression of the PX procedure. In addition, proper definition of a molecular mask (envelope) around the NCS-asymmetric unit has been found to be important for the success of density modification procedures, such as density averaging and solvent flattening. Regardless of the degree of NCS, the PX method appears to work well in all space groups, provided an accurate molecular mask is used along with reasonable initial phases. However, in the cases with space group P1, in addition to requiring a molecular mask, starting the phase extension at a higher resolution (e.g., 6Å) overcame the previously reported problems due to Babinet phases and phase flipping errors.

The role of molecular typing and perfect match transfusion in sickle cell disease and thalassaemia: An innovative transfusion strategy.

PubMed

Putzulu, Rossana; Piccirillo, Nicola; Orlando, Nicoletta; Massini, Giuseppina; Maresca, Maddalena; Scavone, Fernando; Ricerca, Bianca Maria; Zini, Gina

2017-04-01

Chronic red blood cell transfusions remain an essential part of supportive treatment in patients with thalassaemia and sickle cell disease (SCD). Red blood cell (RBC) transfusions expose patients to the risk of developing antibodies: RBC alloimmunization occurs when the immune system meets foreign antigens. We created a register of extensively genotyped donors to achieve a better matched transfusion in order to reduce transfusion alloimmunization. Extended RBC antigen typing was determined and confirmed by molecular biology techniques using Human Erythrocyte Antigen (HEA) BeadChip (BioArray Solutions Ltd., Warren, NJ) in periodic blood donors and in patients with thalassaemia and SCD. During 3 years, we typed extensively 1220 periodic blood donors, 898 male and 322 female. We also studied 10 hematologic patients affected by thalassaemia and sickle cell disease referred to our institution as candidate to periodic transfusions. Our patients (8 females and 2 males with a median age of 48 years, range 24-76 years), extensively typed using molecular techniques and screened for RBC alloantibodies, were transfused with a median of 33.5 RBC units. After three years of molecular typing, the "perfect match" transfusion strategy avoided new alloantibodies development in all studied patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Agarose and Polyacrylamide Gel Electrophoresis Methods for Molecular Mass Analysis of 5–500 kDa Hyaluronan

PubMed Central

Bhilocha, Shardul; Amin, Ripal; Pandya, Monika; Yuan, Han; Tank, Mihir; LoBello, Jaclyn; Shytuhina, Anastasia; Wang, Wenlan; Wisniewski, Hans-Georg; de la Motte, Carol; Cowman, Mary K.

2011-01-01

Agarose and polyacrylamide gel electrophoresis systems for the molecular mass-dependent separation of hyaluronan (HA) in the size range of approximately 5–500 kDa have been investigated. For agarose-based systems, the suitability of different agarose types, agarose concentrations, and buffers systems were determined. Using chemoenzymatically synthesized HA standards of low polydispersity, the molecular mass range was determined for each gel composition, over which the relationship between HA mobility and logarithm of the molecular mass was linear. Excellent linear calibration was obtained for HA molecular mass as low as approximately 9 kDa in agarose gels. For higher resolution separation, and for extension to molecular masses as low as approximately 5 kDa, gradient polyacrylamide gels were superior. Densitometric scanning of stained gels allowed analysis of the range of molecular masses present in a sample, and calculation of weight-average and number-average values. The methods were validated for polydisperse HA samples with viscosity-average molecular masses of 112, 59, 37, and 22 kDa, at sample loads of 0.5 µg (for polyacrylamide) to 2.5 µg (for agarose). Use of the methods for electrophoretic mobility shift assays was demonstrated for binding of the HA-binding region of aggrecan (recombinant human aggrecan G1-IGD-G2 domains) to a 150 kDa HA standard. PMID:21684248

Single molecule counting and assessment of random molecular tagging errors with transposable giga-scale error-correcting barcodes.

PubMed

Lau, Billy T; Ji, Hanlee P

2017-09-21

RNA-Seq measures gene expression by counting sequence reads belonging to unique cDNA fragments. Molecular barcodes commonly in the form of random nucleotides were recently introduced to improve gene expression measures by detecting amplification duplicates, but are susceptible to errors generated during PCR and sequencing. This results in false positive counts, leading to inaccurate transcriptome quantification especially at low input and single-cell RNA amounts where the total number of molecules present is minuscule. To address this issue, we demonstrated the systematic identification of molecular species using transposable error-correcting barcodes that are exponentially expanded to tens of billions of unique labels. We experimentally showed random-mer molecular barcodes suffer from substantial and persistent errors that are difficult to resolve. To assess our method's performance, we applied it to the analysis of known reference RNA standards. By including an inline random-mer molecular barcode, we systematically characterized the presence of sequence errors in random-mer molecular barcodes. We observed that such errors are extensive and become more dominant at low input amounts. We described the first study to use transposable molecular barcodes and its use for studying random-mer molecular barcode errors. Extensive errors found in random-mer molecular barcodes may warrant the use of error correcting barcodes for transcriptome analysis as input amounts decrease.

Improving single molecule force spectroscopy through automated real-time data collection and quantification of experimental conditions

PubMed Central

Scholl, Zackary N.; Marszalek, Piotr E.

2013-01-01

The benefits of single molecule force spectroscopy (SMFS) clearly outweigh the challenges which include small sample sizes, tedious data collection and introduction of human bias during the subjective data selection. These difficulties can be partially eliminated through automation of the experimental data collection process for atomic force microscopy (AFM). Automation can be accomplished using an algorithm that triages usable force-extension recordings quickly with positive and negative selection. We implemented an algorithm based on the windowed fast Fourier transform of force-extension traces that identifies peaks using force-extension regimes to correctly identify usable recordings from proteins composed of repeated domains. This algorithm excels as a real-time diagnostic because it involves <30 ms computational time, has high sensitivity and specificity, and efficiently detects weak unfolding events. We used the statistics provided by the automated procedure to clearly demonstrate the properties of molecular adhesion and how these properties change with differences in the cantilever tip and protein functional groups and protein age. PMID:24001740

Unfolding of titin immunoglobulin domains by steered molecular dynamics simulation.

PubMed

Lu, H; Isralewitz, B; Krammer, A; Vogel, V; Schulten, K

1998-08-01

Titin, a 1-microm-long protein found in striated muscle myofibrils, possesses unique elastic and extensibility properties in its I-band region, which is largely composed of a PEVK region (70% proline, glutamic acid, valine, and lysine residue) and seven-strand beta-sandwich immunoglobulin-like (Ig) domains. The behavior of titin as a multistage entropic spring has been shown in atomic force microscope and optical tweezer experiments to partially depend on the reversible unfolding of individual Ig domains. We performed steered molecular dynamics simulations to stretch single titin Ig domains in solution with pulling speeds of 0.5 and 1.0 A/ps. Resulting force-extension profiles exhibit a single dominant peak for each Ig domain unfolding, consistent with the experimentally observed sequential, as opposed to concerted, unfolding of Ig domains under external stretching forces. This force peak can be attributed to an initial burst of backbone hydrogen bonds, which takes place between antiparallel beta-strands A and B and between parallel beta-strands A' and G. Additional features of the simulations, including the position of the force peak and relative unfolding resistance of different Ig domains, can be related to experimental observations.

α-Helix Unwinding as Force Buffer in Spectrins.

PubMed

Takahashi, Hirohide; Rico, Felix; Chipot, Christophe; Scheuring, Simon

2018-03-27

Spectrins are cytoskeletal proteins located at the inner face of the plasma membrane, making connections between membrane anchors and the actin cortex, and between actin filaments. Spectrins share a common structure forming a bundle of 3 α-helices and play a major role during cell deformation. Here, we used high-speed force spectroscopy and steered molecular dynamics simulations to understand the mechanical stability of spectrin, revealing a molecular force buffering function. We find that spectrin acts as a soft spring at short extensions (70-100 Å). Under continuous external stretching, its α-helices unwind, leading to a viscous mechanical response over larger extensions (100-300 Å), represented by a constant-force plateau in force/extension curves. This viscous force buffering emerges from a quasi-equilibrium competition between disruption and re-formation of α-helical hydrogen bonds. Our results suggest that, in contrast to β-sheet proteins, which unfold in a catastrophic event, α-helical spectrins dominantly unwind, providing a viscous force buffer over extensions about 5 times their folded length.

GIGAS: A set of microwave sensor arrays to detect molecular bremsstrahlung radiation from extensive air shower

NASA Astrophysics Data System (ADS)

Gaïor, R.; Al Samarai, I.; Berat, C.; Blanco Otano, M.; David, J.; Deligny, O.; Lebbolo, H.; Lecoz, S.; Letessier-Selvon, A.; Lhenry-Yvon, I.; Mariş, I. C.; Montanet, F.; Repain, P.; Salamida, F.; Settimo, M.; Stassi, P.; Stutz, A.

2018-04-01

We present the GIGAS (Gigahertz Identification of Giant Air Shower) microwave radio sensor arrays of the EASIER project (Extensive Air Shower Identification with Electron Radiometers), deployed at the site of the Pierre Auger cosmic ray observatory. The aim of these novel arrays is to probe the intensity of the molecular bremsstrahlung radiation expected from the development of the extensive air showers produced by the interaction of ultra high energy cosmic rays in the atmosphere. In the designed setup, the sensors are embedded within the surface detector array of the Pierre Auger observatory allowing us to use the particle signals at ground level to trigger the radio system. A series of seven, then 61 sensors have been deployed in the C-band, followed by a new series of 14 higher sensitivity ones in the C-band and the L-band. The design, the operation, the calibration and the sensitivity to extensive air showers of these arrays are described in this paper.

Design of two-photon molecular tandem architectures for solar cells by ab initio theory

DOE PAGES

Ornso, Kristian B.; Garcia-Lastra, Juan M.; De La Torre, Gema; ...

2015-03-04

An extensive database of spectroscopic properties of molecules from ab initio calculations is used to design molecular complexes for use in tandem solar cells that convert two photons into a single electron–hole pair, thereby increasing the output voltage while covering a wider spectral range. Three different architectures are considered: the first two involve a complex consisting of two dye molecules with appropriately matched frontier orbitals, connected by a molecular diode. Optimized combinations of dye molecules are determined by taking advantage of our computational database of the structural and energetic properties of several thousand porphyrin dyes. The third design is amore » molecular analogy of the intermediate band solar cell, and involves a single dye molecule with strong intersystem crossing to ensure a long lifetime of the intermediate state. Based on the calculated energy levels and molecular orbitals, energy diagrams are presented for the individual steps in the operation of such tandem solar cells. We find that theoretical open circuit voltages of up to 1.8 V can be achieved using these tandem designs. Questions about the practical implementation of prototypical devices, such as the synthesis of the tandem molecules and potential loss mechanisms, are addressed.« less

Control of Ion Selectivity in LeuT: Two Na+ Binding Sites with two different mechanisms

PubMed Central

Noskov, Sergei Y.; Roux, Benoît

2016-01-01

The x-ray structure of LeuT, a bacterial homologue of Na+/Cl−-dependent neurotransmitter transporter, provides a great opportunity to better understand the molecular basis of monovalent cation selectivity in ion-coupled transporters. LeuT possesses two ion-binding sites, NA1 and NA2, which are highly selective for Na+. Extensive all-atom free energy molecular dynamics simulations of LeuT embedded in an explicit membrane are performed at different temperatures and various occupancy states of the binding sites to dissect the molecular mechanism of ion selectivity. The results show that the two binding sites display robust selectivity for Na+ over K+ or Li+, the competing ions of most similar radii. Of particular interest, the mechanism primarily responsible for selectivity for each of the two binding sites appears to be different. In site NA1, selectivity for Na+ over K+ arises predominantly from the strong electrostatic field arising from the negatively charged carboxylate group of the leucine substrate coordinating the ion directly. In site NA2, which comprises only neutral ligands, selectivity for Na+ is enforced by the local structural restraints arising from the hydrogen-bonding network and the covalent connectivity of the poly-peptide chain surrounding the ion according to a snug-fit mechanism. PMID:18280500

Secondary ion emission from arachidic acid LB-layers under Ar +, Xe +, Ga + and SF 5+ primary ion bombardment

NASA Astrophysics Data System (ADS)

Stapel, D.; Brox, O.; Benninghoven, A.

1999-02-01

The influence of primary ion energy, mass and composition on sputtering and secondary ion emission of arachidic acid Langmuir-Blodgett mono- and multilayers, deposited on gold substrates, has been investigated. Ga +, Ar +, 129Xe+ and SF 5+ in the energy range 5-25 keV were used as primary ions. Yields Y, damage cross-sections σ, and ion formation efficiencies E have been determined for selected secondary ions, characterizing the molecular overlayer, the overlayer substrate interface and the substrate. We found a strong influence of layer thickness and of primary ion energy, mass and composition on Y, σ and E. Information depth increases with increasing ion energy and decreasing mass of primary ions, being higher for SF 5+ than for Xe +. Y, σ and E increase with increasing primary ion mass. They are considerably higher for a molecular (SF 5+) than for atomic ions of comparable mass ( 129Xe+). The experimental results supply information on the extension of impact cascades, generated in different substrate materials by different primary ion species and different energies. They demonstrate that in analytical SIMS application information depths can be minimized and yields and ion formation efficiencies can be maximized by the use of molecular primary ions.

[Editorial] Environmental and occupational risk factors associated with different pathological conditions.

PubMed

Signorelli, Salvatore Santo; Ferrante, Margherita

2017-05-01

A wide body of evidence indicates that environmental and occupational risk factors are associated with the development of pathological disorders. The pathogenic role of many environmental pollutants or occupational contaminants is already known and has been extensively investigated. However, the molecular mechanisms of action and the pathogenic effects of many substances remain unknown. Therefore, there is a need to better investigate the role of new environmental and occupational risk factors that may cause the development of several diseases.

GEOMETRY-INDEPENDENT DETERMINATION OF RADIAL DENSITY DISTRIBUTIONS IN MOLECULAR CLOUD CORES AND OTHER ASTRONOMICAL OBJECTS

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

Krčo, Marko; Goldsmith, Paul F., E-mail: marko@astro.cornell.edu

2016-05-01

We present a geometry-independent method for determining the shapes of radial volume density profiles of astronomical objects whose geometries are unknown, based on a single column density map. Such profiles are often critical to understand the physics and chemistry of molecular cloud cores, in which star formation takes place. The method presented here does not assume any geometry for the object being studied, thus removing a significant source of bias. Instead, it exploits contour self-similarity in column density maps, which appears to be common in data for astronomical objects. Our method may be applied to many types of astronomical objectsmore » and observable quantities so long as they satisfy a limited set of conditions, which we describe in detail. We derive the method analytically, test it numerically, and illustrate its utility using 2MASS-derived dust extinction in molecular cloud cores. While not having made an extensive comparison of different density profiles, we find that the overall radial density distribution within molecular cloud cores is adequately described by an attenuated power law.« less

Molecular detection of Toxoplasma gondii infection in slaughtered ruminants (sheep, goats and cattle) in Northwest Tunisia.

PubMed

Amdouni, Yosra; Rjeibi, Mohamed Ridha; Rouatbi, Mariem; Amairia, Safa; Awadi, Sofia; Gharbi, Mohamed

2017-11-01

The present study aimed to estimate the molecular prevalence of T. gondii infection in meat from slaughtered sheep, goats and cattle in Northwest Tunisia (Béja district). PCRs were performed on genomic DNA extracted from 420 meat samples (150 ewes, 120 goats and 150 cows). The overall molecular prevalence of T. gondii in sheep, goats and cattle were 33.3 (50/150), 32.5 (39/120) and 19.3% (29/150), respectively. Toxoplasma gondii molecular prevalences in the three meat ruminant species were significantly higher in adults compared to young animals (p<0.001). The infection prevalence differed significantly within localities in sheep (p<0.001), goats (p<0.001) and cattle (p=0.019). These results provide important information about exposure of humans to T. gondii through the consumption of raw or undercooked ruminants' meat. Extension programmes should be implemented to decrease the risk of infection related to sheep, goats and cattle meat manipulation and raw or undercooked meat consumption. Copyright © 2017 Elsevier Ltd. All rights reserved.

T Cell Allorecognition via Molecular Mimicry

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

Macdonald, Whitney A.; Chen, Zhenjun; Gras, Stephanie

T cells often alloreact with foreign human leukocyte antigens (HLA). Here we showed the LC13 T cell receptor (TCR), selected for recognition on self-HLA-B*0801 bound to a viral peptide, alloreacts with B44 allotypes (HLA-B*4402 and HLA-B*4405) bound to two different allopeptides. Despite extensive polymorphism between HLA-B*0801, HLA-B*4402, and HLA-B*4405 and the disparate sequences of the viral and allopeptides, the LC13 TCR engaged these peptide-HLA (pHLA) complexes identically, accommodating mimicry of the viral peptide by the allopeptide. The viral and allopeptides adopted similar conformations only after TCR ligation, revealing an induced-fit mechanism of molecular mimicry. The LC13 T cells did notmore » alloreact against HLA-B*4403, and the single residue polymorphism between HLA-B*4402 and HLA-B*4403 affected the plasticity of the allopeptide, revealing that molecular mimicry was associated with TCR specificity. Accordingly, molecular mimicry that is HLA and peptide dependent is a mechanism for human T cell alloreactivity between disparate cognate and allogeneic pHLA complexes.« less

Effect of molecular topology on the transport properties of dendrimers in dilute solution at Θ temperature: A Brownian dynamics study

NASA Astrophysics Data System (ADS)

Bosko, Jaroslaw T.; Ravi Prakash, J.

2008-01-01

Structure and transport properties of dendrimers in dilute solution are studied with the aid of Brownian dynamics simulations. To investigate the effect of molecular topology on the properties, linear chain, star, and dendrimer molecules of comparable molecular weights are studied. A bead-spring chain model with finitely extensible springs and fluctuating hydrodynamic interactions is used to represent polymer molecules under Θ conditions. Structural properties as well as the diffusivity and zero-shear-rate intrinsic viscosity of polymers with varied degrees of branching are analyzed. Results for the free-draining case are compared to and found in very good agreement with the Rouse model predictions. Translational diffusivity is evaluated and the difference between the short-time and long-time behavior due to dynamic correlations is observed. Incorporation of hydrodynamic interactions is found to be sufficient to reproduce the maximum in the intrinsic viscosity versus molecular weight observed experimentally for dendrimers. Results of the nonequilibrium Brownian dynamics simulations of dendrimers and linear chain polymers subjected to a planar shear flow in a wide range of strain rates are also reported. The flow-induced molecular deformation of molecules is found to decrease hydrodynamic interactions and lead to the appearance of shear thickening. Further, branching is found to suppress flow-induced molecular alignment and deformation.

High-resolution monitoring of marine protists based on an observation strategy integrating automated on-board filtration and molecular analyses

NASA Astrophysics Data System (ADS)

Metfies, Katja; Schroeder, Friedhelm; Hessel, Johanna; Wollschläger, Jochen; Micheller, Sebastian; Wolf, Christian; Kilias, Estelle; Sprong, Pim; Neuhaus, Stefan; Frickenhaus, Stephan; Petersen, Wilhelm

2016-11-01

Information on recent biomass distribution and biogeography of photosynthetic marine protists with adequate temporal and spatial resolution is urgently needed to better understand the consequences of environmental change for marine ecosystems. Here we introduce and review a molecular-based observation strategy for high-resolution assessment of these protists in space and time. It is the result of extensive technology developments, adaptations and evaluations which are documented in a number of different publications, and the results of the recently completed field testing which are introduced in this paper. The observation strategy is organized at four different levels. At level 1, samples are collected at high spatiotemporal resolution using the remotely controlled automated filtration system AUTOFIM. Resulting samples can either be preserved for later laboratory analyses, or directly subjected to molecular surveillance of key species aboard the ship via an automated biosensor system or quantitative polymerase chain reaction (level 2). Preserved samples are analyzed at the next observational levels in the laboratory (levels 3 and 4). At level 3 this involves molecular fingerprinting methods for a quick and reliable overview of differences in protist community composition. Finally, selected samples can be used to generate a detailed analysis of taxonomic protist composition via the latest next generation sequencing technology (NGS) at level 4. An overall integrated dataset of the results based on the different analyses provides comprehensive information on the diversity and biogeography of protists, including all related size classes. At the same time the cost of the observation is optimized with respect to analysis effort and time.

Differential Interaction of Antimicrobial Peptides with Lipid Structures Studied by Coarse-Grained Molecular Dynamics Simulations.

PubMed

Balatti, Galo E; Ambroggio, Ernesto E; Fidelio, Gerardo D; Martini, M Florencia; Pickholz, Mónica

2017-10-20

In this work; we investigated the differential interaction of amphiphilic antimicrobial peptides with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid structures by means of extensive molecular dynamics simulations. By using a coarse-grained (CG) model within the MARTINI force field; we simulated the peptide-lipid system from three different initial configurations: (a) peptides in water in the presence of a pre-equilibrated lipid bilayer; (b) peptides inside the hydrophobic core of the membrane; and (c) random configurations that allow self-assembled molecular structures. This last approach allowed us to sample the structural space of the systems and consider cooperative effects. The peptides used in our simulations are aurein 1.2 and maculatin 1.1; two well-known antimicrobial peptides from the Australian tree frogs; and molecules that present different membrane-perturbing behaviors. Our results showed differential behaviors for each type of peptide seen in a different organization that could guide a molecular interpretation of the experimental data. While both peptides are capable of forming membrane aggregates; the aurein 1.2 ones have a pore-like structure and exhibit a higher level of organization than those conformed by maculatin 1.1. Furthermore; maculatin 1.1 has a strong tendency to form clusters and induce curvature at low peptide-lipid ratios. The exploration of the possible lipid-peptide structures; as the one carried out here; could be a good tool for recognizing specific configurations that should be further studied with more sophisticated methodologies.

Recent technological advancements in tuberculosis diagnostics - A review.

PubMed

Gupta, Shagun; Kakkar, Vipan

2018-09-15

Early diagnosis and on-time effective treatment are indispensable for Tuberculosis (TB) control - a life threatening infectious communicable disease. The conventional techniques for diagnosing TB normally take two to three weeks. This delay in diagnosis and further increase in detection complexity due to the emerging risks of XDR-TB (Extensively drug Resistant-TB) and MDR-TB (Multidrug Resistant-TB) are evoking interest of researchers in the field of developing rapid TB detection techniques such as biosensing and other point-of-care (POC) techniques. Biosensing technologies along with the collaboration with nanotechnology have enormous potential to boost the MTB detection and for overall management in clinical diagnosis. A diverse range of portable, sensitive and rapid biosensors based on different signal transducer principles and with different biomarkers detection capabilities have been developed for TB detection in the early stages. Further, a lot of progress has been achieved over the years in developing various point-of-care diagnostic tools including non-molecular methods and molecular techniques. The objective of this study is to present a succinct review of the available TB detection techniques that are either in use or under development. The focus of this review is on the current developments occurred in nano-biosensing technologies. A synopsis of ameliorations in different non-molecular diagnostic tools and progress in the field of molecular techniques along with the role of emerging Lab-on-Chip technology for diagnosing and mitigating the TB consequences have also been presented. Copyright © 2018 Elsevier B.V. All rights reserved.

Alleles versus mutations: Understanding the evolution of genetic architecture requires a molecular perspective on allelic origins.

PubMed

Remington, David L

2015-12-01

Perspectives on the role of large-effect quantitative trait loci (QTL) in the evolution of complex traits have shifted back and forth over the past few decades. Different sets of studies have produced contradictory insights on the evolution of genetic architecture. I argue that much of the confusion results from a failure to distinguish mutational and allelic effects, a limitation of using the Fisherian model of adaptive evolution as the lens through which the evolution of adaptive variation is examined. A molecular-based perspective reveals that allelic differences can involve the cumulative effects of many mutations plus intragenic recombination, a model that is supported by extensive empirical evidence. I discuss how different selection regimes could produce very different architectures of allelic effects under a molecular-based model, which may explain conflicting insights on genetic architecture from studies of variation within populations versus between divergently selected populations. I address shortcomings of genome-wide association study (GWAS) practices in light of more suitable models of allelic evolution, and suggest alternate GWAS strategies to generate more valid inferences about genetic architecture. Finally, I discuss how adopting more suitable models of allelic evolution could help redirect research on complex trait evolution toward addressing more meaningful questions in evolutionary biology. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii

PubMed Central

Chen, Ying-Lien; Lehman, Virginia N.; Lewit, Yonathan; Averette, Anna F.; Heitman, Joseph

2013-01-01

The pathogenic yeast Cryptococcus gattii, which is causing an outbreak in the Pacific Northwest region of North America, causes life-threatening pulmonary infections and meningoencephalitis in healthy individuals, unlike Cryptococcus neoformans, which commonly infects immunocompromised patients. In addition to a greater predilection for C. gattii to infect healthy hosts, the C. gattii genome sequence project revealed extensive chromosomal rearrangements compared with C. neoformans, showing genomic differences between the two Cryptococcus species. We investigated the roles of C. gattii calcineurin in three molecular types: VGIIa (R265), VGIIb (R272), and VGI (WM276). We found that calcineurin exhibits a differential requirement for growth on solid medium at 37°, as calcineurin mutants generated from R265 were more thermotolerant than mutants from R272 and WM276. We demonstrated that tolerance to calcineurin inhibitors (FK506, CsA) at 37° is linked with the VGIIa molecular type. The calcineurin mutants from the R272 background showed the most extensive growth and morphological defects (multivesicle and larger ring-like cells), as well as increased fluconazole susceptibility. Our cellular architecture examination showed that C. gattii and C. neoformans calcineurin mutants exhibit plasma membrane disruptions. Calcineurin in the C. gattii VGII molecular type plays a greater role in controlling cation homeostasis compared with that in C. gattii VGI and C. neoformans H99. Importantly, we demonstrate that C. gattii calcineurin is essential for virulence in a murine inhalation model, supporting C. gattii calcineurin as an attractive antifungal drug target. PMID:23450261

Cytological preparations for molecular analysis: A review of technical procedures, advantages and limitations for referring samples for testing.

PubMed

da Cunha Santos, G; Saieg, M A; Troncone, G; Zeppa, P

2018-04-01

Minimally invasive procedures such as endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) must yield not only good quality and quantity of material for morphological assessment, but also an adequate sample for analysis of molecular markers to guide patients to appropriate targeted therapies. In this context, cytopathologists worldwide should be familiar with minimum requirements for refereeing cytological samples for testing. The present manuscript is a review with comprehensive description of the content of the workshop entitled Cytological preparations for molecular analysis: pre-analytical issues for EBUS TBNA, presented at the 40th European Congress of Cytopathology in Liverpool, UK. The present review emphasises the advantages and limitations of different types of cytology substrates used for molecular analysis such as archival smears, liquid-based preparations, archival cytospin preparations and FTA (Flinders Technology Associates) cards, as well as their technical requirements/features. These various types of cytological specimens can be successfully used for an extensive array of molecular studies, but the quality and quantity of extracted nucleic acids rely directly on adequate pre-analytical assessment of those samples. In this setting, cytopathologists must not only be familiar with the different types of specimens and associated technical procedures, but also correctly handle the material provided by minimally invasive procedures, ensuring that there is sufficient amount of material for a precise diagnosis and correct management of the patient through personalised care. © 2018 John Wiley & Sons Ltd.

Lightweight computational steering of very large scale molecular dynamics simulations

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

Beazley, D.M.; Lomdahl, P.S.

1996-09-01

We present a computational steering approach for controlling, analyzing, and visualizing very large scale molecular dynamics simulations involving tens to hundreds of millions of atoms. Our approach relies on extensible scripting languages and an easy to use tool for building extensions and modules. The system is extremely easy to modify, works with existing C code, is memory efficient, and can be used from inexpensive workstations and networks. We demonstrate how we have used this system to manipulate data from production MD simulations involving as many as 104 million atoms running on the CM-5 and Cray T3D. We also show howmore » this approach can be used to build systems that integrate common scripting languages (including Tcl/Tk, Perl, and Python), simulation code, user extensions, and commercial data analysis packages.« less

Cutting the Wires: Modularization of Cellular Networks for Experimental Design

PubMed Central

Lang, Moritz; Summers, Sean; Stelling, Jörg

2014-01-01

Understanding naturally evolved cellular networks requires the consecutive identification and revision of the interactions between relevant molecular species. In this process, initially often simplified and incomplete networks are extended by integrating new reactions or whole subnetworks to increase consistency between model predictions and new measurement data. However, increased consistency with experimental data alone is not sufficient to show the existence of biomolecular interactions, because the interplay of different potential extensions might lead to overall similar dynamics. Here, we present a graph-based modularization approach to facilitate the design of experiments targeted at independently validating the existence of several potential network extensions. Our method is based on selecting the outputs to measure during an experiment, such that each potential network extension becomes virtually insulated from all others during data analysis. Each output defines a module that only depends on one hypothetical network extension, and all other outputs act as virtual inputs to achieve insulation. Given appropriate experimental time-series measurements of the outputs, our modules can be analyzed, simulated, and compared to the experimental data separately. Our approach exemplifies the close relationship between structural systems identification and modularization, an interplay that promises development of related approaches in the future. PMID:24411264

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

Ribezzi-Crivellari, M.; Huguet, J. M.; Ritort, F.

We present a dual-trap optical tweezers setup which directly measures forces using linear momentum conservation. The setup uses a counter-propagating geometry, which allows momentum measurement on each beam separately. The experimental advantages of this setup include low drift due to all-optical manipulation, and a robust calibration (independent of the features of the trapped object or buffer medium) due to the force measurement method. Although this design does not attain the high-resolution of some co-propagating setups, we show that it can be used to perform different single molecule measurements: fluctuation-based molecular stiffness characterization at different forces and hopping experiments on molecularmore » hairpins. Remarkably, in our setup it is possible to manipulate very short tethers (such as molecular hairpins with short handles) down to the limit where beads are almost in contact. The setup is used to illustrate a novel method for measuring the stiffness of optical traps and tethers on the basis of equilibrium force fluctuations, i.e., without the need of measuring the force vs molecular extension curve. This method is of general interest for dual trap optical tweezers setups and can be extended to setups which do not directly measure forces.« less

Weathering trend characterization of medium-molecular weight polycyclic aromatic disulfur heterocycles by Fourier transform ion cyclotron resonance mass spectrometry.

PubMed

Hegazi, Abdelrahman H; Fathalla, Eiman M; Andersson, Jan T

2014-09-01

Different weathering factors act to change petroleum composition once it is spilled into the environment. n-Alkanes, biomarkers, low-molecular weight polyaromatic hydrocarbons and sulfur heterocycles compositional changing in the environment have been extensively studied by different researchers and many parameters have been used for oil source identification and monitoring of weathering and biological degradation processes. In this work, we studied the fate of medium-molecular weight polycyclic aromatic disulfur heterocycles (PAS2Hs), up to ca. 900Da, of artificially weathered Flotta North Sea crude oil by ultra high-resolution Fourier transform ion cyclotron resonance mass spectrometry. It was found that PAS2Hs in studied crude oil having double bond equivalents (DBE) from 5 to 8 with a mass range from ca 316 to 582Da were less influenced even after six months artificial weathering experiment. However, compounds having DBEs 12, 11 and 10 were depleted after two, four and six months weathering, respectively. In addition, DBE 9 series was more susceptible to weathering than those of DBE 7 and 8. Copyright © 2014 Elsevier Ltd. All rights reserved.

Interactions in charged colloidal suspensions: A molecular dynamics simulation study

NASA Astrophysics Data System (ADS)

Padidela, Uday Kumar; Behera, Raghu Nath

2017-07-01

Colloidal suspensions are extensively used in everyday life and find several applications in the pharmaceutical, chemical, food industries, etc. We present the classical molecular dynamics simulation results of the structural and transport properties of charged colloidal suspensions as a function of its size, charge and concentration. The system is viewed as a two-component (colloids and counterions) primitive model consisting of spherical colloid particle (macroion) and the counterions (micro-particles), which are treated explicitly. The solvent is treated as dielectric continuum. A systematic trend in the radial distribution functions g(r), potential of mean force W(r), different thermodynamic properties and diffusion coefficients is obtained as a function of colloid charge, size and concentration. An attractive minimum in W(r) is obtained at short interparticle distance.

Efficient and Flexible Computation of Many-Electron Wave Function Overlaps.

PubMed

Plasser, Felix; Ruckenbauer, Matthias; Mai, Sebastian; Oppel, Markus; Marquetand, Philipp; González, Leticia

2016-03-08

A new algorithm for the computation of the overlap between many-electron wave functions is described. This algorithm allows for the extensive use of recurring intermediates and thus provides high computational efficiency. Because of the general formalism employed, overlaps can be computed for varying wave function types, molecular orbitals, basis sets, and molecular geometries. This paves the way for efficiently computing nonadiabatic interaction terms for dynamics simulations. In addition, other application areas can be envisaged, such as the comparison of wave functions constructed at different levels of theory. Aside from explaining the algorithm and evaluating the performance, a detailed analysis of the numerical stability of wave function overlaps is carried out, and strategies for overcoming potential severe pitfalls due to displaced atoms and truncated wave functions are presented.

Effects of elevated line sources on turbulent mixing in channel flow

NASA Astrophysics Data System (ADS)

Nguyen, Quoc; Papavassiliou, Dimitrios

2016-11-01

Fluids mixing in turbulent flows has been studied extensively, due to the importance of this phenomena in nature and engineering. Convection effects along with motion of three-dimensional coherent structures in turbulent flow disperse a substance more efficiently than molecular diffusion does on its own. We present here, however, a study that explores the conditions under which turbulent mixing does not happen, when different substances are released into the flow field from different vertical locations. The study uses a method which combines Direct Numerical Simulation (DNS) with Lagrangian Scalar Tracking (LST) to simulate a turbulent channel flow and track the motion of passive scalars with different Schmidt numbers (Sc). The particles are released from several instantaneous line sources, ranging from the wall to the center region of the channel. The combined effects of mean velocity difference, molecular diffusion and near-wall coherent structures lead to the observation of different concentrations of particles downstream from the source. We then explore in details the conditions under which particles mixing would not happen. Results from numerical simulation at friction Reynolds number of 300 and 600 will be discussed and for Sc ranging from 0.1 to 2,400.

Genetic and hormonal control of hepatic steatosis in female and male mice.

PubMed

Norheim, Frode; Hui, Simon T; Kulahcioglu, Emre; Mehrabian, Margarete; Cantor, Rita M; Pan, Calvin; Parks, Brian W; Lusis, Aldons J

2017-01-01

The etiology of nonalcoholic fatty liver disease is complex and influenced by factors such as obesity, insulin resistance, hyperlipidemia, and sex. We now report a study on sex difference in hepatic steatosis in the context of genetic variation using a population of inbred strains of mice. While male mice generally exhibited higher concentration of hepatic TG levels on a high-fat high-sucrose diet, sex differences showed extensive interaction with genetic variation. Differences in percentage body fat were the best predictor of hepatic steatosis among the strains and explained about 30% of the variation in both sexes. The difference in percent gonadal fat and HDL explained 9.6% and 6.7% of the difference in hepatic TGs between the sexes, respectively. Genome-wide association mapping of hepatic TG revealed some striking differences in genetic control of hepatic steatosis between females and males. Gonadectomy increased the hepatic TG to body fat percentage ratio among male, but not female, mice. Our data suggest that the difference between the sexes in hepatic TG can be partly explained by differences in body fat distribution, plasma HDL, and genetic regulation. Future studies are required to understand the molecular interactions between sex, genetics, and the environment. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

simulation of the DNA force-extension curve

NASA Astrophysics Data System (ADS)

Shinaberry, Gregory; Mikhaylov, Ivan; Balaeff, Alexander

A molecular dynamics simulation study of the force-extension curve of double-stranded DNA is presented. Extended simulations of the DNA at multiple points along the force-extension curve are conducted with DNA end-to-end length constrained at each point. The calculated force-extension curve qualitatively reproduces the experimental one. The DNA conformational ensemble at each extension shows that the famous plateau of the force-extension curve results from B-DNA melting, whereas the formation of the earlier-predicted novel DNA conformation called 'zip-DNA' takes place at extensions past the plateau. An extensive analysis of the DNA conformational ensemble in terms of base configuration, backbone configuration, solvent interaction energy, etc., is conducted in order to elucidate the physical origin of DNA elasticity and the main interactions responsible for the shape of the force-extension curve.

Molecular interference of fibrin’s divalent polymerization mechanism enables modulation of multiscale material properties

PubMed Central

Brown, Ashley C.; Baker, Stephen; Douglas, Alison; Keating, Mark; Alvarez-Elizondo, Martha; Botvinick, Elliot; Guthold, Martin; Barker, Thomas H.

2015-01-01

Protein based polymers provide an exciting and complex landscape for tunable natural biomaterials through modulation of molecular level interactions. Here we demonstrate the ability to modify protein polymer structural and mechanical properties at multiple length scales by molecular ‘interference’ of fibrin’s native polymerization mechanism. We have previously reported that engagement of fibrin’s polymerization ‘hole b’, also known as ‘b-pockets’, through PEGylated complimentary ‘knob B’ mimics can increase fibrin network porosity but also, somewhat paradoxically, increase network stiffness. Here, we explore the possible mechanistic underpinning of this phenomenon through characterization of the effects of knob B-fibrin interaction at multiple length scales from molecular to bulk polymer. Despite its weak monovalent binding affinity for fibrin, addition of both knob B and PEGylated knob B at concentrations near the binding coefficient, Kd, increased fibrin network porosity, consistent with the reported role of knob B-hole b interactions in promoting lateral growth of fibrin fibers. Addition of PEGylated knob B decreases the extensibility of single fibrin fibers at concentrations near its Kd but increases extensibility of fibers at concentrations above its Kd. The data suggest this bimodal behavior is due to the individual contributions knob B, which decreases fiber extensibility, and PEG, which increase fiber extensibility. Taken together with laser trap-based microrheological and bulk rheological analyses of fibrin polymers, our data strongly suggests that hole b engagement increases in single fiber stiffness that translates to higher storage moduli of fibrin polymers despite their increased porosity. These data point to possible strategies for tuning fibrin polymer mechanical properties through modulation of single fiber mechanics. PMID:25725552

OpenMM 4: A Reusable, Extensible, Hardware Independent Library for High Performance Molecular Simulation.

PubMed

Eastman, Peter; Friedrichs, Mark S; Chodera, John D; Radmer, Randall J; Bruns, Christopher M; Ku, Joy P; Beauchamp, Kyle A; Lane, Thomas J; Wang, Lee-Ping; Shukla, Diwakar; Tye, Tony; Houston, Mike; Stich, Timo; Klein, Christoph; Shirts, Michael R; Pande, Vijay S

2013-01-08

OpenMM is a software toolkit for performing molecular simulations on a range of high performance computing architectures. It is based on a layered architecture: the lower layers function as a reusable library that can be invoked by any application, while the upper layers form a complete environment for running molecular simulations. The library API hides all hardware-specific dependencies and optimizations from the users and developers of simulation programs: they can be run without modification on any hardware on which the API has been implemented. The current implementations of OpenMM include support for graphics processing units using the OpenCL and CUDA frameworks. In addition, OpenMM was designed to be extensible, so new hardware architectures can be accommodated and new functionality (e.g., energy terms and integrators) can be easily added.

OpenMM 4: A Reusable, Extensible, Hardware Independent Library for High Performance Molecular Simulation

PubMed Central

Eastman, Peter; Friedrichs, Mark S.; Chodera, John D.; Radmer, Randall J.; Bruns, Christopher M.; Ku, Joy P.; Beauchamp, Kyle A.; Lane, Thomas J.; Wang, Lee-Ping; Shukla, Diwakar; Tye, Tony; Houston, Mike; Stich, Timo; Klein, Christoph; Shirts, Michael R.; Pande, Vijay S.

2012-01-01

OpenMM is a software toolkit for performing molecular simulations on a range of high performance computing architectures. It is based on a layered architecture: the lower layers function as a reusable library that can be invoked by any application, while the upper layers form a complete environment for running molecular simulations. The library API hides all hardware-specific dependencies and optimizations from the users and developers of simulation programs: they can be run without modification on any hardware on which the API has been implemented. The current implementations of OpenMM include support for graphics processing units using the OpenCL and CUDA frameworks. In addition, OpenMM was designed to be extensible, so new hardware architectures can be accommodated and new functionality (e.g., energy terms and integrators) can be easily added. PMID:23316124

Negative correlation between rates of molecular evolution and flowering cycles in temperate woody bamboos revealed by plastid phylogenomics.

PubMed

Ma, Peng-Fei; Vorontsova, Maria S; Nanjarisoa, Olinirina Prisca; Razanatsoa, Jacqueline; Guo, Zhen-Hua; Haevermans, Thomas; Li, De-Zhu

2017-12-21

Heterogeneous rates of molecular evolution are universal across the tree of life, posing challenges for phylogenetic inference. The temperate woody bamboos (tribe Arundinarieae, Poaceae) are noted for their extremely slow molecular evolutionary rates, supposedly caused by their mysterious monocarpic reproduction. However, the correlation between substitution rates and flowering cycles has not been formally tested. Here we present 15 newly sequenced plastid genomes of temperate woody bamboos, including the first genomes ever sequenced from Madagascar representatives. A data matrix of 46 plastid genomes representing all 12 lineages of Arundinarieae was assembled for phylogenetic and molecular evolutionary analyses. We conducted phylogenetic analyses using different sequences (e.g., coding and noncoding) combined with different data partitioning schemes, revealing conflicting relationships involving internodes among several lineages. A great difference in branch lengths were observed among the major lineages, and topological inconsistency could be attributed to long-branch attraction (LBA). Using clock model-fitting by maximum likelihood and Bayesian approaches, we furthermore demonstrated extensive rate variation among these major lineages. Rate accelerations mainly occurred for the isolated lineages with limited species diversification, totaling 11 rate shifts during the tribe's evolution. Using linear regression analysis, we found a negative correlation between rates of molecular evolution and flowering cycles for Arundinarieae, notwithstanding that the correlation maybe insignificant when taking the phylogenetic structure into account. Using the temperate woody bamboos as an example, we found further evidence that rate heterogeneity is universal in plants, suggesting that this will pose a challenge for phylogenetic reconstruction of bamboos. The bamboos with longer flowering cycles tend to evolve more slowly than those with shorter flowering cycles, in accordance with a putative generation time effect.

Rheology modification with ring polymers

NASA Astrophysics Data System (ADS)

Vlassopoulos, Dimitris

It is now established that experimental unconcatenated ring polymers can be purified effectively by means of fractionation at the critical condition. For molecular weights well above the entanglement threshold, purified rings relax stress via power-law (with an exponent of about -0.4), sharply departing from their linear counterparts. Experimental results are in harmony with modeling predictions and simulations. Here, we present results from recent interdisciplinary efforts and discuss two challenges: (i) the nonlinear shear rheology of purified ring melts is also very different from that of unlinked chains. Whereas the latter exhibit features that can be explained, to a first approach, in the framework in the tube model, the former behave akin to unentangled chains with finite extensibility and exhibit much small deformation at steady state. (ii) blends of rings and linear polymers exhibit unique features in different regimes: The addition of minute amounts of linear chains drastically affects ring dynamics. This relates to ring purity and the ability of unlinked linear chains to thread rings. With the help of simulations, it is possible to rationalize the observed surprisingly slow viscoelastic relaxation, which is attributed to ring-linear and ring-ring penetrations. On the other hand, adding small amounts of rings to linear polymers of different molecular weights influences their linear and nonlinear rheology in an unprecedented way. The blend viscosity exceeds that of the slower component (linear) in this non-interacting mixture, and its dependencies on composition and molecular weight ratio are examined, whereas the role of molecular architecture is also addressed. Consequently, closing the ends of a linear chain can serve as a powerful means for molecular manipulation of its rheology. This presentation reflects collaborative efforts with S. Costanzo, Z-C. Yan, R. Pasquino, M. Kaliva, S. Kamble, Y. Jeong, P. Lutz, J. Allgaier, T. Chang, D. Talikis, V. Mavrantzas and M. Rubinstein.

Ole e 13 is the unique food allergen in olive: Structure-functional, substrates docking, and molecular allergenicity comparative analysis.

PubMed

Jimenez-Lopez, J C; Robles-Bolivar, P; Lopez-Valverde, F J; Lima-Cabello, E; Kotchoni, S O; Alché, J D

2016-05-01

Thaumatin-like proteins (TLPs) are enzymes with important functions in pathogens defense and in the response to biotic and abiotic stresses. Last identified olive allergen (Ole e 13) is a TLP, which may also importantly contribute to food allergy and cross-allergenicity to pollen allergen proteins. The goals of this study are the characterization of the structural-functionality of Ole e 13 with a focus in its catalytic mechanism, and its molecular allergenicity by extensive analysis using different molecular computer-aided approaches covering a) functional-regulatory motifs, b) comparative study of linear sequence, 2-D and 3D structural homology modeling, c) molecular docking with two different β-D-glucans, d) conservational and evolutionary analysis, e) catalytic mechanism modeling, and f) IgE-binding, B- and T-cell epitopes identification and comparison to other allergenic TLPs. Sequence comparison, structure-based features, and phylogenetic analysis identified Ole e 13 as a thaumatin-like protein. 3D structural characterization revealed a conserved overall folding among plants TLPs, with mayor differences in the acidic (catalytic) cleft. Molecular docking analysis using two β-(1,3)-glucans allowed to identify fundamental residues involved in the endo-1,3-β-glucanase activity, and defining E84 as one of the conserved residues of the TLPs responsible of the nucleophilic attack to initiate the enzymatic reaction and D107 as proton donor, thus proposing a catalytic mechanism for Ole e 13. Identification of IgE-binding, B- and T-cell epitopes may help designing strategies to improve diagnosis and immunotherapy to food allergy and cross-allergenic pollen TLPs. Copyright © 2016 Elsevier Inc. All rights reserved.

Breeding of lilies and tulips—Interspecific hybridization and genetic background—

PubMed Central

Marasek-Ciolakowska, Agnieszka; Nishikawa, Tomotaro; Shea, Daniel J.; Okazaki, Keiichi

2018-01-01

Lilies and tulips (Liliaceae family) are economically very important ornamental bulbous plants. Here, we summarize major breeding goals, the role of an integrated method of cut-style pollination and fertilization followed by embryo rescue and mitotic and meiotic polyploidization involved in new assortment development. Both crops have been subjected to extensive interspecific hybridization followed by selection. Additionally, spontaneous polyploidization has played a role in their evolution. In lilies, there is a tendency to replace diploids with polyploid cultivars, whereas in tulip a majority of the cultivars that exist today are still diploid except for triploid Darwin hybrid tulips. The introduction of molecular cytogenetic techniques such as genomic in situ hybridization (GISH) permitted the detailed studies of genome composition in lily and tulip interspecific hybrids and to follow the chromosome inheritance in interspecific crosses. In addition, this review presents the latest information on phylogenetic relationship in lily and tulip and recent developments in molecular mapping using different DNA molecular techniques. PMID:29681746

Study of multi-dimensional radiative energy transfer in molecular gases

NASA Technical Reports Server (NTRS)

Liu, Jiwen; Tiwari, S. N.

1993-01-01

The Monte Carlo method (MCM) is applied to analyze radiative heat transfer in nongray gases. The nongray model employed is based on the statistical arrow band model with an exponential-tailed inverse intensity distribution. Consideration of spectral correlation results in some distinguishing features of the Monte Carlo formulations. Validation of the Monte Carlo formulations has been conducted by comparing results of this method with other solutions. Extension of a one-dimensional problem to a multi-dimensional problem requires some special treatments in the Monte Carlo analysis. Use of different assumptions results in different sets of Monte Carlo formulations. The nongray narrow band formulations provide the most accurate results.

PubMed Central

MOROSETTI, R.; GLIUBIZZI, C.; BROCCOLINI, A.; SANCRICCA, C.; MIRABELLA, M.

2011-01-01

SUMMARY Mesoangioblasts are a class of adult stem cells of mesoderm origin, potentially useful for the treatment of primitive myopathies of different etiology. Extensive in vitro and in vivo studies in animal models of muscular dystrophy have demonstrated the ability of mesoangioblast to repair skeletal muscle when injected intra-arterially. In a previous work we demonstrated that mesoangioblasts obtained from diagnostic muscle biopsies of IBM patients display a defective differentiation down skeletal muscle and this block can be corrected in vitro by transient MyoD transfection. We are currently investigating different pathways involved in mesoangioblasts skeletal muscle differentiation and exploring alternative stimulatory approaches not requiring extensive cell manipulation. This will allow to obtain safe, easy and efficient molecular or pharmacological modulation of pro-myogenic pathways in IBM mesoangioblasts. It is of crucial importance to identify factors (ie. cytokines, growth factors) produced by muscle or inflammatory cells and released in the surrounding milieu that are able to regulate the differentiation ability of IBM mesoangioblasts. To promote myogenic differentiation of endogenous mesoangioblasts in IBM muscle, the modulation of such target molecules selectively dysregulated would be a more handy approach to enhance muscle regeneration compared to transplantation techniques. Studies on the biological characteristics of IBM mesoangioblasts with their aberrant differentiation behavior, the signaling pathways possibly involved in their differentiation block and the possible strategies to overcome it in vivo, might provide new insights to better understand the etiopathogenesis of this crippling disorder and to identify molecular targets susceptible of therapeutic modulation. PMID:21842589

The Physiological Molecular Shape of Spectrin: A Compact Supercoil Resembling a Chinese Finger Trap.

PubMed

Brown, Jeffrey W; Bullitt, Esther; Sriswasdi, Sira; Harper, Sandra; Speicher, David W; McKnight, C James

2015-06-01

The primary, secondary, and tertiary structures of spectrin are reasonably well defined, but the structural basis for the known dramatic molecular shape change, whereby the molecular length can increase three-fold, is not understood. In this study, we combine previously reported biochemical and high-resolution crystallographic data with structural mass spectroscopy and electron microscopic data to derive a detailed, experimentally-supported quaternary structure of the spectrin heterotetramer. In addition to explaining spectrin's physiological resting length of ~55-65 nm, our model provides a mechanism by which spectrin is able to undergo a seamless three-fold extension while remaining a linear filament, an experimentally observed property. According to the proposed model, spectrin's quaternary structure and mechanism of extension is similar to a Chinese Finger Trap: at shorter molecular lengths spectrin is a hollow cylinder that extends by increasing the pitch of each spectrin repeat, which decreases the internal diameter. We validated our model with electron microscopy, which demonstrated that, as predicted, spectrin is hollow at its biological resting length of ~55-65 nm. The model is further supported by zero-length chemical crosslink data indicative of an approximately 90 degree bend between adjacent spectrin repeats. The domain-domain interactions in our model are entirely consistent with those present in the prototypical linear antiparallel heterotetramer as well as recently reported inter-strand chemical crosslinks. The model is consistent with all known physical properties of spectrin, and upon full extension our Chinese Finger Trap Model reduces to the ~180-200 nm molecular model currently in common use.

Cellular consequences of sleep deprivation in the brain.

PubMed

Cirelli, Chiara

2006-10-01

Several recent studies have used transcriptomics approaches to characterize the molecular correlates of sleep, waking, and sleep deprivation. This analysis may help in understanding the benefits that sleep brings to the brain at the cellular level. The studies are still limited in number and focus on a few brain regions, but some consistent findings are emerging. Sleep, spontaneous wakefulness, short-term, and long-term sleep deprivation are each associated with the upregulation of hundreds of genes in the cerebral cortex and other brain areas. In fruit flies as well as in mammals, three categories of genes are consistently upregulated during waking and short-term sleep deprivation relative to sleep. They include genes involved in energy metabolism, synaptic potentiation, and the response to cellular stress. In the rat cerebral cortex, transcriptional changes associated with prolonged sleep loss differ significantly from those observed during short-term sleep deprivation. However, it is too early to draw firm conclusions relative to the molecular consequences of sleep deprivation, and more extensive studies using DNA and protein arrays are needed in different species and in different brain regions.

NanoDesign: Concepts and Software for a Nanotechnology Based on Functionalized Fullerenes

NASA Technical Reports Server (NTRS)

Globus, Al; Jaffe, Richard; Chancellor, Marisa K. (Technical Monitor)

1996-01-01

Eric Drexler has proposed a hypothetical nanotechnology based on diamond and investigated the properties of such molecular systems. While attractive, diamonoid nanotechnology is not physically accessible with straightforward extensions of current laboratory techniques. We propose a nanotechnology based on functionalized fullerenes and investigate carbon nanotube based gears with teeth added via a benzyne reaction known to occur with C60. The gears are single-walled carbon nanotubes with appended coenzyme groups for teeth. Fullerenes are in widespread laboratory use and can be functionalized in many ways. Companion papers computationally demonstrate the properties of these gears (they appear to work) and the accessibility of the benzyne/nanotube reaction. This paper describes the molecular design techniques and rationale as well as the software that implements these design techniques. The software is a set of persistent C++ objects controlled by TCL command scripts. The c++/tcl interface is automatically generated by a software system called tcl_c++ developed by the author and described here. The objects keep track of different portions of the molecular machinery to allow different simulation techniques and boundary conditions to be applied as appropriate. This capability has been required to demonstrate (computationally) our gear's feasibility. A new distributed software architecture featuring a WWW universal client, CORBA distributed objects, and agent software is under consideration. The software architecture is intended to eventually enable a widely disbursed group to develop complex simulated molecular machines.

Genetic engineering of industrial strains of Saccharomyces cerevisiae.

PubMed

Le Borgne, Sylvie

2012-01-01

Genetic engineering has been successfully applied to Saccharomyces cerevisiae laboratory strains for different purposes: extension of substrate range, improvement of productivity and yield, elimination of by-products, improvement of process performance and cellular properties, and extension of product range. The potential of genetically engineered yeasts for the massive production of biofuels as bioethanol and other nonfuel products from renewable resources as lignocellulosic biomass hydrolysates has been recognized. For such applications, robust industrial strains of S. cerevisiae have to be used. Here, some relevant genetic and genomic characteristics of industrial strains are discussed in relation to the problematic of the genetic engineering of such strains. General molecular tools applicable to the manipulation of S. cerevisiae industrial strains are presented and examples of genetically engineered industrial strains developed for the production of bioethanol from lignocellulosic biomass are given.

Molecular-beam, mass-spectrometric studies of wood vapor and model compounds over HZSM-5 catalyst

NASA Astrophysics Data System (ADS)

Evans, Robert J.; Milne, Thomas A.

1987-11-01

The use of molecular beam mass spectrometry (MBMS) for the real time screening of wood pyrolysis product conversion over Mobil's HZSM-5 catalyst allows the evaluation of the performance of different catalysts, reaction conditions and feedstocks. This information can help guide more extensive testing at the bench scale level and provide insight into the chemistry of conversion. The following conclusions can be drawn from the work to date: (1) there can be no breakthrough of primary wood vapor organics until the weight of wood/weight of the catalyst is 1; (2) there are few intermediates from wood on the way to alkenes, light aromatics, and naphthalenes; (3) the light aromatics/alkenes ration is 1 for the nonoptimized conditions studied to date; (4) much of the oxygen is favorably rejected as CO and CO sub 2; (5) the coke yield is about 10 percent in these experiments; and (6) methanol is a poor model for wood because the mechanism of hydrocarbon formation is apparently different.

Collisional excitation of NH3 by atomic and molecular hydrogen

NASA Astrophysics Data System (ADS)

Bouhafs, N.; Rist, C.; Daniel, F.; Dumouchel, F.; Lique, F.; Wiesenfeld, L.; Faure, A.

2017-09-01

We report extensive theoretical calculations on the rotation-inversion excitation of interstellar ammonia (NH3) due to collisions with atomic and molecular hydrogen (both para- and ortho-H2). Close-coupling calculations are performed for total energies in the range 1-2000 cm-1 and rotational cross-sections are obtained for all transitions amongst the lowest 17 and 34 rotation-inversion levels of ortho- and para-NH3, respectively. Rate coefficients are deduced for kinetic temperatures up to 200 K. Propensity rules for the three colliding partners are discussed and we also compare the new results to previous calculations for the spherically symmetrical He and para-H2 projectiles. Significant differences are found between the different sets of calculations. Finally, we test the impact of the new rate coefficients on the calibration of the ammonia thermometer. We find that the calibration curve is only weakly sensitive to the colliding partner and we confirm that the ammonia thermometer is robust.

Right- and left-handed three-helix proteins. II. Similarity and differences in mechanical unfolding of proteins.

PubMed

Glyakina, Anna V; Likhachev, Ilya V; Balabaev, Nikolay K; Galzitskaya, Oxana V

2014-01-01

Here, we study mechanical properties of eight 3-helix proteins (four right-handed and four left-handed ones), which are similar in size under stretching at a constant speed and at a constant force on the atomic level using molecular dynamics simulations. The analysis of 256 trajectories from molecular dynamics simulations with explicit water showed that the right-handed three-helix domains are more mechanically resistant than the left-handed domains. Such results are observed at different extension velocities studied (192 trajectories obtained at the following conditions: v = 0.1, 0.05, and 0.01 Å ps(-1) , T = 300 K) and under constant stretching force (64 trajectories, F = 800 pN, T = 300 K). We can explain this by the fact, at least in part, that the right-handed domains have a larger number of contacts per residue and the radius of cross section than the left-handed domains. Copyright © 2013 Wiley Periodicals, Inc.

Delayed fission and multifragmentation in sub-keV C60 - Au(0 0 1) collisions via molecular dynamics simulations: Mass distributions and activated statistical decay

NASA Astrophysics Data System (ADS)

Bernstein, V.; Kolodney, E.

2017-10-01

We have recently observed, both experimentally and computationally, the phenomenon of postcollision multifragmentation in sub-keV surface collisions of a C60 projectile. Namely, delayed multiparticle breakup of a strongly impact deformed and vibrationally excited large cluster collider into several large fragments, after leaving the surface. Molecular dynamics simulations with extensive statistics revealed a nearly simultaneous event, within a sub-psec time window. Here we study, computationally, additional essential aspects of this new delayed collisional fragmentation which were not addressed before. Specifically, we study here the delayed (binary) fission channel for different impact energies both by calculating mass distributions over all fission events and by calculating and analyzing lifetime distributions of the scattered projectile. We observe an asymmetric fission resulting in a most probable fission channel and we find an activated exponential (statistical) decay. Finally, we also calculate and discuss the fragment mass distribution in (triple) multifragmentation over different time windows, in terms of most abundant fragments.

Constitutive Models for the Force-Extension Behavior of Biological Filaments

NASA Astrophysics Data System (ADS)

Palmer, J. S.; Castro, C. E.; Arslan, M.; Boyce, M. C.

Biopolymer filaments form the molecular backbone of biological structures throughout the body. The biomechanical response of single filaments yields insight into their individual behavior at the molecular level as well as their concerted networked behavior at the cellular and tissue scales. This paper focuses on modeling approaches for axial force vs. extension behavior of single biopolymer filaments within three stiffness regimes: flexible, semiflexible, and stiff. The end-to-end force-extension behaviors of flexible and semiflexible filaments arise as a result of a reduction in configurational space as the filament is straightened and are captured with entropic models including the freely jointed chain model and the worm-like chain model. As the filament is straightened and the end-to-end distance approaches the filament contour length, the contour length is directly axially extended and an internal energy contribution governs the force-extension behavior in this limiting extension regime. On the other hand, for stiff filaments in originally crimped or kinked configurations, the end-to-end force vs. extension behavior results from the unbending (straightening) of the crimped configuration as governed by an internal energy based elastica approximation which is also complemented by an axial stretching contribution once the end-to-end distance approaches the contour length of the filament. Simplified, analytical force-extension relationships are developed for the worm-like chain model for semiflexible filaments, and for the Euler elastica model for stiffer, wavy fibers. For the case of flexible molecules containing modular folded domains, the influence of force-induced unfolding on the force-extension behavior of single molecules and assemblies of multiple molecules is also presented.

HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales

DOE PAGES

Riccardi, Demian M.; Parks, Jerry M.; Johs, Alexander; ...

2015-03-20

HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. We tested the core; it is well-documented and easy to install across computational platforms. Our goal for the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, anmore » abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program.« less

HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales.

PubMed

Riccardi, Demian; Parks, Jerry M; Johs, Alexander; Smith, Jeremy C

2015-04-27

HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. The core is well-tested, well-documented, and easy to install across computational platforms. The goal of the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, an abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program.

HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales

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

Riccardi, Demian M.; Parks, Jerry M.; Johs, Alexander

HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. We tested the core; it is well-documented and easy to install across computational platforms. Our goal for the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, anmore » abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program.« less

Molecular mimicry between cockroach and helminth glutathione S-transferases promotes cross-reactivity and cross-sensitization

USDA-ARS?s Scientific Manuscript database

The extensive similarities between helminth proteins and allergens are thought to contribute to helminth-driven allergic sensitization. We investigated the molecular and structural similarities between Bla g 5, a major glutathione-S transferase (GST) allergen of cockroaches, and the GST of Wucherer...

An Inter-varietal Cucumber Linkage Map with 133 New Microsatellite Markers

USDA-ARS?s Scientific Manuscript database

The cucumber (Cucumis sativus var. sativus L.) recombinant inbred line (RIL) population from inter-variety cross of G421 with H19 has been used extensively in genetic mapping of yield- and fruit quality-related QTLs with molecular markers. However, only ~200 molecular markers, mostly AFLPs and RPADs...

Molecular characterization and functional analysis of ubiquitin extension genes from the potato cyst nematode Globodera rostochiensis

USDA-ARS?s Scientific Manuscript database

Ubiquitin is a highly conserved 76-amino acid protein found in every eukaryotic cell. It has been proposed that ubiquitin has many cellular functions including DNA repair, transcription regulation, regulation of cell cycle and apoptosis. We identified two ubiquitin extension genes (Gr-Ubi1 and Gr-Ub...

Kraft lignin chain extension chemistry via propargylation, oxidative coupling, and Claisen rearrangement.

PubMed

Sen, Sanghamitra; Sadeghifar, Hasan; Argyropoulos, Dimitris S

2013-10-14

Despite its aromatic and polymeric nature, the heterogeneous, stochastic, and reactive characteristics of softwood kraft lignin seriously limit its potential for thermoplastic applications. Our continuing efforts toward creating thermoplastic lignin polymers are now focused at exploring propargylation derivatization chemistry and its potential as a versatile novel route for the eventual utilization of technical lignins with a significant amount of molecular control. To do this, we initially report the systematic propargylation of softwood kraft lignin. The synthesized derivatives were extensively characterized with thermal methods (DSC, TGA), (1)H, (13)C, and quantitative (31)P NMR and IR spectroscopies. Further on, we explore the versatile nature of the lignin pendant propargyl groups by demonstrating two distinct chain extension chemistries; the solution-based, copper-mediated, oxidative coupling and the thermally induced, solid-state, Claissen rearrangement polymerization chemistries. Overall, we show that it is possible to modulate the reactivity of softwood kraft lignin via a combination of methylation and chain extension providing a rational means for the creation of higher molecular weight polymers with the potential for thermoplastic materials and carbon fibers with the desired control of structure-property relations.

The effects of moisture on molecular sieve oxygen concentrators.

PubMed

Ikels, K G; Theis, C F

1985-01-01

Molecular sieve oxygen generating systems are receiving extensive laboratory and flight evaluation. Assessment of the molecular system has generally been conducted in the laboratory using clean dry air. In aircraft, however, the molecular sieve generator is supplied with engine bleed air which may not always be totally free of contaminants and water. Recent studies using bed washout technics have shown that the molecular sieve units, with 50% of the beds deactivated with water, still function normally with respect to product gas flow and O2 concentration. By utilizing the technics described in this paper, the moisture content or state of hydration of the molecular sieve can readily be determined.

Hypoglycemic effect of polysaccharides with different molecular weight of Pseudostellaria heterophylla

PubMed Central

2013-01-01

Abstracts Background The aims of this study were to evaluate the antidiabetic activity and to detect molecular size of Pseudostellaria heterophylla polysaccharide (PHP). Pseudostellaria heterophylla is a medicine extensively used in traditional Chinese medicine formulas to treat diabetes and its complications. Methods Molecular weight of PHP was determined by gel permeation chromatography combined with phenol-sulphuric acid method and the monosaccharides composition was determined by HPLC with a precolumn derivatization. Four polysaccharides with different molecular weight were compared for hypoglycemic active on two animal models both high does alloxan induced type1 diabetic mellitus (T1DM) and high-fat/lower does streptozotocin induced type2 diabetic mellitus (T2DM). Blood sugar, glucose tolerance, and insulin tolerance were detected. Rat serum IL-1β, IL-2, IL-10, Leptin, TNF-α, Acrp30 and CRP were also analyzed by sandwich-ELISA approaches to preliminary probe the hypoglycemic mechanism of PHP. Results The hypoglycemic effects related to molecular size of polysaccharide were more effective against T2DM than T1DM. PHP comprise four monosaccharides of galacturonic acid, glucose, galactose and arabinos. T2DM rats daily receiving oral dose of polysaccharide(100 ~ 400 mg/kg) with 50 ~ 210 kDa molecular weight (PF40) could not only significantly lower blood sugar but also reduce total triglyceride level in serum. PF40 improves in insulin tolerance inhibited the expression of some biomarkers including inflammatory cytokine TNF-α and elevated anti-inflammatory cytokine IL-10, regulated adiponectin Acrp30 and leptin. Conclusions PF40 prevent the cascade of inflammatory events in the treatment of T2DM to block overweight progresses to obesity. PMID:24131482

Development of gel-filter method for high enrichment of low-molecular weight proteins from serum.

PubMed

Chen, Lingsheng; Zhai, Linhui; Li, Yanchang; Li, Ning; Zhang, Chengpu; Ping, Lingyan; Chang, Lei; Wu, Junzhu; Li, Xiangping; Shi, Deshun; Xu, Ping

2015-01-01

The human serum proteome has been extensively screened for biomarkers. However, the large dynamic range of protein concentrations in serum and the presence of highly abundant and large molecular weight proteins, make identification and detection changes in the amount of low-molecular weight proteins (LMW, molecular weight ≤ 30kDa) difficult. Here, we developed a gel-filter method including four layers of different concentration of tricine SDS-PAGE-based gels to block high-molecular weight proteins and enrich LMW proteins. By utilizing this method, we identified 1,576 proteins (n = 2) from 10 μL serum. Among them, 559 (n = 2) proteins belonged to LMW proteins. Furthermore, this gel-filter method could identify 67.4% and 39.8% more LMW proteins than that in representative methods of glycine SDS-PAGE and optimized-DS, respectively. By utilizing SILAC-AQUA approach with labeled recombinant protein as internal standard, the recovery rate for GST spiked in serum during the treatment of gel-filter, optimized-DS, and ProteoMiner was 33.1 ± 0.01%, 18.7 ± 0.01% and 9.6 ± 0.03%, respectively. These results demonstrate that the gel-filter method offers a rapid, highly reproducible and efficient approach for screening biomarkers from serum through proteomic analyses.

GUM 48d: AN EVOLVED H II REGION WITH ONGOING STAR FORMATION

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

Karr, J. L.; Ohashi, N.; Manoj, P.

2009-05-20

High-mass star formation and the evolution of H II regions have a substantial impact on the morphology and star formation history of molecular clouds. The H II region Gum 48d, located in the Centaurus Arm at a distance of 3.5 kpc, is an old, well evolved H II region whose ionizing stars have moved off the main sequence. As such, it represents a phase in the evolution of H II regions that is less well studied than the earlier, more energetic, main-sequence phase. In this paper, we use multiwavelength archive data from a variety of sources to perform a detailedmore » study of this interesting region. Morphologically, Gum 48d displays a ring-like faint H II region associated with diffuse emission from the associated photodissociation region, and is formed from part of a large, massive molecular cloud complex. There is extensive ongoing star formation in the region, at scales ranging from low to high mass, which is consistent with triggered star formation scenarios. We investigate the dynamical history and evolution of this region, and conclude that the original H II region was once larger and more energetic than the faint region currently seen. The proposed history of this molecular cloud complex is one of multiple, linked generations of star formation, over a period of 10 Myr. Gum 48d differs significantly in morphology and star formation from the other H II regions in the molecular cloud; these differences are likely the result of the advanced age of the region, and its different evolutionary status.« less

Design of two-photon molecular tandem architectures for solar cells by ab initio theory† †Electronic supplementary information (ESI) available: Visualizations of molecular orbitals, one-particle mechanisms and a table with Kohn–Sham eigenvalues. See DOI: 10.1039/c4sc03835e

PubMed Central

Garcia-Lastra, Juan M.; De La Torre, Gema; Himpsel, F. J.; Rubio, Angel

2015-01-01

An extensive database of spectroscopic properties of molecules from ab initio calculations is used to design molecular complexes for use in tandem solar cells that convert two photons into a single electron–hole pair, thereby increasing the output voltage while covering a wider spectral range. Three different architectures are considered: the first two involve a complex consisting of two dye molecules with appropriately matched frontier orbitals, connected by a molecular diode. Optimized combinations of dye molecules are determined by taking advantage of our computational database of the structural and energetic properties of several thousand porphyrin dyes. The third design is a molecular analogy of the intermediate band solar cell, and involves a single dye molecule with strong intersystem crossing to ensure a long lifetime of the intermediate state. Based on the calculated energy levels and molecular orbitals, energy diagrams are presented for the individual steps in the operation of such tandem solar cells. We find that theoretical open circuit voltages of up to 1.8 V can be achieved using these tandem designs. Questions about the practical implementation of prototypical devices, such as the synthesis of the tandem molecules and potential loss mechanisms, are addressed. PMID:29142685

[Research progress on the cloning of Mendel's gene in pea (Pisum sativum L.) and its application in genetics teaching].

PubMed

He, Feng-Hua; Zhu, Bi-Yan; Gao, Feng; Li, Shao-Shan; Li, Niang-Hui

2013-07-01

One hundred and fifty years ago, Gregor Mendel investigated the segregation of seven traits in pea (Pisum sativum) and established the law of segregation and the law of independent assortment in genetics. After the two laws of genetics were rediscovered in 1900, the seven traits have been extensively investigated in the fields of plant physiology and biochemistry as well as in the cell and molecular levels. Recently, with the development of molecular technology in genetics, four genes for seed shape (R), stem length (Le), cotyledon colour (I), and flower colour (A) have been cloned and sequenced; and another three genes for immature pod colour (Gp), fasciation (Fa) and pod form (V) have been located in the linkage groups, respectively. The identification and cloning of the four Mendel's genes will help deeply understand the basic concept of gene in many respects: like the diversity of gene function, the different origins for gene mutation in molecular level, and the molecular nature of a dominant gene or a recessive gene. In teaching of genetics, the introduction of most recent research advancements of cloning of Mendel's genes to the students and the interpretation of the Mendel's laws in molecular level will help students promote their learning interests in genetics and help students grasp the whole content from classical genetics to molecular genetics and the developmental direction of this subject.

Molecular structures and metabolic characteristics of protein in brown and yellow flaxseed with altered nutrient traits.

PubMed

Khan, Nazir Ahmad; Booker, Helen; Yu, Peiqiang

2014-07-16

The objectives of this study were to investigate the chemical profiles; crude protein (CP) subfractions; ruminal CP degradation characteristics and intestinal digestibility of rumen undegraded protein (RUP); and protein molecular structures using molecular spectroscopy of newly developed yellow-seeded flax (Linum usitatissimum L.). Seeds from two yellow flaxseed breeding lines and two brown flaxseed varieties were evaluated. The yellow-seeded lines had higher (P < 0.001) contents of oil (44.54 vs 41.42% dry matter (DM)) and CP (24.94 vs 20.91% DM) compared to those of the brown-seeded varieties. The CP in yellow seeds contained lower (P < 0.01) contents of true protein subfraction (81.31 vs 92.71% CP) and more (P < 0.001) extensively degraded (70.8 vs 64.9% CP) in rumen resulting in lower (P < 0.001) content of RUP (29.2 vs 35.1% CP) than that in the brown-seeded varieties. However, the total supply of digestible RUP was not significantly different between the two seed types. Regression equations based on protein molecular structural features gave relatively good estimation for the contents of CP (R(2) = 0.87), soluble CP (R(2) = 0.92), RUP (R(2) = 0.97), and intestinal digestibility of RUP (R(2) = 0.71). In conclusion, molecular spectroscopy can be used to rapidly characterize feed protein molecular structures and predict their nutritive value.

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

Chen, Yinshan; Zhu, Men; Laventure, Audrey

Surface grating decay measurements have been performed on three closely related molecular glasses to study the effect of intermolecular hydrogen bonds on surface diffusion. The three molecules are derivatives of bis(3,5-dimethyl-phenylamino)-1,3,5-triazine and differ only in the functional group R at the 2-position, with R being C 2H 5, OCH 3, and NHCH 3, and referred to as “Et”, “OMe”, and “NHMe”, respectively. Of the three molecules, NHMe forms more extensive intermolecular hydrogen bonds than Et and OMe and was found to have slower surface diffusion. For Et and OMe, surface diffusion is so fast that it replaces viscous flow asmore » the mechanism of surface grating decay as temperature is lowered. In contrast, no such transition was observed for NHMe under the same conditions, indicating significantly slower surface diffusion. This result is consistent with the previous finding that extensive intermolecular hydrogen bonds slow down surface diffusion in molecular glasses and is attributed to the persistence of hydrogen bonds even in the surface environment. Here, this result is also consistent with the lower stability of the vapor-deposited glass of NHMe relative to those of Et and OMe and supports the view that surface mobility controls the stability of vapor-deposited glasses.« less

Predicting solute partitioning in lipid bilayers: Free energies and partition coefficients from molecular dynamics simulations and COSMOmic

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

Jakobtorweihen, S., E-mail: jakobtorweihen@tuhh.de; Ingram, T.; Gerlach, T.

2014-07-28

Quantitative predictions of biomembrane/water partition coefficients are important, as they are a key property in pharmaceutical applications and toxicological studies. Molecular dynamics (MD) simulations are used to calculate free energy profiles for different solutes in lipid bilayers. How to calculate partition coefficients from these profiles is discussed in detail and different definitions of partition coefficients are compared. Importantly, it is shown that the calculated coefficients are in quantitative agreement with experimental results. Furthermore, we compare free energy profiles from MD simulations to profiles obtained by the recent method COSMOmic, which is an extension of the conductor-like screening model for realisticmore » solvation to micelles and biomembranes. The free energy profiles from these molecular methods are in good agreement. Additionally, solute orientations calculated with MD and COSMOmic are compared and again a good agreement is found. Four different solutes are investigated in detail: 4-ethylphenol, propanol, 5-phenylvaleric acid, and dibenz[a,h]anthracene, whereby the latter belongs to the class of polycyclic aromatic hydrocarbons. The convergence of the free energy profiles from biased MD simulations is discussed and the results are shown to be comparable to equilibrium MD simulations. For 5-phenylvaleric acid the influence of the carboxyl group dihedral angle on free energy profiles is analyzed with MD simulations.« less

Role of Prion Replication in the Strain-dependent Brain Regional Distribution of Prions.

PubMed

Hu, Ping Ping; Morales, Rodrigo; Duran-Aniotz, Claudia; Moreno-Gonzalez, Ines; Khan, Uffaf; Soto, Claudio

2016-06-10

One intriguing feature of prion diseases is their strain variation. Prion strains are differentiated by the clinical consequences they generate in the host, their biochemical properties, and their potential to infect other animal species. The selective targeting of these agents to specific brain structures have been extensively used to characterize prion strains. However, the molecular basis dictating strain-specific neurotropism are still elusive. In this study, isolated brain structures from animals infected with four hamster prion strains (HY, DY, 139H, and SSLOW) were analyzed for their content of protease-resistant PrP(Sc) Our data show that these strains have different profiles of PrP deposition along the brain. These patterns of accumulation, which were independent of regional PrP(C) production, were not reproduced by in vitro replication when different brain regions were used as substrate for the misfolding-amplification reaction. On the contrary, our results show that in vitro replication efficiency depended exclusively on the amount of PrP(C) present in each part of the brain. Our results suggest that the variable regional distribution of PrP(Sc) in distinct strains is not determined by differences on prion formation, but on other factors or cellular pathways. Our findings may contribute to understand the molecular mechanisms of prion pathogenesis and strain diversity. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Educational websites--Bioinformatics Tools II.

PubMed

Lomberk, Gwen

2009-01-01

In this issue, the highlighted websites are a continuation of a series of educational websites; this one in particular from a couple of years ago, Bioinformatics Tools [Pancreatology 2005;5:314-315]. These include sites that are valuable resources for many research needs in genomics and proteomics. Bioinformatics has become a laboratory tool to map sequences to databases, develop models of molecular interactions, evaluate structural compatibilities, describe differences between normal and disease-associated DNA, identify conserved motifs within proteins, and chart extensive signaling networks, all in silico. Copyright 2008 S. Karger AG, Basel and IAP.

Roles of different IRES-dependent FGF2 isoforms in the acquisition of the major aggressive features of human metastatic melanoma.

PubMed

Andreucci, Elena; Bianchini, Francesca; Biagioni, Alessio; Del Rosso, Mario; Papucci, Laura; Schiavone, Nicola; Magnelli, Lucia

2017-01-01

Fibroblast growth factor 2 (FGF2) is involved in many physiological and pathological processes. Fgf2 deregulation contributes to the acquisition of malignant features of melanoma and other cancers. FGF2 is an alternative translation product expressed as five isoforms, a low-molecular-weight (18 KDa) and four high-molecular-weight (22, 22.5, 24, 34 KDa) isoforms, with different subcellular distributions. An internal ribosomal entry site (IRES) in its mRNA controls the translation of all the isoforms with the exception for the cap-dependent 34 KDa. The 18-KDa isoform has been extensively studied, while very few is known about the roles of high molecular weight isoforms. FGF2 is known to promote melanoma development and progression. To disclose the differential contribution of FGF2 isoforms in melanoma, we forced the expression of IRES-dependent low-molecular-weight (LMW, 18 KDa) and high-molecular-weight (HMW, 22, 22.5, 24 KDa) isoforms in a human metastatic melanoma cell line. This comparative study highlights that, while LMW isoform confers stem-like features to melanoma cells and promotes angiogenesis, HMW isoforms induce higher migratory ability and contribute to tumor perfusion by promoting vasculogenic mimicry (VM) when endothelial cell-driven angiogenesis is lacking. To conclude, FGF2 isoforms mainly behave in specific, antithetical manners, but can cooperate in different steps of tumor progression, providing melanoma cells with major malignant features. FGF2 is an alternative translation product expressed as different isoforms termed LMW and HMW. FGF2 is involved in melanoma development and progression. HMW FGF2 isoforms enhance in vitro motility of melanoma cells. LMW FGF2 confers stem-like features and increases in vivo metastasization. LMW FGF2 promotes angiogenesis while HMW FGF2 induces vasculogenic mimicry.

Behavior dynamics: One perspective

PubMed Central

Marr, M. Jackson

1992-01-01

Behavior dynamics is a field devoted to analytic descriptions of behavior change. A principal source of both models and methods for these descriptions is found in physics. This approach is an extension of a long conceptual association between behavior analysis and physics. A theme common to both is the role of molar versus molecular events in description and prediction. Similarities and differences in how these events are treated are discussed. Two examples are presented that illustrate possible correspondence between mechanical and behavioral systems. The first demonstrates the use of a mechanical model to describe the molar properties of behavior under changing reinforcement conditions. The second, dealing with some features of concurrent schedules, focuses on the possible utility of nonlinear dynamical systems to the description of both molar and molecular behavioral events as the outcome of a deterministic, but chaotic, process. PMID:16812655

Incremental viscosity by non-equilibrium molecular dynamics and the Eyring model

NASA Astrophysics Data System (ADS)

Heyes, D. M.; Dini, D.; Smith, E. R.

2018-05-01

The viscoelastic behavior of sheared fluids is calculated by Non-Equilibrium Molecular Dynamics (NEMD) simulation, and complementary analytic solutions of a time-dependent extension of Eyring's model (EM) for shear thinning are derived. It is argued that an "incremental viscosity," ηi, or IV which is the derivative of the steady state stress with respect to the shear rate is a better measure of the physical state of the system than the conventional definition of the shear rate dependent viscosity (i.e., the shear stress divided by the strain rate). The stress relaxation function, Ci(t), associated with ηi is consistent with Boltzmann's superposition principle and is computed by NEMD and the EM. The IV of the Eyring model is shown to be a special case of the Carreau formula for shear thinning. An analytic solution for the transient time correlation function for the EM is derived. An extension of the EM to allow for significant local shear stress fluctuations on a molecular level, represented by a gaussian distribution, is shown to have the same analytic form as the original EM but with the EM stress replaced by its time and spatial average. Even at high shear rates and on small scales, the probability distribution function is almost gaussian (apart from in the wings) with the peak shifted by the shear. The Eyring formula approximately satisfies the Fluctuation Theorem, which may in part explain its success in representing the shear thinning curves of a wide range of different types of chemical systems.

The Split Personality of Glutamate Transporters: A Chloride Channel and a Transporter.

PubMed

Cater, Rosemary J; Ryan, Renae M; Vandenberg, Robert J

2016-03-01

Transporters and ion channels are conventionally categorised into distinct classes of membrane proteins. However, some membrane proteins have a split personality and can function as both transporters and ion channels. The excitatory amino acid transporters (EAATs) in particular, function as both glutamate transporters and chloride (Cl(-)) channels. The EAATs couple the transport of glutamate to the co-transport of three Na(+) ions and one H(+) ion into the cell, and the counter-transport of one K(+) ion out of the cell. The EAAT Cl(-) channel is activated by the binding of glutamate and Na(+), but is thermodynamically uncoupled from glutamate transport and involves molecular determinants distinct from those responsible for glutamate transport. Several crystal structures of an EAAT archaeal homologue, GltPh, at different stages of the transport cycle, alongside numerous functional studies and molecular dynamics simulations, have provided extensive insights into the mechanism of substrate transport via these transporters. However, the molecular determinants involved in Cl(-) permeation, and the mechanism by which this channel is activated are not entirely understood. Here we will discuss what is currently known about the molecular determinants involved in EAAT-mediated Cl(-) permeation and the mechanisms that underlie their split personality.

Honeybees (Apis mellifera) learn to discriminate the smell of organic compounds from their respective deuterated isotopomers

PubMed Central

Gronenberg, Wulfila; Raikhelkar, Ajay; Abshire, Eric; Stevens, Jennifer; Epstein, Eric; Loyola, Karin; Rauscher, Michael; Buchmann, Stephen

2014-01-01

The understanding of physiological and molecular processes underlying the sense of smell has made considerable progress during the past three decades, revealing the cascade of molecular steps that lead to the activation of olfactory receptor (OR) neurons. However, the mode of primary interaction of odorant molecules with the OR proteins within the sensory cells is still enigmatic. Two different concepts try to explain these interactions: the ‘odotope hypothesis’ suggests that OR proteins recognize structural aspects of the odorant molecule, whereas the ‘vibration hypothesis’ proposes that intra-molecular vibrations are the basis for the recognition of the odorant by the receptor protein. The vibration hypothesis predicts that OR proteins should be able to discriminate compounds containing deuterium from their common counterparts which contain hydrogen instead of deuterium. This study tests this prediction in honeybees (Apis mellifera) using the proboscis extension reflex learning in a differential conditioning paradigm. Rewarding one odour (e.g. a deuterated compound) with sucrose and not rewarding the respective analogue (e.g. hydrogen-based odorant) shows that honeybees readily learn to discriminate hydrogen-based odorants from their deuterated counterparts and supports the idea that intra-molecular vibrations may contribute to odour discrimination. PMID:24452031

Molecular clumps photoevaporation in ionized regions

NASA Astrophysics Data System (ADS)

Decataldo, D.; Ferrara, A.; Pallottini, A.; Gallerani, S.; Vallini, L.

2017-11-01

We study the photoevaporation of molecular clumps exposed to a UV radiation field including hydrogen-ionizing photons (hν > 13.6 eV) produced by massive stars or quasars. We follow the propagation and collision of shock waves inside clumps and take into account self-shielding effects, determining the evolution of clump size and density with time. The structure of the ionization-photodissociation region is obtained for different initial clump masses (M = 0.01-104 M⊙) and impinging fluxes (G0 = 102-105 in units of the Habing flux). The cases of molecular clumps engulfed in the H II region of an OB star and clumps carried within quasar outflows are treated separately. We find that the clump undergoes in both cases an initial shock-contraction phase and a following expansion phase, which lets the radiation penetrate in until the clump is completely evaporated. Typical evaporation time-scales are ≃0.01 Myr in the stellar case and 0.1 Myr in the quasar case, where the clump mass is 0.1 M⊙ and 103 M⊙, respectively. We find that clump lifetimes in quasar outflows are compatible with their observed extension, suggesting that photoevaporation is the main mechanism regulating the size of molecular outflows.

[Relevance of big data for molecular diagnostics].

PubMed

Bonin-Andresen, M; Smiljanovic, B; Stuhlmüller, B; Sörensen, T; Grützkau, A; Häupl, T

2018-04-01

Big data analysis raises the expectation that computerized algorithms may extract new knowledge from otherwise unmanageable vast data sets. What are the algorithms behind the big data discussion? In principle, high throughput technologies in molecular research already introduced big data and the development and application of analysis tools into the field of rheumatology some 15 years ago. This includes especially omics technologies, such as genomics, transcriptomics and cytomics. Some basic methods of data analysis are provided along with the technology, however, functional analysis and interpretation requires adaptation of existing or development of new software tools. For these steps, structuring and evaluating according to the biological context is extremely important and not only a mathematical problem. This aspect has to be considered much more for molecular big data than for those analyzed in health economy or epidemiology. Molecular data are structured in a first order determined by the applied technology and present quantitative characteristics that follow the principles of their biological nature. These biological dependencies have to be integrated into software solutions, which may require networks of molecular big data of the same or even different technologies in order to achieve cross-technology confirmation. More and more extensive recording of molecular processes also in individual patients are generating personal big data and require new strategies for management in order to develop data-driven individualized interpretation concepts. With this perspective in mind, translation of information derived from molecular big data will also require new specifications for education and professional competence.

Effect of mechanical load on the shuttling operation of molecular muscles

NASA Astrophysics Data System (ADS)

Lee, Seungjun; Lu, Wei

2009-06-01

We use molecular dynamics simulations to investigate the effect of mechanical force on stimulus-induced deformation of rotaxane-based artificial molecular muscles. The study shows that a small external force slows down the shuttling motion and leads to longer actuation time for a muscle to reach its full extension. Further increase in the force can significantly reduce the traveling distance of the ring, leading to reduced strain output. A force larger than 28 pN can completely suppress the shuttling motion, suggesting a limit of force output of molecular muscles.

Supramolecular Based Membrane Sensors

PubMed Central

Ganjali, Mohammad Reza; Norouzi, Parviz; Rezapour, Morteza; Faridbod, Farnoush; Pourjavid, Mohammad Reza

2006-01-01

Supramolecular chemistry can be defined as a field of chemistry, which studies the complex multi-molecular species formed from molecular components that have relatively simpler structures. This field has been subject to extensive research over the past four decades. This review discusses classification of supramolecules and their application in design and construction of ion selective sensors.

Sialyldisaccharide conformations: a molecular dynamics perspective

NASA Astrophysics Data System (ADS)

Selvin, Jeyasigamani F. A.; Priyadarzini, Thanu R. K.; Veluraja, Kasinadar

2012-04-01

Sialyldisaccharides are significant terminal components of glycoconjugates and their negative charge and conformation are extensively utilized in molecular recognition processes. The conformation and flexibility of four biologically important sialyldisaccharides [Neu5Acα(2-3)Gal, Neu5Acα(2-6)Gal, Neu5Acα(2-8)Neu5Ac and Neu5Acα(2-9)Neu5Ac] are studied using Molecular Dynamics simulations of 20 ns duration to deduce the conformational preferences of the sialyldisaccharides and the interactions which stabilize the conformations. This study clearly describes the possible conformational models of sialyldisaccharides deduced from 20 ns Molecular Dynamics simulations and our results confirm the role of water in the structural stabilization of sialyldisaccharides. An extensive analysis on the sialyldisaccharide structures available in PDB also confirms the conformational regions found by experiments are detected in MD simulations of 20 ns duration. The three dimensional structural coordinates for all the MD derived sialyldisaccharide conformations are deposited in the 3DSDSCAR database and these conformational models will be useful for glycobiologists and biotechnologists to understand the biological functions of sialic acid containing glycoconjugates.

Inter-Species Grafting Caused Extensive and Heritable Alterations of DNA Methylation in Solanaceae Plants

PubMed Central

Lin, Yan; Ma, Yiqiao; Liu, Gang; Yu, Xiaoming; Zhong, Silin; Liu, Bao

2013-01-01

Background Grafting has been extensively used to enhance the performance of horticultural crops. Since Charles Darwin coined the term “graft hybrid” meaning that asexual combination of different plant species may generate products that are genetically distinct, highly discrepant opinions exist supporting or against the concept. Recent studies have documented that grafting enables exchanges of both RNA and DNA molecules between the grafting partners, thus providing a molecular basis for grafting-induced genetic variation. DNA methylation is known as prone to alterations as a result of perturbation of internal and external conditions. Given characteristics of grafting, it is interesting to test whether the process may cause an alteration of this epigenetic marker in the grafted organismal products. Methodology/Principal Findings We analyzed relative global DNA methylation levels and locus-specific methylation patterns by the MSAP marker and locus-specific bisulfite-sequencing in the seed plants (wild-type controls), self- and hetero-grafted scions/rootstocks, selfed progenies of scions and their seed-plant controls, involving three Solanaceae species. We quantified expression of putative genes involved in establishing and/or maintaining DNA methylation by q-(RT)-PCR. We found that (1) hetero-grafting caused extensive alteration of DNA methylation patterns in a locus-specific manner, especially in scions, although relative methylation levels remain largely unaltered; (2) the altered methylation patterns in the hetero-grafting-derived scions could be inherited to sexual progenies with some sites showing further alterations or revisions; (3) hetero-grafting caused dynamic changes in steady-state transcript abundance of genes encoding for a set of enzymes functionally relevant to DNA methylation. Conclusions/Significance Our results demonstrate that inter-species grafting in plants could produce extensive and heritable alterations in DNA methylation. We suggest that these readily altered, yet heritable, epigenetic modifications due to interspecies hetero-grafting may shed one facet of insight into the molecular underpinnings for the still contentious concept of graft hybrid. PMID:23614002

Cutting the wires: modularization of cellular networks for experimental design.

PubMed

Lang, Moritz; Summers, Sean; Stelling, Jörg

2014-01-07

Understanding naturally evolved cellular networks requires the consecutive identification and revision of the interactions between relevant molecular species. In this process, initially often simplified and incomplete networks are extended by integrating new reactions or whole subnetworks to increase consistency between model predictions and new measurement data. However, increased consistency with experimental data alone is not sufficient to show the existence of biomolecular interactions, because the interplay of different potential extensions might lead to overall similar dynamics. Here, we present a graph-based modularization approach to facilitate the design of experiments targeted at independently validating the existence of several potential network extensions. Our method is based on selecting the outputs to measure during an experiment, such that each potential network extension becomes virtually insulated from all others during data analysis. Each output defines a module that only depends on one hypothetical network extension, and all other outputs act as virtual inputs to achieve insulation. Given appropriate experimental time-series measurements of the outputs, our modules can be analyzed, simulated, and compared to the experimental data separately. Our approach exemplifies the close relationship between structural systems identification and modularization, an interplay that promises development of related approaches in the future. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Efficient Computation of Difference Vibrational Spectra in Isothermal-Isobaric Ensemble.

PubMed

Joutsuka, Tatsuya; Morita, Akihiro

2016-11-03

Difference spectroscopy between two close systems is widely used to augment its selectivity to the different parts of the observed system, though the molecular dynamics calculation of tiny difference spectra would be computationally extraordinary demanding by subtraction of two spectra. Therefore, we have proposed an efficient computational algorithm of difference spectra without resorting to the subtraction. The present paper reports our extension of the theoretical method in the isothermal-isobaric (NPT) ensemble. The present theory expands our applications of analysis including pressure dependence of the spectra. We verified that the present theory yields accurate difference spectra in the NPT condition as well, with remarkable computational efficiency over the straightforward subtraction by several orders of magnitude. This method is further applied to vibrational spectra of liquid water with varying pressure and succeeded in reproducing tiny difference spectra by pressure change. The anomalous pressure dependence is elucidated in relation to other properties of liquid water.

Gene encoding the human. beta. -hexosaminidase. beta. chain: Extensive homology of intron placement in the. alpha. - and. beta. -chain genes

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

Proia, R.L.

1988-03-01

Lysosomal {beta}-hexosaminidase is composed of two structurally similar chains, {alpha} and {beta}, that are the products of different genes. Mutations in either gene causing {beta}-hexosaminidase deficiency result in the lysosomal storage disease GM2-gangliosidosis. To enable the investigation of the molecular lesions in this disorder and to study the evolutionary relationship between the {alpha} and {beta} chains, the {beta}-chain gene was isolated, and its organization was characterized. The {beta}-chain coding region is divided into 14 exons distributed over {approx}40 kilobases of DNA. Comparison with the {alpha}-chain gene revealed that 12 of the 13 introns interrupt the coding regions at homologous positions.more » This extensive sharing of intron placement demonstrates that the {alpha} and {beta} chains evolved by way of the duplication of a common ancestor.« less

Electrospray ionization mass spectrometry: a technique to access the information beyond the molecular weight of the analyte.

PubMed

Banerjee, Shibdas; Mazumdar, Shyamalava

2012-01-01

The Electrospray Ionization (ESI) is a soft ionization technique extensively used for production of gas phase ions (without fragmentation) of thermally labile large supramolecules. In the present review we have described the development of Electrospray Ionization mass spectrometry (ESI-MS) during the last 25 years in the study of various properties of different types of biological molecules. There have been extensive studies on the mechanism of formation of charged gaseous species by the ESI. Several groups have investigated the origin and implications of the multiple charge states of proteins observed in the ESI-mass spectra of the proteins. The charged analytes produced by ESI can be fragmented by activating them in the gas-phase, and thus tandem mass spectrometry has been developed, which provides very important insights on the structural properties of the molecule. The review will highlight recent developments and emerging directions in this fascinating area of research.

Microdialysis Sampling Techniques Applied to Studies of the Foreign Body Reaction

PubMed Central

Sides, Cynthia R.; Stenken, Julie A.

2014-01-01

Implanted materials including drug delivery devices and chemical sensors undergo what is termed the foreign body reaction (FBR). Depending on the device and its intended application, the FBR can have differing consequences. An extensive scientific research effort has been devoted to elucidating the cellular and molecular mechanisms that drive the FBR. Important, yet relatively unexplored, research includes the localized tissue biochemistry and the chemical signaling events that occur throughout the FBR. This review provides an overview of the mechanisms of the FBR, describes how the FBR affects different implanted devices, and illustrates the role that microdialysis sampling can play in further elucidating the chemical communication processes that drive FBR outcomes. PMID:24269987

Strategic balance of drug lifecycle management options differs between domestic and foreign companies in Japan.

PubMed

Yamanaka, Takayuki; Kano, Shingo

2016-01-01

Drug approvals and patent protections are critical in drug lifecycle management (LCM) in order to maximize drug discovery investment returns. We analyzed drug LCM activities implemented by 10 top companies in Japan, focusing on drug approvals and patent term extensions. Foreign companies acquired numerous drug approvals primarily for new molecular entities (NMEs), while Japanese companies mainly obtained approvals for improved drugs including new indications, and intensively extended patent terms. Furthermore, we discovered three factors likely responsible for differences in drug LCM strategies of Japanese and foreign companies: research and development capacities for drugs, drug lags of foreign-origin NMEs, and cooperation between Research and Development Departments and Intellectual Property Departments.

Dominant Epistasis Between Two Quantitative Trait Loci Governing Sporulation Efficiency in Yeast Saccharomyces cerevisiae

PubMed Central

Bergman, Juraj; Mitrikeski, Petar T.

2015-01-01

Summary Sporulation efficiency in the yeast Saccharomyces cerevisiae is a well-established model for studying quantitative traits. A variety of genes and nucleotides causing different sporulation efficiencies in laboratory, as well as in wild strains, has already been extensively characterised (mainly by reciprocal hemizygosity analysis and nucleotide exchange methods). We applied a different strategy in order to analyze the variation in sporulation efficiency of laboratory yeast strains. Coupling classical quantitative genetic analysis with simulations of phenotypic distributions (a method we call phenotype modelling) enabled us to obtain a detailed picture of the quantitative trait loci (QTLs) relationships underlying the phenotypic variation of this trait. Using this approach, we were able to uncover a dominant epistatic inheritance of loci governing the phenotype. Moreover, a molecular analysis of known causative quantitative trait genes and nucleotides allowed for the detection of novel alleles, potentially responsible for the observed phenotypic variation. Based on the molecular data, we hypothesise that the observed dominant epistatic relationship could be caused by the interaction of multiple quantitative trait nucleotides distributed across a 60--kb QTL region located on chromosome XIV and the RME1 locus on chromosome VII. Furthermore, we propose a model of molecular pathways which possibly underlie the phenotypic variation of this trait. PMID:27904371

Monkey-based research on human disease: the implications of genetic differences.

PubMed

Bailey, Jarrod

2014-11-01

Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90-93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer's disease, Parkinson's disease and stroke. The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology - there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and monkey genetic sequences is of little benefit for biomedical research. The extrapolation of biomedical data from monkeys to humans is therefore highly unreliable, and the use of monkeys must be considered of questionable value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to scientists. 2014 FRAME.

Targeted Approach to Overcoming Treatment Resistance in Advanced Prostate Cancer

DTIC Science & Technology

2013-07-01

molecular   dynamics  as  in  our  previous  works  (Vasilyeva,  A  et  al,  2009;  Vasilyeva,  A   et...results  and  pitfalls.     Molecular  docking  experiments  were  performed  as   follows:   The   molecular  docking  was...al,  2010;Salsbury.  2010).  However,  for  this  work  more  extensive   simulations

Structure and Dynamics of End-to-End Loop Formation of the Penta-Peptide Cys-Ala-Gly-Gln-Trp in Implicit Solvents

DTIC Science & Technology

2009-01-01

implicit solvents on peptide structure and dynamics , we performed extensive molecular dynamics simulations on the penta-peptide Cys-Ala-Gly-Gln-Trp. Two...end-to-end distances and dihedral angles obtained from molecular dynamics simulations with implicit solvent models were in a good agreement with those...to maintain the temperature of the systems. Introduction Molecular dynamics (MD) simulation techniques are widely used to study structure and

Molecular cogs of the insect circadian clock.

PubMed

Shirasu, Naoto; Shimohigashi, Yasuyuki; Tominaga, Yoshiya; Shimohigashi, Miki

2003-08-01

During the last five years, enormous progress has been made in understanding the molecular basis of circadian systems, mainly by molecular genetic studies using the mouse and fly. Extensive evidence has revealed that the core clock machinery involves "clock genes" and "clock proteins" functioning as molecular cogs. These participate in transcriptional/translational feedback loops and many homologous clock-components in the fruit fly Drosophila are also expressed in mammalian clock tissues with circadian rhythms. Thus, the mechanisms of the central clock seem to be conserved across animal kingdom. However, some recent studies imply that the present widely accepted molecular models of circadian clocks may not always be supported by the experimental evidence.

Mesoangioblasts of inclusion-body myositis: a twofold tool to study pathogenic mechanisms and enhance defective muscle regeneration.

PubMed

Morosetti, R; Gliubizzi, C; Broccolini, A; Sancricca, C; Mirabella, M

2011-06-01

Mesoangioblasts are a class of adult stem cells of mesoderm origin, potentially useful for the treatment of primitive myopathies of different etiology. Extensive in vitro and in vivo studies in animal models of muscular dystrophy have demonstrated the ability of mesoangioblast to repair skeletal muscle when injected intra-arterially. In a previous work we demonstrated that mesoangioblasts obtained from diagnostic muscle biopsies of IBM patients display a defective differentiation down skeletal muscle and this block can be corrected in vitro by transient MyoD transfection. We are currently investigating different pathways involved in mesoangioblasts skeletal muscle differentiation and exploring alternative stimulatory approaches not requiring extensive cell manipulation. This will allow to obtain safe, easy and efficient molecular or pharmacological modulation of pro-myogenic pathways in IBM mesoangioblasts. It is of crucial importance to identify factors (ie. cytokines, growth factors) produced by muscle or inflammatory cells and released in the surrounding milieu that are able to regulate the differentiation ability of IBM mesoangioblasts. To promote myogenic differentiation of endogenous mesoangioblasts in IBM muscle, the modulation of such target molecules selectively dysregulated would be a more handy approach to enhance muscle regeneration compared to transplantation techniques. Studies on the biological characteristics of IBM mesoangioblasts with their aberrant differentiation behavior, the signaling pathways possibly involved in their differentiation block and the possible strategies to overcome it in vivo, might provide new insights to better understand the etiopathogenesis of this crippling disorder and to identify molecular targets susceptible of therapeutic modulation.

Block Copolymer-Based Supramolecular Elastomers with High Extensibility and Large Stress Generation Capability

NASA Astrophysics Data System (ADS)

Noro, Atsushi; Hayashi, Mikihiro

We prepared block copolymer-based supramolecular elastomers with high extensibility and large stress generation capability. Reversible addition fragmentation chain transfer polymerizations were conducted under normal pressure and high pressure to synthesize several large molecular weight polystyrene-b-[poly(butyl acrylate)-co-polyacrylamide]-b-polystyrene (S-Ba-S) block copolymers. Tensile tests revealed that the largest S-Ba-S with middle block molecular weight of 3140k achieved a breaking elongation of over 2000% with a maximum tensile stress of 3.6 MPa and a toughness of 28 MJ/m3 while the reference sample without any middle block hydrogen bonds, polystyrene-b-poly(butyl acrylate)-b-polystyrene with almost the same molecular weight, was merely viscous and not self-standing. Hence, incorporation of hydrogen bonds into a long soft middle block was found to be beneficial to attain high extensibility and large stress generation capability probably due to concerted combination of entropic changes and internal potential energy changes originaing from the dissociation of multiple hydrogen bonds by elongation. This work was supported by JSPS KAKENHI Grant Numbers 13J02357, 24685035, 15K13785, and 23655213 for M.H. and A.N. A.N. also expresses his gratitude for Tanaka Rubber Science & Technology Award by Enokagaku-Shinko Foundation, Japan.

Molecular analysis of vector genome structures after liver transduction by conventional and self-complementary adeno-associated viral serotype vectors in murine and nonhuman primate models.

PubMed

Sun, Xun; Lu, You; Bish, Lawrence T; Calcedo, Roberto; Wilson, James M; Gao, Guangping

2010-06-01

Vectors based on several new adeno-associated viral (AAV) serotypes demonstrated strong hepatocyte tropism and transduction efficiency in both small- and large-animal models for liver-directed gene transfer. Efficiency of liver transduction by AAV vectors can be further improved in both murine and nonhuman primate (NHP) animals when the vector genomes are packaged in a self-complementary (sc) format. In an attempt to understand potential molecular mechanism(s) responsible for enhanced transduction efficiency of the sc vector in liver, we performed extensive molecular studies of genome structures of conventional single-stranded (ss) and sc AAV vectors from liver after AAV gene transfer in both mice and NHPs. These included treatment with exonucleases with specific substrate preferences, single-cutter restriction enzyme digestion and polarity-specific hybridization-based vector genome mapping, and bacteriophage phi29 DNA polymerase-mediated and double-stranded circular template-specific rescue of persisted circular genomes. In mouse liver, vector genomes of both genome formats seemed to persist primarily as episomal circular forms, but sc vectors converted into circular forms more rapidly and efficiently. However, the overall differences in vector genome abundance and structure in the liver between ss and sc vectors could not account for the remarkable differences in transduction. Molecular structures of persistent genomes of both ss and sc vectors were significantly more heterogeneous in macaque liver, with noticeable structural rearrangements that warrant further characterizations.

Molecular Analysis of Vector Genome Structures After Liver Transduction by Conventional and Self-Complementary Adeno-Associated Viral Serotype Vectors in Murine and Nonhuman Primate Models

PubMed Central

Sun, Xun; Lu, You; Bish, Lawrence T.; Calcedo, Roberto; Wilson, James M.

2010-01-01

Abstract Vectors based on several new adeno-associated viral (AAV) serotypes demonstrated strong hepatocyte tropism and transduction efficiency in both small- and large-animal models for liver-directed gene transfer. Efficiency of liver transduction by AAV vectors can be further improved in both murine and nonhuman primate (NHP) animals when the vector genomes are packaged in a self-complementary (sc) format. In an attempt to understand potential molecular mechanism(s) responsible for enhanced transduction efficiency of the sc vector in liver, we performed extensive molecular studies of genome structures of conventional single-stranded (ss) and sc AAV vectors from liver after AAV gene transfer in both mice and NHPs. These included treatment with exonucleases with specific substrate preferences, single-cutter restriction enzyme digestion and polarity-specific hybridization-based vector genome mapping, and bacteriophage ϕ29 DNA polymerase-mediated and double-stranded circular template-specific rescue of persisted circular genomes. In mouse liver, vector genomes of both genome formats seemed to persist primarily as episomal circular forms, but sc vectors converted into circular forms more rapidly and efficiently. However, the overall differences in vector genome abundance and structure in the liver between ss and sc vectors could not account for the remarkable differences in transduction. Molecular structures of persistent genomes of both ss and sc vectors were significantly more heterogeneous in macaque liver, with noticeable structural rearrangements that warrant further characterizations. PMID:20113166

Enhancement of linear/nonlinear optical responses of molecular vibrations using metal nanoantennas

NASA Astrophysics Data System (ADS)

Morichika, Ikki; Kusa, Fumiya; Takegami, Akinobu; Ashihara, Satoshi

2017-04-01

Plasmonic enhancements of optical near-fields with metal nanostructures offer extensive potential for amplifying lightmatter interactions. We analytically formulate the enhancement of linear and nonlinear optical responses of molecular vibrations through resonant nanoantennas, based on a coupled-dipole model. We apply the formulae to evaluation of signal enhancement factors in the antenna-enhanced vibrational spectroscopy.

Photoacoustic and luminescence spectroscopy of benzil crystals

NASA Astrophysics Data System (ADS)

Bonno, B.; Laporte, J. L.; Rousset, Y.

1991-06-01

In the present work, both photoacoustic and luminescence techniques were employed to study molecular crystals. This paper presents an extension of the standard Rosencwaig-Gersho photoacoustic model to molecular crystals, which includes finite-deexcitation-time effects and excited-state populations. In the temperature range 100-300 K, the phosphorescence quantum yield and thermal diffusivity of benzil crystals were determined.

Molecular Species Delimitation in the Racomitrium canescens Complex (Grimmiaceae) and Implications for DNA Barcoding of Species Complexes in Mosses

PubMed Central

Stech, Michael; Veldman, Sarina; Larraín, Juan; Muñoz, Jesús; Quandt, Dietmar; Hassel, Kristian; Kruijer, Hans

2013-01-01

In bryophytes a morphological species concept is still most commonly employed, but delimitation of closely related species based on morphological characters is often difficult. Here we test morphological species circumscriptions in a species complex of the moss genus Racomitrium, the R. canescens complex, based on variable DNA sequence markers from the plastid (rps4-trnT-trnL region) and nuclear (nrITS) genomes. The extensive morphological variability within the complex has led to different opinions about the number of species and intraspecific taxa to be distinguished. Molecular phylogenetic reconstructions allowed to clearly distinguish all eight currently recognised species of the complex plus a ninth species that was inferred to belong to the complex in earlier molecular analyses. The taxonomic significance of intraspecific sequence variation is discussed. The present molecular data do not support the division of the R. canescens complex into two groups of species (subsections or sections). Most morphological characters, albeit being in part difficult to apply, are reliable for species identification in the R. canescens complex. However, misidentification of collections that were morphologically intermediate between species questioned the suitability of leaf shape as diagnostic character. Four partitions of the molecular markers (rps4-trnT, trnT-trnL, ITS1, ITS2) that could potentially be used for molecular species identification (DNA barcoding) performed almost equally well concerning amplification and sequencing success. Of these, ITS1 provided the highest species discrimination capacity and should be considered as a DNA barcoding marker for mosses, especially in complexes of closely related species. Molecular species identification should be complemented by redefining morphological characters, to develop a set of easy-to-use molecular and non-molecular identification tools for improving biodiversity assessments and ecological research including mosses. PMID:23341927

Molecular interactions between fenoterol stereoisomers and derivatives and the β₂-adrenergic receptor binding site studied by docking and molecular dynamics simulations.

PubMed

Plazinska, Anita; Kolinski, Michal; Wainer, Irving W; Jozwiak, Krzysztof

2013-11-01

The β2 adrenergic receptor (β2-AR) has become a model system for studying the ligand recognition process and mechanism of the G protein coupled receptors activation. In the present study stereoisomers of fenoterol and some of its derivatives (N = 94 molecules) were used as molecular probes to identify differences in stereo-recognition interactions between β2-AR and structurally similar agonists. The present study aimed at determining the 3D molecular models of the fenoterol derivative-β2-AR complexes. Molecular models of β2-AR have been developed by using the crystal structure of the human β2-AR T4 lysozyme fusion protein with bound (S)-carazolol (PDB ID: 2RH1) and more recently reported structure of a nanobody-stabilized active state of the β2-AR with the bound full agonist BI-167107 (PDB ID: 3P0G). The docking procedure allowed us to study the similarities and differences in the recognition binding site(s) for tested ligands. The agonist molecules occupied the same binding region, between TM III, TM V, TM VI and TM VII. The residues identified by us during docking procedure (Ser203, Ser207, Asp113, Lys305, Asn312, Tyr308, Asp192) were experimentally indicated in functional and biophysical studies as being very important for the agonist-receptor interactions. Moreover, the additional space, an extension of the orthosteric pocket, was identified and described. Furthermore, the molecular dynamics simulations were used to study the molecular mechanism of interaction between ligands ((R,R')- and (S,S')-fenoterol) and β2-AR. Our research offers new insights into the ligand stereoselective interaction with one of the most important GPCR member. This study may also facilitate the design of improved selective medications, which can be used to treat, prevent and control heart failure symptoms.

Transcriptome sequencing of different narrow-leafed lupin tissue types provides a comprehensive uni-gene assembly and extensive gene-based molecular markers

PubMed Central

Kamphuis, Lars G; Hane, James K; Nelson, Matthew N; Gao, Lingling; Atkins, Craig A; Singh, Karam B

2015-01-01

Narrow-leafed lupin (NLL; Lupinus angustifolius L.) is an important grain legume crop that is valuable for sustainable farming and is becoming recognized as a human health food. NLL breeding is directed at improving grain production, disease resistance, drought tolerance and health benefits. However, genetic and genomic studies have been hindered by a lack of extensive genomic resources for the species. Here, the generation, de novo assembly and annotation of transcriptome datasets derived from five different NLL tissue types of the reference accession cv. Tanjil are described. The Tanjil transcriptome was compared to transcriptomes of an early domesticated cv. Unicrop, a wild accession P27255, as well as accession 83A:476, together being the founding parents of two recombinant inbred line (RIL) populations. In silico predictions for transcriptome-derived gene-based length and SNP polymorphic markers were conducted and corroborated using a survey assembly sequence for NLL cv. Tanjil. This yielded extensive indel and SNP polymorphic markers for the two RIL populations. A total of 335 transcriptome-derived markers and 66 BAC-end sequence-derived markers were evaluated, and 275 polymorphic markers were selected to genotype the reference NLL 83A:476 × P27255 RIL population. This significantly improved the completeness, marker density and quality of the reference NLL genetic map. PMID:25060816

RNA Surveillance: Molecular Approaches in Transcript Quality Control and their Implications in Clinical Diseases

PubMed Central

Moraes, Karen CM

2010-01-01

Production of mature mRNAs that encode functional proteins involves highly complex pathways of synthesis, processing and surveillance. At numerous steps during the maturation process, the mRNA transcript undergoes scrutiny by cellular quality control machinery. This extensive RNA surveillance ensures that only correctly processed mature mRNAs are translated and precludes production of aberrant transcripts that could encode mutant or possibly deleterious proteins. Recent advances in elucidating the molecular mechanisms of mRNA processing have demonstrated the existence of an integrated network of events, and have revealed that a variety of human diseases are caused by disturbances in the well-coordinated molecular equilibrium of these events. From a medical perspective, both loss and gain of function are relevant, and a considerable number of different diseases exemplify the importance of the mechanistic function of RNA surveillance in a cell. Here, mechanistic hallmarks of mRNA processing steps are reviewed, highlighting the medical relevance of their deregulation and how the understanding of such mechanisms can contribute to the development of therapeutic strategies. PMID:19829759

An Unusual Hydrophobic Core Confers Extreme Flexibility to HEAT Repeat Proteins

PubMed Central

Kappel, Christian; Zachariae, Ulrich; Dölker, Nicole; Grubmüller, Helmut

2010-01-01

Alpha-solenoid proteins are suggested to constitute highly flexible macromolecules, whose structural variability and large surface area is instrumental in many important protein-protein binding processes. By equilibrium and nonequilibrium molecular dynamics simulations, we show that importin-β, an archetypical α-solenoid, displays unprecedentedly large and fully reversible elasticity. Our stretching molecular dynamics simulations reveal full elasticity over up to twofold end-to-end extensions compared to its bound state. Despite the absence of any long-range intramolecular contacts, the protein can return to its equilibrium structure to within 3 Å backbone RMSD after the release of mechanical stress. We find that this extreme degree of flexibility is based on an unusually flexible hydrophobic core that differs substantially from that of structurally similar but more rigid globular proteins. In that respect, the core of importin-β resembles molten globules. The elastic behavior is dominated by nonpolar interactions between HEAT repeats, combined with conformational entropic effects. Our results suggest that α-solenoid structures such as importin-β may bridge the molecular gap between completely structured and intrinsically disordered proteins. PMID:20816072

Intermolecular Coulombic Decay (ICD) Occuring in Triatomic Molecular Dimer

NASA Astrophysics Data System (ADS)

Iskandar, Wael; Gatton, Averell; Gaire, Bishwanath; Champenois, Elio; Larsen, Kirk; Shivaram, Niranjan; Moradmand, Ali; Severt, Travis; Williams, Joshua; Slaughter, Daniel; Weber, Thorsten

2017-04-01

For over two decades, the production of ICD process has been extensively investigated theoretically and experimentally in different systems bounded by a week force (ex. van-der-Waals or Hydrogen force). Furthermore, the ICD process has been demonstrated a strong implication in biological system (DNA damage and DNA repair mechanism) because of the production of genotoxic low energy electrons during the decay cascade. Studying large complex system such as triatomic molecular dimer may be helpful for further exploration of ``Auger electron driven cancer therapy''. The present experiment investigates the dissociation dynamics happened in collision between a photons and CO2 dimer. We will focus more specifically on the CO2++CO2+ fragmentation channel and the detection in coincidence of the two ionic fragments and the two electrons will be done using a COld Target Recoil Ion Momentum Spectroscopy (COLTRIMS). The measurements of the Kinetic Energy Release of the two fragments and the relative angular distribution of the electrons in the molecular frame reveal that the ICD is the only mechanism responsible for the production of this fragmentation channel.

Chalcogen- and halogen-bonds involving SX2 (X = F, Cl, and Br) with formaldehyde.

PubMed

Mo, Lixin; Zeng, Yanli; Li, Xiaoyan; Zhang, Xueying; Meng, Lingpeng

2016-07-01

The capacity of SX2 (X = F, Cl, and Br) to engage in different kinds of noncovalent bonds was investigated by ab initio calculations. SCl2 (SBr2) has two σ-holes upon extension of Cl (Br)-S bonds, and two σ-holes upon extension of S-Cl (Br) bonds. SF2 contains only two σ-holes upon extension of the F-S bond. Consequently, SCl2 and SBr2 form chalcogen and halogen bonds with the electron donor H2CO while SF2 forms only a chalcogen bond, i.e., no F···O halogen bond was found in the SF2:H2CO complex. The S···O chalcogen bond between SF2 and H2CO is the strongest, while the strongest halogen bond is Br···O between SBr2 and H2CO. The nature of these two types of noncovalent interaction was probed by a variety of methods, including molecular electrostatic potentials, QTAIM, energy decomposition, and electron density shift maps. Termolecular complexes X2S···H2CO···SX'2 (X = F, Cl, Br, and X' = Cl, Br) were constructed to study the interplay between chalcogen bonds and halogen bonds. All these complexes contained S···O and Cl (Br)···O bonds, with longer intermolecular distances, smaller values of electron density, and more positive three-body interaction energies, indicating negative cooperativity between the chalcogen bond and the halogen bond. In addition, for all complexes studied, interactions involving chalcogen bonds were more favorable than those involving halogen bonds. Graphical Abstract Molecular electrostatic potential and contour map of the Laplacian of the electron density in Cl2S···H2CO···SCl2 complex.

Molecular interactions of mussel protective coating protein, mcfp-1, from Mytilus californianus.

PubMed

Lu, Qingye; Hwang, Dong Soo; Liu, Yang; Zeng, Hongbo

2012-02-01

Protective coating of the byssus of mussels (Mytilus sp.) has been suggested as a new paradigm of medical coating due to its high extensibility and hardness co-existence without their mutual detriment. The only known biomacromolecule in the extensible and tough coating on the byssus is mussel foot protein-1 (mfp-1), which is made up with positively charged residues (~20 mol%) and lack of negatively charged residues. Here, adhesion and molecular interaction mechanisms of Mytilus californianus foot protein-1 (mcfp-1) from California blue mussel were investigated using a surface forces apparatus (SFA) in buffer solutions of different ionic concentrations (0.2-0.7 M) and pHs (3.0-5.5). Strong and reversible cohesion between opposed positively charged mcfp-1 films was measured in 0.1 M sodium acetate buffer with 0.1 M KNO(3). Cohesion of mcfp-1 was gradually reduced with increasing the ionic strength, but was not changed with pH variations. Oxidation of 3,4-dihydroxyphenylalanine (DOPA) residues of mcfp-1, a key residue for adhesive and coating proteins of mussel, didn't change the cohesion strength of mcfp-1 films, but the addition of chemicals with aromatic groups (i.e., aspirin and 4-methylcatechol) increased the cohesion. These results suggest that the cohesion of mcfp-1 films is mainly mediated by cation-π interactions between the positively charged residues and benzene rings of DOPA and other aromatic amino acids (~20 mol% of total amino acids of mcfp-1), and π-π interactions between the phenyl groups in mcfp-1. The adhesion mechanism obtained for the mcfp-1 proteins provides important insight into the design and development of functional biomaterials and coatings mimicking the extensible and robust mussel cuticle coating. Copyright © 2011 Elsevier Ltd. All rights reserved.

Subsumed complexity: abiogenesis as a by-product of complex energy transduction.

PubMed

Adam, Z R; Zubarev, D; Aono, M; Cleaves, H James

2017-12-28

The origins of life bring into stark relief the inadequacy of our current synthesis of thermodynamic, chemical, physical and information theory to predict the conditions under which complex, living states of organic matter can arise. Origins research has traditionally proceeded under an array of implicit or explicit guiding principles in lieu of a universal formalism for abiogenesis. Within the framework of a new guiding principle for prebiotic chemistry called subsumed complexity , organic compounds are viewed as by-products of energy transduction phenomena at different scales (subatomic, atomic, molecular and polymeric) that retain energy in the form of bonds that inhibit energy from reaching the ground state. There is evidence for an emergent level of complexity that is overlooked in most conceptualizations of abiogenesis that arises from populations of compounds formed from atomic energy input. We posit that different forms of energy input can exhibit different degrees of dissipation complexity within an identical chemical medium. By extension, the maximum capacity for organic chemical complexification across molecular and macromolecular scales subsumes, rather than emerges from, the underlying complexity of energy transduction processes that drive their production and modification.This article is part of the themed issue 'Reconceptualizing the origins of life'. © 2017 The Author(s).

Subsumed complexity: abiogenesis as a by-product of complex energy transduction

NASA Astrophysics Data System (ADS)

Adam, Z. R.; Zubarev, D.; Aono, M.; Cleaves, H. James

2017-11-01

The origins of life bring into stark relief the inadequacy of our current synthesis of thermodynamic, chemical, physical and information theory to predict the conditions under which complex, living states of organic matter can arise. Origins research has traditionally proceeded under an array of implicit or explicit guiding principles in lieu of a universal formalism for abiogenesis. Within the framework of a new guiding principle for prebiotic chemistry called subsumed complexity, organic compounds are viewed as by-products of energy transduction phenomena at different scales (subatomic, atomic, molecular and polymeric) that retain energy in the form of bonds that inhibit energy from reaching the ground state. There is evidence for an emergent level of complexity that is overlooked in most conceptualizations of abiogenesis that arises from populations of compounds formed from atomic energy input. We posit that different forms of energy input can exhibit different degrees of dissipation complexity within an identical chemical medium. By extension, the maximum capacity for organic chemical complexification across molecular and macromolecular scales subsumes, rather than emerges from, the underlying complexity of energy transduction processes that drive their production and modification. This article is part of the themed issue 'Reconceptualizing the origins of life'.

Bulky Trichomonad Genomes: Encoding a Swiss Army Knife.

PubMed

Barratt, Joel; Gough, Rory; Stark, Damien; Ellis, John

2016-10-01

The trichomonads are a remarkably successful lineage of ancient, predominantly parasitic protozoa. Recent molecular analyses have revealed extensive duplication of certain genetic loci in trichomonads. Consequently, their genomes are exceptionally large compared to other parasitic protozoa. Retention of these large gene expansions across different trichomonad families raises the question: do these duplications afford an advantage? Many duplicated genes are linked to the parasitic lifestyle and some are regulated differently to their paralogues, suggesting they have acquired new functions. It is proposed that these large genomes encode a Swiss army knife of sorts, packed with a multitude of tools for use in many different circumstances. This may have bestowed trichomonads with the extraordinary versatility that has undoubtedly contributed to their success. Copyright © 2016 Elsevier Ltd. All rights reserved.

Time correlation functions of simple liquids: A new insight on the underlying dynamical processes

NASA Astrophysics Data System (ADS)

Garberoglio, Giovanni; Vallauri, Renzo; Bafile, Ubaldo

2018-05-01

Extensive molecular dynamics simulations of liquid sodium have been carried out to evaluate correlation functions of several dynamical quantities. We report the results of a novel analysis of the longitudinal and transverse correlation functions obtained by evaluating directly their self- and distinct contributions at different wavevectors k. It is easily recognized that the self-contribution remains close to its k → 0 limit, which turns out to be exactly the autocorrelation function of the single particle velocity. The wavevector dependence of the longitudinal and transverse spectra and their self- and distinct parts is also presented. By making use of the decomposition of the velocity autocorrelation spectrum in terms of longitudinal and transverse parts, our analysis is able to recognize the effect of different dynamical processes in different frequency ranges.

A Computational and Theoretical Study of Conductance in Hydrogen-bonded Molecular Junctions

NASA Astrophysics Data System (ADS)

Wimmer, Michael

This thesis is devoted to the theoretical and computational study of electron transport in molecular junctions where one or more hydrogen bonds are involved in the process. While electron transport through covalent bonds has been extensively studied, in recent work the focus has been shifted towards hydrogen-bonded systems due to their ubiquitous presence in biological systems and their potential in forming nano-junctions between molecular electronic devices and biological systems. This analysis allows us to significantly expand our comprehension of the experimentally observed result that the inclusion of hydrogen bonding in a molecular junction significantly impacts its transport properties, a fact that has important implications for our understanding of transport through DNA, and nano-biological interfaces in general. In part of this work I have explored the implications of quasiresonant transport in short chains of weakly-bonded molecular junctions involving hydrogen bonds. I used theoretical and computational analysis to interpret recent experiments and explain the role of Fano resonances in the transmission properties of the junction. In a different direction, I have undertaken the study of the transversal conduction through nucleotide chains that involve a variable number of different hydrogen bonds, e.g. NH˙˙˙O, OH˙˙˙O, and NH˙˙˙N, which are the three most prevalent hydrogen bonds in biological systems and organic electronics. My effort here has focused on the analysis of electronic descriptors that allow a simplified conceptual and computational understanding of transport properties. Specifically, I have expanded our previous work where the molecular polarizability was used as a conductance descriptor to include the possibility of atomic and bond partitions of the molecular polarizability. This is important because it affords an alternative molecular description of conductance that is not based on the conventional view of molecular orbitals as transport channels. My findings suggest that the hydrogen-bond networks are crucial in understanding the conductance of these junctions. A broader impact of this work pertains the fact that characterizing transport through hydrogen bonding networks may help in developing faster and cost-effective approaches to personalized medicine, to advance DNA sequencing and implantable electronics, and to progress in the design and application of new drugs.

Structural, dynamic and photophysical properties of a fluorescent dye incorporated in an amorphous hydrophobic polymer bundle.

PubMed

De Mitri, N; Prampolini, G; Monti, S; Barone, V

2014-08-21

The properties of a low molecular weight organic dye, namely 4-naphthyloxy-1-methoxy-2,2,6,6-tetramethylpiperidine, covalently bound to an apolar polyolefin were investigated by means of a multi-level approach, combining classical molecular dynamics simulations, based on purposely parameterized force fields, and quantum mechanical calculations based on density functional theory (DFT) and its time-dependent extension (TD-DFT). The structure and dynamics of the dye in its embedding medium were analyzed and discussed taking the entangling effect of the surrounding polymer into account, and also by comparing the results to those obtained for a different environment, i.e. toluene solution. Finally, the influence was investigated of long lived cages found in the polymeric embedding on photophysical properties, in terms of the slow and fast dye's internal dynamics, by comparing computed IR and UV spectra with their experimental counterparts.

Molecular Targeted Drugs and Biomarkers in NSCLC, the Evolving Role of Individualized Therapy

PubMed Central

Domvri, Kalliopi; Zarogoulidis, Paul; Darwiche, Kaid; Browning, Robert F.; Li, Qiang; Turner, J. Francis; Kioumis, Ioannis; Spyratos, Dionysios; Porpodis, Konstantinos; Papaiwannou, Antonis; Tsiouda, Theodora; Freitag, Lutz; Zarogoulidis, Konstantinos

2013-01-01

Lung cancer first line treatment has been directed from the non-specific cytotoxic doublet chemotherapy to the molecular targeted. The major limitation of the targeted therapies still remains the small number of patients positive to gene mutations. Furthermore, the differentiation between second line and maintenance therapy has not been fully clarified and differs in the clinical practice between cancer centers. The authors present a segregation between maintenance treatment and second line and present a possible definition for the term “maintenance” treatment. In addition, cancer cell evolution induces mutations and therefore either targeted therapies or non-specific chemotherapy drugs in many patients become ineffective. In the present work pathways such as epidermal growth factor, anaplastic lymphoma kinase, met proto-oncogene and PI3K are extensively presented and correlated with current chemotherapy treatment. Future, perspectives for targeted treatment are presented based on the current publications and ongoing clinical trials. PMID:24312144

Solutions of burnt-bridge models for molecular motor transport.

PubMed

Morozov, Alexander Yu; Pronina, Ekaterina; Kolomeisky, Anatoly B; Artyomov, Maxim N

2007-03-01

Transport of molecular motors, stimulated by interactions with specific links between consecutive binding sites (called "bridges"), is investigated theoretically by analyzing discrete-state stochastic "burnt-bridge" models. When an unbiased diffusing particle crosses the bridge, the link can be destroyed ("burned") with a probability p , creating a biased directed motion for the particle. It is shown that for probability of burning p=1 the system can be mapped into a one-dimensional single-particle hopping model along the periodic infinite lattice that allows one to calculate exactly all dynamic properties. For the general case of p<1 a theoretical method is developed and dynamic properties are computed explicitly. Discrete-time and continuous-time dynamics for periodic distribution of bridges and different burning dynamics are analyzed and compared. Analytical predictions are supported by extensive Monte Carlo computer simulations. Theoretical results are applied for analysis of the experiments on collagenase motor proteins.

Modeling Autism by SHANK Gene Mutations in Mice

PubMed Central

Jiang, Yong-hui; Ehlers, Michael D.

2013-01-01

Summary Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene. PMID:23583105

Atomic Physics Effects on Convergent, Child-Langmuir Ion Flow between Nearly Transparent Electrodes

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

Santarius, John F.; Emmert, Gilbert A.

Research during this project at the University of Wisconsin Fusion Technology Institute (UW FTI) on ion and neutral flow through an arbitrary, monotonic potential difference created by nearly transparent electrodes accomplished the following: (1) developed and implemented an integral equation approach for atomic physics effects in helium plasmas; (2) extended the analysis to coupled integral equations that treat atomic and molecular deuterium ions and neutrals; (3) implemented the key deuterium and helium atomic and molecular cross sections; (4) added negative ion production and related cross sections; and (5) benchmarked the code against experimental results. The analysis and codes treat themore » species D0, D20, D+, D2+, D3+, D and, separately at present, He0 and He+. Extensions enhanced the analysis and related computer codes to include He++ ions plus planar and cylindrical geometries.« less

Engineering the entropy-driven free-energy landscape of a dynamic nanoporous protein assembly.

PubMed

Alberstein, Robert; Suzuki, Yuta; Paesani, Francesco; Tezcan, F Akif

2018-04-30

De novo design and construction of stimuli-responsive protein assemblies that predictably switch between discrete conformational states remains an essential but highly challenging goal in biomolecular design. We previously reported synthetic, two-dimensional protein lattices self-assembled via disulfide bonding interactions, which endows them with a unique capacity to undergo coherent conformational changes without losing crystalline order. Here, we carried out all-atom molecular dynamics simulations to map the free-energy landscape of these lattices, validated this landscape through extensive structural characterization by electron microscopy and established that it is predominantly governed by solvent reorganization entropy. Subsequent redesign of the protein surface with conditionally repulsive electrostatic interactions enabled us to predictably perturb the free-energy landscape and obtain a new protein lattice whose conformational dynamics can be chemically and mechanically toggled between three different states with varying porosities and molecular densities.

Determination of the molecular weight of human gamma-3 chains by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate

PubMed Central

Virella, G.; Parkhouse, R. M. E.

1972-01-01

The molecular weights (mol. wt) for heavy chains of human IgG were estimated by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate. Polyclonal IgG and monoclonal IgG proteins of different subclasses were extensively reduced with 50 mM dithioerythritol, in the presence of 2 per cent sodium dodecyl sulphate, at 100°. Four control proteins of known mol. wt (cytochrome C, chymotrypsinogen A, egg albumin, and serum albumin) were used to construct a linear plot of electrophoretic mobility versus log mol. wt. From this plot, the following mol. wts were calculated: 53,650±700 for polyclonal IgG; 54,200±1065 for γ1, γ2, and γ4 chains, and 60,950±585 for γ3 chains. Those results confirm the larger size of γ3 chains reported by Saluk and Clem (1971). PMID:4346255

Exact Solutions of Burnt-Bridge Models for Molecular Motor Transport

NASA Astrophysics Data System (ADS)

Morozov, Alexander; Pronina, Ekaterina; Kolomeisky, Anatoly; Artyomov, Maxim

2007-03-01

Transport of molecular motors, stimulated by interactions with specific links between consecutive binding sites (called ``bridges''), is investigated theoretically by analyzing discrete-state stochastic ``burnt-bridge'' models. When an unbiased diffusing particle crosses the bridge, the link can be destroyed (``burned'') with a probability p, creating a biased directed motion for the particle. It is shown that for probability of burning p=1 the system can be mapped into one-dimensional single-particle hopping model along the periodic infinite lattice that allows one to calculate exactly all dynamic properties. For general case of p<1 a new theoretical method is developed, and dynamic properties are computed explicitly. Discrete-time and continuous-time dynamics, periodic and random distribution of bridges and different burning dynamics are analyzed and compared. Theoretical predictions are supported by extensive Monte Carlo computer simulations. Theoretical results are applied for analysis of the experiments on collagenase motor proteins.

Solutions of burnt-bridge models for molecular motor transport

NASA Astrophysics Data System (ADS)

Morozov, Alexander Yu.; Pronina, Ekaterina; Kolomeisky, Anatoly B.; Artyomov, Maxim N.

2007-03-01

Transport of molecular motors, stimulated by interactions with specific links between consecutive binding sites (called “bridges”), is investigated theoretically by analyzing discrete-state stochastic “burnt-bridge” models. When an unbiased diffusing particle crosses the bridge, the link can be destroyed (“burned”) with a probability p , creating a biased directed motion for the particle. It is shown that for probability of burning p=1 the system can be mapped into a one-dimensional single-particle hopping model along the periodic infinite lattice that allows one to calculate exactly all dynamic properties. For the general case of p<1 a theoretical method is developed and dynamic properties are computed explicitly. Discrete-time and continuous-time dynamics for periodic distribution of bridges and different burning dynamics are analyzed and compared. Analytical predictions are supported by extensive Monte Carlo computer simulations. Theoretical results are applied for analysis of the experiments on collagenase motor proteins.

Drought-Responsive Mechanisms in Plant Leaves Revealed by Proteomics.

PubMed

Wang, Xiaoli; Cai, Xiaofeng; Xu, Chenxi; Wang, Quanhua; Dai, Shaojun

2016-10-18

Plant drought tolerance is a complex trait that requires a global view to understand its underlying mechanism. The proteomic aspects of plant drought response have been extensively investigated in model plants, crops and wood plants. In this review, we summarize recent proteomic studies on drought response in leaves to reveal the common and specialized drought-responsive mechanisms in different plants. Although drought-responsive proteins exhibit various patterns depending on plant species, genotypes and stress intensity, proteomic analyses show that dominant changes occurred in sensing and signal transduction, reactive oxygen species scavenging, osmotic regulation, gene expression, protein synthesis/turnover, cell structure modulation, as well as carbohydrate and energy metabolism. In combination with physiological and molecular results, proteomic studies in leaves have helped to discover some potential proteins and/or metabolic pathways for drought tolerance. These findings provide new clues for understanding the molecular basis of plant drought tolerance.

Drought-Responsive Mechanisms in Plant Leaves Revealed by Proteomics

PubMed Central

Wang, Xiaoli; Cai, Xiaofeng; Xu, Chenxi; Wang, Quanhua; Dai, Shaojun

2016-01-01

Plant drought tolerance is a complex trait that requires a global view to understand its underlying mechanism. The proteomic aspects of plant drought response have been extensively investigated in model plants, crops and wood plants. In this review, we summarize recent proteomic studies on drought response in leaves to reveal the common and specialized drought-responsive mechanisms in different plants. Although drought-responsive proteins exhibit various patterns depending on plant species, genotypes and stress intensity, proteomic analyses show that dominant changes occurred in sensing and signal transduction, reactive oxygen species scavenging, osmotic regulation, gene expression, protein synthesis/turnover, cell structure modulation, as well as carbohydrate and energy metabolism. In combination with physiological and molecular results, proteomic studies in leaves have helped to discover some potential proteins and/or metabolic pathways for drought tolerance. These findings provide new clues for understanding the molecular basis of plant drought tolerance. PMID:27763546

Collagenolytic Matrix Metalloproteinase Structure-Function Relationships: Insights From Molecular Dynamics Studies.

PubMed

Karabencheva-Christova, Tatyana G; Christov, Christo Z; Fields, Gregg B

2017-01-01

Several members of the zinc-dependent matrix metalloproteinase (MMP) family catalyze collagen degradation. Experimental data reveal a collaboration between different MMP domains in order to achieve efficient collagenolysis. Molecular dynamics (MD) simulations have been utilized to provide atomistic details of the collagenolytic process. The triple-helical structure of collagen exhibits local regions of flexibility, with modulation of interchain salt bridges and water bridges contributing to accessibility of individual chains by the enzyme. In turn, the hemopexin-like (HPX) domain of the MMP initially binds the triple helix and facilitates the presentation of individual strands to active site in the catalytic (CAT) domain. Extensive positive and negative correlated motions are observed between the CAT and HPX domains when collagen is bound. Ultimately, the MD simulation studies have complemented structural (NMR spectroscopy, X-ray crystallography) and kinetic analyses to provide a more detailed mechanistic view of MMP-catalyzed collagenolysis. © 2017 Elsevier Inc. All rights reserved.

A Pivotal Role of DELLAs in Regulating Multiple Hormone Signals.

PubMed

Davière, Jean-Michel; Achard, Patrick

2016-01-04

Plant phenotypic plasticity is controlled by diverse hormone pathways, which integrate and convey information from multiple developmental and environmental signals. Moreover, in plants many processes such as growth, development, and defense are regulated in similar ways by multiple hormones. Among them, gibberellins (GAs) are phytohormones with pleiotropic actions, regulating various growth processes throughout the plant life cycle. Previous work has revealed extensive interplay between GAs and other hormones, but the molecular mechanism became apparent only recently. Molecular and physiological studies have demonstrated that DELLA proteins, considered as master negative regulators of GA signaling, integrate multiple hormone signaling pathways through physical interactions with transcription factors or regulatory proteins from different families. In this review, we summarize the latest progress in GA signaling and its direct crosstalk with the main phytohormone signaling, emphasizing the multifaceted role of DELLA proteins with key components of major hormone signaling pathways. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

The ligand binding mechanism to purine nucleoside phosphorylase elucidated via molecular dynamics and machine learning.

PubMed

Decherchi, Sergio; Berteotti, Anna; Bottegoni, Giovanni; Rocchia, Walter; Cavalli, Andrea

2015-01-27

The study of biomolecular interactions between a drug and its biological target is of paramount importance for the design of novel bioactive compounds. In this paper, we report on the use of molecular dynamics (MD) simulations and machine learning to study the binding mechanism of a transition state analogue (DADMe-immucillin-H) to the purine nucleoside phosphorylase (PNP) enzyme. Microsecond-long MD simulations allow us to observe several binding events, following different dynamical routes and reaching diverse binding configurations. These simulations are used to estimate kinetic and thermodynamic quantities, such as kon and binding free energy, obtaining a good agreement with available experimental data. In addition, we advance a hypothesis for the slow-onset inhibition mechanism of DADMe-immucillin-H against PNP. Combining extensive MD simulations with machine learning algorithms could therefore be a fruitful approach for capturing key aspects of drug-target recognition and binding.

The effect of side motion in the dynamics of interacting molecular motors

NASA Astrophysics Data System (ADS)

Midha, Tripti; Gupta, Arvind Kumar; Kolomeisky, Anatoly B.

2017-07-01

To mimic the collective motion of interacting molecular motors, we propose and discuss an open two-lane symmetrically coupled interactive TASEP model that incorporates interaction in the thermodynamically consistent fashion. We study the effect of both repulsive and attractive interaction on the system’s dynamical properties using various cluster mean field analysis and extensive Monte Carlo simulations. The interactions bring correlations into the system, which were found to be reduced due to the side motion of particles. We produce the steady-state phase diagrams for symmetrically split interaction strength. The behavior of the maximal particle current with respect to the interaction energy E is analyzed for different coupling rates and interaction splittings. The results suggest that for strong coupling and large splittings, the maximal flow of the motors occurs at a weak attractive interaction strength which matches with the known experimental results on kinesin motor protein.

Molecular epidemiology of Usher syndrome in Italy.

PubMed

Vozzi, Diego; Aaspõllu, Anu; Athanasakis, Emmanouil; Berto, Anna; Fabretto, Antonella; Licastro, Danilo; Külm, Maigi; Testa, Francesco; Trevisi, Patrizia; Vahter, Marju; Ziviello, Carmela; Martini, Alessandro; Simonelli, Francesca; Banfi, Sandro; Gasparini, Paolo

2011-01-01

Usher syndrome is an autosomal recessive disorder characterized by hearing and vision loss. Usher syndrome is divided into three clinical subclasses (type 1, type 2, and type 3), which differ in terms of the severity and progression of hearing loss and the presence or absence of vestibular symptoms. Usher syndrome is defined by significant genetic heterogeneity, with at least 12 distinct loci described and 9 genes identified. This study aims to provide a molecular epidemiology report of Usher syndrome in Italy. Molecular data have been obtained on 75 unrelated Italian patients using the most up-to date technology available for the screening of Usher syndrome gene mutations, i.e., the genotyping microarray developed by Asper Biotech (Tartu, Estonia), which simultaneously investigates 612 different marker positions using the well established arrayed primer extension methodology (APEX). Using this method, we found that 12% of cases (9 out of 75) harbored homozygous or compound heterozygous mutations in the gene positions analyzed, whereas 20% (15 out of 75) of the patients were characterized by the presence of only one mutated allele based on the positions analyzed. One patient was found to be compound heterozygous for mutations in two different genes and this represents an example of possible digenic inheritance in Usher syndrome. A total of 66.6% of cases (50 out of 75) were found to be completely negative for the presence of Usher syndrome gene mutations in the detected positions. Mutations detected by the array were confirmed by direct sequencing. These findings highlight the efficacy of the APEX-based genotyping approach in the molecular assessment of Usher patients, suggesting the presence of alleles not yet identified and/or the involvement of additional putative genes that may account for the pathogenesis of Usher syndrome.

Molecular epidemiology of Usher syndrome in Italy

PubMed Central

Vozzi, Diego; Aaspõllu, Anu; Athanasakis, Emmanouil; Berto, Anna; Fabretto, Antonella; Licastro, Danilo; Külm, Maigi; Testa, Francesco; Trevisi, Patrizia; Vahter, Marju; Ziviello, Carmela; Martini, Alessandro; Simonelli, Francesca; Banfi, Sandro

2011-01-01

Purpose Usher syndrome is an autosomal recessive disorder characterized by hearing and vision loss. Usher syndrome is divided into three clinical subclasses (type 1, type 2, and type 3), which differ in terms of the severity and progression of hearing loss and the presence or absence of vestibular symptoms. Usher syndrome is defined by significant genetic heterogeneity, with at least 12 distinct loci described and 9 genes identified. This study aims to provide a molecular epidemiology report of Usher syndrome in Italy. Methods Molecular data have been obtained on 75 unrelated Italian patients using the most up-to date technology available for the screening of Usher syndrome gene mutations, i.e., the genotyping microarray developed by Asper Biotech (Tartu, Estonia), which simultaneously investigates 612 different marker positions using the well established arrayed primer extension methodology (APEX). Results Using this method, we found that 12% of cases (9 out of 75) harbored homozygous or compound heterozygous mutations in the gene positions analyzed, whereas 20% (15 out of 75) of the patients were characterized by the presence of only one mutated allele based on the positions analyzed. One patient was found to be compound heterozygous for mutations in two different genes and this represents an example of possible digenic inheritance in Usher syndrome. A total of 66.6% of cases (50 out of 75) were found to be completely negative for the presence of Usher syndrome gene mutations in the detected positions. Mutations detected by the array were confirmed by direct sequencing. Conclusions These findings highlight the efficacy of the APEX-based genotyping approach in the molecular assessment of Usher patients, suggesting the presence of alleles not yet identified and/or the involvement of additional putative genes that may account for the pathogenesis of Usher syndrome. PMID:21738395

Trimethylamine N-oxide (TMAO) and tert-butyl alcohol (TBA) at hydrophobic interfaces: insights from molecular dynamics simulations.

PubMed

Fiore, Andrew; Venkateshwaran, Vasudevan; Garde, Shekhar

2013-06-25

TMAO, a potent osmolyte, and TBA, a denaturant, have similar molecular architecture but somewhat different chemistry. We employ extensive molecular dynamics simulations to quantify their behavior at vapor-water and octane-water interfaces. We show that interfacial structure-density and orientation-and their dependence on solution concentration are markedly different for the two molecules. TMAO molecules are moderately surface active and adopt orientations with their N-O vector approximately parallel to the aqueous interface. That is, not all methyl groups of TMAO at the interface point away from the water phase. In contrast, TBA molecules act as molecular amphiphiles, are highly surface active, and, at low concentrations, adopt orientations with their methyl groups pointing away and the C-O vector pointing directly into water. The behavior of TMAO at aqueous interfaces is only weakly dependent on its solution concentration, whereas that of TBA depends strongly on concentration. We show that this concentration dependence arises from their different hydrogen bonding capabilities-TMAO can only accept hydrogen bonds from water, whereas TBA can accept (donate) hydrogen bonds from (to) water or other TBA molecules. The ability to self-associate, particularly visible in TBA molecules in the interfacial layer, allows them to sample a broad range of orientations at higher concentrations. In light of the role of TMAO and TBA in biomolecular stability, our results provide a reference with which to compare their behavior near biological interfaces. Also, given the ubiquity of aqueous interfaces in biology, chemistry, and technology, our results may be useful in the design of interfacially active small molecules with the aim to control their orientations and interactions.

The effective local potential method: Implementation for molecules and relation to approximate optimized effective potential techniques

NASA Astrophysics Data System (ADS)

Izmaylov, Artur F.; Staroverov, Viktor N.; Scuseria, Gustavo E.; Davidson, Ernest R.; Stoltz, Gabriel; Cancès, Eric

2007-02-01

We have recently formulated a new approach, named the effective local potential (ELP) method, for calculating local exchange-correlation potentials for orbital-dependent functionals based on minimizing the variance of the difference between a given nonlocal potential and its desired local counterpart [V. N. Staroverov et al., J. Chem. Phys. 125, 081104 (2006)]. Here we show that under a mildly simplifying assumption of frozen molecular orbitals, the equation defining the ELP has a unique analytic solution which is identical with the expression arising in the localized Hartree-Fock (LHF) and common energy denominator approximations (CEDA) to the optimized effective potential. The ELP procedure differs from the CEDA and LHF in that it yields the target potential as an expansion in auxiliary basis functions. We report extensive calculations of atomic and molecular properties using the frozen-orbital ELP method and its iterative generalization to prove that ELP results agree with the corresponding LHF and CEDA values, as they should. Finally, we make the case for extending the iterative frozen-orbital ELP method to full orbital relaxation.

Prediction of genetic values of quantitative traits in plant breeding using pedigree and molecular markers.

PubMed

Crossa, José; Campos, Gustavo de Los; Pérez, Paulino; Gianola, Daniel; Burgueño, Juan; Araus, José Luis; Makumbi, Dan; Singh, Ravi P; Dreisigacker, Susanne; Yan, Jianbing; Arief, Vivi; Banziger, Marianne; Braun, Hans-Joachim

2010-10-01

The availability of dense molecular markers has made possible the use of genomic selection (GS) for plant breeding. However, the evaluation of models for GS in real plant populations is very limited. This article evaluates the performance of parametric and semiparametric models for GS using wheat (Triticum aestivum L.) and maize (Zea mays) data in which different traits were measured in several environmental conditions. The findings, based on extensive cross-validations, indicate that models including marker information had higher predictive ability than pedigree-based models. In the wheat data set, and relative to a pedigree model, gains in predictive ability due to inclusion of markers ranged from 7.7 to 35.7%. Correlation between observed and predictive values in the maize data set achieved values up to 0.79. Estimates of marker effects were different across environmental conditions, indicating that genotype × environment interaction is an important component of genetic variability. These results indicate that GS in plant breeding can be an effective strategy for selecting among lines whose phenotypes have yet to be observed.

A rotation-translation invariant molecular descriptor of partial charges and its use in ligand-based virtual screening

PubMed Central

2014-01-01

Background Measures of similarity for chemical molecules have been developed since the dawn of chemoinformatics. Molecular similarity has been measured by a variety of methods including molecular descriptor based similarity, common molecular fragments, graph matching and 3D methods such as shape matching. Similarity measures are widespread in practice and have proven to be useful in drug discovery. Because of our interest in electrostatics and high throughput ligand-based virtual screening, we sought to exploit the information contained in atomic coordinates and partial charges of a molecule. Results A new molecular descriptor based on partial charges is proposed. It uses the autocorrelation function and linear binning to encode all atoms of a molecule into two rotation-translation invariant vectors. Combined with a scoring function, the descriptor allows to rank-order a database of compounds versus a query molecule. The proposed implementation is called ACPC (AutoCorrelation of Partial Charges) and released in open source. Extensive retrospective ligand-based virtual screening experiments were performed and other methods were compared with in order to validate the method and associated protocol. Conclusions While it is a simple method, it performed remarkably well in experiments. At an average speed of 1649 molecules per second, it reached an average median area under the curve of 0.81 on 40 different targets; hence validating the proposed protocol and implementation. PMID:24887178

Solid oxygen revisited

NASA Astrophysics Data System (ADS)

Freiman, Yu. A.; Jodl, H. J.; Crespo, Yanier

2018-05-01

The paper provides an up-to-date review of the experimental and theoretical works on solid oxygen published over the past decade. The most important results presented in this review are the following: Detection of magnetic collapse in neutron studies under the delta-epsilon transition. Identification of the lattice structure of the ɛ phase. In this structure the O2 molecules retain their individuality, but there is an additional link leading to the formation of clusters of molecular quartets with the structural formula (O2)4. Discovery of the unique magnetic properties of the delta phase, which hosts three different magnetic structures in the domain of the same crystallographic structure. The extension of the phase diagram to the high-pressure high-temperature region which was previously beyond the reach for experiment; the molecular η and η‧ phases were found and their structures were identified. Behavior of the melting line up to 60 GPa (1750 K). Discovery of a new molecular θ phase in ultrahigh magnetic fields up to over 190 T and the construction of the thermodynamical magnetic-field-temperature H- T phase diagram on the base of the ultrahigh-field magnetization, optical magneto-transmission, and adiabatic magnetocaloric effect measurements. Prediction of the persistence of the molecular state of solid oxygen up to the pressure of 1.9 TPa which is significantly higher than the corresponding limits in solid hydrogen and nitrogen, other generic molecular solids.

GPU accelerated Discrete Element Method (DEM) molecular dynamics for conservative, faceted particle simulations

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

Spellings, Matthew; Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109; Marson, Ryan L.

Faceted shapes, such as polyhedra, are commonly found in systems of nanoscale, colloidal, and granular particles. Many interesting physical phenomena, like crystal nucleation and growth, vacancy motion, and glassy dynamics are challenging to model in these systems because they require detailed dynamical information at the individual particle level. Within the granular materials community the Discrete Element Method has been used extensively to model systems of anisotropic particles under gravity, with friction. We provide an implementation of this method intended for simulation of hard, faceted nanoparticles, with a conservative Weeks–Chandler–Andersen (WCA) interparticle potential, coupled to a thermodynamic ensemble. This method ismore » a natural extension of classical molecular dynamics and enables rigorous thermodynamic calculations for faceted particles.« less

Molecular mechanics of silk nanostructures under varied mechanical loading.

PubMed

Bratzel, Graham; Buehler, Markus J

2012-06-01

Spider dragline silk is a self-assembling tunable protein composite fiber that rivals many engineering fibers in tensile strength, extensibility, and toughness, making it one of the most versatile biocompatible materials and most inviting for synthetic mimicry. While experimental studies have shown that the peptide sequence and molecular structure of silk have a direct influence on the stiffness, toughness, and failure strength of silk, few molecular-level analyses of the nanostructure of silk assemblies, in particular, under variations of genetic sequences have been reported. In this study, atomistic-level structures of wildtype as well as modified MaSp1 protein from the Nephila clavipes spider dragline silk sequences, obtained using an in silico approach based on replica exchange molecular dynamics and explicit water molecular dynamics, are subjected to simulated nanomechanical testing using different force-control loading conditions including stretch, pull-out, and peel. The authors have explored the effects of the poly-alanine length of the N. clavipes MaSp1 peptide sequence and identify differences in nanomechanical loading conditions on the behavior of a unit cell of 15 strands with 840-990 total residues used to represent a cross-linking β-sheet crystal node in the network within a fibril of the dragline silk thread. The specific loading condition used, representing concepts derived from the protein network connectivity at larger scales, have a significant effect on the mechanical behavior. Our analysis incorporates stretching, pull-out, and peel testing to connect biochemical features to mechanical behavior. The method used in this study could find broad applications in de novo design of silk-like tunable materials for an array of applications. Copyright © 2011 Wiley Periodicals, Inc.

Structural properties of pyruvate carboxylases from chicken liver and other sources

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

Barden, R.E.; Taylor, B.L.; Isohashi, F.

1975-11-01

Varieties of pyruvate carboxylase (pyruvate: CO/sub 2/ ligase (ADP-forming), EC 6.4.1.1) obtained from the livers of several species of vertebrates, including humans, all show the same basic structure. They are composed of large polypeptide chains of molecular weights ranging from 1.2 to 1.3 x 10/sup 5/ for the different varieties of the enzyme. The native form of the enzyme appears to be a tetramer with a molecular weight of about 5 x 10/sup 5/. In the case of pyruvate carboxylase from chicken liver each polypeptide chain contains a biotin moiety, thus supporting the thesis that the tetramer contains four identicalmore » polypeptide chains. Pyruvate carboxylase from yeast appears to be basically similar to those from the vertebrate species and has a tetrameric structure. Each protomer contains a single polypeptide chain with a molecular weight of 1.25 x 10/sup 5/. In contrast, pyruvate carboxylase from two bacterial species, Pseudomonas citronellolis and Azotobacter vinelandii, appears to be a dimer with a molecular weight (2.5 x 10/sup 5/) about half that of the animal and yeast species. As a further difference, each of the protomers of the bacterial enzymes contain two polypeptides of 6.5 and 5.4 x 10/sup 5/ molecular weight in the case of the Pseudomonas enzyme. The larger of the two polypeptides contains the biotin moiety. The functional units of the bacterial enzyme thus appear to contain two polypeptides while that of the liver and yeast enzymes is made up of a single chain. Neither of these arrangements corresponds with those of other biotin enzymes whose structure has been extensively studied (acetyl-CoA carboxylases from liver or Escherichia coli, and transcarboxylase from Propionibacterium). (auth)« less

Molecular regulation of plant cell wall extensibility

NASA Technical Reports Server (NTRS)

Cosgrove, D. J.

1998-01-01

Gravity responses in plants often involve spatial and temporal changes in cell growth, which is regulated primarily by controlling the ability of the cell wall to extend. The wall is thought to be a cellulose-hemicellulose network embedded in a hydrated matrix of complex polysaccharides and a small amount of structural protein. The wall extends by a form of polymer creep, which is mediated by expansins, a novel group of wall-loosening proteins. Expansins were discovered during a molecular dissection of the "acid growth" behavior of cell walls. Expansin alters the rheology of plant walls in profound ways, yet its molecular mechanism of action is still uncertain. It lacks detectable hydrolytic activity against the major components of the wall, but it is able to disrupt noncovalent adhesion between wall polysaccharides. The discovery of a second family of expansins (beta-expansins) sheds light on the biological role of a major group of pollen allergens and implies that expansins have evolved for diverse developmental functions. Finally, the contribution of other processes to wall extensibility is briefly summarized.

Genomic evidence reveals a radiation of placental mammals uninterrupted by the KPg boundary

PubMed Central

Liu, Liang; Zhang, Jin; Rheindt, Frank E.; Lei, Fumin; Qu, Yanhua; Wang, Yu; Zhang, Yu; Sullivan, Corwin; Nie, Wenhui; Wang, Jinhuan; Yang, Fengtang; Chen, Jinping; Edwards, Scott V.; Meng, Jin; Wu, Shaoyuan

2017-01-01

The timing of the diversification of placental mammals relative to the Cretaceous–Paleogene (KPg) boundary mass extinction remains highly controversial. In particular, there have been seemingly irreconcilable differences in the dating of the early placental radiation not only between fossil-based and molecular datasets but also among molecular datasets. To help resolve this discrepancy, we performed genome-scale analyses using 4,388 loci from 90 taxa, including representatives of all extant placental orders and transcriptome data from flying lemurs (Dermoptera) and pangolins (Pholidota). Depending on the gene partitioning scheme, molecular clock model, and genic deviation from molecular clock assumptions, extensive sensitivity analyses recovered widely varying diversification scenarios for placental mammals from a given gene set, ranging from a deep Cretaceous origin and diversification to a scenario spanning the KPg boundary, suggesting that the use of suboptimal molecular clock markers and methodologies is a major cause of controversies regarding placental diversification timing. We demonstrate that reconciliation between molecular and paleontological estimates of placental divergence times can be achieved using the appropriate clock model and gene partitioning scheme while accounting for the degree to which individual genes violate molecular clock assumptions. A birth-death-shift analysis suggests that placental mammals underwent a continuous radiation across the KPg boundary without apparent interruption by the mass extinction, paralleling a genus-level radiation of multituberculates and ecomorphological diversification of both multituberculates and therians. These findings suggest that the KPg catastrophe evidently played a limited role in placental diversification, which, instead, was likely a delayed response to the slightly earlier radiation of angiosperms. PMID:28808022

Genomic evidence reveals a radiation of placental mammals uninterrupted by the KPg boundary.

PubMed

Liu, Liang; Zhang, Jin; Rheindt, Frank E; Lei, Fumin; Qu, Yanhua; Wang, Yu; Zhang, Yu; Sullivan, Corwin; Nie, Wenhui; Wang, Jinhuan; Yang, Fengtang; Chen, Jinping; Edwards, Scott V; Meng, Jin; Wu, Shaoyuan

2017-08-29

The timing of the diversification of placental mammals relative to the Cretaceous-Paleogene (KPg) boundary mass extinction remains highly controversial. In particular, there have been seemingly irreconcilable differences in the dating of the early placental radiation not only between fossil-based and molecular datasets but also among molecular datasets. To help resolve this discrepancy, we performed genome-scale analyses using 4,388 loci from 90 taxa, including representatives of all extant placental orders and transcriptome data from flying lemurs (Dermoptera) and pangolins (Pholidota). Depending on the gene partitioning scheme, molecular clock model, and genic deviation from molecular clock assumptions, extensive sensitivity analyses recovered widely varying diversification scenarios for placental mammals from a given gene set, ranging from a deep Cretaceous origin and diversification to a scenario spanning the KPg boundary, suggesting that the use of suboptimal molecular clock markers and methodologies is a major cause of controversies regarding placental diversification timing. We demonstrate that reconciliation between molecular and paleontological estimates of placental divergence times can be achieved using the appropriate clock model and gene partitioning scheme while accounting for the degree to which individual genes violate molecular clock assumptions. A birth-death-shift analysis suggests that placental mammals underwent a continuous radiation across the KPg boundary without apparent interruption by the mass extinction, paralleling a genus-level radiation of multituberculates and ecomorphological diversification of both multituberculates and therians. These findings suggest that the KPg catastrophe evidently played a limited role in placental diversification, which, instead, was likely a delayed response to the slightly earlier radiation of angiosperms.

Revisiting old vaginal topics: conversion of the Müllerian vagina and origin of the "sinus" vagina.

PubMed

Cai, Yi

2009-01-01

Vaginal development has been a longstanding controversy, which hampers studies on vaginal diseases as well as cervical and uterine diseases. Most concerns center on: why is the vaginal epithelium different from the uterine epithelium; and where does the vagina originate from? It is commonly held that the rodent vagina has a dual origin: the cranial part is derived from the Mullerian duct (Mullerian vagina) and the caudal part derived from the urogenital sinus (sinus vagina). This concept was deduced from morphological observations. However, it cannot explain the difference between the Mullerian vagina and the uterus. Moreover, accumulating new data from genetic and molecular studies contradicts the urogenital sinus origin of the sinus vagina. The present review summarizes previous morphological observations and new findings from genetic and molecular studies, and addresses molecular mechanisms underlying the origin and organogenesis of the vagina in rodents. It provides evidence to show that the whole vagina is derived the Mullerian duct. BMP4 reshapes the intermediate mesoderm-derived Mullerian duct into the vaginal primordium. The latter thus exhibits different features from the uterus, including the stratified squamous epithelium and insensitivity to anti-Mullerian hormone. The sinus vagina is formed by extrinsic BMP4-mediated caudal extension of the Mullerian duct. The present review thus shows how a century of controversy over the origin and organogenesis of the vagina has been resolved. This new understanding will provide additional insight into genetic diseases and tumors of the female reproductive tract.

BAYES’ THEOREM AND EARLY SOLAR SHORT-LIVED RADIONUCLIDES: THE CASE FOR AN UNEXCEPTIONAL ORIGIN FOR THE SOLAR SYSTEM

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

Young, Edward D., E-mail: eyoung@epss.ucla.edu

2016-08-01

The presence of excesses of short-lived radionuclides in the early solar system evidenced in meteorites has been taken as testament to close encounters with exotic nucleosynthetic sources, including supernovae or AGB stars. An analysis of the likelihoods associated with different sources of these extinct nuclides in the early solar system indicates that, rather than being exotic, their abundances were typical of star-forming regions like those observed today in the Galaxy. The radiochemistry of the early solar system is therefore unexceptional, being the consequence of extensive averaging of solids from molecular clouds.

Petri net modelling of biological networks.

PubMed

Chaouiya, Claudine

2007-07-01

Mathematical modelling is increasingly used to get insights into the functioning of complex biological networks. In this context, Petri nets (PNs) have recently emerged as a promising tool among the various methods employed for the modelling and analysis of molecular networks. PNs come with a series of extensions, which allow different abstraction levels, from purely qualitative to more complex quantitative models. Noteworthily, each of these models preserves the underlying graph, which depicts the interactions between the biological components. This article intends to present the basics of the approach and to foster the potential role PNs could play in the development of the computational systems biology.

Raman Spectroscopy of Microbial Pigments

PubMed Central

Edwards, Howell G. M.; Oren, Aharon

2014-01-01

Raman spectroscopy is a rapid nondestructive technique providing spectroscopic and structural information on both organic and inorganic molecular compounds. Extensive applications for the method in the characterization of pigments have been found. Due to the high sensitivity of Raman spectroscopy for the detection of chlorophylls, carotenoids, scytonemin, and a range of other pigments found in the microbial world, it is an excellent technique to monitor the presence of such pigments, both in pure cultures and in environmental samples. Miniaturized portable handheld instruments are available; these instruments can be used to detect pigments in microbiological samples of different types and origins under field conditions. PMID:24682303

Graphene-based nanomaterials for nanobiotechnology and biomedical applications.

PubMed

Krishna, K Vijaya; Ménard-Moyon, Cécilia; Verma, Sandeep; Bianco, Alberto

2013-10-01

Graphene family nanomaterials are currently being extensively explored for applications in the field of nanotechnology. The unique intrinsic properties treasured in their simple molecular design and their ability to work in coherence with other existing nanomaterials make graphene family nanomaterials the most promising candidates for different types of applications. This review highlights the scope and utility of these multifaceted nanomaterials in nanobiotechnology and biomedicine. In a tandem approach, this review presents the smooth inclusion of these nanomaterials into existing designs for creating efficient working models at the nanoscale level as well as discussing their broad future possibilities.

Variability and molecular typing of the woody-tree infecting prunus necrotic ringspot ilarvirus.

PubMed

Vasková, D; Petrzik, K; Karesová, R

2000-01-01

The 3'-part of the movement protein gene, the intergenic region and the complete coat protein gene of sixteen isolates of Prunus necrotic ringspot virus (PNRSV) from five different host species from the Czech Republic were sequenced in order to search for the bases of extensive variability of viroses caused by this pathogen. According to phylogenetic analyses all the 46 isolates sequenced to date split into three main groups, which correlated to a certain extend with their geographic origin. Modelled serological properties showed that all the new isolates belong to one serotype.

Combined quantum mechanics/molecular mechanics (QM/MM) simulations for protein-ligand complexes: free energies of binding of water molecules in influenza neuraminidase.

PubMed

Woods, Christopher J; Shaw, Katherine E; Mulholland, Adrian J

2015-01-22

The applicability of combined quantum mechanics/molecular mechanics (QM/MM) methods for the calculation of absolute binding free energies of conserved water molecules in protein/ligand complexes is demonstrated. Here, we apply QM/MM Monte Carlo simulations to investigate binding of water molecules to influenza neuraminidase. We investigate five different complexes, including those with the drugs oseltamivir and peramivir. We investigate water molecules in two different environments, one more hydrophobic and one hydrophilic. We calculate the free-energy change for perturbation of a QM to MM representation of the bound water molecule. The calculations are performed at the BLYP/aVDZ (QM) and TIP4P (MM) levels of theory, which we have previously demonstrated to be consistent with one another for QM/MM modeling. The results show that the QM to MM perturbation is significant in both environments (greater than 1 kcal mol(-1)) and larger in the more hydrophilic site. Comparison with the same perturbation in bulk water shows that this makes a contribution to binding. The results quantify how electronic polarization differences in different environments affect binding affinity and also demonstrate that extensive, converged QM/MM free-energy simulations, with good levels of QM theory, are now practical for protein/ligand complexes.

Bacteria versus selenium: A view from the inside out

USGS Publications Warehouse

Staicu, Lucian; Oremland, Ronald S.; Tobe, Ryuta; Mihara, Hisaaki

2017-01-01

Bacteria and selenium (Se) are closely interlinked as the element serves both essential nutrient requirements and energy generation functions. However, Se can also behave as a powerful toxicant for bacterial homeostasis. Conversely, bacteria play a tremendous role in the cycling of Se between different environmental compartments, and bacterial metabolism has been shown to participate to all valence state transformations undergone by Se in nature. Bacteria possess an extensive molecular repertoire for Se metabolism. At the end of the 1980s, a novel mode of anaerobic respiration based on Se oxyanions was experimentally documented for the first time. Following this discovery, specific enzymes capable of reducing Se oxyanions and harvesting energy were found in a number of anaerobic bacteria. The genes involved in the expression of these enzymes have later been identified and cloned. This iterative approach undertaken outside-in led to the understanding of the molecular mechanisms of Se transformations in bacteria. Based on the extensive knowledge accumulated over the years, we now have a full(er) view from the inside out, from DNA-encoding genes to enzymes and thermodynamics. Bacterial transformations of Se for assimilatory purposes have been the object of numerous studies predating the investigation of Se respiration. Remarkable contributions related to the understating of the molecular picture underlying seleno-amino acid biosynthesis are reviewed herein. Under certain circumstances, Se is a toxicant for bacterial metabolism and bacteria have evolved strategies to counteract this toxicity, most notably by the formation of elemental Se (nano)particles. Several biotechnological applications, such as the production of functional materials and the biofortification of crop species using Se-utilizing bacteria, are presented in this chapter.

The complete plastome of macaw palm [Acrocomia aculeata (Jacq.) Lodd. ex Mart.] and extensive molecular analyses of the evolution of plastid genes in Arecaceae.

PubMed

de Santana Lopes, Amanda; Gomes Pacheco, Túlio; Nimz, Tabea; do Nascimento Vieira, Leila; Guerra, Miguel P; Nodari, Rubens O; de Souza, Emanuel Maltempi; de Oliveira Pedrosa, Fábio; Rogalski, Marcelo

2018-04-01

The plastome of macaw palm was sequenced allowing analyses of evolution and molecular markers. Additionally, we demonstrated that more than half of plastid protein-coding genes in Arecaceae underwent positive selection. Macaw palm is a native species from tropical and subtropical Americas. It shows high production of oil per hectare reaching up to 70% of oil content in fruits and an interesting plasticity to grow in different ecosystems. Its domestication and breeding are still in the beginning, which makes the development of molecular markers essential to assess natural populations and germplasm collections. Therefore, we sequenced and characterized in detail the plastome of macaw palm. A total of 221 SSR loci were identified in the plastome of macaw palm. Additionally, eight polymorphism hotspots were characterized at level of subfamily and tribe. Moreover, several events of gain and loss of RNA editing sites were found within the subfamily Arecoideae. Aiming to uncover evolutionary events in Arecaceae, we also analyzed extensively the evolution of plastid genes. The analyses show that highly divergent genes seem to evolve in a species-specific manner, suggesting that gene degeneration events may be occurring within Arecaceae at the level of genus or species. Unexpectedly, we found that more than half of plastid protein-coding genes are under positive selection, including genes for photosynthesis, gene expression machinery and other essential plastid functions. Furthermore, we performed a phylogenomic analysis using whole plastomes of 40 taxa, representing all subfamilies of Arecaceae, which placed the macaw palm within the tribe Cocoseae. Finally, the data showed here are important for genetic studies in macaw palm and provide new insights into the evolution of plastid genes and environmental adaptation in Arecaceae.

Investigating carbon dynamics in Siberian peat bogs using molecular-level analyses

NASA Astrophysics Data System (ADS)

Kaiser, K.; Benner, R. H.

2013-12-01

Total hydrolysable carbohydrates, and lignin and cutin acid compounds were analyzed in peat cores collected 56.8 N (SIB04), 58.4 N (SIB06), 63.8 N (G137) and 66.5 N (E113) in the Western Siberian Lowland to investigate vegetation, chemical compositions and the stage of decomposition. Sphagnum mosses dominated peatland vegetation in all four cores. High-resolution molecular analyses revealed rapid vegetation changes on timescales of 50-200 years in the southern cores Sib4 and Sib6. Syringyl and vanillyl (S/V) ratios and cutin acids indicated these vegetation changes were due to varying inputs of angiosperm and gymnosperm and root material. In the G137 and E113 cores lichens briefly replaced sphagnum mosses and vascular plants. Molecular decomposition indicators used in this study tracked the decomposition of different organic constituents of peat organic matter. The carbohydrate decomposition index was sensitive to the polysaccharide component of all peat-forming plants, whereas acid/aldehyde ratios of S and V phenols (Ac/AlS,V) followed the lignin component of vascular plants. Low carbohydrate decomposition indices in peat layers corresponded well with elevated (Ad/Al)S,V ratios. This suggested both classes of biochemicals were simultaneously decomposed, and decomposition processes were associated with extensive total mass loss in these ombrotrophic systems. Selective decomposition or transformation of lignin was observed in the permafrost-influenced northern cores G137 and E113. Both cores exhibited the highest (Ad/Al)S,V ratios, almost four-fold higher than measured in peat-forming plants. The extent of decomposition in the four peat cores did not uniformly increase with age, but showed episodic extensive decomposition events. Variable decomposition events independent of climatic conditions and vegetation shifts highlight the complexity of peatland dynamics.

Extensively Drug-Resistant Klebsiella pneumoniae Causing Nosocomial Bloodstream Infections in China: Molecular Investigation of Antibiotic Resistance Determinants, Informing Therapy, and Clinical Outcomes

PubMed Central

Bi, Wenzi; Liu, Haiyang; Dunstan, Rhys A.; Li, Bin; Torres, Von Vergel L.; Cao, Jianming; Chen, Lijiang; Wilksch, Jonathan J.; Strugnell, Richard A.; Lithgow, Trevor; Zhou, Tieli

2017-01-01

The rise in diversity of antimicrobial resistance phenotypes seen in Klebsiella pneumoniae is becoming a serious antibiotic management problem. We sought to investigate the molecular characteristics and clinical implications of extensively drug-resistant (XDR) K. pneumoniae isolated from different nosocomial bloodstream infections (BSIs) patients from July 2013 to November 2015. Even in combination treatment, meropenem did not protect against mortality of BSIs patients (P = 0.015). In contrast, tigecycline in combination with other antimicrobial agents significantly protected against mortality (P = 0.016). Antimicrobial susceptibility tests, molecular detection of antibiotic resistance determinants, conjugation experiments, multilocus sequence typing (MLST), S1-PFGE, Southern blot, SDS-PAGE, immunoblot analysis, and pulsed-field gel electrophoresis (PFGE) were used to characterize these isolates. These XDR K. pneumoniae strains were resistant to conventional antimicrobials except tigecycline and polymyxin B and co-harbored diverse resistance determinants. rmtB, blaKPC−2 as well as blaCTX−M−9 were located on a transferable plasmid of ~54.2 kb and the most predominant replicon type was IncF. 23 of the 35 isolates belonging the predominant clone were found to incorporate the globally-disseminated sequence type ST11, but others including a unique, previously undiscovered lineage ST2281 (allelic profile: 4-1-1-22-7-4-35) were also found and characterized. The porins OmpK35 and OmpK36 were deficient in two carbapenemase-negative carbapenem-resistant strains, suggesting decreased drug uptake as a mechanism for carbapenem resistance. This study highlights the importance of tracking hospital acquired infections, monitoring modes of antibiotic resistance to improve health outcomes of BSIs patients and to highlight the problems of XDR K. pneumoniae dissemination in healthcare settings. PMID:28713357

Discrete Optimization of Electronic Hyperpolarizabilities in a Chemical Subspace

DTIC Science & Technology

2009-05-01

molecular design. Methods for optimization in discrete spaces have been studied extensively and recently reviewed ( 5). Optimization methods include...integer programming, as in branch-and-bound techniques (including dead-end elimination [ 6]), simulated annealing ( 7), and genetic algorithms ( 8...These algorithms have found renewed interest and application in molecular and materials design (9- 12) . Recently, new approaches have been

Adoption of Lean Principles in a High-Volume Molecular Diagnostic Microbiology Laboratory

PubMed Central

Mitchell, P. Shawn; Mandrekar, Jayawant N.

2014-01-01

Clinical laboratories are constantly facing challenges to do more with less, enhance quality, improve test turnaround time, and reduce operational expenses. Experience with adopting and applying lean concepts and tools used extensively in the manufacturing industry is described for a high-volume clinical molecular microbiology laboratory, illustrating how operational success and benefits can be achieved. PMID:24829247

Enhancing the intense field control of molecular fragmentation.

PubMed

Anis, Fatima; Esry, B D

2012-09-28

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

Neuron-Like Networks Between Ribosomal Proteins Within the Ribosome

NASA Astrophysics Data System (ADS)

Poirot, Olivier; Timsit, Youri

2016-05-01

From brain to the World Wide Web, information-processing networks share common scale invariant properties. Here, we reveal the existence of neural-like networks at a molecular scale within the ribosome. We show that with their extensions, ribosomal proteins form complex assortative interaction networks through which they communicate through tiny interfaces. The analysis of the crystal structures of 50S eubacterial particles reveals that most of these interfaces involve key phylogenetically conserved residues. The systematic observation of interactions between basic and aromatic amino acids at the interfaces and along the extension provides new structural insights that may contribute to decipher the molecular mechanisms of signal transmission within or between the ribosomal proteins. Similar to neurons interacting through “molecular synapses”, ribosomal proteins form a network that suggest an analogy with a simple molecular brain in which the “sensory-proteins” innervate the functional ribosomal sites, while the “inter-proteins” interconnect them into circuits suitable to process the information flow that circulates during protein synthesis. It is likely that these circuits have evolved to coordinate both the complex macromolecular motions and the binding of the multiple factors during translation. This opens new perspectives on nanoscale information transfer and processing.

Nanostructure, hydrogen bonding and rheology in choline chloride deep eutectic solvents as a function of the hydrogen bond donor.

PubMed

Stefanovic, Ryan; Ludwig, Michael; Webber, Grant B; Atkin, Rob; Page, Alister J

2017-01-25

Deep eutectic solvents (DESs) are a mixture of a salt and a molecular hydrogen bond donor, which form a eutectic liquid with a depressed melting point. Quantum mechanical molecular dynamics (QM/MD) simulations have been used to probe the 1 : 2 choline chloride-urea (ChCl : U), choline chloride-ethylene glycol (ChCl : EG) and choline chloride-glycerol (ChCl : Gly) DESs. DES nanostructure and interactions between the ions is used to rationalise differences in DES eutectic point temperatures and viscosity. Simulations show that the structure of the bulk hydrogen bond donor is largely preserved for hydroxyl based hydrogen bond donors (ChCl:Gly and ChCl:EG), resulting in a smaller melting point depression. By contrast, ChCl:U exhibits a well-established hydrogen bond network between the salt and hydrogen bond donor, leading to a larger melting point depression. This extensive hydrogen bond network in ChCl:U also leads to substantially higher viscosity, compared to ChCl:EG and ChCl:Gly. Of the two hydroxyl based DESs, ChCl:Gly also exhibits a higher viscosity than ChCl:EG. This is attributed to the over-saturation of hydrogen bond donor groups in the ChCl:Gly bulk, which leads to more extensive hydrogen bond donor self-interaction and hence higher cohesive forces within the bulk liquid.

Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

PubMed Central

Feltes, Bruno César; de Faria Poloni, Joice; Nunes, Itamar José Guimarães

2014-01-01

Abstract Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulin-associated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment. PMID:24816220

MtDNA mutations are a common cause of severe disease phenotypes in children with Leigh syndrome.

PubMed

Naess, Karin; Freyer, Christoph; Bruhn, Helene; Wibom, Rolf; Malm, Gunilla; Nennesmo, Inger; von Döbeln, Ulrika; Larsson, Nils-Göran

2009-05-01

Leigh syndrome is a common clinical manifestation in children with mitochondrial disease and other types of inborn errors of metabolism. We characterised clinical symptoms, prognosis, respiratory chain function and performed extensive genetic analysis of 25 Swedish children suffering from Leigh syndrome with the aim to obtain insights into the molecular pathophysiology and to provide a rationale for genetic counselling. We reviewed the clinical history of all patients and used muscle biopsies in order to perform molecular, biochemical and genetic investigations, including sequencing the entire mitochondrial DNA (mtDNA), the mitochondrial DNA polymerase (POLGA) gene and the surfeit locus protein 1 (SURF1) gene. Respiratory chain enzyme activity measurements identified five patients with isolated complex I deficiency and five with combined enzyme deficiencies. No patient presented with isolated complex IV deficiency. Seven patients had a decreased ATP production rate. Extensive sequence analysis identified eight patients with pathogenic mtDNA mutations and one patient with mutations in POLGA. Mutations of mtDNA are a common cause of LS and mtDNA analysis should always be included in the diagnosis of LS patients, whereas SURF1 mutations are not a common cause of LS in Sweden. Unexpectedly, age of onset, clinical symptoms and prognosis did not reveal any clear differences in LS patients with mtDNA or nuclear DNA mutations.

Fetal alcohol syndrome, chemo-biology and OMICS: ethanol effects on vitamin metabolism during neurodevelopment as measured by systems biology analysis.

PubMed

Feltes, Bruno César; de Faria Poloni, Joice; Nunes, Itamar José Guimarães; Bonatto, Diego

2014-06-01

Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulin-associated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment.

A Rigidity-Enhanced Antimicrobial Activity: A Case for Linear Cationic α-Helical Peptide HP(2–20) and Its Four Analogues

PubMed Central

Liu, Li; Fang, Ying; Huang, Qingsheng; Wu, Jianhua

2011-01-01

Linear cationic α-helical antimicrobial peptides are referred to as one of the most likely substitutes for common antibiotics, due to their relatively simple structures (≤40 residues) and various antimicrobial activities against a wide range of pathogens. Of those, HP(2–20) was isolated from Helicobacter pylori ribosomal protein. To reveal a mechanical determinant that may mediate the antimicrobial activities, we examined the mechanical properties and structural stabilities of HP(2–20) and its four analogues of same chain length by steered molecular dynamics simulation. The results indicated the following: the resistance of H-bonds to the tensile extension mediated the early extensive stage; with the loss of H-bonds, the tensile force was dispensed to prompt the conformational phase transition; and Young's moduli (N/m2) of the peptides were about 4∼8×109. These mechanical features were sensitive to the variation of the residue compositions. Furthermore, we found that the antimicrobial activity is rigidity-enhanced, that is, a harder peptide has stronger antimicrobial activity. It suggests that the molecular spring constant may be used to seek a new structure-activity relationship for different α-helical peptide groups. This exciting result was reasonably explained by a possible mechanical mechanism that regulates both the membrane pore formation and the peptide insertion. PMID:21283643

Nanoscale movements of cellulose microfibrils in primary cell walls.

PubMed

Zhang, Tian; Vavylonis, Dimitrios; Durachko, Daniel M; Cosgrove, Daniel J

2017-04-28

The growing plant cell wall is commonly considered to be a fibre-reinforced structure whose strength, extensibility and anisotropy depend on the orientation of crystalline cellulose microfibrils, their bonding to the polysaccharide matrix and matrix viscoelasticity 1-4 . Structural reinforcement of the wall by stiff cellulose microfibrils is central to contemporary models of plant growth, mechanics and meristem dynamics 4-12 . Although passive microfibril reorientation during wall extension has been inferred from theory and from bulk measurements 13-15 , nanometre-scale movements of individual microfibrils have not been directly observed. Here we combined nanometre-scale imaging of wet cell walls by atomic force microscopy (AFM) with a stretching device and endoglucanase treatment that induces wall stress relaxation and creep, mimicking wall behaviours during cell growth. Microfibril movements during forced mechanical extensions differ from those during creep of the enzymatically loosened wall. In addition to passive angular reorientation, we observed a diverse repertoire of microfibril movements that reveal the spatial scale of molecular connections between microfibrils. Our results show that wall loosening alters microfibril connectivity, enabling microfibril dynamics not seen during mechanical stretch. These insights into microfibril movements and connectivities need to be incorporated into refined models of plant cell wall structure, growth and morphogenesis.

Processing-microstructure relationships in thermotropic liquid crystalline polymers: Experimental and numerical modeling studies

NASA Astrophysics Data System (ADS)

Fang, Jun

Thermotropic liquid crystalline polymers (TLCPs) are a class of promising engineering materials for high-demanding structural applications. Their excellent mechanical properties are highly correlated to the underlying molecular orientation states, which may be affected by complex flow fields during melt processing. Thus, understanding and eventually predicting how processing flows impact molecular orientation is a critical step towards rational design work in order to achieve favorable, balanced physical properties in finished products. This thesis aims to develop deeper understanding of orientation development in commercial TLCPs during processing by coordinating extensive experimental measurements with numerical computations. In situ measurements of orientation development of LCPs during processing are a focal point of this thesis. An x-ray capable injection molding apparatus is enhanced and utilized for time-resolved measurements of orientation development in multiple commercial TLCPs during injection molding. Ex situ wide angle x-ray scattering is also employed for more thorough characterization of molecular orientation distributions in molded plaques. Incompletely injection molded plaques ("short shots") are studied to gain further insights into the intermediate orientation states during mold filling. Finally, two surface orientation characterization techniques, near edge x-ray absorption fine structure (NEXAFS) and infrared attenuated total reflectance (FTIR-ATR) are combined to investigate the surface orientation distribution of injection molded plaques. Surface orientation states are found to be vastly different from their bulk counterparts due to different kinematics involved in mold filling. In general, complex distributions of orientation in molded plaques reflect the spatially varying competition between shear and extension during mold filling. To complement these experimental measurements, numerical calculations based on the Larson-Doi polydomain model are performed. The implementation of the Larson-Doi in complex processing flows is performed using a commercial process modeling software suite (MOLDFLOWRTM), exploiting a nearly exact analogy between the Larson-Doi model and a fiber orientation model that has been widely used in composites processing simulations. The modeling scheme is first verified by predicting many qualitative and quantitative features of molecular orientation distributions in isothermal extrusion-fed channel flows. In coordination with experiments, the model predictions are found to capture many qualitative features observed in injection molded plaques (including short shots). The final, stringent test of Larson-Doi model performance is prediction of in situ transient orientation data collected during mold filling. The model yields satisfactory results, though certain numerical approximations limit performance near the mold front.

Large-scale molecular dynamics simulation of DNA: implementation and validation of the AMBER98 force field in LAMMPS.

PubMed

Grindon, Christina; Harris, Sarah; Evans, Tom; Novik, Keir; Coveney, Peter; Laughton, Charles

2004-07-15

Molecular modelling played a central role in the discovery of the structure of DNA by Watson and Crick. Today, such modelling is done on computers: the more powerful these computers are, the more detailed and extensive can be the study of the dynamics of such biological macromolecules. To fully harness the power of modern massively parallel computers, however, we need to develop and deploy algorithms which can exploit the structure of such hardware. The Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) is a scalable molecular dynamics code including long-range Coulomb interactions, which has been specifically designed to function efficiently on parallel platforms. Here we describe the implementation of the AMBER98 force field in LAMMPS and its validation for molecular dynamics investigations of DNA structure and flexibility against the benchmark of results obtained with the long-established code AMBER6 (Assisted Model Building with Energy Refinement, version 6). Extended molecular dynamics simulations on the hydrated DNA dodecamer d(CTTTTGCAAAAG)(2), which has previously been the subject of extensive dynamical analysis using AMBER6, show that it is possible to obtain excellent agreement in terms of static, dynamic and thermodynamic parameters between AMBER6 and LAMMPS. In comparison with AMBER6, LAMMPS shows greatly improved scalability in massively parallel environments, opening up the possibility of efficient simulations of order-of-magnitude larger systems and/or for order-of-magnitude greater simulation times.

An Affective Neuroscience Framework for the Molecular Study of Internet Addiction.

PubMed

Montag, Christian; Sindermann, Cornelia; Becker, Benjamin; Panksepp, Jaak

2016-01-01

Internet addiction represents an emerging global health issue. Increasing efforts have been made to characterize risk factors for the development of Internet addiction and consequences of excessive Internet use. During the last years, classic research approaches from psychology considering personality variables as vulnerability factor, especially in conjunction with neuroscience approaches such as brain imaging, have led to coherent theoretical conceptualizations of Internet addiction. Although such conceptualizations can be valuable aid, the research field is currently lacking a comprehensive framework for determining brain-based and neurochemical markers of Internet addiction. The present work aims at providing a framework on the molecular level as a basis for future research on the neural and behavioral level, in order to facilitate a comprehensive neurobiological model of Internet addiction and its clinical symptomatology. To help establish such a molecular framework for the study of Internet addiction, we investigated in N = 680 participants associations between individual differences in tendencies toward Internet addiction measured by the Generalized Problematic Internet Use Scale-2 (GPIUS-2) and individual differences in primary emotional systems as assessed by the Affective Neuroscience Personality Scales (ANPS). Regression analysis revealed that the ANPS scales FEAR and SADNESS were the ANPS scales most robustly positively linked to several (sub)scales of the GPIUS-2. Also the scales SEEKING, CARE and PLAY explain variance in some of the GPIUS-2 subscales. As such, these scales are negatively linked to the GPIUS-2 subscales. As the ANPS has been constructed on substantial available brain data including an extensive molecular body with respect to evolutionary highly conserved emotional circuitry in the ancient mammalian brain, the present study gives first ideas on putative molecular mechanisms underlying different facets of Internet addiction as derived from associations between tendencies toward Internet addiction and individual differences in primary emotional systems. For example, as SADNESS is linked to the overall GPIUS-2 score, and the neuropeptide oxytocin is known to downregulate SADNESS, it is conceivable that the neuropeptide might play a role in Internet addition on the molecular level. Our findings provide a theoretical framework potentially illuminating the molecular underpinnings of Internet addiction. Finally, we also present data on the ANPS and smartphone addiction at the end of the paper. Similar to the reported associations between the ANPS and the GPIUS-2, these correlations might provide an initial outline for a framework guiding future studies that aim to address the molecular basis of smartphone addiction.

An Affective Neuroscience Framework for the Molecular Study of Internet Addiction

PubMed Central

Montag, Christian; Sindermann, Cornelia; Becker, Benjamin; Panksepp, Jaak

2016-01-01

Internet addiction represents an emerging global health issue. Increasing efforts have been made to characterize risk factors for the development of Internet addiction and consequences of excessive Internet use. During the last years, classic research approaches from psychology considering personality variables as vulnerability factor, especially in conjunction with neuroscience approaches such as brain imaging, have led to coherent theoretical conceptualizations of Internet addiction. Although such conceptualizations can be valuable aid, the research field is currently lacking a comprehensive framework for determining brain-based and neurochemical markers of Internet addiction. The present work aims at providing a framework on the molecular level as a basis for future research on the neural and behavioral level, in order to facilitate a comprehensive neurobiological model of Internet addiction and its clinical symptomatology. To help establish such a molecular framework for the study of Internet addiction, we investigated in N = 680 participants associations between individual differences in tendencies toward Internet addiction measured by the Generalized Problematic Internet Use Scale-2 (GPIUS-2) and individual differences in primary emotional systems as assessed by the Affective Neuroscience Personality Scales (ANPS). Regression analysis revealed that the ANPS scales FEAR and SADNESS were the ANPS scales most robustly positively linked to several (sub)scales of the GPIUS-2. Also the scales SEEKING, CARE and PLAY explain variance in some of the GPIUS-2 subscales. As such, these scales are negatively linked to the GPIUS-2 subscales. As the ANPS has been constructed on substantial available brain data including an extensive molecular body with respect to evolutionary highly conserved emotional circuitry in the ancient mammalian brain, the present study gives first ideas on putative molecular mechanisms underlying different facets of Internet addiction as derived from associations between tendencies toward Internet addiction and individual differences in primary emotional systems. For example, as SADNESS is linked to the overall GPIUS-2 score, and the neuropeptide oxytocin is known to downregulate SADNESS, it is conceivable that the neuropeptide might play a role in Internet addition on the molecular level. Our findings provide a theoretical framework potentially illuminating the molecular underpinnings of Internet addiction. Finally, we also present data on the ANPS and smartphone addiction at the end of the paper. Similar to the reported associations between the ANPS and the GPIUS-2, these correlations might provide an initial outline for a framework guiding future studies that aim to address the molecular basis of smartphone addiction. PMID:28018255

A comparative study of the extracellular glucosyl- and fructosyltransferases from cariogenic and non-cariogenic Streptococcus mutans strains of two different serotypes.

PubMed

Asem, K; Cornish-Bowden, A J; Cole, J A

1986-01-01

Extracellular proteins from continuous cultures of serotype c and g Streptococcus mutans strains were separated by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate. Gels stained with raffinose after electrophoresis revealed that although serotype c strains secrete two fructosyltransferases of molecular mass 68 kDa and 79 kDa, no fructosyltransferase was secreted by the serotype g strain K1. A sucrose activity stain was used to detect two glucosyltransferases (GTF) of molecular mass 162 kDa (bifunctional 1,6-alpha-D-glucan 3-alpha- and 6-alpha GTF or 'dextransucrase') and 153 kDa (a 1,3-alpha-D-glucan 3-alpha-GTF) in samples from cariogenic serotype c strains. Neither the 153 kDa protein nor the corresponding GTF activity was secreted by the non-cariogenic mutant C 67-25. The molecular masses of the corresponding 1,3-alpha and 1,6-alpha-GTF proteins from the serotype g strain K1 were 164 kDa and 158 kDa, respectively. All of the GTF proteins were degraded to discrete bands of lower molecular mass on storage at 4 degrees C even after extensive purification. The results provide an explanation for several outstanding controversies in the GTF literature.

Clinical and molecular investigation of 14 Japanese patients with complete TFP deficiency: a comparison with Caucasian cases.

PubMed

Bo, Ryosuke; Yamada, Kenji; Kobayashi, Hironori; Jamiyan, Purevsuren; Hasegawa, Yuki; Taketani, Takeshi; Fukuda, Seiji; Hata, Ikue; Niida, Yo; Shigematsu, Yosuke; Iijima, Kazumoto; Yamaguchi, Seiji

2017-09-01

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder of mitochondrial fatty-acid oxidation. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is often reported in Caucasian countries due to a common mutation. However, the molecular and clinical basis of complete TFP deficiency has not been extensively reported. In this study, 14 Japanese cases (13 families) with complete TFP deficiency, including 9 previously reported cases, were analyzed to clarify the clinical and molecular characteristics of TFP deficiency. The clinical types of the 14 patients were as follows: 12 cases of neonatal (n=7) or myopathic (n=5) types and 2 cases of intermediate type. Peripheral neuropathy was found in four cases and hypocalcemia due to hypoparathyroidism, which is rarely reported in Caucasian patients, had developed in four cases. Maternal hemolysis, elevated liver enzymes and low platelet count syndrome and acute fatty liver of pregnancy were noted in two and one mothers, respectively. Fourteen mutations were identified in 26 alleles in Japanese patients, including two novel mutations (HADHA: c.361C>T, and HADHA-HADHB: g.26233880_ 26248855del), although no common mutations were found. This study suggests that the molecular and clinical aspects of Japanese patients with TFP deficiencies differ from those of Caucasian patients.

Asynchronous Replica Exchange Software for Grid and Heterogeneous Computing.

PubMed

Gallicchio, Emilio; Xia, Junchao; Flynn, William F; Zhang, Baofeng; Samlalsingh, Sade; Mentes, Ahmet; Levy, Ronald M

2015-11-01

Parallel replica exchange sampling is an extended ensemble technique often used to accelerate the exploration of the conformational ensemble of atomistic molecular simulations of chemical systems. Inter-process communication and coordination requirements have historically discouraged the deployment of replica exchange on distributed and heterogeneous resources. Here we describe the architecture of a software (named ASyncRE) for performing asynchronous replica exchange molecular simulations on volunteered computing grids and heterogeneous high performance clusters. The asynchronous replica exchange algorithm on which the software is based avoids centralized synchronization steps and the need for direct communication between remote processes. It allows molecular dynamics threads to progress at different rates and enables parameter exchanges among arbitrary sets of replicas independently from other replicas. ASyncRE is written in Python following a modular design conducive to extensions to various replica exchange schemes and molecular dynamics engines. Applications of the software for the modeling of association equilibria of supramolecular and macromolecular complexes on BOINC campus computational grids and on the CPU/MIC heterogeneous hardware of the XSEDE Stampede supercomputer are illustrated. They show the ability of ASyncRE to utilize large grids of desktop computers running the Windows, MacOS, and/or Linux operating systems as well as collections of high performance heterogeneous hardware devices.

Phylogenomic and Molecular Demarcation of the Core Members of the Polyphyletic Pasteurellaceae Genera Actinobacillus, Haemophilus, and Pasteurella

PubMed Central

Naushad, Sohail; Adeolu, Mobolaji; Goel, Nisha; Khadka, Bijendra; Al-Dahwi, Aqeel; Gupta, Radhey S.

2015-01-01

The genera Actinobacillus, Haemophilus, and Pasteurella exhibit extensive polyphyletic branching in phylogenetic trees and do not represent coherent clusters of species. In this study, we have utilized molecular signatures identified through comparative genomic analyses in conjunction with genome based and multilocus sequence based phylogenetic analyses to clarify the phylogenetic and taxonomic boundary of these genera. We have identified large clusters of Actinobacillus, Haemophilus, and Pasteurella species which represent the “sensu stricto” members of these genera. We have identified 3, 7, and 6 conserved signature indels (CSIs), which are specifically shared by sensu stricto members of Actinobacillus, Haemophilus, and Pasteurella, respectively. We have also identified two different sets of CSIs that are unique characteristics of the pathogen containing genera Aggregatibacter and Mannheimia, respectively. It is now possible to demarcate the genera Actinobacillus sensu stricto, Haemophilus sensu stricto, and Pasteurella sensu stricto on the basis of discrete molecular signatures. The other members of the genera Actinobacillus, Haemophilus, and Pasteurella that do not fall within the “sensu stricto” clades and do not contain these molecular signatures should be reclassified as other genera. The CSIs identified here also provide useful diagnostic targets for the identification of current and novel members of the indicated genera. PMID:25821780

Determination of Ten Macrolide Drugs in Environmental Water Using Molecularly Imprinted Solid-Phase Extraction Coupled with Liquid Chromatography-Tandem Mass Spectrometry.

PubMed

Song, Xuqin; Zhou, Tong; Li, Jiufeng; Zhang, Meiyu; Xie, Jingmeng; He, Limin

2018-05-14

With the extensive application of antibiotics in livestock, their contamination of the aquatic environment has received more attention. Molecularly imprinted polymer (MIP), as an eco-friendly and durable solid-phase extraction material, has shown great potential for the separation and enrichment of antibiotics in water. This study aims at developing a practical and economical method based on molecularly imprinted solid phase extraction (MISPE) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneously detecting ten macrolide drugs in different sources of water samples. The MIP was synthesized by bulk polymerization using tylosin as the template and methacrylic acid as the functional monomer. The MIP exhibited a favorable load-bearing capacity for water (>90 mL), which is more than triple that of non-molecularly imprinted polymers (NIP). The mean recoveries of macrolides at four spiked concentration levels (limit of quantification, 40, 100, and 400 ng/L) were 62.6⁻100.9%, with intra-day and inter-day relative standard deviations below 12.6%. The limit of detection and limit of quantification were 1.0⁻15.0 ng/L and 3.0⁻40.0 ng/L, respectively. Finally, the proposed method was successfully applied to the analysis of real water samples.

Laser Optogalvanic Spectroscopy pf Neon and Argon in a Discharge Plasma and its Significance for Microgravity Combustion

NASA Technical Reports Server (NTRS)

Misra, Prabhakar; Haridass, C.; Major, H.

1999-01-01

A detailed study of combustion mechanisms in flames, employing laser-based diagnostics, has provided good knowledge and understanding of the physical phenomena, and led to better characterization of the dynamical and chemical combustion processes, both under low-gravity (in space) and normal gravity (in ground based facilities, e.g. drop towers). Laser induced fluorescence (LIF), laser-induced incandescence (LII) and LIF thermometry have been widely used to perform nonintrusive measurements and to better understand combustion phenomena. Laser optogalvanic (LOG) spectroscopy has well-established applications in ion mobility measurements, atomic and molecular spectroscopy, ionization rates, recombination rates, velocity measurements and as a combustion probe for trace element detection. Absorption spectra of atomic and molecular species in flames can be obtained via LOG spectroscopy by measuring the voltage and current changes induced by laser irradiation. There are different kinds of processes that contribute to a discharge current, namely: (1) electron impact ionization, (2) collisions among the excited atoms of the discharge species and (3) Penning ionization. In general, at higher discharge currents, the mechanism of electron impact ionization dominates over Penning ionization, whereby the latter is hardly noticeable. In a plasma, whenever the wavelength of a laser coincides with the absorption of an atomic or molecular species, the rate of ionization of the species momentarily increases or decreases due to laser-assisted acceleration of collisional ionization. Such a rate of change in the ionization is monitored as a variation in the transient current by inserting a high voltage electrode into the plasma. Optogalvanic spectroscopy in discharges has been useful for characterizing laser line-widths and for providing convenient calibration lines for tunable dye lasers in the ultraviolet, visible and infrared wavelength regions. Different kinds of quantitative information, such as the electron collisional ionization rate, can be extracted from the complex processes occurring within the discharge. In the optogalvanic effect (OGE), there is no problem of overlap from background emissions, and hence even weak signals can be detected with a high signal-to-noise ratio, which makes the optogalvanic effect sensitive enough to resolve vibrational changes in molecular bonds and differences in energy levels brought about by different electron spins. For calibration purposes, neon and argon gaseous discharges have been employed most extensively, because these gases are commonly used as buffer gases within hollow-cathode lamps and provide an acceptable density of calibration lines. In the present work, our main aim has been to understand the dominant physical processes responsible for the production of the OGE signal, based on the extensive time resolved optogalvanic waveforms recorded, and also to extract quantitative information on the rates of excited state collisional processes.

Middle molecules and small-molecular-weight proteins in ESRD: properties and strategies for their removal.

PubMed

Clark, William R; Winchester, James F

2003-10-01

Molecular weight has traditionally been the parameter most commonly used to classify uremic toxins, with a value of approximately 500 Da frequently used as a demarcation point below which the molecular weights of small nitrogenous waste products fall. This toxin group, the most extensively studied from a clinical perspective, is characterized by a high degree of water solubility and the absence of protein binding. However, uremia is mediated by the retention of a plethora of other compounds having characteristics that differ significantly from those of the previously mentioned group. As opposed to the relative homogeneity of the nitrogenous metabolite class, other uremic toxins collectively are a very heterogeneous group, not only with respect to molecular weight but also other characteristics, such as protein binding and hydrophobicity. A recently proposed classification scheme by the European Uraemic Toxin Work Group subdivides the remainder of molecules into 2 categories: protein-bound solutes and middle molecules. For the latter group, the Work Group proposes a molecular weight range (500-60,000 Da) that incorporates many toxins identified since the original middle molecule hypothesis, for which the upper molecular weight limit was approximately 2,000 Da. In fact, low-molecular-weight peptides and proteins (LMWPs) comprise nearly the entire middle molecule category in the new scheme. The purpose of this article is to provide an overview of the middle molecule class of uremic toxins, with the focus on LMWPs. A brief review of LMWP metabolism under conditions of normal (and in a few cases, abnormal) renal function will be presented. The physical characteristics of several LMWPs will also be presented, including molecular weight, conformation, and charge. Specific LMWPs to be covered will include beta 2-microglobulin, complement proteins (C3a and Factor D), leptin, and proinflammatory cytokines. The article will also include a discussion of the treatment-related factors influencing dialytic removal of middle molecules. Once these factors, which include membrane characteristics, protein-membrane interactions, and solute removal mechanisms, are discussed, an overview of the different therapeutic strategies used to enhance clearance of these compounds is provided.

TCGA analysis of adrenocortical carcinoma - TCGA

Cancer.gov

In the most comprehensive molecular characterization to date of adrenocortical carcinoma, a rare cancer of the adrenal cortex, researchers extensively analyzed 91 cases for alterations in the tumor genomes.

Developments in Molecular Recognition and Sensing at Interfaces

PubMed Central

Ariga, Katsuhiko; Hill, Jonathan P.; Endo, Hiroshi

2007-01-01

In biological systems, molecular recognition events occur mostly within interfacial environments such as at membrane surfaces, enzyme reaction sites, or at the interior of the DNA double helix. Investigation of molecular recognition at model interfaces provides great insights into biological phenomena. Molecular recognition at interfaces not only has relevance to biological systems but is also important for modern applications such as high sensitivity sensors. Selective binding of guest molecules in solution to host molecules located at solid surfaces is crucial for electronic or photonic detection of analyte substances. In response to these demands, molecular recognition at interfaces has been investigated extensively during the past two decades using Langmuir monolayers, self-assembled monolayers, and lipid assemblies as recognition media. In this review, advances of molecular recognition at interfaces are briefly summarized.

Inhibition of amyloid oligomerization into different supramolecular architectures by small molecules: mechanistic insights and design rules.

PubMed

Brahmachari, Sayanti; Paul, Ashim; Segal, Daniel; Gazit, Ehud

2017-05-01

Protein misfolding and aggregation have been associated with several human disorders, including Alzheimer's, Parkinson's and Huntington's diseases, as well as senile systemic amyloidosis and Type II diabetes. However, there is no current disease-modifying therapy available for the treatment of these disorders. In spite of extensive academic, pharmaceutical, medicinal and clinical research, a complete mechanistic model for this family of diseases is still lacking. In this review, we primarily discuss the different types of small molecular entities which have been used for the inhibition of the aggregation process of different amyloidogenic proteins under diseased conditions. These include small peptides, polyphenols, inositols, quinones and their derivatives, and metal chelator molecules. In recent years, these groups of molecules have been extensively studied using in vitro, in vivo and computational models to understand their mechanism of action and common structural features underlying the process of inhibition. A salient feature found to be instrumental in the process of inhibition is the balance between the aromatic unit that functions as the amyloid recognition unit and the hydrophilic amyloid breaker unit. The establishment of structure-function relationship for amyloid-modifying therapies by the various functional entities should serve as an important step toward the development of efficient therapeutics.

Sequence analysis of serum albumins reveals the molecular evolution of ligand recognition properties.

PubMed

Fanali, Gabriella; Ascenzi, Paolo; Bernardi, Giorgio; Fasano, Mauro

2012-01-01

Serum albumin (SA) is a circulating protein providing a depot and carrier for many endogenous and exogenous compounds. At least seven major binding sites have been identified by structural and functional investigations mainly in human SA. SA is conserved in vertebrates, with at least 49 entries in protein sequence databases. The multiple sequence analysis of this set of entries leads to the definition of a cladistic tree for the molecular evolution of SA orthologs in vertebrates, thus showing the clustering of the considered species, with lamprey SAs (Lethenteron japonicum and Petromyzon marinus) in a separate outgroup. Sequence analysis aimed at searching conserved domains revealed that most SA sequences are made up by three repeated domains (about 600 residues), as extensively characterized for human SA. On the contrary, lamprey SAs are giant proteins (about 1400 residues) comprising seven repeated domains. The phylogenetic analysis of the SA family reveals a stringent correlation with the taxonomic classification of the species available in sequence databases. A focused inspection of the sequences of ligand binding sites in SA revealed that in all sites most residues involved in ligand binding are conserved, although the versatility towards different ligands could be peculiar of higher organisms. Moreover, the analysis of molecular links between the different sites suggests that allosteric modulation mechanisms could be restricted to higher vertebrates.

Anesthetics mechanism on a DMPC lipid membrane model: Insights from molecular dynamics simulations.

PubMed

Saeedi, Marzieh; Lyubartsev, Alexander P; Jalili, Seifollah

2017-07-01

To provide insight into the molecular mechanisms of local anesthetic action, we have carried out an extensive investigation of two amide type local anesthetics, lidocaine and articaine in both charged and uncharged forms, interacting with DMPC lipid membrane. We have applied both standard molecular dynamics simulations and metadynamics simulations to provide a detailed description of the free energy landscape of anesthetics embedded in the lipid bilayer. The global minimum of the free energy surface (equilibrium position of anesthetics in the lipid membrane) occurred around 1nm of the bilayer center. The uncharged anesthetics show more affinity to bind to this region compared to the charged drugs. The binding free energy of uncharged lidocaine in the membrane (-30.3kJ/mol) is higher than uncharged articaine (-24.0kJ/mol), which is in good agreement with higher lipid solubility of lidocaine relative to the articaine. The octanol/water partition coefficient of uncharged drugs was also investigated using expanded ensemble simulations. In addition, complementary standard MD simulations were carried out to study the partitioning behavior of multiple anesthetics inside the lipid bilayer. The results obtained here are in line with previously reported simulations and suggest that the different forms of anesthetics induce different structural modifications in the lipid bilayer, which can provide new insights into their complex membrane translocation phenomena. Copyright © 2017 Elsevier B.V. All rights reserved.

A resource for functional profiling of noncoding RNA in the yeast Saccharomyces cerevisiae.

PubMed

Parker, Steven; Fraczek, Marcin G; Wu, Jian; Shamsah, Sara; Manousaki, Alkisti; Dungrattanalert, Kobchai; de Almeida, Rogerio Alves; Estrada-Rivadeneyra, Diego; Omara, Walid; Delneri, Daniela; O'Keefe, Raymond T

2017-08-01

Eukaryotic genomes are extensively transcribed, generating many different RNAs with no known function. We have constructed 1502 molecular barcoded ncRNA gene deletion strains encompassing 443 ncRNAs in the yeast Saccharomyces cerevisiae as tools for ncRNA functional analysis. This resource includes deletions of small nuclear RNAs (snRNAs), transfer RNAs (tRNAs), small nucleolar RNAs (snoRNAs), and other annotated ncRNAs as well as the more recently identified stable unannotated transcripts (SUTs) and cryptic unstable transcripts (CUTs) whose functions are largely unknown. Specifically, deletions have been constructed for ncRNAs found in the intergenic regions, not overlapping genes or their promoters (i.e., at least 200 bp minimum distance from the closest gene start codon). The deletion strains carry molecular barcodes designed to be complementary with the protein gene deletion collection enabling parallel analysis experiments. These strains will be useful for the numerous genomic and molecular techniques that utilize deletion strains, including genome-wide phenotypic screens under different growth conditions, pooled chemogenomic screens with drugs or chemicals, synthetic genetic array analysis to uncover novel genetic interactions, and synthetic dosage lethality screens to analyze gene dosage. Overall, we created a valuable resource for the RNA community and for future ncRNA research. © 2017 Parker et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Stress amplifies sex differences in primate prefrontal profiles of gene expression.

PubMed

Lee, Alex G; Hagenauer, Megan; Absher, Devin; Morrison, Kathleen E; Bale, Tracy L; Myers, Richard M; Watson, Stanley J; Akil, Huda; Schatzberg, Alan F; Lyons, David M

2017-11-02

Stress is a recognized risk factor for mood and anxiety disorders that occur more often in women than men. Prefrontal brain regions mediate stress coping, cognitive control, and emotion. Here, we investigate sex differences and stress effects on prefrontal cortical profiles of gene expression in squirrel monkey adults. Dorsolateral, ventrolateral, and ventromedial prefrontal cortical regions from 18 females and 12 males were collected after stress or no-stress treatment conditions. Gene expression profiles were acquired using HumanHT-12v4.0 Expression BeadChip arrays adapted for squirrel monkeys. Extensive variation between prefrontal cortical regions was discerned in the expression of numerous autosomal and sex chromosome genes. Robust sex differences were also identified across prefrontal cortical regions in the expression of mostly autosomal genes. Genes with increased expression in females compared to males were overrepresented in mitogen-activated protein kinase and neurotrophin signaling pathways. Many fewer genes with increased expression in males compared to females were discerned, and no molecular pathways were identified. Effect sizes for sex differences were greater in stress compared to no-stress conditions for ventromedial and ventrolateral prefrontal cortical regions but not dorsolateral prefrontal cortex. Stress amplifies sex differences in gene expression profiles for prefrontal cortical regions involved in stress coping and emotion regulation. Results suggest molecular targets for new treatments of stress disorders in human mental health.

Molecular phylogenetics of the gomphoid-phalloid fungi with an establishment of the new subclass Phallomycetidae and two new orders

Treesearch

Kentaro Hosaka; Scott T. Bates; Ross E. Beever; Michael A. Castellano; Wesley Colgan; Laura S. Dominguez; Eduardo R. Nouhra; Jozsef Geml; Admir J. Giachini; S. Ray Kenney; Nicholas B. Simpson; Joseph W. Spatafora; James M. Trappe

2006-01-01

Molecular phylogenetic analyses for the gomphoid-phalloid fungi were conducted based on the five gene dataset with extensive taxon sampling. The monophyly of the gomphoid-phalloid clade was strongly supported, and four well supported major subclades were recognized. Three of the four subclades were represented entirely by gastroid taxa, and only Gomphales contained...

Molecular simulations of lipid systems: Edge stability and structure in pure and mixed bilayers

NASA Astrophysics Data System (ADS)

Jiang, Yong

2007-12-01

Understanding the structural, mechanical and dynamical properties of lipid self-assembled systems is fundamental to understand the behavior of the cell membrane. This thesis has investigated the equilibrium properties of lipid systems with edge defects through various molecular simulation techniques. The overall goal of this study is to understand the free energy terms of the edges and to develop efficient methods to sample equilibrium distributions of mixed-lipid systems. In the first main part of my thesis, an atomistic molecular model is used to study lipid ribbon which has two edges on both sides. Details of the edge structures, such as area per lipid and tail torsional statistics are presented. Line tension, calculated from pressure tensor in MD simulation has good agreement with result from other sources. To further investigate edge properties on a longer timescale and larger length scale, we have applied a coarse-grained forcefield on mixed lipid systems and try to interpret the edge fluctuations in terms of free energy parameters such as line tension and bending modulus. We have identified two regimes with quite different edge behavior: a high line tension regime and a low line tension regime. The last part of this thesis focuses on a hybrid Molecular dynamics and Configurational-bias Monte Carlo (MCMD) simulation method in which molecules can change their type by growing and shrinking the terminal acyl united carbon atoms. A two-step extension of the MCMD method has been developed to allow for a larger difference in the components' tail lengths. Results agreed well with previous one-step mutation results for a mixture with a length difference of four carbons. The current method can efficiently sample mixtures with a length difference of eight carbons, with a small portion of lipids of intermediate tail length. Preliminary results are obtained for "bicelle"-type (DMPC/DHPC) ribbons.

The structure of people's hair.

PubMed

Yang, Fei-Chi; Zhang, Yuchen; Rheinstädter, Maikel C

2014-01-01

Hair is a filamentous biomaterial consisting mainly of proteins in particular keratin. The structure of human hair is well known: the medulla is a loosely packed, disordered region near the centre of the hair surrounded by the cortex, which contains the major part of the fibre mass, mainly consisting of keratin proteins and structural lipids. The cortex is surrounded by the cuticle, a layer of dead, overlapping cells forming a protective layer around the hair. The corresponding structures have been studied extensively using a variety of different techniques, such as light, electron and atomic force microscopes, and also X-ray diffraction. We were interested in the question how much the molecular hair structure differs from person to person, between male and female hair, hair of different appearances such as colour and waviness. We included hair from parent and child, identical and fraternal twins in the study to see if genetically similar hair would show similar structural features. The molecular structure of the hair samples was studied using high-resolution X-ray diffraction, which covers length scales from molecules up to the organization of secondary structures. Signals due to the coiled-coil phase of α-helical keratin proteins, intermediate keratin filaments in the cortex and from the lipid layers in the cell membrane complex were observed in the specimen of all individuals, with very small deviations. Despite the relatively small number of individuals (12) included in this study, some conclusions can be drawn. While the general features were observed in all individuals and the corresponding molecular structures were almost identical, additional signals were observed in some specimen and assigned to different types of lipids in the cell membrane complex. Genetics seem to play a role in this composition as identical patterns were observed in hair from father and daughter and identical twins, however, not for fraternal twins. Identification and characterization of these features is an important step towards the detection of abnormalities in the molecular structure of hair as a potential diagnostic tool for certain diseases.

Molecular Dynamics Simulations of the Temperature Induced Unfolding of Crambin Follow the Arrhenius Equation.

PubMed

Dalby, Andrew; Shamsir, Mohd Shahir

2015-01-01

Molecular dynamics simulations have been used extensively to model the folding and unfolding of proteins. The rates of folding and unfolding should follow the Arrhenius equation over a limited range of temperatures. This study shows that molecular dynamic simulations of the unfolding of crambin between 500K and 560K do follow the Arrhenius equation. They also show that while there is a large amount of variation between the simulations the average values for the rate show a very high degree of correlation.

Molecular Dynamics Simulations of the Temperature Induced Unfolding of Crambin Follow the Arrhenius Equation.

PubMed Central

Dalby, Andrew; Shamsir, Mohd Shahir

2015-01-01

Molecular dynamics simulations have been used extensively to model the folding and unfolding of proteins. The rates of folding and unfolding should follow the Arrhenius equation over a limited range of temperatures. This study shows that molecular dynamic simulations of the unfolding of crambin between 500K and 560K do follow the Arrhenius equation. They also show that while there is a large amount of variation between the simulations the average values for the rate show a very high degree of correlation. PMID:26539292

Game On, Science - How Video Game Technology May Help Biologists Tackle Visualization Challenges

PubMed Central

Da Silva, Franck; Empereur-mot, Charly; Chavent, Matthieu; Baaden, Marc

2013-01-01

The video games industry develops ever more advanced technologies to improve rendering, image quality, ergonomics and user experience of their creations providing very simple to use tools to design new games. In the molecular sciences, only a small number of experts with specialized know-how are able to design interactive visualization applications, typically static computer programs that cannot easily be modified. Are there lessons to be learned from video games? Could their technology help us explore new molecular graphics ideas and render graphics developments accessible to non-specialists? This approach points to an extension of open computer programs, not only providing access to the source code, but also delivering an easily modifiable and extensible scientific research tool. In this work, we will explore these questions using the Unity3D game engine to develop and prototype a biological network and molecular visualization application for subsequent use in research or education. We have compared several routines to represent spheres and links between them, using either built-in Unity3D features or our own implementation. These developments resulted in a stand-alone viewer capable of displaying molecular structures, surfaces, animated electrostatic field lines and biological networks with powerful, artistic and illustrative rendering methods. We consider this work as a proof of principle demonstrating that the functionalities of classical viewers and more advanced novel features could be implemented in substantially less time and with less development effort. Our prototype is easily modifiable and extensible and may serve others as starting point and platform for their developments. A webserver example, standalone versions for MacOS X, Linux and Windows, source code, screen shots, videos and documentation are available at the address: http://unitymol.sourceforge.net/. PMID:23483961

Molecular evolution of the CYP2D subfamily in primates: purifying selection on substrate recognition sites without the frequent or long-tract gene conversion.

PubMed

Yasukochi, Yoshiki; Satta, Yoko

2015-03-25

The human cytochrome P450 (CYP) 2D6 gene is a member of the CYP2D gene subfamily, along with the CYP2D7P and CYP2D8P pseudogenes. Although the CYP2D6 enzyme has been studied extensively because of its clinical importance, the evolution of the CYP2D subfamily has not yet been fully understood. Therefore, the goal of this study was to reveal the evolutionary process of the human drug metabolic system. Here, we investigate molecular evolution of the CYP2D subfamily in primates by comparing 14 CYP2D sequences from humans to New World monkey genomes. Window analysis and statistical tests revealed that entire genomic sequences of paralogous genes were extensively homogenized by gene conversion during molecular evolution of CYP2D genes in primates. A neighbor-joining tree based on genomic sequences at the nonsubstrate recognition sites showed that CYP2D6 and CYP2D8 genes were clustered together due to gene conversion. In contrast, a phylogenetic tree using amino acid sequences at substrate recognition sites did not cluster the CYP2D6 and CYP2D8 genes, suggesting that the functional constraint on substrate specificity is one of the causes for purifying selection at the substrate recognition sites. Our results suggest that the CYP2D gene subfamily in primates has evolved to maintain the regioselectivity for a substrate hydroxylation activity between individual enzymes, even though extensive gene conversion has occurred across CYP2D coding sequences. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Game on, science - how video game technology may help biologists tackle visualization challenges.

PubMed

Lv, Zhihan; Tek, Alex; Da Silva, Franck; Empereur-mot, Charly; Chavent, Matthieu; Baaden, Marc

2013-01-01

The video games industry develops ever more advanced technologies to improve rendering, image quality, ergonomics and user experience of their creations providing very simple to use tools to design new games. In the molecular sciences, only a small number of experts with specialized know-how are able to design interactive visualization applications, typically static computer programs that cannot easily be modified. Are there lessons to be learned from video games? Could their technology help us explore new molecular graphics ideas and render graphics developments accessible to non-specialists? This approach points to an extension of open computer programs, not only providing access to the source code, but also delivering an easily modifiable and extensible scientific research tool. In this work, we will explore these questions using the Unity3D game engine to develop and prototype a biological network and molecular visualization application for subsequent use in research or education. We have compared several routines to represent spheres and links between them, using either built-in Unity3D features or our own implementation. These developments resulted in a stand-alone viewer capable of displaying molecular structures, surfaces, animated electrostatic field lines and biological networks with powerful, artistic and illustrative rendering methods. We consider this work as a proof of principle demonstrating that the functionalities of classical viewers and more advanced novel features could be implemented in substantially less time and with less development effort. Our prototype is easily modifiable and extensible and may serve others as starting point and platform for their developments. A webserver example, standalone versions for MacOS X, Linux and Windows, source code, screen shots, videos and documentation are available at the address: http://unitymol.sourceforge.net/.

Molecular evolution tracks macroevolutionary transitions in Cetacea.

PubMed

McGowen, Michael R; Gatesy, John; Wildman, Derek E

2014-06-01

Cetacea (whales, dolphins, and porpoises) is a model group for investigating the molecular signature of macroevolutionary transitions. Recent research has begun to reveal the molecular underpinnings of the remarkable anatomical and behavioral transformation in this clade. This shift from terrestrial to aquatic environments is arguably the best-understood major morphological transition in vertebrate evolution. The ancestral body plan and physiology were extensively modified and, in many cases, these crucial changes are recorded in cetacean genomes. Recent studies have highlighted cetaceans as central to understanding adaptive molecular convergence and pseudogene formation. Here, we review current research in cetacean molecular evolution and the potential of Cetacea as a model for the study of other macroevolutionary transitions from a genomic perspective. Copyright © 2014 Elsevier Ltd. All rights reserved.

Plant Responses to Pathogen Attack: Small RNAs in Focus.

PubMed

Islam, Waqar; Noman, Ali; Qasim, Muhammad; Wang, Liande

2018-02-08

Small RNAs (sRNA) are a significant group of gene expression regulators for multiple biological processes in eukaryotes. In plants, many sRNA silencing pathways produce extensive array of sRNAs with specialized roles. The evidence on record advocates for the functions of sRNAs during plant microbe interactions. Host sRNAs are reckoned as mandatory elements of plant defense. sRNAs involved in plant defense processes via different pathways include both short interfering RNA (siRNA) and microRNA (miRNA) that actively regulate immunity in response to pathogenic attack via tackling pathogen-associated molecular patterns (PAMPs) and other effectors. In response to pathogen attack, plants protect themselves with the help of sRNA-dependent immune systems. That sRNA-mediated plant defense responses play a role during infections is an established fact. However, the regulations of several sRNAs still need extensive research. In this review, we discussed the topical advancements and findings relevant to pathogen attack and plant defense mediated by sRNAs. We attempted to point out diverse sRNAs as key defenders in plant systems. It is hoped that sRNAs would be exploited as a mainstream player to achieve food security by tackling different plant diseases.

Metagenomic assessment of the microbial diversity in ground pork products from markets in the North Central Region of South Korea.

PubMed

Koo, Ok-Kyung; Baker, Christopher A; Kim, Hyun-Jung; Park, Si Hong; Ricke, Steven C

2016-09-01

The purpose of this study was to characterize the microbial community in ground pork using molecular approaches. Forty six ground pork products were purchased from local stores in the north central area of South Korea. Aerobic plate counts varied 4.23 ± 5.14 × 10(5) CFU/g with the range between 5.00 × 10(3) and 1.85 × 10(6) CFU/g for ground pork samples. Four ground meat samples were further processed for metagenomic analysis. Pseudomonas species was the most relative abundant with a wide range occurring (1.72 to 77.7%) as part of the microbial genera in ground pork. Bacteria such as Carnobacterium, Yersinia, Photobacterium were also identified in ground pork. Despite the prominence of certain genera across all samples there was still extensive microbial diversity among ground pork products that originated from different slaughter houses and were processed in different markets. Such diversity indicates that designing interventions to extend shelf life may be hampered by the extensive variability in the microbial consortia associated with pork products. However, this diversity may be useful for developing microbial traceability signatures unique to a slaughter house or a particular market.

Plant Responses to Pathogen Attack: Small RNAs in Focus

PubMed Central

2018-01-01

Small RNAs (sRNA) are a significant group of gene expression regulators for multiple biological processes in eukaryotes. In plants, many sRNA silencing pathways produce extensive array of sRNAs with specialized roles. The evidence on record advocates for the functions of sRNAs during plant microbe interactions. Host sRNAs are reckoned as mandatory elements of plant defense. sRNAs involved in plant defense processes via different pathways include both short interfering RNA (siRNA) and microRNA (miRNA) that actively regulate immunity in response to pathogenic attack via tackling pathogen-associated molecular patterns (PAMPs) and other effectors. In response to pathogen attack, plants protect themselves with the help of sRNA-dependent immune systems. That sRNA-mediated plant defense responses play a role during infections is an established fact. However, the regulations of several sRNAs still need extensive research. In this review, we discussed the topical advancements and findings relevant to pathogen attack and plant defense mediated by sRNAs. We attempted to point out diverse sRNAs as key defenders in plant systems. It is hoped that sRNAs would be exploited as a mainstream player to achieve food security by tackling different plant diseases. PMID:29419801

Electrospray Ionization Mass Spectrometry: A Technique to Access the Information beyond the Molecular Weight of the Analyte

PubMed Central

Banerjee, Shibdas; Mazumdar, Shyamalava

2012-01-01

The Electrospray Ionization (ESI) is a soft ionization technique extensively used for production of gas phase ions (without fragmentation) of thermally labile large supramolecules. In the present review we have described the development of Electrospray Ionization mass spectrometry (ESI-MS) during the last 25 years in the study of various properties of different types of biological molecules. There have been extensive studies on the mechanism of formation of charged gaseous species by the ESI. Several groups have investigated the origin and implications of the multiple charge states of proteins observed in the ESI-mass spectra of the proteins. The charged analytes produced by ESI can be fragmented by activating them in the gas-phase, and thus tandem mass spectrometry has been developed, which provides very important insights on the structural properties of the molecule. The review will highlight recent developments and emerging directions in this fascinating area of research. PMID:22611397

Breakpoint structure of the Anopheles gambiae 2Rb chromosomal inversion.

PubMed

Lobo, Neil F; Sangaré, Djibril M; Regier, Allison A; Reidenbach, Kyanne R; Bretz, David A; Sharakhova, Maria V; Emrich, Scott J; Traore, Sekou F; Costantini, Carlo; Besansky, Nora J; Collins, Frank H

2010-10-25

Alternative arrangements of chromosome 2 inversions in Anopheles gambiae are important sources of population structure, and are associated with adaptation to environmental heterogeneity. The forces responsible for their origin and maintenance are incompletely understood. Molecular characterization of inversion breakpoints provides insight into how they arose, and provides the basis for development of molecular karyotyping methods useful in future studies. Sequence comparison of regions near the cytological breakpoints of 2Rb allowed the molecular delineation of breakpoint boundaries. Comparisons were made between the standard 2R+b arrangement in the An. gambiae PEST reference genome and the inverted 2Rb arrangements in the An. gambiae M and S genome assemblies. Sequence differences between alternative 2Rb arrangements were exploited in the design of a PCR diagnostic assay, which was evaluated against the known chromosomal banding pattern of laboratory colonies and field-collected samples from Mali and Cameroon. The breakpoints of the 7.55 Mb 2Rb inversion are flanked by extensive runs of the same short (72 bp) tandemly organized sequence, which was likely responsible for chromosomal breakage and rearrangement. Application of the molecular diagnostic assay suggested that 2Rb has a single common origin in An. gambiae and its sibling species, Anopheles arabiensis, and also that the standard arrangement (2R+b) may have arisen twice through breakpoint reuse. The molecular diagnostic was reliable when applied to laboratory colonies, but its accuracy was lower in natural populations. The complex repetitive sequence flanking the 2Rb breakpoint region may be prone to structural and sequence-level instability. The 2Rb molecular diagnostic has immediate application in studies based on laboratory colonies, but its usefulness in natural populations awaits development of complementary molecular tools.

Probing the folded state and mechanical unfolding pathways of T4 lysozyme using all-atom and coarse-grained molecular simulation

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

Zheng, Wenjun, E-mail: wjzheng@buffalo.edu; Glenn, Paul

2015-01-21

The Bacteriophage T4 Lysozyme (T4L) is a prototype modular protein comprised of an N-terminal and a C-domain domain, which was extensively studied to understand the folding/unfolding mechanism of modular proteins. To offer detailed structural and dynamic insights to the folded-state stability and the mechanical unfolding behaviors of T4L, we have performed extensive equilibrium and steered molecular dynamics simulations of both the wild-type (WT) and a circular permutation (CP) variant of T4L using all-atom and coarse-grained force fields. Our all-atom and coarse-grained simulations of the folded state have consistently found greater stability of the C-domain than the N-domain in isolation, whichmore » is in agreement with past thermostatic studies of T4L. While the all-atom simulation cannot fully explain the mechanical unfolding behaviors of the WT and the CP variant observed in an optical tweezers study, the coarse-grained simulations based on the Go model or a modified elastic network model (mENM) are in qualitative agreement with the experimental finding of greater unfolding cooperativity in the WT than the CP variant. Interestingly, the two coarse-grained models predict different structural mechanisms for the observed change in cooperativity between the WT and the CP variant—while the Go model predicts minor modification of the unfolding pathways by circular permutation (i.e., preserving the general order that the N-domain unfolds before the C-domain), the mENM predicts a dramatic change in unfolding pathways (e.g., different order of N/C-domain unfolding in the WT and the CP variant). Based on our simulations, we have analyzed the limitations of and the key differences between these models and offered testable predictions for future experiments to resolve the structural mechanism for cooperative folding/unfolding of T4L.« less

Production of extracellular fructans by Gluconobacter nephelii P1464.

PubMed

Semjonovs, P; Shakirova, L; Treimane, R; Shvirksts, K; Auzina, L; Cleenwerck, I; Zikmanis, P

2016-02-01

Bacterial extracellular fructans, known as levans, have potential applications in food, pharmaceutical and cosmetic industries and high fructan producing strains could contribute into the cost reduction and more extensive commercial usage of them. An acetic acid bacteria (AAB) isolate P1464 was obtained from the Microbial Strain Collection of Institute of Microbiology and Biotechnology, University of Latvia and identified as Gluconobacter nephelii by DNA-DNA hybridization and the formation of extracellular fructans by this strain was confirmed. Isolated extracellular fructose polymers were characterized using FT-IR spectroscopy and the structural features of fructan appeared as similar to the reference sample of bacterial levan. Molecular mass estimates showed that the isolated G. nephelii P1464 fructose polymer has a relatively small molecular weight (Mw 1122·939 ± 153·453 kDa) and a sizeable polydispersity (Mw/Mn = 21·57 ± 1·60), as compared with other AAB, which could promote their physiological activity, including the prebiotic effects. Obtained at different cultivation conditions characteristics of fructan production, including the biotechnological indices such as the productivity (Qp) and yield (Yp/s) ranging from 0·774 to 1·244 g l(-1)  h and from 0·181 to 0·436 g g(-1) , respectively, confirmed, that G. nephelii P1464 could be used as promising strain for commercial production of levan. Bacterial fructans, known as levans, have extensive options for practical usage, however, actually limited due to high production costs. Therefore, the searches for efficient producer strains should be an urgent task to reduce costs. This study is the first report on the formation of fructans by a novel strain of acetic acid bacteria (AAB) Gluconobacter nephelii P1464. Characteristics obtained at different cultivation conditions confirmed the operation of a competitive and perspective producer strain. Isolated extracellular fructans are characterized by a lower molecular weight as compared with other AAB which could promote their physiological activity, including the prebiotic effects. © 2015 The Society for Applied Microbiology.

Human neural crest cells display molecular and phenotypic hallmarks of stem cells

PubMed Central

Thomas, Sophie; Thomas, Marie; Wincker, Patrick; Babarit, Candice; Xu, Puting; Speer, Marcy C.; Munnich, Arnold; Lyonnet, Stanislas; Vekemans, Michel; Etchevers, Heather C.

2008-01-01

The fields of both developmental and stem cell biology explore how functionally distinct cell types arise from a self-renewing founder population. Multipotent, proliferative human neural crest cells (hNCC) develop toward the end of the first month of pregnancy. It is assumed that most differentiate after migrating throughout the organism, although in animal models neural crest stem cells reportedly persist in postnatal tissues. Molecular pathways leading over time from an invasive mesenchyme to differentiated progeny such as the dorsal root ganglion, the maxillary bone or the adrenal medulla are altered in many congenital diseases. To identify additional components of such pathways, we derived and maintained self-renewing hNCC lines from pharyngulas. We show that, unlike their animal counterparts, hNCC are able to self-renew ex vivo under feeder-free conditions. While cross species comparisons showed extensive overlap between human, mouse and avian NCC transcriptomes, some molecular cascades are only active in the human cells, correlating with phenotypic differences. Furthermore, we found that the global hNCC molecular profile is highly similar to that of pluripotent embryonic stem cells when compared with other stem cell populations or hNCC derivatives. The pluripotency markers NANOG, POU5F1 and SOX2 are also expressed by hNCC, and a small subset of transcripts can unambiguously identify hNCC among other cell types. The hNCC molecular profile is thus both unique and globally characteristic of uncommitted stem cells. PMID:18689800

Molecular detection of trophic links in a complex insect host-parasitoid food web.

PubMed

Hrcek, Jan; Miller, Scott E; Quicke, Donald L J; Smith, M Alex

2011-09-01

Previously, host-parasitoid links have been unveiled almost exclusively by time-intensive rearing, while molecular methods were used only in simple agricultural host-parasitoid systems in the form of species-specific primers. Here, we present a general method for the molecular detection of these links applied to a complex caterpillar-parasitoid food web from tropical rainforest of Papua New Guinea. We DNA barcoded hosts, parasitoids and their tissue remnants and matched the sequences to our extensive library of local species. We were thus able to match 87% of host sequences and 36% of parasitoid sequences to species and infer subfamily or family in almost all cases. Our analysis affirmed 93 hitherto unknown trophic links between 37 host species from a wide range of Lepidoptera families and 46 parasitoid species from Hymenoptera and Diptera by identifying DNA sequences for both the host and the parasitoid involved in the interaction. Molecular detection proved especially useful in cases where distinguishing host species in caterpillar stage was difficult morphologically, or when the caterpillar died during rearing. We have even detected a case of extreme parasitoid specialization in a pair of Choreutis species that do not differ in caterpillar morphology and ecology. Using the molecular approach outlined here leads to better understanding of parasitoid host specificity, opens new possibilities for rapid surveys of food web structure and allows inference of species associations not already anticipated. Published 2011. This article is a US Government work and is in the public domain in the USA.

The Quest for Molecular Regulation Underlying Unisexual Flower Development

PubMed Central

Sobral, Rómulo; Silva, Helena G.; Morais-Cecílio, Leonor; Costa, Maria M. R.

2016-01-01

The understanding of the molecular mechanisms responsible for the making of a unisexual flower has been a long-standing quest in plant biology. Plants with male and female flowers can be divided mainly into two categories: dioecious and monoecious, and both sexual systems co-exist in nature in ca of 10% of the angiosperms. The establishment of male and female traits has been extensively described in a hermaphroditic flower and requires the interplay of networks, directly and indirectly related to the floral organ identity genes including hormonal regulators, transcription factors, microRNAs, and chromatin-modifying proteins. Recent transcriptomic studies have been uncovering the molecular processes underlying the establishment of unisexual flowers and there are many parallelisms between monoecious, dioecious, and hermaphroditic individuals. Here, we review the paper entitled “Comparative transcriptomic analysis of male and female flowers of monoecious Quercus suber” published in 2014 in the Frontiers of Plant Science (volume 5 |Article 599) and discussed it in the context of recent studies with other dioecious and monoecious plants that utilized high-throughput platforms to obtain transcriptomic profiles of male and female unisexual flowers. In some unisexual flowers, the developmental programs that control organ initiation fail and male or female organs do not form, whereas in other species, organ initiation and development occur but they abort or arrest during different species-specific stages of differentiation. Therefore, a direct comparison of the pathways responsible for the establishment of unisexual flowers in different species are likely to reveal conserved modules of gene regulatory hubs involved in stamen or carpel development, as well as differences that reflect the different stages of development in which male and/or female organ arrest or loss-of-function occurs. PMID:26925078

Adoption of lean principles in a high-volume molecular diagnostic microbiology laboratory.

PubMed

Mitchell, P Shawn; Mandrekar, Jayawant N; Yao, Joseph D C

2014-07-01

Clinical laboratories are constantly facing challenges to do more with less, enhance quality, improve test turnaround time, and reduce operational expenses. Experience with adopting and applying lean concepts and tools used extensively in the manufacturing industry is described for a high-volume clinical molecular microbiology laboratory, illustrating how operational success and benefits can be achieved. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Molecular systematics of terraranas (Anura: Brachycephaloidea) with an assessment of the effects of alignment and optimality criteria.

PubMed

Padial, José M; Grant, Taran; Frost, Darrel R

2014-06-26

Brachycephaloidea is a monophyletic group of frogs with more than 1000 species distributed throughout the New World tropics, subtropics, and Andean regions. Recently, the group has been the target of multiple molecular phylogenetic analyses, resulting in extensive changes in its taxonomy. Here, we test previous hypotheses of phylogenetic relationships for the group by combining available molecular evidence (sequences of 22 genes representing 431 ingroup and 25 outgroup terminals) and performing a tree-alignment analysis under the parsimony optimality criterion using the program POY. To elucidate the effects of alignment and optimality criterion on phylogenetic inferences, we also used the program MAFFT to obtain a similarity-alignment for analysis under both parsimony and maximum likelihood using the programs TNT and GARLI, respectively. Although all three analytical approaches agreed on numerous points, there was also extensive disagreement. Tree-alignment under parsimony supported the monophyly of the ingroup and the sister group relationship of the monophyletic marsupial frogs (Hemiphractidae), while maximum likelihood and parsimony analyses of the MAFFT similarity-alignment did not. All three methods differed with respect to the position of Ceuthomantis smaragdinus (Ceuthomantidae), with tree-alignment using parsimony recovering this species as the sister of Pristimantis + Yunganastes. All analyses rejected the monophyly of Strabomantidae and Strabomantinae as originally defined, and the tree-alignment analysis under parsimony further rejected the recently redefined Craugastoridae and Pristimantinae. Despite the greater emphasis in the systematics literature placed on the choice of optimality criterion for evaluating trees than on the choice of method for aligning DNA sequences, we found that the topological differences attributable to the alignment method were as great as those caused by the optimality criterion. Further, the optimal tree-alignment indicates that insertions and deletions occurred in twice as many aligned positions as implied by the optimal similarity-alignment, confirming previous findings that sequence turnover through insertion and deletion events plays a greater role in molecular evolution than indicated by similarity-alignments. Our results also provide a clear empirical demonstration of the different effects of wildcard taxa produced by missing data in parsimony and maximum likelihood analyses. Specifically, maximum likelihood analyses consistently (81% bootstrap frequency) provided spurious resolution despite a lack of evidence, whereas parsimony correctly depicted the ambiguity due to missing data by collapsing unsupported nodes. We provide a new taxonomy for the group that retains previously recognized Linnaean taxa except for Ceuthomantidae, Strabomantidae, and Strabomantinae. A phenotypically diagnosable superfamily is recognized formally as Brachycephaloidea, with the informal, unranked name terrarana retained as the standard common name for these frogs. We recognize three families within Brachycephaloidea that are currently diagnosable solely on molecular grounds (Brachycephalidae, Craugastoridae, and Eleutherodactylidae), as well as five subfamilies (Craugastorinae, Eleutherodactylinae, Holoadeninae, Phyzelaphryninae, and Pristimantinae) corresponding in large part to previous families and subfamilies. Our analyses upheld the monophyly of all tested genera, but we found numerous subgeneric taxa to be non-monophyletic and modified the taxonomy accordingly.

Gap compression/extension mechanism of bacterial flagellar hook as the molecular universal joint.

PubMed

Furuta, Tadaomi; Samatey, Fadel A; Matsunami, Hideyuki; Imada, Katsumi; Namba, Keiichi; Kitao, Akio

2007-03-01

Bacterial flagellar hook acts as a molecular universal joint, transmitting torque produced by the flagellar basal body, a rotary motor, to the flagellar filament. The hook forms polymorphic supercoil structures and can be considered as an assembly of 11 circularly arranged protofilaments. We investigated the molecular mechanism of the universal joint function of the hook by a approximately two-million-atom molecular dynamics simulation. On the inner side of the supercoil, protein subunits are highly packed along the protofilament and no gaps remain for further compression, whereas subunits are slightly separated and are hydrogen bonded through one layer of water molecules on the outer side. As for the intersubunit interactions between protofilaments, subunits are packed along the 6-start helix in a left-handed supercoil whereas they are highly packed along the 5-start helix in a right-handed supercoil. We conclude that the supercoiled structures of the hook in the left- and right-handed forms make maximal use of the gaps between subunits, which we call "gap compression/extension mechanism". Mutual sliding of subunits at the subunit interface accompanying rearrangements of intersubunit hydrogen bonds is interpreted as a mechanism to allow continuous structural change of the hook during flagellar rotation at low energy cost.

Molecular dynamics simulations reveal the conformational dynamics of Arabidopsis thaliana BRI1 and BAK1 receptor-like kinases.

PubMed

Moffett, Alexander S; Bender, Kyle W; Huber, Steven C; Shukla, Diwakar

2017-07-28

The structural motifs responsible for activation and regulation of eukaryotic protein kinases in animals have been studied extensively in recent years, and a coherent picture of their activation mechanisms has begun to emerge. In contrast, non-animal eukaryotic protein kinases are not as well understood from a structural perspective, representing a large knowledge gap. To this end, we investigated the conformational dynamics of two key Arabidopsis thaliana receptor-like kinases, brassinosteroid-insensitive 1 (BRI1) and BRI1-associated kinase 1 (BAK1), through extensive molecular dynamics simulations of their fully phosphorylated kinase domains. Molecular dynamics simulations calculate the motion of each atom in a protein based on classical approximations of interatomic forces, giving researchers insight into protein function at unparalleled spatial and temporal resolutions. We found that in an otherwise "active" BAK1 the αC helix is highly disordered, a hallmark of deactivation, whereas the BRI1 αC helix is moderately disordered and displays swinging behavior similar to numerous animal kinases. An analysis of all known sequences in the A. thaliana kinome found that αC helix disorder may be a common feature of plant kinases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Synthesis and Characterization of a Magnetically Active 19F Molecular Beacon.

PubMed

Dempsey, Megan E; Marble, Hetal D; Shen, Tun-Li; Fawzi, Nicolas L; Darling, Eric M

2018-02-21

Gene expression is used extensively to describe cellular characteristics and behaviors; however, most methods of assessing gene expression are unsuitable for living samples, requiring destructive processes such as fixation or lysis. Recently, molecular beacons have become a viable tool for live-cell imaging of mRNA molecules in situ. Historically, beacon-mediated imaging has been limited to fluorescence-based approaches. We propose the design and synthesis of a novel molecular beacon for magnetic resonance detection of any desired target nucleotide sequence. The biologically compatible synthesis incorporates commonly used bioconjugation reactions in aqueous conditions and is accessible for laboratories without extensive synthesis capabilities. The resulting beacon uses fluorine ( 19 F) as a reporter, which is broadened, or turned "off", via paramagnetic relaxation enhancement from a stabilized nitroxide radical spin label when the beacon is not bound to its nucleic acid target. Therefore, the 19 F NMR signal of the beacon is quenched in its hairpin conformation when the spin label and the 19 F substituent are held in proximity, but the signal is recovered upon beacon hybridization to its specific complementary nucleotide sequence by physical separation of the radical from the 19 F reporter. This study establishes a path for magnetic resonance-based assessment of specific mRNA expression, providing new possibilities for applying molecular beacon technology in living systems.

Methods for the Study of Gonadal Development.

PubMed

Piprek, Rafal P

2016-01-01

Current knowledge on gonadal development and sex determination is the product of many decades of research involving a variety of scientific methods from different biological disciplines such as histology, genetics, biochemistry, and molecular biology. The earliest embryological investigations, followed by the invention of microscopy and staining methods, were based on histological examinations. The most robust development of histological staining techniques occurred in the second half of the nineteenth century and resulted in structural descriptions of gonadogenesis. These first studies on gonadal development were conducted on domesticated animals; however, currently the mouse is the most extensively studied species. The next key point in the study of gonadogenesis was the advancement of methods allowing for the in vitro culture of fetal gonads. For instance, this led to the description of the origin of cell lines forming the gonads. Protein detection using antibodies and immunolabeling methods and the use of reporter genes were also invaluable for developmental studies, enabling the visualization of the formation of gonadal structure. Recently, genetic and molecular biology techniques, especially gene expression analysis, have revolutionized studies on gonadogenesis and have provided insight into the molecular mechanisms that govern this process. The successive invention of new methods is reflected in the progress of research on gonadal development.

Nature and magnitude of aromatic base stacking in DNA and RNA: Quantum chemistry, molecular mechanics, and experiment.

PubMed

Sponer, Jiří; Sponer, Judit E; Mládek, Arnošt; Jurečka, Petr; Banáš, Pavel; Otyepka, Michal

2013-12-01

Base stacking is a major interaction shaping up and stabilizing nucleic acids. During the last decades, base stacking has been extensively studied by experimental and theoretical methods. Advanced quantum-chemical calculations clarified that base stacking is a common interaction, which in the first approximation can be described as combination of the three most basic contributions to molecular interactions, namely, electrostatic interaction, London dispersion attraction and short-range repulsion. There is not any specific π-π energy term associated with the delocalized π electrons of the aromatic rings that cannot be described by the mentioned contributions. The base stacking can be rather reasonably approximated by simple molecular simulation methods based on well-calibrated common force fields although the force fields do not include nonadditivity of stacking, anisotropy of dispersion interactions, and some other effects. However, description of stacking association in condensed phase and understanding of the stacking role in biomolecules remain a difficult problem, as the net base stacking forces always act in a complex and context-specific environment. Moreover, the stacking forces are balanced with many other energy contributions. Differences in definition of stacking in experimental and theoretical studies are explained. Copyright © 2013 Wiley Periodicals, Inc.

Model systems for single molecule polymer dynamics

PubMed Central

Latinwo, Folarin

2012-01-01

Double stranded DNA (dsDNA) has long served as a model system for single molecule polymer dynamics. However, dsDNA is a semiflexible polymer, and the structural rigidity of the DNA double helix gives rise to local molecular properties and chain dynamics that differ from flexible chains, including synthetic organic polymers. Recently, we developed single stranded DNA (ssDNA) as a new model system for single molecule studies of flexible polymer chains. In this work, we discuss model polymer systems in the context of “ideal” and “real” chain behavior considering thermal blobs, tension blobs, hydrodynamic drag and force–extension relations. In addition, we present monomer aspect ratio as a key parameter describing chain conformation and dynamics, and we derive dynamical scaling relations in terms of this molecular-level parameter. We show that asymmetric Kuhn segments can suppress monomer–monomer interactions, thereby altering global chain dynamics. Finally, we discuss ssDNA in the context of a new model system for single molecule polymer dynamics. Overall, we anticipate that future single polymer studies of flexible chains will reveal new insight into the dynamic behavior of “real” polymers, which will highlight the importance of molecular individualism and the prevalence of non-linear phenomena. PMID:22956980

Modeling Molecular and Cellular Aspects of Human Disease using the Nematode Caenorhabditis elegans

PubMed Central

Silverman, Gary A.; Luke, Cliff J.; Bhatia, Sangeeta R.; Long, Olivia S.; Vetica, Anne C.; Perlmutter, David H.; Pak, Stephen C.

2009-01-01

As an experimental system, Caenorhabditis elegans, offers a unique opportunity to interrogate in vivo the genetic and molecular functions of human disease-related genes. For example, C. elegans has provided crucial insights into fundamental biological processes such as cell death and cell fate determinations, as well as pathological processes such as neurodegeneration and microbial susceptibility. The C. elegans model has several distinct advantages including a completely sequenced genome that shares extensive homology with that of mammals, ease of cultivation and storage, a relatively short lifespan and techniques for generating null and transgenic animals. However, the ability to conduct unbiased forward and reverse genetic screens in C. elegans remains one of the most powerful experimental paradigms for discovering the biochemical pathways underlying human disease phenotypes. The identification of these pathways leads to a better understanding of the molecular interactions that perturb cellular physiology, and forms the foundation for designing mechanism-based therapies. To this end, the ability to process large numbers of isogenic animals through automated work stations suggests that C. elegans, manifesting different aspects of human disease phenotypes, will become the platform of choice for in vivo drug discovery and target validation using high-throughput/content screening technologies. PMID:18852689

Identifying Novel Molecular Structures for Advanced Melanoma by Ligand-Based Virtual Screening

PubMed Central

Wang, Zhao; Lu, Yan; Seibel, William; Miller, Duane D.; Li, Wei

2009-01-01

We recently discovered a new class of thiazole analogs that are highly potent against melanoma cells. To expand the structure-activity relationship study and to explore potential new molecular scaffolds, we performed extensive ligand-based virtual screening against a compound library containing 342,910 small molecules. Two different approaches of virtual screening were carried out using the structure of our lead molecule: 1) connectivity-based search using Scitegic Pipeline Pilot from Accelerys and 2) molecular shape similarity search using Schrodinger software. Using a testing compound library, both approaches can rank similar compounds very high and rank dissimilar compounds very low, thus validating our screening methods. Structures identified from these searches were analyzed, and selected compounds were tested in vitro to assess their activity against melanoma cancer cell lines. Several molecules showed good anticancer activity. While none of the identified compounds showed better activity than our lead compound, they provided important insight into structural modifications for our lead compound and also provided novel platforms on which we can optimize new classes of anticancer compounds. One of the newly synthesized analogs based on this virtual screening has improved potency and selectivity against melanoma. PMID:19445498

Ubiquitin dynamics in complexes reveal molecular recognition mechanisms beyond induced fit and conformational selection.

PubMed

Peters, Jan H; de Groot, Bert L

2012-01-01

Protein-protein interactions play an important role in all biological processes. However, the principles underlying these interactions are only beginning to be understood. Ubiquitin is a small signalling protein that is covalently attached to different proteins to mark them for degradation, regulate transport and other functions. As such, it interacts with and is recognised by a multitude of other proteins. We have conducted molecular dynamics simulations of ubiquitin in complex with 11 different binding partners on a microsecond timescale and compared them with ensembles of unbound ubiquitin to investigate the principles of their interaction and determine the influence of complex formation on the dynamic properties of this protein. Along the main mode of fluctuation of ubiquitin, binding in most cases reduces the conformational space available to ubiquitin to a subspace of that covered by unbound ubiquitin. This behaviour can be well explained using the model of conformational selection. For lower amplitude collective modes, a spectrum of zero to almost complete coverage of bound by unbound ensembles was observed. The significant differences between bound and unbound structures are exclusively situated at the binding interface. Overall, the findings correspond neither to a complete conformational selection nor induced fit scenario. Instead, we introduce a model of conformational restriction, extension and shift, which describes the full range of observed effects.

Differential identity of Filopodia and Tunneling Nanotubes revealed by the opposite functions of actin regulatory complexes.

PubMed

Delage, Elise; Cervantes, Diégo Cordero; Pénard, Esthel; Schmitt, Christine; Syan, Sylvie; Disanza, Andrea; Scita, Giorgio; Zurzolo, Chiara

2016-12-23

Tunneling Nanotubes (TNTs) are actin enriched filopodia-like protrusions that play a pivotal role in long-range intercellular communication. Different pathogens use TNT-like structures as "freeways" to propagate across cells. TNTs are also implicated in cancer and neurodegenerative diseases, making them promising therapeutic targets. Understanding the mechanism of their formation, and their relation with filopodia is of fundamental importance to uncover their physiological function, particularly since filopodia, differently from TNTs, are not able to mediate transfer of cargo between distant cells. Here we studied different regulatory complexes of actin, which play a role in the formation of both these structures. We demonstrate that the filopodia-promoting CDC42/IRSp53/VASP network negatively regulates TNT formation and impairs TNT-mediated intercellular vesicle transfer. Conversely, elevation of Eps8, an actin regulatory protein that inhibits the extension of filopodia in neurons, increases TNT formation. Notably, Eps8-mediated TNT induction requires Eps8 bundling but not its capping activity. Thus, despite their structural similarities, filopodia and TNTs form through distinct molecular mechanisms. Our results further suggest that a switch in the molecular composition in common actin regulatory complexes is critical in driving the formation of either type of membrane protrusion.

Role of Prion Replication in the Strain-dependent Brain Regional Distribution of Prions*

PubMed Central

Hu, Ping Ping; Morales, Rodrigo; Duran-Aniotz, Claudia; Moreno-Gonzalez, Ines; Khan, Uffaf; Soto, Claudio

2016-01-01

One intriguing feature of prion diseases is their strain variation. Prion strains are differentiated by the clinical consequences they generate in the host, their biochemical properties, and their potential to infect other animal species. The selective targeting of these agents to specific brain structures have been extensively used to characterize prion strains. However, the molecular basis dictating strain-specific neurotropism are still elusive. In this study, isolated brain structures from animals infected with four hamster prion strains (HY, DY, 139H, and SSLOW) were analyzed for their content of protease-resistant PrPSc. Our data show that these strains have different profiles of PrP deposition along the brain. These patterns of accumulation, which were independent of regional PrPC production, were not reproduced by in vitro replication when different brain regions were used as substrate for the misfolding-amplification reaction. On the contrary, our results show that in vitro replication efficiency depended exclusively on the amount of PrPC present in each part of the brain. Our results suggest that the variable regional distribution of PrPSc in distinct strains is not determined by differences on prion formation, but on other factors or cellular pathways. Our findings may contribute to understand the molecular mechanisms of prion pathogenesis and strain diversity. PMID:27056328

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

Lindsay, E.A.; Grillo, A.; Ferrero, G.B.

The microphthalmia with linear skin defects (MLS) syndrome (MIM309801) is a severe developmental disorder observed in XX individuals with distal Xp segmental monosomy. The phenotype of this syndrome overlaps with that of both Aicardi (MIM 305050) and Goltz (MIM 305600) syndromes, two X-linked dominant, male-lethal disorders. Here the authors report the clinical, cytogenetic, and molecular characterization of 3 patients with this syndrome. Two of these patients are females with a terminal Xpter-p22.2 deletion. One of these 2 patients had an aborted fetus with anencephaly and the same chromosome abnormality. The third patient is an XX male with Xp/Yp exchange spanningmore » the SRY gene which results in distal Xp monosomy. The extensive clinical variability observed in these patients and the results of the molecular analysis suggest that X-inactivation plays an important role in determining the phenotype of the MLS syndrome. The authors propose that the MLS, Aicardi, and Goltz syndromes are due to the involvement of the same gene(s), and that different patterns of X-inactivation are responsible for the phenotypic differences observed in these 3 disorders. However, they cannot rule out that each component of the MLS phenotype is caused by deletion of a different gene (a contiguous gene syndrome). 24 refs., 4 figs., 1 tab.« less

Theoretical Study of pKa Values for Trivalent Rare-Earth Metal Cations in Aqueous Solution.

PubMed

Yu, Donghai; Du, Ruobing; Xiao, Ji-Chang; Xu, Shengming; Rong, Chunying; Liu, Shubin

2018-01-18

Molecular acidity of trivalent rare-earth metal cations in aqueous solution is an important factor dedicated to the efficiency of their extraction and separation processes. In this work, the aqueous acidity of these metal ions has been quantitatively investigated using a few theoretical approaches. Our computational results expressed in terms of pK a values agree well with the tetrad effect of trivalent rare-earth ions extensively reported in the extraction and separation of these elements. Strong linear relationships have been observed between the acidity and quantum electronic descriptors such as the molecular electrostatic potential on the acidic nucleus and the sum of the valence natural atomic orbitals energies of the dissociating proton. Making use of the predicted pK a values, we have also predicted the major ionic forms of these species in the aqueous environment with different pH values, which can be employed to rationalize the behavior difference of different rare-earth metal cations during the extraction process. Our present results should provide needed insights not only for the qualitatively understanding about the extraction and separation between yttrium and lanthanide elements but also for the prediction of novel and more efficient rare-earth metal extractants in the future.

Evidences of local adaptation in quantitative traits in Prosopis alba (Leguminosae).

PubMed

Bessega, C; Pometti, C; Ewens, M; Saidman, B O; Vilardi, J C

2015-02-01

Signals of selection on quantitative traits can be detected by the comparison between the genetic differentiation of molecular (neutral) markers and quantitative traits, by multivariate extensions of the same model and by the observation of the additive covariance among relatives. We studied, by three different tests, signals of occurrence of selection in Prosopis alba populations over 15 quantitative traits: three economically important life history traits: height, basal diameter and biomass, 11 leaf morphology traits that may be related with heat-tolerance and physiological responses and spine length that is very important from silvicultural purposes. We analyzed 172 G1-generation trees growing in a common garden belonging to 32 open pollinated families from eight sampling sites in Argentina. The multivariate phenotypes differ significantly among origins, and the highest differentiation corresponded to foliar traits. Molecular genetic markers (SSR) exhibited significant differentiation and allowed us to provide convincing evidence that natural selection is responsible for the patterns of morphological differentiation. The heterogeneous selection over phenotypic traits observed suggested different optima in each population and has important implications for gene resource management. The results suggest that the adaptive significance of traits should be considered together with population provenance in breeding program as a crucial point prior to any selecting program, especially in Prosopis where the first steps are under development.

Chimeras of channelrhodopsin-1 and -2 from Chlamydomonas reinhardtii exhibit distinctive light-induced structural changes from channelrhodopsin-2.

PubMed

Inaguma, Asumi; Tsukamoto, Hisao; Kato, Hideaki E; Kimura, Tetsunari; Ishizuka, Toru; Oishi, Satomi; Yawo, Hiromu; Nureki, Osamu; Furutani, Yuji

2015-05-01

Channelrhodopsin-2 (ChR2) from the green alga Chlamydomonas reinhardtii functions as a light-gated cation channel that has been developed as an optogenetic tool to stimulate specific nerve cells in animals and control their behavior by illumination. The molecular mechanism of ChR2 has been extensively studied by a variety of spectroscopic methods, including light-induced difference Fourier transform infrared (FTIR) spectroscopy, which is sensitive to structural changes in the protein upon light activation. An atomic structure of channelrhodopsin was recently determined by x-ray crystallography using a chimera of channelrhodopsin-1 (ChR1) and ChR2. Electrophysiological studies have shown that ChR1/ChR2 chimeras are less desensitized upon continuous illumination than native ChR2, implying that there are some structural differences between ChR2 and chimeras. In this study, we applied light-induced difference FTIR spectroscopy to ChR2 and ChR1/ChR2 chimeras to determine the molecular basis underlying these functional differences. Upon continuous illumination, ChR1/ChR2 chimeras exhibited structural changes distinct from those in ChR2. In particular, the protonation state of a glutamate residue, Glu-129 (Glu-90 in ChR2 numbering), in the ChR chimeras is not changed as dramatically as in ChR2. Moreover, using mutants stabilizing particular photointermediates as well as time-resolved measurements, we identified some differences between the major photointermediates of ChR2 and ChR1/ChR2 chimeras. Taken together, our data indicate that the gating and desensitizing processes in ChR1/ChR2 chimeras are different from those in ChR2 and that these differences should be considered in the rational design of new optogenetic tools based on channelrhodopsins. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Unusual Structure and Magnetism in MnO Nanoclusters

NASA Astrophysics Data System (ADS)

Ganguly, Shreemoyee; Kabir, Mukul; Sanyal, Biplab; Mookerjee, Abhijit

2011-03-01

We report an unusual structural and magnetic evolution in stoichiometric MnO nanoclusters by an extensive and unbiased search through the potential energy surface within density functional theory. The (MnO)n nanoclusters adopt two-dimensional structures in size ranges in which Mnn nanoclusters are three-dimensional and regardless of the size of the nanocluster, the magnetic coupling is found to be antiferromagnetic, and is strikingly different from Mn-based molecular magnets. Both of these features are explained through the inherent electronic structures of the nanoclusters. We gratefully acknowledge financial support from Swedish Research Links program funded by VR/SIDA and Carl Tryggers Foundation, Sweden.

"Group IV Nanomembranes, Nanoribbons, and Quantum Dots: Processing, Characterization, and Novel Devices"

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

liu, feng

This theoretical project has been carried out in close interaction with the experimental project at UW-Madison under the same title led by PI Max Lagally and co-PI Mark Eriksson. Extensive computational studies have been performed to address a broad range of topics from atomic structure, stability, mechanical property, to electronic structure, optoelectronic and transport properties of various nanoarchitectures in the context of Si and other solid nanomembranes. These have been done by using combinations of different theoretical and computational approaches, ranging from first-principles calculations and molecular dynamics (MD) simulations to finite-element (FE) analyses and continuum modeling.

Conflicting character distribution within different data sets on cardueline finches: artifact or history?

PubMed

Fehrer, J

1996-01-01

Cardueline finches (Passeriformes: Fringillidae, Carduelinae) provide an example of unresolved species relationships despite decades of extensive study of the group. Existing morphological studies suffer from numerous cases of assumed parallel evolution due to a conflicting character distribution in different lineages. In this study, results of assumed parallel evolution due to a conflicting character distribution in different lineages. In this study, results of cytochrome b sequence analysis are compared with species relationships suggested by morphological and behavioral evidence. In the molecular analyses, species clusters mutually excluding each other were observed, lowering the statistical support of the internodes, i.e., the branches could not be resolved convincingly. Despite these difficulties, some phylogenetic signal was present in the molecular data as well as in the other approaches. In particular, any species or genus relationship suggested by cytochrome b sequence analysis was reflected by some other evidence. Based on this general congruence of the different data sets and on a considerable cytochrome b tree stability observed independent of species combination, choice of outgroup and tree-generating method, the short internodes are interpreted to reflect a historical reality. A model of cardueline evolution is proposed which assumes a population of cardueline ancestors with considerable polymorphism concerning the mitochondrial DNA and morphological characters alike. Retention of ancestral character states in different lineages and a subsequent rapid radiation are suggested to explain the conflicting character distributions observed in different fields of investigation.

Bottom-up, Robust Graphene Ribbon Electronics in All-Carbon Molecular Junctions.

PubMed

Supur, Mustafa; Van Dyck, Colin; Bergren, Adam J; McCreery, Richard L

2018-02-21

Large-area molecular electronic junctions consisting of 5-carbon wide graphene ribbons (GR) with lengths of 2-12 nm between carbon electrodes were fabricated by electrochemical reduction of diazotized 1,8-diaminonaphthalene. Their conductance greatly exceeds that observed for other molecular junctions of similar thicknesses, by a factor of >1 × 10 4 compared to polyphenylenes and >1 × 10 7 compared to alkane chains. The remarkable increase of conductance of the GR nanolayer results from (i) uninterrupted planarity of fused-arene structure affording extensive π-electron delocalization and (ii) enhanced electronic coupling of molecular layer with the carbon bottom contact by two-point covalent bonding, in agreement with DFT-based simulations.

The potential anticancer effect of beta-blockers and the genetic variations involved in the interindividual difference.

PubMed

He, Ruo-Hui; He, Yi-Jing; Tang, Yong-Jun; Zhou, Hong-Hao; McLeod, Howard L; Liu, Jie

2016-01-01

β-ARs are extensively spread in different tissues of our body, which could be activated by neurotransmitters norepinephrine and epinephrine to mediate physiological function and abnormal states including cancer. Recently, β-AR blockers could have significant implications in cancer therapy. But the precise molecular mechanisms are far from being fully understood. Through identifying the β-AR system signal pathways relevant to cancer, we can understand the mechanisms of β-blockers used for cancer treatment. What's more, retrospective clinical data made β-blockers jump out of the traditional field of cardiovascular disease and strengthened our confidence in cancer therapy. At last, genetic studies of β-adrenergic system offered crucial genes to analyze the effects of polymorphisms on cancer susceptibility, therapy response and prognosis of cancer patients.

Photodissociation of methyl formate: Conical intersections, roaming and triple fragmentation

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

Lin, King-Chuen; Tsai, Po-Yu; Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei 106, Taiwan

2015-12-31

The photodissociation channels of methyl formate have been extensively investigated by two different advanced experimental techniques, ion imaging and Fourier-Transform-Infrared emission spectroscopy, combined with quantum chemical calculations and molecular dynamics simulations. Our aim is to characterize the role of alternative routes to the conventional transition-state mediated pathway: the roaming and the triple fragmentation processes. The photolysis experiments, carried out at a range of laser wavelengths in the vicinity of the triple fragmentation threshold, beside the simulation of large bunches of classical trajectories with different initial conditions, have shown that both mechanisms share a common path that involves a conical intersectionmore » during the relaxation process from the electronic excited state S{sub 1} to the ground state S{sub 0}.« less

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

Marquardt, Drew; Kučerka, Norbert; Wassall, Stephen R.

It is well known that cholesterol modifies the physical properties of lipid bilayers. For example, the much studied liquid-ordered L o phase contains rapidly diffusing lipids with their acyl chains in the all trans configuration, similar to gel phase bilayers. Moreover, the L o phase is commonly associated with cholesterol-enriched lipid rafts, which are thought to serve as platforms for signaling proteins in the plasma membrane. Cholesterol's location in lipid bilayers has been studied extensively, and it has been shown – at least in some bilayers – to align differently from its canonical upright orientation, where its hydroxyl group ismore » in the vicinity of the lipid–water interface. In this study we review recent works describing cholesterol's location in different model membrane systems with emphasis on results obtained from scattering, spectroscopic and molecular dynamics studies.« less

Respiratory Allergens from Furred Mammals: Environmental and Occupational Exposure

PubMed Central

Raulf, Monika

2017-01-01

Furry mammals kept as pets, farm and laboratory animals are important allergen sources. The prevalence of sensitization to furred mammals appears to be increasing worldwide. Several mammalian allergens from diverse species are well characterized with regard to their molecular structure and immunogenicity, and some are already available for component-resolved allergy diagnostics. The distribution of various mammalian allergens has been extensively studied during the past few decades. Animal allergens were found to be ubiquitous in the human environment, even in places where no animals reside, with concentrations differing considerably between locations and geographical regions. This review presents an overview of identified mammalian respiratory allergens classified according to protein families, and compiles the results of allergen exposure assessment studies conducted in different public and occupational environments. PMID:29056697

Onychostoma brevibarba, a new cyprinine fish (Pisces: Teleostei) from the middle Chang Jiang basin in Hunan Province, South China.

PubMed

Song, Xue-Ling; Cao, Liang; Zhang, E

2018-04-16

Onychostoma brevibarba, a new cyprinid species, is described from two tributaries flowing into the Xiang Jiang (= River) of the middle Chang Jiang basin in Hunan Province, South China. The new species is morphologically similar to two Chinese congeners, O. minnanense and O. barbatulum, but differs from them in the anteromedian extension of the postlabial groove. It further differs from O. minnanense in the maxillary-barbel length, shape and body coloration, and from O. barbatulum in the number of lateral-line perforated scales and the width of the mouth opening. The validity of the new species and its close relationship with these two species were affirmed by a molecular phylogenetic analysis based on the mitochondrial cyt b and CO1 genes.

Relative biological effectiveness of light ions in human tumoural cell lines: role of protein p53

NASA Technical Reports Server (NTRS)

Baggio, L.; Cavinato, M.; Cherubini, R.; Conzato, M.; Cucinotta, F.; Favaretto, S.; Gerardi, S.; Lora, S.; Stoppa, P.; Williams, J. R.

2002-01-01

Protons and alpha particles of high linear energy transfer (LET) have shown an increased relative biological effectiveness (RBE) with respect to X/gamma rays for several cellular and molecular endpoints in different in vitro cell systems. To contribute to understanding the biochemical mechanisms involved in the increased effectiveness of high LET radiation, an extensive study has been designed. The present work reports the preliminary result of this study on two human tumoural cell lines, DLD1 and HCT116, (with different p53 status), which indicate that for these cell lines, p53 does not appear to take a part in the response to radiation induced DNA damage, suggesting an alternative p53-independent pathway and a cell biochemical mechanism dependent on the cell type.

Fungal Exopolysaccharide: Production, Composition and Applications

PubMed Central

Mahapatra, Subhadip; Banerjee, Debdulal

2013-01-01

Fungal exopolysaccharides (EPSs) have been recognized as high value biomacromolecules for the last two decades. These products, including pullulan, scleroglucan, and botryosphaeran, have several applications in industries, pharmaceuticals, medicine, foods etc. Although fungal EPSs are highly relevant, to date information concerning fungal biosynthesis is scarce and an extensive search for new fugal species that can produce novel EPSs is still needed. In most cases, the molecular weight variations and sugar compositions of fungal EPSs are dependent to culture medium composition and different physical conditions provided during fermentation. An inclusive and illustrative review on fungal EPS is presented here. The general outline of the present work includes fungal EPS production, their compositions and applications. An emphasis is also given to listing out different fungal strains that can produce EPSs. PMID:24826070

DNA sequence-directed shape change of photopatterned hydrogels via high-degree swelling

NASA Astrophysics Data System (ADS)

Cangialosi, Angelo; Yoon, ChangKyu; Liu, Jiayu; Huang, Qi; Guo, Jingkai; Nguyen, Thao D.; Gracias, David H.; Schulman, Rebecca

2017-09-01

Shape-changing hydrogels that can bend, twist, or actuate in response to external stimuli are critical to soft robots, programmable matter, and smart medicine. Shape change in hydrogels has been induced by global cues, including temperature, light, or pH. Here we demonstrate that specific DNA molecules can induce 100-fold volumetric hydrogel expansion by successive extension of cross-links. We photopattern up to centimeter-sized gels containing multiple domains that undergo different shape changes in response to different DNA sequences. Experiments and simulations suggest a simple design rule for controlled shape change. Because DNA molecules can be coupled to molecular sensors, amplifiers, and logic circuits, this strategy introduces the possibility of building soft devices that respond to diverse biochemical inputs and autonomously implement chemical control programs.

Structural similarity based kriging for quantitative structure activity and property relationship modeling.

PubMed

Teixeira, Ana L; Falcao, Andre O

2014-07-28

Structurally similar molecules tend to have similar properties, i.e. closer molecules in the molecular space are more likely to yield similar property values while distant molecules are more likely to yield different values. Based on this principle, we propose the use of a new method that takes into account the high dimensionality of the molecular space, predicting chemical, physical, or biological properties based on the most similar compounds with measured properties. This methodology uses ordinary kriging coupled with three different molecular similarity approaches (based on molecular descriptors, fingerprints, and atom matching) which creates an interpolation map over the molecular space that is capable of predicting properties/activities for diverse chemical data sets. The proposed method was tested in two data sets of diverse chemical compounds collected from the literature and preprocessed. One of the data sets contained dihydrofolate reductase inhibition activity data, and the second molecules for which aqueous solubility was known. The overall predictive results using kriging for both data sets comply with the results obtained in the literature using typical QSPR/QSAR approaches. However, the procedure did not involve any type of descriptor selection or even minimal information about each problem, suggesting that this approach is directly applicable to a large spectrum of problems in QSAR/QSPR. Furthermore, the predictive results improve significantly with the similarity threshold between the training and testing compounds, allowing the definition of a confidence threshold of similarity and error estimation for each case inferred. The use of kriging for interpolation over the molecular metric space is independent of the training data set size, and no reparametrizations are necessary when more compounds are added or removed from the set, and increasing the size of the database will consequentially improve the quality of the estimations. Finally it is shown that this model can be used for checking the consistency of measured data and for guiding an extension of the training set by determining the regions of the molecular space for which new experimental measurements could be used to maximize the model's predictive performance.

Probing numerical Laplace inversion methods for two and three-site molecular exchange between interconnected pore structures.

PubMed

Silletta, Emilia V; Franzoni, María B; Monti, Gustavo A; Acosta, Rodolfo H

2018-01-01

Two-dimension (2D) Nuclear Magnetic Resonance relaxometry experiments are a powerful tool extensively used to probe the interaction among different pore structures, mostly in inorganic systems. The analysis of the collected experimental data generally consists of a 2D numerical inversion of time-domain data where T 2 -T 2 maps are generated. Through the years, different algorithms for the numerical inversion have been proposed. In this paper, two different algorithms for numerical inversion are tested and compared under different conditions of exchange dynamics; the method based on Butler-Reeds-Dawson (BRD) algorithm and the fast-iterative shrinkage-thresholding algorithm (FISTA) method. By constructing a theoretical model, the algorithms were tested for a two- and three-site porous media, varying the exchange rates parameters, the pore sizes and the signal to noise ratio. In order to test the methods under realistic experimental conditions, a challenging organic system was chosen. The molecular exchange rates of water confined in hierarchical porous polymeric networks were obtained, for a two- and three-site porous media. Data processed with the BRD method was found to be accurate only under certain conditions of the exchange parameters, while data processed with the FISTA method is precise for all the studied parameters, except when SNR conditions are extreme. Copyright © 2017 Elsevier Inc. All rights reserved.

Media effects in modulating the conformational equilibrium of a model compound for tumor necrosis factor converting enzyme inhibition

NASA Astrophysics Data System (ADS)

Banchelli, Martina; Guardiani, Carlo; Sandberg, Robert B.; Menichetti, Stefano; Procacci, Piero; Caminati, Gabriella

2015-07-01

Small-molecule inhibitors of Tumor Necrosis Factor α Converting Enzyme (TACE) are a promising therapeutic tool for Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. Here we report on an extensive chemical-physical analysis of the media effects in modulating the conformational landscape of MBET306, the common scaffold and a synthetic precursor of a family of recently discovered tartrate-based TACE inhibitors. The structural features of this molecule with potential pharmaceutical applications have been disclosed by interpreting extensive photophysical measurements in various solvents with the aid of enhanced sampling molecular dynamics simulations and time dependent density functional calculations. Using a combination of experimental and computational techniques, the paper provides a general protocol for studying the structure in solution of molecular systems characterized by the existence of conformational metastable states.

Pair 2-electron reduced density matrix theory using localized orbitals

NASA Astrophysics Data System (ADS)

Head-Marsden, Kade; Mazziotti, David A.

2017-08-01

Full configuration interaction (FCI) restricted to a pairing space yields size-extensive correlation energies but its cost scales exponentially with molecular size. Restricting the variational two-electron reduced-density-matrix (2-RDM) method to represent the same pairing space yields an accurate lower bound to the pair FCI energy at a mean-field-like computational scaling of O (r3) where r is the number of orbitals. In this paper, we show that localized molecular orbitals can be employed to generate an efficient, approximately size-extensive pair 2-RDM method. The use of localized orbitals eliminates the substantial cost of optimizing iteratively the orbitals defining the pairing space without compromising accuracy. In contrast to the localized orbitals, the use of canonical Hartree-Fock molecular orbitals is shown to be both inaccurate and non-size-extensive. The pair 2-RDM has the flexibility to describe the spectra of one-electron RDM occupation numbers from all quantum states that are invariant to time-reversal symmetry. Applications are made to hydrogen chains and their dissociation, n-acene from naphthalene through octacene, and cadmium telluride 2-, 3-, and 4-unit polymers. For the hydrogen chains, the pair 2-RDM method recovers the majority of the energy obtained from similar calculations that iteratively optimize the orbitals. The localized-orbital pair 2-RDM method with its mean-field-like computational scaling and its ability to describe multi-reference correlation has important applications to a range of strongly correlated phenomena in chemistry and physics.

Quantitative imaging with fluorescent biosensors.

PubMed

Okumoto, Sakiko; Jones, Alexander; Frommer, Wolf B

2012-01-01

Molecular activities are highly dynamic and can occur locally in subcellular domains or compartments. Neighboring cells in the same tissue can exist in different states. Therefore, quantitative information on the cellular and subcellular dynamics of ions, signaling molecules, and metabolites is critical for functional understanding of organisms. Mass spectrometry is generally used for monitoring ions and metabolites; however, its temporal and spatial resolution are limited. Fluorescent proteins have revolutionized many areas of biology-e.g., fluorescent proteins can report on gene expression or protein localization in real time-yet promoter-based reporters are often slow to report physiologically relevant changes such as calcium oscillations. Therefore, novel tools are required that can be deployed in specific cells and targeted to subcellular compartments in order to quantify target molecule dynamics directly. We require tools that can measure enzyme activities, protein dynamics, and biophysical processes (e.g., membrane potential or molecular tension) with subcellular resolution. Today, we have an extensive suite of tools at our disposal to address these challenges, including translocation sensors, fluorescence-intensity sensors, and Förster resonance energy transfer sensors. This review summarizes sensor design principles, provides a database of sensors for more than 70 different analytes/processes, and gives examples of applications in quantitative live cell imaging.

Spatial Rule-Based Modeling: A Method and Its Application to the Human Mitotic Kinetochore

PubMed Central

Ibrahim, Bashar; Henze, Richard; Gruenert, Gerd; Egbert, Matthew; Huwald, Jan; Dittrich, Peter

2013-01-01

A common problem in the analysis of biological systems is the combinatorial explosion that emerges from the complexity of multi-protein assemblies. Conventional formalisms, like differential equations, Boolean networks and Bayesian networks, are unsuitable for dealing with the combinatorial explosion, because they are designed for a restricted state space with fixed dimensionality. To overcome this problem, the rule-based modeling language, BioNetGen, and the spatial extension, SRSim, have been developed. Here, we describe how to apply rule-based modeling to integrate experimental data from different sources into a single spatial simulation model and how to analyze the output of that model. The starting point for this approach can be a combination of molecular interaction data, reaction network data, proximities, binding and diffusion kinetics and molecular geometries at different levels of detail. We describe the technique and then use it to construct a model of the human mitotic inner and outer kinetochore, including the spindle assembly checkpoint signaling pathway. This allows us to demonstrate the utility of the procedure, show how a novel perspective for understanding such complex systems becomes accessible and elaborate on challenges that arise in the formulation, simulation and analysis of spatial rule-based models. PMID:24709796

A molecular dynamics study of ambient and high pressure phases of silica: structure and enthalpy variation with molar volume.

PubMed

Rajappa, Chitra; Sringeri, S Bhuvaneshwari; Subramanian, Yashonath; Gopalakrishnan, J

2014-06-28

Extensive molecular dynamics studies of 13 different silica polymorphs are reported in the isothermal-isobaric ensemble with the Parrinello-Rahman variable shape simulation cell. The van Beest-Kramer-van Santen (BKS) potential is shown to predict lattice parameters for most phases within 2%-3% accuracy, as well as the relative stabilities of different polymorphs in agreement with experiment. Enthalpies of high-density polymorphs - CaCl2-type, α-PbO2-type, and pyrite-type - for which no experimental data are available as yet, are predicted here. Further, the calculated enthalpies exhibit two distinct regimes as a function of molar volume-for low and medium-density polymorphs, it is almost independent of volume, while for high-pressure phases a steep dependence is seen. A detailed analysis indicates that the increased short-range contributions to enthalpy in the high-density phases arise not only from an increased coordination number of silicon but also shorter Si-O bond lengths. Our results indicate that amorphous phases of silica exhibit better optimization of short-range interactions than crystalline phases at the same density while the magnitude of Coulombic contributions is lower in the amorphous phase.

Frequency Dependent Non- Thermal Effects of Oscillating Electric Fields in the Microwave Region on the Properties of a Solvated Lysozyme System: A Molecular Dynamics Study

PubMed Central

Floros, Stelios; Liakopoulou-Kyriakides, Maria; Karatasos, Kostas

2017-01-01

The use of microwaves in every day’s applications raises issues regarding the non thermal biological effects of microwaves. In this work we employ molecular dynamics simulations to advance further the dielectric studies of protein solutions in the case of lysozyme, taking into consideration possible frequency dependent changes in the structural and dynamic properties of the system upon application of electric field in the microwave region. The obtained dielectric spectra are identical with those derived in our previous work using the Fröhlich-Kirkwood approach in the framework of the linear response theory. Noticeable structural changes in the protein have been observed only at frequencies near its absorption maximum. Concerning Cα position fluctuations, different frequencies affected different regions of the protein sequence. Furthermore, the influence of the field on the kinetics of protein-water as well as on the water-water hydrogen bonds in the first hydration shell has been studied; an extension of the Luzar-Chandler kinetic model was deemed necessary for a better fit of the applied field results and for the estimation of more accurate hydrogen bond lifetime values. PMID:28129348

Organization and evolution of highly repeated satellite DNA sequences in plant chromosomes.

PubMed

Sharma, S; Raina, S N

2005-01-01

A major component of the plant nuclear genome is constituted by different classes of repetitive DNA sequences. The structural, functional and evolutionary aspects of the satellite repetitive DNA families, and their organization in the chromosomes is reviewed. The tandem satellite DNA sequences exhibit characteristic chromosomal locations, usually at subtelomeric and centromeric regions. The repetitive DNA family(ies) may be widely distributed in a taxonomic family or a genus, or may be specific for a species, genome or even a chromosome. They may acquire large-scale variations in their sequence and copy number over an evolutionary time-scale. These features have formed the basis of extensive utilization of repetitive sequences for taxonomic and phylogenetic studies. Hybrid polyploids have especially proven to be excellent models for studying the evolution of repetitive DNA sequences. Recent studies explicitly show that some repetitive DNA families localized at the telomeres and centromeres have acquired important structural and functional significance. The repetitive elements are under different evolutionary constraints as compared to the genes. Satellite DNA families are thought to arise de novo as a consequence of molecular mechanisms such as unequal crossing over, rolling circle amplification, replication slippage and mutation that constitute "molecular drive". Copyright 2005 S. Karger AG, Basel.

Nucleic acid tool enzymes-aided signal amplification strategy for biochemical analysis: status and challenges.

PubMed

Qing, Taiping; He, Dinggeng; He, Xiaoxiao; Wang, Kemin; Xu, Fengzhou; Wen, Li; Shangguan, Jingfang; Mao, Zhengui; Lei, Yanli

2016-04-01

Owing to their highly efficient catalytic effects and substrate specificity, the nucleic acid tool enzymes are applied as 'nano-tools' for manipulating different nucleic acid substrates both in the test-tube and in living organisms. In addition to the function as molecular scissors and molecular glue in genetic engineering, the application of nucleic acid tool enzymes in biochemical analysis has also been extensively developed in the past few decades. Used as amplifying labels for biorecognition events, the nucleic acid tool enzymes are mainly applied in nucleic acids amplification sensing, as well as the amplification sensing of biorelated variations of nucleic acids. With the introduction of aptamers, which can bind different target molecules, the nucleic acid tool enzymes-aided signal amplification strategies can also be used to sense non-nucleic targets (e.g., ions, small molecules, proteins, and cells). This review describes and discusses the amplification strategies of nucleic acid tool enzymes-aided biosensors for biochemical analysis applications. Various analytes, including nucleic acids, ions, small molecules, proteins, and cells, are reviewed briefly. This work also addresses the future trends and outlooks for signal amplification in nucleic acid tool enzymes-aided biosensors.

Molecular receptive range variation among mouse odorant receptors for aliphatic carboxylic acids

PubMed Central

Repicky, Sarah E.; Luetje, Charles W.

2009-01-01

The ability of mammals to identify and distinguish among many thousands of different odorants suggests a combinatorial use of odorant receptors, with each receptor detecting multiple odorants and each odorant interacting with multiple receptors. Numerous receptors may be devoted to the sampling of particularly important regions of odor space. Here we explore the similarities and differences in the molecular receptive ranges of four mouse odorant receptors (MOR23-1, MOR31-4, MOR32-11 and MOR40-4), which have previously been identified as receptors for aliphatic carboxylic acids. Each receptor was expressed in Xenopus oocytes, along with Gαolf and the cystic fibrosis transmembrane regulator to allow electrophysiological assay of receptor responses. We find that even though these receptors are relatively unrelated, there is extensive overlap among their receptive ranges. That is, these receptors sample a similar region of odor space. However, the receptive range of each receptor is unique. Thus, these receptors contribute to the depth of coverage of this small region of odor space. Such a group of receptors with overlapping, but distinct receptive ranges, may participate in making fine distinctions among complex mixtures of closely related odorant compounds. PMID:19166503

Parallel confocal detection of single biomolecules using diffractive optics and integrated detector units.

PubMed

Blom, H; Gösch, M

2004-04-01

The past few years we have witnessed a tremendous surge of interest in so-called array-based miniaturised analytical systems due to their value as extremely powerful tools for high-throughput sequence analysis, drug discovery and development, and diagnostic tests in medicine (see articles in Issue 1). Terminologies that have been used to describe these array-based bioscience systems include (but are not limited to): DNA-chip, microarrays, microchip, biochip, DNA-microarrays and genome chip. Potential technological benefits of introducing these miniaturised analytical systems include improved accuracy, multiplexing, lower sample and reagent consumption, disposability, and decreased analysis times, just to mention a few examples. Among the many alternative principles of detection-analysis (e.g.chemiluminescence, electroluminescence and conductivity), fluorescence-based techniques are widely used, examples being fluorescence resonance energy transfer, fluorescence quenching, fluorescence polarisation, time-resolved fluorescence, and fluorescence fluctuation spectroscopy (see articles in Issue 11). Time-dependent fluctuations of fluorescent biomolecules with different molecular properties, like molecular weight, translational and rotational diffusion time, colour and lifetime, potentially provide all the kinetic and thermodynamic information required in analysing complex interactions. In this mini-review article, we present recent extensions aimed to implement parallel laser excitation and parallel fluorescence detection that can lead to even further increase in throughput in miniaturised array-based analytical systems. We also report on developments and characterisations of multiplexing extension that allow multifocal laser excitation together with matched parallel fluorescence detection for parallel confocal dynamical fluorescence fluctuation studies at the single biomolecule level.

skelesim: an extensible, general framework for population genetic simulation in R.

PubMed

Parobek, Christian M; Archer, Frederick I; DePrenger-Levin, Michelle E; Hoban, Sean M; Liggins, Libby; Strand, Allan E

2017-01-01

Simulations are a key tool in molecular ecology for inference and forecasting, as well as for evaluating new methods. Due to growing computational power and a diversity of software with different capabilities, simulations are becoming increasingly powerful and useful. However, the widespread use of simulations by geneticists and ecologists is hindered by difficulties in understanding these softwares' complex capabilities, composing code and input files, a daunting bioinformatics barrier and a steep conceptual learning curve. skelesim (an R package) guides users in choosing appropriate simulations, setting parameters, calculating genetic summary statistics and organizing data output, in a reproducible pipeline within the R environment. skelesim is designed to be an extensible framework that can 'wrap' around any simulation software (inside or outside the R environment) and be extended to calculate and graph any genetic summary statistics. Currently, skelesim implements coalescent and forward-time models available in the fastsimcoal2 and rmetasim simulation engines to produce null distributions for multiple population genetic statistics and marker types, under a variety of demographic conditions. skelesim is intended to make simulations easier while still allowing full model complexity to ensure that simulations play a fundamental role in molecular ecology investigations. skelesim can also serve as a teaching tool: demonstrating the outcomes of stochastic population genetic processes; teaching general concepts of simulations; and providing an introduction to the R environment with a user-friendly graphical user interface (using shiny). © 2016 John Wiley & Sons Ltd.

skeleSim: an extensible, general framework for population genetic simulation in R

PubMed Central

Parobek, Christian M.; Archer, Frederick I.; DePrenger-Levin, Michelle E.; Hoban, Sean M.; Liggins, Libby; Strand, Allan E.

2016-01-01

Simulations are a key tool in molecular ecology for inference and forecasting, as well as for evaluating new methods. Due to growing computational power and a diversity of software with different capabilities, simulations are becoming increasingly powerful and useful. However, the widespread use of simulations by geneticists and ecologists is hindered by difficulties in understanding these softwares’ complex capabilities, composing code and input files, a daunting bioinformatics barrier, and a steep conceptual learning curve. skeleSim (an R package) guides users in choosing appropriate simulations, setting parameters, calculating genetic summary statistics, and organizing data output, in a reproducible pipeline within the R environment. skeleSim is designed to be an extensible framework that can ‘wrap’ around any simulation software (inside or outside the R environment) and be extended to calculate and graph any genetic summary statistics. Currently, skeleSim implements coalescent and forward-time models available in the fastsimcoal2 and rmetasim simulation engines to produce null distributions for multiple population genetic statistics and marker types, under a variety of demographic conditions. skeleSim is intended to make simulations easier while still allowing full model complexity to ensure that simulations play a fundamental role in molecular ecology investigations. skeleSim can also serve as a teaching tool: demonstrating the outcomes of stochastic population genetic processes; teaching general concepts of simulations; and providing an introduction to the R environment with a user-friendly graphical user interface (using shiny). PMID:27736016

Modeling the polydomain-monodomain transition of liquid crystal elastomers.

PubMed

Whitmer, Jonathan K; Roberts, Tyler F; Shekhar, Raj; Abbott, Nicholas L; de Pablo, Juan J

2013-02-01

We study the mechanism of the polydomain-monodomain transition in liquid crystalline elastomers at the molecular scale. A coarse-grained model is proposed in which mesogens are described as ellipsoidal particles. Molecular dynamics simulations are used to examine the transition from a polydomain state to a monodomain state in the presence of uniaxial strain. Our model demonstrates soft elasticity, similar to that exhibited by side-chain elastomers in the literature. By analyzing the growth dynamics of nematic domains during uniaxial extension, we provide direct evidence that at a molecular level the polydomain-monodomain transition proceeds through cluster rotation and domain growth.

Analyzing the Coordinated Gene Network Underlying Temperature-Dependent Sex Determination in Reptiles

PubMed Central

Shoemaker, Christina M.; Crews, David

2009-01-01

Although gonadogenesis has been extensively studied in vertebrates with genetic sex determination, investigations at the molecular level in nontraditional model organisms with temperature-dependent sex determination are a relatively new area of research. Results show that while the key players of the molecular network underlying gonad development appear to be retained, their functions range from conserved to novel roles. In this review, we summarize experiments investigating candidate molecular players underlying temperature-dependent sex determination. We discuss some of the problems encountered unraveling this network, pose potential solutions, and suggest rewarding future directions of research. PMID:19022389

Molecular modeling, theoretical calculations and property evaluation of three muscarinic agonists. X-ray structures of LU 25-109 and WAL 2014

NASA Astrophysics Data System (ADS)

Dolmella, A.; Bandoli, G.; Cavallin, M.

2000-08-01

LU 25-109 ( II) and WAL 2014 (talsaclidine, III) are two M1 muscarinic agonists chemically related to the natural substance arecoline ( I). All these compounds have beneficial effects on memory and cognition in animals and humans, and they have been proposed in the treatment of Alzheimer's disease, but only III will likely find a place in therapy. In this work we have investigated the solid state structures of II and III, and the X-ray structures of the two molecules and of the parent compound I have been used to input a series of computational chemistry efforts. In particular, the X-ray geometries have been manipulated to model 20 molecular structures ( 1- 20) which have been submitted to ab initio, semiempirical quantum mechanics and molecular mechanics calculations. The conformational space accessible to the 20 structures has been assessed by means of potential energy maps. The reactivities of 1- 20 have been estimated by examining at the graphics terminal the composition and the extension of the frontier orbitals (HOMOs and LUMOs) and of the molecular electrostatic potential. The information obtained has been interpreted to explain the different degrees of activity shown by I- III. Our data indicate that III has better in vivo activity for its intermediate size, less polar surface, conformational rigidity and orientation of reactive domains.

Microglia: An Interface between the Loss of Neuroplasticity and Depression

PubMed Central

Singhal, Gaurav; Baune, Bernhard T.

2017-01-01

Depression has been widely accepted as a major psychiatric disease affecting nearly 350 million people worldwide. Research focus is now shifting from studying the extrinsic and social factors of depression to the underlying molecular causes. Microglial activity is shown to be associated with pathological conditions, such as psychological stress, pathological aging, and chronic infections. These are primary immune effector cells in the CNS and regulate the extensive dialogue between the nervous and the immune systems in response to different immunological, physiological, and psychological stressors. Studies have suggested that during stress and pathologies, microglia play a significant role in the disruption of neuroplasticity and have detrimental effects on neuroprotection causing neuroinflammation and exacerbation of depression. After a systematic search of literature databases, relevant articles on the microglial regulation of bidirectional neuroimmune pathways affecting neuroplasticity and leading to depression were reviewed. Although, several hypotheses have been proposed for the microglial role in the onset of depression, it is clear that all molecular pathways to depression are linked through microglia-associated neuroinflammation and hippocampal degeneration. Molecular factors such as an excess of glucocorticoids and changes in gene expression of neurotrophic factors, as well as neuro active substances secreted by gut microbiota have also been shown to affect microglial morphology and phenotype resulting in depression. This review aims to critically analyze the various molecular pathways associated with the microglial role in depression. PMID:28943841

Atomistic models for free energy evaluation of drug binding to membrane proteins.

PubMed

Durdagi, S; Zhao, C; Cuervo, J E; Noskov, S Y

2011-01-01

The binding of various molecules to integral membrane proteins with optimal affinity and specificity is central to normal function of cell. While membrane proteins represent about one third of the whole cell proteome, they are a majority of common drug targets. The quest for the development of computational models capable of accurate evaluation of binding affinities, decomposition of the binding into its principal components and thus mapping molecular mechanisms of binding remains one of the main goals of modern computational biophysics and related drug development. The primary scope of this review will be on the recent extension of computational methods for the study of drug binding to membrane proteins. Several examples of such applications will be provided ranging from secondary transporters to voltage gated channels. In this mini-review, we will provide a short summary on the breadth of different methods for binding affinity evaluation. These methods include molecular docking with docking scoring functions, molecular dynamics (MD) simulations combined with post-processing analysis using Molecular Mechanics/Poisson Boltzmann (Generalized Born) Surface Area (MM/PB(GB)SA), as well as direct evaluation of free energies from Free Energy Perturbation (FEP) with constraining schemes, and Potential of Mean Force (PMF) computations. We will compare advantages and shortcomings of popular techniques and provide discussion on the integrative strategies for drug development aimed at targeting membrane proteins.

Resin/graphite fiber composites

NASA Technical Reports Server (NTRS)

Cavano, P. J.

1974-01-01

Techniques were developed that provided thermo-oxidatively stable A-type polyimide/graphite fiber composites using the approach of in situ polymerization of monomeric reactants directly on reinforcing fibers, rather than employing separately prepared prepolymer varnish. This was accomplished by simply mixing methylene dianiline and two ester-acids and applying this solution to the fibers for subsequent molding. Five different formulated molecular weight resins were examined, and an optimized die molding procedure established for the 1500 formulated molecular weight system. Extensive ultrasonic inspection of composites was successfully utilized as a technique for monitoring laminate quality. Composite mechanical property studies were conducted with this polyimide resin at room temperature and after various time exposures in a thermo-oxidative environment at 561 K (550 F), 589 K (600 F) and 617 K (650 F). It was determined that such composites have a long term life in the temperature range of 561 K to 589 K. The final phase involved the fabrication and evaluation of a series of demonstration airfoil specimens.

Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function in Health and Disease.

PubMed

Sullivan, E Madison; Pennington, Edward Ross; Green, William D; Beck, Melinda A; Brown, David A; Shaikh, Saame Raza

2018-05-01

Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a role in maintaining cellular homeostasis and proper calcium concentrations, building critical components of hormones and other signaling molecules, and controlling apoptosis. Structurally, mitochondria are unique because they have 2 membranes that allow for compartmentalization. The composition and molecular organization of these membranes are crucial to the maintenance and function of mitochondria. In this review, we first present a general overview of mitochondrial membrane biochemistry and biophysics followed by the role of different dietary saturated and unsaturated fatty acids in modulating mitochondrial membrane structure-function. We focus extensively on long-chain n-3 (ω-3) polyunsaturated fatty acids and their underlying mechanisms of action. Finally, we discuss implications of understanding molecular mechanisms by which dietary n-3 fatty acids target mitochondrial structure-function in metabolic diseases such as obesity, cardiac-ischemia reperfusion injury, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and select cancers.

Visualization of polymer relaxation in viscoelastic turbulent micro-channel flow.

PubMed

Tai, Jiayan; Lim, Chun Ping; Lam, Yee Cheong

2015-11-13

In micro-channels, the flow of viscous liquids e.g. water, is laminar due to the low Reynolds number in miniaturized dimensions. An aqueous solution becomes viscoelastic with a minute amount of polymer additives; its flow behavior can become drastically different and turbulent. However, the molecules are typically invisible. Here we have developed a novel visualization technique to examine the extension and relaxation of polymer molecules at high flow velocities in a viscoelastic turbulent flow. Using high speed videography to observe the fluorescein labeled molecules, we show that viscoelastic turbulence is caused by the sporadic, non-uniform release of energy by the polymer molecules. This developed technique allows the examination of a viscoelastic liquid at the molecular level, and demonstrates the inhomogeneity of viscoelastic liquids as a result of molecular aggregation. It paves the way for a deeper understanding of viscoelastic turbulence, and could provide some insights on the high Weissenberg number problem. In addition, the technique may serve as a useful tool for the investigations of polymer drag reduction.

Visualization of polymer relaxation in viscoelastic turbulent micro-channel flow

NASA Astrophysics Data System (ADS)

Tai, Jiayan; Lim, Chun Ping; Lam, Yee Cheong

2015-11-01

In micro-channels, the flow of viscous liquids e.g. water, is laminar due to the low Reynolds number in miniaturized dimensions. An aqueous solution becomes viscoelastic with a minute amount of polymer additives; its flow behavior can become drastically different and turbulent. However, the molecules are typically invisible. Here we have developed a novel visualization technique to examine the extension and relaxation of polymer molecules at high flow velocities in a viscoelastic turbulent flow. Using high speed videography to observe the fluorescein labeled molecules, we show that viscoelastic turbulence is caused by the sporadic, non-uniform release of energy by the polymer molecules. This developed technique allows the examination of a viscoelastic liquid at the molecular level, and demonstrates the inhomogeneity of viscoelastic liquids as a result of molecular aggregation. It paves the way for a deeper understanding of viscoelastic turbulence, and could provide some insights on the high Weissenberg number problem. In addition, the technique may serve as a useful tool for the investigations of polymer drag reduction.

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization

PubMed Central

2018-01-01

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applying an energetic cutoff, followed by geometric clustering, we demonstrate the striking robustness and efficiency of the approach in identifying highly populated conformational states of cyclic peptides. The resulting structural and thermodynamic information is benchmarked against interproton distances from NMR experiments and conformational states identified by X-ray crystallography. Using three different model systems of varying size and flexibility, we show that the method reliably reproduces experimentally determined structural ensembles and is capable of identifying key conformational states that include the bioactive conformation. Thus, the described approach is a robust method to generate conformations of peptidic macrocycles and holds promise for structure-based drug design. PMID:29652495

NH2- in a cold ion trap with He buffer gas: Ab initio quantum modeling of the interaction potential and of state-changing multichannel dynamics

NASA Astrophysics Data System (ADS)

Hernández Vera, Mario; Yurtsever, Ersin; Wester, Roland; Gianturco, Franco A.

2018-05-01

We present an extensive range of accurate ab initio calculations, which map in detail the spatial electronic potential energy surface that describes the interaction between the molecular anion NH2 - (1A1) in its ground electronic state and the He atom. The time-independent close-coupling method is employed to generate the corresponding rotationally inelastic cross sections, and then the state-changing rates over a range of temperatures from 10 to 30 K, which is expected to realistically represent the experimental trapping conditions for this ion in a radio frequency ion trap filled with helium buffer gas. The overall evolutionary kinetics of the rotational level population involving the molecular anion in the cold trap is also modelled during a photodetachment experiment and analyzed using the computed rates. The present results clearly indicate the possibility of selectively detecting differences in behavior between the ortho- and para-anions undergoing photodetachment in the trap.

Changing patterns of peanut agglutinin labelling in the dorsal cochlear nucleus correspond to axonal ingrowth.

PubMed Central

Riggs, G H; Schweitzer, L

1994-01-01

Various studies have suggested that glycoconjugates may influence connectivity and lamination in the developing central nervous system and may function as barriers to neuritic extension. It has been proposed that the peanut agglutinin lectin labels a glycoconjugate subserving a barrier function. We chose to investigate the distribution of this peanut-agglutinin-labelled glycoconjugate in the dorsal cochlear nucleus of the developing hamster since the development of the dorsal cochlear nucleus is well characterised and its axons obey laminar boundaries. The distribution of peanut agglutinin label throughout the cochlear nucleus delineated zones that cochlear axons fail to invade. In the dorsal cochlear nucleus, laminar differences were reduced on postnatal d 13 and virtually disappearing by postnatal d 23. Label in the molecular layer dissipated as axons and dendrites grew into this layer. These patterns of peanut agglutinin binding correspond to axonal ingrowth and are consistent with a barrier function for glycoconjugates in the molecular layer. Images Fig. 1 Fig. 2 Fig. 4 PMID:7961144

Experimental and theoretical evidence for bilayer-by-bilayer surface melting of crystalline ice

PubMed Central

Sánchez, M. Alejandra; Kling, Tanja; Ishiyama, Tatsuya; van Zadel, Marc-Jan; Mezger, Markus; Jochum, Mara N.; Cyran, Jenée D.; Smit, Wilbert J.; Bakker, Huib J.; Shultz, Mary Jane; Morita, Akihiro; Donadio, Davide; Nagata, Yuki; Bonn, Mischa; Backus, Ellen H. G.

2017-01-01

On the surface of water ice, a quasi-liquid layer (QLL) has been extensively reported at temperatures below its bulk melting point at 273 K. Approaching the bulk melting temperature from below, the thickness of the QLL is known to increase. To elucidate the precise temperature variation of the QLL, and its nature, we investigate the surface melting of hexagonal ice by combining noncontact, surface-specific vibrational sum frequency generation (SFG) spectroscopy and spectra calculated from molecular dynamics simulations. Using SFG, we probe the outermost water layers of distinct single crystalline ice faces at different temperatures. For the basal face, a stepwise, sudden weakening of the hydrogen-bonded structure of the outermost water layers occurs at 257 K. The spectral calculations from the molecular dynamics simulations reproduce the experimental findings; this allows us to interpret our experimental findings in terms of a stepwise change from one to two molten bilayers at the transition temperature. PMID:27956637

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization.

PubMed

Kamenik, Anna S; Lessel, Uta; Fuchs, Julian E; Fox, Thomas; Liedl, Klaus R

2018-05-29

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applying an energetic cutoff, followed by geometric clustering, we demonstrate the striking robustness and efficiency of the approach in identifying highly populated conformational states of cyclic peptides. The resulting structural and thermodynamic information is benchmarked against interproton distances from NMR experiments and conformational states identified by X-ray crystallography. Using three different model systems of varying size and flexibility, we show that the method reliably reproduces experimentally determined structural ensembles and is capable of identifying key conformational states that include the bioactive conformation. Thus, the described approach is a robust method to generate conformations of peptidic macrocycles and holds promise for structure-based drug design.

Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures.

PubMed

Schwalbe, E C; Hicks, D; Rafiee, G; Bashton, M; Gohlke, H; Enshaei, A; Potluri, S; Matthiesen, J; Mather, M; Taleongpong, P; Chaston, R; Silmon, A; Curtis, A; Lindsey, J C; Crosier, S; Smith, A J; Goschzik, T; Doz, F; Rutkowski, S; Lannering, B; Pietsch, T; Bailey, S; Williamson, D; Clifford, S C

2017-10-18

Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.

Visualization of polymer relaxation in viscoelastic turbulent micro-channel flow

PubMed Central

Tai, Jiayan; Lim, Chun Ping; Lam, Yee Cheong

2015-01-01

In micro-channels, the flow of viscous liquids e.g. water, is laminar due to the low Reynolds number in miniaturized dimensions. An aqueous solution becomes viscoelastic with a minute amount of polymer additives; its flow behavior can become drastically different and turbulent. However, the molecules are typically invisible. Here we have developed a novel visualization technique to examine the extension and relaxation of polymer molecules at high flow velocities in a viscoelastic turbulent flow. Using high speed videography to observe the fluorescein labeled molecules, we show that viscoelastic turbulence is caused by the sporadic, non-uniform release of energy by the polymer molecules. This developed technique allows the examination of a viscoelastic liquid at the molecular level, and demonstrates the inhomogeneity of viscoelastic liquids as a result of molecular aggregation. It paves the way for a deeper understanding of viscoelastic turbulence, and could provide some insights on the high Weissenberg number problem. In addition, the technique may serve as a useful tool for the investigations of polymer drag reduction. PMID:26563615

Shugoshins function as a guardian for chromosomal stability in nuclear division.

PubMed

Yao, Yixin; Dai, Wei

2012-07-15

Accurate chromosome segregation during mitosis and meiosis is regulated and secured by several distinctly different yet intricately connected regulatory mechanisms. As chromosomal instability is a hallmark of a majority of tumors as well as a cause of infertility for germ cells, extensive research in the past has focused on the identification and characterization of molecular components that are crucial for faithful chromosome segregation during cell division. Shugoshins, including Sgo1 and Sgo2, are evolutionarily conserved proteins that function to protect sister chromatid cohesion, thus ensuring chromosomal stability during mitosis and meiosis in eukaryotes. Recent studies reveal that Shugoshins in higher animals play an essential role not only in protecting centromeric cohesion of sister chromatids and assisting bi-orientation attachment at the kinetochores, but also in safeguarding centriole cohesion/engagement during early mitosis. Many molecular components have been identified that play essential roles in modulating/mediating Sgo functions. This review primarily summarizes recent advances on the mechanisms of action of Shugoshins in suppressing chromosomal instability during nuclear division in eukaryotic organisms.

Fluorescent proteins as biomarkers and biosensors: throwing color lights on molecular and cellular processes.

PubMed

Stepanenko, Olesya V; Verkhusha, Vladislav V; Kuznetsova, Irina M; Uversky, Vladimir N; Turoverov, K K

2008-08-01

Green fluorescent protein (GFP) from jellyfish Aequorea victoria is the most extensively studied and widely used in cell biology protein. GFP-like proteins constitute a fast growing family as several naturally occurring GFP-like proteins have been discovered and enhanced mutants of Aequorea GFP have been created. These mutants differ from wild-type GFP by conformational stability, quantum yield, spectroscopic properties (positions of absorption and fluorescence spectra) and by photochemical properties. GFP-like proteins are very diverse, as they can be not only green, but also blue, orange-red, far-red, cyan, and yellow. They also can have dual-color fluorescence (e.g., green and red) or be non-fluorescent. Some of them possess kindling property, some are photoactivatable, and some are photoswitchable. This review is an attempt to characterize the main color groups of GFP-like proteins, describe their structure and mechanisms of chromophore formation, systemize data on their conformational stability and summarize the main trends of their utilization as markers and biosensors in cell and molecular biology.

Molecular insights into the origin of the Hox-TALE patterning system

PubMed Central

Hudry, Bruno; Thomas-Chollier, Morgane; Volovik, Yael; Duffraisse, Marilyne; Dard, Amélie; Frank, Dale; Technau, Ulrich; Merabet, Samir

2014-01-01

Despite tremendous body form diversity in nature, bilaterian animals share common sets of developmental genes that display conserved expression patterns in the embryo. Among them are the Hox genes, which define different identities along the anterior–posterior axis. Hox proteins exert their function by interaction with TALE transcription factors. Hox and TALE members are also present in some but not all non-bilaterian phyla, raising the question of how Hox–TALE interactions evolved to provide positional information. By using proteins from unicellular and multicellular lineages, we showed that these networks emerged from an ancestral generic motif present in Hox and other related protein families. Interestingly, Hox-TALE networks experienced additional and extensive molecular innovations that were likely crucial for differentiating Hox functions along body plans. Together our results highlight how homeobox gene families evolved during eukaryote evolution to eventually constitute a major patterning system in Eumetazoans. DOI: http://dx.doi.org/10.7554/eLife.01939.001 PMID:24642410

Molecular insights into the origin of the Hox-TALE patterning system.

PubMed

Hudry, Bruno; Thomas-Chollier, Morgane; Volovik, Yael; Duffraisse, Marilyne; Dard, Amélie; Frank, Dale; Technau, Ulrich; Merabet, Samir

2014-03-18

Despite tremendous body form diversity in nature, bilaterian animals share common sets of developmental genes that display conserved expression patterns in the embryo. Among them are the Hox genes, which define different identities along the anterior-posterior axis. Hox proteins exert their function by interaction with TALE transcription factors. Hox and TALE members are also present in some but not all non-bilaterian phyla, raising the question of how Hox-TALE interactions evolved to provide positional information. By using proteins from unicellular and multicellular lineages, we showed that these networks emerged from an ancestral generic motif present in Hox and other related protein families. Interestingly, Hox-TALE networks experienced additional and extensive molecular innovations that were likely crucial for differentiating Hox functions along body plans. Together our results highlight how homeobox gene families evolved during eukaryote evolution to eventually constitute a major patterning system in Eumetazoans. DOI: http://dx.doi.org/10.7554/eLife.01939.001.

Characterization and Epidemiology of Pigeon Paramyxovirus Type-1 Viruses (PPMV-1) Isolated in Macedonia.

PubMed

Dodovski, A; Cvetkovikj, I; Krstevski, K; Naletoski, I; Savić, Vladimir

2017-06-01

We have characterized in this study 10 PPMV-1 isolated from domestic pigeons and one PPMV-1 isolated from a feral pigeon in the period 2007-2012, using both classical methods (HI test and ICPI test) and molecular methods (RT-qPCR, RT-PCR, and nucleotide sequencing). Using phylogenetic analysis of partial fusion gene sequences, these viruses clustered with recent European PPMV-1 isolates (EU/re) within the genotype VIb/1. All isolates possessed virulent cleavage site motifs with variable morbidity and mortality in pigeons. The intracerebral pathogenecity indices of the five isolates ranged from 0.59 to 1.53. The repetitive isolation of PPMV-1 viruses for several consecutive years led toward establishing enzootic presence of the disease in pigeons. A high nucleotide sequence homology between the Macedonian isolates and EU/re isolates was shown. Co-circulation of different isolates in the same holdings was detected. This is the first study to extensively describe the molecular epidemiology of PPMV-1 isolated in Macedonia.

Tocotrienols, the Vitamin E of the 21st Century: It’s Potential Against Cancer and Other Chronic Diseases

PubMed Central

Aggarwal, Bharat B.; Sundaram, Chitra; Prasad, Seema; Kannappan, Ramaswamy

2010-01-01

Initially discovered in 1938 as a “fertility factor,” vitamin E now refers to eight different isoforms that belong to two categories, four saturated analogues (α, β, γ, and δ) called tocopherols and four unsaturated analogues referred to as tocotrienols. While the tocopherols have been investigated extensively, little is known about the tocotrienols. Very limited studies suggest that both the molecular and therapeutic targets of the tocotrienols are distinct from those of the tocopherols. For instance, suppression of inflammatory transcription factor NF-κB, which is closely linked to tumorigenesis and inhibition of HMG-CoA reductase, mammalian DNA polymerases and certain protein tyrosine kinases, is unique to the tocotrienols. This review examines in detail the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, and cardiovascular and neurological diseases at both preclinical and clinical levels. As disappointment with the therapeutic value of the tocopherols grows, the potential of these novel vitamin E analogues awaits further investigation. PMID:20696139

Inorganic/organic nanocomposites: Reaching a high filler content without increasing viscosity using core-shell structured nanoparticles

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

Benhadjala, W., E-mail: warda.benhadjala@cea.fr; CEA, LETI, Minatec Campus, 38000 Grenoble; Gravoueille, M.

2015-11-23

Extensive research is being conducted on the development of inorganic/organic nanocomposites for a wide variety of applications in microelectronics, biotechnologies, photonics, adhesives, or optical coatings. High filler contents are usually required to fully optimize the nanocomposites properties. However, numerous studies demonstrated that traditional composite viscosity increases with increasing the filler concentration reducing therefore significantly the material processability. In this work, we synthesized inorganic/organic core-shell nanocomposites with different shell thicknesses. By reducing the shell thickness while maintaining a constant core size, the nanoparticle molecular mass decreases but the nanocomposite filler fraction is correlatively increased. We performed viscosity measurements, which clearly highlightedmore » that intrinsic viscosity of hybrid nanoparticles decreases as the molecular mass decreases, and thus, as the filler fraction increases, as opposed to Einstein predictions about the viscosity of traditional inorganic/polymer two-phase mixtures. This exceptional behavior, modeled by Mark-Houwink-Sakurada equation, proves to be a significant breakthrough for the development of industrializable nanocomposites with high filler contents.« less

Getting the Right Answers for the Right Reasons: Toward Predictive Molecular Simulations of Water with Many-Body Potential Energy Functions.

PubMed

Paesani, Francesco

2016-09-20

The central role played by water in fundamental processes relevant to different disciplines, including chemistry, physics, biology, materials science, geology, and climate research, cannot be overemphasized. It is thus not surprising that, since the pioneering work by Stillinger and Rahman, many theoretical and computational studies have attempted to develop a microscopic description of the unique properties of water under different thermodynamic conditions. Consequently, numerous molecular models based on either molecular mechanics or ab initio approaches have been proposed over the years. However, despite continued progress, the correct prediction of the properties of water from small gas-phase clusters to the liquid phase and ice through a single molecular model remains challenging. To large extent, this is due to the difficulties encountered in the accurate modeling of the underlying hydrogen-bond network in which both number and strength of the hydrogen bonds vary continuously as a result of a subtle interplay between energetic, entropic, and nuclear quantum effects. In the past decade, the development of efficient algorithms for correlated electronic structure calculations of small molecular complexes, accompanied by tremendous progress in the analytical representation of multidimensional potential energy surfaces, opened the doors to the design of highly accurate potential energy functions built upon rigorous representations of the many-body expansion (MBE) of the interaction energies. This Account provides a critical overview of the performance of the MB-pol many-body potential energy function through a systematic analysis of energetic, structural, thermodynamic, and dynamical properties as well as of vibrational spectra of water from the gas to the condensed phase. It is shown that MB-pol achieves unprecedented accuracy across all phases of water through a quantitative description of each individual term of the MBE, with a physically correct representation of both short- and long-range many-body contributions. Comparisons with experimental data probing different regions of the water potential energy surface from clusters to bulk demonstrate that MB-pol represents a major step toward the long-sought-after "universal model" capable of accurately describing the molecular properties of water under different conditions and in different environments. Along this path, future challenges include the extension of the many-body scheme adopted by MB-pol to the description of generic solutes as well as the integration of MB-pol in an efficient theoretical and computational framework to model acid-base reactions in aqueous environments. In this context, given the nontraditional form of the MB-pol energy and force expressions, synergistic efforts by theoretical/computational chemists/physicists and computer scientists will be critical for the development of high-performance software for many-body molecular dynamics simulations.

Molecular markers reveal infestation dynamics of the bed bug (Hemiptera: Cimicidae) within apartment buildings.

PubMed

Booth, Warren; Saenz, Virna L; Santangelo, Richard G; Wang, Changlu; Schal, Coby; Vargo, Edward L

2012-05-01

The bed bug, Cimex lectularius L. (Hemiptera: Cimicidae), has experienced an extraordinary global resurgence in recent years, the reasons for which remain poorly understood. Once considered a pest of lower socioeconomic classes, bed bugs are now found extensively across all residential settings, with widespread infestations established in multiapartment buildings. Within such buildings, understanding the population genetic structure and patterns of dispersal may prove critical to the development of effective control strategies. Here, we describe the development of 24 high-resolution microsatellite markers through next generation 454 pyrosequencing and their application to elucidate infestation dynamics within three multistory apartment buildings in the United States. Results reveal contrasting characteristics potentially representative of geographic or locale differences. In Raleigh, NC, an infestation within an apartment building seemed to have started from a single introduction followed by extensive spread. In Jersey City, NJ, two or more introductions followed by spread are evident in two buildings. Populations within single apartments in all buildings were characterized by high levels of relatedness and low levels of diversity, indicative of foundation from small, genetically depauperate propagules. Regardless of the number of unique introductions, genetic data indicate that spread within buildings is extensive, supporting both active and human-mediated dispersal within and between adjacent rooms or apartments spanning multiple floors.

Nanomechanics of multidomain neuronal cell adhesion protein contactin revealed by single molecule AFM and SMD.

PubMed

Mikulska-Ruminska, Karolina; Kulik, Andrej J; Benadiba, Carine; Bahar, Ivet; Dietler, Giovanni; Nowak, Wieslaw

2017-08-18

Contactin-4 (CNTN4) is a complex cell adhesion molecule (CAM) localized at neuronal membranes, playing a key role in maintaining the mechanical integrity and signaling properties of the synapse. CNTN4 consists of six immunoglobulin C2 type (IgC2) domains and four fibronectin type III (FnIII) domains that are shared with many other CAMs. Mutations in CNTN4 gene have been linked to various psychiatric disorders. Toward elucidating the response of this modular protein to mechanical stress, we studied its force-induced unfolding using single molecule atomic force microscopy (smAFM) and steered molecular dynamics (SMD) simulations. Extensive smAFM and SMD data both indicate the distinctive mechanical behavior of the two types of modules distinguished by unique force-extension signatures. The data also reveal the heterogeneity of the response of the individual FNIII and IgC2 modules, which presumably plays a role in the adaptability of CNTN4 to maintaining cell-cell communication and adhesion properties under different conditions. Results show that extensive sampling of force spectra, facilitated by robot-enhanced AFM, can help reveal the existence of weak stabilizing interactions between the domains of multidomain proteins, and provide insights into the nanomechanics of such multidomain or heteromeric proteins.

A fast recursive algorithm for molecular dynamics simulation

NASA Technical Reports Server (NTRS)

Jain, A.; Vaidehi, N.; Rodriguez, G.

1993-01-01

The present recursive algorithm for solving molecular systems' dynamical equations of motion employs internal variable models that reduce such simulations' computation time by an order of magnitude, relative to Cartesian models. Extensive use is made of spatial operator methods recently developed for analysis and simulation of the dynamics of multibody systems. A factor-of-450 speedup over the conventional O(N-cubed) algorithm is demonstrated for the case of a polypeptide molecule with 400 residues.

Controlling carbon-nanotube-phospholipid solubility by curvature-dependent self-assembly.

PubMed

Määttä, Jukka; Vierros, Sampsa; Sammalkorpi, Maria

2015-03-12

Control of aqueous dispersion is central in the processing and usage of nanoscale hydrophobic objects. However, selecting dispersive agents based on the size and form of the hydrophobic object and the role of coating morphology in dispersion efficiency remain important open questions. Here, the effect of the substrate and the dispersing molecule curvature, as well as, the influence of dispersant concentration on the adsorption morphology are examined by molecular simulations of graphene and carbon nanotube (CNT) substrates with phospholipids of varying curvature as the dispersing agents. Lipid spontaneous curvature is increased from close to zero (effectively cylindrical lipid) to highly positive (effectively conical lipid) by studying double tailed dipalmitoylphosphadidylcholine (DPPC) and single tailed lysophosphadidylcholine (LPC) which differ in the number of acyl chains but have identical headgroup. We find that lipids are good dispersion agents for both planar and curved nanoparticles and induce a dispersive barrier nonsize selectively. Differences in dispersion efficiency arise from lipid headgroup density and their extension from the hydrophobic substrate in the adsorption morphology. We map the packing morphology contributing factors and report that the aggregate morphologies depend on the competition of interactions rising from (1) hydrophobicity driven maximization of lipid-substrate contacts and lipid self-adhesion, (2) tail bending energy cost, (3) preferential alignment along the graphitic substrate principal axes, and (4) lipid headgroup preferential packing. Curved substrates adjust the morphology by changing the balance between the interaction strengths. Jointly, the findings show substrate curvature and dimensions are a way to tune lipid adsorption to desired, self-assembling patterns. Besides engineering dispersion efficiency, the findings could bear significance in designing materials with defined molecular scale, molecular coatings for orientation specific CNT assembly or lipid-based molecular masks and patterning on graphene.

Inelastic neutron scattering of large molecular systems: The case of the original benzylic amide [2]catenane

NASA Astrophysics Data System (ADS)

Caciuffo, Roberto; Esposti, Alessandra Degli; Deleuze, Michael S.; Leigh, David A.; Murphy, Aden; Paci, Barbara; Parker, Stewart F.; Zerbetto, Francesco

1998-12-01

The inelastic neutron scattering (INS) spectrum of the original benzylic amide [2]catenane is recorded and simulated by a semiempirical quantum chemical procedure coupled with the most comprehensive approach available to date, the CLIMAX program. The successful simulation of the spectrum indicates that the modified neglect of differential overlap (MNDO) model can reproduce the intramolecular vibrations of a molecular system as large as a catenane (136 atoms). Because of the computational costs involved and some numerical instabilities, a less expensive approach is attempted which involves the molecular mechanics-based calculation of the INS response in terms of the most basic formulation for the scattering activity. The encouraging results obtained validate the less computationally intensive procedure and allow its extension to the calculation of the INS spectrum for a second, theoretical, co-conformer, which, although structurally and energetically reasonable, is not, in fact, found in the solid state. The second structure was produced by a Monte Carlo simulated annealing method run in the conformational space (a procedure that would have been prohibitively expensive at the semiempirical level) and is characterized by a higher degree of intramolecular hydrogen bonding than the x-ray structure. The two alternative structures yield different simulated spectra, only one of which, the authentic one, is compatible with the experimental data. Comparison of the two simulated and experimental spectra affords the identification of an inelastic neutron scattering spectral signature of the correct hydrogen bonding motif in the region slightly above 700 cm-1. The study illustrates that combinations of simulated INS data and experimental results can be successfully used to discriminate between different proposed structures or possible hydrogen bonding motifs in large functional molecular systems.

Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties

PubMed Central

Martinho, Nuno; Silva, Liana C; Florindo, Helena F; Brocchini, Steve; Zloh, Mire; Barata, Teresa S

2017-01-01

Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure–activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(l-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behavior. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD-PG-G4 can provide a suitable scaffold to be used for biophysical studies of surface-modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system. PMID:29026301

Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties.

PubMed

Martinho, Nuno; Silva, Liana C; Florindo, Helena F; Brocchini, Steve; Zloh, Mire; Barata, Teresa S

2017-01-01

Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure-activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(l-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behavior. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD-PG-G4 can provide a suitable scaffold to be used for biophysical studies of surface-modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system.

[Gliomatosis cerebri].

PubMed

Bruna, J; Velasco, R

2010-04-01

gliomatosis cerebri (GC) is a rare, diffusely growing glial tumour characterized by extensive brain infiltration. The diversity of histological subtype and grade on presentation among different subjects, in addition to the usually poor response to treatment make GC an uncertain entity where many questions still remain unanswered. One article in this issue of NEUROLOGIA describes a series of 22 patients with GC, where clinical, therapeutic and outcome results are detailed. clinical presentation of GC is non-specific and, although the neuroimage is characteristic, the spectrum of differential diagnosis is wide. Despite the fact that known prognostic factors in glioma also seem to be involved in GC, the heterogeneity of pathology and molecular findings on biopsy samples makes it difficult to characterise GC correctly. Therefore, variability of outcome and response to therapy is the rule. Evidence on therapeutic strategies is based on case-series. According to this, the optimal treatment is not well established. Part of current research is focused on identifying molecular predictor factors of response to chemotherapy. the addition of chemotherapy in the classic treatment schedule based on radiotherapy seems to produce better responses in GC patients. However, the outcome of these patients remains poor with low survival rates. Phase III multi-centre trials to evaluate different therapeutic strategies in GC are essential. Further knowledge on the histological profile and molecular prognostic factors is also required. Patients should be stratified according to the prognostic factors identified. Published by Elservier España, S.L. All rights reserved.

Role of chronic lymphocytic thyroiditis in central node metastasis of papillary thyroid carcinoma.

PubMed

Paulson, Lorien M; Shindo, Maisie L; Schuff, Kathryn G

2012-09-01

(1) To investigate the role of chronic lymphocytic thyroiditis (CLT) in central node metastasis of papillary thyroid carcinoma (PTC) and (2) to evaluate the presence of chronic lymphocytic thyroiditis according to PTC-specific molecular markers. Historical cohort study. Academic medical center. All patients who underwent total thyroidectomy with central neck dissection for PTC at Oregon Health & Science University between 2005 and 2010 were screened for the presence of CLT and reviewed for clinical prognostic factors. Patients with inadequate central neck dissections were excluded. Molecular markers for PTC were analyzed on archived tumor samples. A total of 139 patients met selection criteria. The rate of CLT was 43.8%. The rate of central node positivity was 63%. Presence of CLT was associated with a significantly lower proportion of central node metastases (49% vs 74%, P = .003) and angiolymphatic invasion (31% vs 15%, P = .03). There was no significant difference in mean age, tumor size, and extracapsular extension. Molecular genotyping did not reveal a significant difference in the types of mutations found in both groups. The data indicate a lower incidence of central compartment lymph node metastasis in those with CLT in this patient population, suggesting a potential protective role in tumor spread. The equal distribution of tumor mutations between the carcinomas with and without evidence of CLT argues against a mutation-specific antigen as the immunologic stimulus. Further research is needed to characterize the role of autoimmunity in thyroid cancer.

Biomarker profiling in reef corals of Tonga’s Ha’apai and Vava’u archipelagos

PubMed Central

Chen, Chii-Shiarng; Dempsey, Alexandra C.

2017-01-01

Given the significant threats towards Earth’s coral reefs, there is an urgent need to document the current physiological condition of the resident organisms, particularly the reef-building scleractinians themselves. Unfortunately, most of the planet’s reefs are understudied, and some have yet to be seen. For instance, the Kingdom of Tonga possesses an extensive reef system, with thousands of hectares of unobserved reefs; little is known about their ecology, nor is there any information on the health of the resident corals. Given such knowledge deficiencies, 59 reefs across three Tongan archipelagos were surveyed herein, and pocilloporid corals were sampled from approximately half of these surveyed sites; 10 molecular-scale response variable were assessed in 88 of the sampled colonies, and 12 colonies were found to be outliers based on employment of a multivariate statistics-based aberrancy detection system. These outliers differed from the statistically normally behaving colonies in having not only higher RNA/DNA ratios but also elevated expression levels of three genes: 1) Symbiodinium zinc-induced facilitator-like 1-like, 2) host coral copper-zinc superoxide dismutase, and 3) host green fluorescent protein-like chromoprotein. Outliers were also characterized by significantly higher variation amongst the molecular response variables assessed, and the response variables that contributed most significantly to colonies being delineated as outliers differed between the two predominant reef coral species sampled, Pocillopora damicornis and P. acuta. These closely related species also displayed dissimilar temporal fluctuation patterns in their molecular physiologies, an observation that may have been driven by differences in their feeding strategies. Future works should attempt to determine whether corals displaying statistically aberrant molecular physiology, such as the 12 Tongan outliers identified herein, are indeed characterized by a diminished capacity for acclimating to the rapid changes in their abiotic milieu occurring as a result of global climate change. PMID:29091723

Molecular characterization of Cryptococcus neoformans isolated from the environment in Beijing, China.

PubMed

Dou, Hongtao; Wang, Huizhu; Xie, Shaowei; Chen, Xinxin; Xu, Zhipeng; Xu, Yingchun

2017-10-01

The molecular type of environmental Cryptococcus neoformans in Beijing was not clear. Our study aims to reveal the molecular characterization of C. neoformans complex from environment in Beijing, China. A total of 435 samples of pigeon droppings from 11 different homes in Beijing were collected from August to November in 2015. Pigeon droppings were inoculated onto caffeic acid cornmeal agar (CACA) to screen C. neoformans complex. Bruker Biotyper matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was performed for species identification. Serotype and mating type was determined by specific primers. Restriction fragment length polymorphisms of URA5 (URA5-RFLP) were applied to genotype. Multi-locus sequence typing (MLST) was done for further identification and sequence type (ST) determination. Altogether, 81 isolates of C. neoformans AFLP1/VNI were recognized from 435 pigeon droppings in this study. The positive rate for C. neoformans AFLP1/VNI from pigeon droppings in different homes varied from 5.0% to 52.6%, the average was 20.2%. All of these cryptococcal strains were serotype A, MATα. They were genotyped as VNI by URA5-RFLP and were confirmed by MLST. No other molecular types of C. neoformans and Cryptococcus gattii isolates were isolated. Their STs were identified as ST 31 (n = 54, 66.7%), followed by ST 53 (n = 10), ST 191 (n = 8), ST 5 (n = 5), ST 57 (n = 3), and ST 38 (n = 1). We concluded that not only clinical but also environmental isolates of C. neoformans need to be investigated more deeply and more extensively. The virulence difference between ST 5 and ST 31 need to be explored in the future. © The Author 2017. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Extensive Mobilome-Driven Genome Diversification in Mouse Gut-Associated Bacteroides vulgatus mpk.

PubMed

Lange, Anna; Beier, Sina; Steimle, Alex; Autenrieth, Ingo B; Huson, Daniel H; Frick, Julia-Stefanie

2016-04-25

Like many other Bacteroides species, Bacteroides vulgatus strain mpk, a mouse fecal isolate which was shown to promote intestinal homeostasis, utilizes a variety of mobile elements for genome evolution. Based on sequences collected by Pacific Biosciences SMRT sequencing technology, we discuss the challenges of assembling and studying a bacterial genome of high plasticity. Additionally, we conducted comparative genomics comparing this commensal strain with the B. vulgatus type strain ATCC 8482 as well as multiple other Bacteroides and Parabacteroides strains to reveal the most important differences and identify the unique features of B. vulgatus mpk. The genome of B. vulgatus mpk harbors a large and diverse set of mobile element proteins compared with other sequenced Bacteroides strains. We found evidence of a number of different horizontal gene transfer events and a genome landscape that has been extensively altered by different mobilization events. A CRISPR/Cas system could be identified that provides a possible mechanism for preventing the integration of invading external DNA. We propose that the high genome plasticity and the introduced genome instabilities of B. vulgatus mpk arising from the various mobilization events might play an important role not only in its adaptation to the challenging intestinal environment in general, but also in its ability to interact with the gut microbiota. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Characterization of 1,577 Primary Prostate Cancers Reveals Novel Biological and Clinicopathological Insights into Molecular Subtypes

PubMed Central

Tomlins, Scott A.; Alshalalfa, Mohammed; Davicioni, Elai; Erho, Nicholas; Yousefi, Kasra; Zhao, Shuang; Haddad, Zaid; Den, Robert B.; Dicker, Adam P.; Trock, Bruce; DeMarzo, Angelo; Ross, Ashley; Schaeffer, Edward M.; Klein, Eric A.; Magi-Galluzzi, Cristina; Karnes, Jeffery R.; Jenkins, Robert B.; Feng, Felix Y.

2015-01-01

Background Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG) and SPINK1 over-expression. Clinical assessment may aid in disease stratification, complementing available prognostic tests. Objective To determine the analytical validity and clinicopatholgical associations of microarray-based molecular subtyping. Design, Setting and Participants We analyzed Affymetrix GeneChip expression profiles for 1,577 patients from eight radical prostatectomy (RP) cohorts, including 1,351 cases assessed using the Decipher prognostic assay (performed in a CLIA-certified laboratory). A microarray-based (m-) random forest ERG classification model was trained and validated. Outlier expression analysis was used to predict other mutually exclusive non-ERG ETS gene rearrangements (ETS+) or SPINK1 over-expression (SPINK1+). Outcome Measurements Associations with clinical features and outcomes by multivariable logistic regression analysis and receiver operating curves. Results and Limitations The m-ERG classifier showed 95% accuracy in an independent validation subset (n=155 samples). Across cohorts, 45%, 9%, 8% and 38% of PCa were classified as m-ERG+, m-ETS+, m-SPINK1+, and triple negative (m-ERG−/m-ETS−/m-SPINK1−), respectively. Gene expression profiling supports three underlying molecularly defined groups (m-ERG+, m-ETS+ and m-SPINK1+/triple negative). On multivariable analysis, m-ERG+ tumors were associated with lower preoperative serum PSA and Gleason scores, but enriched for extraprostatic extension (p<0.001). m-ETS+ tumors were associated with seminal vesicle invasion (p=0.01), while m-SPINK1+/triple negative tumors had higher Gleason scores and were more frequent in Black/African American patients (p<0.001). Clinical outcomes were not significantly different between subtypes. Conclusions A clinically available prognostic test (Decipher) can also assess PCa molecular subtypes, obviating the need for additional testing. Clinicopathological differences were found among subtypes based on global expression patterns. PMID:25964175

Diffusive molecular dynamics simulations of lithiation of silicon nanopillars

NASA Astrophysics Data System (ADS)

Mendez, J. P.; Ponga, M.; Ortiz, M.

2018-06-01

We report diffusive molecular dynamics simulations concerned with the lithiation of Si nano-pillars, i.e., nano-sized Si rods held at both ends by rigid supports. The duration of the lithiation process is of the order of milliseconds, well outside the range of molecular dynamics but readily accessible to diffusive molecular dynamics. The simulations predict an alloy Li15Si4 at the fully lithiated phase, exceedingly large and transient volume increments up to 300% due to the weakening of Sisbnd Si iterations, a crystalline-to-amorphous-to-lithiation phase transition governed by interface kinetics, high misfit strains and residual stresses resulting in surface cracks and severe structural degradation in the form of extensive porosity, among other effects.

Biology of Healthy Aging and Longevity.

PubMed

Carmona, Juan José; Michan, Shaday

2016-01-01

As human life expectancy is prolonged, age-related diseases are thriving. Aging is a complex multifactorial process of molecular and cellular decline that affects tissue function over time, rendering organisms frail and susceptible to disease and death. Over the last decades, a growing body of scientific literature across different biological models, ranging from yeast, worms, flies, and mice to primates, humans and other long-lived animals, has contributed greatly towards identifying conserved biological mechanisms that ward off structural and functional deterioration within living systems. Collectively, these data offer powerful insights into healthy aging and longevity. For example, molecular integrity of the genome, telomere length, epigenetic landscape stability, and protein homeostasis are all features linked to "youthful" states. These molecular hallmarks underlie cellular functions associated with aging like mitochondrial fitness, nutrient sensing, efficient intercellular communication, stem cell renewal, and regenerative capacity in tissues. At present, calorie restriction remains the most robust strategy for extending health and lifespan in most biological models tested. Thus, pathways that mediate the beneficial effects of calorie restriction by integrating metabolic signals to aging processes have received major attention, such as insulin/insulin growth factor-1, sirtuins, mammalian target of rapamycin, and 5' adenosine monophosphate-activated protein kinase. Consequently, small-molecule targets of these pathways have emerged in the impetuous search for calorie restriction mimetics, of which resveratrol, metformin, and rapamycin are the most extensively studied. A comprehensive understanding of the molecular and cellular mechanisms that underlie age-related deterioration and repair, and how these pathways interconnect, remains a major challenge for uncovering interventions to slow human aging while extending molecular and physiological youthfulness, vitality, and health. This review summarizes key molecular mechanisms underlying the biology of healthy aging and longevity.

PROGNOSTIC SIGNIFICANCE OF CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR CHARACTERISTICS OF MEDULLOBLASTOMAS IN THE PROSPECTIVE HIT2000 MULTICENTER CLINICAL TRIAL COHORT

PubMed Central

Pietsch, Torsten; Schmidt, Rene; Remke, Marc; Korshunov, Andrey; Hovestadt, Volker; Jones, David TW; Felsberg, Jörg; Kaulich, Kerstin; Goschzik, Tobias; Kool, Marcel; Northcott, Paul A.; von Hoff, Katja; von Bueren, André O.; Friedrich, Carsten; Skladny, Heyko; Fleischhack, Gudrun; Taylor, Michael D.; Cremer, Friedrich; Lichter, Peter; Faldum, Andreas; Reifenberger, Guido; Rutkowski, Stefan; Pfister, Stefan M.

2014-01-01

BACKGROUND: This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. METHODS: Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a validation (n = 57) dataset. All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. RESULTS: By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, TOP2A copy-number, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining “intermediate molecular risk” population dependent on age, M-stage, pattern of synaptophysin expression, and MYCN copy-number status was identified and validated, with speckled synaptophysin expression indicating worse outcome. CONCLUSIONS: Methylation subgrouping and CTNNB1 mutation status represent robust tools for the risk-stratification of medulloblastoma. A simple clinico-pathological risk score for “intermediate molecular risk” patients was identified, which deserves further validation. SECONDARY CATEGORY: Pediatrics.

Using molecular diagnostic testing to personalize the treatment of patients with gastrointestinal stromal tumors.

PubMed

Bannon, Amber E; Klug, Lillian R; Corless, Christopher L; Heinrich, Michael C

2017-05-01

The diagnosis and treatment of gastrointestinal stromal tumor (GIST) has emerged as a paradigm for modern cancer treatment ('precision medicine'), as it highlights the importance of matching molecular defects with specific therapies. Over the past two decades, the molecular classification and diagnostic work up of GIST has been radically transformed, accompanied by the development of molecular therapies for specific subgroups of GIST. This review summarizes the developments in the field of molecular diagnosis of GIST, particularly as they relate to optimizing medical therapy. Areas covered: Based on an extensive literature search of the molecular and clinical aspects of GIST, the authors review the most important developments in this field with an emphasis on the differential diagnosis of GIST including mutation testing, therapeutic implications of each molecular subtype, and emerging technologies relevant to the field. Expert commentary: The use of molecular diagnostics to classify GIST has been shown to be successful in optimizing patient treatment, but these methods remain under-utilized. In order to facilitate efficient and comprehensive molecular testing, the authors have developed a decision tree to aid clinicians.

Molecular epidemiological survey of bacteremia by multidrug resistant Pseudomonas aeruginosa: the relevance of intrinsic resistance mechanisms

PubMed Central

Dantas, Raquel Cristina Cavalcanti; Silva, Rebecca Tavares e; Ferreira, Melina Lorraine; Gonçalves, Iara Rossi; Araújo, Bruna Fuga; de Campos, Paola Amaral; Royer, Sabrina; Batistão, Deivid William da Fonseca; Gontijo-Filho, Paulo Pinto; Ribas, Rosineide Marques

2017-01-01

The bacterial factors associated with bacteremia by multidrug-resistant and extensively drug-resistant P. aeruginosa, including overexpression of efflux pumps, AmpC overproduction, and loss/alteration of the OprD porin in isolates that are non-Metallo-β-Lactamase producing were analyzed in a retrospective study. Molecular analyses included strain typing by Pulsed Field Gel Electrophoresis and identification of key genes via qualitative and quantitative PCR-based assays. Previous use of carbapenems and tracheostomy was independently associated with the development of bacteremia by extensively drug-resistant and multidrug-resistant strains of P. aeruginosa. A high consumption of antimicrobials was observed, and 75.0% of the isolates contained amplicons with the blaSPM-1 and blaVIM genes. Of the 47 non-Metallo-β-Lactamase isolates, none had another type of carbapenemase. However, the isolates exhibited high rates of hyperproduction of AmpC, loss of the OprD porin (71.4%) and the presence of MexABOprM (57.1%) and MexXY (64.3%). This study suggests that in non-Metallo-β-Lactamase isolates, the association of intrinsic resistance mechanisms could contributes to the expression of multidrug-resistant/extensively drug-resistant phenotypes. PMID:28481953

pysimm: A Python Package for Simulation of Molecular Systems

NASA Astrophysics Data System (ADS)

Fortunato, Michael; Colina, Coray

pysimm, short for python simulation interface for molecular modeling, is a python package designed to facilitate the structure generation and simulation of molecular systems through convenient and programmatic access to object-oriented representations of molecular system data. This poster presents core features of pysimm and design philosophies that highlight a generalized methodology for incorporation of third-party software packages through API interfaces. The integration with the LAMMPS simulation package is explained to demonstrate this methodology. pysimm began as a back-end python library that powered a cloud-based application on nanohub.org for amorphous polymer simulation. The extension from a specific application library to general purpose simulation interface is explained. Additionally, this poster highlights the rapid development of new applications to construct polymer chains capable of controlling chain morphology such as molecular weight distribution and monomer composition.

Vapor-pressure osmometric study of the molecular weight and aggregation tendency of a reference-soil fulvic acid

USGS Publications Warehouse

Marinsky, J.A.; Reddy, M.M.

1990-01-01

The molecular weight and aggregation tendency of a reference-soil fulvic acid in Armadale horizon Bh were determined by vapor-pressure osmometry using tetrahydrofuran and water as solvents. With tetrahydrofuran, number-average molecular weight values of 767 ?? 34 and 699 ?? 8 daltons were obtained from two separate sets of measurements. Two sets of measurements with water also yielded values within this range (754 ?? 70 daltons) provided that the fulvic acid concentration in water did not exceed 7 mg ml-1; at higher concentrations (9.1-13.7 mg ml-1) a number-average molecular weight of 956 ?? 25 daltons was resolved, providing evidence of molecular aggregation. Extension of these studies to 80% neutralized fulvic acid showed that a sizeable fraction of the sodium counter ion is not osmotically active.

Microbial community composition and trophic role along a marked salinity gradient in Laguna Puilar, Salar de Atacama, Chile.

PubMed

Dorador, Cristina; Fink, Patrick; Hengst, Martha; Icaza, Gonzalo; Villalobos, Alvaro S; Vejar, Drina; Meneses, Daniela; Zadjelovic, Vinko; Burmann, Lisa; Moelzner, Jana; Harrod, Chris

2018-05-09

The geological, hydrological and microbiological features of the Salar de Atacama, the most extensive evaporitic sedimentary basin in the Atacama Desert of northern Chile, have been extensively studied. In contrast, relatively little attention has been paid to the composition and roles of microbial communities in hypersaline lakes which are a unique feature in the Salar. In the present study biochemical, chemical and molecular biological tools were used to determine the composition and roles of microbial communities in water, microbial mats and sediments along a marked salinity gradient in Laguna Puilar which is located in the "Los Flamencos" National Reserve. The bacterial communities at the sampling sites were dominated by members of the phyla Bacteroidetes, Chloroflexi, Cyanobacteria and Proteobacteria. Stable isotope and fatty acid analyses revealed marked variability in the composition of microbial mats at different sampling sites both horizontally (at different sites) and vertically (in the different layers). The Laguna Puilar was shown to be a microbially dominated ecosystem in which more than 60% of the fatty acids at particular sites are of bacterial origin. Our pioneering studies also suggest that the energy budgets of avian consumers (three flamingo species) and dominant invertebrates (amphipods and gastropods) use minerals as a source of energy and nutrients. Overall, the results of this study support the view that the Salar de Atacama is a heterogeneous and fragile ecosystem where small changes in environmental conditions may alter the balance of microbial communities with possible consequences at different trophic levels.

Atomic and Molecular Systems in Intense Ultrashort Laser Pulses

NASA Astrophysics Data System (ADS)

Saenz, A.

2008-07-01

The full quantum mechanical treatment of atomic and molecular systems exposed to intense laser pulses is a so far unsolved challenge, even for systems as small as molecular hydrogen. Therefore, a number of simplified qualitative and quantitative models have been introduced in order to provide at least some interpretational tools for experimental data. The assessment of these models describing the molecular response is complicated, since a comparison to experiment requires often a number of averages to be performed. This includes in many cases averaging of different orientations of the molecule with respect to the laser field, focal volume effects, etc. Furthermore, the pulse shape and even the peak intensity is experimentally not known with very high precision; considering, e.g., the exponential intensity dependence of the ionization signal. Finally, experiments usually provide only relative yields. As a consequence of all these averagings and uncertainties, it is possible that different models may successfully explain some experimental results or features, although these models disagree substantially, if their predictions are compared before averaging. Therefore, fully quantum-mechanical approaches at least for small atomic and molecular systems are highly desirable and have been developed in our group. This includes efficient codes for solving the time-dependent Schrodinger equation of atomic hydrogen, helium or other effective one- or two-electron atoms as well as for the electronic motion in linear (effective) one-and two-electron diatomic molecules like H_2.Very recently, a code for larger molecular systems that adopts the so-called single-active electron approximation was also successfully implemented and applied. In the first part of this talk popular models describing intense laser-field ionization of atoms and their extensions to molecules are described. Then their validity is discussed on the basis of quantum-mechanical calculations. Finally, some peculiar molecular strong-field effects and the possibility of strong-field control mechanisms will be demonstrated. This includes phenomena like enhanced ionization and bond softening as well as the creation of vibrational wavepacket in the non-ionized electronic ground state of H_2 by creating a Schrodinger-cat state between the ionized and the non-ionized molecules. The latter, theoretically predicted phenomenon was very recently experimentally observed and lead to the real-time observation of the so far fastest molecular motion.

Coupling Between Metabolism and Compartmentalization: Vesicle Growth in the Presence of Dipeptides

NASA Astrophysics Data System (ADS)

Wei, C.; Pohorille, A.

2017-07-01

Extensive molecular dynamics simulations demonstrate low energy pathway for fast fusion of vesicle mediated by membrane-bound hydrophobic dipeptides and facilitated flip-flop transport of fatty acid molecule for transmembrane proton transfer.

Molecular Survey for the Invasive Leafminer Pest Liriomyza huidobrensis (Diptera: Agromyzidae) in California Uncovers Only the Native Pest Liriomyza langei.

PubMed

Scheffer, Sonja J; Lewis, Matthew L; Gaimari, Stephen D; Reitz, Stuart R

2014-10-01

Liriomyza huidobrensis (Blanchard) is a highly destructive invasive leafminer pest currently causing extensive damage to vegetable and horticultural crops around the world. Liriomyza langei Frick is a leafminer pest native to California that cannot currently be morphologically distinguished from L. huidobrensis. We used a DNA-barcoding approach, a published PCR-RFLP method, and a new multiplex PCR method to analyze 664 flies matching the morphological description of huidobrensis-langei. We found no evidence for the presence of L. huidobrensis in our extensive samples from California. In addition to the new molecular method, this work is important because it provides definitive data that the California "pea leafminer" is currently, and has probably always been, L. langei. These data will also be important in the event that the highly invasive L. huidobrensis ever becomes established. © 2014 Entomological Society of America.

A Molecular–Structure Hypothesis

PubMed Central

Boeyens, Jan C. A.

2010-01-01

The self-similar symmetry that occurs between atomic nuclei, biological growth structures, the solar system, globular clusters and spiral galaxies suggests that a similar pattern should characterize atomic and molecular structures. This possibility is explored in terms of the current molecular structure-hypothesis and its extension into four-dimensional space-time. It is concluded that a quantum molecule only has structure in four dimensions and that classical (Newtonian) structure, which occurs in three dimensions, cannot be simulated by quantum-chemical computation. PMID:21151437

Spectroscopic data for an astronomy database

NASA Technical Reports Server (NTRS)

Parkinson, W. H.; Smith, Peter L.

1995-01-01

Very few of the atomic and molecular data used in analyses of astronomical spectra are currently available in World Wide Web (WWW) databases that are searchable with hypertext browsers. We have begun to rectify this situation by making extensive atomic data files available with simple search procedures. We have also established links to other on-line atomic and molecular databases. All can be accessed from our database homepage with URL: http:// cfa-www.harvard.edu/ amp/ data/ amdata.html.

VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins.

PubMed

Couvineau, Alain; Laburthe, Marc

2012-05-01

The vasoactive intestinal peptide (VIP) is a neuropeptide with wide distribution in both central and peripheral nervous systems, where it plays important regulatory role in many physiological processes. VIP displays a large biological functions including regulation of exocrine secretions, hormone release, fetal development, immune responses, etc. VIP appears to exert beneficial effect in neuro-degenerative and inflammatory diseases. The mechanism of action of VIP implicates two subtypes of receptors (VPAC1 and VPAC2), which are members of class B receptors belonging to the super-family of GPCR. This article reviews the current knowledge regarding the structure and molecular pharmacology of VPAC receptors. The structure-function relationship of VPAC1 receptor has been extensively studied, allowing to understand the molecular basis for receptor affinity, specificity, desensitization and coupling to adenylyl cyclase. Those studies have clearly demonstrated the crucial role of the N-terminal ectodomain (N-ted) of VPAC1 receptor in VIP recognition. By using different approaches including directed mutagenesis, photoaffinity labelling, NMR, molecular modelling and molecular dynamic simulation, it has been shown that the VIP molecule interacts with the N-ted of VPAC1 receptor, which is itself structured as a 'Sushi' domain. VPAC1 receptor also interacts with a few accessory proteins that play a role in cell signalling of receptors. Recent advances in the structural characterization of VPAC receptor and more generally of class B GPCRs will lead to the design of new molecules, which could have considerable interest for the treatment of inflammatory and neuro-degenerative diseases. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Viscoelastic properties of model segments of collagen molecules.

PubMed

Gautieri, Alfonso; Vesentini, Simone; Redaelli, Alberto; Buehler, Markus J

2012-03-01

Collagen is the prime construction material in vertebrate biology, determining the mechanical behavior of connective tissues such as tendon, bone and skin. Despite extensive efforts in the investigation of the origin of collagen unique mechanical properties, a deep understanding of the relationship between molecular structure and mechanical properties remains elusive, hindered by the complex hierarchical structure of collagen-based tissues. In particular, although extensive studies of viscoelastic properties have been pursued at the macroscopic (fiber/tissue) level, fewer investigations have been performed at the smaller scales, including in particular collagen molecules and fibrils. These scales are, however, important for a complete understanding of the role of collagen as an important constituent in the extracellular matrix. Here, using an atomistic modeling approach, we perform in silico creep tests of a collagen-like peptide, monitoring the strain-time response for different values of applied external load. The results show that individual collagen molecules exhibit a nonlinear viscoelastic behavior, with a Young's modulus increasing from 6 to 16GPa (for strains up to 20%), a viscosity of 3.84.±0.38Pa·s, and a relaxation time in the range of 0.24-0.64ns. The single molecule viscosity, for the first time reported here, is several orders of magnitude lower than the viscosity found for larger-scale single collagen fibrils, suggesting that the viscous behavior of collagen fibrils and fibers involves additional mechanisms, such as molecular sliding between collagen molecules within the fibril or the effect of relaxation of larger volumes of solvent. Based on our molecular modeling results we propose a simple structural model that describes collagen tissue as a hierarchical structure, providing a bottom-up description of elastic and viscous properties form the properties of the tissue basic building blocks. Copyright © 2011 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

Back to the future with the AGP–Ca2+ flux capacitor

PubMed Central

Lamport, Derek T. A.; Varnai, Peter; Seal, Charlotte E.

2014-01-01

Background Arabinogalactan proteins (AGPs) are ubiquitous in green plants. AGPs comprise a widely varied group of hydroxyproline (Hyp)-rich cell surface glycoproteins (HRGPs). However, the more narrowly defined classical AGPs massively predominate and cover the plasma membrane. Extensive glycosylation by pendant polysaccharides O-linked to numerous Hyp residues like beads of a necklace creates a unique ionic compartment essential to a wide range of physiological processes including germination, cell extension and fertilization. The vital clue to a precise molecular function remained elusive until the recent isolation of small Hyp–arabinogalactan polysaccharide subunits; their structural elucidation by nuclear magentic resonance imaging, molecular simulations and direct experiment identified a 15-residue consensus subunit as a β-1,3-linked galactose trisaccharide with two short branched sidechains each with a single glucuronic acid residue that binds Ca2+ when paired with its adjacent sidechain. Scope AGPs bind Ca2+ (Kd ∼ 6 μm) at the plasma membrane (PM) at pH ∼5·5 but release it when auxin-dependent PM H+-ATPase generates a low periplasmic pH that dissociates AGP–Ca2+ carboxylates (pka ∼3); the consequential large increase in free Ca2+ drives entry into the cytosol via Ca2+ channels that may be voltage gated. AGPs are thus arguably the primary source of cytosolic oscillatory Ca2+ waves. This differs markedly from animals, in which cytosolic Ca2+ originates mostly from internal stores such as the sarcoplasmic reticulum. In contrast, we propose that external dynamic Ca2+ storage by a periplasmic AGP capacitor co-ordinates plant growth, typically involving exocytosis of AGPs and recycled Ca2+, hence an AGP–Ca2+ oscillator. Conclusions The novel concept of dynamic Ca2+ recycling by an AGP–Ca2+ oscillator solves the long-standing problem of a molecular-level function for classical AGPs and thus integrates three fields: AGPs, Ca2+ signalling and auxin. This accounts for the involvement of AGPs in plant morphogenesis, including tropic and nastic movements. PMID:25139429

High-Throughput Sequencing to Reveal Genes Involved in Reproduction and Development in Bactrocera dorsalis (Diptera: Tephritidae)

PubMed Central

Zheng, Weiwei; Peng, Tao; He, Wei; Zhang, Hongyu

2012-01-01

Background Tephritid fruit flies in the genus Bactrocera are of major economic significance in agriculture causing considerable loss to the fruit and vegetable industry. Currently, there is no ideal control program. Molecular means is an effective method for pest control at present, but genomic or transcriptomic data for members of this genus remains limited. To facilitate molecular research into reproduction and development mechanisms, and finally effective control on these pests, an extensive transcriptome for the oriental fruit fly Bactrocera dorsalis was produced using the Roche 454-FLX platform. Results We obtained over 350 million bases of cDNA derived from the whole body of B. dorsalis at different developmental stages. In a single run, 747,206 sequencing reads with a mean read length of 382 bp were obtained. These reads were assembled into 28,782 contigs and 169,966 singletons. The mean contig size was 750 bp and many nearly full-length transcripts were assembled. Additionally, we identified a great number of genes that are involved in reproduction and development as well as genes that represent nearly all major conserved metazoan signal transduction pathways, such as insulin signal transduction. Furthermore, transcriptome changes during development were analyzed. A total of 2,977 differentially expressed genes (DEGs) were detected between larvae and pupae libraries, while there were 1,621 DEGs between adults and larvae, and 2,002 between adults and pupae. These DEGs were functionally annotated with KEGG pathway annotation and 9 genes were validated by qRT-PCR. Conclusion Our data represent the extensive sequence resources available for B. dorsalis and provide for the first time access to the genetic architecture of reproduction and development as well as major signal transduction pathways in the Tephritid fruit fly pests, allowing us to elucidate the molecular mechanisms underlying courtship, ovipositing, development and detailed analyses of the signal transduction pathways. PMID:22570719

Plant lectins: the ties that bind in root symbiosis and plant defense.

PubMed

De Hoff, Peter L; Brill, Laurence M; Hirsch, Ann M

2009-07-01

Lectins are a diverse group of carbohydrate-binding proteins that are found within and associated with organisms from all kingdoms of life. Several different classes of plant lectins serve a diverse array of functions. The most prominent of these include participation in plant defense against predators and pathogens and involvement in symbiotic interactions between host plants and symbiotic microbes, including mycorrhizal fungi and nitrogen-fixing rhizobia. Extensive biological, biochemical, and molecular studies have shed light on the functions of plant lectins, and a plethora of uncharacterized lectin genes are being revealed at the genomic scale, suggesting unexplored and novel diversity in plant lectin structure and function. Integration of the results from these different types of research is beginning to yield a more detailed understanding of the function of lectins in symbiosis, defense, and plant biology in general.

Cholesterol's location in lipid bilayers

DOE PAGES

Marquardt, Drew; Kučerka, Norbert; Wassall, Stephen R.; ...

2016-04-04

It is well known that cholesterol modifies the physical properties of lipid bilayers. For example, the much studied liquid-ordered L o phase contains rapidly diffusing lipids with their acyl chains in the all trans configuration, similar to gel phase bilayers. Moreover, the L o phase is commonly associated with cholesterol-enriched lipid rafts, which are thought to serve as platforms for signaling proteins in the plasma membrane. Cholesterol's location in lipid bilayers has been studied extensively, and it has been shown – at least in some bilayers – to align differently from its canonical upright orientation, where its hydroxyl group ismore » in the vicinity of the lipid–water interface. In this study we review recent works describing cholesterol's location in different model membrane systems with emphasis on results obtained from scattering, spectroscopic and molecular dynamics studies.« less

Cooperative expression of atomic chirality in inorganic nanostructures.

PubMed

Wang, Peng-Peng; Yu, Shang-Jie; Govorov, Alexander O; Ouyang, Min

2017-02-02

Cooperative chirality phenomena extensively exist in biomolecular and organic systems via intra- and inter-molecular interactions, but study of inorganic materials has been lacking. Here we report, experimentally and theoretically, cooperative chirality in colloidal cinnabar mercury sulfide nanocrystals that originates from chirality interplay between the crystallographic lattice and geometric morphology at different length scales. A two-step synthetic scheme is developed to allow control of critical parameters of these two types of handedness, resulting in different chiral interplays expressed as observables through materials engineering. Furthermore, we adopt an electromagnetic model with the finite element method to elucidate cooperative chirality in inorganic systems, showing excellent agreement with experimental results. Our study enables an emerging class of nanostructures with tailored cooperative chirality that is vital for fundamental understanding of nanoscale chirality as well as technology applications based on new chiroptical building blocks.

Cooperative expression of atomic chirality in inorganic nanostructures

PubMed Central

Wang, Peng-peng; Yu, Shang-Jie; Govorov, Alexander O; Ouyang, Min

2017-01-01

Cooperative chirality phenomena extensively exist in biomolecular and organic systems via intra- and inter-molecular interactions, but study of inorganic materials has been lacking. Here we report, experimentally and theoretically, cooperative chirality in colloidal cinnabar mercury sulfide nanocrystals that originates from chirality interplay between the crystallographic lattice and geometric morphology at different length scales. A two-step synthetic scheme is developed to allow control of critical parameters of these two types of handedness, resulting in different chiral interplays expressed as observables through materials engineering. Furthermore, we adopt an electromagnetic model with the finite element method to elucidate cooperative chirality in inorganic systems, showing excellent agreement with experimental results. Our study enables an emerging class of nanostructures with tailored cooperative chirality that is vital for fundamental understanding of nanoscale chirality as well as technology applications based on new chiroptical building blocks. PMID:28148957

Global Studies of Molecular Clouds in the Galaxy, the Magellanic Cloud and M31

NASA Technical Reports Server (NTRS)

Thaddeus, Patrick

1998-01-01

Over the past five years we have used our extensive CO surveys of the Galaxy and M31 in conjunction with spacecraft observations to address central problems in galactic structure and the astrophysics of molecular clouds. These problems included the nature of the molecular ring and its relation to the spiral arms and central bar, the cosmic ray distribution, the origin of the diffuse X-ray background, the distribution and properties of x-ray sources and supernova remnants, and the Galactic stellar mass distribution. For many of these problems, the nearby spiral M31 provided an important complementary perspective.

FlyBase: genes and gene models

PubMed Central

Drysdale, Rachel A.; Crosby, Madeline A.

2005-01-01

FlyBase (http://flybase.org) is the primary repository of genetic and molecular data of the insect family Drosophilidae. For the most extensively studied species, Drosophila melanogaster, a wide range of data are presented in integrated formats. Data types include mutant phenotypes, molecular characterization of mutant alleles and aberrations, cytological maps, wild-type expression patterns, anatomical images, transgenic constructs and insertions, sequence-level gene models and molecular classification of gene product functions. There is a growing body of data for other Drosophila species; this is expected to increase dramatically over the next year, with the completion of draft-quality genomic sequences of an additional 11 Drosphila species. PMID:15608223

Methane Adsorption in Zr-Based MOFs: Comparison and Critical Evaluation of Force Fields

PubMed Central

2017-01-01

The search for nanoporous materials that are highly performing for gas storage and separation is one of the contemporary challenges in material design. The computational tools to aid these experimental efforts are widely available, and adsorption isotherms are routinely computed for huge sets of (hypothetical) frameworks. Clearly the computational results depend on the interactions between the adsorbed species and the adsorbent, which are commonly described using force fields. In this paper, an extensive comparison and in-depth investigation of several force fields from literature is reported for the case of methane adsorption in the Zr-based Metal–Organic Frameworks UiO-66, UiO-67, DUT-52, NU-1000, and MOF-808. Significant quantitative differences in the computed uptake are observed when comparing different force fields, but most qualitative features are common which suggests some predictive power of the simulations when it comes to these properties. More insight into the host–guest interactions is obtained by benchmarking the force fields with an extensive number of ab initio computed single molecule interaction energies. This analysis at the molecular level reveals that especially ab initio derived force fields perform well in reproducing the ab initio interaction energies. Finally, the high sensitivity of uptake predictions on the underlying potential energy surface is explored. PMID:29170687

Using Morphological, Molecular and Climatic Data to Delimitate Yews along the Hindu Kush-Himalaya and Adjacent Regions

PubMed Central

Poudel, Ram C.; Möller, Michael; Gao, Lian-Ming; Ahrends, Antje; Baral, Sushim R.; Liu, Jie; Thomas, Philip; Li, De-Zhu

2012-01-01

Background Despite the availability of several studies to clarify taxonomic problems on the highly threatened yews of the Hindu Kush-Himalaya (HKH) and adjacent regions, the total number of species and their exact distribution ranges remains controversial. We explored the use of comprehensive sets of morphological, molecular and climatic data to clarify taxonomy and distributions of yews in this region. Methodology/Principal Findings A total of 743 samples from 46 populations of wild yew and 47 representative herbarium specimens were analyzed. Principle component analyses on 27 morphological characters and 15 bioclimatic variables plus altitude and maximum parsimony analysis on molecular ITS and trnL-F sequences indicated the existence of three distinct species occurring in different ecological (climatic) and altitudinal gradients along the HKH and adjacent regions Taxus contorta from eastern Afghanistan to the eastern end of Central Nepal, T. wallichiana from the western end of Central Nepal to Northwest China, and the first report of the South China low to mid-elevation species T. mairei in Nepal, Bhutan, Northeast India, Myanmar and South Vietnam. Conclusion/Significance The detailed sampling and combination of different data sets allowed us to identify three clearly delineated species and their precise distribution ranges in the HKH and adjacent regions, which showed no overlap or no distinct hybrid zone. This might be due to differences in the ecological (climatic) requirements of the species. The analyses further provided the selection of diagnostic morphological characters for the identification of yews occurring in the HKH and adjacent regions. Our work demonstrates that extensive sampling combined with the analysis of diverse data sets can reliably address the taxonomy of morphologically challenging plant taxa. PMID:23056501

A rigorous detection of interstellar CH3NCO: An important missing species in astrochemical networks.

PubMed

Cernicharo, J; Kisiel, Z; Tercero, B; Kolesniková, L; Medvedev, I R; López, A; Fortman, S; Winnewisser, M; de Lucia, F C; Alonso, J L; Guillemin, J-C

2016-03-01

The recent analysis of the composition of the frozen surface of comet 67P/Churyumov-Gerasimenko has revealed a significant number of complex organic molecules. Methyl isocyanate (CH 3 NCO) is one of the more abundant species detected on the comet surface. In this work we report extensive characterization of its rotational spectrum resulting in a list of 1269 confidently assigned laboratory lines and its detection in space towards the Orion clouds where 399 lines of the molecule have been unambiguously identified. We find that the limited mm-wave laboratory data reported prior to our work require some revision. The abundance of CH 3 NCO in Orion is only a factor of ten below those of HNCO and CH 3 CN. Unlike the molecular abundances in the coma of comets, which correlate with those of warm molecular clouds, molecular abundances in the gas phase in Orion are only weakly correlated with those measured on the comet surface. We also compare our abundances with those derived recently for this molecule towards Sgr B2 (Halfen et al. 2015). A more accurate abundance of CH 3 NCO is provided for this cloud based on our extensive laboratory work.

Conformational Sampling and Nucleotide-Dependent Transitions of the GroEL Subunit Probed by Unbiased Molecular Dynamics Simulations

PubMed Central

Skjaerven, Lars; Grant, Barry; Muga, Arturo; Teigen, Knut; McCammon, J. Andrew; Reuter, Nathalie; Martinez, Aurora

2011-01-01

GroEL is an ATP dependent molecular chaperone that promotes the folding of a large number of substrate proteins in E. coli. Large-scale conformational transitions occurring during the reaction cycle have been characterized from extensive crystallographic studies. However, the link between the observed conformations and the mechanisms involved in the allosteric response to ATP and the nucleotide-driven reaction cycle are not completely established. Here we describe extensive (in total long) unbiased molecular dynamics (MD) simulations that probe the response of GroEL subunits to ATP binding. We observe nucleotide dependent conformational transitions, and show with multiple 100 ns long simulations that the ligand-induced shift in the conformational populations are intrinsically coded in the structure-dynamics relationship of the protein subunit. Thus, these simulations reveal a stabilization of the equatorial domain upon nucleotide binding and a concomitant “opening” of the subunit, which reaches a conformation close to that observed in the crystal structure of the subunits within the ADP-bound oligomer. Moreover, we identify changes in a set of unique intrasubunit interactions potentially important for the conformational transition. PMID:21423709

A rigorous detection of interstellar CH3NCO: An important missing species in astrochemical networks⋆,⋆⋆

PubMed Central

Cernicharo, J.; Kisiel, Z.; Tercero, B.; Kolesniková, L.; Medvedev, I.R.; López, A.; Fortman, S.; Winnewisser, M.; de Lucia, F. C.; Alonso, J. L.; Guillemin, J.-C.

2016-01-01

The recent analysis of the composition of the frozen surface of comet 67P/Churyumov-Gerasimenko has revealed a significant number of complex organic molecules. Methyl isocyanate (CH3NCO) is one of the more abundant species detected on the comet surface. In this work we report extensive characterization of its rotational spectrum resulting in a list of 1269 confidently assigned laboratory lines and its detection in space towards the Orion clouds where 399 lines of the molecule have been unambiguously identified. We find that the limited mm-wave laboratory data reported prior to our work require some revision. The abundance of CH3NCO in Orion is only a factor of ten below those of HNCO and CH3CN. Unlike the molecular abundances in the coma of comets, which correlate with those of warm molecular clouds, molecular abundances in the gas phase in Orion are only weakly correlated with those measured on the comet surface. We also compare our abundances with those derived recently for this molecule towards Sgr B2 (Halfen et al. 2015). A more accurate abundance of CH3NCO is provided for this cloud based on our extensive laboratory work. PMID:27274565

MU OPIOID RECEPTORS IN PAIN MANAGEMENT

PubMed Central

Pasternak, Gavril; Pan, Ying-Xian

2014-01-01

Most of the potent analgesics currently in use act through the mu opioid receptor. Although they are classified as mu opioids, clinical experience suggests differences among them. The relative potencies of the agents can vary from patient to patient, as well as the side-effect profiles. These observations, coupled with pharmacological approaches in preclinical models, led to the suggestion of multiple subtypes of mu receptors. The explosion in molecular biology has led to the identification of a single gene encoding mu opioid receptors. It now appears that this gene undergoes extensive splicing, in which a single gene can generate multiple proteins. Evidence now suggests that these splice variants may help explain the clinical variability in responses among patients. PMID:21453899

Cutaneous immunology: basics and new concepts.

PubMed

Yazdi, Amir S; Röcken, Martin; Ghoreschi, Kamran

2016-01-01

As one of the largest organs, the skin forms a mechanical and immunological barrier to the environment. The skin immune system harbors cells of the innate immune system and cells of the adaptive immune system. Signals of the innate immune system typically initiate skin immune responses, while cells and cytokines of the adaptive immune system perpetuate the inflammation. Skin immune responses ensure effective host defense against pathogens but can also cause inflammatory skin diseases. An extensive crosstalk between the different cell types of the immune system, tissue cells, and pathogens is responsible for the complexity of skin immune reactions. Here we summarize the major cellular and molecular components of the innate and adaptive skin immune system.

Improving validation methods for molecular diagnostics: application of Bland-Altman, Deming and simple linear regression analyses in assay comparison and evaluation for next-generation sequencing

PubMed Central

Misyura, Maksym; Sukhai, Mahadeo A; Kulasignam, Vathany; Zhang, Tong; Kamel-Reid, Suzanne; Stockley, Tracy L

2018-01-01

Aims A standard approach in test evaluation is to compare results of the assay in validation to results from previously validated methods. For quantitative molecular diagnostic assays, comparison of test values is often performed using simple linear regression and the coefficient of determination (R2), using R2 as the primary metric of assay agreement. However, the use of R2 alone does not adequately quantify constant or proportional errors required for optimal test evaluation. More extensive statistical approaches, such as Bland-Altman and expanded interpretation of linear regression methods, can be used to more thoroughly compare data from quantitative molecular assays. Methods We present the application of Bland-Altman and linear regression statistical methods to evaluate quantitative outputs from next-generation sequencing assays (NGS). NGS-derived data sets from assay validation experiments were used to demonstrate the utility of the statistical methods. Results Both Bland-Altman and linear regression were able to detect the presence and magnitude of constant and proportional error in quantitative values of NGS data. Deming linear regression was used in the context of assay comparison studies, while simple linear regression was used to analyse serial dilution data. Bland-Altman statistical approach was also adapted to quantify assay accuracy, including constant and proportional errors, and precision where theoretical and empirical values were known. Conclusions The complementary application of the statistical methods described in this manuscript enables more extensive evaluation of performance characteristics of quantitative molecular assays, prior to implementation in the clinical molecular laboratory. PMID:28747393

Architectonics: Design of Molecular Architecture for Functional Applications.

PubMed

Avinash, M B; Govindaraju, Thimmaiah

2018-02-20

The term architectonics has its roots in the architectural and philosophical (as early as 1600s) literature that refers to "the theory of structure" and "the structure of theory", respectively. The concept of architectonics has been adapted to advance the field of molecular self-assembly and termed as molecular architectonics. In essence, the methodology of organizing molecular units in the required and controlled configurations to develop advanced functional systems for materials and biological applications comprises the field of molecular architectonics. This concept of designing noncovalent systems enables to focus on different functional aspects of designer molecules for biological and nonbiological applications and also strengthens our efforts toward the mastery over the art of controlled molecular self-assemblies. Programming complex molecular interactions and assemblies for specific functions has been one of the most challenging tasks in the modern era. Meticulously ordered molecular assemblies can impart remarkable developments in several areas spanning energy, health, and environment. For example, the well-defined nano-, micro-, and macroarchitectures of functional molecules with specific molecular ordering possess potential applications in flexible electronics, photovoltaics, photonic crystals, microreactors, sensors, drug delivery, biomedicine, and superhydrophobic coatings, among others. The functional molecular architectures having unparalleled properties are widely evident in various designs of Nature. By drawing inspirations from Nature, intended molecular architectures can be designed and developed to harvest various functions, as there is an inexhaustible resource and scope. In this Account, we present exquisite designer molecules developed by our group and others with an objective to master the art of molecular recognition and self-assembly for functional applications. We demonstrate the tailor-ability of molecular self-assemblies by employing biomolecules like amino acids and nucleobases as auxiliaries. Naphthalenediimide (NDI), perylenediimide (PDI), and few other molecular systems serve as functional modules. The effects of stereochemistry and minute structural modifications in the molecular designs on the supramolecular interactions, and construction of self-assembled zero-dimensional (OD), one-dimensional (1D), and two-dimensional (2D) nano- and microarchitectures like particles, spheres, cups, bowls, fibers, belts, helical belts, supercoiled helices, sheets, fractals, and honeycomb-like arrays are discussed in extensive detail. Additionally, we present molecular systems that showcase the elegant designs of coassembly, templated assembly, hierarchical assembly, transient self-assembly, chiral denaturation, retentive helical memory, self-replication, supramolecular regulation, supramolecular speciation, supernon linearity, dynamic pathway complexity, supramolecular heterojunction, living supramolecular polymerization, and molecular machines. Finally, we describe the molecular engineering principles learnt over the years that have led to several applications, namely, organic electronics, self-cleaning, high-mechanical strength, and tissue engineering.

Interlocked molecules: Moving into another dimension

NASA Astrophysics Data System (ADS)

Fournel-Marotte, Karine; Coutrot, Frédéric

2017-02-01

Molecular daisy-chain structures are typically made up of two interlocked components and can exhibit muscle-like contraction and extension in one dimension. Zinc-based multicomponent systems that can operate in two and three dimensions have now been designed and synthesized.

Linking Arsenic Metabolism and Toxic Effects

EPA Science Inventory

Although arsenic has been long recognized as a toxicant and a carcinogen, the molecular basis for few of its adverse effects are well understood. Like other metalloids, arsenic undergoes extensive metabolism involving oxidation state changes and formation of methyl-arsenic bonds ...

An Overview of Mesoscale Modeling Software for Energetic Materials Research

DTIC Science & Technology

2010-03-01

12 2.9 Large-scale Atomic/Molecular Massively Parallel Simulator ( LAMMPS ...13 Table 10. LAMMPS summary...extensive reviews, lectures and workshops are available on multiscale modeling of materials applications (76-78). • Multi-phase mixtures of

Varying Susceptibility of the Female Mammary Gland to In Utero Windows of BPA Exposure.

PubMed

Hindman, Andrea R; Mo, Xiaokui Molly; Helber, Hannah L; Kovalchin, Claire E; Ravichandran, Nanditha; Murphy, Alina R; Fagan, Abigail M; St John, Pamela M; Burd, Craig J

2017-10-01

In utero exposure to the endocrine disrupting compound bisphenol A (BPA) is known to disrupt mammary gland development and increase tumor susceptibility in rodents. It is unclear whether different periods of in utero development might be more susceptible to BPA exposure. We exposed pregnant CD-1 mice to BPA at different times during gestation that correspond to specific milestones of in utero mammary gland development. The mammary glands of early-life and adult female mice, exposed in utero to BPA, were morphologically and molecularly (estrogen receptor-α and Ki67) evaluated for developmental abnormalities. We found that BPA treatment occurring before mammary bud invasion into the mesenchyme [embryonic day (E)12.5] incompletely resulted in the measured phenotypes of mammary gland defects. Exposing mice up to the point at which the epithelium extends into the precursor fat pad (E16.5) resulted in a nearly complete BPA phenotype and exposure during epithelial extension (E15.5 to E18.5) resulted in a partial phenotype. Furthermore, the relative differences in phenotypes between exposure windows highlight the substantial correlations between early-life molecular changes (estrogen receptor-α and Ki67) in the stroma and the epithelial elongation defects in mammary development. These data further implicate BPA action in the stroma as a critical mediator of epithelial phenotypes. Copyright © 2017 Endocrine Society.

De novo comparative transcriptome analysis of genes involved in fruit morphology of pumpkin cultivars with extreme size difference and development of EST-SSR markers.

PubMed

Xanthopoulou, Aliki; Ganopoulos, Ioannis; Psomopoulos, Fotis; Manioudaki, Maria; Moysiadis, Theodoros; Kapazoglou, Aliki; Osathanunkul, Maslin; Michailidou, Sofia; Kalivas, Apostolos; Tsaftaris, Athanasios; Nianiou-Obeidat, Irini; Madesis, Panagiotis

2017-07-30

The genetic basis of fruit size and shape was investigated for the first time in Cucurbita species and genetic loci associated with fruit morphology have been identified. Although extensive genomic resources are available at present for tomato (Solanum lycopersicum), cucumber (Cucumis sativus), melon (Cucumis melo) and watermelon (Citrullus lanatus), genomic databases for Cucurbita species are limited. Recently, our group reported the generation of pumpkin (Cucurbita pepo) transcriptome databases from two contrasting cultivars with extreme fruit sizes. In the current study we used these databases to perform comparative transcriptome analysis in order to identify genes with potential roles in fruit morphology and fruit size. Differential Gene Expression (DGE) analysis between cv. 'Munchkin' (small-fruit) and cv. 'Big Moose' (large-fruit) revealed a variety of candidate genes associated with fruit morphology with significant differences in gene expression between the two cultivars. In addition, we have set the framework for generating EST-SSR markers, which discriminate different C. pepo cultivars and show transferability to related Cucurbitaceae species. The results of the present study will contribute to both further understanding the molecular mechanisms regulating fruit morphology and furthermore identifying the factors that determine fruit size. Moreover, they may lead to the development of molecular marker tools for selecting genotypes with desired morphological traits. Copyright © 2017. Published by Elsevier B.V.

Three amino acid derivatives of valproic acid: design, synthesis, theoretical and experimental evaluation as anticancer agents.

PubMed

Luna-Palencia, Gabriela R; Martinez-Ramos, Federico; Vasquez-Moctezuma, Ismael; Fragoso-Vazquez, Manuel Jonathan; Mendieta-Wejebe, Jessica Elena; Padilla-Martínez, Itzia I; Sixto-Lopez, Yudibeth; Mendez-Luna, David; Trujillo-Ferrara, Jose; Meraz-Rios, Marco A; Fonseca-Sabater, Yadira; Correa-Basurto, Jose

2014-01-01

Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater antiproliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment.

MaMiCo: Transient multi-instance molecular-continuum flow simulation on supercomputers

NASA Astrophysics Data System (ADS)

Neumann, Philipp; Bian, Xin

2017-11-01

We present extensions of the macro-micro-coupling tool MaMiCo, which was designed to couple continuum fluid dynamics solvers with discrete particle dynamics. To enable local extraction of smooth flow field quantities especially on rather short time scales, sampling over an ensemble of molecular dynamics simulations is introduced. We provide details on these extensions including the transient coupling algorithm, open boundary forcing, and multi-instance sampling. Furthermore, we validate the coupling in Couette flow using different particle simulation software packages and particle models, i.e. molecular dynamics and dissipative particle dynamics. Finally, we demonstrate the parallel scalability of the molecular-continuum simulations by using up to 65 536 compute cores of the supercomputer Shaheen II located at KAUST. Program Files doi:http://dx.doi.org/10.17632/w7rgdrhb85.1 Licensing provisions: BSD 3-clause Programming language: C, C++ External routines/libraries: For compiling: SCons, MPI (optional) Subprograms used: ESPResSo, LAMMPS, ls1 mardyn, waLBerla For installation procedures of the MaMiCo interfaces, see the README files in the respective code directories located in coupling/interface/impl. Journal reference of previous version: P. Neumann, H. Flohr, R. Arora, P. Jarmatz, N. Tchipev, H.-J. Bungartz. MaMiCo: Software design for parallel molecular-continuum flow simulations, Computer Physics Communications 200: 324-335, 2016 Does the new version supersede the previous version?: Yes. The functionality of the previous version is completely retained in the new version. Nature of problem: Coupled molecular-continuum simulation for multi-resolution fluid dynamics: parts of the domain are resolved by molecular dynamics or another particle-based solver whereas large parts are covered by a mesh-based CFD solver, e.g. a lattice Boltzmann automaton. Solution method: We couple existing MD and CFD solvers via MaMiCo (macro-micro coupling tool). Data exchange and coupling algorithmics are abstracted and incorporated in MaMiCo. Once an algorithm is set up in MaMiCo, it can be used and extended, even if other solvers are used (as soon as the respective interfaces are implemented/available). Reasons for the new version: We have incorporated a new algorithm to simulate transient molecular-continuum systems and to automatically sample data over multiple MD runs that can be executed simultaneously (on, e.g., a compute cluster). MaMiCo has further been extended by an interface to incorporate boundary forcing to account for open molecular dynamics boundaries. Besides support for coupling with various MD and CFD frameworks, the new version contains a test case that allows to run molecular-continuum Couette flow simulations out-of-the-box. No external tools or simulation codes are required anymore. However, the user is free to switch from the included MD simulation package to LAMMPS. For details on how to run the transient Couette problem, see the file README in the folder coupling/tests, Remark on MaMiCo V1.1. Summary of revisions: Open boundary forcing; Multi-instance MD sampling; support for transient molecular-continuum systems Restrictions: Currently, only single-centered systems are supported. For access to the LAMMPS-based implementation of DPD boundary forcing, please contact Xin Bian, xin.bian@tum.de. Additional comments: Please see file license_mamico.txt for further details regarding distribution and advertising of this software.

Genetics and pathological mechanisms of Usher syndrome.

PubMed

Yan, Denise; Liu, Xue Z

2010-06-01

Usher syndrome (USH) comprises a group of autosomal recessively inherited disorders characterized by a dual sensory impairment of the audiovestibular and visual systems. Three major clinical subtypes (USH type I, USH type II and USH type III) are distinguished on the basis of the severity of the hearing loss, the presence or absence of vestibular dysfunction and the age of onset of retinitis pigmentosa (RP). Since the cloning of the first USH gene (MYO7A) in 1995, there have been remarkable advances in elucidating the genetic basis for this disorder, as evidence for 11 distinct loci have been obtained and genes for 9 of them have been identified. The USH genes encode proteins of different classes and families, including motor proteins, scaffold proteins, cell adhesion molecules and transmembrane receptor proteins. Extensive information has emerged from mouse models and molecular studies regarding pathogenesis of this disorder and the wide phenotypic variation in both audiovestibular and/or visual function. A unifying hypothesis is that the USH proteins are integrated into a protein network that regulates hair bundle morphogenesis in the inner ear. This review addresses genetics and pathological mechanisms of USH. Understanding the molecular basis of phenotypic variation and pathogenesis of USH is important toward discovery of new molecular targets for diagnosis, prevention and treatment of this debilitating disorder.

Observational Constraints for Modeling Diffuse Molecular Clouds

NASA Astrophysics Data System (ADS)

Federman, S. R.

2014-02-01

Ground-based and space-borne observations of diffuse molecular clouds suggest a number of areas where further improvements to modeling efforts is warranted. I will highlight those that have the widest applicability. The range in CO fractionation caused by selective isotope photodissociation, in particular the large 12C16O/13C16O ratios observed toward stars in Ophiuchus, is not reproduced well by current models. Our ongoing laboratory measurements of oscillator strengths and predissociation rates for Rydberg transitions in CO isotopologues may help clarify the situtation. The CH+ abundance continues to draw attention. Small scale structure seen toward ζ Per may provide additional constraints on the possible synthesis routes. The connection between results from optical transitions and those from radio and sub-millimeter wave transitions requires further effort. A study of OH+ and OH toward background stars reveals that these species favor different environments. This brings to focus the need to model each cloud along the line of sight separately, and to allow the physical conditions to vary within an individual cloud, in order to gain further insight into the chemistry. Now that an extensive set of data on molecular excitation is available, the models should seek to reproduce these data to place further constraints on the modeling results.

H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations.

PubMed

Anandakrishnan, Ramu; Aguilar, Boris; Onufriev, Alexey V

2012-07-01

The accuracy of atomistic biomolecular modeling and simulation studies depend on the accuracy of the input structures. Preparing these structures for an atomistic modeling task, such as molecular dynamics (MD) simulation, can involve the use of a variety of different tools for: correcting errors, adding missing atoms, filling valences with hydrogens, predicting pK values for titratable amino acids, assigning predefined partial charges and radii to all atoms, and generating force field parameter/topology files for MD. Identifying, installing and effectively using the appropriate tools for each of these tasks can be difficult for novice and time-consuming for experienced users. H++ (http://biophysics.cs.vt.edu/) is a free open-source web server that automates the above key steps in the preparation of biomolecular structures for molecular modeling and simulations. H++ also performs extensive error and consistency checking, providing error/warning messages together with the suggested corrections. In addition to numerous minor improvements, the latest version of H++ includes several new capabilities and options: fix erroneous (flipped) side chain conformations for HIS, GLN and ASN, include a ligand in the input structure, process nucleic acid structures and generate a solvent box with specified number of common ions for explicit solvent MD.

Label-Free Bioanalyte Detection from Nanometer to Micrometer Dimensions-Molecular Imprinting and QCMs †.

PubMed

Mujahid, Adnan; Mustafa, Ghulam; Dickert, Franz L

2018-06-01

Modern diagnostic tools and immunoassay protocols urges direct analyte recognition based on its intrinsic behavior without using any labeling indicator. This not only improves the detection reliability, but also reduces sample preparation time and complexity involved during labeling step. Label-free biosensor devices are capable of monitoring analyte physiochemical properties such as binding sensitivity and selectivity, affinity constants and other dynamics of molecular recognition. The interface of a typical biosensor could range from natural antibodies to synthetic receptors for example molecular imprinted polymers (MIPs). The foremost advantages of using MIPs are their high binding selectivity comparable to natural antibodies, straightforward synthesis in short time, high thermal/chemical stability and compatibility with different transducers. Quartz crystal microbalance (QCM) resonators are leading acoustic devices that are extensively used for mass-sensitive measurements. Highlight features of QCM devices include low cost fabrication, room temperature operation, and most importantly ability to monitor extremely low mass shifts, thus potentially a universal transducer. The combination of MIPs with quartz QCM has turned out as a prominent sensing system for label-free recognition of diverse bioanalytes. In this article, we shall encompass the potential applications of MIP-QCM sensors exclusively label-free recognition of bacteria and virus species as representative micro and nanosized bioanalytes.

Redefining metamorphosis in spiny lobsters: molecular analysis of the phyllosoma to puerulus transition in Sagmariasus verreauxi

PubMed Central

Ventura, Tomer; Fitzgibbon, Quinn P.; Battaglene, Stephen C.; Elizur, Abigail

2015-01-01

The molecular understanding of crustacean metamorphosis is hindered by small sized individuals and inability to accurately define molt stages. We used the spiny lobster Sagmariasus verreauxi where the large, transparent larvae enable accurate tracing of the transition from a leaf-shaped phyllosoma to an intermediate larval-juvenile phase (puerulus). Transcriptomic analysis of larvae at well-defined stages prior to, during, and following this transition show that the phyllosoma-puerulus metamorphic transition is accompanied by vast transcriptomic changes exceeding 25% of the transcriptome. Notably, genes previously identified as regulating metamorphosis in other crustaceans do not fluctuate during this transition but in the later, morphologically-subtle puerulus-juvenile transition, indicating that the dramatic phyllosoma-puerulus morphological shift relies on a different, yet to be identified metamorphic mechanism. We examined the change in expression of domains and gene families, with focus on several key genes. Our research implies that the separation in molecular triggering systems between the phyllosoma-puerulus and puerulus-juvenile transitions might have enabled the extension of the oceanic phase in spiny lobsters. Study of similar transitions, where metamorphosis is uncoupled from the transition into the benthic juvenile form, in other commercially important crustacean groups might show common features to point on the evolutionary advantage of this two staged regulation. PMID:26311524

A new reference implementation of the PSICQUIC web service.

PubMed

del-Toro, Noemi; Dumousseau, Marine; Orchard, Sandra; Jimenez, Rafael C; Galeota, Eugenia; Launay, Guillaume; Goll, Johannes; Breuer, Karin; Ono, Keiichiro; Salwinski, Lukasz; Hermjakob, Henning

2013-07-01

The Proteomics Standard Initiative Common QUery InterfaCe (PSICQUIC) specification was created by the Human Proteome Organization Proteomics Standards Initiative (HUPO-PSI) to enable computational access to molecular-interaction data resources by means of a standard Web Service and query language. Currently providing >150 million binary interaction evidences from 28 servers globally, the PSICQUIC interface allows the concurrent search of multiple molecular-interaction information resources using a single query. Here, we present an extension of the PSICQUIC specification (version 1.3), which has been released to be compliant with the enhanced standards in molecular interactions. The new release also includes a new reference implementation of the PSICQUIC server available to the data providers. It offers augmented web service capabilities and improves the user experience. PSICQUIC has been running for almost 5 years, with a user base growing from only 4 data providers to 28 (April 2013) allowing access to 151 310 109 binary interactions. The power of this web service is shown in PSICQUIC View web application, an example of how to simultaneously query, browse and download results from the different PSICQUIC servers. This application is free and open to all users with no login requirement (http://www.ebi.ac.uk/Tools/webservices/psicquic/view/main.xhtml).

Ser/Thr Motifs in Transmembrane Proteins: Conservation Patterns and Effects on Local Protein Structure and Dynamics

PubMed Central

del Val, Coral; White, Stephen H.

2014-01-01

We combined systematic bioinformatics analyses and molecular dynamics simulations to assess the conservation patterns of Ser and Thr motifs in membrane proteins, and the effect of such motifs on the structure and dynamics of α-helical transmembrane (TM) segments. We find that Ser/Thr motifs are often present in β-barrel TM proteins. At least one Ser/Thr motif is present in almost half of the sequences of α-helical proteins analyzed here. The extensive bioinformatics analyses and inspection of protein structures led to the identification of molecular transporters with noticeable numbers of Ser/Thr motifs within the TM region. Given the energetic penalty for burying multiple Ser/Thr groups in the membrane hydrophobic core, the observation of transporters with multiple membrane-embedded Ser/Thr is intriguing and raises the question of how the presence of multiple Ser/Thr affects protein local structure and dynamics. Molecular dynamics simulations of four different Ser-containing model TM peptides indicate that backbone hydrogen bonding of membrane-buried Ser/Thr hydroxyl groups can significantly change the local structure and dynamics of the helix. Ser groups located close to the membrane interface can hydrogen bond to solvent water instead of protein backbone, leading to an enhanced local solvation of the peptide. PMID:22836667

EGF targeted fluorescence molecular tomography as a predictor of PDT outcomes in pancreas cancer models

NASA Astrophysics Data System (ADS)

Samkoe, Kimberley S.; Davis, Scott C.; Srinivasan, Subhadra; Isabelle, Martin E.; O'Hara, Julia; Hasan, Tayyaba; Pogue, Brian W.

2010-02-01

Verteporfin photodynamic therapy (PDT) is a promising adjuvant therapy for pancreas cancer and investigations for its use are currently underway in both orthotopic xenograft mouse models and in human clinical trials. The mouse models have been studied extensively using magnetic resonance (MR) imaging as a measure of surrogate response to verteporfin PDT and it was found that tumor lines with different levels of aggression respond with varying levels to PDT. MR imaging was successful in determining the necrotic volume caused by PDT but there was difficultly in distinguishing inflamed tissues and regions of surviving tumor. In order to understand the molecular changes within the tumor immediately post-PDT we propose the implementation of MR-guided fluorescence molecular tomography (FMT) in conjunction with an exogenously administered fluorescently labeled epidermal growth factor (EGF-IRDye800CW, LI-COR Biosciences). We have previously shown that MR-guided FMT is feasible in the mouse abdomen when multiple regions of fluorescence are considered from contributing internal organs. In this case the highly aggressive AsPC-1 (+EGFR) orthotopic tumor was implanted in SCID mice, interstitial verteporfin PDT (1mg/kg, 20J/cm) was performed when the tumor reached ~60mm3 and both tumor volume and EGF binding were followed with MR-guided FMT.

Redefining metamorphosis in spiny lobsters: molecular analysis of the phyllosoma to puerulus transition in Sagmariasus verreauxi.

PubMed

Ventura, Tomer; Fitzgibbon, Quinn P; Battaglene, Stephen C; Elizur, Abigail

2015-08-27

The molecular understanding of crustacean metamorphosis is hindered by small sized individuals and inability to accurately define molt stages. We used the spiny lobster Sagmariasus verreauxi where the large, transparent larvae enable accurate tracing of the transition from a leaf-shaped phyllosoma to an intermediate larval-juvenile phase (puerulus). Transcriptomic analysis of larvae at well-defined stages prior to, during, and following this transition show that the phyllosoma-puerulus metamorphic transition is accompanied by vast transcriptomic changes exceeding 25% of the transcriptome. Notably, genes previously identified as regulating metamorphosis in other crustaceans do not fluctuate during this transition but in the later, morphologically-subtle puerulus-juvenile transition, indicating that the dramatic phyllosoma-puerulus morphological shift relies on a different, yet to be identified metamorphic mechanism. We examined the change in expression of domains and gene families, with focus on several key genes. Our research implies that the separation in molecular triggering systems between the phyllosoma-puerulus and puerulus-juvenile transitions might have enabled the extension of the oceanic phase in spiny lobsters. Study of similar transitions, where metamorphosis is uncoupled from the transition into the benthic juvenile form, in other commercially important crustacean groups might show common features to point on the evolutionary advantage of this two staged regulation.

Light-Induced Conversion of Chemical Permeability to Enhance Electron and Molecular Transfer in Nanoscale Assemblies

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

Balgley, Renata; de Ruiter, Graham; Evmenenko, Guennadi

In this paper, we demonstrate how photochemically enhancing the permeability of metal–organic assemblies results in a significant enhancement of the electrochemical activity of metal complexes located within the assembly. The molecular assemblies consist of different layers of redox-active metal complexes ([M(mbpy-py)3][PF6]2; M = Ru or Os) that are separated by redox-inactive spacers consisting of 1,4-bis[2-(4-pyridyl)ethenyl]benzene (BPEB) and PdCl2 of variable thicknesses (0–13.4 nm). UV-irradiation (λ = 254 nm) of our assemblies induces a photochemical reaction in the redox-inactive spacer increasing the permeability of the assembly. The observed increase was evident by trapping organic (nBu4NBF4) and inorganic (NiCl2) salts inside themore » assemblies, and by evaluating the electrochemical response of quinones absorbed inside the molecular assemblies before and after UV irradiation. The increase in permeability is reflected by higher currents and a change in the directionality of electron transfer, i.e., from mono- to bidirectional, between the redox-active metal complexes and the electrode surface. The supramolecular structure of the assemblies dominates the overall electron transfer properties and overrules possible electron transfer mediated by the extensive π-conjugation of its individual organic components.« less

Molecular Basis of Citrus sunki Susceptibility and Poncirus trifoliata Resistance Upon Phytophthora parasitica Attack.

PubMed

Dalio, Ronaldo José Durigan; Máximo, Heros José; Oliveira, Tiago Silva; Azevedo, Thamara de Medeiros; Felizatti, Henrique Leme; Campos, Magnólia de Araújo; Machado, Marcos Antonio

2018-03-01

Coevolution has shaped the molecular basis of an extensive number of defense mechanisms in plant-pathogen interactions. Phytophthora parasitica, a hemibiothrophic oomycete pathogen and the causal agent of citrus root rot and gummosis, interacts differently with Citrus sunki and Poncirus trifoliata, two commonly favored citrus rootstocks that are recognized as susceptible and resistant, respectively, to P. parasitica. The molecular core of these interactions remains elusive. Here, we provide evidence on the defense strategies employed by both susceptible and resistant citrus rootstocks, in parallel with P. parasitica deployment of effectors. Time course expression analysis (quantitative real-time polymerase chain reaction) of several defense-related genes were evaluated during i) plant disease development, ii) necrosis, and iii) pathogen effector gene expression. In C. sunki, P. parasitica deploys effectors, including elicitins, NPP1 (necrosis-inducing Phytophthora protein 1), CBEL (cellulose-binding elicitor and lectin activity), RxLR, and CRN (crinkler), and, consequently, this susceptible plant activates its main defense signaling pathways that result in the hypersensitive response and necrosis. Despite the strong plant-defense response, it fails to withstand P. parasitica invasion, confirming its hemibiothrophic lifestyle. In Poncirus trifoliata, the effectors were strongly expressed, nevertheless failing to induce any immunity manipulation and disease development, suggesting a nonhost resistance type, in which the plant relies on preformed biochemical and anatomical barriers.

Deep eutectic solvent formation: a structural view using molecular dynamics simulations with classical force fields

NASA Astrophysics Data System (ADS)

Mainberger, Sebastian; Kindlein, Moritz; Bezold, Franziska; Elts, Ekaterina; Minceva, Mirjana; Briesen, Heiko

2017-06-01

Deep eutectic solvents (DES) have gained a reputation as inexpensive and easy to handle ionic liquid analogues. This work employs molecular dynamics (MD) to simulate a variety of DES. The hydrogen bond acceptor (HBA) choline chloride was paired with the hydrogen bond donors (HBD) glycerol, 1,4-butanediol, and levulinic acid. Levulinic acid was also paired with the zwitterionic HBA betaine. In order to evaluate the reliability of data MD simulations can provide for DES, two force fields were compared: the Merck Molecular Force Field and the General Amber Force Field with two different sets of partial charges for the latter. The force fields were evaluated by comparing available experimental thermodynamic and transport properties against simulated values. Structural analysis was performed on the eutectic systems and compared to non-eutectic compositions. All force fields could be validated against certain experimental properties, but performance varied depending on the system and property in question. While extensive hydrogen bonding was found for all systems, details about the contribution of individual groups strongly varied among force fields. Interaction potentials revealed that HBA-HBA interactions weaken linearly with increasing HBD ratio, while HBD-HBD interactions grew disproportionally in magnitude, which might hint at the eutectic composition of a system.

Formaldehyde in the Diffuse Interstellar Cloud MBM40

NASA Astrophysics Data System (ADS)

Joy, Mackenzie; Magnani, Loris A.

2018-06-01

MBM40, a high-latitude molecular cloud, has been extensively studied using different molecular tracers. It appears that MBM40 is composed of a relatively dense, helical filament embedded in a more diffuse substrate of low density molecular gas. In order to study the transition between the two regimes, this project presents the first high-resolution mapping of MBM40 using the 110-111 hyperfine transition of formaldehyde (H2CO) at 4.83 GHz. We used H2CO spectra obtained with the Arecibo telescope more than a decade ago to construct this map. The results can be compared to previous maps made from the CO(1-0) transition to gain further understanding of the structure of the cloud. The intensity of the H2CO emission was compared to the CO emission. Although a correlation exists between the H2CO and CO emissivity, there seems to be a saturation of H2CO line strength for stronger CO emissivity. This is probably a radiative transfer effect of the CO emission. We have also found that the velocity dispersion of H2CO in the lower ridge of the cloud is significantly lower than in the rest of the cloud. This may indicate that this portion of the cloud is a coherent structure (analogous to an eddy) in a turbulent flow.

Molecular signatures of selection on reproductive character displacement of flower color in Phlox drummondii.

PubMed

Hopkins, Robin; Levin, Donald A; Rausher, Mark D

2012-02-01

Character displacement, which arises when species diverge in sympatry to decrease competition for resources or reproductive interference, has been observed in a wide variety of plants and animals. A classic example of reproductive character displacement, presumed to be caused by reinforcing selection, is flower-color variation in the native Texas wildflower Phlox drummondii. Here, we use population genetic analyses to investigate molecular signatures of selection on flower-color variation in this species. First, we quantify patterns of neutral genetic variation across the range of P. drummondii to demonstrate that restricted gene flow and genetic drift cannot explain the pattern of flower-color divergence in this species. There is evidence of extensive gene flow across populations with different flower colors, suggesting selection caused flower-color divergence. Second, analysis of sequence variation in the genes underlying this divergence reveals a signature of a selective sweep in one of the two genes, further indicating selection is responsible for divergence in sympatry. The lack of a signature of selection at the second locus does not necessarily indicate a lack of selection on this locus but instead brings attention to the uncertainty in depending on molecular signatures to identify selection. © 2011 The Author(s). Evolution© 2011 The Society for the Study of Evolution.

Understanding M-ligand bonding and mer-/fac-isomerism in tris(8-hydroxyquinolinate) metallic complexes.

PubMed

Lima, Carlos F R A C; Taveira, Ricardo J S; Costa, José C S; Fernandes, Ana M; Melo, André; Silva, Artur M S; Santos, Luís M N B F

2016-06-28

Tris(8-hydroxyquinolinate) metallic complexes, Mq3, are one of the most important classes of organic semiconductor materials. Herein, the nature of the chemical bond in Mq3 complexes and its implications on their molecular properties were investigated by a combined experimental and computational approach. Various Mq3 complexes, resulting from the alteration of the metal and substitution of the 8-hydroxyquinoline ligand in different positions, were prepared. The mer-/fac-isomerism in Mq3 was explored by FTIR and NMR spectroscopy, evidencing that, irrespective of the substituent, mer- and fac-are the most stable molecular configurations of Al(iii) and In(iii) complexes, respectively. The relative M-ligand bond dissociation energies were evaluated experimentally by electrospray ionization tandem mass spectrometry (ESI-MS-MS), showing a non-monotonous variation along the group (Al > In > Ga). The results reveal a strong covalent character in M-ligand bonding, which allows for through-ligand electron delocalization, and explain the preferred molecular structures of Mq3 complexes as resulting from the interplay between bonding and steric factors. The mer-isomer reduces intraligand repulsions, being preferred for smaller metals, while the fac-isomer is favoured for larger metals where stronger covalent M-ligand bonds can be formed due to more extensive through-ligand conjugation mediated by metal "d" orbitals.

Frequencies of genes for coat colour and horns in Nordic cattle breeds

PubMed Central

Kantanen, Juha; Olsaker, Ingrid; Brusgaard, Klaus; Eythorsdottir, Emma; Holm, Lars-Erik; Lien, Sigbjørn; Danell, Birgitta; Adalsteinsson, Stefan

2000-01-01

Gene frequencies of coat colour and horn types were assessed in 22 Nordic cattle breeds in a project aimed at establishing genetic profiles of the breeds under study. The coat colour loci yielding information on genetic variation were: extension, agouti, spotting, brindle, dun dilution and colour sided. The polled locus was assessed for two alleles. A profound variation between breeds was observed in the frequencies of both colour and horn alleles, with the older breeds generally showing greater variation in observed colour, horn types and segregating alleles than the modern breeds. The correspondence between the present genetic distance matrix and previous molecular marker distance matrices was low (r = 0.08 – 0.12). The branching pattern of a neighbour-joining tree disagreed to some extent with the molecular data structure. The current data indicates that 70% of the total genetic variation could be explained by differences between the breeds, suggesting a much greater breed differentiation than typically found at protein and microsatellite loci. The marked differentiation of the cattle breeds and observed disagreements with the results from the previous molecular data in the topology of the phylogenetic trees are most likely a result of selection on phenotypic characters analysed in this study. PMID:14736370

Omics approaches on fresh-cut lettuce reveal global molecular responses to sodium hypochlorite and peracetic acid treatment.

PubMed

Daddiego, Loretta; Bianco, Linda; Capodicasa, Cristina; Carbone, Fabrizio; Dalmastri, Claudia; Daroda, Lorenza; Del Fiore, Antonella; De Rossi, Patrizia; Di Carli, Mariasole; Donini, Marcello; Lopez, Loredana; Mengoni, Alessio; Paganin, Patrizia; Perrotta, Gaetano; Bevivino, Annamaria

2018-01-01

Lettuce is a leafy vegetable that is extensively commercialized as a ready-to-eat product because of its widespread use in human nutrition as salad. It is well known that washing treatments can severely affect the quality and shelf-life of ready-to-eat vegetables. The study presented here evaluated the effect of two washing procedures on fresh-cut lettuce during storage. An omics approach was applied to reveal global changes at molecular level induced by peracetic acid washing in comparison with sodium hypochlorite treatment. Microbiological analyses were also performed to quantify total bacterial abundance and composition. The study revealed wide metabolic alterations induced by the two sanitizers. In particular, transcriptomic and proteomic analyses pointed out a number of transcripts and proteins differentially accumulated in response to peracetic acid washing, mainly occurring on the first day of storage. In parallel, different microbiota composition and significant reduction in total bacterial load following washing were also observed. The results provide useful information for the fresh-cut industry to select an appropriate washing procedure preserving fresh-like attributes as much as possible during storage of the end product. Molecular evidence indicated peracetic acid to be a valid alternative to sodium hypochlorite as sanitizer solution. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Developing a molecular picture for polymer glasses under large deformation

NASA Astrophysics Data System (ADS)

Wang, Shi-Qing; Cheng, Shiwang; Wang, Panpan

2014-03-01

Polymer glasses differ from most other types of glassy materials because they can be ductile under tensile extension. Remarkably, a ductile polymer can turn brittle and vice versa. For example, upon cooling, the glass changes from ductile to brittle at a temperature known as the brittle-ductile transition temperature (BDT). Aging causes the ductile glass to be brittle. Mechanical ``rejuvenation'' or pressurization brings a brittle glass into a ductile state. Finally, one glass can be ductile 100 degrees below Tg while another polymer is already brittle even just 10 degree below Tg. Polystyrene and bisphenol A polycarbonate are at the two extremes in the family of polymer glasses. How to rationale such a wide range of behavior in terms of a molecular picture has been a challenging task. What is the role of ``chain entanglement''? Since many of the procedures including the temperature change do not alter the ``chain entanglement'', it is clearly insufficient to explain the nature of the BDT in terms of the entanglement density. Our work attempts to answer the question of what then is the role of chain networking. We have formulated a molecular picture that presents a unifying and coherent explanation for all the known phenomenology concerning the BDT and condition for crazing. This work is supported, in part, by NSF (CMMI-0926522 and DMR-1105135).

On the thermodynamic and kinetic investigations of a [c2]daisy chain polymer

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

Hmadeh, Mohamad; Fang, Lei; Trabolsi, Ali

2010-01-01

We report a variety of [c2]daisy chain molecules which undergo quantitative, efficient, and fully reversible molecular movements upon the addition of base/acid in organic solvents. Such externally triggered molecular movements can induce the contraction and extension of the [c2]daisy chain molecule as a whole. A linear polymer of such a bistable [c2]daisy chain exerts similar types of movements and can be looked upon as a candidate for the development of artificial muscles. The spectrophotometric investigations of both the monomeric and polymeric bistable [c2]daisy chains, as well as the corresponding model compounds, were performed in MeCN at room temperature, in ordermore » to obtain the thermodynamic parameters for these mechanically interlocked molecules. Based on their spectrophotometric and thermodynamic characteristics, kinetic analysis of the acid/base-induced contraction and extension of the [c2]daisy chain monomer and polymer were conducted by employing a stopped-flow technique. These kinetic data suggest that the rates of contraction and extension for these [c2]daisy chain molecules are determined by the thermodynamic stabilities of the corresponding kinetic intermediates. Faster switching rates for both the contraction and extension processes of the polymeric [c2]daisy chain were observed when compared to those of its monomeric counterpart. These kinetic and thermodynamic investigations on [c2]daisy chain-based muscle-like compounds provide important information for those seeking an understanding of the mechanisms of actuation in mechanically interlocked macromolecules.« less

Design, Synthesis, and Self-Assembly of Well-Defined Hybrid Materials Including Polymer Amphiphiles and Giant Tetrahedra Molecules Based on Poss Nanoparticles

NASA Astrophysics Data System (ADS)

Huang, Mingjun

"Bottom-up" techniques-based self-assembly are always attracting people's interests since this technology provides relatively low economic cost and fast route to construct organized structures at different scales. Considering unprecedented benefits from polymer materials, self-assemblies utilizing polymer building blocks have been extensively studied to achieve diverse hierarchical structures and various attractive properties. However, precise controls of chemical primary structures and compositions and exact constructions of hierarchal ordered structures in synthetic polymers are far from being fully appreciated. In this dissertation, a novel approach has been utilized to construct diverse well-defined nano-building blocks, giant molecules, via conjugating different, and functionalized molecular nanoparticles (MNPs) which are shape- and volume-persistent nano-objects with precise molecular structure and specific symmetry. The representative examples of the three basic categories of giant molecules, "giant polyhedra", "giant surfactants", and "giant shape amphiphiles" were discussed in details. First, a class of precisely defined, nanosized giant tetrahedra was constructed by placing different polyhedral oligomeric silsesquioxane (POSS) molecular nanoparticles at the vertices of a rigid tetrahedral framework. Designed symmetry breaking of these giant tetrahedra introduces accurate positional interactions and results in diverse selectively assembled, highly ordered supramolecular lattices including a Frank-Kasper (FK) A15 phase. The FK and quasicrystal phases are originally identified in metal alloys and only sporadically observed in soft matters. It remains unclear how to correlate their stability with the chemical composition and molecular topology in the self-assembling systems. We then for this purpose designed and studied the self-assembly phase transition sequences of four series of hybrid giant surfactants based on hydrophilic POSS cages tethered with one to four polystyrene (PS) tails. With increasing the number of tails, molecular topological variations not only affect phase boundaries in terms of the PS volume fraction, but also open a window to stabilize supramolecular FK and quasicrystal phases in the spherical phase region, demonstrating the critical role of molecular topology in dictating the formation of unconventional supramolecular lattices of "soft" spherical motifs. The FK A15 phase was even surprisingly observed in the giant shape amphiphile molecule, triphenylene-6BPOSS, which has a disk-like flat triphenylene core connected with six hydrophobic POSS cages by sides. Without conical molecular shape, triphenylene-6BPOSS self-assembled and stabilized into supramolecular sphere via pi-pi interactions through a completely different mechanism with precious two cases. These studies indicate that "bottom-up" self-assemble based on well-defined giant molecules approach can be rather powerful to fabricate usually complicated hierarchical structures and open up a wide field of supramolecular self-assembly with unexpected structure and properties.

Two endogenous proteins that induce cell wall extension in plants

NASA Technical Reports Server (NTRS)

McQueen-Mason, S.; Durachko, D. M.; Cosgrove, D. J.

1992-01-01

Plant cell enlargement is regulated by wall relaxation and yielding, which is thought to be catalyzed by elusive "wall-loosening" enzymes. By employing a reconstitution approach, we found that a crude protein extract from the cell walls of growing cucumber seedlings possessed the ability to induce the extension of isolated cell walls. This activity was restricted to the growing region of the stem and could induce the extension of isolated cell walls from various dicot stems and the leaves of amaryllidaceous monocots, but was less effective on grass coleoptile walls. Endogenous and reconstituted wall extension activities showed similar sensitivities to pH, metal ions, thiol reducing agents, proteases, and boiling in methanol or water. Sequential HPLC fractionation of the active wall extract revealed two proteins with molecular masses of 29 and 30 kD associated with the activity. Each protein, by itself, could induce wall extension without detectable hydrolytic breakdown of the wall. These proteins appear to mediate "acid growth" responses of isolated walls and may catalyze plant cell wall extension by a novel biochemical mechanism.

Non-3D domain swapped crystal structure of truncated zebrafish alphaA crystallin

PubMed Central

Laganowsky, A; Eisenberg, D

2010-01-01

In previous work on truncated alpha crystallins (Laganowsky et al., Protein Sci 2010; 19:1031–1043), we determined crystal structures of the alpha crystallin core, a seven beta-stranded immunoglobulin-like domain, with its conserved C-terminal extension. These extensions swap into neighboring cores forming oligomeric assemblies. The extension is palindromic in sequence, binding in either of two directions. Here, we report the crystal structure of a truncated alphaA crystallin (AAC) from zebrafish (Danio rerio) revealing C-terminal extensions in a non three-dimensional (3D) domain swapped, “closed” state. The extension is quasi-palindromic, bound within its own zebrafish core domain, lying in the opposite direction to that of bovine AAC, which is bound within an adjacent core domain (Laganowsky et al., Protein Sci 2010; 19:1031–1043). Our findings establish that the C-terminal extension of alpha crystallin proteins can be either 3D domain swapped or non-3D domain swapped. This duality provides another molecular mechanism for alpha crystallin proteins to maintain the polydispersity that is crucial for eye lens transparency. PMID:20669149

The Tribolium castaneum Ortholog of Sex combs reduced Controls Dorsal Ridge Development

PubMed Central

Shippy, Teresa D.; Rogers, Carmelle D.; Beeman, Richard W.; Brown, Susan J.; Denell, Robin E.

2006-01-01

In insects, the boundary between the embryonic head and thorax is formed by the dorsal ridge, a fused structure composed of portions of the maxillary and labial segments. However, the mechanisms that promote development of this unusual structure remain a mystery. In Drosophila, mutations in the Hox genes Sex combs reduced and Deformed have been reported to cause abnormal dorsal ridge formation, but the significance of these abnormalities is not clear. We have identified three mutant allele classes of Cephalothorax, the Tribolium castaneum (red flour beetle) ortholog of Sex combs reduced, each of which has a different effect on dorsal ridge development. By using Engrailed expression to monitor dorsal ridge development in these mutants, we demonstrate that Cephalothorax promotes the fusion and subsequent dorsolateral extension of the maxillary and labial Engrailed stripes (posterior compartments) during dorsal ridge formation. Molecular and genetic analysis of these alleles indicates that the N terminus of Cephalothorax is important for the fusion step, but is dispensable for Engrailed stripe extension. Thus, we find that specific regions of Cephalothorax are required for discrete steps in dorsal ridge formation. PMID:16849608

High levels of diversity characterize mandrill (Mandrillus sphinx) Mhc-DRB sequences.

PubMed

Abbott, Kristin M; Wickings, E Jean; Knapp, Leslie A

2006-08-01

The major histocompatibility complex (MHC) is highly polymorphic in most primate species studied thus far. The rhesus macaque (Macaca mulatta) has been studied extensively and the Mhc-DRB region demonstrates variability similar to humans. The extent of MHC diversity is relatively unknown for other Old World monkeys (OWM), especially among genera other than Macaca. A molecular survey of the Mhc-DRB region in mandrills (Mandrillus sphinx) revealed extensive variability, suggesting that other OWMs may also possess high levels of Mhc-DRB polymorphism. In the present study, 33 Mhc-DRB loci were identified from only 13 animals. Eleven were wild-born and presumed to be unrelated and two were captive-born twins. Two to seven different sequences were identified for each individual, suggesting that some mandrills may have as many as four Mhc-DRB loci on a single haplotype. From these sequences, representatives of at least six Mhc-DRB loci or lineages were identified. As observed in other primates, some new lineages may have arisen through the process of gene conversion. These findings indicate that mandrills have Mhc-DRB diversity not unlike rhesus macaques and humans.

Molecular Modeling and Evaluation of Novel Dibenzopyrrole Derivatives as Telomerase Inhibitors and Potential Drug for Cancer Therapy.

PubMed

Kalathiya, Umesh; Padariya, Monikaben; Baginski, Maciej

2014-01-01

During previous years, many studies on synthesis, as well as on anti-tumor, anti-inflammatory and anti-bacterial activities of the pyrazole derivatives have been described. Certain pyrazole derivatives exhibit important pharmacological activities and have proved to be useful template in drug research. Considering importance of pyrazole template, in current work the series of novel inhibitors were designed by replacing central ring of acridine with pyrazole ring. These heterocyclic compounds were proposed as a new potential base for telomerase inhibitors. Obtained dibenzopyrrole structure was used as a novel scaffold structure and extension of inhibitors was done by different functional groups. Docking of newly designed compounds in the telomerase active site (telomerase catalytic subunit TERT) was carried out. All dibenzopyrrole derivatives were evaluated by three docking programs: CDOCKER, Ligandfit docking (Scoring Functions) and AutoDock. Compound C_9g, C_9k and C_9l performed best in comparison to all designed inhibitors during the docking in all methods and in interaction analysis. Introduction of pyrazole and extension of dibenzopyrrole in compounds confirm that such compound may act as potential telomerase inhibitors.

Xenopus egg extract: A powerful tool to study genome maintenance mechanisms.

PubMed

Hoogenboom, Wouter S; Klein Douwel, Daisy; Knipscheer, Puck

2017-08-15

DNA repair pathways are crucial to maintain the integrity of our genome and prevent genetic diseases such as cancer. There are many different types of DNA damage and specific DNA repair mechanisms have evolved to deal with these lesions. In addition to these repair pathways there is an extensive signaling network that regulates processes important for repair, such as cell cycle control and transcription. Despite extensive research, DNA damage repair and signaling are not fully understood. In vitro systems such as the Xenopus egg extract system, have played, and still play, an important role in deciphering the molecular details of these processes. Xenopus laevis egg extracts contain all factors required to efficiently perform DNA repair outside a cell, using mechanisms conserved in humans. These extracts have been used to study several genome maintenance pathways, including mismatch repair, non-homologous end joining, ICL repair, DNA damage checkpoint activation, and replication fork stability. Here we describe how the Xenopus egg extract system, in combination with specifically designed DNA templates, contributed to our detailed understanding of these pathways. Copyright © 2017. Published by Elsevier Inc.

Occurrence and prevalence of antibiotic resistance in landfill leachate.

PubMed

Wang, Yangqing; Tang, Wei; Qiao, Jing; Song, Liyan

2015-08-01

Antibiotic resistance (AR) is extensively present in various environments, posing emerging threat to public and environmental health. Landfill receives unused and unwanted antibiotics through household waste and AR within waste (e.g., activated sludge and illegal clinical waste) and is supposed to serve as an important AR reservoir. In this study, we used culture-dependent methods and quantitative molecular techniques to detect and quantify antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in 12 landfill leachate samples from six geographic different landfills, China. Five tested ARGs (tetO, tetW, bla(TEM), sulI, and sulII) and seven kinds of antibiotic-resistant heterotrophic ARB were extensively detected in all samples, demonstrating their occurrence in landfill. The detected high ratio (10(-2) to 10(-5)) of ARGs to 16S ribosomal RNA (rRNA) gene copies implied that ARGs are prevalent in landfill. Correlation analysis showed that ARGs (tetO, tetW, sulI, and sulII) significantly correlated to ambient bacterial 16S rRNA gene copies, suggesting that the abundance of bacteria in landfill leachate may play an important role in the horizontal spread of ARGs.

Hierarchical atom type definitions and extensible all-atom force fields.

PubMed

Jin, Zhao; Yang, Chunwei; Cao, Fenglei; Li, Feng; Jing, Zhifeng; Chen, Long; Shen, Zhe; Xin, Liang; Tong, Sijia; Sun, Huai

2016-03-15

The extensibility of force field is a key to solve the missing parameter problem commonly found in force field applications. The extensibility of conventional force fields is traditionally managed in the parameterization procedure, which becomes impractical as the coverage of the force field increases above a threshold. A hierarchical atom-type definition (HAD) scheme is proposed to make extensible atom type definitions, which ensures that the force field developed based on the definitions are extensible. To demonstrate how HAD works and to prepare a foundation for future developments, two general force fields based on AMBER and DFF functional forms are parameterized for common organic molecules. The force field parameters are derived from the same set of quantum mechanical data and experimental liquid data using an automated parameterization tool, and validated by calculating molecular and liquid properties. The hydration free energies are calculated successfully by introducing a polarization scaling factor to the dispersion term between the solvent and solute molecules. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Optoelectronics Material Center: A Collaborative Program Including Center for High Technology Materials of the University of New Mexico, Stanford University, California Institute of Technology

DTIC Science & Technology

1992-09-01

SI by Ion-Assisted Molecular Beam Enltaxy Currently there is considerable interest in misfit accommodation in hetero- epitaxy for integration of device...of misfit accommodation. In the last quarter, we have demonstrated, using ion-assisted molecular beam epitaxy : * Reduction of dislocation density in... beam epitaxy (MOMBE) hardware, and demonstration of state-of-the-art MOMBE AlGaAs (1990). MOCVD Materials Growth Facilities and Eauipment Extension to

Microsatellites: Evolutionary and methodological background and empirical applications at individual, population, and phylogenetic levels

USGS Publications Warehouse

Scribner, Kim T.; Pearce, John M.; Baker, Allan J.

2000-01-01

The recent proliferation and greater accessibility of molecular genetic markers has led to a growing appreciation of the ecological and evolutionary inferences that can be drawn from molecular characterizations of individuals and populations (Burke et al. 1992, Avise 1994). Different techniques have the ability to target DNA sequences which have different patterns of inheritance, different modes and rates of evolution and, concomitantly, different levels of variation. In the quest for 'the right marker for the right job', microsatellites have been widely embraced as the marker of choice for many empirical genetic studies. The proliferation of microsatellite loci for various species and the voluminous literature compiled in very few years associated with their evolution and use in various research applications, exemplifies their growing importance as a research tool in the biological sciences.The ability to define allelic states based on variation at the nucleotide level has afforded unparalleled opportunities to document the actual mutational process and rates of evolution at individual microsatellite loci. The scrutiny to which these loci have been subjected has resulted in data that raise issues pertaining to assumptions formerly stated, but largely untestable for other marker classes. Indeed this is an active arena for theoretical and empirical work. Given the extensive and ever-increasing literature on various statistical methodologies and cautionary notes regarding the uses of microsatellites, some consideration should be given to the unique characteristics of these loci when determining how and under what conditions they can be employed.

ROCK inhibition in models of neurodegeneration and its potential for clinical translation.

PubMed

Koch, Jan Christoph; Tatenhorst, Lars; Roser, Anna-Elisa; Saal, Kim-Ann; Tönges, Lars; Lingor, Paul

2018-04-03

Neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis are affecting a rapidly increasing population worldwide. While common pathomechanisms such as protein aggregation, axonal degeneration, dysfunction of protein clearing and an altered immune response have been characterized, no disease-modifying therapies have been developed so far. Interestingly, a significant involvement of the Rho kinase (ROCK) signaling pathway has been described in all of these mechanisms making it a promising target for new therapeutic approaches. In this article, we first review current knowledge of the involvement of ROCK in neurodegenerative disorders and the utility of its inhibition as a disease-modifying therapy in different neurodegenerative disorders. After a detailed description of the biochemical characteristics of ROCK and its molecular interactors, differences of ROCK-expression under physiological and pathological conditions are compared. Next, different pharmacological and molecular-genetic strategies to inhibit ROCK-function are discussed, focusing on pharmacological ROCK-inhibitors. The role of the ROCK-pathway in cellular processes that are central in neurodegenerative disorders pathology like axonal degeneration, autophagy, synaptic and glial function is explained in detail. Finally, all available data on ROCK-inhibition in different animal models of neurodegenerative disorders is reviewed and first approaches for translation into human patients are discussed. Taken together, there is now extensive evidence from preclinical studies in several neurodegenerative disorders that characterize ROCK as a promising drug target for further translational research in neurodegenerative disorders. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

A multimodal imaging platform with integrated simultaneous photoacoustic microscopy, optical coherence tomography, optical Doppler tomography and fluorescence microscopy

NASA Astrophysics Data System (ADS)

Dadkhah, Arash; Zhou, Jun; Yeasmin, Nusrat; Jiao, Shuliang

2018-02-01

Various optical imaging modalities with different optical contrast mechanisms have been developed over the past years. Although most of these imaging techniques are being used in many biomedical applications and researches, integration of these techniques will allow researchers to reach the full potential of these technologies. Nevertheless, combining different imaging techniques is always challenging due to the difference in optical and hardware requirements for different imaging systems. Here, we developed a multimodal optical imaging system with the capability of providing comprehensive structural, functional and molecular information of living tissue in micrometer scale. This imaging system integrates photoacoustic microscopy (PAM), optical coherence tomography (OCT), optical Doppler tomography (ODT) and fluorescence microscopy in one platform. Optical-resolution PAM (OR-PAM) provides absorption-based imaging of biological tissues. Spectral domain OCT is able to provide structural information based on the scattering property of biological sample with no need for exogenous contrast agents. In addition, ODT is a functional extension of OCT with the capability of measurement and visualization of blood flow based on the Doppler effect. Fluorescence microscopy allows to reveal molecular information of biological tissue using autofluoresce or exogenous fluorophores. In-vivo as well as ex-vivo imaging studies demonstrated the capability of our multimodal imaging system to provide comprehensive microscopic information on biological tissues. Integrating all the aforementioned imaging modalities for simultaneous multimodal imaging has promising potential for preclinical research and clinical practice in the near future.

Activity coefficients from molecular simulations using the OPAS method

NASA Astrophysics Data System (ADS)

Kohns, Maximilian; Horsch, Martin; Hasse, Hans

2017-10-01

A method for determining activity coefficients by molecular dynamics simulations is presented. It is an extension of the OPAS (osmotic pressure for the activity of the solvent) method in previous work for studying the solvent activity in electrolyte solutions. That method is extended here to study activities of all components in mixtures of molecular species. As an example, activity coefficients in liquid mixtures of water and methanol are calculated for 298.15 K and 323.15 K at 1 bar using molecular models from the literature. These dense and strongly interacting mixtures pose a significant challenge to existing methods for determining activity coefficients by molecular simulation. It is shown that the new method yields accurate results for the activity coefficients which are in agreement with results obtained with a thermodynamic integration technique. As the partial molar volumes are needed in the proposed method, the molar excess volume of the system water + methanol is also investigated.

Comprehensive Carrier Screening and Molecular Diagnostic Testing for Recessive Childhood Diseases

PubMed Central

Kingsmore, Stephen

2012-01-01

Of 7,028 disorders with suspected Mendelian inheritance, 1,139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~18% of pediatric hospitalizations. Molecular diagnostic testing is currently available for only ~300 recessive disorders. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening and molecular diagnostic testing to most recessive disease genes has hitherto been impractical. Recently, we reported a preconception carrier screen / molecular diagnostic test for 448 recessive childhood diseases. The current status of this test is reviewed here. Currently, this reports analytical validity of the comprehensive carrier test. As the clinical validity and clinical utility in the contexts described is ascertained, this article will be updated. PMID:22872815

Molecularly thin fluoro-polymeric nanolubricant films: tribology, rheology, morphology, and applications.

PubMed

Chung, Pil Seung; Jhon, Myung S; Choi, Hyoung Jin

2016-03-21

Molecularly thin perfluoropolyether (PFPE) has been used extensively as a high-performance lubricant in various applications and, more importantly, on carbon overcoats to enhance the reliability and lubrication of micro-/nanoelectro-mechanical systems, where the tribological performance caused by its molecular architecture is a critical issue, as are its physical properties and rheological characteristics. This Highlight addresses recent trends in the development of fluoro-polymeric lubricant films with regard to their tribology, rheology, and physio-chemical properties as they relate to heat-assisted magnetic recording. Nanorheology has been employed to examine the dynamic response of nonfunctional and functional PFPEs, while the viscoelastic properties of nanoscale PFPE films and the relaxation processes as a function of molecular structure and end-group functionality were analyzed experimentally; furthermore, the characteristics of binary blends were reported.

Computer-aided design of polymers and composites

NASA Technical Reports Server (NTRS)

Kaelble, D. H.

1985-01-01

This book on computer-aided design of polymers and composites introduces and discusses the subject from the viewpoint of atomic and molecular models. Thus, the origins of stiffness, strength, extensibility, and fracture toughness in composite materials can be analyzed directly in terms of chemical composition and molecular structure. Aspects of polymer composite reliability are considered along with characterization techniques for composite reliability, relations between atomic and molecular properties, computer aided design and manufacture, polymer CAD/CAM models, and composite CAD/CAM models. Attention is given to multiphase structural adhesives, fibrous composite reliability, metal joint reliability, polymer physical states and transitions, chemical quality assurance, processability testing, cure monitoring and management, nondestructive evaluation (NDE), surface NDE, elementary properties, ionic-covalent bonding, molecular analysis, acid-base interactions, the manufacturing science, and peel mechanics.

Extensively Reversible Thermal Transformations of a Bistable, Fluorescence-Switchable Molecular Solid: Entry into Functional Molecular Phase-Change Materials.

PubMed

Srujana, P; Radhakrishnan, T P

2015-06-15

Functional phase-change materials (PCMs) are conspicuously absent among molecular materials in which the various attributes of inorganic solids have been realized. While organic PCMs are primarily limited to thermal storage systems, the amorphous-crystalline transformation of materials like Ge-Sb-Te find use in advanced applications such as information storage. Reversible amorphous-crystalline transformations in molecular solids require a subtle balance between robust supramolecular assembly and flexible structural elements. We report novel diaminodicyanoquinodimethanes that achieve this transformation by interlinked helical assemblies coupled with conformationally flexible alkoxyalkyl chains. They exhibit highly reversible thermal transformations between bistable (crystalline/amorphous) forms, along with a prominent switching of the fluorescence emission energy and intensity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nonequilibrium steady state of biochemical cycle kinetics under non-isothermal conditions

NASA Astrophysics Data System (ADS)

Jin, Xiao; Ge, Hao

2018-04-01

The nonequilibrium steady state of isothermal biochemical cycle kinetics has been extensively studied, but that under non-isothermal conditions has been much less extensively investigated. When the heat exchange between subsystems is slow, the isothermal assumption of the whole system breaks down, as is true for many types of living organisms. Here, starting with a four-state model of molecular transporter across the cell membrane, we generalize the nonequilibrium steady-state theory of isothermal biochemical cycle kinetics to the circumstances with non-uniform temperatures of subsystems in terms of general master equation models. We obtain a new thermodynamic relationship between the chemical reaction rates and thermodynamic potentials in non-isothermal circumstances, based on the overdamped dynamics along the continuous reaction coordinate. We show that the entropy production can vary up to 3% in real cells, even when the temperature difference across the cell membrane is only approximately 1 K. We then decompose the total thermodynamic driving force into its thermal and chemical components and predict that the net flux of molecules transported by the molecular transporter can potentially go against the temperature gradient in the absence of a chemical driving force. Furthermore, we demonstrate that the simple application of the isothermal transition-state rate formula for each chemical reaction in terms of only the reactant’ temperature is not thermodynamically consistent. Therefore, we mathematically derive several revised reaction rate formulas that are not only consistent with the new thermodynamic relationship but also approximate the exact reaction rate better than Kramers’ rate formula under isothermal conditions.

Phenotypic Variability Among Café-au-lait Macules in NF1

PubMed Central

Boyd, Kevin P.; Gao, Liyan; Feng, Rui; Beasley, Mark; Messiaen, Ludwine; Korf, Bruce R.; Theos, Amy

2009-01-01

Background Cafe-au-lait macules (CALMs) in NF1 are an early and accessible phenotype in NF1, but have not been extensively studied. Objective To more fully characterize the phenotype of CALMs in patients with NF1. Methods Twenty-four patients with a diagnosis of NF1 confirmed through clinical diagnosis or molecular genetic testing were recruited from patients seen in the Genetics Department at the University of Alabama at Birmingham. CALM locations were mapped using standard digital photography. Pigment intensity was measured with a narrowband spectrophotometer, which estimates the relative amount of melanin (M) based on its absorption of visible light. The major response was defined as the difference between the mean M from the CALM and the mean M from the surrounding skin. The major response for each spot was compared to spots within an individual and across individuals in the study population. Results There was significant variability of the major response, primarily attributable to intrapersonal variability (48.4%, <0.0001) and secondly to interpersonal variability (33.0%, <0.0094). Subsequent analysis based on genetic mutation type showed significantly darker spots in individuals with germline mutations leading to haploinsufficiency. Limitations The study was performed on a small population of patients and the method utilized has not yet been used extensively for this purpose. Conclusions CALMs vary in pigment intensity not only across individuals, but also within individuals and this variability was unrelated to sun exposure. Further studies may help elucidate the molecular basis of this finding, leading to an increased understanding of the pathogenesis of CALMs in NF1. PMID:20605257

Differential Gene Expression between Leaf and Rhizome in Atractylodes lancea: A Comparative Transcriptome Analysis

PubMed Central

Huang, Qianqian; Huang, Xiao; Deng, Juan; Liu, Hegang; Liu, Yanwen; Yu, Kun; Huang, Bisheng

2016-01-01

The rhizome of Atractylodes lancea is extensively used in the practice of Traditional Chinese Medicine because of its broad pharmacological activities. This study was designed to characterize the transcriptome profiling of the rhizome and leaf of Atractylodes lancea in an attempt to uncover the molecular mechanisms regulating rhizome formation and growth. Over 270 million clean reads were assembled into 92,366 unigenes, 58% of which are homologous with sequences in public protein databases (NR, Swiss-Prot, GO, and KEGG). Analysis of expression levels showed that genes involved in photosynthesis, stress response, and translation were the most abundant transcripts in the leaf, while transcripts involved in stress response, transcription regulation, translation, and metabolism were dominant in the rhizome. Tissue-specific gene analysis identified distinct gene families active in the leaf and rhizome. Differential gene expression analysis revealed a clear difference in gene expression pattern, identifying 1518 up-regulated genes and 3464 down-regulated genes in the rhizome compared with the leaf, including a series of genes related to signal transduction, primary and secondary metabolism. Transcription factor (TF) analysis identified 42 TF families, with 67 and 60 TFs up-regulated in the rhizome and leaf, respectively. A total of 104 unigenes were identified as candidates for regulating rhizome formation and development. These data offer an overview of the gene expression pattern of the rhizome and leaf and provide essential information for future studies on the molecular mechanisms of controlling rhizome formation and growth. The extensive transcriptome data generated in this study will be a valuable resource for further functional genomics studies of A. lancea. PMID:27066021

The Effects of Smoking on the Developing Lung: Insights from a Biologic Model for Lung Development, Homeostasis, and Repair

PubMed Central

Asotra, Kamlesh; Torday, John S.

2010-01-01

There is extensive epidemiologic and experimental evidence from both animal and human studies that demonstrates detrimental long-term pulmonary outcomes in the offspring of mothers who smoke during pregnancy. However, the molecular mechanisms underlying these associations are not understood. Therefore, it is not surprising that that there is no effective intervention to prevent the damaging effects of perinatal smoke exposure. Using a biologic model of lung development, homeostasis, and repair, we have determined that in utero nicotine exposure disrupts specific molecular paracrine communications between epithelium and interstitium that are driven by parathyroid hormone-related protein and peroxisome proliferator-activated receptor (PPAR)γ, resulting in transdifferentiation of lung lipofibroblasts to myofibroblasts, i.e., the conversion of the lipofibroblast phenotype to a cell type that is not conducive to alveolar homeostasis, and is the cellular hallmark of chronic lung disease, including asthma. Furthermore, we have shown that by molecularly targeting PPARγ expression, nicotine-induced lung injury can not only be significantly averted, it can also be reverted. The concept outlined by us differs from the traditional paradigm of teratogenic and toxicological effects of tobacco smoke that has been proposed in the past. We have argued that since nicotine alters the normal homeostatic epithelial-mesenchymal paracrine signaling in the developing alveolus, rather than causing totally disruptive structural changes, it offers a unique opportunity to prevent, halt, and/or reverse this process through targeted molecular manipulations. PMID:19641967

The shear flow processing of controlled DNA tethering and stretching for organic molecular electronics.

PubMed

Yu, Guihua; Kushwaha, Amit; Lee, Jungkyu K; Shaqfeh, Eric S G; Bao, Zhenan

2011-01-25

DNA has been recently explored as a powerful tool for developing molecular scaffolds for making reproducible and reliable metal contacts to single organic semiconducting molecules. A critical step in the process of exploiting DNA-organic molecule-DNA (DOD) array structures is the controlled tethering and stretching of DNA molecules. Here we report the development of reproducible surface chemistry for tethering DNA molecules at tunable density and demonstrate shear flow processing as a rationally controlled approach for stretching/aligning DNA molecules of various lengths. Through enzymatic cleavage of λ-phage DNA to yield a series of DNA chains of various lengths from 17.3 μm down to 4.2 μm, we have investigated the flow/extension behavior of these tethered DNA molecules under different flow strengths in the flow-gradient plane. We compared Brownian dynamic simulations for the flow dynamics of tethered λ-DNA in shear, and found our flow-gradient plane experimental results matched well with our bead-spring simulations. The shear flow processing demonstrated in our studies represents a controllable approach for tethering and stretching DNA molecules of various lengths. Together with further metallization of DNA chains within DOD structures, this bottom-up approach can potentially enable efficient and reliable fabrication of large-scale nanoelectronic devices based on single organic molecules, therefore opening opportunities in both fundamental understanding of charge transport at the single molecular level and many exciting applications for ever-shrinking molecular circuits.

Molecular Dynamics Analysis of Lysozyme Protein in Ethanol-Water Mixed Solvent Environment

NASA Astrophysics Data System (ADS)

Ochije, Henry Ikechukwu

Effect of protein-solvent interaction on the protein structure is widely studied using both experimental and computational techniques. Despite such extensive studies molecular level understanding of proteins and some simple solvents is still not fully understood. This work focuses on detailed molecular dynamics simulations to study of solvent effect on lysozyme protein, using water, alcohol and different concentrations of water-alcohol mixtures as solvents. The lysozyme protein structure in water, alcohol and alcohol-water mixture (0-12% alcohol) was studied using GROMACS molecular dynamics simulation code. Compared to water environment, the lysozome structure showed remarkable changes in solvents with increasing alcohol concentration. In particular, significant changes were observed in the protein secondary structure involving alpha helices. The influence of alcohol on the lysozyme protein was investigated by studying thermodynamic and structural properties. With increasing ethanol concentration we observed a systematic increase in total energy, enthalpy, root mean square deviation (RMSD), and radius of gyration. a polynomial interpolation approach. Using the resulting polynomial equation, we could determine above quantities for any intermediate alcohol percentage. In order to validate this approach, we selected an intermediate ethanol percentage and carried out full MD simulation. The results from MD simulation were in reasonably good agreement with that obtained using polynomial approach. Hence, the polynomial approach based method proposed here eliminates the need for computationally intensive full MD analysis for the concentrations within the range (0-12%) studied in this work.

Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors.

PubMed

Sato, Yoshiyuki; Onozaki, Yu; Sugimoto, Tetsuya; Kurihara, Hideki; Kamijo, Kaori; Kadowaki, Chie; Tsujino, Toshiaki; Watanabe, Akiko; Otsuki, Sachie; Mitsuya, Morihiro; Iida, Masato; Haze, Kyosuke; Machida, Takumitsu; Nakatsuru, Yoko; Komatani, Hideya; Kotani, Hidehito; Iwasawa, Yoshikazu

2009-08-15

A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.

Commentary: Prerequisite Knowledge

ERIC Educational Resources Information Center

Taylor, Ann T. S.

2013-01-01

Most biochemistry, genetics, cell biology, and molecular biology classes have extensive prerequisite or co-requisite requirements, often including introductory chemistry, introductory biology, and organic chemistry coursework. But what is the function of these prerequisites? While it seems logical that a basic understanding of biological and…

The role of molecular diagnostic testing in the management of thyroid nodules.

PubMed

Moore, Maureen D; Panjwani, Suraj; Gray, Katherine D; Finnerty, Brendan M; Zarnegar, Rasa; Fahey, Thomas J

2017-06-01

Fine needle aspiration (FNA) with cytologic examination remains the standard of care for investigation of thyroid nodules. However, as many as 30% of FNA samples are cytologically indeterminate for malignancy, which confounds clinical management. To reduce the burden of repeat diagnostic testing and unnecessary surgery, there has been extensive investigation into molecular markers that can be detected on FNA specimens to more accurately stratify a patient's risk of malignancy. Areas covered: In this review, the authors discuss recent evidence and progress in molecular markers used in the diagnosis of thyroid cancer highlighting somatic gene alterations, molecular technologies and microRNA analysis. Expert commentary: The goal of molecular markers is to improve diagnostic accuracy and aid clinicians in the preoperative management of thyroid lesions. Modalities such as direct mutation analysis, mRNA gene expression profiling, next-generation sequencing, and miRNA expression profiling have been explored to improve the diagnostic accuracy of thyroid nodule FNA. Although no perfect test has been discovered, molecular diagnostic testing has revolutionized the management of thyroid nodules.

Defining the molecular structure of teixobactin analogues and understanding their role in antibacterial activities.

PubMed

Parmar, Anish; Prior, Stephen H; Iyer, Abhishek; Vincent, Charlotte S; Van Lysebetten, Dorien; Breukink, Eefjan; Madder, Annemieke; Taylor, Edward J; Singh, Ishwar

2017-02-07

The discovery of the highly potent antibiotic teixobactin, which kills the bacteria without any detectable resistance, has stimulated interest in its structure-activity relationship. However, a molecular structure-activity relationship has not been established so far for teixobactin. Moreover, the importance of the individual amino acids in terms of their l/d configuration and their contribution to the molecular structure and biological activity are still unknown. For the first time, we have defined the molecular structure of seven teixobactin analogues through the variation of the d/l configuration of its key residues, namely N-Me-d-Phe, d-Gln, d-allo-Ile and d-Thr. Furthermore, we have established the role of the individual d amino acids and correlated this with the molecular structure and biological activity. Through extensive NMR and structural calculations, including molecular dynamics simulations, we have revealed the residues for maintaining a reasonably unstructured teixobactin which is imperative for biological activity.

The unique stem cell system of the immortal larva of the human parasite Echinococcus multilocularis

PubMed Central

2014-01-01

Background It is believed that in tapeworms a separate population of undifferentiated cells, the germinative cells, is the only source of cell proliferation throughout the life cycle (similar to the neoblasts of free living flatworms). In Echinococcus multilocularis, the metacestode larval stage has a unique development, growing continuously like a mass of vesicles that infiltrate the tissues of the intermediate host, generating multiple protoscoleces by asexual budding. This unique proliferation potential indicates the existence of stem cells that are totipotent and have the ability for extensive self-renewal. Results We show that only the germinative cells proliferate in the larval vesicles and in primary cell cultures that undergo complete vesicle regeneration, by using a combination of morphological criteria and by developing molecular markers of differentiated cell types. The germinative cells are homogeneous in morphology but heterogeneous at the molecular level, since only sub-populations express homologs of the post-transcriptional regulators nanos and argonaute. Important differences are observed between the expression patterns of selected neoblast marker genes of other flatworms and the E. multilocularis germinative cells, including widespread expression in E. multilocularis of some genes that are neoblast-specific in planarians. Hydroxyurea treatment results in the depletion of germinative cells in larval vesicles, and after recovery following hydroxyurea treatment, surviving proliferating cells grow as patches that suggest extensive self-renewal potential for individual germinative cells. Conclusions In E. multilocularis metacestodes, the germinative cells are the only proliferating cells, presumably driving the continuous growth of the larval vesicles. However, the existence of sub-populations of the germinative cells is strongly supported by our data. Although the germinative cells are very similar to the neoblasts of other flatworms in function and in undifferentiated morphology, their unique gene expression pattern and the evolutionary loss of conserved stem cells regulators suggest that important differences in their physiology exist, which could be related to the unique biology of E. multilocularis larvae. PMID:24602211

Differential correlation for sequencing data.

PubMed

Siska, Charlotte; Kechris, Katerina

2017-01-19

Several methods have been developed to identify differential correlation (DC) between pairs of molecular features from -omics studies. Most DC methods have only been tested with microarrays and other platforms producing continuous and Gaussian-like data. Sequencing data is in the form of counts, often modeled with a negative binomial distribution making it difficult to apply standard correlation metrics. We have developed an R package for identifying DC called Discordant which uses mixture models for correlations between features and the Expectation Maximization (EM) algorithm for fitting parameters of the mixture model. Several correlation metrics for sequencing data are provided and tested using simulations. Other extensions in the Discordant package include additional modeling for different types of differential correlation, and faster implementation, using a subsampling routine to reduce run-time and address the assumption of independence between molecular feature pairs. With simulations and breast cancer miRNA-Seq and RNA-Seq data, we find that Spearman's correlation has the best performance among the tested correlation methods for identifying differential correlation. Application of Spearman's correlation in the Discordant method demonstrated the most power in ROC curves and sensitivity/specificity plots, and improved ability to identify experimentally validated breast cancer miRNA. We also considered including additional types of differential correlation, which showed a slight reduction in power due to the additional parameters that need to be estimated, but more versatility in applications. Finally, subsampling within the EM algorithm considerably decreased run-time with negligible effect on performance. A new method and R package called Discordant is presented for identifying differential correlation with sequencing data. Based on comparisons with different correlation metrics, this study suggests Spearman's correlation is appropriate for sequencing data, but other correlation metrics are available to the user depending on the application and data type. The Discordant method can also be extended to investigate additional DC types and subsampling with the EM algorithm is now available for reduced run-time. These extensions to the R package make Discordant more robust and versatile for multiple -omics studies.

Skin lesions on yellowfin tuna Thunnus albacares from Gulf of Mexico outer continental shelf: Morphological, molecular, and histological diagnosis of infection by a capsalid monogenoid.

PubMed

Bullard, Stephen A; Womble, Matthew R; Maynard, Margaret K; Orélis-Ribeiro, Raphael; Arias, Cova R

2015-12-01

We characterize lesion-associated capsaline infections on yellowfin tuna, Thunnus albacares, in the Gulf of Mexico by comparing our specimens with published descriptions and museum specimens ascribed to Capsala biparasiticum and its synonyms: vouchers of C. biparasiticum from parasitic copepods; the holotype of Capsala neothunni; and vouchers of Capsala abidjani. Those from parasitic copepods differed by having a small, rounded body, large anterior attachment organs, closely spaced dorsomarginal body sclerites, small testes, and a short and wide testicular field. No morphometric feature in the holotype of C. neothunni ranged outside of that reported for the newly-collected specimens, indicating conspecificity of our specimens. The specimens of C. abidjani differed by having a large anterior attachment organ, few and dendritic testes, and a short, wide testicular field. Large subunit ribosomal DNA (28S) sequences grouped our specimens and Capsala sp. as sister taxa and indicated a phylogenetic affinity of Nasicola klawei. The haptoral attachment site comprised a crater-like depression surrounded by a blackish-colored halo of extensively rugose skin, with abundant pockmarked-like, irregularly-shaped oblong or semi-circular epidermal pits surrounding these attachment sites. Histology confirmed extensive folding of epidermis and underlying stratum laxum, likely epidermal hyperplasia, foci of weak cell-to-cell adhesions among apical malpighian cells as well as that between stratum germinativum and stratum laxum, myriad goblet cells in epidermis, rodlet cells in apical layer of epidermis, and lymphocytic infiltrates and melanin in dermis. The present study comprises (i) the first published report of this parasite from yellowfin tuna captured in the Gulf of Mexico-NW Atlantic Ocean Basin, (ii) confirmation of its infection on the skin (rather than on a parasitic copepod), (iii) the first molecular data for this capsaline, and (iv) the first observations of histopathological changes associated with a capsalid infection on a wild-caught epipelagic fish. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The unique stem cell system of the immortal larva of the human parasite Echinococcus multilocularis.

PubMed

Koziol, Uriel; Rauschendorfer, Theresa; Zanon Rodríguez, Luis; Krohne, Georg; Brehm, Klaus

2014-03-06

It is believed that in tapeworms a separate population of undifferentiated cells, the germinative cells, is the only source of cell proliferation throughout the life cycle (similar to the neoblasts of free living flatworms). In Echinococcus multilocularis, the metacestode larval stage has a unique development, growing continuously like a mass of vesicles that infiltrate the tissues of the intermediate host, generating multiple protoscoleces by asexual budding. This unique proliferation potential indicates the existence of stem cells that are totipotent and have the ability for extensive self-renewal. We show that only the germinative cells proliferate in the larval vesicles and in primary cell cultures that undergo complete vesicle regeneration, by using a combination of morphological criteria and by developing molecular markers of differentiated cell types. The germinative cells are homogeneous in morphology but heterogeneous at the molecular level, since only sub-populations express homologs of the post-transcriptional regulators nanos and argonaute. Important differences are observed between the expression patterns of selected neoblast marker genes of other flatworms and the E. multilocularis germinative cells, including widespread expression in E. multilocularis of some genes that are neoblast-specific in planarians. Hydroxyurea treatment results in the depletion of germinative cells in larval vesicles, and after recovery following hydroxyurea treatment, surviving proliferating cells grow as patches that suggest extensive self-renewal potential for individual germinative cells. In E. multilocularis metacestodes, the germinative cells are the only proliferating cells, presumably driving the continuous growth of the larval vesicles. However, the existence of sub-populations of the germinative cells is strongly supported by our data. Although the germinative cells are very similar to the neoblasts of other flatworms in function and in undifferentiated morphology, their unique gene expression pattern and the evolutionary loss of conserved stem cells regulators suggest that important differences in their physiology exist, which could be related to the unique biology of E. multilocularis larvae.

F429 Regulation of Tunnels in Cytochrome P450 2B4: A Top Down Study of Multiple Molecular Dynamics Simulations

PubMed Central

Mancini, Giordano; Zazza, Costantino

2015-01-01

The root causes of the outcomes of the single-site mutation in enzymes remain by and large not well understood. This is the case of the F429H mutant of the cytochrome P450 (CYP) 2B4 enzyme where the substitution, on the proximal surface of the active site, of a conserved phenylalanine 429 residue with histidine seems to hamper the formation of the active species, Compound I (porphyrin cation radical-Fe(IV) = O, Cpd I) from the ferric hydroperoxo (Fe(III)OOH-, Cpd 0) precursor. Here we report a study based on extensive molecular dynamic (MD) simulations of 4 CYP-2B4 point mutations compared to the WT enzyme, having the goal of better clarifying the importance of the proximal Phe429 residue on CYP 2B4 catalytic properties. To consolidate the huge amount of data coming from five simulations and extract the most distinct structural features of the five species studied we made an extensive use of cluster analysis. The results show that all studied single polymorphisms of F429, with different side chain properties: i) drastically alter the reservoir of conformations accessible by the protein, perturbing global dynamics ii) expose the thiolate group of residue Cys436 to the solvent, altering the electronic properties of Cpd0 and iii) affect the various ingress and egress channels connecting the distal sites with the bulk environment, altering the reversibility of these channels. In particular, it was observed that the wild type enzyme exhibits unique structural features as compared to all mutant species in terms of weak interactions (hydrogen bonds) that generate a completely different dynamical behavior of the complete system. Albeit not conclusive, the current computational investigation sheds some light on the subtle and critical effects that proximal single-site mutations can exert on the functional mechanisms of human microsomal CYPs which should go rather far beyond local structure characterization. PMID:26415031

F429 Regulation of Tunnels in Cytochrome P450 2B4: A Top Down Study of Multiple Molecular Dynamics Simulations.

PubMed

Mancini, Giordano; Zazza, Costantino

2015-01-01

The root causes of the outcomes of the single-site mutation in enzymes remain by and large not well understood. This is the case of the F429H mutant of the cytochrome P450 (CYP) 2B4 enzyme where the substitution, on the proximal surface of the active site, of a conserved phenylalanine 429 residue with histidine seems to hamper the formation of the active species, Compound I (porphyrin cation radical-Fe(IV) = O, Cpd I) from the ferric hydroperoxo (Fe(III)OOH-, Cpd 0) precursor. Here we report a study based on extensive molecular dynamic (MD) simulations of 4 CYP-2B4 point mutations compared to the WT enzyme, having the goal of better clarifying the importance of the proximal Phe429 residue on CYP 2B4 catalytic properties. To consolidate the huge amount of data coming from five simulations and extract the most distinct structural features of the five species studied we made an extensive use of cluster analysis. The results show that all studied single polymorphisms of F429, with different side chain properties: i) drastically alter the reservoir of conformations accessible by the protein, perturbing global dynamics ii) expose the thiolate group of residue Cys436 to the solvent, altering the electronic properties of Cpd0 and iii) affect the various ingress and egress channels connecting the distal sites with the bulk environment, altering the reversibility of these channels. In particular, it was observed that the wild type enzyme exhibits unique structural features as compared to all mutant species in terms of weak interactions (hydrogen bonds) that generate a completely different dynamical behavior of the complete system. Albeit not conclusive, the current computational investigation sheds some light on the subtle and critical effects that proximal single-site mutations can exert on the functional mechanisms of human microsomal CYPs which should go rather far beyond local structure characterization.

The Seminal fluid proteome of the polyandrous Red junglefowl offers insights into the molecular basis of fertility, reproductive ageing and domestication

PubMed Central

Borziak, Kirill; Álvarez-Fernández, Aitor; L. Karr, Timothy; Pizzari, Tommaso; Dorus, Steve

2016-01-01

Seminal fluid proteins (SFPs) are emerging as fundamental contributors to sexual selection given their role in post-mating reproductive events, particularly in polyandrous species where the ejaculates of different males compete for fertilisation. SFP identification however remains taxonomically limited and little is known about avian SFPs, despite extensive work on sexual selection in birds. We characterize the SF proteome of the polyandrous Red junglefowl, Gallus gallus, the wild species that gave rise to the domestic chicken. We identify 1,141 SFPs, including proteins involved in immunity and antimicrobial defences, sperm maturation, and fertilisation, revealing a functionally complex SF proteome. This includes a predominant contribution of blood plasma proteins that is conserved with human SF. By comparing the proteome of young and old males with fast or slow sperm velocity in a balanced design, we identify proteins associated with ageing and sperm velocity, and show that old males that retain high sperm velocity have distinct proteome characteristics. SFP comparisons with domestic chickens revealed both qualitative and quantitative differences likely associated with domestication and artificial selection. Collectively, these results shed light onto the functional complexity of avian SF, and provide a platform for molecular studies of fertility, reproductive ageing, and domestication. PMID:27804984

The Warthin-Like Variant of Papillary Thyroid Carcinoma: A Comparison with Classic Type in the Patients with Coexisting Hashimoto's Thyroiditis.

PubMed

Yeo, Min-Kyung; Bae, Ja Seong; Lee, Sohee; Kim, Min-Hee; Lim, Dong-Jun; Lee, Youn Soo; Jung, Chan Kwon

2015-01-01

Background. The Warthin-like variant of papillary thyroid (WLPTC) is a rare subtype of papillary thyroid carcinoma (PTC) resembling Warthin tumors of the salivary glands. Due to its rarity, the clinicopathologic and molecular features of WLPTC remain unclear. Methods. Of the 2,139 patients who underwent surgical treatment for PTC from 2012 to 2013, 40 patients with WLPTC were identified and compared to 200 consecutive patients with classic PTC. BRAF mutation was tested with pyrosequencing. Results. There were no significant differences in age, predilection for women, multifocality, extrathyroidal extension, or lymph node metastasis between WLPTC and classic PTC. However, WLPTCs were more commonly associated with Hashimoto's thyroiditis than classic PTCs (93% versus 36%, resp., P < 0.001) and showed significantly lower rate of BRAF mutation when compared to classic PTCs (65% versus 84%, resp., P = 0.007). In classic PTC, the frequency of BRAF mutations was negatively correlated with coexisting Hashimoto's thyroiditis. When we compared WLPTC and classic PTC in the patients with coexisting Hashimoto's thyroiditis, there were no significant differences in clinicopathologic characteristics or the BRAF mutational rate between the two groups. Conclusions. Patients with WLPTC have similar demographic, clinical, pathologic, and molecular characteristics to those with classic PTC coexisting with Hashimoto's thyroiditis.

The Warthin-Like Variant of Papillary Thyroid Carcinoma: A Comparison with Classic Type in the Patients with Coexisting Hashimoto's Thyroiditis

PubMed Central

Yeo, Min-kyung; Bae, Ja Seong; Lim, Dong-Jun; Lee, Youn Soo

2015-01-01

Background. The Warthin-like variant of papillary thyroid (WLPTC) is a rare subtype of papillary thyroid carcinoma (PTC) resembling Warthin tumors of the salivary glands. Due to its rarity, the clinicopathologic and molecular features of WLPTC remain unclear. Methods. Of the 2,139 patients who underwent surgical treatment for PTC from 2012 to 2013, 40 patients with WLPTC were identified and compared to 200 consecutive patients with classic PTC. BRAF mutation was tested with pyrosequencing. Results. There were no significant differences in age, predilection for women, multifocality, extrathyroidal extension, or lymph node metastasis between WLPTC and classic PTC. However, WLPTCs were more commonly associated with Hashimoto's thyroiditis than classic PTCs (93% versus 36%, resp., P < 0.001) and showed significantly lower rate of BRAF mutation when compared to classic PTCs (65% versus 84%, resp., P = 0.007). In classic PTC, the frequency of BRAF mutations was negatively correlated with coexisting Hashimoto's thyroiditis. When we compared WLPTC and classic PTC in the patients with coexisting Hashimoto's thyroiditis, there were no significant differences in clinicopathologic characteristics or the BRAF mutational rate between the two groups. Conclusions. Patients with WLPTC have similar demographic, clinical, pathologic, and molecular characteristics to those with classic PTC coexisting with Hashimoto's thyroiditis. PMID:25983754

Molecular structure, vibrational spectra and quantum chemical MP2/DFT studies toward the rational design of hydroxyurea imprinted polymer

NASA Astrophysics Data System (ADS)

Prasad, Bhim Bali; Rai, Garima

2013-03-01

In this study, both experimental and theoretical vibrational spectra of template (hydroxyurea, HU), monomer (N-(4,6-bisacryloyl amino-[1,3,5] triazine-2-yl-)-acryl amide, TAT), and HU-TAT complexes were compared and these were respectively found to be in good agreement. Binding energies of HU, when complexed with different monomers, were computed using second order Moller Plesset theory (MP2) at 6-311++G(d,p) level both in the gas as well as solution phases. HU is an antineoplastic agent extensively being used in the treatment of polycythaemia Vera and thrombocythemia. It is also used to reduce the frequency of painful attacks in sickle cell anemia. It has antiretroviral property in disease like AIDS. All spectral characterizations were made using Density Functional Theory (DFT) at B3LYP employing 6-31+g(2d, 2p) basis set. The theoretical values for 13C and 1H NMR chemical shifts were found to be in accordance with the corresponding experimental values. Of all different monomers studied for the synthesis of molecularly imprinted polymer (MIP) systems, the monomer TAT (2 mol) was typically found to have a best binding score requisite for complexation with HU (1 mol) at the ground state.

The Seminal fluid proteome of the polyandrous Red junglefowl offers insights into the molecular basis of fertility, reproductive ageing and domestication.

PubMed

Borziak, Kirill; Álvarez-Fernández, Aitor; L Karr, Timothy; Pizzari, Tommaso; Dorus, Steve

2016-11-02

Seminal fluid proteins (SFPs) are emerging as fundamental contributors to sexual selection given their role in post-mating reproductive events, particularly in polyandrous species where the ejaculates of different males compete for fertilisation. SFP identification however remains taxonomically limited and little is known about avian SFPs, despite extensive work on sexual selection in birds. We characterize the SF proteome of the polyandrous Red junglefowl, Gallus gallus, the wild species that gave rise to the domestic chicken. We identify 1,141 SFPs, including proteins involved in immunity and antimicrobial defences, sperm maturation, and fertilisation, revealing a functionally complex SF proteome. This includes a predominant contribution of blood plasma proteins that is conserved with human SF. By comparing the proteome of young and old males with fast or slow sperm velocity in a balanced design, we identify proteins associated with ageing and sperm velocity, and show that old males that retain high sperm velocity have distinct proteome characteristics. SFP comparisons with domestic chickens revealed both qualitative and quantitative differences likely associated with domestication and artificial selection. Collectively, these results shed light onto the functional complexity of avian SF, and provide a platform for molecular studies of fertility, reproductive ageing, and domestication.

Side-chain conformation at the selectivity filter shapes the permeation free-energy landscape of an ion channel.

PubMed

Harpole, Tyler J; Grosman, Claudio

2014-08-05

On the basis of single-channel currents recorded from the muscle nicotinic acetylcholine receptor (AChR), we have recently hypothesized that the conformation adopted by the glutamate side chains at the first turn of the pore-lining α-helices is a key determinant of the rate of ion permeation. In this paper, we set out to test these ideas within a framework of atomic detail and stereochemical rigor by conducting all-atom molecular dynamics and Brownian dynamics simulations on an extensively validated model of the open-channel muscle AChR. Our simulations provided ample support to the notion that the different rotamers of these glutamates partition into two classes that differ markedly in their ability to catalyze ion conduction, and that the conformations of the four wild-type glutamates are such that two of them "fall" in each rotamer class. Moreover, the simulations allowed us to identify the mm (χ(1) ≅ -60°; χ(2) ≅ -60°) and tp (χ(1) ≅ 180°; χ(2) ≅ +60°) rotamers as the likely conduction-catalyzing conformations of the AChR's selectivity-filter glutamates. More generally, our work shows an example of how experimental benchmarks can guide molecular simulations into providing a type of structural and mechanistic insight that seems otherwise unattainable.

Molecular Dynamics Study of the Solubility Curve of Polyglutamine for the PLUM Model.

NASA Astrophysics Data System (ADS)

Kutlu, Songul; Haaga, Jason; Gunton, James D.

A recent study by Crick et al determined the saturation (solubility) curve for polyglutamine (PolyQ) for several different repeat lengths, n, of Qn, and for different flanking sequences, such as K2. The degree of supersaturation S, (S =ln(Co/Ce), where Co and Ce are the metastable and equilibrium saturation monomer concentrations, respectively) plays a crucial role in the kinetics of aggregation of misfolded proteins containing polyQ. Thus the degree of supersaturation is an important factor in diseases such as Huntington's disease for which polyQ is a major component. We present here preliminary results of a molecular dynamics study for the solubility curve for a PLUM model of Q10. (An extensive study of the kinetics of aggregation for this model is being carried out in a separate study) Our results display a normal solubility curve behavior, with the saturation concentration increasing with increasing temperature. This is only in partial qualitative agreement with the experimental results, which show a retrograde behavior at low temperatures. We are extending this study to other repeat lengths, including Q40. ∖ ∖ ∖ ∖ This work is supported by the G. Harold and Leila Y. Mathers Foundation and used an allocation of time from XSEDE.

Characterization of 1577 primary prostate cancers reveals novel biological and clinicopathologic insights into molecular subtypes.

PubMed

Tomlins, Scott A; Alshalalfa, Mohammed; Davicioni, Elai; Erho, Nicholas; Yousefi, Kasra; Zhao, Shuang; Haddad, Zaid; Den, Robert B; Dicker, Adam P; Trock, Bruce J; DeMarzo, Angelo M; Ross, Ashley E; Schaeffer, Edward M; Klein, Eric A; Magi-Galluzzi, Cristina; Karnes, R Jeffrey; Jenkins, Robert B; Feng, Felix Y

2015-10-01

Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG) and SPINK1 overexpression. Clinical assessment may aid in disease stratification, complementing available prognostic tests. To determine the analytical validity and clinicopatholgic associations of microarray-based molecular subtyping. We analyzed Affymetrix GeneChip expression profiles for 1577 patients from eight radical prostatectomy cohorts, including 1351 cases assessed using the Decipher prognostic assay (GenomeDx Biosciences, San Diego, CA, USA) performed in a laboratory with Clinical Laboratory Improvements Amendment certification. A microarray-based (m-) random forest ERG classification model was trained and validated. Outlier expression analysis was used to predict other mutually exclusive non-ERG ETS gene rearrangements (ETS(+)) or SPINK1 overexpression (SPINK1(+)). Associations with clinical features and outcomes by multivariate logistic regression analysis and receiver operating curves. The m-ERG classifier showed 95% accuracy in an independent validation subset (155 samples). Across cohorts, 45% of PCas were classified as m-ERG(+), 9% as m-ETS(+), 8% as m-SPINK1(+), and 38% as triple negative (m-ERG(-)/m-ETS(-)/m-SPINK1(-)). Gene expression profiling supports three underlying molecularly defined groups: m-ERG(+), m-ETS(+), and m-SPINK1(+)/triple negative. On multivariate analysis, m-ERG(+) tumors were associated with lower preoperative serum prostate-specific antigen and Gleason scores, but greater extraprostatic extension (p<0.001). m-ETS(+) tumors were associated with seminal vesicle invasion (p=0.01), while m-SPINK1(+)/triple negative tumors had higher Gleason scores and were more frequent in Black/African American patients (p<0.001). Clinical outcomes were not significantly different among subtypes. A clinically available prognostic test (Decipher) can also assess PCa molecular subtypes, obviating the need for additional testing. Clinicopathologic differences were found among subtypes based on global expression patterns. Molecular subtyping of prostate cancer can be achieved using extra data generated from a clinical-grade, genome-wide expression-profiling prognostic assay (Decipher). Transcriptomic and clinical analysis support three distinct molecular subtypes: (1) m-ERG(+), (2) m-ETS(+), and (3) m-SPINK1(+)/triple negative (m-ERG(-)/m-ETS(-)/m-SPINK1(-)). Incorporation of subtyping into a clinically available assay may facilitate additional applications beyond routine prognosis. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Nosocomial outbreak of extensively drug-resistant Pseudomonas aeruginosa associated with aromatherapy.

PubMed

Mayr, Astrid; Hinterberger, Guido; Lorenz, Ingo H; Kreidl, Peter; Mutschlechner, Wolfgang; Lass-Flörl, Cornelia

2017-04-01

An increase of extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) in various clinical specimens among intensive care unit patients (n = 7) initiated an outbreak investigation consisting of patient data analyses, control of adherence to infection control guidelines, microbiologic surveys, and molecular-based studies. XDR-PA was detected in a jointly used aroma-oil nursing bottle for aromatherapy. We implemented the restriction of oil sharing among patients. Hence, the outbreak was controlled successfully. Copyright © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Reinventing atomic magnetic simulations with spin-orbit coupling

DOE PAGES

Perera, Meewanage Dilina N.; Eisenbach, Markus; Nicholson, Don M.; ...

2016-02-10

We propose a powerful extension to the combined molecular and spin dynamics method that fully captures the coupling between the atomic and spin subsystems via spin-orbit interactions. Moreover, the foundation of this method lies in the inclusion of the local magnetic anisotropies that arise as a consequence of the lattice symmetry breaking due to phonons or crystallographic defects. By using canonical simulations of bcc iron with the system coupled to a phonon heat bath, we show that our extension enables the previously unachievable angular momentum exchange between the atomic and spin degrees of freedom.

Avian sex, sex chromosomes, and dosage compensation in the age of genomics.

PubMed

Graves, Jennifer A Marshall

2014-04-01

Comparisons of the sex chromosome systems in birds and mammals are widening our view and deepening our understanding of vertebrate sex chromosome organization, function, and evolution. Birds have a very conserved ZW system of sex determination in which males have two copies of a large, gene-rich Z chromosome, and females have a single Z and a female-specific W chromosome. The avian ZW system is quite the reverse of the well-studied mammalian XY chromosome system, and evolved independently from different autosomal blocs. Despite the different gene content of mammal and bird sex chromosomes, there are many parallels. Genes on the bird Z and the mammal X have both undergone selection for male-advantage functions, and there has been amplification of male-advantage genes and accumulation of LINEs. The bird W and mammal Y have both undergone extensive degradation, but some birds retain early stages and some mammals terminal stages of the process, suggesting that the process is more advanced in mammals. Different sex-determining genes, DMRT1 and SRY, define the ZW and XY systems, but DMRT1 is involved in downstream events in mammals. Birds show strong cell autonomous specification of somatic sex differences in ZZ and ZW tissue, but there is growing evidence for direct X chromosome effects on sexual phenotype in mammals. Dosage compensation in birds appears to be phenotypically and molecularly quite different from X inactivation, being partial and gene-specific, but both systems use tools from the same molecular toolbox and there are some signs that galliform birds represent an early stage in the evolution of a coordinated system.

Geographic distribution of the muscle-dwelling nematode Parelaphostrongylus odocoilei in North America, using molecular identification of first-stage larvae.

PubMed

Jenkins, Emily J; Appleyard, Greg D; Hoberg, Eric P; Rosenthal, Benjamin M; Kutz, Susan J; Veitch, Alasdair M; Schwantje, Helen M; Elkin, Brett T; Polley, Lydden

2005-06-01

Molecular identification of dorsal-spined larvae (DSL) from fecal samples indicates that the protostrongylid parasite Parelaphostrongylus odocoilei occupies a broader geographic range in western North America than has been previously reported. We analyzed 2,124 fecal samples at 29 locations from thinhorn sheep (Ovis dalli dalli and O. d. stonei), bighorn sheep (Ovis canadensis canadensis and O. c. californiana), mountain goats (Oreamnos americanus), woodland caribou (Rangifer tarandus caribou), mule deer (Odocoileus hemionus hemionus), and black-tailed deer (O. h. columbianus). The DSL were recovered from populations of thinhorn sheep south, but not north, of the Arctic Circle, and they were not recovered from any of the bighorn sheep populations that we examined. In total, DSL were recovered from 20 locations in the United States and Canada (Alaska, Yukon Territory, Northwest Territories, British Columbia, Alberta, and California). The DSL were identified as P. odocoilei by comparing sequences of the second internal transcribed spacer (ITS2) region of ribosomal RNA among 9 protostrongylid species validated by adult comparative morphology. The ITS2 sequences were markedly different between Parelaphostrongylus and other protostrongylid genera. Smaller fixed differences served as diagnostic markers for the 3 species of Parelaphostrongylus. The ITS2 sequences (n = 60) of P. odocoilei were strongly conserved across its broad geographic range from California to Alaska. Polymorphism at 5 nucleotide positions was consistent with multiple copies of the ITS2 within individual specimens of P. odocoilei. This work combines extensive fecal surveys, comparative morphology, and molecular diagnostic techniques to describe comprehensively the host associations and geographic distribution of a parasitic helminth.

Melvin P. Tucker | NREL

Science.gov Websites

biomass to biofuels and products, with extensive expertise in high solids pretreatment, high solids techniques, high-performance liquid chromatography, and spectroscopic techniques (Fourier transform infrared , biochemists, chemists, and molecular biologist to deconstruct biomass into high concentration, low toxicity

Virtual Screening of Receptor Sites for Molecularly Imprinted Polymers.

PubMed

Bates, Ferdia; Cela-Pérez, María Concepción; Karim, Kal; Piletsky, Sergey; López-Vilariño, José Manuel

2016-08-01

Molecularly Imprinted Polymers (MIPs) are highly advantageous in the field of analytical chemistry. However, interference from secondary molecules can also impede capture of a target by a MIP receptor. This greatly complicates the design process and often requires extensive laboratory screening which is time consuming, costly, and creates substantial waste products. Herein, is presented a new technique for screening of "virtually imprinted receptors" for rebinding of the molecular template as well as secondary structures, correlating the virtual predictions with experimentally acquired data in three case studies. This novel technique is particularly applicable to the evaluation and prediction of MIP receptor specificity and efficiency in complex aqueous systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular computational elements encode large populations of small objects

NASA Astrophysics Data System (ADS)

Prasanna de Silva, A.; James, Mark R.; McKinney, Bernadine O. F.; Pears, David A.; Weir, Sheenagh M.

2006-10-01

Since the introduction of molecular computation, experimental molecular computational elements have grown to encompass small-scale integration, arithmetic and games, among others. However, the need for a practical application has been pressing. Here we present molecular computational identification (MCID), a demonstration that molecular logic and computation can be applied to a widely relevant issue. Examples of populations that need encoding in the microscopic world are cells in diagnostics or beads in combinatorial chemistry (tags). Taking advantage of the small size (about 1nm) and large `on/off' output ratios of molecular logic gates and using the great variety of logic types, input chemical combinations, switching thresholds and even gate arrays in addition to colours, we produce unique identifiers for members of populations of small polymer beads (about 100μm) used for synthesis of combinatorial libraries. Many millions of distinguishable tags become available. This method should be extensible to far smaller objects, with the only requirement being a `wash and watch' protocol. Our focus on converting molecular science into technology concerning analog sensors, turns to digital logic devices in the present work.

Molecular computational elements encode large populations of small objects.

PubMed

de Silva, A Prasanna; James, Mark R; McKinney, Bernadine O F; Pears, David A; Weir, Sheenagh M

2006-10-01

Since the introduction of molecular computation, experimental molecular computational elements have grown to encompass small-scale integration, arithmetic and games, among others. However, the need for a practical application has been pressing. Here we present molecular computational identification (MCID), a demonstration that molecular logic and computation can be applied to a widely relevant issue. Examples of populations that need encoding in the microscopic world are cells in diagnostics or beads in combinatorial chemistry (tags). Taking advantage of the small size (about 1 nm) and large 'on/off' output ratios of molecular logic gates and using the great variety of logic types, input chemical combinations, switching thresholds and even gate arrays in addition to colours, we produce unique identifiers for members of populations of small polymer beads (about 100 microm) used for synthesis of combinatorial libraries. Many millions of distinguishable tags become available. This method should be extensible to far smaller objects, with the only requirement being a 'wash and watch' protocol. Our focus on converting molecular science into technology concerning analog sensors, turns to digital logic devices in the present work.

Extensive Evaluation of the Conductor-like Screening Model for Real Solvents Method in Predicting Liquid-Liquid Equilibria in Ternary Systems of Ionic Liquids with Molecular Compounds.

PubMed

Paduszyński, Kamil

2018-04-12

A conductor-like screening model for real solvents (COSMO-RS) is nowadays one of the most popular and commonly applied tools for the estimation of thermodynamic properties of complex fluids. The goal of this work is to provide a comprehensive review and analysis of the performance of this approach in calculating liquid-liquid equilibrium (LLE) phase diagrams in ternary systems composed of ionic liquid and two molecular compounds belonging to diverse families of chemicals (alkanes, aromatics, S/N-compounds, alcohols, ketones, ethers, carboxylic acid, esters, and water). The predictions are presented for extensive experimental database, including 930 LLE data sets and more than 9000 data points (LLE tie lines) reported for 779 unique ternary mixtures. An impact of the type of molecular binary subsystem on the accuracy of predictions is demonstrated and discussed on the basis of representative examples. The model's capability of capturing qualitative trends in the LLE distribution ratio and selectivity is also checked for a number of structural effects. Comparative analysis of two levels of quantum chemical theory (BP-TZVP-COSMO vs BP-TZVPD-FINE) for the input molecular data for COSMO-RS is presented. Finally, some general recommendations for the applicability of the model are indicated based on the analysis of the global performance as well as on the results obtained for systems relevant from the point of view of important separation problems.

The molecular kink paradigm for rubber elasticity: Numerical simulations of explicit polyisoprene networks at low to moderate tensile strains

NASA Astrophysics Data System (ADS)

Hanson, David E.

2011-08-01

Based on recent molecular dynamics and ab initio simulations of small isoprene molecules, we propose a new ansatz for rubber elasticity. We envision a network chain as a series of independent molecular kinks, each comprised of a small number of backbone units, and the strain as being imposed along the contour of the chain. We treat chain extension in three distinct force regimes: (Ia) near zero strain, where we assume that the chain is extended within a well defined tube, with all of the kinks participating simultaneously as entropic elastic springs, (II) when the chain becomes sensibly straight, giving rise to a purely enthalpic stretching force (until bond rupture occurs) and, (Ib) a linear entropic regime, between regimes Ia and II, in which a force limit is imposed by tube deformation. In this intermediate regime, the molecular kinks are assumed to be gradually straightened until the chain becomes a series of straight segments between entanglements. We assume that there exists a tube deformation tension limit that is inversely proportional to the chain path tortuosity. Here we report the results of numerical simulations of explicit three-dimensional, periodic, polyisoprene networks, using these extension-only force models. At low strain, crosslink nodes are moved affinely, up to an arbitrary node force limit. Above this limit, non-affine motion of the nodes is allowed to relax unbalanced chain forces. Our simulation results are in good agreement with tensile stress vs. strain experiments.

The molecular kink paradigm for rubber elasticity: numerical simulations of explicit polyisoprene networks at low to moderate tensile strains.

PubMed

Hanson, David E

2011-08-07

Based on recent molecular dynamics and ab initio simulations of small isoprene molecules, we propose a new ansatz for rubber elasticity. We envision a network chain as a series of independent molecular kinks, each comprised of a small number of backbone units, and the strain as being imposed along the contour of the chain. We treat chain extension in three distinct force regimes: (Ia) near zero strain, where we assume that the chain is extended within a well defined tube, with all of the kinks participating simultaneously as entropic elastic springs, (II) when the chain becomes sensibly straight, giving rise to a purely enthalpic stretching force (until bond rupture occurs) and, (Ib) a linear entropic regime, between regimes Ia and II, in which a force limit is imposed by tube deformation. In this intermediate regime, the molecular kinks are assumed to be gradually straightened until the chain becomes a series of straight segments between entanglements. We assume that there exists a tube deformation tension limit that is inversely proportional to the chain path tortuosity. Here we report the results of numerical simulations of explicit three-dimensional, periodic, polyisoprene networks, using these extension-only force models. At low strain, crosslink nodes are moved affinely, up to an arbitrary node force limit. Above this limit, non-affine motion of the nodes is allowed to relax unbalanced chain forces. Our simulation results are in good agreement with tensile stress vs. strain experiments.

A theoretical signal processing framework for linear diffusion MRI: Implications for parameter estimation and experiment design.

PubMed

Varadarajan, Divya; Haldar, Justin P

2017-11-01

The data measured in diffusion MRI can be modeled as the Fourier transform of the Ensemble Average Propagator (EAP), a probability distribution that summarizes the molecular diffusion behavior of the spins within each voxel. This Fourier relationship is potentially advantageous because of the extensive theory that has been developed to characterize the sampling requirements, accuracy, and stability of linear Fourier reconstruction methods. However, existing diffusion MRI data sampling and signal estimation methods have largely been developed and tuned without the benefit of such theory, instead relying on approximations, intuition, and extensive empirical evaluation. This paper aims to address this discrepancy by introducing a novel theoretical signal processing framework for diffusion MRI. The new framework can be used to characterize arbitrary linear diffusion estimation methods with arbitrary q-space sampling, and can be used to theoretically evaluate and compare the accuracy, resolution, and noise-resilience of different data acquisition and parameter estimation techniques. The framework is based on the EAP, and makes very limited modeling assumptions. As a result, the approach can even provide new insight into the behavior of model-based linear diffusion estimation methods in contexts where the modeling assumptions are inaccurate. The practical usefulness of the proposed framework is illustrated using both simulated and real diffusion MRI data in applications such as choosing between different parameter estimation methods and choosing between different q-space sampling schemes. Copyright © 2017 Elsevier Inc. All rights reserved.

Improving validation methods for molecular diagnostics: application of Bland-Altman, Deming and simple linear regression analyses in assay comparison and evaluation for next-generation sequencing.

PubMed

Misyura, Maksym; Sukhai, Mahadeo A; Kulasignam, Vathany; Zhang, Tong; Kamel-Reid, Suzanne; Stockley, Tracy L

2018-02-01

A standard approach in test evaluation is to compare results of the assay in validation to results from previously validated methods. For quantitative molecular diagnostic assays, comparison of test values is often performed using simple linear regression and the coefficient of determination (R 2 ), using R 2 as the primary metric of assay agreement. However, the use of R 2 alone does not adequately quantify constant or proportional errors required for optimal test evaluation. More extensive statistical approaches, such as Bland-Altman and expanded interpretation of linear regression methods, can be used to more thoroughly compare data from quantitative molecular assays. We present the application of Bland-Altman and linear regression statistical methods to evaluate quantitative outputs from next-generation sequencing assays (NGS). NGS-derived data sets from assay validation experiments were used to demonstrate the utility of the statistical methods. Both Bland-Altman and linear regression were able to detect the presence and magnitude of constant and proportional error in quantitative values of NGS data. Deming linear regression was used in the context of assay comparison studies, while simple linear regression was used to analyse serial dilution data. Bland-Altman statistical approach was also adapted to quantify assay accuracy, including constant and proportional errors, and precision where theoretical and empirical values were known. The complementary application of the statistical methods described in this manuscript enables more extensive evaluation of performance characteristics of quantitative molecular assays, prior to implementation in the clinical molecular laboratory. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Characterization of Polyhydroxyalkanoate Produced by Bacillus megaterium VB89 Isolated from Nisargruna Biogas Plant.

PubMed

Baikar, Vishakha; Rane, Ashwini; Deopurkar, Rajendra

2017-09-01

Polyhydroxyalkanoates (PHAs) are naturally occurring biodegradable polymers that can curb the extensive use of polypropylene based plastics. In contrast to chemically synthesized polypropylene plastics, PHAs are biodegradable and thus environmentally safe. PHAs have attracted much attention as biocompatible and biodegradable thermoplastics. The present study involves isolation of bacteria from different environments capable of synthesizing PHAs. The bacterium producing highest yield of PHA (0.672 ± 0.041 g/L) was identified as Bacillus megaterium VB89 by biochemical and molecular techniques such as 16S rDNA sequence analysis. Strain VB89 produced polyhydroxybutyrate (PHB) as revealed by FTIR and NMR. This PHB had an average molecular weight of 2.89 × 10 5  Da and a polydispersity index of 2.37. Thermal properties of the PHB included a glass transition temperature of 13.97 °C, a melting temperature of 181.74 °C, and a decomposition temperature of 234 °C. All these properties indicated that VB89 produced PHB of high purity and good thermal stability.

Fluorescent hybridization probes for nucleic acid detection.

PubMed

Guo, Jia; Ju, Jingyue; Turro, Nicholas J

2012-04-01

Due to their high sensitivity and selectivity, minimum interference with living biological systems, and ease of design and synthesis, fluorescent hybridization probes have been widely used to detect nucleic acids both in vivo and in vitro. Molecular beacons (MBs) and binary probes (BPs) are two very important hybridization probes that are designed based on well-established photophysical principles. These probes have shown particular applicability in a variety of studies, such as mRNA tracking, single nucleotide polymorphism (SNP) detection, polymerase chain reaction (PCR) monitoring, and microorganism identification. Molecular beacons are hairpin oligonucleotide probes that present distinctive fluorescent signatures in the presence and absence of their target. Binary probes consist of two fluorescently labeled oligonucleotide strands that can hybridize to adjacent regions of their target and generate distinctive fluorescence signals. These probes have been extensively studied and modified for different applications by modulating their structures or using various combinations of fluorophores, excimer-forming molecules, and metal complexes. This review describes the applicability and advantages of various hybridization probes that utilize novel and creative design to enhance their target detection sensitivity and specificity.

The Function of Embryonic Stem Cell-expressed RAS (E-RAS), a Unique RAS Family Member, Correlates with Its Additional Motifs and Its Structural Properties.

PubMed

Nakhaei-Rad, Saeideh; Nakhaeizadeh, Hossein; Kordes, Claus; Cirstea, Ion C; Schmick, Malte; Dvorsky, Radovan; Bastiaens, Philippe I H; Häussinger, Dieter; Ahmadian, Mohammad Reza

2015-06-19

E-RAS is a member of the RAS family specifically expressed in embryonic stem cells, gastric tumors, and hepatic stellate cells. Unlike classical RAS isoforms (H-, N-, and K-RAS4B), E-RAS has, in addition to striking and remarkable sequence deviations, an extended 38-amino acid-long unique N-terminal region with still unknown functions. We investigated the molecular mechanism of E-RAS regulation and function with respect to its sequence and structural features. We found that N-terminal extension of E-RAS is important for E-RAS signaling activity. E-RAS protein most remarkably revealed a different mode of effector interaction as compared with H-RAS, which correlates with deviations in the effector-binding site of E-RAS. Of all these residues, tryptophan 79 (arginine 41 in H-RAS), in the interswitch region, modulates the effector selectivity of RAS proteins from H-RAS to E-RAS features. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Molecular targets of curcumin for cancer therapy: an updated review.

PubMed

Kasi, Pandima Devi; Tamilselvam, Rajavel; Skalicka-Woźniak, Krystyna; Nabavi, Seyed Fazel; Daglia, Maria; Bishayee, Anupam; Pazoki-Toroudi, Hamidreza; Nabavi, Seyed Mohammad

2016-10-01

In recent years, natural edible products have been found to be important therapeutic agents for the treatment of chronic human diseases including cancer, cardiovascular disease, and neurodegeneration. Curcumin is a well-known diarylheptanoid constituent of turmeric which possesses anticancer effects under both pre-clinical and clinical conditions. Moreover, it is well known that the anticancer effects of curcumin are primarily due to the activation of apoptotic pathways in the cancer cells as well as inhibition of tumor microenvironments like inflammation, angiogenesis, and tumor metastasis. In particular, extensive studies have demonstrated that curcumin targets numerous therapeutically important cancer signaling pathways such as p53, Ras, PI3K, AKT, Wnt-β catenin, mTOR and so on. Clinical studies also suggested that either curcumin alone or as combination with other drugs possess promising anticancer effect in cancer patients without causing any adverse effects. In this article, we critically review the available scientific evidence on the molecular targets of curcumin for the treatment of different types of cancer. In addition, we also discuss its chemistry, sources, bioavailability, and future research directions.

Molecular dynamics simulation studies of caffeine aggregation in aqueous solution.

PubMed

Tavagnacco, Letizia; Schnupf, Udo; Mason, Philip E; Saboungi, Marie-Louise; Cesàro, Attilio; Brady, John W

2011-09-22

Molecular dynamics simulations were carried out on a system of eight independent caffeine molecules in a periodic box of water at 300 K, representing a solution near the solubility limit for caffeine at room temperature, using a newly developed CHARMM-type force field for caffeine in water. Simulations were also conducted for single caffeine molecules in water using two different water models (TIP3P and TIP4P). Water was found to structure in a complex fashion around the planar caffeine molecules, which was not sensitive to the water model used. As expected, extensive aggregation of the caffeine molecules was observed, with the molecules stacking their flat faces against one another like coins, with their methylene groups staggered to avoid steric clashes. A dynamic equilibrum was observed between large n-mers, including stacks with all eight solute molecules, and smaller clusters, with the calculated osmotic coefficient being in acceptable agreement with the experimental value. The insensitivity of the results to water model and the congruence with experimental thermodynamic data suggest that the observed stacking interactions are a realistic representation of the actual association mechanism in aqueous caffeine solutions.

Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues

PubMed Central

Madaan, Kanika; Kumar, Sandeep; Poonia, Neelam; Lather, Viney; Pandita, Deepti

2014-01-01

Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity. PMID:25035633