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Sample records for evolutionarily fine-tuned molecular

  1. Fine tuning of molecular rotor function in photochemical molecular switches

    NARCIS (Netherlands)

    ter Wiel, Matthijs K. J.; Feringa, Ben L.

    2009-01-01

    Molecular switches are used as scaffolds for the construction of controlled molecular rotors. The internal position of the switching entity in the molecule controls the dynamic behaviour of the rotor moiety in the molecule. Six new molecular motors with o-xylyl rotor moieties were prepared on the

  2. Perspective: Extremely fine tuning of doping enabled by combinatorial molecular-beam epitaxy

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    J. Wu

    2015-06-01

    Full Text Available Chemical doping provides an effective method to control the electric properties of complex oxides. However, the state-of-art accuracy in controlling doping is limited to about 1%. This hampers elucidation of the precise doping dependences of physical properties and phenomena of interest, such as quantum phase transitions. Using the combinatorial molecular beam epitaxy, we improve the accuracy in tuning the doping level by two orders of magnitude. We illustrate this novel method by two examples: a systematic investigation of the doping dependence of interface superconductivity, and a study of the competing ground states in the vicinity of the insulator-to-superconductor transition.

  3. PDI Derivative through Fine-Tuning Molecular Structure for Fullerene-Free Organic Solar Cells

    KAUST Repository

    Sun, Hua

    2017-08-10

    A perylenediimide (PDI)-based small molecular (SM) acceptor with both an extended π-conjugation and a three dimensional structure concurrently is critical for achieving high performance PDI-based fullerene-free organic solar cells (OSCs). In this work, we designed and synthesized a novel PDI-based SM acceptor possessing both characteristics by fusing PDI units with a spiro core of 4,4’-spirobi[cyclopenta[2,1-b;3,4-b’]dithiophene(SCPDT) through the -position of the thiophene rings. An enhanced strong absorption in the range of 350–520 nm and arisen LUMO energy level of FSP was observed, compared with previous reported acceptor SCPDT-PDI4, in which the PDI units and SCPDT are not fused. OSCs based on PTB7-Th donor and FSP acceptor were fabricated and achieved a power conversion efficiency of up to 8.89% with DPE as an additive. Efficient and complementary photo absorption, favorable phase separation and balanced carrier mobilites in the blend film account for the high photovoltaic performance. This study offers an effective strategy to design high performance PDI-based acceptors.

  4. Fine-Tuning in a Design Experiment

    Science.gov (United States)

    Ho, Foo Him; Toh, Pee Choon; Toh, Tin Lam

    2013-01-01

    Quek, Tay, Toh, Leong, and Dindyal (2011) proposed that a design-theory-practice troika should always be considered for a designed package to be acceptable to the research users who, in this case, are teachers and schools. This paper describes the fine-tuning to the MProSE problem-solving design made by the teachers in the school after first round…

  5. Defending The Fallacy of Fine-Tuning

    CERN Document Server

    Stenger, Victor J

    2012-01-01

    In 2011, I published a popular-level book, The Fallacy of Fine-Tuning: Why the Universe is Not Designed for Us. It investigated a common claim found in contemporary religious literature that the parameters of physics and cosmology are so delicately balanced, so "fine-tuned," that any slight change and life in the universe would have been impossible. I concluded that while the precise form of life we find on Earth would not exist with slight changes in these parameters, some form of life could have evolved over a parameter range that is not infinitesimal, as often claimed. Postdoctoral fellow Luke Barnes has written a lengthy, highly technical review [arXiv:1112.4647] of the scientific literature on the fine-tuning problem. I have no significant disagreement with that literature and no prominent physicist or cosmologist has disputed my basic conclusions. Barnes does not invalidate these conclusions and misunderstands and misrepresents much of what is in the book.

  6. In situ synthesis-gelation at room temperature vs. heating-cooling procedure. Fine tuning of molecular gels derived from succinic acid and L-valine.

    Science.gov (United States)

    Fontanillo, Miriam; Angulo-Pachón, César A; Escuder, Beatriu; Miravet, Juan F

    2013-12-15

    The reaction between succinic anhydride and a diamine derived from L-valine should afford efficiently a molecular gelator. Based on this reaction, it should be feasible to prepare molecular gels at room temperature, avoiding the conventional thermal treatment required for the solubilization of the gelator, by in situ, simultaneous, synthesis and gelation. The gels prepared by in situ and conventional heating-cooling protocols could present important differences relevant for potential practical applications of these materials. The gelator was synthesized by reaction of succinic anhydride and a diamine derived from L-valine, affording two new amide bonds. The molecular gels were studied by IR, NMR, electron microscopy, X-ray diffraction and DSC. The results indicate that different polymorphic fibrillar networks are formed depending on the gel preparation method, highlighting how the properties of molecular gels can be tuned in this way. Significant differences between thermal and in situ gels were found in properties such as thermal stability, thixotropic behavior or release of an entrapped dye. In situ synthesis-gelation has also been shown to provide gels in media such as oleic acid which cannot be jellified by conventional heating-cooling procedures. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Beyond Fine Tuning: Adding capacity to leverage few labels

    Energy Technology Data Exchange (ETDEWEB)

    Hodas, Nathan O.; Shaffer, Kyle J.; Yankov, Artem; Corley, Courtney D.; Anderson, Aryk L.

    2017-12-09

    In this paper we present a technique to train neural network models on small amounts of data. Current methods for training neural networks on small amounts of rich data typically rely on strategies such as fine-tuning a pre-trained neural networks or the use of domain-specific hand-engineered features. Here we take the approach of treating network layers, or entire networks, as modules and combine pre-trained modules with untrained modules, to learn the shift in distributions between data sets. The central impact of using a modular approach comes from adding new representations to a network, as opposed to replacing representations via fine-tuning. Using this technique, we are able surpass results using standard fine-tuning transfer learning approaches, and we are also able to significantly increase performance over such approaches when using smaller amounts of data.

  8. On the MSSM Higgsino mass and fine tuning

    CERN Document Server

    Ross, Graham G.

    2016-08-10

    It is often argued that low fine tuning in the MSSM necessarily requires a rather light Higgsino. In this note we show that this need not be the case when a more complete set of soft SUSY breaking mass terms are included. In particular an Higgsino mass term, that correlates the $\\mu-$term contribution with the soft SUSY-breaking Higgsino masses, significantly reduces the fine tuning even for Higgsinos in the TeV mass range where its relic abundance means it can make up all the dark matter.

  9. The Fine-Tuning of the Universe for Intelligent Life

    CERN Document Server

    Barnes, Luke A

    2011-01-01

    The fine-tuning of the universe for intelligent life has received a great deal of attention in recent years, both in the philosophical and scientific literature. The claim is that in the space of possible physical laws, parameters and initial conditions, the set that permits the evolution of intelligent life is very small. I present here a review of the scientific literature, outlining cases of fine-tuning in the classic works of Carter, Carr and Rees, and Barrow and Tipler, as well as more recent work. To sharpen the discussion, the role of the antagonist will be played by Victor Stenger's recent book The Fallacy of Fine-Tuning: Why the Universe is Not Designed for Us. Stenger claims that all known fine-tuning cases can be explained without the need for a multiverse. Many of Stenger's claims will be found to be highly problematic. We will touch on such issues as the logical necessity of the laws of nature; objectivity, invariance and symmetry; theoretical physics and possible universes; entropy in cosmology;...

  10. Technical fine-tuning problem in renormalized perturbation theory

    Energy Technology Data Exchange (ETDEWEB)

    Foda, O.E.

    1983-01-01

    The technical - as opposed to physical - fine tuning problem, i.e. the stability of tree-level gauge hierarchies at higher orders in renormalized perturbation theory, in a number of different models is studied. These include softly-broken supersymmetric models, and non-supersymmetric ones with a hierarchy of spontaneously-broken gauge symmetries. The models are renormalized using the BPHZ prescription, with momentum subtractions. Explicit calculations indicate that the tree-level hierarchy is not upset by the radiative corrections, and consequently no further fine-tuning is required to maintain it. Furthermore, this result is shown to run counter to that obtained via Dimensional Renormalization, (the only scheme used in previous literature on the subject). The discrepancy originates in the inherent local ambiguity in the finite parts of subtracted Feynman integrals. Within fully-renormalized perturbation theory the answer to the technical fine-tuning question (in the sense of whether the radiative corrections will ''readily'' respect the tree level gauge hierarchy or not) is contingent on the renormalization scheme used to define the model at the quantum level, rather than on the model itself. In other words, the need for fine-tuning, when it arises, is an artifact of the application of a certain class of renormalization schemes.

  11. Fine Tuning Mission to reach those influenced by Darwinism

    Directory of Open Access Journals (Sweden)

    Roger Tucker

    2014-01-01

    Full Text Available The scientifically aware section of the South African population is increasing. Many are being exposed to the concept of Darwinian evolution. Exposure has generated a religious sub �people group� who have problems with Christianity because they have been influenced by the naturalistic element in Darwinian philosophy. Christian antagonism towards evolution has often prejudiced them unfavourably towards the gospel. Recent discoveries concerning the fine-tuning of the universe have now presented a window of opportunity for overcoming this. It may enable the church to �fine-tune� its missionary approach to present them with the gospel in a more acceptable manner. It is suggested that Paul�s Areopagus speech provides a model for such cross-cultural evangelism. A section is included at the end, describing some objections that have been raised against the cosmological fine-tuning apologetic.

  12. Cosmologically safe QCD axion without fine-tuning

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Masaki [Tokyo Univ., Chiba (Japan). Kavli IPMU (WPI), UTIAS; Tokyo Univ., Chiba (Japan). Inst. for Cosmic Ray Research; DESY Hamburg (Germany); Yanagida, Tsutomu T.; Yonekura, Kazuya [Tokyo Univ., Chiba (Japan). Kavli IPMU (WPI), UTIAS

    2015-10-15

    Although QCD axion models are widely studied as solutions to the strong CP problem, they generically confront severe fine-tuning problems to guarantee the anomalous PQ symmetry. In this letter, we propose a simple QCD axion model without any fine-tunings. We introduce an extra dimension and a pair of extra quarks living on two branes separately, which is also charged under a bulk Abelian gauge symmetry. We assume a monopole condensation on our brane at an intermediate scale, which implies that the extra quarks develop the chiral symmetry breaking and the PQ symmetry is broken. In contrast to the original Kim's model, our model explains the origin of the PQ symmetry thanks to the extra dimension and avoids the cosmological domain wall problem because of the chiral symmetry breaking in the Abelian gauge theory.

  13. NMC and the Fine-Tuning Problem on the Brane

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    A. Safsafi

    2014-01-01

    Full Text Available We propose a new solution to the fine-tuning problem related to coupling constant λ of the potential. We study a quartic potential of the form λϕ4 in the framework of the Randall-Sundrum type II braneworld model in the presence of a Higgs field which interacts nonminimally with gravity via a possible interaction term of the form -(ξ/2ϕ2R. Using the conformal transformation techniques, the slow-roll parameters in high energy limit are reformulated in the case of a nonminimally coupled scalar field. We show that, for some value of a coupling parameter ξ and brane tension T, we can eliminate the fine-tuning problem. Finally, we present graphically the solutions of several values of the free parameters of the model.

  14. Possible explanations for fine-tuning of the universe

    Science.gov (United States)

    Kawana, Kiyoharu

    2017-04-01

    The Froggatt-Nielsen mechanism and the multilocal field theory are interesting and promising candidates for solving the naturalness problem in the universe. These theories are based on the different physical principles: The former assumes the microcanonical partition function ∫𝒟ϕ∏iδ(Si - Ii), and the latter assumes the partition function ∫𝒟ϕexp(iSM) where SM is the multilocal action ∑iciSi +∑i,jci,jSiSj + ⋯. Our main purpose is to show that they are equivalent in the sense that they predict the same fine-tuning mechanism. In order to clarify our argument, we first study (review) the similarity between the Froggatt-Nielsen mechanism and statistical mechanics in detail, and show that the dynamical fine-tuning in the former picture can be understood completely in the same way as the determination of the temperature in the latter picture. Afterward, we discuss the multilocal theory and the equivalence between it and the Froggatt-Nielsen mechanism. Because the multilocal field theory can be obtained from physics at the Planck/String scale, this equivalence indicates that the microcanonical picture can also originate in such physics. As a concrete example, we also review the IIB matrix model as an origin of the multilocal theory.

  15. Hearing aid fine-tuning based on Dutch descriptions.

    Science.gov (United States)

    Thielemans, Thijs; Pans, Donné; Chenault, Michelene; Anteunis, Lucien

    2017-07-01

    The aim of this study was to derive an independent fitting assistant based on expert consensus. Two questions were asked: (1) what (Dutch) terms do hearing impaired listeners use nowadays to describe their specific hearing aid fitting problems? (2) What is the expert consensus on how to resolve these complaints by adjusting hearing aid parameters? Hearing aid dispensers provided descriptors that impaired listeners use to describe their reactions to specific hearing aid fitting problems. Hearing aid fitting experts were asked "How would you adjust the hearing aid if its user reports that the aid sounds…?" with the blank filled with each of the 40 most frequently mentioned descriptors. 112 hearing aid dispensers and 15 hearing aid experts. The expert solution with the highest weight value was considered the best solution for that descriptor. Principal component analysis (PCA) was performed to identify a factor structure in fitting problems. Nine fitting problems could be identified resulting in an expert-based, hearing aid manufacturer independent, fine-tuning fitting assistant for clinical use. The construction of an expert-based, hearing aid manufacturer independent, fine-tuning fitting assistant to be used as an additional tool in the iterative fitting process is feasible.

  16. Soflty broken supersymmetry and the fine-tuning problem

    Energy Technology Data Exchange (ETDEWEB)

    Foda, O.E.

    1984-02-20

    The supersymmetry of the simple Wess-Zumino model is broken, in the tree-approximation, by adding all possible parity-even(mass)-dimension 2 and 3 terms. The model is then renormalized using BPHZ and the normal product algorithm, such that supersymmetry is only softly broken (in the original sense of Schroer and Symanzik). We show that, within the above renormalization scheme, none of the added breaking terms give rise to technical fine-tuning problems (defined in the sense of Gildener) in larger models, with scalar multiplets and hierarchy of mass scales, which is in contrast to what we obtain via analytic schemes such as dimensional renormalization, or supersymmetry extension of which. The discrepancy (which can be shown to persist in more general models) originates in the inherent local ambiguity in the finite parts of subtracted Feynman integrals. Emphasizing that the issue is purely technical (as opposed to physical) in origin, and that all physical properties are scheme-independent (as they should be), we conclude that the technical fine-tuning problem, in the specific sense used in this paper, being scheme dependent, is not a well-defined issue within the context of renormalized perturbation theory. 30 references.

  17. A fortunate universe life in a finely tuned cosmos

    CERN Document Server

    Lewis, Geraint F

    2016-01-01

    Over the last forty years, scientists have uncovered evidence that if the Universe had been forged with even slightly different properties, life as we know it - and life as we can imagine it - would be impossible. Join us on a journey through how we understand the Universe, from its most basic particles and forces, to planets, stars and galaxies, and back through cosmic history to the birth of the cosmos. Conflicting notions about our place in the Universe are defined, defended and critiqued from scientific, philosophical and religious viewpoints. The authors' engaging and witty style addresses what fine-tuning might mean for the future of physics and the search for the ultimate laws of nature. Tackling difficult questions and providing thought-provoking answers, this volumes challenges us to consider our place in the cosmos, regardless of our initial convictions.

  18. Fine-tuning tomato agronomic properties by computational genome redesign.

    Directory of Open Access Journals (Sweden)

    Javier Carrera

    Full Text Available Considering cells as biofactories, we aimed to optimize its internal processes by using the same engineering principles that large industries are implementing nowadays: lean manufacturing. We have applied reverse engineering computational methods to transcriptomic, metabolomic and phenomic data obtained from a collection of tomato recombinant inbreed lines to formulate a kinetic and constraint-based model that efficiently describes the cellular metabolism from expression of a minimal core of genes. Based on predicted metabolic profiles, a close association with agronomic and organoleptic properties of the ripe fruit was revealed with high statistical confidence. Inspired in a synthetic biology approach, the model was used for exploring the landscape of all possible local transcriptional changes with the aim of engineering tomato fruits with fine-tuned biotechnological properties. The method was validated by the ability of the proposed genomes, engineered for modified desired agronomic traits, to recapitulate experimental correlations between associated metabolites.

  19. Fine-tuning of the setting of critical day length by two casein kinases in rice photoperiodic flowering.

    Science.gov (United States)

    Nemoto, Yasue; Hori, Kiyosumi; Izawa, Takeshi

    2018-01-23

    Many short-day plants have a critical day length that fixes the schedule for flowering time, limiting the range of natural growth habitats (or growth and cultivation areas). Thus, fine-tuning of the critical day-length setting in photoperiodic flowering determines ecological niches within latitudinal clines; however, little is known about the molecular mechanisms controlling the fine-tuning of the critical day-length setting in plants. Previously, we determined that florigen genes are regulated by day length, and identified several key genes involved in setting the critical day length in rice. Using a set of chromosomal segment substitution lines with the genetic background of an elite temperate japonica cultivar, we performed a series of expression analyses of flowering-time genes to identify those responsible for setting the critical day-length in rice. Here, we identified two casein kinase genes, Hd16 and Hd6, which modulate the expression of florigen genes within certain restricted ranges of photoperiod, thereby fine-tuning the critical day length. In addition, we determined that Hd16 functions as an enhancer of the bifunctional action of Hd1 (the Arabidopsis CONSTANS ortholog) in rice. Utilization of the natural variation in Hd16 and Hd6 was only found among temperate japonica cultivars adapted to northern areas. Therefore, this fine-tuning of the setting of the critical day length may contribute to the potential northward expansion of rice cultivation areas. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  20. Confronting electroweak fine-tuning with No-Scale Supergravity

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    Tristan Leggett

    2015-01-01

    Full Text Available Applying No-Scale Supergravity boundary conditions at a heavy unification scale to the Flipped SU(5 grand unified theory with extra TeV-scale vector-like multiplets, i.e. No-Scale F-SU(5, we express the Z-boson mass MZ as an explicit function of the boundary gaugino mass M1/2, MZ2=MZ2(M1/22, with implicit dependence upon a dimensionless ratio c of the supersymmetric Higgs mixing parameter μ and M1/2. Setting the top Yukawa coupling consistent with mt=174.3 GeV at MZ=91.2 GeV, the value of c naturally tends toward c≃1, which indirectly suggests underlying action of the Giudice–Masiero mechanism. Proportional dependence of all model scales upon the unified gaugino mass M1/2 in the No-Scale F-SU(5 model suggests one possible mechanism of confronting the electroweak fine-tuning problem.

  1. Pentagone internalises glypicans to fine-tune multiple signalling pathways

    Science.gov (United States)

    Norman, Mark; Vuilleumier, Robin; Springhorn, Alexander; Gawlik, Jennifer; Pyrowolakis, George

    2016-01-01

    Tight regulation of signalling activity is crucial for proper tissue patterning and growth. Here we investigate the function of Pentagone (Pent), a secreted protein that acts in a regulatory feedback during establishment and maintenance of BMP/Dpp morphogen signalling during Drosophila wing development. We show that Pent internalises the Dpp co-receptors, the glypicans Dally and Dally-like protein (Dlp), and propose that this internalisation is important in the establishment of a long range Dpp gradient. Pent-induced endocytosis and degradation of glypicans requires dynamin- and Rab5, but not clathrin or active BMP signalling. Thus, Pent modifies the ability of cells to trap and transduce BMP by fine-tuning the levels of the BMP reception system at the plasma membrane. In addition, and in accordance with the role of glypicans in multiple signalling pathways, we establish a requirement of Pent for Wg signalling. Our data propose a novel mechanism by which morphogen signalling is regulated. DOI: http://dx.doi.org/10.7554/eLife.13301.001 PMID:27269283

  2. A noise tolerant fine tuning algorithm for the Naïve Bayesian learning algorithm

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    Khalil El Hindi

    2014-07-01

    Full Text Available This work improves on the FTNB algorithm to make it more tolerant to noise. The FTNB algorithm augments the Naïve Bayesian (NB learning algorithm with a fine-tuning stage in an attempt to find better estimations of the probability terms involved. The fine-tuning stage has proved to be effective in improving the classification accuracy of the NB; however, it makes the NB algorithm more sensitive to noise in a training set. This work presents several modifications of the fine tuning stage to make it more tolerant to noise. Our empirical results using 47 data sets indicate that the proposed methods greatly enhance the algorithm tolerance to noise. Furthermore, one of the proposed methods improved the performance of the fine tuning method on many noise-free data sets.

  3. Fine-tuned Bee-Flower Coevolutionary State Hidden within Multiple Pollination Interactions

    OpenAIRE

    Akira Shimizu; Ikumi Dohzono; Masayoshi Nakaji; Roff, Derek A.; Donald G. Miller III; Sara Osato; Takuya Yajima; Shûhei Niitsu; Nozomu Utsugi; Takashi Sugawara; Jin Yoshimura

    2014-01-01

    Relationships between flowers and pollinators are generally considered cases of mutualism since both agents gain benefits. Fine-tuned adaptations are usually found in the form of strict one-to-one coevolution between species. Many insect pollinators are, however, considered generalists, visiting numerous kinds of flowers, and many flower species (angiosperms) are also considered generalists, visited by many insect pollinators. We here describe a fine-tuned coevolutionary state of a flower-vis...

  4. Innate immune sensing 2.0 - from linear activation pathways to fine tuned and regulated innate immune networks.

    Science.gov (United States)

    Volz, Thomas; Kaesler, Susanne; Biedermann, Tilo

    2012-01-01

    The innate immune system is based on pathogen recognition receptors that bind conserved microbial molecular structures, so called pathogen-associated molecular patterns (PAMPs). The characterization of the innate immune system was long based on a linear step-wise concept of recognition, activation pathways and effector defense mechanisms. Only more recently it was recognized that the innate immune system needs regulatory elements, sideways and crosstalks that allows it to fine tune and adapt its response. Thus, it is an emerging field within innate immunity research to try to understand how the immune outcome of innate immune sensing is regulated and why immune responses can be substantially different, even though the same PAMPs may have been 'sensed' at the surface organs such as the skin. Only the expansion of the innate immune system from 'pure' linear activation pathways to fine tuned and regulated innate immune networks allows us to integrate the generation of gradually accentuated and qualitatively different effector and tolerogenic immune responses. This article provides a review of the basic concepts and players of the innate immune system and will present some of the newer data defining the innate immune networks effectively regulating the immune homoeostasis and immune effector mechanisms with special focus on the skin as one of the organs involved in regulating the immune interface between the environment and the organism. © 2011 John Wiley & Sons A/S.

  5. Can an Eternal Life Start From the Minimal Fine-Tuning for Intelligence?

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    Ward Blondé

    2016-10-01

    Full Text Available Since modern physicists made more and more advances in precisely measuring the fundamental constants in nature, cosmologists have been confronted with this problem: how do we declare that nature’s constants are fine-tuned for the emergence of life? Many cosmologists assume nowadays that the big bang universe originates from a multiverse that consists of very many universes. Some of these must be fine-tuned for life. A fascinating question arises: Would there be any chance on a life after our death in this multiverse? In this paper, I show two things about the multiverse. First, universes in the multiverse acquire an unlimited amount of additional fine-tuning for intelligent life over the course of many universe generations. Such additional fine-tuning may consist of travelling between universes and an afterlife on a distant planet. Second, evolutionary conservation in the evolution of universes in the multiverse provides a declaration why we observe a universe that roughly has the minimal fine-tuning to support intelligent life.

  6. Fine-tuned bee-flower coevolutionary state hidden within multiple pollination interactions.

    Science.gov (United States)

    Shimizu, Akira; Dohzono, Ikumi; Nakaji, Masayoshi; Roff, Derek A; Miller, Donald G; Osato, Sara; Yajima, Takuya; Niitsu, Shûhei; Utsugi, Nozomu; Sugawara, Takashi; Yoshimura, Jin

    2014-02-05

    Relationships between flowers and pollinators are generally considered cases of mutualism since both agents gain benefits. Fine-tuned adaptations are usually found in the form of strict one-to-one coevolution between species. Many insect pollinators are, however, considered generalists, visiting numerous kinds of flowers, and many flower species (angiosperms) are also considered generalists, visited by many insect pollinators. We here describe a fine-tuned coevolutionary state of a flower-visiting bee that collects both nectar and pollen from an early spring flower visited by multiple pollinators. Detailed morphology of the bee proboscis is shown to be finely adjusted to the floral morphology and nectar production of the flower. Behavioral observations also confirm the precision of this mutualism. Our results suggest that a fine-tuned one-to-one coevolutionary state between a flower species and a pollinator species might be common, but frequently overlooked, in multiple flower-pollinator interactions.

  7. Convolutional Neural Networks for Medical Image Analysis: Full Training or Fine Tuning?

    Science.gov (United States)

    Tajbakhsh, Nima; Shin, Jae Y; Gurudu, Suryakanth R; Hurst, R Todd; Kendall, Christopher B; Gotway, Michael B; Jianming Liang

    2016-05-01

    Training a deep convolutional neural network (CNN) from scratch is difficult because it requires a large amount of labeled training data and a great deal of expertise to ensure proper convergence. A promising alternative is to fine-tune a CNN that has been pre-trained using, for instance, a large set of labeled natural images. However, the substantial differences between natural and medical images may advise against such knowledge transfer. In this paper, we seek to answer the following central question in the context of medical image analysis: Can the use of pre-trained deep CNNs with sufficient fine-tuning eliminate the need for training a deep CNN from scratch? To address this question, we considered four distinct medical imaging applications in three specialties (radiology, cardiology, and gastroenterology) involving classification, detection, and segmentation from three different imaging modalities, and investigated how the performance of deep CNNs trained from scratch compared with the pre-trained CNNs fine-tuned in a layer-wise manner. Our experiments consistently demonstrated that 1) the use of a pre-trained CNN with adequate fine-tuning outperformed or, in the worst case, performed as well as a CNN trained from scratch; 2) fine-tuned CNNs were more robust to the size of training sets than CNNs trained from scratch; 3) neither shallow tuning nor deep tuning was the optimal choice for a particular application; and 4) our layer-wise fine-tuning scheme could offer a practical way to reach the best performance for the application at hand based on the amount of available data.

  8. Constraining fine tuning in composite Higgs models with partially composite leptons

    Science.gov (United States)

    Barnard, James; Murnane, Daniel; White, Martin; Williams, Anthony G.

    2017-09-01

    Minimal Composite Higgs Models (MCHM) have long provided a solution to the hierarchy problem of the Standard Model, yet suffer from various sources of fine tuning that are becoming increasingly problematic with the lack of new physics observations at the LHC. We develop a new fine tuning measure that accurately counts each contribution to fine tuning (single, double, triple, etc) that can occur in a theory with n p parameters, that must reproduce n o observables. We then use a novel scanning procedure to perform a comprehensive study of three different two-site, 4D, SO(5) → SO(4) MCHMs with all third generation fermions included, distinguished by the choice of the lepton embeddings. These are the MCHM 5 - 5 - 5 5 - 5 - 5 , MCHM 14 - 14 - 10 5 - 5 - 5 and MCHM 14 - 1 - 10 5 - 5 - 5 , where MCHM l - τ - ν q - t - b has the lepton doublet partner in representation l, tau partner in representation τ, and so on. We find that embedding at least one massive lepton in the symmetric 14 of SO(5) moderately reduces the tuning for the case of low top partner masses (in line with previous results), but that this is balanced against the increased complexity of the model when one properly accounts for all sources of fine tuning. We study both the current relative fine-tuning of each scenario, and the future prospects. Noting that the different scenarios behave differently with respect to future improvements in collider measurements, we find that the MCHM 14 - 1 - 10 5 - 5 - 5 enjoys a relatively low increase in fine tuning even for a future lower bound on the top partner masses of 3.4 TeV (or equivalently a maximum Higgs-fermion or Higgs-gluon coupling deviation of 2%).

  9. Fine-tuning problem in renormalized perturbation theory: Spontaneously-broken gauge models

    Energy Technology Data Exchange (ETDEWEB)

    Foda, O.E. (Purdue Univ., Lafayette, IN (USA). Dept. of Physics)

    1983-04-28

    We study the stability of tree-level gauge hierarchies at higher orders in renormalized perturbation theory, in a model with spontaneously-broken gauge symmetries. We confirm previous results indicating that if the model is renormalized using BPHZ, then the tree-level hierarchy is not upset by the radiative corrections. Consequently, no fine-tuning of the initial parameters is required to maintain it, in contrast to the result obtained using Dimensional Renormalization. This verifies the conclusion that the need for fine-tuning, when it arises, is an artifact of the application of a certain class of renormalization schemes.

  10. The fine-tuning cost of the likelihood in SUSY models

    CERN Document Server

    Ghilencea, D M

    2013-01-01

    In SUSY models, the fine tuning of the electroweak (EW) scale with respect to their parameters gamma_i={m_0, m_{1/2}, mu_0, A_0, B_0,...} and the maximal likelihood L to fit the experimental data are usually regarded as two different problems. We show that, if one regards the EW minimum conditions as constraints that fix the EW scale, this commonly held view is not correct and that the likelihood contains all the information about fine-tuning. In this case we show that the corrected likelihood is equal to the ratio L/Delta of the usual likelihood L and the traditional fine tuning measure Delta of the EW scale. A similar result is obtained for the integrated likelihood over the set {gamma_i}, that can be written as a surface integral of the ratio L/Delta, with the surface in gamma_i space determined by the EW minimum constraints. As a result, a large likelihood actually demands a large ratio L/Delta or equivalently, a small chi^2_{new}=chi^2_{old}+2*ln(Delta). This shows the fine-tuning cost to the likelihood ...

  11. Fine tuning of track impact parameter resolution of the DELPHI detector

    CERN Document Server

    Borisov, G

    1996-01-01

    The fine tuning of the charged track impact parameter resolution for data and simulation in the DELPHI detector at LEP is described. This tuning was implemented in the software for the tagging of $B$ hadrons and has been applied in many precise measurements.

  12. Higher-order Lorentz-invariance violation, quantum gravity and fine-tuning

    Directory of Open Access Journals (Sweden)

    Carlos M. Reyes

    2015-06-01

    Full Text Available The issue of Lorentz fine-tuning in effective theories containing higher-order operators is studied. To this end, we focus on the Myers–Pospelov extension of QED with dimension-five operators in the photon sector and standard fermions. We compute the fermion self-energy at one-loop order considering its even and odd CPT contributions. In the even sector we find small radiative corrections to the usual parameters of QED which also turn to be finite. In the odd sector the axial operator is shown to contain unsuppressed effects of Lorentz violation leading to a possible fine-tuning. We use dimensional regularization to deal with the divergencies and a generic preferred four-vector. Taking the first steps in the renormalization procedure for Lorentz violating theories we arrive to acceptable small corrections allowing to set the bound ξ<6×10−3.

  13. Improving the Fine-Tuning of Metaheuristics: An Approach Combining Design of Experiments and Racing Algorithms

    Directory of Open Access Journals (Sweden)

    Eduardo Batista de Moraes Barbosa

    2017-01-01

    Full Text Available Usually, metaheuristic algorithms are adapted to a large set of problems by applying few modifications on parameters for each specific case. However, this flexibility demands a huge effort to correctly tune such parameters. Therefore, the tuning of metaheuristics arises as one of the most important challenges in the context of research of these algorithms. Thus, this paper aims to present a methodology combining Statistical and Artificial Intelligence methods in the fine-tuning of metaheuristics. The key idea is a heuristic method, called Heuristic Oriented Racing Algorithm (HORA, which explores a search space of parameters looking for candidate configurations close to a promising alternative. To confirm the validity of this approach, we present a case study for fine-tuning two distinct metaheuristics: Simulated Annealing (SA and Genetic Algorithm (GA, in order to solve the classical traveling salesman problem. The results are compared considering the same metaheuristics tuned through a racing method. Broadly, the proposed approach proved to be effective in terms of the overall time of the tuning process. Our results reveal that metaheuristics tuned by means of HORA achieve, with much less computational effort, similar results compared to the case when they are tuned by the other fine-tuning approach.

  14. An Ensemble of Fine-Tuned Convolutional Neural Networks for Medical Image Classification.

    Science.gov (United States)

    Kumar, Ashnil; Kim, Jinman; Lyndon, David; Fulham, Michael; Feng, Dagan

    2017-01-01

    The availability of medical imaging data from clinical archives, research literature, and clinical manuals, coupled with recent advances in computer vision offer the opportunity for image-based diagnosis, teaching, and biomedical research. However, the content and semantics of an image can vary depending on its modality and as such the identification of image modality is an important preliminary step. The key challenge for automatically classifying the modality of a medical image is due to the visual characteristics of different modalities: some are visually distinct while others may have only subtle differences. This challenge is compounded by variations in the appearance of images based on the diseases depicted and a lack of sufficient training data for some modalities. In this paper, we introduce a new method for classifying medical images that uses an ensemble of different convolutional neural network (CNN) architectures. CNNs are a state-of-the-art image classification technique that learns the optimal image features for a given classification task. We hypothesise that different CNN architectures learn different levels of semantic image representation and thus an ensemble of CNNs will enable higher quality features to be extracted. Our method develops a new feature extractor by fine-tuning CNNs that have been initialized on a large dataset of natural images. The fine-tuning process leverages the generic image features from natural images that are fundamental for all images and optimizes them for the variety of medical imaging modalities. These features are used to train numerous multiclass classifiers whose posterior probabilities are fused to predict the modalities of unseen images. Our experiments on the ImageCLEF 2016 medical image public dataset (30 modalities; 6776 training images, and 4166 test images) show that our ensemble of fine-tuned CNNs achieves a higher accuracy than established CNNs. Our ensemble also achieves a higher accuracy than methods in

  15. Fine-Tuning on the Effective Patch Radius Expression of the Circular Microstrip Patch Antennas

    Directory of Open Access Journals (Sweden)

    A. E. Yilmaz

    2010-09-01

    Full Text Available In this study, the effective patch radius expression for the circular microstrip antennas is improved by means of several manipulations. Departing from previously proposed equations in the literature, one of the most accurate equations is picked up, and this equation is fine-tuned by means of Particle Swarm Optimization technique. Throughout the study, impacts of other parameters (such as the definition of the fitness/objective function, the degree-of-freedom in the proposed effective patch radius expression, the number of measured resonant frequency values are observed in a controlled manner. Finally, about 3% additional improvement is achieved over a very accurate formula, which was proposed earlier.

  16. Auto-Regulatory RNA Editing Fine-Tunes mRNA Re-Coding and Complex Behaviour in Drosophila

    Science.gov (United States)

    Savva, Yiannis A.; Jepson, James E.C; Sahin, Asli; Sugden, Arthur U.; Dorsky, Jacquelyn S.; Alpert, Lauren; Lawrence, Charles; Reenan, Robert A.

    2014-01-01

    Auto-regulatory feedback loops are a common molecular strategy used to optimize protein function. In Drosophila many mRNAs involved in neuro-transmission are re-coded at the RNA level by the RNA editing enzyme dADAR, leading to the incorporation of amino acids that are not directly encoded by the genome. dADAR also re-codes its own transcript, but the consequences of this auto-regulation in vivo are unclear. Here we show that hard-wiring or abolishing endogenous dADAR auto-regulation dramatically remodels the landscape of re-coding events in a site-specific manner. These molecular phenotypes correlate with altered localization of dADAR within the nuclear compartment. Furthermore, auto-editing exhibits sexually dimorphic patterns of spatial regulation and can be modified by abiotic environmental factors. Finally, we demonstrate that modifying dAdar auto-editing affects adaptive complex behaviors. Our results reveal the in vivo relevance of auto-regulatory control over post-transcriptional mRNA re-coding events in fine-tuning brain function and organismal behavior. PMID:22531175

  17. Rate of hydrolysis in ATP synthase is fine-tuned by  -subunit motif controlling active site conformation

    KAUST Repository

    Beke-Somfai, T.

    2013-01-23

    Computer-designed artificial enzymes will require precise understanding of how conformation of active sites may control barrier heights of key transition states, including dependence on structure and dynamics at larger molecular scale. F(o)F(1) ATP synthase is interesting as a model system: a delicate molecular machine synthesizing or hydrolyzing ATP using a rotary motor. Isolated F(1) performs hydrolysis with a rate very sensitive to ATP concentration. Experimental and theoretical results show that, at low ATP concentrations, ATP is slowly hydrolyzed in the so-called tight binding site, whereas at higher concentrations, the binding of additional ATP molecules induces rotation of the central γ-subunit, thereby forcing the site to transform through subtle conformational changes into a loose binding site in which hydrolysis occurs faster. How the 1-Å-scale rearrangements are controlled is not yet fully understood. By a combination of theoretical approaches, we address how large macromolecular rearrangements may manipulate the active site and how the reaction rate changes with active site conformation. Simulations reveal that, in response to γ-subunit position, the active site conformation is fine-tuned mainly by small α-subunit changes. Quantum mechanics-based results confirm that the sub-Ångström gradual changes between tight and loose binding site structures dramatically alter the hydrolysis rate.

  18. Comparative molecular analysis of evolutionarily distant glyceraldehyde-3-phosphate dehydrogenase from Sardina pilchardus and Octopus vulgaris.

    Science.gov (United States)

    Baibai, Tarik; Oukhattar, Laila; Mountassif, Driss; Assobhei, Omar; Serrano, Aurelio; Soukri, Abdelaziz

    2010-12-01

    The NAD(+)-dependent cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12), which is recognized as a key to central carbon metabolism in glycolysis and gluconeogenesis and as an important allozymic polymorphic biomarker, was purified from muscles of two marine species: the skeletal muscle of Sardina pilchardus Walbaum (Teleost, Clupeida) and the incompressible arm muscle of Octopus vulgaris (Mollusca, Cephalopoda). Comparative biochemical studies have revealed that they differ in their subunit molecular masses and in pI values. Partial cDNA sequences corresponding to an internal region of the GapC genes from Sardina and Octopus were obtained by polymerase chain reaction using degenerate primers designed from highly conserved protein motifs. Alignments of the deduced amino acid sequences were used to establish the 3D structures of the active site of two enzymes as well as the phylogenetic relationships of the sardine and octopus enzymes. These two enzymes are the first two GAPDHs characterized so far from teleost fish and cephalopod, respectively. Interestingly, phylogenetic analyses indicated that the sardina GAPDH is in a cluster with the archetypical enzymes from other vertebrates, while the octopus GAPDH comes together with other molluscan sequences in a distant basal assembly closer to bacterial and fungal orthologs, thus suggesting their different evolutionary scenarios.

  19. Facile Access to Twisted Intramolecular Charge-Transfer Fluorogens Bearing Highly Pretwisted Donor-Acceptor Systems Together with Readily Fine-Tuned Charge-Transfer Characters.

    Science.gov (United States)

    Luo, Yanju; Wang, Yan; Chen, Shiqi; Wang, Ning; Qi, Yige; Zhang, Xiaogen; Yang, Minghui; Huang, Yan; Li, Ming; Yu, Junsheng; Luo, Daibing; Lu, Zhiyun

    2017-05-01

    Twisted intramolecular charge-transfer (TICT) fluorogens bearing highly pretwisted geometries and readily-fine-tuned charge-transfer characters are quite promising sensor and electroluminescence (EL) materials. In this study, by using 4-aryloxy-1,8-naphthalimide derivatives as the molecular framework, it is demonstrated for the first time that a CO bond could serve as the central bond to construct new TICT D-A systems. Photophysical and quantum chemical studies confirm that rotation around central CO bonds is responsible for the formation of a stable TICT state in these compounds. More importantly, owing to the structural adjustability of the aryl moiety and the strong steric interactions between the naphthalimide and the aryl ring systems, these compounds can display readily-fine-tuned TICT characters, hence exhibiting an adjustable solvent polarity threshold for aggregation-induced emission (AIE) activity, and could be AIE-active even in less-polar toluene and nonpolar cyclohexane. Furthermore, these compounds could possess highly-pretwisted ground-state geometries, hence could show good EL performance. The findings reveal a facile but effective molecular constructive strategy for versatile, high-performance optoelectronic TICT compounds. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Fine-tuning with brane-localized flux in 6D supergravity

    Energy Technology Data Exchange (ETDEWEB)

    Niedermann, Florian; Schneider, Robert [Arnold Sommerfeld Center for Theoretical Physics, Ludwig-Maximilians-Universität,Theresienstraße 37, 80333 Munich (Germany); Excellence Cluster Universe,Boltzmannstraße 2, 85748 Garching (Germany)

    2016-02-03

    There are claims in the literature that the cosmological constant problem could be solved in a braneworld model with two large (micron-sized) supersymmetric extra dimensions. The mechanism relies on two basic ingredients: first, the cosmological constant only curves the compact bulk geometry into a rugby shape while the 4D curvature stays flat. Second, a brane-localized flux term is introduced in order to circumvent Weinberg’s fine-tuning argument, which otherwise enters here through a backdoor via the flux quantization condition. In this paper, we show that the latter mechanism does not work in the way it was designed: the only localized flux coupling that guarantees a flat on-brane geometry is one which preserves the scale invariance of the bulk theory. Consequently, Weinberg’s argument applies, making a fine-tuning necessary again. The only remaining window of opportunity lies within scale invariance breaking brane couplings, for which the tuning could be avoided. Whether the corresponding 4D curvature could be kept under control and in agreement with the observed value will be answered in our companion paper http://arxiv.org/abs/1512.03800.

  1. Fine-tuning with brane-localized flux in 6D supergravity

    Science.gov (United States)

    Niedermann, Florian; Schneider, Robert

    2016-02-01

    There are claims in the literature that the cosmological constant problem could be solved in a braneworld model with two large (micron-sized) supersymmetric extra dimensions. The mechanism relies on two basic ingredients: first, the cosmological constant only curves the compact bulk geometry into a rugby shape while the 4D curvature stays flat. Second, a brane-localized flux term is introduced in order to circumvent Weinberg's fine-tuning argument, which otherwise enters here through a backdoor via the flux quantization condition. In this paper, we show that the latter mechanism does not work in the way it was designed: the only localized flux coupling that guarantees a flat on-brane geometry is one which preserves the scale invariance of the bulk theory. Consequently, Weinberg's argument applies, making a fine-tuning necessary again. The only remaining window of opportunity lies within scale invariance breaking brane couplings, for which the tuning could be avoided. Whether the corresponding 4D curvature could be kept under control and in agreement with the observed value will be answered in our companion paper [1].

  2. Chiral Symmetry Restoration, Naturalness and the Absence of Fine-Tuning I: Global Theories

    CERN Document Server

    Lynn, Bryan W.

    2013-01-01

    The Standard Model (SM), and the scalar sector of its zero-gauge-coupling limit -- the chiral-symmetric limit of the Gell Mann-Levy Model (GML) -- have been shown not to suffer from a Higgs Fine-Tuning (FT) problem. All ultraviolet quadratic divergences (UVQD) are absorbed into the mass-squared of pseudo Nambu-Goldstone (pNGB) bosons, in GML. Since chiral SU(2)_{L-R} symmetry is restored as the pNGB mass-squared or as the Higgs vacuum expectation value (VEV) are taken to 0, small values of these quantities and of the Higgs mass are natural, and therefore not Fine-Tuned. In this letter, we extend our results on the absence of FT to a wide class of high-mass-scale (M_{Heavy}>>m_{Higgs}) extensions to a simplified SO(2) version of GML. We explicitly demonstrate naturalness and no-FT for two examples of heavy physics, both SO(2) singlets: a heavy (M_S >> m_{Higgs}) real scalar field (with or without a VEV); and a right-handed Type 1 See-Saw Majorana neutrino with M_R >> m_{Higgs}. We prove that for |q^2| <<...

  3. Fine-tuning convolutional deep features for MRI based brain tumor classification

    Science.gov (United States)

    Ahmed, Kaoutar B.; Hall, Lawrence O.; Goldgof, Dmitry B.; Liu, Renhao; Gatenby, Robert A.

    2017-03-01

    Prediction of survival time from brain tumor magnetic resonance images (MRI) is not commonly performed and would ordinarily be a time consuming process. However, current cross-sectional imaging techniques, particularly MRI, can be used to generate many features that may provide information on the patient's prognosis, including survival. This information can potentially be used to identify individuals who would benefit from more aggressive therapy. Rather than using pre-defined and hand-engineered features as with current radiomics methods, we investigated the use of deep features extracted from pre-trained convolutional neural networks (CNNs) in predicting survival time. We also provide evidence for the power of domain specific fine-tuning in improving the performance of a pre-trained CNN's, even though our data set is small. We fine-tuned a CNN initially trained on a large natural image recognition dataset (Imagenet ILSVRC) and transferred the learned feature representations to the survival time prediction task, obtaining over 81% accuracy in a leave one out cross validation.

  4. Anthropic Reasoning about Fine-Tuning, and Neoclassical Cosmology: Providence, Omnipresence, and Observation Selection Theory

    Science.gov (United States)

    Walker, Theodore, Jr.

    2011-10-01

    Anthropic reasoning about observation selection effects upon the appearance of cosmic providential fine-tuning (fine-tuning that provides for life) is often motivated by a desire to avoid theological implications (implications favoring the idea of a divine cosmic provider) without appealing to sheer lucky-for-us-cosmic-jackpot happenstance and coincidence. Cosmic coincidence can be rendered less incredible by appealing to a multiverse context. Cosmic providence can be rendered non-theological by appealing to an agent-less providential purpose, or by appealing to less-than-omnipresent/local providers, such as alien intelligences creating life- providing baby universes. Instead of choosing either cosmic coincidence or cosmic providence, as though they were mutually exclusive; it is better to accept both. Neoclassical thought accepts coincidence and providence, plus many local providers and one omnipresent provider. Moreover, fundamental observation selection theory should distinguish the many local observers of some events from the one omnipresent observer of all events. Accepting both coincidence and providence avoids classical theology (providence without coincidence) and classical atheism (coincidence without providence), but not neoclassical theology (providence with coincidence). Cosmology cannot avoid the idea of an all-inclusive omnipresent providential dice-throwing living-creative whole of reality, an idea essential to neoclassical theology, and to neoclassical cosmology.

  5. Thyroid Nodule Classification in Ultrasound Images by Fine-Tuning Deep Convolutional Neural Network.

    Science.gov (United States)

    Chi, Jianning; Walia, Ekta; Babyn, Paul; Wang, Jimmy; Groot, Gary; Eramian, Mark

    2017-08-01

    With many thyroid nodules being incidentally detected, it is important to identify as many malignant nodules as possible while excluding those that are highly likely to be benign from fine needle aspiration (FNA) biopsies or surgeries. This paper presents a computer-aided diagnosis (CAD) system for classifying thyroid nodules in ultrasound images. We use deep learning approach to extract features from thyroid ultrasound images. Ultrasound images are pre-processed to calibrate their scale and remove the artifacts. A pre-trained GoogLeNet model is then fine-tuned using the pre-processed image samples which leads to superior feature extraction. The extracted features of the thyroid ultrasound images are sent to a Cost-sensitive Random Forest classifier to classify the images into "malignant" and "benign" cases. The experimental results show the proposed fine-tuned GoogLeNet model achieves excellent classification performance, attaining 98.29% classification accuracy, 99.10% sensitivity and 93.90% specificity for the images in an open access database (Pedraza et al. 16), while 96.34% classification accuracy, 86% sensitivity and 99% specificity for the images in our local health region database.

  6. Non-universal gaugino masses and fine tuning implications for SUSY searches in the MSSM and the GNMSSM

    Energy Technology Data Exchange (ETDEWEB)

    Kaminska, Anna [Oxford Univ. (United Kingdom). Centre for Theoretical Physics; Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Ross, Graham G. [Oxford Univ. (United Kingdom). Centre for Theoretical Physics; Schmidt-Hoberg, Kai [European Lab. for Particle Physics (CERN), Geneva (Switzerland)

    2013-08-15

    For the case of the MSSM and the most general form of the NMSSM (GNMSSM) we determine the reduction in the fine tuning that follows from allowing gaugino masses to be non-degenerate at the unification scale, taking account of the LHC8 bounds on SUSY masses, the Higgs mass bound, gauge coupling unification and the requirement of an acceptable dark matter density. We show that low-fine tuned points fall in the region of gaugino mass ratios predicted by specific unified and string models. For the case of the MSSM the minimum fine tuning is still large, approximately 1:60 allowing for a 3 GeV uncertainty in the Higgs mass (1:500 for the central value), but for the GNMSSM it is below 1:20. We find that the spectrum of SUSY states corresponding to the low-fine tuned points in the GNMSSM is often compressed, weakening the LHC bounds on coloured states. The prospect for testing the remaining low-fine-tuned regions at LHC14 is discussed.

  7. Radiatively generated maximal mixing scenario for the Higgs boson mass and the least fine-tuned minimal supersymmetric standard model.

    Science.gov (United States)

    Dermísek, Radovan; Kim, Hyung Do

    2006-06-02

    We argue that given the experimental constraints on the Higgs boson mass the least fine-tuned parameter space of the minimal supersymmetric standard model is with negative top-squark masses squared at the grand unification scale. While the top-squark mass squared is typically driven to positive values at the weak scale, the contribution to the Higgs boson mass squared parameter from the running can be arbitrarily small, which reduces the fine-tuning of electroweak symmetry breaking. At the same time the top-squark mixing is necessarily enhanced and the maximal mixing scenario for the Higgs boson mass can be generated radiatively even when starting with negligible mixing at the unification scale. This highly alleviates constraints on possible models for supersymmetry breaking in which fine-tuning is absent.

  8. Enhancement of impact strength of poly (methyl methacrylate) with surface fine-tuned nano-silica

    Science.gov (United States)

    Wen, Bin; Dong, Yixiao; Wu, Lili; Long, Chao; Zhang, Chaocan

    2015-07-01

    Highly dispersible nanoparticles in organic solvent always receive wide interests due to their compatibility with polymer materials. This paper reported a kind of isopropanol alcohol silica dispersion which obtained using a method of azeotropic distillation. The isopropanol alcohol dispersed silica (IPADS) were treated with coupling agents to fine-tune their surface properties. Polymethyl methacrylate (PMMA) was then used as a research object to test the compatibility between IPADS and polymer. UV-vis spectra indicate that IPADS would reach its high compatibility with PMMA if coupling with trimethoxypropylsilane (PTMS). Followed experiments on PMMA proved that the high compatibility can prominently enhance the impact strength about 30%. The results may provide reference both for nano-silica modification and better understanding of nano-enhanced materials.

  9. arXiv Precision Tests and Fine Tuning in Twin Higgs Models

    CERN Document Server

    Contino, Roberto; Mahbubani, Rakhi; Rattazzi, Riccardo; Torre, Riccardo

    2017-11-29

    We analyze the parametric structure of twin Higgs (TH) theories and assess the gain in fine tuning which they enable compared to extensions of the standard model with colored top partners. Estimates show that, at least in the simplest realizations of the TH idea, the separation between the mass of new colored particles and the electroweak scale is controlled by the coupling strength of the underlying UV theory, and that a parametric gain is achieved only for strongly-coupled dynamics. Motivated by this consideration we focus on one of these simple realizations, namely composite TH theories, and study how well such constructions can reproduce electroweak precision data. The most important effect of the twin states is found to be the infrared contribution to the Higgs quartic coupling, while direct corrections to electroweak observables are subleading and negligible. We perform a careful fit to the electroweak data including the leading-logarithmic corrections to the Higgs quartic up to three loops. Our analysi...

  10. Fine-tuning of electronic properties in donor–acceptor conjugated polymers based on oligothiophenes

    Science.gov (United States)

    Imae, Ichiro; Sagawa, Hitoshi; Harima, Yutaka

    2018-03-01

    A novel series of donor–acceptor conjugated polymers having oligothiophenes with well-defined structures were synthesized and their optical, electrochemical, and photovoltaic properties were investigated. It was found that the absorption bands of polymers were red-shifted with increasing number of ethylenedioxy groups added to each oligothiophene unit and that their band edges reached over 1000 nm. The systematical fine-tuning of the electronic properties was achieved using the chemical structures of oligothiophene units. Photovoltaic cells based on polymer/(6,6)-phenyl C61 butyric acid methyl ester (PC61BM) exhibited power conversion efficiencies in the range from 0.004 to 1.10%, reflecting the electronic properties of the polymers.

  11. A systematic approach for fine-tuning of fuzzy controllers applied to WWTPs

    DEFF Research Database (Denmark)

    Ruano, M.V.; Ribes, J.; Sin, Gürkan

    2010-01-01

    A systematic approach for fine-tuning fuzzy controllers has been developed and evaluated for an aeration control system implemented in a WWTR The challenge with the application of fuzzy controllers to WWTPs is simply that they contain many parameters, which need to be adjusted for different WWTP...... applications. To this end, a methodology based on model simulations is used that employs three statistical methods: (i) Monte-Carlo procedure: to find proper initial conditions, (ii) Identifiability analysis: to find an identifiable parameter subset of the fuzzy controller and (iii) minimization algorithm......) of the controllers. Moreover, the methodology overcomes the dependency of the initial parameter space issue typical of local identifiability analysis. All in all this systematic approach is expected to facilitate the design and application of fuzzy controllers in particular to WWTPs compared to the time...

  12. Spontaneous fine-tuning to environment in many-species chemical reaction networks

    Science.gov (United States)

    Horowitz, Jordan M.; England, Jeremy L.

    2017-07-01

    A chemical mixture that continually absorbs work from its environment may exhibit steady-state chemical concentrations that deviate from their equilibrium values. Such behavior is particularly interesting in a scenario where the environmental work sources are relatively difficult to access, so that only the proper orchestration of many distinct catalytic actors can power the dissipative flux required to maintain a stable, far-from-equilibrium steady state. In this article, we study the dynamics of an in silico chemical network with random connectivity in an environment that makes strong thermodynamic forcing available only to rare combinations of chemical concentrations. We find that the long-time dynamics of such systems are biased toward states that exhibit a fine-tuned extremization of environmental forcing.

  13. Spontaneous fine-tuning to environment in many-species chemical reaction networks.

    Science.gov (United States)

    Horowitz, Jordan M; England, Jeremy L

    2017-07-18

    A chemical mixture that continually absorbs work from its environment may exhibit steady-state chemical concentrations that deviate from their equilibrium values. Such behavior is particularly interesting in a scenario where the environmental work sources are relatively difficult to access, so that only the proper orchestration of many distinct catalytic actors can power the dissipative flux required to maintain a stable, far-from-equilibrium steady state. In this article, we study the dynamics of an in silico chemical network with random connectivity in an environment that makes strong thermodynamic forcing available only to rare combinations of chemical concentrations. We find that the long-time dynamics of such systems are biased toward states that exhibit a fine-tuned extremization of environmental forcing.

  14. Synthetic Core Promoters as Universal Parts for Fine-Tuning Expression in Different Yeast Species.

    Science.gov (United States)

    Portela, Rui M C; Vogl, Thomas; Kniely, Claudia; Fischer, Jasmin E; Oliveira, Rui; Glieder, Anton

    2017-03-17

    Synthetic biology and metabolic engineering experiments frequently require the fine-tuning of gene expression to balance and optimize protein levels of regulators or metabolic enzymes. A key concept of synthetic biology is the development of modular parts that can be used in different contexts. Here, we have applied a computational multifactor design approach to generate de novo synthetic core promoters and 5' untranslated regions (UTRs) for yeast cells. In contrast to upstream cis-regulatory modules (CRMs), core promoters are typically not subject to specific regulation, making them ideal engineering targets for gene expression fine-tuning. 112 synthetic core promoter sequences were designed on the basis of the sequence/function relationship of natural core promoters, nucleosome occupancy and the presence of short motifs. The synthetic core promoters were fused to the Pichia pastoris AOX1 CRM, and the resulting activity spanned more than a 200-fold range (0.3% to 70.6% of the wild type AOX1 level). The top-ten synthetic core promoters with highest activity were fused to six additional CRMs (three in P. pastoris and three in Saccharomyces cerevisiae). Inducible CRM constructs showed significantly higher activity than constitutive CRMs, reaching up to 176% of natural core promoters. Comparing the activity of the same synthetic core promoters fused to different CRMs revealed high correlations only for CRMs within the same organism. These data suggest that modularity is maintained to some extent but only within the same organism. Due to the conserved role of eukaryotic core promoters, this rational design concept may be transferred to other organisms as a generic engineering tool.

  15. Expression of evolutionarily novel genes in tumors

    OpenAIRE

    A. P. Kozlov

    2016-01-01

    The evolutionarily novel genes originated through different molecular mechanisms are expressed in tumors. Sometimes the expression of evolutionarily novel genes in tumors is highly specific. Moreover positive selection of many human tumor-related genes in primate lineage suggests their involvement in the origin of new functions beneficial to organisms. It is suggested to consider the expression of evolutionarily young or novel genes in tumors as a new biological phenomenon, a phenomenon of TS...

  16. Fine tuning of the lactate and diacetyl production through promoter engineering in Lactococcus lactis.

    Directory of Open Access Journals (Sweden)

    Tingting Guo

    Full Text Available Lactococcus lactis is a well-studied bacterium widely used in dairy fermentation and capable of producing metabolites with organoleptic and nutritional characteristics. For fine tuning of the distribution of glycolytic flux at the pyruvate branch from lactate to diacetyl and balancing the production of the two metabolites under aerobic conditions, a constitutive promoter library was constructed by randomizing the promoter sequence of the H(2O-forming NADH oxidase gene in L. lactis. The library consisted of 30 promoters covering a wide range of activities from 7,000 to 380,000 relative fluorescence units using a green fluorescent protein as reporter. Eleven typical promoters of the library were selected for the constitutive expression of the H(2O-forming NADH oxidase gene in L. lactis, and the NADH oxidase activity increased from 9.43 to 58.17-fold of the wild-type strain in small steps of activity change under aerobic conditions. Meanwhile, the lactate yield decreased from 21.15 ± 0.08 mM to 9.94 ± 0.07 mM, and the corresponding diacetyl production increased from 1.07 ± 0.03 mM to 4.16 ± 0.06 mM with the intracellular NADH/NAD(+ ratios varying from 0.711 ± 0.005 to 0.383 ± 0.003. The results indicated that the reduced pyruvate to lactate flux was rerouted to the diacetyl with an almost linear flux variation via altered NADH/NAD(+ ratios. Therefore, we provided a novel strategy to precisely control the pyruvate distribution for fine tuning of the lactate and diacetyl production through promoter engineering in L. lactis. Interestingly, the increased H(2O-forming NADH oxidase activity led to 76.95% lower H(2O(2 concentration in the recombinant strain than that of the wild-type strain after 24 h of aerated cultivation. The viable cells were significantly elevated by four orders of magnitude within 28 days of storage at 4°C, suggesting that the increased enzyme activity could eliminate H(2O(2 accumulation and prolong cell survival.

  17. Fibroblast Growth Factor 21 Protects against Atherosclerosis via Fine-Tuning the Multiorgan Crosstalk

    Directory of Open Access Journals (Sweden)

    Leigang Jin

    2016-02-01

    Full Text Available Fibroblast growth factor 21 (FGF21 is a metabolic hormone with pleiotropic effects on energy metabolism and insulin sensitivity. Besides its antiobese and antidiabetic activity, FGF21 also possesses the protective effects against atherosclerosis. Circulating levels of FGF21 are elevated in patients with atherosclerosis, macrovascular and microvascular complications of diabetes, possibly due to a compensatory upregulation. In apolipoprotein E-deficient mice, formation of atherosclerotic plaques is exacerbated by genetic depletion of FGF21, but is attenuated upon replenishment with recombinant FGF21. However, the blood vessel is not the direct target of FGF21, and the antiatherosclerotic activity of FGF21 is attributed to its actions in adipose tissues and liver. In adipocytes, FGF21 promotes secretion of adiponectin, which in turn acts directly on blood vessels to reduce endothelial dysfunction, inhibit proliferation of smooth muscle cells and block conversion of macrophages to foam cells. Furthermore, FGF21 suppresses cholesterol biosynthesis and attenuates hypercholesterolemia by inhibiting the transcription factor sterol regulatory element-binding protein-2 in hepatocytes. The effects of FGF21 on elevation of adiponectin and reduction of hypercholesterolemia are also observed in a phase-1b clinical trial in patients with obesity and diabetes. Therefore, FGF21 exerts its protection against atherosclerosis by fine-tuning the interorgan crosstalk between liver, brain, adipose tissue, and blood vessels.

  18. Improving Genetic Algorithm with Fine-Tuned Crossover and Scaled Architecture

    Directory of Open Access Journals (Sweden)

    Ajay Shrestha

    2016-01-01

    Full Text Available Genetic Algorithm (GA is a metaheuristic used in solving combinatorial optimization problems. Inspired by evolutionary biology, GA uses selection, crossover, and mutation operators to efficiently traverse the solution search space. This paper proposes nature inspired fine-tuning to the crossover operator using the untapped idea of Mitochondrial DNA (mtDNA. mtDNA is a small subset of the overall DNA. It differentiates itself by inheriting entirely from the female, while the rest of the DNA is inherited equally from both parents. This unique characteristic of mtDNA can be an effective mechanism to identify members with similar genes and restrict crossover between them. It can reduce the rate of dilution of diversity and result in delayed convergence. In addition, we scale the well-known Island Model, where instances of GA are run independently and population members exchanged periodically, to a Continental Model. In this model, multiple web services are executed with each web service running an island model. We applied the concept of mtDNA in solving Traveling Salesman Problem and to train Neural Network for function approximation. Our implementation tests show that leveraging these new concepts of mtDNA and Continental Model results in relative improvement of the optimization quality of GA.

  19. Neuronal target identification requires AHA-1-mediated fine-tuning of Wnt signaling in C. elegans.

    Directory of Open Access Journals (Sweden)

    Jingyan Zhang

    2013-06-01

    Full Text Available Electrical synaptic transmission through gap junctions is a vital mode of intercellular communication in the nervous system. The mechanism by which reciprocal target cells find each other during the formation of gap junctions, however, is poorly understood. Here we show that gap junctions are formed between BDU interneurons and PLM mechanoreceptors in C. elegans and the connectivity of BDU with PLM is influenced by Wnt signaling. We further identified two PAS-bHLH family transcription factors, AHA-1 and AHR-1, which function cell-autonomously within BDU and PLM to facilitate the target identification process. aha-1 and ahr-1 act genetically upstream of cam-1. CAM-1, a membrane-bound receptor tyrosine kinase, is present on both BDU and PLM cells and likely serves as a Wnt antagonist. By binding to a cis-regulatory element in the cam-1 promoter, AHA-1 enhances cam-1 transcription. Our study reveals a Wnt-dependent fine-tuning mechanism that is crucial for mutual target cell identification during the formation of gap junction connections.

  20. A ROP2-RIC1 pathway fine-tunes microtubule reorganization for salt tolerance in Arabidopsis.

    Science.gov (United States)

    Li, Changjiang; Lu, Hanmei; Li, Wei; Yuan, Ming; Fu, Ying

    2017-07-01

    The reorganization of microtubules induced by salt stress is required for Arabidopsis survival under high salinity conditions. RIC1 is an effector of Rho-related GTPase from plants (ROPs) and a known microtubule-associated protein. In this study, we demonstrated that RIC1 expression decreased with long-term NaCl treatment, and ric1-1 seedlings exhibited a higher survival rate under salt stress. We found that RIC1 reduced the frequency of microtubule transition from shortening to growing status and knockout of RIC1 improved the reassembly of depolymerized microtubules caused by either oryzalin treatment or salt stress. Further investigation showed that constitutively active ROP2 promoted the reassembly of microtubules and the survival of seedlings under salt stress. A rop2-1 ric1-1 double mutant rescued the salt-sensitive phenotype of rop2-1, indicating that ROP2 functions in salt tolerance through RIC1. Although ROP2 did not regulate RIC1 expression upon salt stress, a quick but mild increase of ROP2 activity was induced, led to reduction of RIC1 on microtubules. Collectively, our study reveals an ROP2-RIC1 pathway that fine-tunes microtubule dynamics in response to salt stress in Arabidopsis. This finding not only reveals a new regulatory mechanism for microtubule reorganization under salt stress but also the importance of ROP signalling for salinity tolerance. © 2017 John Wiley & Sons Ltd.

  1. Lidar Applications for Fine Tuning Forest Inventory Estimates in the Nonforest and Understory Carbon Pools

    Science.gov (United States)

    Johnson, K. D.; Birdsey, R.; Huang, W.; Dolan, K. A.; Finley, A. O.; Domke, G. M.; Russell, M.; ONeil-Dunne, J.; Dubayah, R.; Hurtt, G. C.

    2016-12-01

    The Forest Inventory and Analysis (FIA) program within the USDA Forest Service maintains permanent sample plots that provide valuable data for robust and consistent estimates of major forest carbon pools in the United States, and are currently used for official estimates to the greenhouse gas inventories compiled by EPA and reported to the UNFCCC and other entities. Nonetheless, there exist some carbon accounting gaps and indirectly measured pools that may be improved. Carbon in both "trees outside forest" and the understory is not currently measured directly in FIA plots. Understory carbon is predicted as a portion of total aboveground biomass, rather than from measurements of shrub, forbs or graminoid mass. In the current study, lidar data obtained at FIA plot locations was used to predict carbon in "trees outside forest" and the understory in the forests of Pennsylvania, Maryland, and Delaware, USA, potentially improving current estimates. Results indicate that carbon in "trees outside forests" represent a significant and under-estimated stock in this region. Understory carbon remains difficult to quantify at the plot level, but meaningful relationships with lidar canopy height (a proxy for stand succession) suggest that reliable population estimates may be aided by lidar data. Fine tuning these estimates is important, not only for improving the accuracy of estimates, but also for reconciling estimates with independently created forest carbon maps.

  2. Fine-tuned ATP signals are acute mediators in osteocyte mechanotransduction.

    Science.gov (United States)

    Kringelbach, Tina M; Aslan, Derya; Novak, Ivana; Ellegaard, Maria; Syberg, Susanne; Andersen, Christina K B; Kristiansen, Kim A; Vang, Ole; Schwarz, Peter; Jørgensen, Niklas R

    2015-12-01

    Osteocytes are considered the primary mechanosensors of bone, but the signaling pathways they apply in mechanotransduction are still incompletely investigated and characterized. A growing body of data strongly indicates that P2 receptor signaling among osteoblasts and osteoclasts has regulatory effects on bone remodeling. Therefore, we hypothesized that ATP signaling is also applied by osteocytes in mechanotransduction. We applied a short fluid pulse on MLO-Y4 osteocyte-like cells during real-time detection of ATP and demonstrated that mechanical stimulation activates the acute release of ATP and that these acute ATP signals are fine-tuned according to the magnitude of loading. ATP release was then challenged by pharmacological inhibitors, which indicated a vesicular release pathway for acute ATP signals. Finally, we showed that osteocytes express functional P2X2 and P2X7 receptors and respond to even low concentrations of nucleotides by increasing intracellular calcium concentration. These results indicate that in osteocytes, vesicular ATP release is an acute mediator of mechanical signals and the magnitude of loading. These and previous results, therefore, implicate purinergic signaling as an early signaling pathway in osteocyte mechanotransduction. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Fine-tuning the ubiquitin code at DNA double-strand breaks: deubiquitinating enzymes at work

    Directory of Open Access Journals (Sweden)

    Elisabetta eCitterio

    2015-09-01

    Full Text Available Ubiquitination is a reversible protein modification broadly implicated in cellular functions. Signaling processes mediated by ubiquitin are crucial for the cellular response to DNA double-strand breaks (DSBs, one of the most dangerous types of DNA lesions. In particular, the DSB response critically relies on active ubiquitination by the RNF8 and RNF168 ubiquitin ligases at the chromatin, which is essential for proper DSB signaling and repair. How this pathway is fine-tuned and what the functional consequences are of its deregulation for genome integrity and tissue homeostasis are subject of intense investigation. One important regulatory mechanism is by reversal of substrate ubiquitination through the activity of specific deubiquitinating enzymes (DUBs, as supported by the implication of a growing number of DUBs in DNA damage response (DDR processes. Here, we discuss the current knowledge of how ubiquitin-mediated signaling at DSBs is controlled by deubiquitinating enzymes, with main focus on DUBs targeting histone H2A and on their recent implication in stem cell biology and cancer.

  4. Fungal Endophytes as a Metabolic Fine-Tuning Regulator for Wine Grape.

    Directory of Open Access Journals (Sweden)

    Ming-Zhi Yang

    Full Text Available Endophytes proved to exert multiple effects on host plants, including growth promotion, stress resistance. However, whether endophytes have a role in metabolites shaping of grape has not been fully understood. Eight endophytic fungal strains which originally isolated from grapevines were re-inoculated to field-grown grapevines in this study, and their effects on both leaves and berries of grapevines at maturity stage were assessed, with special focused on secondary metabolites and antioxidant activities. High-density inoculation of all these endophytic fungal strains modified the physio-chemical status of grapevine to different degrees. Fungal inoculations promoted the content of reducing sugar (RS, total flavonoids (TF, total phenols (TPh, trans-resveratrol (Res and activities of phenylalanine ammonia-lyase (PAL, in both leaves and berries of grapevine. Inoculation of endophytic fungal strains, CXB-11 (Nigrospora sp. and CXC-13 (Fusarium sp. conferred greater promotion effects in grape metabolic re-shaping, compared to other used fungal strains. Additionally, inoculation of different strains of fungal endophytes led to establish different metabolites patterns of wine grape. The work implies the possibility of using endophytic fungi as fine-tuning regulator to shape the quality and character of wine grape.

  5. Fine-tuning of defensive behaviors in the dorsal periaqueductal gray by atypical neurotransmitters

    Directory of Open Access Journals (Sweden)

    M.V. Fogaça

    2012-04-01

    Full Text Available This paper presents an up-to-date review of the evidence indicating that atypical neurotransmitters such as nitric oxide (NO and endocannabinoids (eCBs play an important role in the regulation of aversive responses in the periaqueductal gray (PAG. Among the results supporting this role, several studies have shown that inhibitors of neuronal NO synthase or cannabinoid receptor type 1 (CB1 receptor agonists cause clear anxiolytic responses when injected into this region. The nitrergic and eCB systems can regulate the activity of classical neurotransmitters such as glutamate and γ-aminobutyric acid (GABA that control PAG activity. We propose that they exert a ‘fine-tuning’ regulatory control of defensive responses in this area. This control, however, is probably complex, which may explain the usually bell-shaped dose-response curves observed with drugs that act on NO- or CB1-mediated neurotransmission. Even if the mechanisms responsible for this complex interaction are still poorly understood, they are beginning to be recognized. For example, activation of transient receptor potential vanilloid type-1 channel (TRPV1 receptors by anandamide seems to counteract the anxiolytic effects induced by CB1 receptor activation caused by this compound. Further studies, however, are needed to identify other mechanisms responsible for this fine-tuning effect.

  6. The Parametric Study and Fine-Tuning of Bow-Tie Slot Antenna with Loaded Stub.

    Science.gov (United States)

    Shafiei, M M; Moghavvemi, Mahmoud; Wan Mahadi, Wan Nor Liza

    2017-01-01

    A printed Bow-Tie slot antenna with loaded stub is proposed and the effects of changing the dimensions of the slot area, the stub and load sizes are considered in this paper. These parameters have a considerable effect on the antenna characteristics as well as its performance. An in-depth parametric study of these dimensions is presented. This paper proposes the necessary conditions for initial approximation of dimensions needed to design this antenna. In order to achieve the desired performance of the antenna fine tuning of all sizes of these parameters is required. The parametric studies used in this paper provide proper trends for initiation and tuning the design. A prototype of the antenna for 1.7GHz to 2.6GHz band is fabricated. Measurements conducted verify that the designed antenna has wideband characteristics with 50% bandwidth around the center frequency of 2.1GHz. Conducted measurements for reflection coefficient (S11) and radiation pattern also validate our simulation results.

  7. Fine-tuning optical and electronic properties of graphene oxide for highly efficient perovskite solar cells.

    Science.gov (United States)

    Liu, Tongfa; Kim, Dongcheon; Han, Hongwei; Yusoff, Abd Rashid bin Mohd; Jang, Jin

    2015-06-28

    Simplifying the process of fine-tuning the electronic and optical properties of graphene oxide (GO) is of importance in order to fully utilize it as the hole interfacial layer (HIL). We introduced silver trifluoromethanesulfonate (AgOTf), an inorganic chemical dopant, that tunes and controls the properties of single-layered GO films synthesized by chemical vapor deposition. The morphology, work function, mobility, sheet resistance, and transmittance of the GO film were systematically tuned by various doping concentrations. We further developed a solution-processable low-temperature hole interfacial layer (HIL) poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) ( PSS):AgOTf-doped GO HIL in highly efficient perovskite solar cells. The PSS:AgOTf-doped GO HIL grants the desirable charge-collection in the HIL allowing the entire device to be prepared at temperatures less than 120 °C. The fabricated perovskite solar cells utilize a rigid substrate and demonstrate compelling photovoltaic performance with a power conversion efficiency (PCE) of 11.90%. Moreover, flexible devices prepared using a polyethylene terephthalate (PET)/ITO demonstrate a PCE of 9.67%, while ITO-free flexible devices adopting PET/aluminum doped zinc oxide (AZO)/silver (Ag)/AZO demonstrate a PCE of 7.97%. This study shows that the PSS:AgOTf-doped GO HIL has significant potential to contribute to the development of low-cost solar cells.

  8. Maternal expression of communicative intentions and pragmatic fine tuning in early infancy.

    Science.gov (United States)

    Rivero, Magda

    2010-12-01

    This study focuses on pragmatic characteristics of infant-directed speech and pragmatic fine tuning during the first 18 months of life. The subjects of the study were a mother-child dyad involved in a longitudinal/observational study in a familial context. Audiovisual recordings were transcribed according to the conventions of the Child Language Data Exchange System (MacWhinney, 2000; MacWhinney & Snow, 1990). The Ninio and Wheeler's (1988) system for coding communicative intentions was adapted. The results of this research show that most of the communicative exchanges identified at 14, 20 and 32 months by Snow, Pan, Imbens-Bailey, and Herman (1996) appear in mother-child interaction from the beginning, while other communicative interchanges appear later. With respect to speech acts, the results highlight, from an early age, the general tendencies discussed by Snow et al. and some novelties. Interestingly, changes in some pragmatic measures were identified around 8 months of age, and the appearance of new communicative interchanges also took place around this age. These changes are interpreted as maternal adjustments to the child's communicative competence. Copyright © 2010 Elsevier Inc. All rights reserved.

  9. Fine tuning and six-dimensional gauged N =(1, 0) supergravity vacua

    Science.gov (United States)

    Güven, R.; Liu, James T.; Pope, C. N.; Sezgin, E.

    2004-02-01

    We find a new family of supersymmetric vacuum solutions in the six-dimensional chiral gauged N = (1, 0) supergravity theory. They are generically of the form AdS3 × S3, where the 3-sphere is squashed homogeneously along its Hopf fibres. The squashing is freely adjustable, corresponding to changing the 3-form charge, and the solution is supersymmetric for all squashings. In a limit where the length of the Hopf fibres goes to zero, one recovers, after a compensating rescaling of the fibre coordinate, a solution that is locally the same as the well-known (Minkowski)4 × S2 vacuum of this theory. It can now be viewed as a fine tuning of the new more general family. The traditional 'cosmological constant problem' is replaced in this theory by the problem of why the four-dimensional (Minkowski)4 × S2 vacuum should be selected over other members of the equally supersymmetric AdS3 × S3 family. We also obtain a family of dyonic string solutions in the gauged N = (1, 0) theory, whose near-horizon limits approach the AdS3 times squashed S3 solutions.

  10. Regulation of inositol metabolism is fine-tuned by inositol pyrophosphates in Saccharomyces cerevisiae.

    Science.gov (United States)

    Ye, Cunqi; Bandara, W M M S; Greenberg, Miriam L

    2013-08-23

    Although inositol pyrophosphates have diverse roles in phosphate signaling and other important cellular processes, little is known about their functions in the biosynthesis of inositol and phospholipids. Here, we show that KCS1, which encodes an inositol pyrophosphate kinase, is a regulator of inositol metabolism. Deletion of KCS1, which blocks synthesis of inositol pyrophosphates on the 5-hydroxyl of the inositol ring, causes inositol auxotrophy and decreased intracellular inositol and phosphatidylinositol. These defects are caused by a profound decrease in transcription of INO1, which encodes myo-inositol-3-phosphate synthase. Expression of genes that function in glycolysis, transcription, and protein processing is not affected in kcs1Δ. Deletion of OPI1, the INO1 transcription repressor, does not fully rescue INO1 expression in kcs1Δ. Both the inositol pyrophosphate kinase and the basic leucine zipper domains of KCS1 are required for INO1 expression. Kcs1 is regulated in response to inositol, as Kcs1 protein levels are increased in response to inositol depletion. The Kcs1-catalyzed production of inositol pyrophosphates from inositol pentakisphosphate but not inositol hexakisphosphate is indispensable for optimal INO1 transcription. We conclude that INO1 transcription is fine-tuned by the synthesis of inositol pyrophosphates, and we propose a model in which modulation of Kcs1 controls INO1 transcription by regulating synthesis of inositol pyrophosphates.

  11. Timing is everything: Fine-tuned molecular machines orchestrate paramyxovirus entry

    Energy Technology Data Exchange (ETDEWEB)

    Bose, Sayantan, E-mail: sayantan_bose@hms.harvard.edu [Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500 (United States); Jardetzky, Theodore S. [Department of Structural Biology and Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305 (United States); Lamb, Robert A., E-mail: ralamb@northwestern.edu [Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500 (United States); Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208-3500 (United States)

    2015-05-15

    The Paramyxoviridae include some of the great and ubiquitous disease-causing viruses of humans and animals. In most paramyxoviruses, two viral membrane glycoproteins, fusion protein (F) and receptor binding protein (HN, H or G) mediate a concerted process of recognition of host cell surface molecules followed by fusion of viral and cellular membranes, resulting in viral nucleocapsid entry into the cytoplasm. The interactions between the F and HN, H or G viral glycoproteins and host molecules are critical in determining host range, virulence and spread of these viruses. Recently, atomic structures, together with biochemical and biophysical studies, have provided major insights into how these two viral glycoproteins successfully interact with host receptors on cellular membranes and initiate the membrane fusion process to gain entry into cells. These studies highlight the conserved core mechanisms of paramyxovirus entry that provide the fundamental basis for rational anti-viral drug design and vaccine development. - Highlights: • New structural and functional insights into paramyxovirus entry mechanisms. • Current data on paramyxovirus glycoproteins suggest a core conserved entry mechanism. • Diverse mechanisms preventing premature fusion activation exist in these viruses. • Precise spacio-temporal interplay between paramyxovirus glycoproteins initiate entry.

  12. Body appendages fine-tune posture and moments in freely manoeuvring fruit flies.

    Science.gov (United States)

    Berthé, Ruben; Lehmann, Fritz-Olaf

    2015-10-01

    The precise control of body posture by turning moments is key to elevated locomotor performance in flying animals. Although elevated moments for body stabilization are typically produced by wing aerodynamics, animals also steer using drag on body appendages, shifting their centre of body mass, and changing moments of inertia caused by active alterations in body shape. To estimate the instantaneous contribution of each of these components for posture control in an insect, we three-dimensionally reconstructed body posture and movements of body appendages in freely manoeuvring fruit flies (Drosophila melanogaster) by high-speed video and experimentally scored drag coefficients of legs and body trunk at low Reynolds number. The results show that the sum of leg- and abdomen-induced yaw moments dominates wing-induced moments during 17% of total flight time but is, on average, 7.2-times (roll, 3.4-times) smaller during manoeuvring. Our data reject a previous hypothesis on synergistic moment support, indicating that drag on body appendages and mass-shift inhibit rather than support turning moments produced by the wings. Numerical modelling further shows that hind leg extension alters the moments of inertia around the three main body axes of the animal by not more than 6% during manoeuvring, which is significantly less than previously reported for other insects. In sum, yaw, pitch and roll steering by body appendages probably fine-tune turning behaviour and body posture, without providing a significant advantage for posture stability and moment support. Motion control of appendages might thus be part of the insect's trimming reflexes, which reduce imbalances in moment generation caused by unilateral wing damage and abnormal asymmetries of the flight apparatus. © 2015. Published by The Company of Biologists Ltd.

  13. Lysine succinylation of Mycobacterium tuberculosis isocitrate lyase (ICL) fine-tunes the microbial resistance to antibiotics.

    Science.gov (United States)

    Zhou, Mingliang; Xie, Longxiang; Yang, Zhaozhen; Zhou, Jiahai; Xie, Jianping

    2017-04-01

    Lysine succinylation (Ksucc) is a newly identified protein posttranslational modification (PTM), which may play an important role in cellular physiology. However, the role of lysine succinylation in antibiotic resistance remains elusive. Isocitrate lyase (ICL) is crucial for broad-spectrum antibiotics tolerance in Mycobacterium tuberculosis (Mtb). We previously found that MtbICL (Rv0467) has at least three succinylated lysine residues, namely K189, K322, and K334.To explore the effect of succinylation on the activity of MtbICL, mutants' mimicry of the lysine succinylation were generated by site-directed mutagenesis. ICL-K189E mutant strain is more sensitive than the wild-type to rifampicin and streptomycin, but not isoniazid. For the in vitro activity of the purified isocitrate lyase, only K189E mutant showed significantly decreased activity. Crystal structure analysis showed that Lys189 Glu dramatically increased the pKa of Glu188 and decreased the pKa of Lys190, whereas had negligible effect on other residues within 5 Å as well as disruption of the electrostatic interaction between Lys189 and Glu182, which might prevent the closure of the active site loop and cause severe reduction of the enzyme activity. Considering the genetic, biochemical, and crystallographical evidences together, the succinylation of specific ICL residue can fine-tune the bacterial resistance to selected antibiotics. The decreased enzymatic activity resulting from the succinylation-changed electrostatic interaction might underlie this phenotype. This study provided the first insight into the link between lysine succinylation and antibiotic resistance.

  14. Leaf color is fine-tuned on the solar spectra to avoid strand direct solar radiation.

    Science.gov (United States)

    Kume, Atsushi; Akitsu, Tomoko; Nasahara, Kenlo Nishida

    2016-07-01

    The spectral distributions of light absorption rates by intact leaves are notably different from the incident solar radiation spectra, for reasons that remain elusive. Incident global radiation comprises two main components; direct radiation from the direction of the sun, and diffuse radiation, which is sunlight scattered by molecules, aerosols and clouds. Both irradiance and photon flux density spectra differ between direct and diffuse radiation in their magnitude and profile. However, most research has assumed that the spectra of photosynthetically active radiation (PAR) can be averaged, without considering the radiation classes. We used paired spectroradiometers to sample direct and diffuse solar radiation, and obtained relationships between the PAR spectra and the absorption spectra of photosynthetic pigments and organs. As monomers in solvent, the spectral absorbance of Chl a decreased with the increased spectral irradiance (W m(-2) nm(-1)) of global PAR at noon (R(2) = 0.76), and was suitable to avoid strong spectral irradiance (λmax = 480 nm) rather than absorb photon flux density (μmol m(-2) s(-1) nm(-1)) efficiently. The spectral absorption of photosystems and the intact thallus and leaves decreased linearly with the increased spectral irradiance of direct PAR at noon (I dir-max), where the wavelength was within the 450-650 nm range (R(2) = 0.81). The higher-order structure of photosystems systematically avoided the strong spectral irradiance of I dir-max. However, when whole leaves were considered, leaf anatomical structure and light scattering in leaf tissues made the leaves grey bodies for PAR and enabled high PAR use efficiency. Terrestrial green plants are fine-tuned to spectral dynamics of incident solar radiation and PAR absorption is increased in various structural hierarchies.

  15. New approach to assess sperm DNA fragmentation dynamics: Fine-tuning mathematical models.

    Science.gov (United States)

    Ortiz, Isabel; Dorado, Jesús; Morrell, Jane; Gosálvez, Jaime; Crespo, Francisco; Jiménez, Juan M; Hidalgo, Manuel

    2017-01-01

    Sperm DNA fragmentation (sDF) has been proved to be an important parameter in order to predict in vitro the potential fertility of a semen sample. Colloid centrifugation could be a suitable technique to select those donkey sperm more resistant to DNA fragmentation after thawing. Previous studies have shown that to elucidate the latent damage of the DNA molecule, sDF should be assessed dynamically, where the rate of fragmentation between treatments indicates how resistant the DNA is to iatrogenic damage. The rate of fragmentation is calculated using the slope of a linear regression equation. However, it has not been studied if sDF dynamics fit this model. The objectives of this study were to evaluate the effect of different after-thawing centrifugation protocols on sperm DNA fragmentation and elucidate the most accurate mathematical model (linear regression, exponential or polynomial) for DNA fragmentation over time in frozen-thawed donkey semen. After submitting post-thaw semen samples to no centrifugation (UDC), sperm washing (SW) or single layer centrifugation (SLC) protocols, sDF values after 6 h of incubation were significantly lower in SLC samples than in SW or UDC. Coefficient of determination (R2) values were significantly higher for a second order polynomial model than for linear or exponential. The highest values for acceleration of fragmentation (aSDF) were obtained for SW, followed by SLC and UDC. SLC after thawing seems to preserve longer DNA longevity in comparison to UDC and SW. Moreover, the fine-tuning of models has shown that sDF dynamics in frozen-thawed donkey semen fit a second order polynomial model, which implies that fragmentation rate is not constant and fragmentation acceleration must be taken into account to elucidate hidden damage in the DNA molecule.

  16. Fine-tuning of NADH oxidase decreases byproduct accumulation in respiration deficient xylose metabolic Saccharomyces cerevisiae.

    Science.gov (United States)

    Hou, Jin; Suo, Fan; Wang, Chengqiang; Li, Xiaowei; Shen, Yu; Bao, Xiaoming

    2014-02-14

    Efficiently utilizing all available carbon from lignocellulosic feedstock presents a major barrier to the production of economically feasible biofuel. Previously, to enable xylose utilization, we introduced a cofactor-dependent xylose reductase (XR) and xylitol dehydrogenase (XDH) pathway, or a cofactor-independent xylose isomerase (XI) pathway, into Saccharomyces cerevisiae. The resulting strains metabolized xylose with high efficiency. However, in both pathway recombinant strains, the cofactor imbalance caused accumulation of the byproducts glycerol and/or xylitol and reduced the ethanol production efficiency. In this study, we introduced NADH oxidase from Lactococcus lactis into both XI and XR-XDH pathway recombinant strains. To reduce byproduct accumulation while maintaining xylose metabolism, we optimized the expression level of NADH oxidase by comparing its expression under the control of different promoters and plasmids. In recombinant XI strains, NADH oxidase was expressed at different levels, regulated by the GPD2 promoter or TEF1 promoter in the 2 μ plasmid. The expression under the control of GPD2 promoter decreased glycerol production by 84% and increased the ethanol yield and specific growth rate by 8% and 12%, respectively. In contrast, in the recombinant XR-XDH strains, such expression level was not efficient enough to decrease the byproduct accumulation. Therefore, higher NADH oxidase expression levels were tested. In the strain expressing NADH oxidase under the control of the TEF1 promoter in the centromeric plasmids, xylitol and glycerol production were reduced by 60% and 83%, respectively, without significantly affecting xylose consumption. By fine-tuning NADH oxidase expression, we decreased the glycerol or/and xylitol production in both recombinant XI and XR-XDH xylose-metabolizing yeast strains. The optimal NADH oxidase expression levels depend on metabolic pathways. Similar cofactor engineering strategies could maximize the production of

  17. Multiple excitatory and inhibitory neural signals converge to fine-tune Caenorhabditis elegans feeding to food availability

    Science.gov (United States)

    Dallière, Nicolas; Bhatla, Nikhil; Luedtke, Zara; Ma, Dengke K.; Woolman, Jonathan; Walker, Robert J.; Holden-Dye, Lindy; O’Connor, Vincent

    2016-01-01

    How an animal matches feeding to food availability is a key question for energy homeostasis. We addressed this in the nematode Caenorhabditis elegans, which couples feeding to the presence of its food (bacteria) by regulating pharyngeal activity (pumping). We scored pumping in the presence of food and over an extended time course of food deprivation in wild-type and mutant worms to determine the neural substrates of adaptive behavior. Removal of food initially suppressed pumping but after 2 h this was accompanied by intermittent periods of high activity. We show pumping is fine-tuned by context-specific neural mechanisms and highlight a key role for inhibitory glutamatergic and excitatory cholinergic/peptidergic drives in the absence of food. Additionally, the synaptic protein UNC-31 [calcium-activated protein for secretion (CAPS)] acts through an inhibitory pathway not explained by previously identified contributions of UNC-31/CAPS to neuropeptide or glutamate transmission. Pumping was unaffected by laser ablation of connectivity between the pharyngeal and central nervous system indicating signals are either humoral or intrinsic to the enteric system. This framework in which control is mediated through finely tuned excitatory and inhibitory drives resonates with mammalian hypothalamic control of feeding and suggests that fundamental regulation of this basic animal behavior may be conserved through evolution from nematode to human.—Dallière, N., Bhatla, N., Luedtke, Z., Ma, D. K., Woolman, J., Walker, R. J., Holden-Dye, L., O’Connor, V. Multiple excitatory and inhibitory neural signals converge to fine-tune Caenorhabditis elegans feeding to food availability. PMID:26514165

  18. Escherichia coli strains with promoter libraries constructed by Red/ET recombination pave the way for transcriptional fine tuning

    DEFF Research Database (Denmark)

    Braatsch, Stephan; Helmark, Søren; Kranz, Harald

    2008-01-01

    System-oriented applications of genetic engineering, such as metabolic engineering, often require the serial optimization of enzymatic reaction steps, which can be achieved by transcriptional, fine-tuning. However, approaches to changing gene expression are usually limited to deletion and/or strong...... expression. Red/ET recombination perfectly complements SPL technology, since it enables easy modification of the Escherichia Coli genome and can be accomplished with linear DNA (i.e., the SPL). To demonstrate the synergistic use of Red/ET and SPL for metabolic engineering applications, we replaced the native...

  19. Post-translational regulation of macrophage migration inhibitory factor: Basis for functional fine-tuning

    Directory of Open Access Journals (Sweden)

    Lisa Schindler

    2018-05-01

    Full Text Available Macrophage migration inhibitory factor (MIF is a chemokine-like protein and an important mediator in the inflammatory response. Unlike most other pro-inflammatory cytokines, a number of cell types constitutively express MIF and secretion occurs from preformed stores. MIF is an evolutionarily conserved protein that shows a remarkable functional diversity, including specific binding to surface CD74 and chemokine receptors and the presence of two intrinsic tautomerase and oxidoreductase activities. Several studies have shown that MIF is subject to post-translational modification, particularly redox-dependent modification of the catalytic proline and cysteine residues. In this review, we summarize and discuss MIF post-translational modifications and their effects on the biological properties of this protein. We propose that the redox-sensitive residues in MIF will be modified at sites of inflammation and that this will add further depth to the functional diversity of this intriguing cytokine.

  20. Multiple excitatory and inhibitory neural signals converge to fine-tune Caenorhabditis elegans feeding to food availability.

    Science.gov (United States)

    Dallière, Nicolas; Bhatla, Nikhil; Luedtke, Zara; Ma, Dengke K; Woolman, Jonathan; Walker, Robert J; Holden-Dye, Lindy; O'Connor, Vincent

    2016-02-01

    How an animal matches feeding to food availability is a key question for energy homeostasis. We addressed this in the nematode Caenorhabditis elegans, which couples feeding to the presence of its food (bacteria) by regulating pharyngeal activity (pumping). We scored pumping in the presence of food and over an extended time course of food deprivation in wild-type and mutant worms to determine the neural substrates of adaptive behavior. Removal of food initially suppressed pumping but after 2 h this was accompanied by intermittent periods of high activity. We show pumping is fine-tuned by context-specific neural mechanisms and highlight a key role for inhibitory glutamatergic and excitatory cholinergic/peptidergic drives in the absence of food. Additionally, the synaptic protein UNC-31 [calcium-activated protein for secretion (CAPS)] acts through an inhibitory pathway not explained by previously identified contributions of UNC-31/CAPS to neuropeptide or glutamate transmission. Pumping was unaffected by laser ablation of connectivity between the pharyngeal and central nervous system indicating signals are either humoral or intrinsic to the enteric system. This framework in which control is mediated through finely tuned excitatory and inhibitory drives resonates with mammalian hypothalamic control of feeding and suggests that fundamental regulation of this basic animal behavior may be conserved through evolution from nematode to human. © FASEB.

  1. Direct flow cytometry measurements reveal a fine-tuning of symbiotic cell dynamics according to the host developmental needs in aphid symbiosis.

    Science.gov (United States)

    Simonet, Pierre; Duport, Gabrielle; Gaget, Karen; Weiss-Gayet, Michèle; Colella, Stefano; Febvay, Gérard; Charles, Hubert; Viñuelas, José; Heddi, Abdelaziz; Calevro, Federica

    2016-01-29

    Endosymbiotic associations constitute a driving force in the ecological and evolutionary diversification of metazoan organisms. Little is known about whether and how symbiotic cells are coordinated according to host physiology. Here, we use the nutritional symbiosis between the insect pest, Acyrthosiphon pisum, and its obligate symbiont, Buchnera aphidicola, as a model system. We have developed a novel approach for unculturable bacteria, based on flow cytometry, and used this method to estimate the absolute numbers of symbionts at key stages of aphid life. The endosymbiont population increases exponentially throughout nymphal development, showing a growing rate which has never been characterized by indirect molecular techniques. Using histology and imaging techniques, we have shown that the endosymbiont-bearing cells (bacteriocytes) increase significantly in number and size during the nymphal development, and clustering in the insect abdomen. Once adulthood is reached and the laying period has begun, the dynamics of symbiont and host cells is reversed: the number of endosymbionts decreases progressively and the bacteriocyte structure degenerates during insect aging. In summary, these results show a coordination of the cellular dynamics between bacteriocytes and primary symbionts and reveal a fine-tuning of aphid symbiotic cells to the nutritional demand imposed by the host physiology throughout development.

  2. Fine-Tuned Intrinsically Ultramicroporous Polymers Redefine the Permeability/Selectivity Upper Bounds of Membrane-Based Air and Hydrogen Separations

    KAUST Repository

    Swaidan, Raja

    2015-08-20

    Intrinsically ultramicroporous (<7 Å) polymers represent a new paradigm in materials development for membrane-based gas separation. In particular, they demonstrate that uniting intrachain “rigidity”, the traditional design metric of highly permeable polymers of intrinsic microporosity (PIMs), with gas-sieving ultramicroporosity yields high-performance gas separation membranes. Highly ultramicroporous PIMs have redefined the state-of-the-art in large-scale air (e.g., O2/N2) and hydrogen recovery (e.g., H2/N2, H2/CH4) applications with unprecedented molecular sieving gas transport properties. Accordingly, presented herein are new 2015 permeability/selectivity “upper bounds” for large-scale commercial membrane-based air and hydrogen applications that accommodate the substantial performance enhancements of recent PIMs over preceding polymers. A subtle balance between intrachain rigidity and interchain spacing has been achieved in the amorphous microstructures of PIMs, fine-tuned using unique bridged-bicyclic building blocks (i.e., triptycene, ethanoanthracene and Tröger’s base) in both ladder and semiladder (e.g., polyimide) structures.

  3. The molecular clock in terms of quantum information processing of coherent states, entanglement and replication of evolutionarily selected decohered isomers.

    Science.gov (United States)

    Cooper, W Grant

    2011-06-01

    Evolutionary pressures have selected quantum uncertainty limits -ΔxΔp ( x ) ≥ 1/2ħ-to operate on metastable amino DNA protons. This introduces a probability of molecular clock arrangement, keto-amino → enol-imine, where product protons are entangled and participate in coupled quantum oscillation at frequencies of ∼ 10(13) s(-1). The ket "seen by" the transcriptase, reading a coherent enol-imine G'-state, is |φ >= α| + + > +β|+- > +γ|-+ > +δ|-->. The transcriptase implements its measurement and generates an output qubit of observable genetic specificity information in an interval Δt ≪ 10(-13) s. These quantum measurements can specify the relative distribution of coherent G'-C' states at time of measurement. The ensuing quantum entanglement between coherent protons and transcriptase units is utilized as a resource to generate proper decoherence and introduce selected time-dependent substitutions, ts, and deletions, td. Topal-Fresco ts are G'202 → T, G'002 → C, *G020(0) → A and *C202(2) → T, whereas td are exhibited at coherent *A-*T sites. Variation in clock 'tic-rate' is a consequence of clock introduction of initiation codons - UUG, CUG, AUG, GUG - and stop codons, UAA, UAG, UGA. Using approximate quantum methods for times t coherent states populating human genes, including inherited (CAG)( n ) repeat tracts.

  4. Semiempirical fine-tuning for Hartree–Fock ionization potentials of atomic ions with non-integral atomic number

    Energy Technology Data Exchange (ETDEWEB)

    Cordero, Nicolás A. [Departamento de Física, Universidad de Burgos, C Villadiego s/n, E-09001 Burgos (Spain); March, Norman H. [Department of Physics, University of Antwerp (RUCA), 171 Groenenborgerlaan, B-2020 Antwerp (Belgium); Oxford University, Oxford (United Kingdom); Alonso, Julio A. [Departamento de Física Teórica, Atómica y Óptica, Universidad de Valladolid, E-47011 Valladolid (Spain)

    2013-12-02

    Amovilli and March (2006) [8] used diffusion quantum Monte Carlo techniques to calculate the non-relativistic ionization potential I(Z) in He-like atomic ions for the range of (fractional) nuclear charges Z lying between the known critical value Z{sub c}=0.911 at which I(Z) tends to zero and Z=2. They showed that it is possible to fit I(Z) to a simple quadratic expression. Following that idea, we present here a semiempirical fine-tuning of Hartree–Fock ionization potentials for the isoelectronic series of He, Be, Ne, Mg and Ar-like atomic ions that leads to excellent estimations of Z{sub c} for these series. The empirical information involved is experimental ionization and electron affinity data. It is clearly demonstrated that Hartree–Fock theory provides an excellent starting point for determining I(Z) for these series.

  5. Fine-tuning the antimicrobial profile of biocompatible gold nanoparticles by sequential surface functionalization using polyoxometalates and lysine.

    Directory of Open Access Journals (Sweden)

    Hemant K Daima

    Full Text Available Antimicrobial action of nanomaterials is typically assigned to the nanomaterial composition, size and/or shape, whereas influence of complex corona stabilizing the nanoparticle surface is often neglected. We demonstrate sequential surface functionalization of tyrosine-reduced gold nanoparticles (AuNPs(Tyr with polyoxometalates (POMs and lysine to explore controlled chemical functionality-driven antimicrobial activity. Our investigations reveal that highly biocompatible gold nanoparticles can be tuned to be a strong antibacterial agent by fine-tuning their surface properties in a controllable manner. The observation from the antimicrobial studies on a gram negative bacterium Escherichia coli were further validated by investigating the anticancer properties of these step-wise surface-controlled materials against A549 human lung carcinoma cells, which showed a similar toxicity pattern. These studies highlight that the nanomaterial toxicity and biological applicability are strongly governed by their surface corona.

  6. Using membrane composition to fine-tune the pKa of an optical liposome pH sensor.

    Science.gov (United States)

    Clear, Kasey J; Virga, Katelyn; Gray, Lawrence; Smith, Bradley D

    2016-04-14

    Liposomes containing membrane-anchored pH-sensitive optical probes are valuable sensors for monitoring pH in various biomedical samples. The dynamic range of the sensor is maximized when the probe pKa is close to the expected sample pH. While some biomedical samples are close to neutral pH there are several circumstances where the pH is 1 or 2 units lower. Thus, there is a need to fine-tune the probe pKa in a predictable way. This investigation examined two lipid-conjugated optical probes, each with appended deep-red cyanine dyes containing indoline nitrogen atoms that are protonated in acid. The presence of anionic phospholipids in the liposomes stabilized the protonated probes and increased the probe pKa values by sensor for optimal pH sensing performance.

  7. Fine-tuning the onset of myogenesis by homeobox proteins that interact with the Myf5 limb enhancer

    Directory of Open Access Journals (Sweden)

    Philippe Daubas

    2015-12-01

    Full Text Available Skeletal myogenesis in vertebrates is initiated at different sites of skeletal muscle formation during development, by activation of specific control elements of the myogenic regulatory genes. In the mouse embryo, Myf5 is the first myogenic determination gene to be expressed and its spatiotemporal regulation requires multiple enhancer sequences, extending over 120 kb upstream of the Mrf4-Myf5 locus. An enhancer, located at −57/−58 kb from Myf5, is responsible for its activation in myogenic cells derived from the hypaxial domain of the somite, that will form limb muscles. Pax3 and Six1/4 transcription factors are essential activators of this enhancer, acting on a 145-bp core element. Myogenic progenitor cells that will form the future muscle masses of the limbs express the factors necessary for Myf5 activation when they delaminate from the hypaxial dermomyotome and migrate into the forelimb bud, however they do not activate Myf5 and the myogenic programme until they have populated the prospective muscle masses. We show that Msx1 and Meox2 homeodomain-containing transcription factors bind in vitro and in vivo to specific sites in the 145-bp element, and are implicated in fine-tuning activation of Myf5 in the forelimb. Msx1, when bound between Pax and Six sites, prevents the binding of these key activators, thus inhibiting transcription of Myf5 and consequent premature myogenic differentiation. Meox2 is required for Myf5 activation at the onset of myogenesis via direct binding to other homeodomain sites in this sequence. Thus, these homeodomain factors, acting in addition to Pax3 and Six1/4, fine-tune the entry of progenitor cells into myogenesis at early stages of forelimb development.

  8. MicroRNA-15a fine-tunes the level of Delta-like 1 homolog (DLK1) in proliferating 3T3-L1 preadipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Andersen, Ditte C. [Laboratory of Molecular and Cellular Cardiology, Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital/Department of Cardiovascular and Renal Research, University of Southern Denmark, Winslowparken 21.3, DK-5000 Odense C (Denmark); Jensen, Charlotte H., E-mail: charken@health.sdu.dk [Department of Cancer and Inflammation Research, University of Southern Denmark, Winslowparken 21.1, DK-5000 Odense C (Denmark); Schneider, Mikael [Laboratory of Molecular and Cellular Cardiology, Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital/Department of Cardiovascular and Renal Research, University of Southern Denmark, Winslowparken 21.3, DK-5000 Odense C (Denmark); Nossent, Anne Yael [Laboratory of Molecular and Cellular Cardiology, Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital/Department of Cardiovascular and Renal Research, University of Southern Denmark, Winslowparken 21.3, DK-5000 Odense C (Denmark); Laboratory for Molecular Cardiology, The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Neuroscience and Pharmacology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N (Denmark); Eskildsen, Tilde [Laboratory of Molecular and Cellular Cardiology, Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital/Department of Cardiovascular and Renal Research, University of Southern Denmark, Winslowparken 21.3, DK-5000 Odense C (Denmark); Hansen, Jakob L. [Laboratory for Molecular Cardiology, The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Neuroscience and Pharmacology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N (Denmark); Teisner, Borge [Department of Cancer and Inflammation Research, University of Southern Denmark, Winslowparken 21.1, DK-5000 Odense C (Denmark); and others

    2010-06-10

    Delta like 1 homolog (Dlk1) exists in both transmembrane and soluble molecular forms, and is implicated in cellular growth and plays multiple roles in development, tissue regeneration, and cancer. Thus, DLK1 levels are critical for cell function, and abnormal DLK1 expression can be lethal; however, little is known about the underlying mechanisms. We here report that miR-15a modulates DLK1 levels in preadipocytes thus providing a mechanism for DLK1 regulation that further links it to cell cycle arrest and cancer since miR-15a is deregulated in these processes. In preadipocytes, miR-15a increases with cell density, and peaks at the same stage where membrane DLK1{sup M} and soluble DLK1{sup S} are found at maximum levels. Remarkably, miR-15a represses the amount of all Dlk1 variants at the mRNA level but also the level of DLK1{sup M} protein while it increases the amount of DLK1{sup S} supporting a direct repression of DLK1 and a parallel effect on the protease that cleaves off the DLK1 from the membrane. In agreement with previous studies, we found that miR-15a represses cell numbers, but additionally, we report that miR-15a also increases cell size. Conversely, anti-miR-15a treatment decreases cell size while increasing cell numbers, scenarios that were completely rescued by addition of purified DLK1{sup S}. Our data thus imply that miR-15a regulates cell size and proliferation by fine-tuning Dlk1 among others, and further emphasize miR-15a and DLK1 levels to play important roles in growth signaling networks.

  9. Fine-tuning the CAR spacer improves T-cell potency.

    Science.gov (United States)

    Watanabe, Norihiro; Bajgain, Pradip; Sukumaran, Sujita; Ansari, Salma; Heslop, Helen E; Rooney, Cliona M; Brenner, Malcolm K; Leen, Ann M; Vera, Juan F

    2016-01-01

    The adoptive transfer of genetically engineered T cells expressing chimeric antigen receptors (CARs) has emerged as a transformative cancer therapy with curative potential, precipitating a wave of preclinical and clinical studies in academic centers and the private sector. Indeed, significant effort has been devoted to improving clinical benefit by incorporating accessory genes/CAR endodomains designed to enhance cellular migration, promote in vivo expansion/persistence or enhance safety by genetic programming to enable the recognition of a tumor signature. However, our efforts centered on exploring whether CAR T-cell potency could be enhanced by modifying pre-existing CAR components. We now demonstrate how molecular refinements to the CAR spacer can impact multiple biological processes including tonic signaling, cell aging, tumor localization, and antigen recognition, culminating in superior in vivo antitumor activity.

  10. Fine-tuning the space, time, and host distribution of mycobacteria in wildlife

    Directory of Open Access Journals (Sweden)

    de la Fuente Jose

    2011-02-01

    highlights the suitability of molecular typing for surveys at small spatial and temporal scales.

  11. Virome and Inflammasomes, a Finely Tuned Balance with Important Consequences for the Host Health.

    Science.gov (United States)

    Freer, Giulia; Maggi, Fabrizio; Pistello, Mauro

    2017-10-05

    The virome is a multifaceted network of viruses inhabiting humans in health and disease. The virome forms a conspicuous portion of the so-called microbiome. Massive amount of data recently emerging demonstrates that the microbiome, once generically referred to as human (or animal) flora, is not a static entity but closely reflects what we eat, how and where we live, what we do, and many other unexpected variables. Composition, location, and amount of the microbiome have a direct impact on innate and adaptive host immune defences. Indeed, the microbiome may activate inflammasomes, multiprotein complexes that assemble in most human cells and that are responsible for the downstream effects of sensing microorganisms. Depending on their interplay with microbes, inflammasomes instruct host defences to tolerate or forfeit a specific microorganism. Indeed, the microbiome not only colonizes the gut and facilitates food digestion and absorption, but also shapes human immune defences and contributes to inflammatory processes by quenching or increasing them. Viruses that make up the virome play their part in shaping the immune system. Anelloviruses, one of the recently discovered families that are part of the virome, form a large fraction of human virome. They are present in most, if not all, human beings, where they replicate persistently without causing apparent disease. This review illustrates the role of the virome in modulating inflammation in cancer and various degenerative diseases and provides strong evidence for Anelloviruses as useful and practical molecular markers to monitor inflammatory processes and immune system competence. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Fine-tuning the space, time, and host distribution of mycobacteria in wildlife

    Science.gov (United States)

    2011-01-01

    molecular typing for surveys at small spatial and temporal scales. PMID:21288321

  13. Fine-tuning translation kinetics selection as the driving force of codon usage bias in the hepatitis A virus capsid.

    Directory of Open Access Journals (Sweden)

    Lluís Aragonès

    2010-03-01

    Full Text Available Hepatitis A virus (HAV, the prototype of genus Hepatovirus, has several unique biological characteristics that distinguish it from other members of the Picornaviridae family. Among these, the need for an intact eIF4G factor for the initiation of translation results in an inability to shut down host protein synthesis by a mechanism similar to that of other picornaviruses. Consequently, HAV must inefficiently compete for the cellular translational machinery and this may explain its poor growth in cell culture. In this context of virus/cell competition, HAV has strategically adopted a naturally highly deoptimized codon usage with respect to that of its cellular host. With the aim to optimize its codon usage the virus was adapted to propagate in cells with impaired protein synthesis, in order to make tRNA pools more available for the virus. A significant loss of fitness was the immediate response to the adaptation process that was, however, later on recovered and more associated to a re-deoptimization rather than to an optimization of the codon usage specifically in the capsid coding region. These results exclude translation selection and instead suggest fine-tuning translation kinetics selection as the underlying mechanism of the codon usage bias in this specific genome region. Additionally, the results provide clear evidence of the Red Queen dynamics of evolution since the virus has very much evolved to re-adapt its codon usage to the environmental cellular changing conditions in order to recover the original fitness.

  14. Fine Tuning of MOF-505 Analogues To Reduce Low-Pressure Methane Uptake and Enhance Methane Working Capacity.

    Science.gov (United States)

    Zhang, Mingxing; Zhou, Wei; Pham, Tony; Forrest, Katherine A; Liu, Wenlong; He, Yabing; Wu, Hui; Yildirim, Taner; Chen, Banglin; Space, Brian; Pan, Yi; Zaworotko, Michael J; Bai, Junfeng

    2017-09-11

    We present a crystal engineering strategy to fine tune the pore chemistry and CH4 -storage performance of a family of isomorphic MOFs based upon PCN-14. These MOFs exhibit similar pore size, pore surface, and surface area (around 3000 m(2)  g(-1) ) and were prepared with the goal to enhance CH4 working capacity. [Cu2 (L2)(H2 O)2 ]n (NJU-Bai 41: NJU-Bai for Nanjing University Bai's group), [Cu2 (L3)(H2 O)2 ]n (NJU-Bai 42), and [Cu2 (L4)(DMF)2 ]n (NJU-Bai 43) were prepared and we observed that the CH4 volumetric working capacity and volumetric uptake values are influenced by subtle changes in structure and chemistry. In particular, the CH4 working capacity of NJU-Bai 43 reaches 198 cm(3) (STP: 273.15 K, 1 atm) cm(-3) at 298 K and 65 bar, which is amongst the highest reported for MOFs under these conditions and is much higher than the corresponding value for PCN-14 (157 cm(3) (STP) cm(-3) ). © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Human Cardiac-Derived Stem/Progenitor Cells Fine-Tune Monocyte-Derived Descendants Activities toward Cardiac Repair

    Directory of Open Access Journals (Sweden)

    Noémie Dam

    2017-10-01

    Full Text Available Cardiac repair following MI relies on a finely regulated immune response involving sequential recruitment of monocytes to the injured tissue. Monocyte-derived cells are also critical for tissue homeostasis and healing process. Our previous findings demonstrated the interaction of T and natural killer cells with allogeneic human cardiac-derived stem/progenitor cells (hCPC and suggested their beneficial effect in the context of cardiac repair. Therefore, we investigated here whether monocytes and their descendants could be also modulated by allogeneic hCPC toward a repair/anti-inflammatory phenotype. Through experimental in vitro assays, we assessed the impact of allogeneic hCPC on the recruitment, functions and differentiation of monocytes. We found that allogeneic hCPC at steady state or under inflammatory conditions can incite CCL-2/CCR2-dependent recruitment of circulating CD14+CD16− monocytes and fine-tune their activation toward an anti-inflammatory profile. Allogeneic hCPC also promoted CD14+CD16− monocyte polarization into anti-inflammatory/immune-regulatory macrophages with high phagocytic capacity and IL10 secretion. Moreover, hCPC bended the differentiation of CD14+CD16− monocytes to dendritic cells (DCs toward anti-inflammatory macrophage-like features and impaired their antigen-presenting function in favor of immune-modulation. Collectively, our results demonstrate that allogeneic hCPC could reshape monocytes, macrophages as well as DCs responses by favoring their anti-inflammatory/tolerogenic activation/polarization. Thereby, therapeutic allogeneic hCPC might also contribute to post-infarct myocardial healing by modeling the activities of monocytes and their derived descendants.

  16. Tomato yield heterosis is triggered by a dosage sensitivity of the florigen pathway that fine-tunes shoot architecture.

    Directory of Open Access Journals (Sweden)

    Ke Jiang

    Full Text Available The superiority of hybrids has long been exploited in agriculture, and although many models explaining "heterosis" have been put forth, direct empirical support is limited. Particularly elusive have been cases of heterozygosity for single gene mutations causing heterosis under a genetic model known as overdominance. In tomato (Solanum lycopersicum, plants carrying mutations in SINGLE FLOWER TRUSS (SFT encoding the flowering hormone florigen are severely delayed in flowering, become extremely large, and produce few flowers and fruits, but when heterozygous, yields are dramatically increased. Curiously, this overdominance is evident only in the background of "determinate" plants, in which the continuous production of side shoots and inflorescences gradually halts due to a defect in the flowering repressor SELF PRUNING (SP. How sp facilitates sft overdominance is unclear, but is thought to relate to the opposing functions these genes have on flowering time and shoot architecture. We show that sft mutant heterozygosity (sft/+ causes weak semi-dominant delays in flowering of both primary and side shoots. Using transcriptome sequencing of shoot meristems, we demonstrate that this delay begins before seedling meristems become reproductive, followed by delays in subsequent side shoot meristems that, in turn, postpone the arrest of shoot and inflorescence production. Reducing SFT levels in sp plants by artificial microRNAs recapitulates the dose-dependent modification of shoot and inflorescence production of sft/+ heterozygotes, confirming that fine-tuning levels of functional SFT transcripts provides a foundation for higher yields. Finally, we show that although flowering delays by florigen mutant heterozygosity are conserved in Arabidopsis, increased yield is not, likely because cyclical flowering is absent. We suggest sft heterozygosity triggers a yield improvement by optimizing plant architecture via its dosage response in the florigen pathway

  17. Fine-tuning of Hh signaling by the RNA-binding protein Quaking to control muscle development.

    Science.gov (United States)

    Lobbardi, Riadh; Lambert, Guillaume; Zhao, Jue; Geisler, Robert; Kim, Hyejeong R; Rosa, Frederic M

    2011-05-01

    The development of the different muscles within the somite is a complex process that involves the Hedgehog (Hh) signaling pathway. To specify the proper number of muscle cells and organize them spatially and temporally, the Hh signaling pathway needs to be precisely regulated at different levels, but only a few factors external to the pathway have been described. Here, we report for the first time the role of the STAR family RNA-binding protein Quaking A (QkA) in somite muscle development. We show in zebrafish that the loss of QkA function affects fast muscle fiber maturation as well as Hh-induced muscle derivative specification and/or morphogenesis. Mosaic analysis reveals that fast fiber maturation depends on the activity of QkA in the environment of fast fiber progenitors. We further show that Hh signaling requires QkA activity for muscle development. By an in silico approach, we screened the 3'UTRs of known Hh signaling component mRNAs for the Quaking response element and found the transcription factor Gli2a, a known regulator of muscle fate development. Using destabilized GFP as a reporter, we show that the gli2a mRNA 3'UTR is a functional QkA target. Consistent with this notion, the loss of QkA function rescued slow muscle fibers in yot mutant embryos, which express a dominant-negative Gli2a isoform. Thus, our results reveal a new mechanism to ensure muscle cell fate diversity by fine-tuning of the Hh signaling pathway via RNA-binding proteins.

  18. Dynamically avoiding fine-tuning the cosmological constant: the ''Relaxed Universe''

    Energy Technology Data Exchange (ETDEWEB)

    Bauer, Florian; Solà, Joan [High Energy Physics Group, Dept. ECM, and Institut de Ciències del Cosmos Univ. de Barcelona, Av. Diagonal 647, E-08028 Barcelona, Catalonia (Spain); Štefancić, Hrvoje, E-mail: fbauer@ecm.ub.es, E-mail: sola@ecm.ub.es, E-mail: shrvoje@thphys.irb.hr [Theoretical Physics Division, Rudjer Bošković Institute, PO Box 180, HR-10002 Zagreb (Croatia)

    2010-12-01

    We demonstrate that there exists a large class of F(R,G) action functionals of the scalar curvature and of the Gauß-Bonnet invariant which are able to relax dynamically a large cosmological constant (CC), whatever it be its starting value in the early universe. Hence, it is possible to understand, without fine-tuning, the very small current value Λ{sub 0} ∼ H{sub 0}{sup 2} of the CC as compared to its theoretically expected large value in quantum field theory and string theory. In our framework, this relaxation appears as a pure gravitational effect, where no ad hoc scalar fields are needed. The action involves a positive power of a characteristic mass parameter, M, whose value can be, interestingly enough, of the order of a typical particle physics mass of the Standard Model of the strong and electroweak interactions or extensions thereof, including the neutrino mass. The model universe emerging from this scenario (the ''Relaxed Universe'') falls within the class of the so-called ΛXCDM models of the cosmic evolution. Therefore, there is a ''cosmon'' entity X (represented by an effective object, not a field), which in this case is generated by the effective functional F(R,G) and is responsible for the dynamical adjustment of the cosmological constant. This model universe successfully mimics the essential past epochs of the standard (or ''concordance'') cosmological model (ΛCDM). Furthermore, it provides interesting clues to the coincidence problem and it may even connect naturally with primordial inflation.

  19. Fine-tune optical absorption and light emitting behavior of the CdS/PVA hybridized film nanocomposite

    Science.gov (United States)

    Heiba, Z. K.; Mohamed, Mohamed Bakr; Imam, N. G.

    2017-05-01

    CdS nanoparticles (NPs) nucleated at different temperatures were composited with PVA to control and fine-tune optical absorption and emission of the nano-hybrid composite by varying the sizes of the CdS NPs which in turn depends on the nucleation temperature. The implanting of CdS NPs into PVA matrix was confirmed by XRD hand in hand with absorption and photoluminescence spectroscopic techniques. UV/VIS absorption spectra confirm the formation of hybridized film CdS/PVA nanocomposite with refractive index in the range of 2-4. UV/VIS measurements were also used in calculating different optical and dielectric parameters such as refractive index, extinction coefficient, dielectric constants, and optical conductivity. The optical parameters varied with the incorporation of CdS NPs within PVA matrix; accordingly, the optical constants of the nanocomposite films could be controlled by size of CdS content. Tauc's relation was used to determine the optical band gap and to determine the type of electronic transition. It is found that the direct allowed transition is more probable in CdS/PVA nanocomposite film of direct band gap around 3.8 eV. Blue and green light emissions from CdS/PVA nanocomposite film have been observed. Further, the PL studies indicated the emission peak observed at UV band represents band to band transition, while the blue and green emissions could be assigned to the optical transition of the first excitonic state of the CdS NPs and emission from interstitial sulfur respectively. The blue shift in the PL spectra was parallel to the shift observed in UV/VIS spectra. Because of its excellent fluorescence and highly transparent performance, the composite film of CdS nucleated at 200 °C was found to be suitable for bio-related applications such as bio-labeling, bio-imaging, drug delivery, and LEDs as well as a window layer in solar cell.

  20. A Transcriptional Regulatory Mechanism Finely Tunes the Firing of Type VI Secretion System in Response to Bacterial Enemies

    Science.gov (United States)

    Lazzaro, Martina; Feldman, Mario F.

    2017-01-01

    ABSTRACT The ability to detect and measure danger from an environmental signal is paramount for bacteria to respond accordingly, deploying strategies that halt or counteract potential cellular injury and maximize survival chances. Type VI secretion systems (T6SSs) are complex bacterial contractile nanomachines able to target toxic effectors into neighboring bacteria competing for the same colonization niche. Previous studies support the concept that either T6SSs are constitutively active or they fire effectors in response to various stimuli, such as high bacterial density, cell-cell contact, nutrient depletion, or components from dead sibling cells. For Serratia marcescens, it has been proposed that its T6SS is stochastically expressed, with no distinction between harmless or aggressive competitors. In contrast, we demonstrate that the Rcs regulatory system is responsible for finely tuning Serratia T6SS expression levels, behaving as a transcriptional rheostat. When confronted with harmless bacteria, basal T6SS expression levels suffice for Serratia to eliminate the competitor. A moderate T6SS upregulation is triggered when, according to the aggressor-prey ratio, an unbalanced interplay between homologous and heterologous effectors and immunity proteins takes place. Higher T6SS expression levels are achieved when Serratia is challenged by a contender like Acinetobacter, which indiscriminately fires heterologous effectors able to exert lethal cellular harm, threatening the survival of the Serratia population. We also demonstrate that Serratia’s RcsB-dependent T6SS regulatory mechanism responds not to general stress signals but to the action of specific effectors from competitors, displaying an exquisite strategy to weigh risks and keep the balance between energy expenditure and fitness costs. PMID:28830939

  1. Escaping the large fine-tuning and little hierarchy problems in the next to minimal supersymmetric model and h --> aa decays.

    Science.gov (United States)

    Dermísek, Radovan; Gunion, John F

    2005-07-22

    We demonstrate that the next to minimal supersymmetric model can have small fine-tuning and modest top-squark mass while still evading all experimental constraints. For small tan(beta (large tan(beta), the relevant scenarios are such that there is always (often) a standard-model-like Higgs boson that decays to two lighter--possibly much lighter--Higgs pseudoscalars.

  2. Distinct roles of a tyrosine-associated hydrogen-bond network in fine-tuning the structure and function of heme proteins: two cases designed for myoglobin.

    Science.gov (United States)

    Liao, Fei; Yuan, Hong; Du, Ke-Jie; You, Yong; Gao, Shu-Qin; Wen, Ge-Bo; Lin, Ying-Wu; Tan, Xiangshi

    2016-10-20

    A hydrogen-bond (H-bond) network, specifically a Tyr-associated H-bond network, plays key roles in regulating the structure and function of proteins, as exemplified by abundant heme proteins in nature. To explore an approach for fine-tuning the structure and function of artificial heme proteins, we herein used myoglobin (Mb) as a model protein and introduced a Tyr residue in the secondary sphere of the heme active site at two different positions (107 and 138). We performed X-ray crystallography, UV-Vis spectroscopy, stopped-flow kinetics, and electron paramagnetic resonance (EPR) studies for the two single mutants, I107Y Mb and F138Y Mb, and compared to that of wild-type Mb under the same conditions. The results showed that both Tyr107 and Tyr138 form a distinct H-bond network involving water molecules and neighboring residues, which fine-tunes ligand binding to the heme iron and enhances the protein stability, respectively. Moreover, the Tyr107-associated H-bond network was shown to fine-tune both H2O2 binding and activation. With two cases demonstrated for Mb, this study suggests that the Tyr-associated H-bond network has distinct roles in regulating the protein structure, properties and functions, depending on its location in the protein scaffold. Therefore, it is possible to design a Tyr-associated H-bond network in general to create other artificial heme proteins with improved properties and functions.

  3. Metal–organic frameworks to satisfy gas upgrading demands: fine-tuning the soc-MOF platform for the operative removal of H2S

    KAUST Repository

    Belmabkhout, Youssef

    2017-01-06

    A cooperative experimental/modeling strategy was used to unveil the structure/gas separation performance relationship for a series of isostructural metal-organic frameworks (MOFs) with soc-topology (square-octahedral) hosting different extra-framework counter ions (NO3-, Cl- and Br-). In3+-, Fe3+-, Ga3+-and the newly isolated Al(III)-based isostructural soc-MOF were extensively studied and evaluated for the separation-based production of high-quality fuels (i.e., CH4, C3H8 and n-C4H10) and olefins. The structural/chemical fine-tuning of the soc-MOF platform promoted equilibrium-based selectivity toward C2+ (C2H6, C2H4, C3H6 C3H8 and n-C4H10) and conferred the desired chemical stability toward H2S. The noted dual chemical stability and gas/vapor selectivity, which have rarely been reported for equilibrium-based separation agents, are essential for the production of high-purity H-2, CH4 and C2+ fractions in high yields. Interestingly, the evaluated soc-MOF analogues exhibited high selectivity for C2H4, C3H6 and n-C4H10. In particular, the Fe, Ga and Al analogues presented relatively enhanced C2+/CH4 adsorption selectivities. Notably, the Ga and Al analogues were found to be technically preferable because their structural integrities and separation performances were maintained upon exposure to H2S, indicating that these materials are highly tolerant to H2S. Therefore, the Ga-soc-MOF was further examined for the selective adsorption of H2S in the presence of CO2-and CH4-containing streams, such as refinery-off gases (ROG) and natural gas (NG). Grand canonical Monte Carlo (GCMC) simulations based on a specific force field describing the interactions between the guest molecules and the Ga sites supported and confirmed the considerably higher affinity of the Ga-soc-MOF for C2+ (as exemplified by n-C4H10) than for CH4. The careful selection of an appropriate metal for the trinuclear inorganic molecular building block (MBB), i. e., a Ga metal center, imbues the soc

  4. Survey of Current Practice in the Fitting and Fine-Tuning of Common Signal-Processing Features in Hearing Aids for Adults.

    Science.gov (United States)

    Anderson, Melinda C; Arehart, Kathryn H; Souza, Pamela E

    2018-02-01

    Current guidelines for adult hearing aid fittings recommend the use of a prescriptive fitting rationale with real-ear verification that considers the audiogram for the determination of frequency-specific gain and ratios for wide dynamic range compression. However, the guidelines lack recommendations for how other common signal-processing features (e.g., noise reduction, frequency lowering, directional microphones) should be considered during the provision of hearing aid fittings and fine-tunings for adult patients. The purpose of this survey was to identify how audiologists make clinical decisions regarding common signal-processing features for hearing aid provision in adults. An online survey was sent to audiologists across the United States. The 22 survey questions addressed four primary topics including demographics of the responding audiologists, factors affecting selection of hearing aid devices, the approaches used in the fitting of signal-processing features, and the strategies used in the fine-tuning of these features. A total of 251 audiologists who provide hearing aid fittings to adults completed the electronically distributed survey. The respondents worked in a variety of settings including private practice, physician offices, university clinics, and hospitals/medical centers. Data analysis was based on a qualitative analysis of the question responses. The survey results for each of the four topic areas (demographics, device selection, hearing aid fitting, and hearing aid fine-tuning) are summarized descriptively. Survey responses indicate that audiologists vary in the procedures they use in fitting and fine-tuning based on the specific feature, such that the approaches used for the fitting of frequency-specific gain differ from other types of features (i.e., compression time constants, frequency lowering parameters, noise reduction strength, directional microphones, feedback management). Audiologists commonly rely on prescriptive fitting formulas and

  5. Improving putrescine production by Corynebacterium glutamicum by fine-tuning ornithine transcarbamoylase activity using a plasmid addiction system.

    Science.gov (United States)

    Schneider, Jens; Eberhardt, Dorit; Wendisch, Volker F

    2012-07-01

    Corynebacterium glutamicum shows a great potential for the production of the polyamide monomer putrescine (1,4-diaminobutane). Previously, we constructed the putrescine-producing strain PUT1 by deletion of argF, the gene for ornithine transcarbamoylase (OTC), and argR, encoding the L-arginine repressor, combined with heterologous expression of the Escherichia coli gene for L-ornithine decarboxylase SpeC. As a consequence of argF deletion, this strain requires supplementation of L-arginine and shows growth-decoupled putrescine production. To avoid costly supplementation with L-arginine and the strong feedback inhibition of the key enzyme N-acetylglutamate kinase (ArgB) by L-arginine, a plasmid addiction system for low-level argF expression was developed. By fine-tuning argF expression through modifications of the promoter, the translational start codon and/or the ribosome binding site, high productivity and titer could be obtained. OTC activity varied almost thousandfold between 960 and 1 mU mg⁻¹ resulting in putrescine yields on glucose from less than 0.001 up to 0.26 g g⁻¹, the highest yield in bacteria reported to date. The most promising strain, designated PUT21, was characterized comprehensively. PUT21 strain grew with a rate of 0.19 h⁻¹ in mineral salt medium without the need for L-arginine supplementation and produced putrescine with a yield of 0.16 g g⁻¹ glucose at a volumetric productivity of 0.57 g L⁻¹ h⁻¹ and a specific productivity of 0.042 g g⁻¹ h⁻¹. The carbon balance suggested that no major unidentified by-product was produced. Compared to the first-generation strain PUT1, the putrescine yield observed with PUT21 was increased by 60%. In fed-batch cultivation with C. glutamicum PUT21, a putrescine titer of 19 g L⁻¹ at a volumetric productivity of 0.55 g L⁻¹ h⁻¹ and a yield of 0.16 g g⁻¹ glucose could be achieved. Moreover, while plasmid segregation of the initial strain required antibiotic selection

  6. Thioredoxins in evolutionarily primitive organisms

    Science.gov (United States)

    Buchanan, B. B.

    1986-01-01

    Thioredoxins are low molecular weight redox proteins, alternating between the S-S (oxidized) and SH (reduced) states, that function in a number of biochemical processes, including DNA synthesis, DNA replication, and enzyme regulation. Until recently, reduced ferredoxin was known to serve as the source of reducing power for the reduction of thioredoxins only in oxygenic photosynthetic cells. In all other organisms, the source of hydrogen (electrons) for thioredoxin reduction was considered to be NADPH. It was found that Clostridium pasteurianum, an anaerobic organism normally living in the soil unexposed to light, resembles photosynthetic cells in using ferredoxin for the reduction of thioredoxin. The results reveal the existence of a pathway in which ferredoxin, provides the reducing power for the reduction of thioredoxin via the flavoprotein enzyme, ferredoxinthioredoxin reductase. In related studies, it was found that Chromatium vinosum, an anaerobic photosynthetic purple sulfur bacterium, resembles evolutionarily more advanced micro-organisms in having an NADP-thioredoxin system composed of a single thioredoxin which is reduced by NADPH via NADP-thioredoxin reductase. The adoption of the NADP-thioredoxin system by Chromatium seems appropriate in view of evidence tha the organi sm utilizes ATP-driven reverse electron transport. Finally, results of research directed towards the identification of target enzymes of the ferredoxin/thioredoxin system in a cyanobacterium (Nostoc muscorum), show that thioredoxin-linked photosynthetic enzymes of cyanobateria are similar to those of chloroplasts. It now seems that the ferredoxin/thioredoxin system functions in regulating CO2 assimilation via the reductive pentose phosphate cycle in oxygenic but not anoxygenic photosynthetic cells.

  7. Effects of providing and withholding postfitting fine-tuning adjustments on outcome measures in novice hearing aid users: a pilot study.

    Science.gov (United States)

    Cunningham, D R; Williams, K J; Goldsmith, L J

    2001-06-01

    This pilot study was designed to examine the effects of either providing or withholding subject-driven, postfitting electroacoustic changes (fine tuning) on hearing aid performance as measured by tests of speech recognition in noise, sound quality, and benefit. A group of adult first-time hearing aid users with moderate, high-frequency sensorineural hearing loss was studied over a 5-month postfitting period. Half of the group served as a control group; half constituted the treatment group. Treatment consisted of making as many postfitting electroacoustic manipulations as the participants' complaints/observations required. These adjustments were withheld from the control group individuals. Group performance differences were assessed using the COSI, two versions of the APHAB, a Satisfaction scale, a Sound Quality tool, and the SIN test. Analysis revealed no statistically significant differences in the control and treatment groups' performances or perceived benefit at any of the five postfitting test sessions. These data suggested that there was no measurable advantage to be derived from making postfitting frequency-gain adjustments of 10 dB or less to hearing aids with wide dynamic range compression fitted in the manner described in this article. Definitive studies of the effects of postfitting electroacoustic fine tuning must be undertaken.

  8. An Evolutionarily Informed Education Science

    Science.gov (United States)

    Geary, David C.

    2008-01-01

    Schools are a central interface between evolution and culture. They are the contexts in which children learn the evolutionarily novel abilities and knowledge needed to function as adults in modern societies. Evolutionary educational psychology is the study of how an evolved bias in children's learning and motivational systems influences their…

  9. Fine-Tuning of Polymeric Resins and their Interfaces with Amorphous Calcium Phosphate. A Strategy for Designing Effective Remineralizing Dental Composites

    Directory of Open Access Journals (Sweden)

    Drago Skrtic

    2010-09-01

    Full Text Available For over a decade our group has been designing, preparing and evaluating bioactive, remineralizing composites based on amorphous calcium phosphate (ACP fillers embedded in polymerized methacrylate resin matrices. In these studies a major focus has been on exploring structure-property relationships of the matrix phase of these composites on their anti-cariogenic potential. The main challenges were to gain a better understanding of polymer matrix/filler interfacial properties through controlling the surface properties of the fillers or through fine-tuning of the resin matrix. In this work, we describe the effect of chemical structure and composition of the resin matrices on some of the critical physicochemical properties of the copolymers and their ACP composites. Such structure-property studies are essential in formulating clinically effective products, and this knowledge base is likely to have strong impact on the future design of therapeutic materials, appropriate for mineral restoration in defective tooth structures.

  10. Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons

    Directory of Open Access Journals (Sweden)

    Marilyn Scandaglia

    2017-10-01

    Full Text Available During development, chromatin-modifying enzymes regulate both the timely establishment of cell-type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme, the intellectual-disability-linked lysine demethylase 5C (Kdm5c, in the developing and adult brain, we conducted parallel behavioral, transcriptomic, and epigenomic studies in Kdm5c-null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation. Although the importance of these functions declines after birth, Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons.

  11. SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in Streptococcus pyogenes.

    Science.gov (United States)

    Port, Gary C; Cusumano, Zachary T; Tumminello, Paul R; Caparon, Michael G

    2017-03-28

    SpxA is a unique transcriptional regulator highly conserved among members of the phylum Firmicutes that binds RNA polymerase and can act as an antiactivator. Why some Firmicutes members have two highly similar SpxA paralogs is not understood. Here, we show that the SpxA paralogs of the pathogen Streptococcus pyogenes, SpxA1 and SpxA2, act coordinately to regulate virulence by fine-tuning toxin expression and stress resistance. Construction and analysis of mutants revealed that SpxA1(-) mutants were defective for growth under aerobic conditions, while SpxA2(-) mutants had severely attenuated responses to multiple stresses, including thermal and oxidative stresses. SpxA1(-) mutants had enhanced resistance to the cationic antimicrobial molecule polymyxin B, while SpxA2(-) mutants were more sensitive. In a murine model of soft tissue infection, a SpxA1(-) mutant was highly attenuated. In contrast, the highly stress-sensitive SpxA2(-) mutant was hypervirulent, exhibiting more extensive tissue damage and a greater bacterial burden than the wild-type strain. SpxA1(-) attenuation was associated with reduced expression of several toxins, including the SpeB cysteine protease. In contrast, SpxA2(-) hypervirulence correlated with toxin overexpression and could be suppressed to wild-type levels by deletion of speB These data show that SpxA1 and SpxA2 have opposing roles in virulence and stress resistance, suggesting that they act coordinately to fine-tune toxin expression in response to stress. SpxA2(-) hypervirulence also shows that stress resistance is not always essential for S. pyogenes pathogenesis in soft tissue.IMPORTANCE For many pathogens, it is generally assumed that stress resistance is essential for pathogenesis. For Streptococcus pyogenes, environmental stress is also used as a signal to alter toxin expression. The amount of stress likely informs the bacterium of the strength of the host's defense response, allowing it to adjust its toxin expression to produce the

  12. Enhancement of magnetic domain topologies in Co/Pt thin films by fine tuning the magnetic field path throughout the hysteresis loop

    Energy Technology Data Exchange (ETDEWEB)

    Westover, Andrew S. [Physics Department, Brigham Young University, Provo, UT 84602 (United States); Chesnel, Karine, E-mail: kchesnel@byu.edu [Physics Department, Brigham Young University, Provo, UT 84602 (United States); Hatch, Kelsey; Salter, Philip [Physics Department, Brigham Young University, Provo, UT 84602 (United States); Hellwig, Olav [HGST a Western Digital Company, San Jose, CA 95135 (United States)

    2016-02-01

    We have studied the influence of magnetic history on the topology of perpendicular magnetic domains in a thin ferromagnetic film made of [Co(8 Å)/Pt(7 Å)]{sub 50} multilayers. More specifically, we have followed the morphological changes in the domain pattern when applying a magnetic field perpendicular to the layer, throughout minor and major magnetization loops, and in the resulting remanent state. We carried out this study by using MFM microscopy with an in-situ magnetic field. We find that the morphology of the magnetic domain pattern is greatly influenced by the magnetic history of the material and that some features, such as the degree of bubbliness (i.e., the extent of bubble domain formation) and density of isolated domains can be enhanced by fine tuning the magnetic field path within the major hysteresis loop towards different remanent states. In particular, we see how hysteresis is correlated to irreversible changes in the domain morphology. More interestingly, we find that the magnetic domain morphology at remanence can be changed from an interconnected labyrinthine stripe state to a state of many separated bubble domains by fine tuning the magnitude of the field previously applied to the material. These results agree well with other findings, such as the magnetic reversal behavior and magnetic memory effects in Co/Pt multilayers, and provide opportunities for potential technological applications. - Highlights: • Morphology of magnetic domains in Co/Pt thin films changes with magnetic history. • Domain morphology evolves from a maze to a bubble pattern when field approaches H{sub p}. • Domain morphology at remanence depends on magnitude H{sub m} of previously applied field. • A topological maze-to-bubble phase transition occurs at remanence when H{sub m} is near H{sup ⁎}. • Density of oppositely aligned domains peaks up when H{sub m} is near H{sup ⁎}.

  13. Fine tuning of the catalytic activity of colicin e7 nuclease domain by systematic n-terminal mutations

    DEFF Research Database (Denmark)

    Németh, Eszter; Körtvélyesi, Tamás; Thulstrup, Peter W.

    2014-01-01

    -binding affinity were unaffected by the mutations as revealed by linear and circular dichroism spectroscopy, isothermal calorimetric titrations, and gel mobility shift experiments. Semiempirical quantum chemical calculations and molecular dynamics simulations revealed that K446, K449, and/or the N-terminal amino...

  14. The microRNA-132/212 family fine-tunes multiple targets in Angiotensin II signalling in cardiac fibroblasts

    DEFF Research Database (Denmark)

    Eskildsen, Tilde V; Schneider, Mikael; Sandberg, Maria B

    2015-01-01

    INTRODUCTION: MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular......, signalling molecules and transcription factors. Subsequent comprehensive in silico analysis identified 24 target genes, of which 22 genes were qPCR validated. We identified seven genes involved in AngII signalling pathways. CONCLUSION: We here report novel insight of an extensive network of molecular...

  15. Fine Tuning of Tissues' Viscosity and Surface Tension through Contractility Suggests a New Role for α-Catenin

    Science.gov (United States)

    Stirbat, Tomita Vasilica; Mgharbel, Abbas; Bodennec, Selena; Ferri, Karine; Mertani, Hichem C.; Rieu, Jean-Paul; Delanoë-Ayari, Hélène

    2013-01-01

    What governs tissue organization and movement? If molecular and genetic approaches are able to give some answers on these issues, more and more works are now giving a real importance to mechanics as a key component eventually triggering further signaling events. We chose embryonic cell aggregates as model systems for tissue organization and movement in order to investigate the origin of some mechanical constraints arising from cells organization. Steinberg et al. proposed a long time ago an analogy between liquids and tissues and showed that indeed tissues possess a measurable tissue surface tension and viscosity. We question here the molecular origin of these parameters and give a quantitative measurement of adhesion versus contractility in the framework of the differential interfacial tension hypothesis. Accompanying surface tension measurements by angle measurements (at vertexes of cell-cell contacts) at the cell/medium interface, we are able to extract the full parameters of this model: cortical tensions and adhesion energy. We show that a tunable surface tension and viscosity can be achieved easily through the control of cell-cell contractility compared to cell-medium one. Moreover we show that -catenin is crucial for this regulation to occur: these molecules appear as a catalyser for the remodeling of the actin cytoskeleton underneath cell-cell contact, enabling a differential contractility between the cell-medium and cell-cell interface to take place. PMID:23390488

  16. Time-resolved in silico modeling of fine-tuned cAMP signaling in platelets: feedback loops, titrated phosphorylations and pharmacological modulation

    Directory of Open Access Journals (Sweden)

    Dandekar Thomas

    2011-10-01

    Full Text Available Abstract Background Hemostasis is a critical and active function of the blood mediated by platelets. Therefore, the prevention of pathological platelet aggregation is of great importance as well as of pharmaceutical and medical interest. Endogenous platelet inhibition is predominantly based on cyclic nucleotides (cAMP, cGMP elevation and subsequent cyclic nucleotide-dependent protein kinase (PKA, PKG activation. In turn, platelet phosphodiesterases (PDEs and protein phosphatases counterbalance their activity. This main inhibitory pathway in human platelets is crucial for countervailing unwanted platelet activation. Consequently, the regulators of cyclic nucleotide signaling are of particular interest to pharmacology and therapeutics of atherothrombosis. Modeling of pharmacodynamics allows understanding this intricate signaling and supports the precise description of these pivotal targets for pharmacological modulation. Results We modeled dynamically concentration-dependent responses of pathway effectors (inhibitors, activators, drug combinations to cyclic nucleotide signaling as well as to downstream signaling events and verified resulting model predictions by experimental data. Experiments with various cAMP affecting compounds including anti-platelet drugs and their combinations revealed a high fidelity, fine-tuned cAMP signaling in platelets without cross-talk to the cGMP pathway. The model and the data provide evidence for two independent feedback loops: PKA, which is activated by elevated cAMP levels in the platelet, subsequently inhibits adenylyl cyclase (AC but as well activates PDE3. By multi-experiment fitting, we established a comprehensive dynamic model with one predictive, optimized and validated set of parameters. Different pharmacological conditions (inhibition, activation, drug combinations, permanent and transient perturbations are successfully tested and simulated, including statistical validation and sensitivity analysis

  17. Making oxidation potentials predictable: Coordination of additives applied to the electronic fine tuning of an iron(II) complex

    KAUST Repository

    Haslinger, Stefan

    2014-11-03

    This work examines the impact of axially coordinating additives on the electronic structure of a bioinspired octahedral low-spin iron(II) N-heterocyclic carbene (Fe-NHC) complex. Bearing two labile trans-acetonitrile ligands, the Fe-NHC complex, which is also an excellent oxidation catalyst, is prone to axial ligand exchange. Phosphine- and pyridine-based additives are used for substitution of the acetonitrile ligands. On the basis of the resulting defined complexes, predictability of the oxidation potentials is demonstrated, based on a correlation between cyclic voltammetry experiments and density functional theory calculated molecular orbital energies. Fundamental insights into changes of the electronic properties upon axial ligand exchange and the impact on related attributes will finally lead to target-oriented manipulation of the electronic properties and consequently to the effective tuning of the reactivity of bioinspired systems.

  18. The microRNA-132/212 family fine-tunes multiple targets in Angiotensin II signalling in cardiac fibroblasts

    DEFF Research Database (Denmark)

    Eskildsen, Tilde V; Schneider, Mikael; Sandberg, Maria B

    2015-01-01

    function including regulation of cardiac hypertrophy, heart failure and blood pressure possibly through AT1R signalling. However, the miR-132/212 targets in the heart remain unknown. MATERIALS AND METHODS: To understand the role of these miRNAs in cardiac signalling networks, we undertook comprehensive......INTRODUCTION: MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular...... in silico and in vitro experiments to identify miR-132/212 molecular targets in primary rat cardiac fibroblasts. RESULTS: MiR-132/212 overexpression increased fibroblast cell size and mRNA arrays detected several hundred genes that were differentially expressed, including a wide panel of receptors...

  19. CX3CL1, a chemokine finely tuned to adhesion: critical roles of the stalk glycosylation and the membrane domain

    Directory of Open Access Journals (Sweden)

    Mariano A. Ostuni

    2014-11-01

    Full Text Available The multi-domain CX3CL1 transmembrane chemokine triggers leukocyte adherence without rolling and migration by presenting its chemokine domain (CD to its receptor CX3CR1. Through the combination of functional adhesion assays with structural analysis using FRAP, we investigated the functional role of the other domains of CX3CL1, i.e., its mucin stalk, transmembrane domain, and cytosolic domain. Our results indicate that the CX3CL1 molecular structure is finely adapted to capture CX3CR1 in circulating cells and that each domain has a specific purpose: the mucin stalk is stiffened by its high glycosylation to present the CD away from the membrane, the transmembrane domain generates the permanent aggregation of an adequate amount of monomers to guarantee adhesion and prevent rolling, and the cytosolic domain ensures adhesive robustness by interacting with the cytoskeleton. We propose a model in which quasi-immobile CX3CL1 bundles are organized to quickly generate adhesive patches with sufficiently high strength to capture CX3CR1+ leukocytes but with sufficiently low strength to allow their patrolling behavior.

  20. Calreticulin is a fine tuning molecule in epibrassinolide-induced apoptosis through activating endoplasmic reticulum stress in colon cancer cells.

    Science.gov (United States)

    Obakan-Yerlikaya, Pinar; Arisan, Elif Damla; Coker-Gurkan, Ajda; Adacan, Kaan; Ozbey, Utku; Somuncu, Berna; Baran, Didem; Palavan-Unsal, Narcin

    2017-06-01

    Epibrassinolide (EBR), a member of brassinostreoids plant hormones with cell proliferation promoting role in plants, is a natural polyhydroxysteroid with structural similarity to steroid hormones of vertebrates. EBR has antiproliferative and apoptosis-inducing effect in various cancer cells. Although EBR has been shown to affect survival and mitochondria-mediated apoptosis pathways in a p53-independent manner, the exact molecular targets of EBR are still under investigation. Our recent SILAC (Stable Isotope Labeling by Amino Acids in Cell Culture) data showed that the most significantly altered protein after EBR treatment was calreticulin (CALR). CALR, a chaperone localized in endoplasmic reticulum (ER) lumen, plays role in protein folding and buffering Ca2+ ions. The alteration of CALR may cause ER stress and unfolded protein response correspondingly the induction of apoptosis. Unfolded proteins are conducted to 26S proteasomal degradation following ubiquitination. Our study revealed that EBR treatment caused ER stress and UPR by altering CALR expression causing caspase-dependent apoptosis in HCT 116, HT29, DLD-1, and SW480 colon cancer cells. Furthermore, 48 h EBR treatment did not caused UPR in Fetal Human Colon cells (FHC) and Mouse Embryonic Fibroblast cells (MEF). In addition our findings showed that HCT 116 colon cancer cells lacking Bax and Puma expression still undergo UPR and related apoptosis. CALR silencing and rapamycin co-treatment prevented EBR-induced UPR and apoptosis, whereas 26S proteasome inhibition further increased the effect of EBR in colon cancer cells. All these findings showed that EBR is an ER stress and apoptotic inducer in colon cancer cells without affecting non-malignant cells. © 2017 Wiley Periodicals, Inc.

  1. Plasma Membrane CRPK1-Mediated Phosphorylation of 14-3-3 Proteins Induces Their Nuclear Import to Fine-Tune CBF Signaling during Cold Response.

    Science.gov (United States)

    Liu, Ziyan; Jia, Yuxin; Ding, Yanglin; Shi, Yiting; Li, Zhen; Guo, Yan; Gong, Zhizhong; Yang, Shuhua

    2017-04-06

    In plant cells, changes in fluidity of the plasma membrane may serve as the primary sensor of cold stress; however, the precise mechanism and how the cell transduces and fine-tunes cold signals remain elusive. Here we show that the cold-activated plasma membrane protein cold-responsive protein kinase 1 (CRPK1) phosphorylates 14-3-3 proteins. The phosphorylated 14-3-3 proteins shuttle from the cytosol to the nucleus, where they interact with and destabilize the key cold-responsive C-repeat-binding factor (CBF) proteins. Consistent with this, the crpk1 and 14-3-3κλ mutants show enhanced freezing tolerance, and transgenic plants overexpressing 14-3-3λ show reduced freezing tolerance. Further study shows that CRPK1 is essential for the nuclear translocation of 14-3-3 proteins and for 14-3-3 function in freezing tolerance. Thus, our study reveals that the CRPK1-14-3-3 module transduces the cold signal from the plasma membrane to the nucleus to modulate CBF stability, which ensures a faithfully adjusted response to cold stress of plants. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Listeria monocytogenes CadC Regulates Cadmium Efflux and Fine-tunes Lipoprotein Localization to Escape the Host Immune Response and Promote Infection.

    Science.gov (United States)

    Pombinho, Rita; Camejo, Ana; Vieira, Ana; Reis, Olga; Carvalho, Filipe; Almeida, Maria Teresa; Pinheiro, Jorge Campos; Sousa, Sandra; Cabanes, Didier

    2017-05-01

    Listeria monocytogenes is a major intracellular human foodborne bacterial pathogen. We previously revealed L. monocytogenes cadC as highly expressed during mouse infection. Here we show that L. monocytogenes CadC is a sequence-specific, DNA-binding and cadmium-dependent regulator of CadA, an efflux pump conferring cadmium resistance. CadC but not CadA is required for L. monocytogenes infection in vivo. Interestingly, CadC also directly represses lspB, a gene encoding a lipoprotein signal peptidase whose expression appears detrimental for infection. lspB overexpression promotes the release of the LpeA lipoprotein to the extracellular medium, inducing tumor necrosis factor α and interleukin 6 expression, thus impairing L. monocytogenes survival in macrophages. We propose that L. monocytogenes uses CadC to repress lspB expression during infection to avoid LpeA exposure to the host immune system, diminishing inflammatory cytokine expression and promoting intramacrophagic survival and virulence. CadC appears as the first metal efflux pump regulator repurposed during infection to fine-tune lipoprotein processing and host responses. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  3. Fine-tuning pore size by shifting coordination sites of ligands and surface polarization of metal-organic frameworks to sharply enhance the selectivity for CO2.

    Science.gov (United States)

    Du, Liting; Lu, Zhiyong; Zheng, Kaiyuan; Wang, Junyi; Zheng, Xin; Pan, Yi; You, Xiaozeng; Bai, Junfeng

    2013-01-16

    Based upon the (3,6)-connected metal-organic framework {Cu(L1)·2H(2)O·1.5DMF}(∞) (L1 = 5-(pyridin-4-yl)isophthalic acid) (SYSU, for Sun Yat-Sen University), iso-reticular {Cu(L2)·DMF}(∞) (L2 = 5-(pyridin-3-yl)isophthalic acid) (NJU-Bai7; NJU-Bai for Nanjing University Bai group) and {Cu(L3)·DMF·H(2)O}(∞) (L3 = 5-(pyrimidin-5-yl)isophthalic acid) (NJU-Bai8) were designed by shifting the coordination sites of ligands to fine-tune pore size and polarizing the inner surface with uncoordinated nitrogen atoms, respectively, with almost no changes in surface area or porosity. Compared with those of the prototype SYSU, both the adsorption enthalpy and selectivity of CO(2) for NJU-Bai7 and NJU-Bai8 have been greatly enhanced, which makes NJU-Bai7 and NJU-Bai8 good candidates for postcombustion CO(2) capture. Notably, the CO(2) adsorption enthalpy of NJU-Bai7 is the highest reported so far among the MOFs without any polarizing functional groups or open metal sites. Meanwhile, NJU-Bai8 exhibits high uptake of CO(2) and good CO(2)/CH(4) selectivity at high pressure, which are quite valuable characteristics in the purification of natural gases.

  4. Full phosphorescent white-light organic light-emitting diodes with improved color stability and efficiency by fine tuning primary emission contributions

    Directory of Open Access Journals (Sweden)

    Wang Hua

    2014-02-01

    Full Text Available In this paper, a novel type of white-light organic light emitting diode (OLED with high color stability was reported, in which the yellow-light emission layer of (4,4′-N,N′-dicarbazolebiphenyl (CBP : tris(2-phenylquinoline-C2,N′iridium(III (Ir(2-phq3 was sandwiched by double blue-light emission layers of 1,1-bis-[(di-4-tolylaminopheny1]cyclohexane (TAPC : bis[4,6-(di-fluorophenyl-pyridinato-N,C2′]picolinate (FIrpic and tris[3-(3-pyridylmesityl]borane (3TPYMB:FIrpic. And, it exhibited the maximum current efficiency of 33.1 cd/A, the turn-on voltage at about 3 V and the maximum luminance in excess of 20000 cd/m2. More important, it realized very stable white-light emission, and its CIE(x, y coordinates only shift from (0.34, 0.37 to (0.33, 0.37 as applied voltage increased from 5 V to 12 V. It is believed that the new scheme in emission layer of white-light OLED can fine tune the contribution of primary emission with applied voltage changed, resulting in high quality white-light OLED.

  5. Full phosphorescent white-light organic light-emitting diodes with improved color stability and efficiency by fine tuning primary emission contributions

    Energy Technology Data Exchange (ETDEWEB)

    Hua, Wang, E-mail: wmsu2008@sinano.ac.cn, E-mail: wanghua001@tyut.edu.cn; Du, Xiaogang [Key Laboratory of Interface Science and Engineering in Advanced Materials, Taiyuan University of Technology, Ministry of Education, Taiyuan 030024 (China); Research Center of Advanced Materials Science and Technology, Taiyuan University of Technology, Taiyuan 030024 (China); Su, Wenming, E-mail: wmsu2008@sinano.ac.cn, E-mail: wanghua001@tyut.edu.cn; Zhang, Dongyu [Printable Electronics Research Centre, Suzhou Institute of Nano-Tech and Nano-Bionics, CAS, suzhou 215123 (China); Lin, Wenjing [Key Laboratory of Interface Science and Engineering in Advanced Materials, Taiyuan University of Technology, Ministry of Education, Taiyuan 030024 (China); Research Center of Advanced Materials Science and Technology, Taiyuan University of Technology, Taiyuan 030024 (China); Printable Electronics Research Centre, Suzhou Institute of Nano-Tech and Nano-Bionics, CAS, suzhou 215123 (China)

    2014-02-15

    In this paper, a novel type of white-light organic light emitting diode (OLED) with high color stability was reported, in which the yellow-light emission layer of (4,4{sup ′}-N,N{sup ′}-dicarbazole)biphenyl (CBP) : tris(2-phenylquinoline-C2,N{sup ′})iridium(III) (Ir(2-phq){sub 3}) was sandwiched by double blue-light emission layers of 1,1-bis-[(di-4-tolylamino)pheny1]cyclohexane (TAPC) : bis[4,6-(di-fluorophenyl)-pyridinato-N,C2{sup ′}]picolinate (FIrpic) and tris[3-(3-pyridyl)mesityl]borane (3TPYMB):FIrpic. And, it exhibited the maximum current efficiency of 33.1 cd/A, the turn-on voltage at about 3 V and the maximum luminance in excess of 20000 cd/m{sup 2}. More important, it realized very stable white-light emission, and its CIE(x, y) coordinates only shift from (0.34, 0.37) to (0.33, 0.37) as applied voltage increased from 5 V to 12 V. It is believed that the new scheme in emission layer of white-light OLED can fine tune the contribution of primary emission with applied voltage changed, resulting in high quality white-light OLED.

  6. An Accurate CT Saturation Classification Using a Deep Learning Approach Based on Unsupervised Feature Extraction and Supervised Fine-Tuning Strategy

    Directory of Open Access Journals (Sweden)

    Muhammad Ali

    2017-11-01

    Full Text Available Current transformer (CT saturation is one of the significant problems for protection engineers. If CT saturation is not tackled properly, it can cause a disastrous effect on the stability of the power system, and may even create a complete blackout. To cope with CT saturation properly, an accurate detection or classification should be preceded. Recently, deep learning (DL methods have brought a subversive revolution in the field of artificial intelligence (AI. This paper presents a new DL classification method based on unsupervised feature extraction and supervised fine-tuning strategy to classify the saturated and unsaturated regions in case of CT saturation. In other words, if protection system is subjected to a CT saturation, proposed method will correctly classify the different levels of saturation with a high accuracy. Traditional AI methods are mostly based on supervised learning and rely heavily on human crafted features. This paper contributes to an unsupervised feature extraction, using autoencoders and deep neural networks (DNNs to extract features automatically without prior knowledge of optimal features. To validate the effectiveness of proposed method, a variety of simulation tests are conducted, and classification results are analyzed using standard classification metrics. Simulation results confirm that proposed method classifies the different levels of CT saturation with a remarkable accuracy and has unique feature extraction capabilities. Lastly, we provided a potential future research direction to conclude this paper.

  7. Fine-Tuned Search for Kilonova Emission in a Short Gamma-Ray Burst: Implications for the Progenitors, Advanced LIGO, and r-Process Nucleosynthesis

    Science.gov (United States)

    Berger, Edo

    2017-08-01

    Short-duration gamma-ray bursts have long been suspected to result from the catastrophic mergers of binaries composed of two neutron stars (NS-NS) and/or a neutron star and a black hole (NS-BH). This possible association is of fundamental importance since these binaries are also strong gravitational wave emitters, and the short GRB connection can therefore guide electromagnetic follow-up of Advanced LIGO gravitational wave sources. An important direct signature of NS-NS/NS-BH progenitors is near-infrared emission powered by radioactive r-process material synthesized by the ejection of neutron-rich matter during the merger, a so-called kilonova. HST observations of the short GRB130603B provided the first tantalizing evidence for such an emission component, but unfortunately lacked detailed spectral and temporal information. Here, we propose fine-tuned TOO observations of a future short GRB that will definitively establish the presence of a kilonova and will also allow us to distinguish an NS-NS from an NS-BH merger, based on the ejecta mass ( 0.01 vs. 0.1 Msun, respectively). The results will not only serve as a smoking gun for compact object merger progenitors, but they will also guide our plans for optical/infrared follow-up of Advanced LIGO sources, and establish whether compact object mergers are the primary site for cosmic r-process nucleosynthesis. To support and interpret the proposed HST observations, and to rule out alternative explanations for any detected emission, we will obtain a wide range of observations spanning radio to X-rays using active programs at Gemini, Magellan, MMT, VLA, Chandra, and XMM.

  8. Necroptosis: Molecular Signalling and Translational Implications

    Directory of Open Access Journals (Sweden)

    Claudia Giampietri

    2014-01-01

    Full Text Available Necroptosis is a form of programmed necrosis whose molecular players are partially shared with apoptotic cell death. Here we summarize what is known about molecular signalling of necroptosis, particularly focusing on fine tuning of FLIP and IAP proteins in the apoptosis/necroptosis balance. We also emphasize necroptosis involvement in physiological and pathological conditions, particularly in the regulation of immune homeostasis.

  9. Pendant chain engineering to fine-tune the nanomorphologies and solid state luminescence of naphthalimide AIEEgens: application to phenolic nitro-explosive detection in water.

    Science.gov (United States)

    Meher, Niranjan; Iyer, Parameswar Krishnan

    2017-06-08

    Strategically, a series of five angular "V" shaped naphthalimide AIEEgens with varying pendant chains (butyl, hexyl, octyl, cyclohexyl and methylcyclohexyl) have been synthesized to fine-tune their nanomorphological and photophysical properties. With similar aromatic cores and electronic states, unexpected tuning of the condensed state emission colors and nanomorphologies (reproducible on any kind of surface) of naphthalimides has been achieved for the first time simply by varying their side chains. Conclusive analysis by various spectroscopic techniques (SC-XRD, powder-XRD, DLS, FESEM) and DFT computational studies confirmed the full control of the pendant chain (in terms of bulkiness around the naphthalimide core, which restricts the ease of intermolecular π-π interactions) over the nanoaggregate morphology and solid state emissive properties of the AIEEgens; this can be rationalized to all aggregation-prone systems. These comprehensive studies establish a conceptually unique yet simple and effective method to precisely tune the nanomorphologies and the emission colors of aggregation-prone small organic molecules by judicious choice of the non-conjugated pendant chain. Thus, considering the prime role of the active layer nanomorphology in all organic optoelectronic devices, this methodology may emerge as a promising tool to improve device performance. Among all the congeners, the hexyl chain-containing congener (HNQ) forms well-defined nanoribbons with smaller diameters (as confirmed from DLS: 166 nm and FESEM: 150 nm) and provides a larger surface area. Consequently, the HNQ-nanoribbons were employed as a fluorescent sensor for the discriminative detection of trinitrophenol (TNP) in pure aqueous media. FE-SEM images revealed that, upon gradual addition of TNP (10 nM to 100 μM), these nanoribbons undergo an aggregation/disaggregation process, forming non-fluorescent co-aggregates with TNP, and provide highly enhanced sensitivity compared to existing state

  10. Functional Characterization of MODY2 Mutations Highlights the Importance of the Fine-Tuning of Glucokinase and Its Role in Glucose Sensing

    Science.gov (United States)

    García-Herrero, Carmen-María; Rubio-Cabezas, Oscar; Azriel, Sharona; Gutierrez-Nogués, Angel; Aragonés, Angel; Vincent, Olivier; Campos-Barros, Angel; Argente, Jesús; Navas, María-Angeles

    2012-01-01

    Glucokinase (GK) acts as a glucose sensor in the pancreatic beta-cell and regulates insulin secretion. Heterozygous mutations in the human GK-encoding GCK gene that reduce the activity index increase the glucose-stimulated insulin secretion threshold and cause familial, mild fasting hyperglycaemia, also known as Maturity Onset Diabetes of the Young type 2 (MODY2). Here we describe the biochemical characterization of five missense GK mutations: p.Ile130Thr, p.Asp205His, p.Gly223Ser, p.His416Arg and p.Ala449Thr. The enzymatic analysis of the corresponding bacterially expressed GST-GK mutant proteins show that all of them impair the kinetic characteristics of the enzyme. In keeping with their position within the protein, mutations p.Ile130Thr, p.Asp205His, p.Gly223Ser, and p.His416Arg strongly decrease the activity index of GK, affecting to one or more kinetic parameters. In contrast, the p.Ala449Thr mutation, which is located in the allosteric activator site, does not affect significantly the activity index of GK, but dramatically modifies the main kinetic parameters responsible for the function of this enzyme as a glucose sensor. The reduced Kcat of the mutant (3.21±0.28 s−1 vs 47.86±2.78 s−1) is balanced by an increased glucose affinity (S0.5 = 1.33±0.08 mM vs 7.86±0.09 mM) and loss of cooperativity for this substrate. We further studied the mechanism by which this mutation impaired GK kinetics by measuring the differential effects of several competitive inhibitors and one allosteric activator on the mutant protein. Our results suggest that this mutation alters the equilibrium between the conformational states of glucokinase and highlights the importance of the fine-tuning of GK and its role in glucose sensing. PMID:22291974

  11. Gene expression analyses in tomato near isogenic lines provide evidence for ethylene and abscisic acid biosynthesis fine-tuning during arbuscular mycorrhiza development.

    Science.gov (United States)

    Fracetto, Giselle Gomes Monteiro; Peres, Lázaro Eustáquio Pereira; Lambais, Marcio Rodrigues

    2017-07-01

    colonization in tomato roots, indicating that, besides hormonal interactions, a fine-tuning of each hormone level is required for AM development.

  12. Cellular prion protein is required for neuritogenesis: fine-tuning of multiple signaling pathways involved in focal adhesions and actin cytoskeleton dynamics

    Directory of Open Access Journals (Sweden)

    Alleaume-Butaux A

    2013-07-01

    Full Text Available Aurélie Alleaume-Butaux,1,2 Caroline Dakowski,1,2 Mathéa Pietri,1,2 Sophie Mouillet-Richard,1,2 Jean-Marie Launay,3,4 Odile Kellermann,1,2 Benoit Schneider1,2 1INSERM, UMR-S 747, 2Paris Descartes University, Sorbonne Paris Cité, UMR-S 747, 3Public Hospital of Paris, Department of Biochemistry, INSERM UMR-S 942, Lariboisière Hospital, Paris, France; 4Pharma Research Department, Hoffmann La Roche Ltd, Basel, Switzerland Abstract: Neuritogenesis is a dynamic phenomenon associated with neuronal differentiation that allows a rather spherical neuronal stem cell to develop dendrites and axon, a prerequisite for the integration and transmission of signals. The acquisition of neuronal polarity occurs in three steps: (1 neurite sprouting, which consists of the formation of buds emerging from the postmitotic neuronal soma; (2 neurite outgrowth, which represents the conversion of buds into neurites, their elongation and evolution into axon or dendrites; and (3 the stability and plasticity of neuronal polarity. In neuronal stem cells, remodeling and activation of focal adhesions (FAs associated with deep modifications of the actin cytoskeleton is a prerequisite for neurite sprouting and subsequent neurite outgrowth. A multiple set of growth factors and interactors located in the extracellular matrix and the plasma membrane orchestrate neuritogenesis by acting on intracellular signaling effectors, notably small G proteins such as RhoA, Rac, and Cdc42, which are involved in actin turnover and the dynamics of FAs. The cellular prion protein (PrPC, a glycosylphosphatidylinositol (GPI-anchored membrane protein mainly known for its role in a group of fatal neurodegenerative diseases, has emerged as a central player in neuritogenesis. Here, we review the contribution of PrPC to neuronal polarization and detail the current knowledge on the signaling pathways fine-tuned by PrPC to promote neurite sprouting, outgrowth, and maintenance. We emphasize that Pr

  13. The γc family of cytokines: fine-tuning signals from IL-2 and IL-21 in the regulation of the immune response [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Rosanne Spolski

    2017-10-01

    Full Text Available Interleukin (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on the sharing of a receptor component, the common cytokine receptor γ chain, γc, which is encoded by the gene mutated in humans with X-linked severe combined immunodeficiency (XSCID. Together, these cytokines play critical roles in lymphoid development, differentiation, growth, and survival as well as mediating effector function. Here, we provide an overview of the main actions of members of this cytokine family but then primarily focus on IL-2 and IL-21, discussing their dynamic interplay and contributions to a fine-tuned immune response. Moreover, we discuss the therapeutic utility of modulating their actions, particularly for autoimmunity and cancer.

  14. Precise Modulation of the Breathing Behavior and Pore Surface in Zr-MOFs by Reversible Post-Synthetic Variable-Spacer Installation to Fine-Tune the Expansion Magnitude and Sorption Properties.

    Science.gov (United States)

    Chen, Cheng-Xia; Wei, Zhangwen; Jiang, Ji-Jun; Fan, Yan-Zhong; Zheng, Shao-Ping; Cao, Chen-Chen; Li, Yu-Hao; Fenske, Dieter; Su, Cheng-Yong

    2016-08-16

    To combine flexibility and modifiability towards a more controllable complexity of MOFs, a post-synthetic variable-spacer installation (PVSI) strategy is used to implement kinetic installation/ uninstallation of secondary ligands into/from a robust yet flexible proto-Zr-MOF. This PVSI process features precise positioning of spacers with different length, size, number, and functionality, enabling accurate fixation of successive breathing stages and fine-tuning of pore surface. It shows unprecedented synthetic tailorability to create complicated MOFs in a predictable way for property modification, for example, CO2 and R22 adsorption/separation, thermal/chemical stability, and extended breathing behavior. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Anion tuning and polymer templating in a simple low molecular weight organogelator.

    Science.gov (United States)

    Piepenbrock, Marc-Oliver M; Clarke, Nigel; Foster, Jonathan A; Steed, Jonathan W

    2011-02-21

    A simple triethoxysilane appended bis(urea) low molecular weight gelator (LMWG) affords strong gels in organic solvents that are susceptible to fine tuning by anion binding, while the gel structure can be rigidified into a porous hybrid polymer material by hydrolysis of the triethoxysilane end groups.

  16. Evolutionarily conserved sequences on human chromosome 21

    Energy Technology Data Exchange (ETDEWEB)

    Frazer, Kelly A.; Sheehan, John B.; Stokowski, Renee P.; Chen, Xiyin; Hosseini, Roya; Cheng, Jan-Fang; Fodor, Stephen P.A.; Cox, David R.; Patil, Nila

    2001-09-01

    Comparison of human sequences with the DNA of other mammals is an excellent means of identifying functional elements in the human genome. Here we describe the utility of high-density oligonucleotide arrays as a rapid approach for comparing human sequences with the DNA of multiple species whose sequences are not presently available. High-density arrays representing approximately 22.5 Mb of nonrepetitive human chromosome 21 sequence were synthesized and then hybridized with mouse and dog DNA to identify sequences conserved between humans and mice (human-mouse elements) and between humans and dogs (human-dog elements). Our data show that sequence comparison of multiple species provides a powerful empiric method for identifying actively conserved elements in the human genome. A large fraction of these evolutionarily conserved elements are present in regions on chromosome 21 that do not encode known genes.

  17. A belief-based evolutionarily stable strategy.

    Science.gov (United States)

    Deng, Xinyang; Wang, Zhen; Liu, Qi; Deng, Yong; Mahadevan, Sankaran

    2014-11-21

    As an equilibrium refinement of the Nash equilibrium, evolutionarily stable strategy (ESS) is a key concept in evolutionary game theory and has attracted growing interest. An ESS can be either a pure strategy or a mixed strategy. Even though the randomness is allowed in mixed strategy, the selection probability of pure strategy in a mixed strategy may fluctuate due to the impact of many factors. The fluctuation can lead to more uncertainty. In this paper, such uncertainty involved in mixed strategy has been further taken into consideration: a belief strategy is proposed in terms of Dempster-Shafer evidence theory. Furthermore, based on the proposed belief strategy, a belief-based ESS has been developed. The belief strategy and belief-based ESS can reduce to the mixed strategy and mixed ESS, which provide more realistic and powerful tools to describe interactions among agents. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Fine tuning the HOMO energy levels of polythieno[3,4-b]thiophene derivatives by incorporation of thiophene-3,4-dicarboxylate moiety for photovoltaic applications

    DEFF Research Database (Denmark)

    Hu, Xiao-Lian; Zuo, Li-Jian; Nan, Ya-Xiong

    2012-01-01

    To lower the HOMO (highest occupied molecular orbital) energy level of polythieno[3,4-b]thiophene (∼−4.5eV), a series of ester-functionalized polythieno[3,4-b]thiophene derivatives (P1–P3) were designed and synthesized by Stille cross coupling reaction. The resulting copolymers exhibited broad...... and strong absorption bands from visible to near infrared region with low optical band gaps of 1.23–1.42eV. Through cyclic voltammetry measurements, it was found that the HOMO energy levels of the copolymers gradually decreased with increasing the content of the thiophene-3,4-dicarboxylate moiety, i.e. −4.......91eV for P1, −5.00eV for P2, and −5.11eV for P3. Preliminary photovoltaic properties of the copolymers blended with [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) as electron acceptor were investigated. Among the three copolymers, P1 exhibited the best photovoltaic performance with an open circuit...

  19. Fine Tuning of Open-Circuit Voltage by Chlorination in Thieno[3,4- b ]thiophene–Benzodithiophene Terpolymers toward Enhanced Solar Energy Conversion

    Energy Technology Data Exchange (ETDEWEB)

    Qu, Shiwei; Wang, Huan; Mo, Daize; Chao, Pengjie; Yang, Zhen; Li, Longji; Tian, Leilei; Chen, Wei [Materials; Institute; He, Feng

    2017-06-22

    A new family of thieno[3,4-b]thiophene benzodithiophene terpolymers (PBTClx) have been designed and synthesized, in which the chlorine/fluorine content has been adjusted and optimized. As the content of chlorine is increased in polymers, the twist angle between the donor and acceptor is increased, which leads to a diminishment in the planarity and conjugation. As a result, the UV vis absorption is continuous blue-shifted, and the band gap increases from 1.57 to 2.04 eV when the chlorinated moieties increased from 0 to 100%. The highest occupied molecular orbital (HOMO) levels of those polymers are decreased by increasing the content of chlorinated moiety, which opens a window to constantly modify the V-oc values and eventually meets a balance point for optimized solar energy conversion. The highest power conversion efficiency of 8.31% is obtained by using PBTCl25 as the donor and PC71BM as the acceptor in polymer solar cells (PSCs), in which the Voc increased from 0.79 to 0.82 V after 25% chlorinated monomer involved in copolymerization. Herein, the chlorine replacement could be a good method to further pump the solar conversion by increasing the open circuit voltage without reducing other factors of the polymer solar cells.

  20. A Fine-Tuned MOF for Gas and Vapor Separation: A Multipurpose Adsorbent for Acid Gas Removal, Dehydration, and BTX Sieving

    KAUST Repository

    Haja Mohideen, Mohamed Infas

    2017-10-19

    Summary The development of highly stable separation agents is recognized as a decisive step toward the successful deployment of energy-efficient and cost-effective separation processes. Here, we report the synthesis and construction of a metal-organic framework (MOF), kag-MOF-1, that has adequate structural and chemical features and affords a stable adsorbent with unique and appropriate adsorption properties for gas processing akin to acid gas removal, dehydration, and benzene-toluene-xylene (BTX) sieving. A combination of X-ray diffraction experiments, adsorption studies, mixed-gas breakthrough adsorption column testing, calorimetric measurements, and molecular simulations corroborated the exceptional separation performance of kag-MOF-1 and its prospective use as a multifunctional adsorbent. The unique adsorption properties of kag-MOF-1, resulting from the contracted pore system with aligned periodic array of exposed functionalities, attest to the prominence of this new generation of ultra-microporous material as a prospective practical adsorbent toward cost-effective and more simplified gas and vapor processing flowcharts for natural gas upgrading and flue gas scrubbing.

  1. The diatom Phaeodactylum tricornutum adjusts nonphotochemical fluorescence quenching capacity in response to dynamic light via fine-tuned Lhcx and xanthophyll cycle pigment synthesis.

    Science.gov (United States)

    Lepetit, Bernard; Gélin, Gautier; Lepetit, Mariana; Sturm, Sabine; Vugrinec, Sascha; Rogato, Alessandra; Kroth, Peter G; Falciatore, Angela; Lavaud, Johann

    2017-04-01

    Diatoms contain a highly flexible capacity to dissipate excessively absorbed light by nonphotochemical fluorescence quenching (NPQ) based on the light-induced conversion of diadinoxanthin (Dd) into diatoxanthin (Dt) and the presence of Lhcx proteins. Their NPQ fine regulation on the molecular level upon a shift to dynamic light conditions is unknown. We investigated the regulation of Dd + Dt amount, Lhcx gene and protein synthesis and NPQ capacity in the diatom Phaeodactylum tricornutum after a change from continuous low light to 3 d of sine (SL) or fluctuating (FL) light conditions. Four P. tricornutum strains with different NPQ capacities due to different expression of Lhcx1 were included. All strains responded to dynamic light comparably, independently of initial NPQ capacity. During SL, NPQ capacity was strongly enhanced due to a gradual increase of Lhcx2 and Dd + Dt amount. During FL, cells enhanced their NPQ capacity on the first day due to increased Dd + Dt, Lhcx2 and Lhcx3; already by the second day light acclimation was accomplished. While quenching efficiency of Dt was strongly lowered during SL conditions, it remained high throughout the whole FL exposure. Our results highlight a more balanced and cost-effective photoacclimation strategy of P. tricornutum under FL than under SL conditions. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  2. Engineering the fragment crystallizable (Fc) region of human IgG1 multimers and monomers to fine-tune interactions with sialic acid-dependent receptors.

    Science.gov (United States)

    Blundell, Patricia A; Le, Ngoc Phuong Lan; Allen, Joel; Watanabe, Yasunori; Pleass, Richard J

    2017-08-04

    Multimeric fragment crystallizable (Fc) regions and Fc-fusion proteins are actively being explored as biomimetic replacements for IVIG therapy, which is deployed to manage many diseases and conditions but is expensive and not always efficient. The Fc region of human IgG1 (IgG1-Fc) can be engineered into multimeric structures (hexa-Fcs) that bind their cognate receptors with high avidity. The critical influence of the unique N-linked glycan attached at Asn-297 on the structure and function of IgG1-Fc is well documented; however, whether the N-linked glycan has a similarly critical role in multimeric, avidly binding Fcs, is unknown. Hexa-Fc contains two N-linked sites at Asn-77 (equivalent to Asn-297 in the Fc of IgG1) and Asn-236 (equivalent to Asn-563 in the tail piece of IgM). We report here that glycosylation at Asn-297 is critical for interactions with Fc receptors and complement and that glycosylation at Asn-563 is essential for controlling multimerization. We also found that introduction of an additional fully occupied N-linked glycosylation site at the N terminus at position 1 (equivalent to Asp-221 in the Fc of IgG1) dramatically enhances overall sialic acid content of the Fc multimers. Furthermore, replacement of Cys-575 in the IgM tail piece of multimers resulted in monomers with enhanced sialic acid content and differential receptor-binding profiles. Thus insertion of additional N-linked glycans into either the hinge or tail piece of monomers or multimers leads to molecules with enhanced sialylation that may be suitable for managing inflammation or blocking pathogen invasion. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Earthworms and Humans in Vitro: Characterizing Evolutionarily Conserved Stress and Immune Responses to Silver Nanoparticles

    DEFF Research Database (Denmark)

    Hayashi, Yuya; Engelmann, Péter; Foldbjerg, Rasmus

    2012-01-01

    on the conserved biological processes, and provide the first in vitro analysis of molecular and cellular toxicity mechanisms in the earthworm Eisenia fetida exposed to AgNPs (83 ± 22 nm). While we observed a clear difference in cytotoxicity of dissolved silver salt on earthworm coelomocytes and human cells (THP-1...... in the coelomocytes and THP-1 cells. Our findings provide mechanistic clues on cellular innate immunity toward AgNPs that is likely to be evolutionarily conserved across the animal kingdom....

  4. Fine-Tuning ADAS Algorithm Parameters

    Data.gov (United States)

    U.S. Environmental Protection Agency — With the development of the Connected Vehicle technology that facilitates wirelessly communication among vehicles and road-side infrastructure, the Advanced Driver...

  5. Fine-tuning critical services maintenance.

    Science.gov (United States)

    Lam, K C

    2006-09-01

    Readers are recommended to make good use of the concepts of "Failure Model Effects and Criticality Analysis" as discussed above. These should provide a more comprehensive study of reliability and availability of building services. The assessment methodology presented in this article is to a certain extent subjective. It is considered that a more quantitative and comprehensive study based on reliability and availability data from similar hospitals over recent years will help the analysis. Building services maintenance involves risk. Risks must be assessed before a design is fully implemented. The risks associated with building services installation have to be assessed at all stages, from concept to dismantling and disposal. This will ensure that risks are acceptable and manageable within the parameters defined by the overall cost and engineering requirements, statutory obligations and good practice.

  6. Riboregulators: Fine-Tuning Virulence in Shigella.

    Science.gov (United States)

    Fris, Megan E; Murphy, Erin R

    2016-01-01

    Within the past several years, RNA-mediated regulation (ribo-regulation) has become increasingly recognized for its importance in controlling critical bacterial processes. Regulatory RNA molecules, or riboregulators, are perpetually responsive to changes within the micro-environment of a bacterium. Notably, several characterized riboregulators control virulence in pathogenic bacteria, as is the case for each riboregulator characterized to date in Shigella. The timing of virulence gene expression and the ability of the pathogen to adapt to rapidly changing environmental conditions is critical to the establishment and progression of infection by Shigella species; ribo-regulators mediate each of these important processes. This mini review will present the current state of knowledge regarding RNA-mediated regulation in Shigella by detailing the characterization and function of each identified riboregulator in these pathogens.

  7. Fine Tuning Gene Expression: The Epigenome

    Science.gov (United States)

    Mohtat, Davoud; Susztak, Katalin

    2011-01-01

    An epigenetic trait is a stably inherited phenotype resulting from changes in a chromosome without alterations in the DNA sequence. Epigenetic modifications, such as; DNA methylation, together with covalent modification of histones, are thought to alter chromatin density and accessibility of the DNA to cellular machinery, thereby modulating the transcriptional potential of the underlying DNA sequence. As epigenetic marks under environmental influence, epigenetics provides an added layer of variation that might mediate the relationship between genotype and internal and external environmental factors. Integration of our knowledge in genetics, epigenomics and genomics with the use of systems biology tools may present investigators with new powerful tools to study many complex human diseases such as kidney disease. PMID:21044758

  8. Transcriptomics of the interaction between the monopartite phloem-limited geminivirus tomato yellow leaf curl Sardinia virus and Solanum lycopersicum highlights a role for plant hormones, autophagy and plant immune system fine tuning during infection.

    Directory of Open Access Journals (Sweden)

    Laura Miozzi

    Full Text Available Tomato yellow leaf curl Sardinia virus (TYLCSV, a DNA virus belonging to the genus Begomovirus, causes severe losses in tomato crops. It infects only a limited number of cells in the vascular tissues, making difficult to detect changes in host gene expression linked to its presence. Here we present the first microarray study of transcriptional changes induced by the phloem-limited geminivirus TYLCSV infecting tomato, its natural host. The analysis was performed on the midrib of mature leaves, a material naturally enriched in vascular tissues. A total of 2206 genes were up-regulated and 1398 were down-regulated in infected plants, with an overrepresentation of genes involved in hormone metabolism and responses, nucleic acid metabolism, regulation of transcription, ubiquitin-proteasome pathway and autophagy among those up-regulated, and in primary and secondary metabolism, phosphorylation, transcription and methylation-dependent chromatin silencing among those down-regulated. Our analysis showed a series of responses, such as the induction of GA- and ABA-responsive genes, the activation of the autophagic process and the fine tuning of the plant immune system, observed only in TYLCSV-tomato compatible interaction so far. On the other hand, comparisons with transcriptional changes observed in other geminivirus-plant interactions highlighted common host responses consisting in the deregulation of biotic stress responsive genes, key enzymes in the ethylene biosynthesis and methylation cycle, components of the ubiquitin proteasome system and DNA polymerases II. The involvement of conserved miRNAs and of solanaceous- and tomato-specific miRNAs in geminivirus infection, investigated by integrating differential gene expression data with miRNA targeting data, is discussed.

  9. Localization of an evolutionarily conserved protein proton pyrophosphatase in evolutionarily distant plants oryza sativa and physcomitrella patens

    Science.gov (United States)

    Proton Pyrophosphatase (H+-PPase) is a highly evolutionarily conserved protein that is prevalent in the plant kingdom. One of the salient features of H+-PPase expression pattern, at least in vascular plants like Arabidopsis, is its conspicuous localization in both actively dividing cells and the phl...

  10. Molecular and Supramolecular Engineering of Thiophene Based Materials for Application in Organic Electronics and Bioimaging

    OpenAIRE

    Di Maria, Francesca Giulia

    2016-01-01

    Thiophene based oligomers and polymers are of great current interest from a scientific and technological point of view for their numerous properties: they are electroactive, fluorescent, chemically stable and allow a great diversity in molecular structures and a fine tuning of functional characteristics. They display ‘plasticity’ in adapting their geometry to the environment in the solid state and in creating supramolecular architectures by self-organization. Moreover, they have the capabilit...

  11. Fine-Tuning of PI3K/AKT Signalling by the Tumour Suppressor PTEN Is Required for Maintenance of Flight Muscle Function and Mitochondrial Integrity in Ageing Adult Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Lawrence B Mensah

    Full Text Available Insulin/insulin-like growth factor signalling (IIS, acting primarily through the PI3-kinase (PI3K/AKT kinase signalling cassette, plays key evolutionarily conserved regulatory roles in nutrient homeostasis, growth, ageing and longevity. The dysfunction of this pathway has been linked to several age-related human diseases including cancer, Type 2 diabetes and neurodegenerative disorders. However, it remains unclear whether minor defects in IIS can independently induce the age-dependent functional decline in cells that accompany some of these diseases or whether IIS alters the sensitivity to other aberrant signalling. We identified a novel hypomorphic allele of PI3K's direct antagonist, Phosphatase and tensin homologue on chromosome 10 (Pten, in the fruit fly, Drosophila melanogaster. Adults carrying combinations of this allele, Pten5, combined with strong loss-of-function Pten mutations exhibit subtle or no increase in mass, but are highly susceptible to a wide range of stresses. They also exhibit dramatic upregulation of the oxidative stress response gene, GstD1, and a progressive loss of motor function that ultimately leads to defects in climbing and flight ability. The latter phenotype is associated with mitochondrial disruption in indirect flight muscles, although overall muscle structure appears to be maintained. We show that the phenotype is partially rescued by muscle-specific expression of the Bcl-2 homologue Buffy, which in flies, maintains mitochondrial integrity, modulates energy homeostasis and suppresses cell death. The flightless phenotype is also suppressed by mutations in downstream IIS signalling components, including those in the mechanistic Target of Rapamycin Complex 1 (mTORC1 pathway, suggesting that elevated IIS is responsible for functional decline in flight muscle. Our data demonstrate that IIS levels must be precisely regulated by Pten in adults to maintain the function of the highly metabolically active indirect flight

  12. Unifying the genomics-based classes of cancer fusion gene partners: large cancer fusion genes are evolutionarily conserved.

    Science.gov (United States)

    Pava, Libia M; Morton, Daniel T; Chen, Ren; Blanck, George

    2012-11-01

    Genes that fuse to cause cancer have been studied to determine molecular bases for proliferation, to develop diagnostic tools, and as targets for drugs. To facilitate identification of additional, cancer fusion genes, following observation of a chromosomal translocation, we have characterized the genomic features of the fusion gene partners. Previous work indicated that cancer fusion gene partners, are either large or evolutionarily conserved in comparison to the neighboring genes in the region of a chromosomal translocation. These results raised the question of whether large cancer fusion gene partners were also evolutionarily conserved. We developed two methods for quantifying evolutionary conservation values, allowing the conclusion that both large and small cancer fusion gene partners are more evolutionarily conserved than their neighbors. Additionally, we determined that cancer fusion gene partners have more 3' untranslated region secondary structures than do their neighbors. Coupled with previous algorithms, with or without transcriptome approaches, we expect these results to assist in the rapid and efficient use of chromosomal translocations to identify cancer fusion genes. The above parameters for any gene of interest can be accessed at www.cancerfusiongenes.com.

  13. Measuring the Evolutionarily Important Goals of Situations: Situational Affordances for Adaptive Problems

    National Research Council Canada - National Science Library

    Brown, Nicolas A; Neel, Rebecca; Sherman, Ryne A

    2015-01-01

    .... This article introduces the Situational Affordances for Adaptive Problems (SAAP), a measure of situation characteristics that promotes or prevents the achievement of these evolutionarily important goals...

  14. Evolutionarily advanced ant farmers rear polyploid fungal crops

    DEFF Research Database (Denmark)

    Kooij, Pepijn Wilhelmus; Aanen, D.K.; Schiøtt, Morten

    2015-01-01

    Innovative evolutionary developments are often related to gene or genome duplications. The crop fungi of attine fungus-growing ants are suspected to have enhanced genetic variation reminiscent of polyploidy, but this has never been quantified with cytological data and genetic markers. We estimated...... the number of nuclei per fungal cell for 42 symbionts reared by 14 species of Panamanian fungus-growing ants. This showed that domesticated symbionts of higher attine ants are polykaryotic with 7-17 nuclei per cell, whereas nonspecialized crops of lower attines are dikaryotic similar to most free...... of the basal higher attine genera Trachymyrmex and Sericomyrmex was only slightly enhanced, but the evolutionarily derived crop fungi of Atta and Acromyrmex leaf-cutting ants had much higher genetic variation. Our opposite ploidy models indicated that the symbionts of Trachymyrmex and Sericomyrmex are likely...

  15. The fine tuning of carotenoid-chlorophyll interactions in light-harvesting complexes: an important requisite to guarantee efficient photoprotection via triplet-triplet energy transfer in the complex balance of the energy transfer processes

    Science.gov (United States)

    Di Valentin, Marilena; Carbonera, Donatella

    2017-08-01

    Triplet-triplet energy transfer (TTET) from the chlorophyll to the carotenoid triplet state is the process exploited by photosynthetic systems to protect themselves from singlet oxygen formation under light-stress conditions. A deep comprehension of the molecular strategies adopted to guarantee TTET efficiency, while at the same time maintaining minimal energy loss and efficient light-harvesting capability, is still lacking. The paramagnetic nature of the triplet state makes electron paramagnetic resonance (EPR) the method of choice when investigating TTET. In this review, we focus on our extended comparative study of two photosynthetic antenna complexes, the Peridinin-chlorophyll a-protein of dinoflagellates and the light-harvesting complex II of higher plants, in order to point out important aspects of the molecular design adopted in the photoprotection strategy. We have demonstrated that a proper analysis of the EPR data allows one to identify the pigments involved in TTET and, consequently, gain an insight into the structure of the photoprotective sites. The structural information has been complemented by a detailed description of the electronic structure provided by hyperfine spectroscopy. All these elements represent the fundamental building blocks toward a deeper understanding of the requirements for efficient photoprotection, which is fundamental to guarantee the prolonged energy conversion action of photosynthesis.

  16. Fine-Tuning the Energy Levels of a Nonfullerene Small-Molecule Acceptor to Achieve a High Short-Circuit Current and a Power Conversion Efficiency over 12% in Organic Solar Cells.

    Science.gov (United States)

    Kan, Bin; Zhang, Jiangbin; Liu, Feng; Wan, Xiangjian; Li, Chenxi; Ke, Xin; Wang, Yunchuang; Feng, Huanran; Zhang, Yamin; Long, Guankui; Friend, Richard H; Bakulin, Artem A; Chen, Yongsheng

    2018-01-01

    Organic solar cell optimization requires careful balancing of current-voltage output of the materials system. Here, such optimization using ultrafast spectroscopy as a tool to optimize the material bandgap without altering ultrafast photophysics is reported. A new acceptor-donor-acceptor (A-D-A)-type small-molecule acceptor NCBDT is designed by modification of the D and A units of NFBDT. Compared to NFBDT, NCBDT exhibits upshifted highest occupied molecular orbital (HOMO) energy level mainly due to the additional octyl on the D unit and downshifted lowest unoccupied molecular orbital (LUMO) energy level due to the fluorination of A units. NCBDT has a low optical bandgap of 1.45 eV which extends the absorption range toward near-IR region, down to ≈860 nm. However, the 60 meV lowered LUMO level of NCBDT hardly changes the Voc level, and the elevation of the NCBDT HOMO does not have a substantial influence on the photophysics of the materials. Thus, for both NCBDT- and NFBDT-based systems, an unusually slow (≈400 ps) but ultimately efficient charge generation mediated by interfacial charge-pair states is observed, followed by effective charge extraction. As a result, the PBDB-T:NCBDT devices demonstrate an impressive power conversion efficiency over 12%-among the best for solution-processed organic solar cells. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Sperm protein "DE" mediates gamete fusion through an evolutionarily conserved site of the CRISP family.

    Science.gov (United States)

    Ellerman, Diego A; Cohen, Débora J; Da Ros, Vanina G; Morgenfeld, Mauro M; Busso, Dolores; Cuasnicú, Patricia S

    2006-09-01

    The first member of the cysteine-rich secretory protein (CRISP) family was described by our laboratory in the rat epididymis, and it is known as DE or CRISP-1. Since then, numerous CRISPs exhibiting a high amino acid sequence similarity have been identified in animals, plants and fungi, although their functions remain largely unknown. CRISP-1 proteins are candidates to mediate gamete fusion in the rat, mouse and human through their binding to complementary sites on the egg surface. To elucidate the molecular mechanisms underlying CRISP-1 function, in the present work, deletion mutants of protein DE were generated and examined for their ability to bind to the rat egg and interfere with gamete fusion. Results revealed that the egg-binding ability of DE resides within a 45-amino acid N-terminal region containing the two motifs of the CRISP family named Signature 1 and Signature 2. Subsequent assays using synthetic peptides and other CRISPs support that the egg-binding site of DE falls in the 12-amino-acid region corresponding to Signature 2. The interesting finding that the binding site of DE resides in an evolutionarily conserved region of the molecule provides novel information on the molecular mechanisms underlying CRISP-1 function in gamete fusion with important implications on the structure-function relationship of other members of the widely distributed CRISP family.

  18. A novel mechanism whereby BRCA1/1a/1b fine tunes the dynamic complex interplay between SUMO-dependent/independent activities of Ubc9 on E2-induced ERalpha activation/repression and degradation in breast cancer cells.

    Science.gov (United States)

    Xu, J; Watkins, T; Reddy, A; Reddy, E S P; Rao, V N

    2009-04-01

    BRCA1 dysfunction is associated with hormone-responsive cancers. We have identified a consensus SUMO modification site in the amino-terminal region of BRCA1/1a/1b proteins and the mutation in this potential SUMO acceptor site (K 109 to R) impaired their ability to bind and repress ligand-dependent ERalpha transcriptional activity in breast cancer cells. Furthermore, we have found SUMO E2-conjugating enzyme Ubc9 to bind BRCA1 proteins. We have mapped BRCA1 [within amino acids (aa) 1-182] as the minimum domain that is sufficient for in vitro binding to Ubc9 as well as for regulating ERalpha activity. BRCA1 Mutant #1 (K109 to R) was impaired in its ability to both bind, as well as modulate Ubc9 mediated SUMO-dependent/independent E2-induced ERalpha transcriptional activity in breast cancer cells. Similarly, BRCA1 cancer-predisposing mutation (61Cys-Gly) abrogated the ability to both bind Ubc9 as well as inhibit ERalpha activity suggesting physiological significance. Addition of BRCA1 but not Mutant #1 to E2-induced ERalpha in the presence of SUMO-1 and Ubc9 resulted in the degradation of ERalpha suggesting BRCA1 to be a putative SUMO-1 and Ubc9-dependent E3 ubiquitin ligase for ERalpha. This is the first report demonstrating the participation of Ubc9 in BRCA1 E3 ubiquitin ligase mediated degradation of ERalpha. These results suggest a novel function for BRCA1 in regulating the dynamic cycles of SUMO and ubiquitin modifications required for ERalpha turn over and deregulation of this molecular switch due to lack of BRCA1 results in ERalpha-negative/positive breast cancers. This study will help in designing novel BRCA1 function-based targeted treatment for breast cancers.

  19. Commentary on: "Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy." Li Z, Alyamani M, Li J, Rogacki K, Abazeed M, Upadhyay SK, Balk SP, Taplin ME, Auchus RJ, Sharifi N. Nature. 2016 May 25;533(7604):547-51.

    Science.gov (United States)

    Lee, Byron H

    2017-09-01

    Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater antitumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumor-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Evolutionarily conserved TRH neuropeptide pathway regulates growth in Caenorhabditis elegans.

    Science.gov (United States)

    Van Sinay, Elien; Mirabeau, Olivier; Depuydt, Geert; Van Hiel, Matthias Boris; Peymen, Katleen; Watteyne, Jan; Zels, Sven; Schoofs, Liliane; Beets, Isabel

    2017-05-16

    In vertebrates thyrotropin-releasing hormone (TRH) is a highly conserved neuropeptide that exerts the hormonal control of thyroid-stimulating hormone (TSH) levels as well as neuromodulatory functions. However, a functional equivalent in protostomian animals remains unknown, although TRH receptors are conserved in proto- and deuterostomians. Here we identify a TRH-like neuropeptide precursor in Caenorhabditis elegans that belongs to a bilaterian family of TRH precursors. Using CRISPR/Cas9 and RNAi reverse genetics, we show that TRH-like neuropeptides, through the activation of their receptor TRHR-1, promote growth in Celegans TRH-like peptides from pharyngeal motor neurons are required for normal body size, and knockdown of their receptor in pharyngeal muscle cells reduces growth. Mutants deficient for TRH signaling have no defects in pharyngeal pumping or isthmus peristalsis rates, but their growth defect depends on the bacterial diet. In addition to the decrease in growth, trh-1 mutants have a reduced number of offspring. Our study suggests that TRH is an evolutionarily ancient neuropeptide, having its origin before the divergence of protostomes and deuterostomes, and may ancestrally have been involved in the control of postembryonic growth and reproduction.

  1. Aligning science and policy to achieve evolutionarily enlightened conservation.

    Science.gov (United States)

    Cook, Carly N; Sgrò, Carla M

    2017-06-01

    There is increasing recognition among conservation scientists that long-term conservation outcomes could be improved through better integration of evolutionary theory into management practices. Despite concerns that the importance of key concepts emerging from evolutionary theory (i.e., evolutionary principles and processes) are not being recognized by managers, there has been little effort to determine the level of integration of evolutionary theory into conservation policy and practice. We assessed conservation policy at 3 scales (international, national, and provincial) on 3 continents to quantify the degree to which key evolutionary concepts, such as genetic diversity and gene flow, are being incorporated into conservation practice. We also evaluated the availability of clear guidance within the applied evolutionary biology literature as to how managers can change their management practices to achieve better conservation outcomes. Despite widespread recognition of the importance of maintaining genetic diversity, conservation policies provide little guidance about how this can be achieved in practice and other relevant evolutionary concepts, such as inbreeding depression, are mentioned rarely. In some cases the poor integration of evolutionary concepts into management reflects a lack of decision-support tools in the literature. Where these tools are available, such as risk-assessment frameworks, they are not being adopted by conservation policy makers, suggesting that the availability of a strong evidence base is not the only barrier to evolutionarily enlightened management. We believe there is a clear need for more engagement by evolutionary biologists with policy makers to develop practical guidelines that will help managers make changes to conservation practice. There is also an urgent need for more research to better understand the barriers to and opportunities for incorporating evolutionary theory into conservation practice. © 2016 Society for Conservation

  2. Fine tuning the roughness of powder blasted surfaces

    NARCIS (Netherlands)

    Wensink, H.; Schlautmann, Stefan; Goedbloed, M.H.; Elwenspoek, Michael Curt

    Powder blasting (abrasive jet machining) has recently been introduced as a bulk-micromachining technique for brittle materials. The surface roughness that is created with this technique is much higher (with a value of Ra between 1-2.5 μm) compared to general micromachining techniques. In this paper

  3. Using collective intelligence to fine-tune public health policy.

    Science.gov (United States)

    Marsh, Andy; Carroll, Denis; Foggie, Richard

    2010-01-01

    The European Union Future Internet Assembly, the roadmap for the Web heading towards semantic interoperability and building on the UK's adoption of the Internet and social media are accelerating the development of Web 3.0. A number of health portals are opening, some with facilities for the capture of Patient Based Records. Collective Intelligence will be generated that, applied to health, has potential to support Public Health policy. By using the Internet, millions of people in the course of their daily activities contribute to uncertified data stores, some explicitly collaborating to create collective knowledge bases, some contributing implicitly through the patterns of their choices and actions. An application of soft computing, called Collective Health Intelligence, that reasons uncertified and certified data could enhance the social pool of existing health knowledge available to the public health agencies. Collective Health Intelligence could be used to complement national programmes by employing innovative sampling techniques, cost-effectively generating anonymous data trends that would quantify policy, indicate epidemiological effects and supply metrics to test policy efficacy.

  4. Thymidine kinase 1 regulatory fine-tuning through tetramer formation

    DEFF Research Database (Denmark)

    Mutahir, Zeeshan; Clausen, Anders R.; Andersson, Karl-Magnus

    2013-01-01

    Abstract: Thymidine kinase 1 (TK1) provides a crucial precursor, deoxythymidine monophosphate, for nucleic acid synthesis, and the activity of TK1 increases by up to 200-fold during the S-phase of cell division in humans. An important part of the regulatory checkpoints is the ATP and enzyme...... in higher vertebrates and was especially pronounced in mammalian and bird TK1s. We suggest that the dimer form is the original form and that the tetramer originated in the animal lineage after the split of Dictyostelium and the lineages leading to invertebrates and vertebrates. The efficient switching...

  5. Fine Tuning of a Type 1 Interferon Antagonist.

    Directory of Open Access Journals (Sweden)

    Victoria Urin

    Full Text Available Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.

  6. Fine Tuning Cell Migration by a Disintegrin and Metalloproteinases.

    Science.gov (United States)

    Dreymueller, D; Theodorou, K; Donners, M; Ludwig, A

    2017-01-01

    Cell migration is an instrumental process involved in organ development, tissue homeostasis, and various physiological processes and also in numerous pathologies. Both basic cell migration and migration towards chemotactic stimulus consist of changes in cell polarity and cytoskeletal rearrangement, cell detachment from, invasion through, and reattachment to their neighboring cells, and numerous interactions with the extracellular matrix. The different steps of immune cell, tissue cell, or cancer cell migration are tightly coordinated in time and place by growth factors, cytokines/chemokines, adhesion molecules, and receptors for these ligands. This review describes how a disintegrin and metalloproteinases interfere with several steps of cell migration, either by proteolytic cleavage of such molecules or by functions independent of proteolytic activity.

  7. Herpesvirus gB: A Finely Tuned Fusion Machine

    National Research Council Canada - National Science Library

    Cooper, Rebecca S; Heldwein, Ekaterina E

    2015-01-01

    .... Surprisingly, in herpesviruses, these functions are distributed among multiple proteins: the conserved fusogen gB, the conserved gH/gL heterodimer of poorly defined function, and various non-conserved receptor-binding proteins...

  8. Sigma-1 Receptors Fine-Tune the Neuronal Networks.

    Science.gov (United States)

    Tsai, Shang-Yi Anne; Su, Tsung-Ping

    2017-01-01

    The endoplasmic reticular (ER) protein sigma-1 receptor (Sig-1R) has been implicated in CNS disorders including but not limited to neurodegenerative diseases, depression , amnesia, and substance abuse. Sig-1Rs are particularly enriched in the specific domain where ER membranes make contacts with the mitochondria (MAM). Within that specific domain, Sig-1Rs play significant roles governing calcium signaling and reactive oxygen species homeostasis to maintain proper neuronal functions. Studies showed that the Sig-1R is pivotal to regulate neuroplasticity and neural survival via multiple aspects of mechanism. Numerous reports have been focusing on Sig-1R's regulatory effects in ER stress, mitochondrial function, oxidative stress and protein chaperoning. In this book chapter, we will discuss the emerging role of Sig-1R in balancing the populations of neuron and glia and their implications in CNS diseases.

  9. Fine-tuning structural RNA alignments in the twilight zone

    Directory of Open Access Journals (Sweden)

    Schirmer Stefanie

    2010-04-01

    Full Text Available Abstract Background A widely used method to find conserved secondary structure in RNA is to first construct a multiple sequence alignment, and then fold the alignment, optimizing a score based on thermodynamics and covariance. This method works best around 75% sequence similarity. However, in a "twilight zone" below 55% similarity, the sequence alignment tends to obscure the covariance signal used in the second phase. Therefore, while the overall shape of the consensus structure may still be found, the degree of conservation cannot be estimated reliably. Results Based on a combination of available methods, we present a method named planACstar for improving structure conservation in structural alignments in the twilight zone. After constructing a consensus structure by alignment folding, planACstar abandons the original sequence alignment, refolds the sequences individually, but consistent with the consensus, aligns the structures, irrespective of sequence, by a pure structure alignment method, and derives an improved sequence alignment from the alignment of structures, to be re-submitted to alignment folding, etc.. This circle may be iterated as long as structural conservation improves, but normally, one step suffices. Conclusions Employing the tools ClustalW, RNAalifold, and RNAforester, we find that for sequences with 30-55% sequence identity, structural conservation can be improved by 10% on average, with a large variation, measured in terms of RNAalifold's own criterion, the structure conservation index.

  10. Fine-tuning the activity of oxygen evolution catalysts

    DEFF Research Database (Denmark)

    Paoli, Elisa Antares; Masini, Federico; Frydendal, Rasmus

    2016-01-01

    Water splitting is hindered by the sluggish kinetics of the oxygen evolution reaction (OER). The choice of materials for this reaction in acid is limited to the platinum group metals; high loading required of these scarce and expensive elements severely limit the scalability of such technology....... Ruthenium oxide is among the best catalysts for OER, however the reported activity and stability can vary tremendously depending on the preparation conditions and pre-treatment. Herein, we investigate the effect of oxidation treatment on mass-selected Ru nanoparticles in the size range between 2 and 10 nm....... The effect of two distinct oxidation pre-treatments on the activity and stability have been investigated: (1) thermal oxidation; and (2) oxidation with an oxygen plasma under vacuum. We report that activity and stability can be tuned by using different oxidation pre-treatments. Thermally oxidized particles...

  11. Fine Tuning Cell Migration by a Disintegrin and Metalloproteinases

    Science.gov (United States)

    Theodorou, K.

    2017-01-01

    Cell migration is an instrumental process involved in organ development, tissue homeostasis, and various physiological processes and also in numerous pathologies. Both basic cell migration and migration towards chemotactic stimulus consist of changes in cell polarity and cytoskeletal rearrangement, cell detachment from, invasion through, and reattachment to their neighboring cells, and numerous interactions with the extracellular matrix. The different steps of immune cell, tissue cell, or cancer cell migration are tightly coordinated in time and place by growth factors, cytokines/chemokines, adhesion molecules, and receptors for these ligands. This review describes how a disintegrin and metalloproteinases interfere with several steps of cell migration, either by proteolytic cleavage of such molecules or by functions independent of proteolytic activity. PMID:28260841

  12. Spanish "fine tuning" of language to describe depression and anxiety.

    Science.gov (United States)

    Noguera, Antonio; Centeno, Carlos; Carvajal, Ana; Tejedor, María Angustias Portela; Urdiroz, Juliana; Martínez, Marina

    2009-08-01

    On screening tools for emotional distress, the terms "depression" and "anxiety" are commonly used for patients with advanced cancer. However, these terms could have negative connotations in Spanish such that cultural and unexpected differences in perception may invalidate or skew the results of the screening if the best terms are not chosen. The goal of this study was to determine the best expression that can be used to explore anxiety and depression in Spanish. A prospective study of 100 Spanish-speaking patients was performed. Spanish patients with cancer completed the Hospital Anxiety and Depression Scale (HADS) and six Verbal Numerical Scales (VNS) exploring the level of anxiety using the terms ansioso (anxious), nervioso (nervous), or intranquilo (uneasy/disquiet), and the level of depression using the terms deprimido (depressed), desanimado (discouraged), or triste (sad). The correlation, sensitivity, and specificity for all the VNS and HADS (8 and 11 cutoff points) were analyzed. The correlation (Spearman rho) between HADS and the anxiety VNS was r = 0.557 using "anxious"; r = 0.603 using "nervous"; and r = 0.594 using "uneasy." The correlation for the depression VNS was r = 0.662 using "depression"; r = 0.759 using "discouraged" and r = 0.596 using "sad"; alpha anxiety achieved the best levels for sensitivity (0.80) and specificity (0.70). The term "discouraged" with a cutoff point of 4 of 10 shows a sensitivity of 0.89, a specificity of 0.84, as well as a predictive positive value of 0.77 and a negative value of 0.93. In Spanish, the term desanimado seems to be more suitable in screening for depression. Alternate terms could be used to explore anxiety in Spanish. Exploring depression with simple questions in Spanish achieves greater accuracy than the same approach to exploring anxiety.

  13. An evolutionarily conserved sexual signature in the primate brain.

    Directory of Open Access Journals (Sweden)

    Björn Reinius

    2008-06-01

    Full Text Available The question of a potential biological sexual signature in the human brain is a heavily disputed subject. In order to provide further insight into this issue, we used an evolutionary approach to identify genes with sex differences in brain expression level among primates. We reasoned that expression patterns important to uphold key male and female characteristics may be conserved during evolution. We selected cortex for our studies because this specific brain region is responsible for many higher behavioral functions. We compared gene expression profiles in the occipital cortex of male and female humans (Homo sapiens, a great ape and cynomolgus macaques (Macaca fascicularis, an old world monkey, two catarrhine species that show abundant morphological sexual dimorphism, as well as in common marmosets (Callithrix Jacchus, a new world monkey which are relatively sexually monomorphic. We identified hundreds of genes with sex-biased expression patterns in humans and macaques, while fewer than ten were differentially expressed between the sexes in marmosets. In primates, a general rule is that many of the morphological and behavioral sexual dimorphisms seen in polygamous species, such as macaques, are typically less pronounced in monogamous species such as the marmosets. Our observations suggest that this correlation may also be reflected in the extent of sex-biased gene expression in the brain. We identified 85 genes with common sex-biased expression, in both human and macaque and 2 genes, X inactivation-specific transcript (XIST and Heat shock factor binding protein 1 (HSBP1, that were consistently sex-biased in the female direction in human, macaque, and marmoset. These observations imply a conserved signature of sexual gene expression dimorphism in cortex of primates. Further, we found that the coding region of female-biased genes is more evolutionarily constrained compared to the coding region of both male-biased and non sex-biased brain

  14. Prediction of enzyme function based on 3D templates of evolutionarily important amino acids

    Directory of Open Access Journals (Sweden)

    Chen Brian Y

    2008-01-01

    Full Text Available Abstract Background Structural genomics projects such as the Protein Structure Initiative (PSI yield many new structures, but often these have no known molecular functions. One approach to recover this information is to use 3D templates – structure-function motifs that consist of a few functionally critical amino acids and may suggest functional similarity when geometrically matched to other structures. Since experimentally determined functional sites are not common enough to define 3D templates on a large scale, this work tests a computational strategy to select relevant residues for 3D templates. Results Based on evolutionary information and heuristics, an Evolutionary Trace Annotation (ETA pipeline built templates for 98 enzymes, half taken from the PSI, and sought matches in a non-redundant structure database. On average each template matched 2.7 distinct proteins, of which 2.0 share the first three Enzyme Commission digits as the template's enzyme of origin. In many cases (61% a single most likely function could be predicted as the annotation with the most matches, and in these cases such a plurality vote identified the correct function with 87% accuracy. ETA was also found to be complementary to sequence homology-based annotations. When matches are required to both geometrically match the 3D template and to be sequence homologs found by BLAST or PSI-BLAST, the annotation accuracy is greater than either method alone, especially in the region of lower sequence identity where homology-based annotations are least reliable. Conclusion These data suggest that knowledge of evolutionarily important residues improves functional annotation among distant enzyme homologs. Since, unlike other 3D template approaches, the ETA method bypasses the need for experimental knowledge of the catalytic mechanism, it should prove a useful, large scale, and general adjunct to combine with other methods to decipher protein function in the structural proteome.

  15. Disruption of an Evolutionarily Novel Synaptic Expression Pattern in Autism.

    Directory of Open Access Journals (Sweden)

    Xiling Liu

    2016-09-01

    Full Text Available Cognitive defects in autism spectrum disorder (ASD include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans.

  16. Broadening the application of evolutionarily based genetic pest management.

    Science.gov (United States)

    Gould, Fred

    2008-02-01

    Insect- and tick-vectored diseases such as malaria, dengue fever, and Lyme disease cause human suffering, and current approaches for prevention are not adequate. Invasive plants and animals such as Scotch broom, zebra mussels, and gypsy moths continue to cause environmental damage and economic losses in agriculture and forestry. Rodents transmit diseases and cause major pre- and postharvest losses, especially in less affluent countries. Each of these problems might benefit from the developing field of Genetic Pest Management that is conceptually based on principles of evolutionary biology. This article briefly describes the history of this field, new molecular tools in this field, and potential applications of those tools. There will be a need for evolutionary biologists to interact with researchers and practitioners in a variety of other fields to determine the most appropriate targets for genetic pest management, the most appropriate methods for specific targets, and the potential of natural selection to diminish the effectiveness of genetic pest management. In addition to producing environmentally sustainable pest management solutions, research efforts in this area could lead to new insights about the evolution of selfish genetic elements in natural systems and will provide students with the opportunity to develop a more sophisticated understanding of the role of evolutionary biology in solving societal problems.

  17. Tryptophan as an evolutionarily conserved signal to brain serotonin : Molecular evidence and psychiatric implications

    NARCIS (Netherlands)

    Russo, Sascha; Kema, Ido P.; Bosker, Fokko; Haavik, Jan; Korf, Jakob

    2009-01-01

    The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is

  18. Unidirectional molecular assembly alignment on graphene enabled by nanomechanical symmetry breaking.

    Science.gov (United States)

    Hong, Liu; Nishihara, Taishi; Hijikata, Yuh; Miyauchi, Yuhei; Itami, Kenichiro

    2018-02-05

    Precise fabrication of molecular assemblies on a solid surface has long been of central interest in surface science. Their perfectly oriented growth only along a desired in-plane direction, however, remains a challenge, because of the thermodynamical equivalence of multiple axis directions on a solid-surface lattice. Here we demonstrate the successful fabrication of an in-plane, unidirectional molecular assembly on graphene. Our methodology relies on nanomechanical symmetry breaking effects under atomic force microscopy tip scanning, which has never been used in molecular alignment. Individual one-dimensional (1D) molecular assemblies were aligned along a selected symmetry axis of the graphene lattice under finely-tuned scanning conditions after removing initially-adsorbed molecules. Experimental statistics and computational simulations suggest that the anisotropic tip scanning locally breaks the directional equivalence of the graphene surface, which enables nucleation of the unidirectional 1D assemblies. Our findings will open new opportunities in the molecular alignment control on various atomically flat surfaces.

  19. On Nash Equilibrium and Evolutionarily Stable States That Are Not Characterised by the Folk Theorem.

    Directory of Open Access Journals (Sweden)

    Jiawei Li

    Full Text Available In evolutionary game theory, evolutionarily stable states are characterised by the folk theorem because exact solutions to the replicator equation are difficult to obtain. It is generally assumed that the folk theorem, which is the fundamental theory for non-cooperative games, defines all Nash equilibria in infinitely repeated games. Here, we prove that Nash equilibria that are not characterised by the folk theorem do exist. By adopting specific reactive strategies, a group of players can be better off by coordinating their actions in repeated games. We call it a type-k equilibrium when a group of k players coordinate their actions and they have no incentive to deviate from their strategies simultaneously. The existence and stability of the type-k equilibrium in general games is discussed. This study shows that the sets of Nash equilibria and evolutionarily stable states have greater cardinality than classic game theory has predicted in many repeated games.

  20. On Nash Equilibrium and Evolutionarily Stable States That Are Not Characterised by the Folk Theorem

    Science.gov (United States)

    Li, Jiawei; Kendall, Graham

    2015-01-01

    In evolutionary game theory, evolutionarily stable states are characterised by the folk theorem because exact solutions to the replicator equation are difficult to obtain. It is generally assumed that the folk theorem, which is the fundamental theory for non-cooperative games, defines all Nash equilibria in infinitely repeated games. Here, we prove that Nash equilibria that are not characterised by the folk theorem do exist. By adopting specific reactive strategies, a group of players can be better off by coordinating their actions in repeated games. We call it a type-k equilibrium when a group of k players coordinate their actions and they have no incentive to deviate from their strategies simultaneously. The existence and stability of the type-k equilibrium in general games is discussed. This study shows that the sets of Nash equilibria and evolutionarily stable states have greater cardinality than classic game theory has predicted in many repeated games. PMID:26288088

  1. Protection of CpG islands from DNA methylation is DNA-encoded and evolutionarily conserved.

    Science.gov (United States)

    Long, Hannah K; King, Hamish W; Patient, Roger K; Odom, Duncan T; Klose, Robert J

    2016-08-19

    DNA methylation is a repressive epigenetic modification that covers vertebrate genomes. Regions known as CpG islands (CGIs), which are refractory to DNA methylation, are often associated with gene promoters and play central roles in gene regulation. Yet how CGIs in their normal genomic context evade the DNA methylation machinery and whether these mechanisms are evolutionarily conserved remains enigmatic. To address these fundamental questions we exploited a transchromosomic animal model and genomic approaches to understand how the hypomethylated state is formed in vivo and to discover whether mechanisms governing CGI formation are evolutionarily conserved. Strikingly, insertion of a human chromosome into mouse revealed that promoter-associated CGIs are refractory to DNA methylation regardless of host species, demonstrating that DNA sequence plays a central role in specifying the hypomethylated state through evolutionarily conserved mechanisms. In contrast, elements distal to gene promoters exhibited more variable methylation between host species, uncovering a widespread dependence on nucleotide frequency and occupancy of DNA-binding transcription factors in shaping the DNA methylation landscape away from gene promoters. This was exemplified by young CpG rich lineage-restricted repeat sequences that evaded DNA methylation in the absence of co-evolved mechanisms targeting methylation to these sequences, and species specific DNA binding events that protected against DNA methylation in CpG poor regions. Finally, transplantation of mouse chromosomal fragments into the evolutionarily distant zebrafish uncovered the existence of a mechanistically conserved and DNA-encoded logic which shapes CGI formation across vertebrate species. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  2. Evolutionarily stable learning schedules and cumulative culture in discrete generation models.

    Science.gov (United States)

    Aoki, Kenichi; Wakano, Joe Yuichiro; Lehmann, Laurent

    2012-06-01

    Individual learning (e.g., trial-and-error) and social learning (e.g., imitation) are alternative ways of acquiring and expressing the appropriate phenotype in an environment. The optimal choice between using individual learning and/or social learning may be dictated by the life-stage or age of an organism. Of special interest is a learning schedule in which social learning precedes individual learning, because such a schedule is apparently a necessary condition for cumulative culture. Assuming two obligatory learning stages per discrete generation, we obtain the evolutionarily stable learning schedules for the three situations where the environment is constant, fluctuates between generations, or fluctuates within generations. During each learning stage, we assume that an organism may target the optimal phenotype in the current environment by individual learning, and/or the mature phenotype of the previous generation by oblique social learning. In the absence of exogenous costs to learning, the evolutionarily stable learning schedules are predicted to be either pure social learning followed by pure individual learning ("bang-bang" control) or pure individual learning at both stages ("flat" control). Moreover, we find for each situation that the evolutionarily stable learning schedule is also the one that optimizes the learned phenotype at equilibrium. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Molecular Mechanisms of Taste Recognition: Considerations about the Role of Saliva

    Directory of Open Access Journals (Sweden)

    Tibor Károly Fábián

    2015-03-01

    Full Text Available The gustatory system plays a critical role in determining food preferences and food intake, in addition to nutritive, energy and electrolyte balance. Fine tuning of the gustatory system is also crucial in this respect. The exact mechanisms that fine tune taste sensitivity are as of yet poorly defined, but it is clear that various effects of saliva on taste recognition are also involved. Specifically those metabolic polypeptides present in the saliva that were classically considered to be gut and appetite hormones (i.e., leptin, ghrelin, insulin, neuropeptide Y, peptide YY were considered to play a pivotal role. Besides these, data clearly indicate the major role of several other salivary proteins, such as salivary carbonic anhydrase (gustin, proline-rich proteins, cystatins, alpha-amylases, histatins, salivary albumin and mucins. Other proteins like glucagon-like peptide-1, salivary immunoglobulin-A, zinc-α-2-glycoprotein, salivary lactoperoxidase, salivary prolactin-inducible protein and salivary molecular chaperone HSP70/HSPAs were also expected to play an important role. Furthermore, factors including salivary flow rate, buffer capacity and ionic composition of saliva should also be considered. In this paper, the current state of research related to the above and the overall emerging field of taste-related salivary research alongside basic principles of taste perception is reviewed.

  4. Data from "Crossing to safety: Dispersal, colonization and mate choice in evolutionarily distinct populations of Steller sea lions, Eumetopias jubatus."

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Data sets used to support analysis published by O'Corry-Crowe et al (2014) Crossing to safety: Dispersal, colonization and mate choice in evolutionarily distinct...

  5. Solvent effects on the thermal isomerization of a rotary molecular motor.

    Science.gov (United States)

    Lubbe, Anouk S; Kistemaker, Jos C M; Smits, Esther J; Feringa, Ben L

    2016-09-29

    As molecular machines move to exciting applications in various environments, the study of medium effects becomes increasingly relevant. It is difficult to predict how, for example, the large apolar structure of a light-driven rotary molecular motor is affected by a biological setting or surface proximity, while for future nanotechnology precise fine tuning and full understanding of the isomerization process are of the utmost importance. Previous investigations into solvent effects have mainly focused on the relatively large solvent-solute interaction of hydrogen bonding or polarization induced by the isomerization process. We present a detailed study of a key step in the rotary process i.e. the thermal helix inversion of a completely apolar rotary molecular motor in 50 different solvents and solvent mixtures. Due to the relative inertness of this probe, we are able to study the influence of subtle solvent-solvent interactions upon the rate of rotation. Statistical analysis reveals which solvent parameters govern the isomerization process.

  6. [Amphioxus ortholog of ECSIT, an evolutionarily conserved adaptor in the Toll and BMP signaling pathways].

    Science.gov (United States)

    Lin, Y H; Zhang, W; Li, J W; Zhang, H W; Chen, D Y

    2017-01-01

    In vertebrates, evolutionarily conserved signaling intermediate in the Toll pathway (ECSIT) interacts with the TNF-receptor associated factor 6 (TRAF6) to regulate the processing of MEKK1, activate NF-κB, and also control BMP target genes. However, the role of ECSIT in invertebrates remains largely unexplored. We performed comparative investigations of the expression, gene structure, and phylogeny of ECSIT, Toll-like receptor (TLR), and Smad4 in the cephalochordate Branchiostoma belcheri. Phylogenetic analysis indicated that, in amphioxus, ECSIT, TLR, and Smad4 form independent clusters at the base of Chordate   clusters. Interestingly, overall gene structures were comparable to those in vertebrate orthologs. Transcripts of AmphiECSIT were detectable at the mid-neural stage, and continued to be expressed in the epithelium of the pharyngeal region at later stages. In adult animals, strong expression was observed in the nerve cord, endostyle, epithelial cells of the gut and wheel organ, genital membrane of the testis, and coelom and lymphoid cavities, what is highly similar to AmphiTLR and AmphiSmad4 expression patterns during development and in adult organisms. Our data suggests that ECSIT is evolutionarily conserved. Its amphioxus ortholog functions during embryonic development and as part of the innate immune system and may be involved in TLR/BMP signaling.

  7. Evolutionary stability of mutualism: interspecific population regulation as an evolutionarily stable strategy

    Science.gov (United States)

    Holland, J. Nathaniel; DeAngelis, Donald L.; Schultz, Stewart T.

    2004-01-01

    Interspecific mutualisms are often vulnerable to instability because low benefit : cost ratios can rapidly lead to extinction or to the conversion of mutualism to parasite–host or predator–prey interactions. We hypothesize that the evolutionary stability of mutualism can depend on how benefits and costs to one mutualist vary with the population density of its partner, and that stability can be maintained if a mutualist can influence demographic rates and regulate the population density of its partner. We test this hypothesis in a model of mutualism with key features of senita cactus (Pachycereus schottii) – senita moth (Upiga virescens) interactions, in which benefits of pollination and costs of larval seed consumption to plant fitness depend on pollinator density. We show that plants can maximize their fitness by allocating resources to the production of excess flowers at the expense of fruit. Fruit abortion resulting from excess flower production reduces pre–adult survival of the pollinating seed–consumer, and maintains its density beneath a threshold that would destabilize the mutualism. Such a strategy of excess flower production and fruit abortion is convergent and evolutionarily stable against invasion by cheater plants that produce few flowers and abort few to no fruit. This novel mechanism of achieving evolutionarily stable mutualism, namely interspecific population regulation, is qualitatively different from other mechanisms invoking partner choice or selective rewards, and may be a general process that helps to preserve mutualistic interactions in nature.

  8. The lateral line confers evolutionarily derived sleep loss in the Mexican cavefish.

    Science.gov (United States)

    Jaggard, James; Robinson, Beatriz G; Stahl, Bethany A; Oh, Ian; Masek, Pavel; Yoshizawa, Masato; Keene, Alex C

    2017-01-15

    Sleep is an essential behavior exhibited by nearly all animals, and disruption of this process is associated with an array of physiological and behavioral deficits. Sleep is defined by changes in sensory gating that reduce sensory input to the brain, but little is known about the neural basis for interactions between sleep and sensory processing. Blind Mexican cavefish comprise an extant surface dwelling form and 29 cave morphs that have independently evolved increased numbers of mechanoreceptive lateral line neuromasts and convergent evolution of sleep loss. Ablation of the lateral line enhanced sleep in the Pachón cavefish population, suggesting that heightened sensory input underlies evolutionarily derived sleep loss. Targeted lateral line ablation and behavioral analysis localized the wake-promoting neuromasts in Pachón cavefish to superficial neuromasts of the trunk and cranial regions. Strikingly, lateral line ablation did not affect sleep in four other cavefish populations, suggesting that distinct neural mechanisms regulate the evolution of sleep loss in independently derived cavefish populations. Cavefish are subject to seasonal changes in food availability, raising the possibility that sensory modulation of sleep is influenced by metabolic state. We found that starvation promotes sleep in Pachón cavefish, and is not enhanced by lateral line ablation, suggesting that functional interactions occur between sensory and metabolic regulation of sleep. Taken together, these findings support a model where sensory processing contributes to evolutionarily derived changes in sleep that are modulated in accordance with food availability. © 2017. Published by The Company of Biologists Ltd.

  9. Affinity and competition for TBP are molecular determinants of gene expression noise.

    Science.gov (United States)

    Ravarani, Charles N J; Chalancon, Guilhem; Breker, Michal; de Groot, Natalia Sanchez; Babu, M Madan

    2016-02-02

    Cell-to-cell variation in gene expression levels (noise) generates phenotypic diversity and is an important phenomenon in evolution, development and disease. TATA-box binding protein (TBP) is an essential factor that is required at virtually every eukaryotic promoter to initiate transcription. While the presence of a TATA-box motif in the promoter has been strongly linked with noise, the molecular mechanism driving this relationship is less well understood. Through an integrated analysis of multiple large-scale data sets, computer simulation and experimental validation in yeast, we provide molecular insights into how noise arises as an emergent property of variable binding affinity of TBP for different promoter sequences, competition between interaction partners to bind the same surface on TBP (to either promote or disrupt transcription initiation) and variable residence times of TBP complexes at a promoter. These determinants may be fine-tuned under different conditions and during evolution to modulate eukaryotic gene expression noise.

  10. Acid-Labile Acyclic Cucurbit[n]uril Molecular Containers for Controlled Release.

    Science.gov (United States)

    Mao, Dake; Liang, Yajun; Liu, Yamin; Zhou, Xianhao; Ma, Jiaqi; Jiang, Biao; Liu, Jia; Ma, Da

    2017-10-02

    Stimuli-responsive molecular containers are of great importance for controlled drug delivery and other biomedical applications. A new type of acid labile acyclic cucurbit[n]uril (CB[n]) molecular containers is presented that can degrade and release the encapsulated cargo at accelerated rates under mildly acidic conditions (pH 5.5-6.5). These containers retain the excellent recognition properties of CB[n]-type hosts. A cell culture study demonstrated that the cellular uptake of cargos could be fine-tuned by complexation with different containers. The release and cell uptake of cargo dye was promoted by acidic pH. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Most m6A RNA modifications in protein-coding regions are evolutionarily unconserved and likely nonfunctional.

    Science.gov (United States)

    Liu, Zhen; Zhang, Jianzhi

    2017-12-08

    Methylation of the adenosine base at the nitrogen-6 position (m6A) is the most prevalent internal posttranscriptional modification of mRNAs in many eukaryotes. Despite the rapid progress in the transcriptome-wide mapping of m6As, identification of proteins responsible for writing, reading, and erasing m6As, and elucidation of m6A functions in splicing, RNA stability, translation, and other processes, it is unknown whether most observed m6A modifications are functional. To address this question, we respectively analyze the evolutionary conservation of yeast and human m6As in protein-coding regions. Relative to comparable unmethylated As, m6As are overall no more conserved in yeasts and only slightly more conserved in mammals. Furthermore, yeast m6As and comparable unmethylated As have no significant difference in single nucleotide polymorphism (SNP) density or SNP site frequency spectrum. The same is true in human. The methylation status of a gene, not necessarily the specific sites methylated in the gene, is subject to purifying selection for no more than ∼20% of m6A-modified genes. These observations suggest that most m6A modifications in protein-coding regions are nonfunctional and nonadaptive, probably resulting from off-target activities of m6A methyltransferases. In addition, our reanalysis invalidates the recent claim of positive selection for newly acquired m6A modifications in human evolution. Regarding the small number of evolutionarily conserved m6As, evidence suggests that a large proportion of them are likely functional; they should be prioritized in future functional characterizations of m6As. Together, these findings have important implications for understanding the biological significance of m6A and other posttranscriptional modifications. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. Evolutionarily Conserved Repulsive Guidance Role of Slit in the Silkworm Bombyx mori

    Science.gov (United States)

    Liu, Chun; Cui, Wei-Zheng; Mu, Zhi-Mei; Zhao, Xiao; Liu, Qing-Xin

    2014-01-01

    Axon guidance molecule Slit is critical for the axon repulsion in neural tissues, which is evolutionarily conserved from planarians to humans. However, the function of Slit in the silkworm Bombyx mori was unknown. Here we showed that the structure of Bombyx mori Slit (BmSlit) was different from that in most other species in its C-terminal sequence. BmSlit was localized in the midline glial cell, the neuropil, the tendon cell, the muscle and the silk gland and colocalized with BmRobo1 in the neuropil, the muscle and the silk gland. Knock-down of Bmslit by RNA interference (RNAi) resulted in abnormal development of axons and muscles. Our results suggest that BmSlit has a repulsive role in axon guidance and muscle migration. Moreover, the localization of BmSlit in the silk gland argues for its important function in the development of the silk gland. PMID:25285792

  13. Evolutionarily conserved coupling of adaptive and excitable networks mediates eukaryotic chemotaxis

    Science.gov (United States)

    Tang, Ming; Wang, Mingjie; Shi, Changji; Iglesias, Pablo A.; Devreotes, Peter N.; Huang, Chuan-Hsiang

    2014-10-01

    Numerous models explain how cells sense and migrate towards shallow chemoattractant gradients. Studies show that an excitable signal transduction network acts as a pacemaker that controls the cytoskeleton to drive motility. Here we show that this network is required to link stimuli to actin polymerization and chemotactic motility and we distinguish the various models of chemotaxis. First, signalling activity is suppressed towards the low side in a gradient or following removal of uniform chemoattractant. Second, signalling activities display a rapid shut off and a slower adaptation during which responsiveness to subsequent test stimuli decline. Simulations of various models indicate that these properties require coupled adaptive and excitable networks. Adaptation involves a G-protein-independent inhibitor, as stimulation of cells lacking G-protein function suppresses basal activities. The salient features of the coupled networks were observed for different chemoattractants in Dictyostelium and in human neutrophils, suggesting an evolutionarily conserved mechanism for eukaryotic chemotaxis.

  14. EAG2 potassium channel with evolutionarily conserved function as a brain tumor target

    Science.gov (United States)

    Huang, Xi; He, Ye; Dubuc, Adrian M.; Hashizume, Rintaro; Zhang, Wei; Reimand, Jüri; Yang, Huanghe; Wang, Tongfei A.; Stehbens, Samantha J.; Younger, Susan; Barshow, Suzanne; Zhu, Sijun; Cooper, Michael K.; Peacock, John; Ramaswamy, Vijay; Garzia, Livia; Wu, Xiaochong; Remke, Marc; Forester, Craig M.; Kim, Charles C.; Weiss, William A.; James, C. David; Shuman, Marc A.; Bader, Gary D.; Mueller, Sabine; Taylor, Michael D.; Jan, Yuh Nung; Jan, Lily Yeh

    2015-01-01

    Over 20% of the drugs for treating human diseases target ion channels, however, no cancer drug approved by the U.S. Food and Drug Administration (FDA) is intended to target an ion channel. Here, we demonstrate the evolutionarily conserved function of EAG2 potassium channel in promoting brain tumor growth and metastasis, delineate downstream pathways and uncover a mechanism for different potassium channels to functionally corporate and regulate mitotic cell volume and tumor progression. We show that EAG2 potassium channel is enriched at the trailing edge of migrating MB cells to regulate local cell volume dynamics, thereby facilitating cell motility. We identify the FDA-approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings thus illustrate the potential of targeting ion channels in cancer treatment. PMID:26258683

  15. Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges.

    Science.gov (United States)

    Lovci, Michael T; Ghanem, Dana; Marr, Henry; Arnold, Justin; Gee, Sherry; Parra, Marilyn; Liang, Tiffany Y; Stark, Thomas J; Gehman, Lauren T; Hoon, Shawn; Massirer, Katlin B; Pratt, Gabriel A; Black, Douglas L; Gray, Joe W; Conboy, John G; Yeo, Gene W

    2013-12-01

    Alternative splicing (AS) enables programmed diversity of gene expression across tissues and development. We show here that binding in distal intronic regions (>500 nucleotides (nt) from any exon) by Rbfox splicing factors important in development is extensive and is an active mode of splicing regulation. Similarly to exon-proximal sites, distal sites contain evolutionarily conserved GCATG sequences and are associated with AS activation and repression upon modulation of Rbfox abundance in human and mouse experimental systems. As a proof of principle, we validated the activity of two specific Rbfox enhancers in KIF21A and ENAH distal introns and showed that a conserved long-range RNA-RNA base-pairing interaction (an RNA bridge) is necessary for Rbfox-mediated exon inclusion in the ENAH gene. Thus we demonstrate a previously unknown RNA-mediated mechanism for AS control by distally bound RNA-binding proteins.

  16. The dinoflagellates Durinskia baltica and Kryptoperidinium foliaceum retain functionally overlapping mitochondria from two evolutionarily distinct lineages

    Directory of Open Access Journals (Sweden)

    Keeling Patrick J

    2007-09-01

    Full Text Available Abtract Background The dinoflagellates Durinskia baltica and Kryptoperidinium foliaceum are distinguished by the presence of a tertiary plastid derived from a diatom endosymbiont. The diatom is fully integrated with the host cell cycle and is so altered in structure as to be difficult to recognize it as a diatom, and yet it retains a number of features normally lost in tertiary and secondary endosymbionts, most notably mitochondria. The dinoflagellate host is also reported to retain mitochondrion-like structures, making these cells unique in retaining two evolutionarily distinct mitochondria. This redundancy raises the question of whether the organelles share any functions in common or have distributed functions between them. Results We show that both host and endosymbiont mitochondrial genomes encode genes for electron transport proteins. We have characterized cytochrome c oxidase 1 (cox1, cytochrome oxidase 2 (cox2, cytochrome oxidase 3 (cox3, cytochrome b (cob, and large subunit of ribosomal RNA (LSUrRNA of endosymbiont mitochondrial ancestry, and cox1 and cob of host mitochondrial ancestry. We show that all genes are transcribed and that those ascribed to the host mitochondrial genome are extensively edited at the RNA level, as expected for a dinoflagellate mitochondrion-encoded gene. We also found evidence for extensive recombination in the host mitochondrial genes and that recombination products are also transcribed, as expected for a dinoflagellate. Conclusion Durinskia baltica and K. foliaceum retain two mitochondria from evolutionarily distinct lineages, and the functions of these organelles are at least partially overlapping, since both express genes for proteins in electron transport.

  17. RNA editing in bacteria recodes multiple proteins and regulates an evolutionarily conserved toxin-antitoxin system.

    Science.gov (United States)

    Bar-Yaacov, Dan; Mordret, Ernest; Towers, Ruth; Biniashvili, Tammy; Soyris, Clara; Schwartz, Schraga; Dahan, Orna; Pilpel, Yitzhak

    2017-10-01

    Adenosine (A) to inosine (I) RNA editing is widespread in eukaryotes. In prokaryotes, however, A-to-I RNA editing was only reported to occur in tRNAs but not in protein-coding genes. By comparing DNA and RNA sequences of Escherichia coli, we show for the first time that A-to-I editing occurs also in prokaryotic mRNAs and has the potential to affect the translated proteins and cell physiology. We found 15 novel A-to-I editing events, of which 12 occurred within known protein-coding genes where they always recode a tyrosine (TAC) into a cysteine (TGC) codon. Furthermore, we identified the tRNA-specific adenosine deaminase (tadA) as the editing enzyme of all these editing sites, thus making it the first identified RNA editing enzyme that modifies both tRNAs and mRNAs. Interestingly, several of the editing targets are self-killing toxins that belong to evolutionarily conserved toxin-antitoxin pairs. We focused on hokB, a toxin that confers antibiotic tolerance by growth inhibition, as it demonstrated the highest level of such mRNA editing. We identified a correlated mutation pattern between the edited and a DNA hard-coded Cys residue positions in the toxin and demonstrated that RNA editing occurs in hokB in two additional bacterial species. Thus, not only the toxin is evolutionarily conserved but also the editing itself within the toxin is. Finally, we found that RNA editing in hokB increases as a function of cell density and enhances its toxicity. Our work thus demonstrates the occurrence, regulation, and functional consequences of RNA editing in bacteria. © 2017 Bar-Yaacov et al.; Published by Cold Spring Harbor Laboratory Press.

  18. Topology and parameter data of thirteen non-natural amino acids for molecular simulations with CHARMM22.

    Science.gov (United States)

    Olubiyi, Olujide O; Strodel, Birgit

    2016-12-01

    In this article we provide a data package containing the topology files and parameters compatible with the CHARMM22 force field for thirteen non-natural amino acids. The force field parameters were derived based on quantum mechanical (QM) calculations involving geometry optimization and potential energy surface scanning at the HF 6-31G(d) and HF 6-311G(d,p) levels of theory. The resulting energy data points were fitted to mathematical functions representing each component of the CHARMM22 force field. Further fine-tuning of the parameters utilized molecular mechanics energies, which were iteratively calculated and compared to the corresponding QM values until the latter were satisfactorily reproduced. The final force field data were validated with molecular dynamics simulations in explicit solvent conditions.

  19. Topology and parameter data of thirteen non-natural amino acids for molecular simulations with CHARMM22

    Directory of Open Access Journals (Sweden)

    Olujide O. Olubiyi

    2016-12-01

    Full Text Available In this article we provide a data package containing the topology files and parameters compatible with the CHARMM22 force field for thirteen non-natural amino acids. The force field parameters were derived based on quantum mechanical (QM calculations involving geometry optimization and potential energy surface scanning at the HF 6-31G(d and HF 6-311G(d,p levels of theory. The resulting energy data points were fitted to mathematical functions representing each component of the CHARMM22 force field. Further fine-tuning of the parameters utilized molecular mechanics energies, which were iteratively calculated and compared to the corresponding QM values until the latter were satisfactorily reproduced. The final force field data were validated with molecular dynamics simulations in explicit solvent conditions.

  20. Membrane vesiculation induced by proteins of the dengue virus envelope studied by molecular dynamics simulations

    Science.gov (United States)

    de Oliveira dos Santos Soares, Ricardo; Oliveira Bortot, Leandro; van der Spoel, David; Caliri, Antonio

    2017-12-01

    Biological membranes are continuously remodeled in the cell by specific membrane-shaping machineries to form, for example, tubes and vesicles. We examine fundamental mechanisms involved in the vesiculation processes induced by a cluster of envelope (E) and membrane (M) proteins of the dengue virus (DENV) using molecular dynamics simulations and a coarse-grained model. We show that an arrangement of three E-M heterotetramers (EM3) works as a bending unit and an ordered cluster of five such units generates a closed vesicle, reminiscent of the virus budding process. In silico mutagenesis of two charged residues of the anchor helices of the envelope proteins of DENV shows that Arg-471 and Arg-60 are fundamental to produce bending stress on the membrane. The fine-tuning between the size of the EM3 unit and its specific bending action suggests this protein unit is an important factor in determining the viral particle size.

  1. Molecular Syntheses of Extended Materials

    Science.gov (United States)

    Paley, Daniel W.

    Bottom-up molecular synthesis is a route to chemically and crystallographically uniform polymers and solid-state materials. Through the use of molecular precursors, we gain atomic-level control of functionality and fine-tuning of the collective properties of materials. This dissertation presents two studies that demonstrate this approach. Ring-opening alkyne metathesis polymerization is a possible approach to monodisperse conjugated polymers, but its applications have been limited by difficult syntheses and high air sensitivity of known organometallic ROAMP initiators. We designed a dimeric, air-stable molybdenum alkylidyne with a tris(phenolate) supporting ligand. The precatalyst is activated by addition of methanol and polymerizes cyclooctynes with excellent chemical selectivity and functional group tolerance. The Nuckolls and Roy groups have introduced a new family of solid-state compounds synthesized from cobalt chalcogenide clusters Co6Q 8(PR3)6 and fullerenes. The first examples of these materials crystallized in superatom lattices with the symmetry of simple inorganic solids CdI2 (P-3m1) and NaCl (Fm-3m). This dissertation reveals that further members of the family feature extraordinary diversity of structure, including a pseudo-trigonal array of fulleride dimers in [Co 6Te8(PEt3)6]2[C140 ][C70]2 and a heterolayered van der Waals cocrystal [Co6Se8(PEt2phen)6][C 60]5. In addition to these unusual crystal structures, this dissertation presents a method for assigning redox states from crystallographic data in Co6Q8 clusters. Finally, a detailed guide to the collection and solution of single-crystal X-ray data is presented. The guide is intended for independent study by new crystallographers.

  2. Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety.

    Science.gov (United States)

    Birn, R M; Shackman, A J; Oler, J A; Williams, L E; McFarlin, D R; Rogers, G M; Shelton, S E; Alexander, A L; Pine, D S; Slattery, M J; Davidson, R J; Fox, A S; Kalin, N H

    2014-08-01

    Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate. Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain regions underlies primates' capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex, a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.

  3. An evolutionarily conserved glycine-tyrosine motif forms a folding core in outer membrane proteins.

    Directory of Open Access Journals (Sweden)

    Marcin Michalik

    Full Text Available An intimate interaction between a pair of amino acids, a tyrosine and glycine on neighboring β-strands, has been previously reported to be important for the structural stability of autotransporters. Here, we show that the conservation of this interacting pair extends to nearly all major families of outer membrane β-barrel proteins, which are thought to have originated through duplication events involving an ancestral ββ hairpin. We analyzed the function of this motif using the prototypical outer membrane protein OmpX. Stopped-flow fluorescence shows that two folding processes occur in the millisecond time regime, the rates of which are reduced in the tyrosine mutant. Folding assays further demonstrate a reduction in the yield of folded protein for the mutant compared to the wild-type, as well as a reduction in thermal stability. Taken together, our data support the idea of an evolutionarily conserved 'folding core' that affects the folding, membrane insertion, and thermal stability of outer membrane protein β-barrels.

  4. Genetic differentiation and selection against migrants in evolutionarily replicated extreme environments.

    Science.gov (United States)

    Plath, Martin; Pfenninger, Markus; Lerp, Hannes; Riesch, Rüdiger; Eschenbrenner, Christoph; Slattery, Patrick A; Bierbach, David; Herrmann, Nina; Schulte, Matthias; Arias-Rodriguez, Lenin; Rimber Indy, Jeane; Passow, Courtney; Tobler, Michael

    2013-09-01

    We investigated mechanisms of reproductive isolation in livebearing fishes (genus Poecilia) inhabiting sulfidic and nonsulfidic habitats in three replicate river drainages. Although sulfide spring fish convergently evolved divergent phenotypes, it was unclear if mechanisms of reproductive isolation also evolved convergently. Using microsatellites, we found strongly reduced gene flow between adjacent populations from different habitat types, suggesting that local adaptation to sulfidic habitats repeatedly caused the emergence of reproductive isolation. Reciprocal translocation experiments indicate strong selection against immigrants into sulfidic waters, but also variation among drainages in the strength of selection against immigrants into nonsulfidic waters. Mate choice experiments revealed the evolution of assortative mating preferences in females from nonsulfidic but not from sulfidic habitats. The inferred strength of sexual selection against immigrants (RI(s)) was negatively correlated with the strength of natural selection (RI(m)), a pattern that could be attributed to reinforcement, whereby natural selection strengthens behavioral isolation due to reduced hybrid fitness. Overall, reproductive isolation and genetic differentiation appear to be replicated and direct consequences of local adaptation to sulfide spring environments, but the relative contributions of different mechanisms of reproductive isolation vary across these evolutionarily independent replicates, highlighting both convergent and nonconvergent evolutionary trajectories of populations in each drainage. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

  5. Honesty and cheating in cleaning symbioses: evolutionarily stable strategies defined by variable pay-offs.

    Science.gov (United States)

    Freckleton, Robert P; Côté, Isabelle M

    2003-01-01

    Game-theory models have indicated that the evolution of mixed strategies of cheating and honesty in many mutualisms is unlikely. Moreover, the mutualistic nature of interspecific interactions has often been difficult to demonstrate empirically. We present a game-theory analysis that addresses these issues using cleaning symbioses among fishes as a model system. We show that the assumption of constant pay-offs in existing models prevents the evolution of evolutionarily stable mixed strategies of cheating and honesty. However, when interaction pay-offs are assumed to be density dependent, mixed strategies of cheating and honesty become possible. In nature, cheating by clients often takes the form of retaliation by clients against cheating cleaners, and we show that mixed strategies of cheating and honesty evolve within the cleaner population when clients retaliate. The dynamics of strategies include both negative and positive effects of interactions, as well as density-dependent interactions. Consequently, the effects of perturbations to the model are nonlinear. In particular, we show that under certain conditions the removal of cleaners may have little impact on client populations. This indicates that the underlying mutualistic nature of some interspecific interactions may be difficult to demonstrate using simple manipulation experiments. PMID:12614580

  6. Ecological interactions are evolutionarily conserved across the entire tree of life.

    Science.gov (United States)

    Gómez, José M; Verdú, Miguel; Perfectti, Francisco

    2010-06-17

    Ecological interactions are crucial to understanding both the ecology and the evolution of organisms. Because the phenotypic traits regulating species interactions are largely a legacy of their ancestors, it is widely assumed that ecological interactions are phylogenetically conserved, with closely related species interacting with similar partners. However, the existing empirical evidence is inadequate to appropriately evaluate the hypothesis of phylogenetic conservatism in ecological interactions, because it is both ecologically and taxonomically biased. In fact, most studies on the evolution of ecological interactions have focused on specialized organisms, such as some parasites or insect herbivores, belonging to a limited subset of the overall tree of life. Here we study the evolution of host use in a large and diverse group of interactions comprising both specialist and generalist acellular, unicellular and multicellular organisms. We show that, as previously found for specialized interactions, generalized interactions can be evolutionarily conserved. Significant phylogenetic conservatism of interaction patterns was equally likely to occur in symbiotic and non-symbiotic interactions, as well as in mutualistic and antagonistic interactions. Host-use differentiation among species was higher in phylogenetically conserved clades, irrespective of their generalization degree and taxonomic position within the tree of life. Our findings strongly suggest a shared pattern in the organization of biological systems through evolutionary time, mediated by marked conservatism of ecological interactions among taxa.

  7. The effect of travel loss on evolutionarily stable distributions of populations in space.

    Science.gov (United States)

    Deangelis, Donald L; Wolkowicz, Gail S K; Lou, Yuan; Jiang, Yuexin; Novak, Mark; Svanbäck, Richard; Araújo, Márcio S; Jo, Youngseung; Cleary, Erin A

    2011-07-01

    A key assumption of the ideal free distribution (IFD) is that there are no costs in moving between habitat patches. However, because many populations exhibit more or less continuous population movement between patches and traveling cost is a frequent factor, it is important to determine the effects of costs on expected population movement patterns and spatial distributions. We consider a food chain (tritrophic or bitrophic) in which one species moves between patches, with energy cost or mortality risk in movement. In the two-patch case, assuming forced movement in one direction, an evolutionarily stable strategy requires bidirectional movement, even if costs during movement are high. In the N-patch case, assuming that at least one patch is linked bidirectionally to all other patches, optimal movement rates can lead to source-sink dynamics where patches with negative growth rates are maintained by other patches with positive growth rates. As well, dispersal between patches is not balanced (even in the two-patch case), leading to a deviation from the IFD. Our results indicate that cost-associated forced movement can have important consequences for spatial metapopulation dynamics. Relevance to marine reserve design and the study of stream communities subject to drift is discussed.

  8. An Evolutionarily Conserved Pathway Essential for Orsay Virus Infection of Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Hongbing Jiang

    2017-09-01

    Full Text Available Many fundamental biological discoveries have been made in Caenorhabditis elegans. The discovery of Orsay virus has enabled studies of host-virus interactions in this model organism. To identify host factors critical for Orsay virus infection, we designed a forward genetic screen that utilizes a virally induced green fluorescent protein (GFP reporter. Following chemical mutagenesis, two Viro (virus induced reporter off mutants that failed to express GFP were mapped to sid-3, a nonreceptor tyrosine kinase, and B0280.13 (renamed viro-2, an ortholog of human Wiskott-Aldrich syndrome protein (WASP. Both mutants yielded Orsay virus RNA levels comparable to that of the residual input virus, suggesting that they are not permissive for Orsay virus replication. In addition, we demonstrated that both genes affect an early prereplication stage of Orsay virus infection. Furthermore, it is known that the human ortholog of SID-3, activated CDC42-associated kinase (ACK1/TNK2, is capable of phosphorylating human WASP, suggesting that VIRO-2 may be a substrate for SID-3 in C. elegans. A targeted RNA interference (RNAi knockdown screen further identified the C. elegans gene nck-1, which has a human ortholog that interacts with TNK2 and WASP, as required for Orsay virus infection. Thus, genetic screening in C. elegans identified critical roles in virus infection for evolutionarily conserved genes in a known human pathway.

  9. The evolutionarily conserved E3 ubiquitin ligase AtCHIP contributes to plant immunity

    Directory of Open Access Journals (Sweden)

    Xin eLi

    2016-03-01

    Full Text Available Plants possess a sophisticated immune system to recognize and respond to microbial threats in their environment. The level of immune signaling must be tightly regulated so that immune responses can be quickly activated in the presence of pathogens, while avoiding autoimmunity. HSP90s, along with their diverse array of co-chaperones, forms chaperone complexes that have been shown to play both positive and negative roles in regulating the accumulation of immune receptors and regulators. In this study, we examined the role of AtCHIP, an evolutionarily conserved E3 ligase that was known to interact with chaperones including HSP90s in multicellular organisms including fruit fly, C. elegans, plants and human. Atchip knockout mutants display enhanced disease susceptibility to a virulent oomycete pathogen, and overexpression of AtCHIP causes enhanced disease resistance at low temperature. Although CHIP was reported to target HSP90 for ubiquitination and degradation, accumulation of HSP90.3 was not affected in Atchip plants. In addition, protein accumulation of nucleotide-binding, leucine-rich repeat domain immune receptor (NLR SNC1 is not altered in Atchip mutant. Thus, while AtCHIP plays a role in immunity, it does not seem to regulate the turnover of HSP90 or SNC1. Further investigation is needed in order to determine the exact mechanism behind AtCHIP’s role in regulating plant immune responses.

  10. A comprehensive test of evolutionarily increased competitive ability in a highly invasive plant species

    Science.gov (United States)

    Joshi, Srijana; Gruntman, Michal; Bilton, Mark; Seifan, Merav; Tielbörger, Katja

    2014-01-01

    Background and Aims A common hypothesis to explain plants' invasive success is that release from natural enemies in the introduced range selects for reduced allocation to resistance traits and a subsequent increase in resources available for growth and competitive ability (evolution of increased competitive ability, EICA). However, studies that have investigated this hypothesis have been incomplete as they either did not test for all aspects of competitive ability or did not select appropriate competitors. Methods Here, the prediction of increased competitive ability was examined with the invasive plant Lythrum salicaria (purple loosestrife) in a set of common-garden experiments that addressed these aspects by carefully distinguishing between competitive effect and response of invasive and native plants, and by using both intraspecific and interspecific competition settings with a highly vigorous neighbour, Urtica dioica (stinging nettle), which occurs in both ranges. Key Results While the intraspecific competition results showed no differences in competitive effect or response between native and invasive plants, the interspecific competition experiment revealed greater competitive response and effect of invasive plants in both biomass and seed production. Conclusions The use of both intra- and interspecific competition experiments in this study revealed opposing results. While the first experiment refutes the EICA hypothesis, the second shows strong support for it, suggesting evolutionarily increased competitive ability in invasive populations of L. salicaria. It is suggested that the use of naturally co-occurring heterospecifics, rather than conspecifics, may provide a better evaluation of the possible evolutionary shift towards greater competitive ability. PMID:25301818

  11. ELISA: Structure-Function Inferences based on statistically significant and evolutionarily inspired observations

    Directory of Open Access Journals (Sweden)

    DeLisi Charles

    2003-09-01

    Full Text Available Abstract The problem of functional annotation based on homology modeling is primary to current bioinformatics research. Researchers have noted regularities in sequence, structure and even chromosome organization that allow valid functional cross-annotation. However, these methods provide a lot of false negatives due to limited specificity inherent in the system. We want to create an evolutionarily inspired organization of data that would approach the issue of structure-function correlation from a new, probabilistic perspective. Such organization has possible applications in phylogeny, modeling of functional evolution and structural determination. ELISA (Evolutionary Lineage Inferred from Structural Analysis, http://romi.bu.edu/elisa is an online database that combines functional annotation with structure and sequence homology modeling to place proteins into sequence-structure-function "neighborhoods". The atomic unit of the database is a set of sequences and structural templates that those sequences encode. A graph that is built from the structural comparison of these templates is called PDUG (protein domain universe graph. We introduce a method of functional inference through a probabilistic calculation done on an arbitrary set of PDUG nodes. Further, all PDUG structures are mapped onto all fully sequenced proteomes allowing an easy interface for evolutionary analysis and research into comparative proteomics. ELISA is the first database with applicability to evolutionary structural genomics explicitly in mind. Availability: The database is available at http://romi.bu.edu/elisa.

  12. Specific expression of LATERAL SUPPRESSOR is controlled by an evolutionarily conserved 3' enhancer.

    Science.gov (United States)

    Raatz, Bodo; Eicker, Andrea; Schmitz, Gregor; Fuss, Elisabeth; Müller, Dörte; Rossmann, Susanne; Theres, Klaus

    2011-11-01

    Aerial plant architecture is largely based on the activity of axillary meristems (AMs), initiated in the axils of leaves. The Arabidopsis gene LATERAL SUPPRESSOR (LAS), which is expressed in well-defined domains at the adaxial boundary of leaf primordia, is a key regulator of AM formation. The precise definition of organ boundaries is an essential step for the formation of new organs in general and for meristem initiation; however, mechanisms leading to these specific patterns are not well understood. To increase understanding of how the highly specific transcript accumulation in organ boundary regions is established, we investigated the LAS promoter. Analysis of deletion constructs revealed that an essential enhancer necessary for complementation is situated about 3.2 kb downstream of the LAS open reading frame. This enhancer is sufficient to confer promoter specificity as upstream sequences in LAS could be replaced by non-specific promoters, such as the 35S minimal promoter. Further promoter swapping experiments using the PISTILLATA or the full 35S promoter demonstrated that the LAS 3' enhancer also has suppressor functions, largely overwriting the activity of different 5' promoters. Phylogenetic analyses suggest that LAS function and regulation are evolutionarily highly conserved. Homologous elements in downstream regulatory sequences were found in all LAS orthologs, including grasses. Transcomplementation experiments demonstrated the functional conservation of non-coding sequences between Solanum lycopersicum (tomato) and Arabidopsis. In summary, our results show that a highly conserved enhancer/suppressor element is the main regulatory module conferring the boundary-specific expression of LAS. © 2011 The Authors. The Plant Journal © 2011 Blackwell Publishing Ltd.

  13. FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells.

    Science.gov (United States)

    Katoh, Yuriko; Katoh, Masaru

    2006-03-01

    WNT, FGF and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. FGF16, FGF18, and FGF20 genes are targets of WNT-mediated TCF/LEF-beta-catenin-BCL9/BCL9L-PYGO transcriptional complex. SPROUTY (SPRY) and SPRED family genes encode inhibitors for receptor tyrosine kinase signaling cascades, such as those of FGF receptor family members and EGF receptor family members. Here, transcriptional regulation of SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3 genes by WNT/beta-catenin signaling cascade was investigated by using bioinformatics and human intelligence (humint). Because double TCF/LEF-binding sites were identified within the 5'-promoter region of human SPRY4 gene, comparative genomics analyses on SPRY4 orthologs were further performed. SPRY4-FGF1 locus at human chromosome 5q31.3 and FGF2-NUDT6-SPATA5-SPRY1 locus at human chromosome 4q27-q28.1 were paralogous regions within the human genome. Chimpanzee SPRY4 gene was identified within NW_107083.1 genome sequence. Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved. SPRY4 gene was identified as the evolutionarily conserved target of WNT/beta-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian SPRY4 orthologs. Human SPRY4 mRNA was expressed in embryonic stem (ES) cells, brain, pancreatic islet, colon cancer, head and neck tumor, melanoma, and pancreatic cancer. WNT signaling activation in progenitor cells leads to the growth regulation of progenitor cells themselves through SPRY4 induction, and also to the growth stimulation of proliferating cells through FGF secretion. Epigenetic silencing and loss-of-function mutations of SPRY4 gene in progenitor cells could lead to carcinogenesis. SPRY4 is the pharmacogenomics target in the fields of oncology and regenerative medicine.

  14. Damping capacity is evolutionarily conserved in the radial silk of orb-weaving spiders.

    Science.gov (United States)

    Kelly, Sean P; Sensenig, Andrew; Lorentz, Kimberly A; Blackledge, Todd A

    2011-09-01

    Orb-weaving spiders depend upon their two-dimensional silk traps to stop insects in mid flight. While the silks used to construct orb webs must be extremely tough to absorb the tremendous kinetic energy of insect prey, webs must also minimize the return of that energy to prey to prevent insects from bouncing out of oscillating webs. We therefore predict that the damping capacity of major ampullate spider silk, which forms the supporting frames and radial threads of orb webs, should be evolutionarily conserved among orb-weaving spiders. We test this prediction by comparing silk from six diverse species of orb spiders. Silk was taken directly from the radii of orb webs and a Nano Bionix test system was used either to sequentially extend the silk to 25% strain in 5% increments while relaxing it fully between each cycle, or to pull virgin silk samples to 15% strain. Damping capacity was then calculated as the percent difference in loading and unloading energies. Damping capacity increased after yield for all species and typically ranged from 40 to 50% within each cycle for sequentially pulled silk and from 50 to 70% for virgin samples. Lower damping at smaller strains may allow orb webs to withstand minor perturbations from wind and small prey while still retaining the ability to capture large insects. The similarity in damping capacity of silk from the radii spun by diverse spiders highlights the importance of energy absorption by silk for orb-weaving spiders. Copyright © 2011 Elsevier GmbH. All rights reserved.

  15. An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression.

    Science.gov (United States)

    Ucar, Olga; Tykocinski, Lars-Oliver; Dooley, James; Liston, Adrian; Kyewski, Bruno

    2013-07-01

    The establishment and maintenance of central tolerance depends to a large extent on the ability of medullary thymic epithelial cells to express a variety of tissue-restricted antigens, the so-called promiscuous gene expression (pGE). Autoimmune regulator (Aire) is to date the best characterised transcriptional regulator known to at least partially coordinate pGE. There is accruing evidence that the expression of Aire-dependent and -independent genes is modulated by higher order chromatin configuration, epigenetic modifications and post-transcriptional control. Given the involvement of microRNAs (miRNAs) as potent post-transcriptional modulators of gene expression, we investigated their role in the regulation of pGE in purified mouse and human thymic epithelial cells (TECs). Microarray profiling of TEC subpopulations revealed evolutionarily conserved cell type and differentiation-specific miRNA signatures with a subset of miRNAs being significantly upregulated during terminal medullary thymic epithelial cell differentiation. The differential regulation of this subset of miRNAs was correlated with Aire expression and some of these miRNAs were misexpressed in the Aire knockout thymus. In turn, the specific absence of miRNAs in TECs resulted in a progressive reduction of Aire expression and pGE, affecting both Aire-dependent and -independent genes. In contrast, the absence of miR-29a only affected the Aire-dependent gene pool. These findings reveal a mutual interdependence of miRNA and Aire. © 2013 The Authors. European Journal of Immunology published byWiley-VCH Verlag GmbH & Co. KGaA Weinheim.

  16. Unique amino acid signatures that are evolutionarily conserved distinguish simple-type, epidermal and hair keratins

    Science.gov (United States)

    Strnad, Pavel; Usachov, Valentyn; Debes, Cedric; Gräter, Frauke; Parry, David A. D.; Omary, M. Bishr

    2011-01-01

    Keratins (Ks) consist of central α-helical rod domains that are flanked by non-α-helical head and tail domains. The cellular abundance of keratins, coupled with their selective cell expression patterns, suggests that they diversified to fulfill tissue-specific functions although the primary structure differences between them have not been comprehensively compared. We analyzed keratin sequences from many species: K1, K2, K5, K9, K10, K14 were studied as representatives of epidermal keratins, and compared with K7, K8, K18, K19, K20 and K31, K35, K81, K85, K86, which represent simple-type (single-layered or glandular) epithelial and hair keratins, respectively. We show that keratin domains have striking differences in their amino acids. There are many cysteines in hair keratins but only a small number in epidermal keratins and rare or none in simple-type keratins. The heads and/or tails of epidermal keratins are glycine and phenylalanine rich but alanine poor, whereas parallel domains of hair keratins are abundant in prolines, and those of simple-type epithelial keratins are enriched in acidic and/or basic residues. The observed differences between simple-type, epidermal and hair keratins are highly conserved throughout evolution. Cysteines and histidines, which are infrequent keratin amino acids, are involved in de novo mutations that are markedly overrepresented in keratins. Hence, keratins have evolutionarily conserved and domain-selectively enriched amino acids including glycine and phenylalanine (epidermal), cysteine and proline (hair), and basic and acidic (simple-type epithelial), which reflect unique functions related to structural flexibility, rigidity and solubility, respectively. Our findings also support the importance of human keratin ‘mutation hotspot’ residues and their wild-type counterparts. PMID:22215855

  17. A comprehensive test of evolutionarily increased competitive ability in a highly invasive plant species.

    Science.gov (United States)

    Joshi, Srijana; Gruntman, Michal; Bilton, Mark; Seifan, Merav; Tielbörger, Katja

    2014-12-01

    A common hypothesis to explain plants' invasive success is that release from natural enemies in the introduced range selects for reduced allocation to resistance traits and a subsequent increase in resources available for growth and competitive ability (evolution of increased competitive ability, EICA). However, studies that have investigated this hypothesis have been incomplete as they either did not test for all aspects of competitive ability or did not select appropriate competitors. Here, the prediction of increased competitive ability was examined with the invasive plant Lythrum salicaria (purple loosestrife) in a set of common-garden experiments that addressed these aspects by carefully distinguishing between competitive effect and response of invasive and native plants, and by using both intraspecific and interspecific competition settings with a highly vigorous neighbour, Urtica dioica (stinging nettle), which occurs in both ranges. While the intraspecific competition results showed no differences in competitive effect or response between native and invasive plants, the interspecific competition experiment revealed greater competitive response and effect of invasive plants in both biomass and seed production. The use of both intra- and interspecific competition experiments in this study revealed opposing results. While the first experiment refutes the EICA hypothesis, the second shows strong support for it, suggesting evolutionarily increased competitive ability in invasive populations of L. salicaria. It is suggested that the use of naturally co-occurring heterospecifics, rather than conspecifics, may provide a better evaluation of the possible evolutionary shift towards greater competitive ability. © The Author 2014. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Evolutionarily conserved cytogenetic changes in hematological malignancies of dogs and humans--man and his best friend share more than companionship.

    Science.gov (United States)

    Breen, Matthew; Modiano, Jaime F

    2008-01-01

    The pathophysiological similarities shared by many forms of human and canine disease, combined with the sophisticated genomic resources now available for the dog, have placed 'man's best friend' in a position of high visibility as a model system for a variety of biomedical concerns, including cancer. The importance of nonrandom cytogenetic abnormalities in human leukemia and lymphoma was recognized over 40 years ago, but the mechanisms of genome reorganization remain incompletely understood. The development of molecular cytogenetics, using fluorescence in situ hybridization (FISH) technology, has played a significant role in our understanding of cancer biology by providing a means for 'interrogating' tumor cells for a variety of gross genetic changes in the form of either numerical or structural chromosome aberrations. Here, we have identified cytogenetic abnormalities in naturally occurring canine hematopoietic tumors that are evolutionarily conserved compared with those that are considered characteristic of the corresponding human condition. These data suggest that humans and dogs share an ancestrally retained pathogenetic basis for cancer and that cytogenetic evaluation of canine tumors may provide greater insight into the biology of tumorigenesis.

  19. An evolutionarily conserved arginine is essential for Tre1 G protein-coupled receptor function during germ cell migration in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Angela R Kamps

    Full Text Available BACKGROUND: G protein-coupled receptors (GPCRs play central roles in mediating cellular responses to environmental signals leading to changes in cell physiology and behaviors, including cell migration. Numerous clinical pathologies including metastasis, an invasive form of cell migration, have been linked to abnormal GPCR signaling. While the structures of some GPCRs have been defined, the in vivo roles of conserved amino acid residues and their relationships to receptor function are not fully understood. Trapped in endoderm 1 (Tre1 is an orphan receptor of the rhodopsin class that is necessary for primordial germ cell migration in Drosophila melanogaster embryos. In this study, we employ molecular genetic approaches to identify residues in Tre1 that are critical to its functions in germ cell migration. METHODOLOGY/PRINCIPAL FINDINGS: First, we show that the previously reported scattershot mutation is an allele of tre1. The scattershot allele results in an in-frame deletion of 8 amino acids at the junction of the third transmembrane domain and the second intracellular loop of Tre1 that dramatically impairs the function of this GPCR in germ cell migration. To further refine the molecular basis for this phenotype, we assayed the effects of single amino acid substitutions in transgenic animals and determined that the arginine within the evolutionarily conserved E/N/DRY motif is critical for receptor function in mediating germ cell migration within an intact developing embryo. CONCLUSIONS/SIGNIFICANCE: These structure-function studies of GPCR signaling in native contexts will inform future studies into the basic biology of this large and clinically important family of receptors.

  20. First-principles studies on electronic properties of Oligo-p-phenylene molecular device

    Science.gov (United States)

    Nagarajan, V.; Chandiramouli, R.

    2018-01-01

    The electronic properties of Oligo-p-phenylene molecular device are studied through density functional theory (DFT) in combination with non-equilibrium Green's function (NEGF). The electronic transport properties of Oligo-p-phenylene molecular device are investigated in terms of I-V characteristics, transmission spectrum and total density of states (TDOS). The TDOS gets modified with the number of phenyl units present in the device and also the applied bias voltage influence Oligo-p-phenylene molecular device. The density of charge along Oligo-p-phenylene molecular device is observed in both the conduction band and in the valence band upon increasing bias voltage. The transmission spectrum of Oligo-p-phenylene molecular device provides the insights on the transition of electrons across various energy intervals. The results of the present work clearly show that Oligo-p-phenylene molecular device can be utilized as negative differential resistance (NDR) device and its NDR property can be fine-tuned with the bias voltage and also by the number of phenyl units.

  1. [Molecular Mechanisms of Circadian Rhythm and Sleep Homeostasis].

    Science.gov (United States)

    Kon, Kazuhiro; Ode, Koji L; Ueda, Hiroki R

    2017-03-01

    Sleep-wake cycle is controlled by the interplay between circadian rhythm and sleep homeostasis. Genetic studies, through the discovery of mutants with altered sleep-wake behaviors, have explored the molecular components that regulate our daily rhythms. In mammalian circadian clocks, negative-feedback loops composed of a set of transcription activators and inhibitors generate a cell-autonomous oscillation of transcriptional activity. Recent studies further discovered that such transcriptional feedback is controlled through post-translational modifications for the fine-tuning of the oscillation period. Compared to circadian clocks, the canonical molecular model for sleep homeostasis is not established yet. However, recent advances in mammalian forward and reverse genetic studies discovered several genes that regulate sleep duration. Interestingly, these genes include ion channels and kinases, which potentially modify these channels. A part of sleep-related ion channels is involved in Ca2+-dependent hyperpolarization of the neuronal membrane potential. Computational models suggest that the hyperpolarization pathway underlies the firing patterns observed in the cortical pyramidal neurons during sleep. Thus, ion channels controlling the membrane potential of the cortical neurons may be involved in sleep homeostasis.

  2. Efficient human immunodeficiency virus replication requires a fine-tuned level of transcription

    NARCIS (Netherlands)

    Marzio, Giuseppe; Vink, Monique; Verhoef, Koen; de Ronde, Anthony; Berkhout, Ben

    2002-01-01

    Transcription represents a crucial step in the life cycle of human immunodeficiency virus (HIV) and is highly regulated. Here we show that the strength of the viral long terminal repeat (LTR) promoter is optimized for efficient replication. Artificially increasing the rate of LTR-driven

  3. Fine-tuning the 'plant domestication-reduced defense' hypothesis: specialist vs generalist herbivores.

    Science.gov (United States)

    Gaillard, Mickaël D P; Glauser, Gaétan; Robert, Christelle A M; Turlings, Ted C J

    2017-09-06

    Domesticated plants are assumed to have weakened chemical defenses. We argue, however, that artificial selection will have maintained defense traits against specialized herbivores that have coexisted with the crops throughout their domestication. We assessed the performance of eight species of insect herbivores from three feeding guilds on six European maize lines and six populations of their wild ancestor, teosinte. A metabolomics approach was used in an attempt to identify compounds responsible for observed differences in insect performance. Insects consistently performed better on maize than on teosinte. As hypothesized, this difference was greater for generalist herbivores that are normally not found on teosinte. We also found clear differences in defense metabolites among the different genotypes, but none that consistently correlated with differences in performance. Concentrations of benzoxazinoids, the main chemical defense in maize, tended to be higher in leaves of teosinte, but the reverse was true for the roots. It appears that chemical defenses that target specialized insects are still present at higher concentrations in cultivated maize than compounds that are more effective against generalists. These weakened broad-spectrum defenses in crops may explain the successes of novel pests. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  4. Intracellular accommodation of rhizobia in legume host cell: the fine-tuning of the endomembrane system

    NARCIS (Netherlands)

    Gavrin, A.Y.

    2015-01-01

    The symbiosis of legumes with rhizobia leads to the formation of root nodules. Rhizobia which are hosted inside specialized infected cells are surrounded by hostderived membranes, forming symbiosomes. Although it is known that symbiosome formation involves proliferation of membranes and changing of

  5. Dancing to a Different Tune: Adaptive Evolution Fine-Tunes Protein Dynamics

    Science.gov (United States)

    2015-09-01

    reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite...29] Murshudov, GN, Vagin , AA, and Dodson, EJ. (1997) Refinement of macromolecular structures by the maximum-likelihood method, Acta Crystallogr...Benkovic, SJ. (2008) Allosteric regulation and catalysis emerge via a common route , Nat. Chem. Biol. 4, 474-482. [27] Ma, B, Tsai, CJ, Haliloglu, T, and

  6. Spelling Development: Fine-Tuning Strategy-Use and Capitalising on the Connections between Words

    Science.gov (United States)

    Devonshire, Victoria; Fluck, Michael

    2010-01-01

    English spelling, as well as in many other languages, consists of three elements: morphology, etymology and phonology. Spelling instruction, however, focuses primarily on phonology and there is a dearth of intervention studies that examine the effect of explicitly teaching all three elements to children. We report two studies, which examined 5- to…

  7. Fine-tuned transcriptional regulation of malate operons in Enterococcus faecalis.

    Science.gov (United States)

    Mortera, Pablo; Espariz, Martín; Suárez, Cristian; Repizo, Guillermo; Deutscher, Josef; Alarcón, Sergio; Blancato, Víctor; Magni, Christian

    2012-03-01

    In Enterococcus faecalis, the mae locus is constituted by two putative divergent operons, maePE and maeKR. The first operon encodes a putative H(+)/malate symporter (MaeP) and a malic enzyme (MaeE) previously shown to be essential for malate utilization in this bacterium. The maeKR operon encodes two putative proteins with significant similarity to two-component systems involved in sensing malate and activating its assimilation in bacteria. Our transcriptional and genetic assays showed that maePE and maeKR are induced in response to malate by the response regulator MaeR. In addition, we observed that both operons were partially repressed in the presence of glucose. Accordingly, the cometabolism of this sugar and malate was detected. The binding of the complex formed by CcpA and its corepressor P-Ser-HPr to a cre site located in the mae region was demonstrated in vitro and explains the carbon catabolite repression (CCR) observed for the maePE operon. However, our results also provide evidence for a CcpA-independent CCR mechanism regulating the expression of both operons. Finally, a biomass increment of 40 or 75% was observed compared to the biomass of cells grown only on glucose or malate, respectively. Cells cometabolizing both carbon sources exhibit a higher rate of glucose consumption and a lower rate of malate utilization. The growth improvement achieved by E. faecalis during glucose-malate cometabolism might explain why this microorganism employs different regulatory systems to tightly control the assimilation of both carbon sources.

  8. Fine-tuning of choline metabolism is important for pneumococcal colonization

    NARCIS (Netherlands)

    Johnston, C.; Hauser, C.; Hermans, P.W.M.; Martin, B.; Polard, P.; Bootsma, H.J.; Claverys, J.P.

    2016-01-01

    The human pathogen Streptococcus pneumoniae (the pneumococcus) is rare in having a strict requirement for the amino alcohol choline, which decorates pneumococcal teichoic acids. This process relies on the lic locus, containing the lic1 and lic2 operons. These operons produce eight proteins that

  9. A fine-tuned Metal-Organic Framework for Autonomous Indoor Moisture Control .

    KAUST Repository

    Abdul Halim, Racha Ghassan

    2017-06-29

    Conventional adsorbents, namely zeolites and silica gel, are often used to control humidity by adsorbing water; however, adsorbents capable of dual functionality of humidification and dehumidification, offering the desired control of the moisture level at room temperature, has yet to be explored. Here we report Y-shp-MOF-5, a hybrid microporous highly-connected Rare-Earth based metal-organic framework (MOF), with dual functionality for moisture control within the recommended range of relative humidity (45% to 65% RH) set by the American Society of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE). Y-shp-MOF-5 exhibits exceptional structural integrity, robustness and unique humidity-control performance as confirmed by the large number (thousand) of conducted water vapor adsorption-desorption cycles. The retained structural integrity and the mechanism of water sorption were corroborated using in situ single crystal X-ray diffraction (SCXRD) studies. The resultant working water uptake of 0.45 g.g-1 is solely regulated by a simple adjustment of the relative humidity, positioning this hydrolytically stable MOF as a prospective adsorbent for humidity control in confined spaces such as space shuttles, aircraft cabins and air-conditioned buildings.

  10. The insulator protein SU(HW fine-tunes nuclear lamina interactions of the Drosophila genome.

    Directory of Open Access Journals (Sweden)

    Joke G van Bemmel

    Full Text Available Specific interactions of the genome with the nuclear lamina (NL are thought to assist chromosome folding inside the nucleus and to contribute to the regulation of gene expression. High-resolution mapping has recently identified hundreds of large, sharply defined lamina-associated domains (LADs in the human genome, and suggested that the insulator protein CTCF may help to demarcate these domains. Here, we report the detailed structure of LADs in Drosophila cells, and investigate the putative roles of five insulator proteins in LAD organization. We found that the Drosophila genome is also organized in discrete LADs, which are about five times smaller than human LADs but contain on average a similar number of genes. Systematic comparison to new and published insulator binding maps shows that only SU(HW binds preferentially at LAD borders and at specific positions inside LADs, while GAF, CTCF, BEAF-32 and DWG are mostly absent from these regions. By knockdown and overexpression studies we demonstrate that SU(HW weakens genome - NL interactions through a local antagonistic effect, but we did not obtain evidence that it is essential for border formation. Our results provide insights into the evolution of LAD organization and identify SU(HW as a fine-tuner of genome - NL interactions.

  11. Glycan shield and fusion activation of a deltacoronavirus spike glycoprotein fine-tuned for enteric infections

    NARCIS (Netherlands)

    Xiong, Xiaoli; Tortorici, M Alejandra; Snijder, Joost|info:eu-repo/dai/nl/338018328; Yoshioka, Craig; Walls, Alexandra C; Li, Wentao|info:eu-repo/dai/nl/411296272; McGuire, Andrew T; Rey, Félix A; Bosch, Berend-Jan|info:eu-repo/dai/nl/273306049; Veesler, David

    2017-01-01

    Coronaviruses recently emerged as major human pathogens causing outbreaks of severe acute respiratory syndrome and Middle-East respiratory syndrome. They utilize the spike (S) glycoprotein anchored in the viral envelope to mediate host attachment and fusion of the viral and cellular membranes to

  12. Platinum Interference with siRNA Non-seed Regions Fine-Tunes Silencing Capacity

    DEFF Research Database (Denmark)

    Hedman, Hanna K; Kirpekar, Finn; Elmroth, Sofi K C

    2011-01-01

    RNA processing and function, understanding its influence on mRNA targeting and the silencing ability of individual miRNAs, e.g., under pathological conditions, remains a scientific challenge. In the present study, a model system is presented where the influence of the two clinically used anticancer drugs......, cisplatin and oxaliplatin, on siRNA's silencing capacity has been evaluated. More specifically, siRNAs targeting the 3' UTR region of Wnt-5a mRNA (NM_003352) were constructed, and the biologically active antisense RNA strand was pre-platinated. Platinum adducts were detected and characterized...

  13. Host-Toxoplasma gondii Coadaptation Leads to Fine Tuning of the Immune Response.

    Science.gov (United States)

    Brasil, Thaís Rigueti; Freire-de-Lima, Celio Geraldo; Morrot, Alexandre; Vetö Arnholdt, Andrea Cristina

    2017-01-01

    Toxoplasma gondii has successfully developed strategies to evade host's immune response and reach immune privileged sites, which remains in a controlled environment inside quiescent tissue cysts. In this review, we will approach several known mechanisms used by the parasite to modulate mainly the murine immune system at its favor. In what follows, we review recent findings revealing interference of host's cell autonomous immunity and cell signaling, gene expression, apoptosis, and production of microbicide molecules such as nitric oxide and oxygen reactive species during parasite infection. Modulation of host's metalloproteinases of extracellular matrix is also discussed. These immune evasion strategies are determinant to parasite dissemination throughout the host taking advantage of cells from the immune system to reach brain and retina, crossing crucial hosts' barriers.

  14. NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma.

    Science.gov (United States)

    Lai, Robin Kit-Ho; Xu, Iris Ming-Jing; Chiu, David Kung-Chun; Tse, Aki Pui-Wah; Wei, Larry Lai; Law, Cheuk-Ting; Lee, Derek; Wong, Chun-Ming; Wong, Maria Pik; Ng, Irene Oi-Lin; Wong, Carmen Chak-Lui

    2016-06-15

    Hepatocellular carcinoma (HCC) lacks effective curative therapy. Hypoxia is commonly found in HCC. Hypoxia elicits a series of protumorigenic responses through hypoxia-inducible factor-1 (HIF1). Better understanding of the metabolic adaptations of HCC cells during hypoxia is essential to the design of new therapeutic regimen. Expressions of genes involved in the electron transport chain (ETC) in HCC cell lines (20% and 1% O2) and human HCC samples were analyzed by transcriptome sequencing. Expression of NDUFA4L2, a less active subunit in complex I of the ETC, in 100 pairs of HCC and nontumorous liver tissues were analyzed by qRT-PCR. Student t test and Kaplan-Meier analyses were used for clinicopathologic correlation and survival studies. Orthotopic HCC implantation model was used to evaluate the efficiency of HIF inhibitor. NDUFA4L2 was drastically overexpressed in human HCC and induced by hypoxia. NDUFA4L2 overexpression was closely associated with tumor microsatellite formation, absence of tumor encapsulation, and poor overall survival in HCC patients. We confirmed that NDUFA4L2 was HIF1-regulated in HCC cells. Inactivation of HIF1/NDUFA4L2 increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and apoptosis. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vivo HIF inhibitor, digoxin, significantly suppressed growth of tumors that expressed high level of NDUFA4L2. Our study has provided the first clinical relevance of NDUFA4L2 in human cancer and suggested that HCC patients with NDUFA4L2 overexpression may be suitable candidates for HIF inhibitor treatment. Clin Cancer Res; 22(12); 3105-17. ©2016 AACR. ©2016 American Association for Cancer Research.

  15. Arabidopsis ATRX Modulates H3.3 Occupancy and Fine-Tunes Gene Expression

    KAUST Repository

    Duc, Céline

    2017-07-07

    Histones are essential components of the nucleosome, the major chromatin subunit that structures linear DNA molecules and regulates access of other proteins to DNA. Specific histone chaperone complexes control the correct deposition of canonical histones and their variants to modulate nucleosome structure and stability. In this study, we characterize the Arabidopsis Alpha Thalassemia-mental Retardation X-linked (ATRX) ortholog and show that ATRX is involved in histone H3 deposition. Arabidopsis ATRX mutant alleles are viable, but show developmental defects and reduced fertility. Their combination with mutants of the histone H3.3 chaperone HIRA (Histone Regulator A) results in impaired plant survival, suggesting that HIRA and ATRX function in complementary histone deposition pathways. Indeed, ATRX loss of function alters cellular histone H3.3 pools and in consequence modulates the H3.1/H3.3 balance in the cell. H3.3 levels are affected especially at genes characterized by elevated H3.3 occupancy, including the 45S ribosomal DNA (45S rDNA) loci, where loss of ATRX results in altered expression of specific 45S rDNA sequence variants. At the genome-wide scale, our data indicate that ATRX modifies gene expression concomitantly to H3.3 deposition at a set of genes characterized both by elevated H3.3 occupancy and high expression. Altogether, our results show that ATRX is involved in H3.3 deposition and emphasize the role of histone chaperones in adjusting genome expression.

  16. Reed Warbler Hosts Fine-Tune their Defenses to Track Three Decades of Cuckoo Decline

    Science.gov (United States)

    Thorogood, Rose; Davies, Nicholas B

    2013-01-01

    Interactions between avian hosts and brood parasites can provide a model for how animals adapt to a changing world. Reed warbler (Acrocephalus scirpaceus) hosts employ costly defenses to combat parasitism by common cuckoos (Cuculus canorus). During the past three decades cuckoos have declined markedly across England, reducing parasitism at our study site (Wicken Fen) from 24% of reed warbler nests in 1985 to 1% in 2012. Here we show with experiments that host mobbing and egg rejection defenses have tracked this decline in local parasitism risk: the proportion of reed warbler pairs mobbing adult cuckoos (assessed by responses to cuckoo mounts and models) has declined from 90% to 38%, and the proportion rejecting nonmimetic cuckoo eggs (assessed by responses to model eggs) has declined from 61% to 11%. This is despite no change in response to other nest enemies or mimetic model eggs. Individual variation in both defenses is predicted by parasitism risk during the host’s egg-laying period. Furthermore, the response of our study population to temporal variation in parasitism risk can also explain spatial variation in egg rejection behavior in other populations across Europe. We suggest that spatial and temporal variation in parasitism risk has led to the evolution of plasticity in reed warbler defenses. PMID:24299407

  17. Fine-tuning of mast cell activation by FceRIbeta chain

    Directory of Open Access Journals (Sweden)

    Chisei eRa

    2012-05-01

    Full Text Available Mast cells play the key role in allergic reaction and disorders, being activated by the high affinity receptor for IgE, FceRI. There are two types of FceRI expressed on the cell surface of human mast cells, abg2 type and ag2 type (without b chain, while in mouse mast cells only the tetrameric abg2 type is expressed. In the lesion of allergic inflammation such as atopic conjunctivitis and atopic dermatitis, mast cells increase in number and exclusively express the abg2 type FceRI, in contrast in healthy conjunctiva and skin most mast cells express the ag2 type. The human and mouse FceRI genes contain seven exons and in the human gene we found a repressor element locates in the forth intron. Through the repressor element HDACs are recruited to the FceRIb gene by MZF-1/FHL3/NFY complex and repress b transcription by deacetylation of histones in the presence of GM-CSF. It has been long recognized that the function of the b chain ITAM is a signal amplifier, but we have recently revealed bidirectional (positive and negative functions of the b chain ITAM in the regulation of the mast cell activation and effector functions. Namely, the b chain enhances the mast cell activation signal triggered with low intensity stimulation such as lower dose antigen than threshold while it suppresses the signal of high intensity stimulation. Employing mouse model of CHS induced by oxazolone, we have revealed that IgE-mediated mast cell activation is required for CHS and that the b chain is crucially involved in this model. On the other hand diverse immune receptors including TLRs, SCF receptor and GPCRs are known to mediate signals which modulate FceRI・adenosine receptors, one of GPCRs, trigger synergistic degranulation response in mast cells even when the FceRI stimulation is of ‘lower intensity’ than the threshold. We have recently elucidated, in this synergistic degranulation response, b chain ITAM plays positive role, possibly reflecting in vivo allergic response.

  18. UTP-induced ATP release is a fine-tuned signalling pathway in osteocytes

    DEFF Research Database (Denmark)

    Kringelbach, Tina M.; Aslan, Derya; Novak, Ivana

    2014-01-01

    the intracellular calcium concentration and that they release ATP dose-dependently upon stimulation with 1-10 μM UTP. In addition to this, osteocytes release large amounts of ATP upon cell rupture, which might also be a source for other nucleotides, such as UTP. These findings indicate that mechanically induced ATP...... the luciferin-luciferase assay and the release pathway was investigated using pharmacological inhibition. The P2Y receptor profile was analysed using gene expression analysis by reverse transcription polymerase chain reaction, while functional testing was performed using measurements of intracellular calcium...

  19. Fine tuning of transmission features in nanoporous anodic alumina distributed Bragg reflectors

    Science.gov (United States)

    Lim, Siew Yee; Law, Cheryl Suwen; Santos, Abel

    2018-01-01

    This study introduces an innovative apodisation strategy to tune the filtering features of distributed Bragg reflectors based on nanoporous anodic alumina (NAA-DBRs). The effective medium of NAA-DBRs, which is modulated in a stepwise fashion by a pulse-like anodisation approach, is apodised following a logarithmic negative function to engineer the transmission features of NAA-DBRs. We investigate the effect of various apodisation parameters such as apodisation amplitude difference, anodisation period, current density offset and pore widening time, to tune and optimise the optical properties of NAA-DBRs in terms of central wavelength position, full width at half maximum and quality of photonic stop band. The transmission features of NAA-DBRs are shown to be fully controllable with precision across the spectral regions by means of the apodisation parameters. Our study demonstrates that an apodisation strategy can significantly narrow the width and enhance the quality of the characteristic photonic stop band of NAA-DBRs. This rationally designed anodisation approach based on the combination of apodisation and stepwise pulse anodisation enables the development of optical filters with tuneable filtering features to be integrated into optical technologies acting as essential photonic elements in devices such as optical sensors and biosensors.

  20. Fine-Tuning in Regulation of Clp Protein Content in Bacillus subtilis†

    OpenAIRE

    Gerth, Ulf; Kirstein, Janine; Mostertz, Jörg; Waldminghaus, Torsten; Miethke, Marcus; Kock, Holger; Hecker, Michael

    2004-01-01

    Clp-controlled proteolysis in Bacillus subtilis seems to play a substantial role, particularly under stress conditions. Calibrated Western blot analyses were used to estimate the approximate numbers of heat-inducible Clp molecules within a single cell. According to these numbers, the different Clp ATPases do not seem to compete for the proteolytic subunit ClpP. Coimmunoprecipitation experiments revealed the predicted specific ClpX-ClpP, ClpC-ClpP, and ClpE-ClpP interactions. ClpE and ClpX are...

  1. Fine-tuning of the flavonoid and monolignol pathways during apple early fruit development.

    Science.gov (United States)

    Baldi, Paolo; Moser, Mirko; Brilli, Matteo; Vrhovsek, Urska; Pindo, Massimo; Si-Ammour, Azeddine

    2017-05-01

    A coordinated regulation of different branches of the flavonoid pathway was highlighted that may contribute to elucidate the role of this important class of compounds during the early stages of apple fruit development. Apple (Malus × domestica Borkh.) is an economically important fruit appreciated for its organoleptic characteristics and its benefits for human health. The first stages after fruit set represent a very important and still poorly characterized developmental process. To enable the profiling of genes involved in apple early fruit development, we combined the suppression subtractive hybridization (SSH) protocol to next-generation sequencing. We identified and characterized genes induced and repressed during fruit development in the apple cultivar 'Golden Delicious'. Our results showed an opposite regulation of genes coding for enzymes belonging to flavonoid and monolignol pathways, with a strong induction of the former and a simultaneous repression of the latter. Two isoforms of phenylalanine ammonia-lyase and 4-coumarate:CoA ligase, key enzymes located at the branching point between flavonoid and monolignol pathways, showed opposite expression patterns during the period in analysis, suggesting a possible regulation mechanism. A targeted metabolomic analysis supported the SSH results and revealed an accumulation of the monomers catechin and epicatechin as well as several forms of procyanidin oligomers in apple fruitlets starting early after anthesis, together with a decreased production of other classes of flavonoids such as some flavonols and the dihydrochalcone phlorizin. Moreover, gene expression and metabolites accumulation of 'Golden Delicious' were compared to a wild apple genotype of Manchurian crabapple (Malus mandshurica (Maxim.) Kom.). Significant differences in both gene expression and metabolites accumulation were found between the two genotypes.

  2. Fine-tuned ATP signals are acute mediators in osteocyte mechanotransduction

    DEFF Research Database (Denmark)

    Kringelbach, Tina M.; Aslan, Derya; Novak, Ivana

    2015-01-01

    effects on bone remodeling. Therefore, we hypothesized that ATP signaling is also applied by osteocytes in mechanotransduction. We applied a short fluid pulse on MLO-Y4 osteocyte-like cells during real-time detection of ATP and demonstrated that mechanical stimulation activates the acute release of ATP...

  3. Fine tuning by human CD1e of lipid-specific immune responses.

    Science.gov (United States)

    Facciotti, Federica; Cavallari, Marco; Angénieux, Catherine; Garcia-Alles, Luis F; Signorino-Gelo, François; Angman, Lena; Gilleron, Martine; Prandi, Jacques; Puzo, Germain; Panza, Luigi; Xia, Chengfeng; Wang, Peng George; Dellabona, Paolo; Casorati, Giulia; Porcelli, Steven A; de la Salle, Henri; Mori, Lucia; De Libero, Gennaro

    2011-08-23

    CD1e is a member of the CD1 family that participates in lipid antigen presentation without interacting with the T-cell receptor. It binds lipids in lysosomes and facilitates processing of complex glycolipids, thus promoting editing of lipid antigens. We find that CD1e may positively or negatively affect lipid presentation by CD1b, CD1c, and CD1d. This effect is caused by the capacity of CD1e to facilitate rapid formation of CD1-lipid complexes, as shown for CD1d, and also to accelerate their turnover. Similar results were obtained with antigen-presenting cells from CD1e transgenic mice in which lipid complexes are assembled more efficiently and show faster turnover than in WT antigen-presenting cells. These effects maximize and temporally narrow CD1-restricted responses, as shown by reactivity to Sphingomonas paucimobilis-derived lipid antigens. CD1e is therefore an important modulator of both group 1 and group 2 CD1-restricted responses influencing the lipid antigen availability as well as the generation and persistence of CD1-lipid complexes.

  4. Desalination of masonry structures: Fine tuning of pore size distribution of poultices to substrate properties

    NARCIS (Netherlands)

    Lubelli, B.A.; Hees, R.P.J. van

    2010-01-01

    Desalination is a relatively new intervention in the field of conservation of architectural heritage. Especially the desalination of immovable objects, such as masonry structures, is still a trial-error practice. In the field, different desalination materials and methods are used, sometimes with

  5. Fine tuning of mixed ionic and hydrogen bond interactions for plasmid delivery using lipoplexes.

    Science.gov (United States)

    Seguin, Johanne; Dhotel, Hélène; Kai-Luen, René; Bessodes, Michel; Mignet, Nathalie

    2015-02-01

    Non viral gene transfection has been mostly reached via cationic polymer and lipid, required for DNA complexation and cell internalisation. However, cationic charges often induce cytotoxicity and limit the efficacy of the lipoplexes in vivo due to their fast elimination from the blood stream. Few years ago, we had developed noncationic lipid interacting with DNA via hydrogen bond interactions. To take advantage of both the internalisation efficacy of cationic complexes and the higher DNA release efficacy of non cationic lipids, we chose to mix both ionic and hydrogen bond interactions within one lipoplex. The idea behind this strategy would be to reduce the overall charge while maintaining a high level of transfection. Four mixed formulations of cationic lipid and thiourea lipid were prepared. We found that decreasing ionic interactions and increasing hydrogen bond interactions improved cationic lipoplexes properties. Indeed, we showed that replacement of net positive charges by hydrogen bond interactions with DNA phosphates led to efficient lipoplexes for in vitro DNA transfection at lower cationic charge content, which consequently reduced lipoplex cytotoxicity. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Involvement of ICU families in decisions: fine-tuning the partnership

    National Research Council Canada - National Science Library

    Azoulay, Elie; Chaize, Marine; Kentish-Barnes, Nancy

    2014-01-01

    Families of patients are not simple visitors to the ICU. They have just been separated from a loved one, often someone they live with, either abruptly or, in nearly half the cases, because a chronic condition has suddenly worsened...

  7. Fine tuning of optical transition energy of twisted bilayer graphene via interlayer distance modulation

    Czech Academy of Sciences Publication Activity Database

    del Corro, Elena; Peňa-Álvarez, Miriam; Sato, K.; Morales-García, A.; Bouša, Milan; Mračko, Michal; Kolman, Radek; Pacáková, Barbara; Kavan, Ladislav; Kalbáč, Martin; Frank, Otakar

    2017-01-01

    Roč. 95, č. 8 (2017), č. článku 085138. ISSN 2469-9950 R&D Projects: GA ČR GA14-15357S; GA MŠk LL1301; GA ČR GA16-03823S Institutional support: RVO:61388955 ; RVO:61388998 ; RVO:68378271 Keywords : twisted bilayer graphene * tuning * silicon Subject RIV: CG - Electrochemistry OBOR OECD: Electrochemistry (dry cells, batteries, fuel cells, corrosion metals, electrolysis) Impact factor: 3.836, year: 2016

  8. Fidelity in the Field: Developing Infrastructure and Fine-tuning Measurement.

    Science.gov (United States)

    Herschell, Amy D

    2010-09-01

    Mazzucchelli and Sanders (2010) provide a thoughtful, detailed, and complex description of how to encourage flexible fidelity to one well-established, evidence-based treatment, the Triple P- Positive Parenting Program. As the authors highlight, many of the "lessons learned" from this wealth of treatment, research, and implementation experience were developed over decades and can be applied to other evidence based treatments. Underlying many of the recommendations provided by Mazzucchelli and Sanders (2010) is a well-refined infrastructure to support implementation and the need to refine the measurement of fidelity in the field. This commentary will discuss each of those topics. It seems that we have many lessons to learn and hurdles to clear in this emerging area of science, which will be hastened by pioneers like Mazzucchelli and Sanders.

  9. The Fine-Tuning of Linguistic Expectations over the Course of L2 Learning

    Science.gov (United States)

    Leal, Tania; Slabakova, Roumyana; Farmer, Thomas A.

    2017-01-01

    This study investigates the degree to which native-English-speaking learners of Spanish can generate expectations for information likely to occur in upcoming portions of an unfolding linguistic signal. We examine Spanish clitic left dislocation, a long-distance dependency between a topicalized object and an agreeing clitic, whose felicity depends…

  10. Fine-tuning of proton sponges by precise diaminoethanes and histidines in pDNA polyplexes.

    Science.gov (United States)

    Lächelt, Ulrich; Kos, Petra; Mickler, Frauke M; Herrmann, Annika; Salcher, Eveline E; Rödl, Wolfgang; Badgujar, Naresh; Bräuchle, Christoph; Wagner, Ernst

    2014-01-01

    The cationizable nature of 'proton-sponge' transfection agents facilitates pDNA delivery in several steps. Protonated amines account for electrostatic DNA binding and cellular uptake, buffering amines mediate polyplex escape from acidifying intracellular vesicles. As demonstrated with a sequence-defined library of oligo(ethanamino)amides containing selected oligoethanamino acids and histidines, the total protonation capacity as well as the cationization pH profile within the endolysosomal range have critical impact on gene transfer. Building blocks with even numbered amine groups (Gtt, Sph) exhibited higher total endolysosomal buffer capacity than odd number (Stp) analogs. Within the endolysosomal range, Gtt has the highest buffer capacity around pH5, whereas Stp has its maximum around pH7. Histidines increased the total buffer capacity, resulted in a more continuous cationization pH profile and greatly improved transgene expression in vitro and in vivo. Using receptor targeted and polyethylene glycol shielded polyplexes, better endosomal escape and >100-fold enhanced transfection was detected. Proton-sponge transfection agents for pDNA delivery are characterized in this study, demonstrating over 100-fold enhanced transection and better endosomal escape by using receptor targeted and polyethylene glycol shielded polyplexes. © 2013.

  11. Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling

    Czech Academy of Sciences Publication Activity Database

    Charles, C.; Hovořáková, Mária; Ahn, Y.; Lyons, D. B.; Marangoni, P.; Churavá, Svatava; Biehs, B.; Jheon, A.; Lesot, H.; Balooch, G.; Krumlauf, R.; Viriot, L.; Peterková, Renata; Klein, O. D.

    2011-01-01

    Roč. 138, č. 18 (2011), s. 4063-4073 ISSN 0950-1991 R&D Projects: GA ČR GA304/09/1579; GA ČR GA304/07/0223 Institutional research plan: CEZ:AV0Z50390512 Keywords : FGF signaling * Sprouty genes * Incisor Subject RIV: EA - Cell Biology Impact factor: 6.596, year: 2011

  12. Fine Tuning of Basic Forces through the Existence of Carbon-Based Life

    CERN Multimedia

    CERN. Geneva

    2001-01-01

    The bulk of the carbon in our universe is produced in the triple-alpha process in helium-burning red giant stars. We calculated the change of the triple-alpha reaction rate in a microscopic twelve-nucleon model of the 12C nucleus and looked for the effects of minimal variations of the strengths of the underlying strong and Coulomb interactions. Stellar model calculations are performed using the alternative reaction rates. We show that outside a narrow window of 0.5% of the strength or range of the strong interaction the stellar production of carbon or oxygen is reduced by factors of 130 to 1000. Therefore, outside this window the existence of carbon-based life in our universe would be strongly disfavored. These anthropically allowed strengths of the strong and electromagnetic forces also constrain the sum of the light quark masses and the Higgs vacuum expectation value.

  13. Paediatric frontal chest radiograph screening with fine-tuned convolutional neural networks

    CSIR Research Space (South Africa)

    Gerrand, Jonathan D

    2017-07-01

    Full Text Available stream_source_info Gerrand_19522_2017.pdf.txt stream_content_type text/plain stream_size 1380 Content-Encoding ISO-8859-1 stream_name Gerrand_19522_2017.pdf.txt Content-Type text/plain; charset=ISO-8859-1 Annual...

  14. Competitive Coordination Strategy to Finely Tune Pore Environment of Zirconium-Based Metal-Organic Frameworks.

    Science.gov (United States)

    He, Ting; Ni, Bing; Xu, Xiaobin; Li, Haoyi; Lin, Haifeng; Yuan, Wenjuan; Luo, Jun; Hu, Wenping; Wang, Xun

    2017-07-12

    Metal-organic frameworks (MOFs) are a class of crystalline porous materials with reticular architectures. Precisely tuning pore environment of MOFs has drawn tremendous attention but remains a great challenge. In this work, we demonstrate a competitive coordination approach to synthesize a series of zirconium-metalloporphyrinic MOFs through introducing H2O and monocarboxylic acid as modulating reagents, in which well-ordered mesoporous channels could be observed clearly under conventional transmission electron microscopy. Owing to plenty of unsaturated Lewis acid catalytic sites exposed in the visualized mesoporous channels, these structures exhibit outstanding catalytic activity and excellent stability in the chemical fixation of carbon dioxide to cyclic carbonates. The zirconium-based MOFs with ordered channel structures are expected to pave the way to expand the potential applications of MOFs.

  15. The magnetic map sense and its use in fine-tuning the migration programme of birds.

    Science.gov (United States)

    Heyers, D; Elbers, D; Bulte, M; Bairlein, F; Mouritsen, H

    2017-07-01

    The Earth's magnetic field is one of several natural cues, which migratory birds can use to derive directional ("compass") information for orientation on their biannual migratory journeys. Moreover, magnetic field effects on prominent aspects of the migratory programme of birds, such as migratory restlessness behaviour, fuel deposition and directional orientation, implicate that geomagnetic information can also be used to derive positional ("map") information. While the magnetic "compass" in migratory birds is likely to be based on radical pair-forming molecules embedded in their visual system, the sensory correlates underlying a magnetic "map" sense currently remain elusive. Behavioural, physiological and neurobiological findings indicate that the sensor is most likely innervated by the ophthalmic branch of the trigeminal nerve and based on magnetic iron particles. Information from this unknown sensor is neither necessary nor sufficient for a functional magnetic compass, but instead could contribute important components of a multifactorial "map" for global positioning. Positional information could allow migratory birds to make vitally important dynamic adaptations of their migratory programme at any relevant point during their journeys.

  16. Local temperature fine-tunes the timing of spring migration in birds

    DEFF Research Database (Denmark)

    Tøttrup, Anders P.; Rainio, Kalle; Coppack, Timothy

    2010-01-01

    Evidence for climate-driven phenological changes is rapidly increasing at all trophic levels. Our current poor knowledge of the detailed control of bird migration from the level of genes and hormonal control to direct physiological and behavioral responses hampers our ability to understand...... and predict consequences of climatic change for migratory birds. In order to better understand migration phenology and adaptation in environmental changes, we here assess the scale at which weather affects timing of spring migration in passerine birds. We use three commonly used proxies of spring...... breeding area. Local temperature was the best single predictor of phenology with the highest explanatory power achieved in combination with NAO. Furthermore, early individuals are more affected by climatic variation compared to individuals on later passage, indicating that climatic change affects subsets...

  17. Promoter mutagenesis for fine-tuning expression of essential genes in Mycobacterium tuberculosis.

    Science.gov (United States)

    Boldrin, Francesca; Degiacomi, Giulia; Serafini, Agnese; Kolly, Gaëlle S; Ventura, Marcello; Sala, Claudia; Provvedi, Roberta; Palù, Giorgio; Cole, Stewart T; Manganelli, Riccardo

    2018-01-01

    A range of regulated gene expression systems has been developed for mycobacteria in the last few years to facilitate the study of essential genes, validate novel drug targets and evaluate their vulnerability. Among these, the TetR/Pip-OFF repressible promoter system was successfully used in several mycobacterial species both in vitro and in vivo. In the first version of the system, the repressible promoter was Pptr , a strong Pip-repressible promoter of Streptomyces pristinaespiralis, which might hamper effective downregulation of genes with a low basal expression level. Here, we report an enhanced system that allows more effective control of genes expressed at low level. To this end, we subjected Pptr to targeted mutagenesis and produced 16 different promoters with different strength. Three of them, weaker than the wild-type promoter, were selected and characterized showing that they can indeed improve the performances of TetR/Pip-OFF repressible system both in vitro and in vivo increasing its stringency. Finally, we used these promoters to construct a series of bacterial biosensors with different sensitivity to DprE1 inhibitors and developed a whole-cell screening assay to identify inhibitors of this enzyme. © 2017 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

  18. Fine tuning of the Bacillus cereus stress respons: role of transcriptional regulators

    NARCIS (Netherlands)

    Voort, van der M.

    2008-01-01

    The bacterium Bacillus cereus is able to survive and grow in a high diversity of environments, including foods, such as milk and pasta. Consequently, B. cereus can cause foodborne illnesses and food spoilage. During its time in food B. cereus encounters many changes in its environment, as the food

  19. Fine-tuning of substrate architecture and surface chemistry promotes muscle tissue development.

    Science.gov (United States)

    Guex, A G; Kocher, F M; Fortunato, G; Körner, E; Hegemann, D; Carrel, T P; Tevaearai, H T; Giraud, M N

    2012-04-01

    Tissue engineering has been increasingly brought to the scientific spotlight in response to the tremendous demand for regeneration, restoration or substitution of skeletal or cardiac muscle after traumatic injury, tumour ablation or myocardial infarction. In vitro generation of a highly organized and contractile muscle tissue, however, crucially depends on an appropriate design of the cell culture substrate. The present work evaluated the impact of substrate properties, in particular morphology, chemical surface composition and mechanical properties, on muscle cell fate. To this end, aligned and randomly oriented micron (3.3±0.8 μm) or nano (237±98 nm) scaled fibrous poly(ε-caprolactone) non-wovens were processed by electrospinning. A nanometer-thick oxygen functional hydrocarbon coating was deposited by a radio frequency plasma process. C2C12 muscle cells were grown on pure and as-functionalized substrates and analysed for viability, proliferation, spatial orientation, differentiation and contractility. Cell orientation has been shown to depend strongly on substrate architecture, being most pronounced on micron-scaled parallel-oriented fibres. Oxygen functional hydrocarbons, representing stable, non-immunogenic surface groups, were identified as strong triggers for myotube differentiation. Accordingly, the highest myotube density (28±15% of total substrate area), sarcomeric striation and contractility were found on plasma-coated substrates. The current study highlights the manifold material characteristics to be addressed during the substrate design process and provides insight into processes to improve bio-interfaces. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  20. Attention fine-tunes auditory-motor processing of speech sounds.

    Science.gov (United States)

    Möttönen, Riikka; van de Ven, Gido M; Watkins, Kate E

    2014-03-12

    The earliest stages of cortical processing of speech sounds take place in the auditory cortex. Transcranial magnetic stimulation (TMS) studies have provided evidence that the human articulatory motor cortex contributes also to speech processing. For example, stimulation of the motor lip representation influences specifically discrimination of lip-articulated speech sounds. However, the timing of the neural mechanisms underlying these articulator-specific motor contributions to speech processing is unknown. Furthermore, it is unclear whether they depend on attention. Here, we used magnetoencephalography and TMS to investigate the effect of attention on specificity and timing of interactions between the auditory and motor cortex during processing of speech sounds. We found that TMS-induced disruption of the motor lip representation modulated specifically the early auditory-cortex responses to lip-articulated speech sounds when they were attended. These articulator-specific modulations were left-lateralized and remarkably early, occurring 60-100 ms after sound onset. When speech sounds were ignored, the effect of this motor disruption on auditory-cortex responses was nonspecific and bilateral, and it started later, 170 ms after sound onset. The findings indicate that articulatory motor cortex can contribute to auditory processing of speech sounds even in the absence of behavioral tasks and when the sounds are not in the focus of attention. Importantly, the findings also show that attention can selectively facilitate the interaction of the auditory cortex with specific articulator representations during speech processing.

  1. Fine-Tuning ER Stress Signal Transducers to Treat Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Medinas, Danilo B; González, Jose V; Falcon, Paulina; Hetz, Claudio

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motoneurons and paralysis. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting disturbances in motoneuron proteostasis. Endoplasmic reticulum (ER) stress has emerged as an early pathogenic event underlying motoneuron vulnerability and denervation in ALS. Maintenance of ER proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). Inositol-requiring enzyme 1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a major ER stress transducer, mediating the establishment of adaptive and pro-apoptotic programs. Here we discuss current evidence supporting the role of ER stress in motoneuron demise in ALS and build the rational to target IRE1 to ameliorate neurodegeneration.

  2. Fine Tuning the CJ Detonation Speed of a High Explosive products Equation of State

    Energy Technology Data Exchange (ETDEWEB)

    Menikoff, Ralph [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-05-12

    For high explosive (HE) simulations, inaccuracies of a per cent or two in the detonation wave speed can result from not suficiently resolving the reaction zone width or from small inaccuracies in calibrating the products equation of state (EOS) or from variation of HE lots. More accurate detonation speeds can be obtained by ne tuning the equation of state to compensate. Here we show that two simple EOS transformations can be used to adjust the CJ detonation speed by a couple of per cent with minimal effect on the CJ release isentrope. The two transformations are (1) a shift in the energy origin and (2) a linear scaling of the speci c volume. The effectiveness of the transformations is demonstrated with simulations of the cylinder test for PBX 9502 starting with a products EOS for which the CJ detonation speed is 1 per cent too low.

  3. Diel vertical migration in deep sea plankton is finely tuned to latitudinal and seasonal day length.

    Science.gov (United States)

    van Haren, Hans; Compton, Tanya J

    2013-01-01

    Diel vertical migration (DVM) is a ubiquitous phenomenon in marine and freshwater plankton communities. Most commonly, plankton migrate to surface waters at dusk and return to deeper waters at dawn. Up until recently, it was thought that DVM was triggered by a relative change in visible light intensity. However, evidence has shown that DVM also occurs in the deep sea where no direct and background sunlight penetrates. To identify whether such DVM is associated with latitudinal and seasonal day light variation, one and a half years of recorded acoustic data, a measure of zooplankton abundance and movement, were examined. Acoustic Doppler current profilers, moored at eight different sub-tropical latitudes in the North-Atlantic Ocean, measured in the vertical range of 500-1600 m. DVM was observed to follow day length variation with a change in season and latitude at all depths. DVM followed the rhythm of local sunrise and sunset precisely between 500 and 650 m. It continued below 650 m, where the deepest penetrable irradiance level are plankton shortened their time at depth by up to about 63% at 1600 m. This suggests light was no longer a cue for DVM. This trend stayed consistent both across latitudes and between the different seasons. It is hypothesized that another mechanism, rather than light, viz. a precise biochemical clock could maintain the solar diurnal and seasonal rhythms in deep sea plankton motions. In accordance with this hypothesis, the deepest plankton were consistently the first to migrate upwards.

  4. Skeletal Muscle Function during Exercise—Fine-Tuning of Diverse Subsystems by Nitric Oxide

    Directory of Open Access Journals (Sweden)

    Wilhelm Bloch

    2013-03-01

    Full Text Available Skeletal muscle is responsible for altered acute and chronic workload as induced by exercise. Skeletal muscle adaptations range from immediate change of contractility to structural adaptation to adjust the demanded performance capacities. These processes are regulated by mechanically and metabolically induced signaling pathways, which are more or less involved in all of these regulations. Nitric oxide is one of the central signaling molecules involved in functional and structural adaption in different cell types. It is mainly produced by nitric oxide synthases (NOS and by non-enzymatic pathways also in skeletal muscle. The relevance of a NOS-dependent NO signaling in skeletal muscle is underlined by the differential subcellular expression of NOS1, NOS2, and NOS3, and the alteration of NO production provoked by changes of workload. In skeletal muscle, a variety of highly relevant tasks to maintain skeletal muscle integrity and proper signaling mechanisms during adaptation processes towards mechanical and metabolic stimulations are taken over by NO signaling. The NO signaling can be mediated by cGMP-dependent and -independent signaling, such as S-nitrosylation-dependent modulation of effector molecules involved in contractile and metabolic adaptation to exercise. In this review, we describe the most recent findings of NO signaling in skeletal muscle with a special emphasis on exercise conditions. However, to gain a more detailed understanding of the complex role of NO signaling for functional adaptation of skeletal muscle (during exercise, additional sophisticated studies are needed to provide deeper insights into NO-mediated signaling and the role of non-enzymatic-derived NO in skeletal muscle physiology.

  5. Fine-Tuning ER Stress Signal Transducers to Treat Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Danilo B. Medinas

    2017-07-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease characterized by the progressive loss of motoneurons and paralysis. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting disturbances in motoneuron proteostasis. Endoplasmic reticulum (ER stress has emerged as an early pathogenic event underlying motoneuron vulnerability and denervation in ALS. Maintenance of ER proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR. Inositol-requiring enzyme 1 (IRE1 is an ER-located kinase and endoribonuclease that operates as a major ER stress transducer, mediating the establishment of adaptive and pro-apoptotic programs. Here we discuss current evidence supporting the role of ER stress in motoneuron demise in ALS and build the rational to target IRE1 to ameliorate neurodegeneration.

  6. Fine-Tuning Summer Research Programs to Promote Underrepresented Students’ Persistence in the STEM Pathway

    Science.gov (United States)

    Ghee, Medeva; Keels, Micere; Collins, Deborah; Neal-Spence, Cynthia; Baker, Earnestine

    2016-01-01

    Although the importance of undergraduate research experiences in preparing students for graduate study and research careers is well documented, specific examination of program components is needed to assess the impact of these programs on underrepresented (UR) students. The Leadership Alliance, a consortium of leading PhD-granting and minority-serving institutions (MSIs), has leveraged its diverse partnership to place UR students from MSI and non-MSI institutions in competitive research environments through its national Summer Research Early Identification Program. Using longitudinal pre/post data collected from student surveys, we applied social cognitive career theory as a conceptual framework to examine how research engagement, skill development, and mentorship aspects of a summer research program affect students’ commitment to pursue research careers. Self-reported knowledge of research skills, time engaged in research activity, and students’ understanding of and attitudes toward pursuing graduate study were measured in relation to the classification of students’ home undergraduate institution, level of students’ pre-existing research experience, and demographic factors. Our results provide evidence of specific programmatic components that are beneficial for UR students from varying academic and cultural backgrounds. This study describes important aspects of summer research programs that will contribute to students’ ability to persist in science careers. PMID:27496359

  7. Fine-Tuning Summer Research Programs to Promote Underrepresented Students' Persistence in the STEM Pathway.

    Science.gov (United States)

    Ghee, Medeva; Keels, Micere; Collins, Deborah; Neal-Spence, Cynthia; Baker, Earnestine

    Although the importance of undergraduate research experiences in preparing students for graduate study and research careers is well documented, specific examination of program components is needed to assess the impact of these programs on underrepresented (UR) students. The Leadership Alliance, a consortium of leading PhD-granting and minority-serving institutions (MSIs), has leveraged its diverse partnership to place UR students from MSI and non-MSI institutions in competitive research environments through its national Summer Research Early Identification Program. Using longitudinal pre/post data collected from student surveys, we applied social cognitive career theory as a conceptual framework to examine how research engagement, skill development, and mentorship aspects of a summer research program affect students' commitment to pursue research careers. Self-reported knowledge of research skills, time engaged in research activity, and students' understanding of and attitudes toward pursuing graduate study were measured in relation to the classification of students' home undergraduate institution, level of students' pre-existing research experience, and demographic factors. Our results provide evidence of specific programmatic components that are beneficial for UR students from varying academic and cultural backgrounds. This study describes important aspects of summer research programs that will contribute to students' ability to persist in science careers. © 2016 M. Ghee et al. CBE—Life Sciences Education © 2016 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  8. Fine-tuning Cartilage Tissue Engineering by Applying Principles from Embryonic Development

    NARCIS (Netherlands)

    C.A. Hellingman (Catharine)

    2012-01-01

    textabstractCartilage has a very poor capacity for regeneration in vivo. In head and neck surgery cartilage defects are usually reconstructed with autologous cartilage from for instance the external ear or the ribs. Cartilage tissue engineering may be a promising alternative to supply tissue for

  9. Harnessing Genes and Diet to Fine-Tune the Gut Microbial Fitness.

    Science.gov (United States)

    Cani, Patrice D; Everard, Amandine

    2015-11-03

    Microbe communication with host mammalian cells and external factors such as diet influences this multifaceted ecosystem. A recent study shows that interactions between microbial genes and dietary elements are dynamic processes that may help to characterize an organism's niche and eventually its impact on the overall community and host metabolism. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Fine-Tuning ADAS Algorithm Parameters for Optimizing Traffic Safety and Mobility in Connected Vehicle Environment

    Science.gov (United States)

    With the development of the Connected Vehicle technology that facilitates wirelessly communication among vehicles and road-side infrastructure, the Advanced Driver Assistance Systems (ADAS) can be adopted as an effective tool for accelerating traffic safety and mobility optimizat...

  11. Protein degradation and dynamic tRNA thiolation fine-tune translation at elevated temperatures.

    Science.gov (United States)

    Tyagi, Kshitiz; Pedrioli, Patrick G A

    2015-05-19

    Maintenance of protein quality control has implications in various processes such as neurodegeneration and ageing. To investigate how environmental insults affect this process, we analysed the proteome of yeast continuously exposed to mild heat stress. In agreement with previous transcriptomics studies, amongst the most marked changes, we found up-regulation of cytoprotective factors; a shift from oxidative phosphorylation to fermentation; and down-regulation of translation. Importantly, we also identified a novel, post-translationally controlled, component of the heat shock response. The abundance of Ncs2p and Ncs6p, two members of the URM1 pathway responsible for the thiolation of wobble uridines in cytoplasmic tRNAs tK(UUU), tQ(UUG) and tE(UUC), is down-regulated in a proteasomal dependent fashion. Using random forests we show that this results in differential translation of transcripts with a biased content for the corresponding codons. We propose that the role of this pathway in promoting catabolic and inhibiting anabolic processes, affords cells with additional time and resources needed to attain proper protein folding under periods of stress. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  12. Hospital and community ampicillin-resistant Enterococcus faecium are evolutionarily closely linked but have diversified through niche adaptation.

    Directory of Open Access Journals (Sweden)

    Marieke J A de Regt

    Full Text Available BACKGROUND: Ampicillin-resistant Enterococcus faecium (ARE has emerged as a nosocomial pathogen. Here, we quantified ARE carriage in different community sources and determined genetic relatedness with hospital ARE. METHODS AND RESULTS: ARE was recovered from rectal swabs of 24 of 79 (30% dogs, 11 of 85 (13% cats and 0 of 42 horses and from 3 of 40 (8% faecal samples of non-hospitalized humans receiving amoxicillin. Multi-locus Sequence Typing revealed 21 sequence types (STs, including 5 STs frequently associated with hospital-acquired infections. Genes previously found to be enriched in hospital ARE, such as IS16, orf903, orf905, orf907, were highly prevalent in community ARE (≥79%, while genes with a proposed role in pathogenesis, such as esp, hyl and ecbA, were found rarely (≤5% in community isolates. Comparative genome analysis of 2 representative dog isolates revealed that the dog strain of ST192 was evolutionarily closely linked to two previously sequenced hospital ARE, but had, based on gene content, more genes in common with the other, evolutionarily more distantly related, dog strain (ST266. CONCLUSION: ARE were detected in dogs, cats and sporadically in healthy humans, with evolutionary linkage to hospital ARE. Yet, their accessory genome has diversified, probably as a result of niche adaptation.

  13. An evolutionarily conserved gene, FUWA, plays a role in determining panicle architecture, grain shape and grain weight in rice.

    Science.gov (United States)

    Chen, Jun; Gao, He; Zheng, Xiao-Ming; Jin, Mingna; Weng, Jian-Feng; Ma, Jin; Ren, Yulong; Zhou, Kunneng; Wang, Qi; Wang, Jie; Wang, Jiu-Lin; Zhang, Xin; Cheng, Zhijun; Wu, Chuanyin; Wang, Haiyang; Wan, Jian-Min

    2015-08-01

    Plant breeding relies on creation of novel allelic combinations for desired traits. Identification and utilization of beneficial alleles, rare alleles and evolutionarily conserved genes in the germplasm (referred to as 'hidden' genes) provide an effective approach to achieve this goal. Here we show that a chemically induced null mutation in an evolutionarily conserved gene, FUWA, alters multiple important agronomic traits in rice, including panicle architecture, grain shape and grain weight. FUWA encodes an NHL domain-containing protein, with preferential expression in the root meristem, shoot apical meristem and inflorescences, where it restricts excessive cell division. Sequence analysis revealed that FUWA has undergone a bottleneck effect, and become fixed in landraces and modern cultivars during domestication and breeding. We further confirm a highly conserved role of FUWA homologs in determining panicle architecture and grain development in rice, maize and sorghum through genetic transformation. Strikingly, knockdown of the FUWA transcription level by RNA interference results in an erect panicle and increased grain size in both indica and japonica genetic backgrounds. This study illustrates an approach to create new germplasm with improved agronomic traits for crop breeding by tapping into evolutionary conserved genes. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

  14. Subcellular targeting of an evolutionarily conserved plant defensin MtDef4.2 determines the outcome of plant-pathogen interaction in transgenic Arabidopsis.

    Science.gov (United States)

    Kaur, Jagdeep; Thokala, Mercy; Robert-Seilaniantz, Alexandre; Zhao, Patrick; Peyret, Hadrien; Berg, Howard; Pandey, Sona; Jones, Jonathan; Shah, Dilip

    2012-12-01

    The Medicago truncatula gene encoding an evolutionarily conserved antifungal defensin MtDef4.2 was cloned and characterized. In silico expression analysis indicated that MtDef4.2 is expressed in many tissues during the normal growth and development of M. truncatula. MtDef4.2 exhibits potent broad-spectrum antifungal activity against various Fusarium spp. Transgenic Arabidopsis thaliana lines in which MtDef4.2 was targeted to three different subcellular compartments were generated. These lines were tested for resistance to the obligate biotrophic oomycete Hyaloperonospora arabidopsidis Noco2 and the hemibiotrophic fungal pathogen Fusarium graminearum PH-1. MtDef4.2 directed to the extracellular space, but not to the vacuole or retained in the endoplasmic reticulum, conferred robust resistance to H. arabidopsidis. Siliques of transgenic Arabidopsis lines expressing either extracellularly or intracellularly targeted MtDef4.2 displayed low levels of resistance to F. graminearum, but accumulated substantially reduced levels of the mycotoxin deoxynivalenol. The data presented here suggest that extracellularly targeted MtDef4.2 is sufficient to provide strong resistance to the biotrophic oomycete, consistent with the extracellular lifestyle of this pathogen. However, the co-expression of extracellular and intracellular MtDef4.2 is probably required to achieve strong resistance to the hemibiotrophic pathogen F. graminearum which grows extracellularly and intracellularly. © 2012 THE AUTHORS. MOLECULAR PLANT PATHOLOGY © 2012 BSPP AND BLACKWELL PUBLISHING LTD.

  15. Peptides derived from evolutionarily conserved domains in Beclin-1 and Beclin-2 enhance the entry of lentiviral vectors into human cells.

    Science.gov (United States)

    Majdoul, Saliha; Cosette, Jeremie; Seye, Ababacar K; Bernard, Eric; Frin, Sophie; Holic, Nathalie; Chazal, Nathalie; Briant, Laurence; Espert, Lucile; Galy, Anne; Fenard, David

    2017-11-10

    Autophagy-related proteins such as Beclin-1 are involved in an array of complex processes, including antiviral responses, and may also modulate the efficiency of gene therapy viral vectors. The Tat-Beclin-1 (TB1) peptide has been reported as an autophagy-inducing factor inhibiting the replication of pathogens such as HIV, type 1 (HIV-1). However, autophagy-related proteins are also essential for the early steps of HIV-1 infection. Therefore, we examined the effects of the Beclin-1 evolutionarily conserved domain in TB1 on viral transduction and autophagy in single-round HIV infection or with nonreplicative HIV-1-derived lentiviral vectors. TB1 enhanced transduction with various pseudotypes but without inducing the autophagy process. TB1 augmented the transduction of human CD34+ hematopoietic stem/progenitor cells while maintaining their capacity to engraft in vivo into humanized mice. TB1 was as effective as other transduction additives and functioned by enhancing the adhesion and fusion of viral particles with target cells but not their aggregation. We also found that the N-terminal L1 loop was critical for TB1 transduction-enhancing activity. Interestingly, the Tat-Beclin-2 (TB2) peptide, derived from the human Beclin-2 protein, was even more potent than TB1 in promoting viral transduction and infection. Taken together, our findings suggest that the TB1 and TB2 peptides enhance the viral entry step. Tat-Beclin peptides therefore represent a new family of viral transduction enhancers for potential use in gene therapy. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. WASP and SCAR are evolutionarily conserved in actin-filled pseudopod-based motility

    OpenAIRE

    Fritz-Laylin, Lillian K.; Lord, Samuel J.; Mullins, R Dyche

    2017-01-01

    Diverse eukaryotic cells crawl through complex environments using distinct modes of migration. To understand the underlying mechanisms and their evolutionary relationships, we must define each mode and identify its phenotypic and molecular markers. In this study, we focus on a widely dispersed migration mode characterized by dynamic actin-filled pseudopods that we call ??-motility.? Mining genomic data reveals a clear trend: only organisms with both WASP and SCAR/WAVE?activators of branched a...

  17. Evolutionarily divergent, unstable filamentous actin is essential for gliding motility in apicomplexan parasites.

    Science.gov (United States)

    Skillman, Kristen M; Diraviyam, Karthikeyan; Khan, Asis; Tang, Keliang; Sept, David; Sibley, L David

    2011-10-01

    Apicomplexan parasites rely on a novel form of actin-based motility called gliding, which depends on parasite actin polymerization, to migrate through their hosts and invade cells. However, parasite actins are divergent both in sequence and function and only form short, unstable filaments in contrast to the stability of conventional actin filaments. The molecular basis for parasite actin filament instability and its relationship to gliding motility remain unresolved. We demonstrate that recombinant Toxoplasma (TgACTI) and Plasmodium (PfACTI and PfACTII) actins polymerized into very short filaments in vitro but were induced to form long, stable filaments by addition of equimolar levels of phalloidin. Parasite actins contain a conserved phalloidin-binding site as determined by molecular modeling and computational docking, yet vary in several residues that are predicted to impact filament stability. In particular, two residues were identified that form intermolecular contacts between different protomers in conventional actin filaments and these residues showed non-conservative differences in apicomplexan parasites. Substitution of divergent residues found in TgACTI with those from mammalian actin resulted in formation of longer, more stable filaments in vitro. Expression of these stabilized actins in T. gondii increased sensitivity to the actin-stabilizing compound jasplakinolide and disrupted normal gliding motility in the absence of treatment. These results identify the molecular basis for short, dynamic filaments in apicomplexan parasites and demonstrate that inherent instability of parasite actin filaments is a critical adaptation for gliding motility.

  18. Evolutionarily divergent, unstable filamentous actin is essential for gliding motility in apicomplexan parasites.

    Directory of Open Access Journals (Sweden)

    Kristen M Skillman

    2011-10-01

    Full Text Available Apicomplexan parasites rely on a novel form of actin-based motility called gliding, which depends on parasite actin polymerization, to migrate through their hosts and invade cells. However, parasite actins are divergent both in sequence and function and only form short, unstable filaments in contrast to the stability of conventional actin filaments. The molecular basis for parasite actin filament instability and its relationship to gliding motility remain unresolved. We demonstrate that recombinant Toxoplasma (TgACTI and Plasmodium (PfACTI and PfACTII actins polymerized into very short filaments in vitro but were induced to form long, stable filaments by addition of equimolar levels of phalloidin. Parasite actins contain a conserved phalloidin-binding site as determined by molecular modeling and computational docking, yet vary in several residues that are predicted to impact filament stability. In particular, two residues were identified that form intermolecular contacts between different protomers in conventional actin filaments and these residues showed non-conservative differences in apicomplexan parasites. Substitution of divergent residues found in TgACTI with those from mammalian actin resulted in formation of longer, more stable filaments in vitro. Expression of these stabilized actins in T. gondii increased sensitivity to the actin-stabilizing compound jasplakinolide and disrupted normal gliding motility in the absence of treatment. These results identify the molecular basis for short, dynamic filaments in apicomplexan parasites and demonstrate that inherent instability of parasite actin filaments is a critical adaptation for gliding motility.

  19. Evolutionarily conserved transcription factor Apontic controls the G1/S progression by inducing cyclin e during eye development

    KAUST Repository

    Liu, Qingxin

    2014-06-16

    During Drosophila eye development, differentiation initiates in the posterior region of the eye disk and progresses anteriorly as a wave marked by the morphogenetic furrow (MF), which demarcates the boundary between anterior undifferentiated cells and posterior differentiated photoreceptors. However, the mechanism underlying the regulation of gene expression immediately before the onset of differentiation remains unclear. Here, we show that Apontic (Apt), which is an evolutionarily conserved transcription factor, is expressed in the differentiating cells posterior to the MF. Moreover, it directly induces the expression of cyclin E and is also required for the G1-to-S phase transition, which is known to be essential for the initiation of cell differentiation at the MF. These observations identify a pathway crucial for eye development, governed by a mechanism in which Cyclin E promotes the G1-to-S phase transition when regulated by Apt.

  20. The disequilibrium of nucleosomes distribution along chromosomes plays a functional and evolutionarily role in regulating gene expression

    KAUST Repository

    Cui, Peng

    2011-08-19

    To further understand the relationship between nucleosome-space occupancy (NO) and global transcriptional activity in mammals, we acquired a set of genome-wide nucleosome distribution and transcriptome data from the mouse cerebrum and testis based on ChIP (H3)-seq and RNA-seq, respectively. We identified a nearly consistent NO patterns among three mouse tissues-cerebrum, testis, and ESCs-and found, through clustering analysis for transcriptional activation, that the NO variations among chromosomes are closely associated with distinct expression levels between house-keeping (HK) genes and tissue-specific (TS) genes. Both TS and HK genes form clusters albeit the obvious majority. This feature implies that NO patterns, i.e. nucleosome binding and clustering, are coupled with gene clustering that may be functionally and evolutionarily conserved in regulating gene expression among different cell types. © 2011 Cui et al.

  1. Reiterated WG/GW motifs form functionally and evolutionarily conserved ARGONAUTE-binding platforms in RNAi-related components

    Science.gov (United States)

    El-Shami, Mahmoud; Pontier, Dominique; Lahmy, Sylvie; Braun, Laurence; Picart, Claire; Vega, Danielle; Hakimi, Mohamed-Ali; Jacobsen, Steven E.; Cooke, Richard; Lagrange, Thierry

    2007-01-01

    Two forms of RNA Polymerase IV (PolIVa/PolIVb) have been implicated in RNA-directed DNA methylation (RdDM) in Arabidopsis. Prevailing models imply a distinct function for PolIVb by association of Argonaute4 (AGO4) with the C-terminal domain (CTD) of its largest subunit NRPD1b. Here we show that the extended CTD of NRPD1b-type proteins exhibits conserved Argonaute-binding capacity through a WG/GW-rich region that functionally distinguishes Pol IVb from Pol IVa, and that is essential for RdDM. Site-specific mutagenesis and domain-swapping experiments between AtNRPD1b and the human protein GW182 demonstrated that reiterated WG/GW motifs form evolutionarily and functionally conserved Argonaute-binding platforms in RNA interference (RNAi)-related components. PMID:17938239

  2. The disequilibrium of nucleosomes distribution along chromosomes plays a functional and evolutionarily role in regulating gene expression.

    Directory of Open Access Journals (Sweden)

    Peng Cui

    Full Text Available To further understand the relationship between nucleosome-space occupancy (NO and global transcriptional activity in mammals, we acquired a set of genome-wide nucleosome distribution and transcriptome data from the mouse cerebrum and testis based on ChIP (H3-seq and RNA-seq, respectively. We identified a nearly consistent NO patterns among three mouse tissues--cerebrum, testis, and ESCs--and found, through clustering analysis for transcriptional activation, that the NO variations among chromosomes are closely associated with distinct expression levels between house-keeping (HK genes and tissue-specific (TS genes. Both TS and HK genes form clusters albeit the obvious majority. This feature implies that NO patterns, i.e. nucleosome binding and clustering, are coupled with gene clustering that may be functionally and evolutionarily conserved in regulating gene expression among different cell types.

  3. Intrinsically disordered proteins drive enamel formation via an evolutionarily conserved self-assembly motif

    Czech Academy of Sciences Publication Activity Database

    Wald, Tomáš; Špoutil, František; Osičková, Adriana; Procházková, Michaela; Benada, Oldřich; Kašpárek, Petr; Bumba, Ladislav; Klein, O. D.; Sedláček, Radislav; Šebo, Peter; Procházka, Jan; Osička, Radim

    2017-01-01

    Roč. 114, č. 9 (2017), s. 1641-1650 ISSN 0027-8424 R&D Projects: GA MŠk(CZ) LM2015064; GA MŠk(CZ) LQ1604; GA MŠk(CZ) LM2011032; GA MŠk(CZ) LM2015040; GA MŠk(CZ) LO1509; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk ED2.1.00/19.0395 Grant - others:Ministerstvo pro místní rozvoj(CZ) CZ2.16/3.1.00/24023 Institutional support: RVO:61388971 ; RVO:68378050 Keywords : ameloblastin * amelogenin * biomineralization Subject RIV: EE - Microbiology, Virology; EB - Genetics ; Molecular Biology (UMG-J) Impact factor: 9.661, year: 2016

  4. Latency transition of plasminogen activator inhibitor type 1 is evolutionarily conserved

    DEFF Research Database (Denmark)

    Jendroszek, Agnieszka; Sønnichsen, Malene; Chana Munoz, Andres

    2017-01-01

    latency transition must have been a specific selection criterion for the evolution of PAI-1. It appears that all PAI-1 molecules must harbour latency transition to fulfil their physiological function, stressing the importance to further pursue a complete understanding of this molecular phenomenon......Plasminogen activator inhibitor type 1 (PAI-1) is a central regulator of fibrinolysis and tissue remodelling. PAI-1 belongs to the serpin superfamily and unlike other inhibitory serpins undergoes a spontaneous inactivation process under physiological conditions, termed latency transition. During...... latency transition the solvent exposed reactive centre loop is inserted into the central β-sheet A of the molecule, and is no longer accessible to reaction with the protease. More than three decades of research on mammalian PAI-1 has not been able to clarify the evolutionary advantage and physiological...

  5. Dissecting the Gene Network of Dietary Restriction to Identify Evolutionarily Conserved Pathways and New Functional Genes

    Science.gov (United States)

    Wuttke, Daniel; Connor, Richard; Vora, Chintan; Craig, Thomas; Li, Yang; Wood, Shona; Vasieva, Olga; Shmookler Reis, Robert; Tang, Fusheng; de Magalhães, João Pedro

    2012-01-01

    Dietary restriction (DR), limiting nutrient intake from diet without causing malnutrition, delays the aging process and extends lifespan in multiple organisms. The conserved life-extending effect of DR suggests the involvement of fundamental mechanisms, although these remain a subject of debate. To help decipher the life-extending mechanisms of DR, we first compiled a list of genes that if genetically altered disrupt or prevent the life-extending effects of DR. We called these DR–essential genes and identified more than 100 in model organisms such as yeast, worms, flies, and mice. In order for other researchers to benefit from this first curated list of genes essential for DR, we established an online database called GenDR (http://genomics.senescence.info/diet/). To dissect the interactions of DR–essential genes and discover the underlying lifespan-extending mechanisms, we then used a variety of network and systems biology approaches to analyze the gene network of DR. We show that DR–essential genes are more conserved at the molecular level and have more molecular interactions than expected by chance. Furthermore, we employed a guilt-by-association method to predict novel DR–essential genes. In budding yeast, we predicted nine genes related to vacuolar functions; we show experimentally that mutations deleting eight of those genes prevent the life-extending effects of DR. Three of these mutants (OPT2, FRE6, and RCR2) had extended lifespan under ad libitum, indicating that the lack of further longevity under DR is not caused by a general compromise of fitness. These results demonstrate how network analyses of DR using GenDR can be used to make phenotypically relevant predictions. Moreover, gene-regulatory circuits reveal that the DR–induced transcriptional signature in yeast involves nutrient-sensing, stress responses and meiotic transcription factors. Finally, comparing the influence of gene expression changes during DR on the interactomes of multiple

  6. The determinants of stability and folding in evolutionarily diverged cytochromes c.

    Science.gov (United States)

    Thielges, Megan C; Zimmermann, Jörg; Dawson, Philip E; Romesberg, Floyd E

    2009-04-24

    Cytochrome c has served as a paradigm for the study of protein stability, folding, and molecular evolution, but it remains unclear how these aspects of the protein are related. For example, while the bovine and equine cytochromes c are known to have different stabilities, and possibly different folding mechanisms, it is not known how these differences arise from just three amino acid substitutions introduced during divergence. Using site-selectively incorporated carbon-deuterium bonds, we show that like the equine protein, bovine cytochrome c is induced to unfold by guanidine hydrochloride via a stepwise mechanism, but it does not populate an intermediate as is observed with the equine protein. The increased stability also results in more similar free energies of unfolding observed at different sites within the protein, giving the appearance of a more concerted mechanism. Furthermore, we show that the differences in stability and folding appear to result from a single amino acid substitution that stabilizes a helix by allowing for increased solvation of its N-terminus.

  7. Elucidation of clathrin-mediated endocytosis in tetrahymena reveals an evolutionarily convergent recruitment of dynamin.

    Directory of Open Access Journals (Sweden)

    Nels C Elde

    2005-11-01

    Full Text Available Ciliates, although single-celled organisms, contain numerous subcellular structures and pathways usually associated with metazoans. How this cell biological complexity relates to the evolution of molecular elements is unclear, because features in these cells have been defined mainly at the morphological level. Among these ciliate features are structures resembling clathrin-coated, endocytic pits associated with plasma membrane invaginations called parasomal sacs. The combination of genome-wide sequencing in Tetrahymena thermophila with tools for gene expression and replacement has allowed us to examine this pathway in detail. Here we demonstrate that parasomal sacs are sites of clathrin-dependent endocytosis and that AP-2 localizes to these sites. Unexpectedly, endocytosis in Tetrahymena also involves a protein in the dynamin family, Drp1p (Dynamin-related protein 1. While phylogenetic analysis of AP subunits indicates a primitive origin for clathrin-mediated endocytosis, similar analysis of dynamin-related proteins suggests, strikingly, that the recruitment of dynamin-family proteins to the endocytic pathway occurred independently during the course of the ciliate and metazoan radiations. Consistent with this, our functional analysis suggests that the precise roles of dynamins in endocytosis, as well as the mechanisms of targeting, differ in metazoans and ciliates.

  8. Elucidation of Clathrin-Mediated Endocytosis in Tetrahymena Reveals an Evolutionarily Convergent Recruitment of Dynamin.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available Ciliates, although single-celled organisms, contain numerous subcellular structures and pathways usually associated with metazoans. How this cell biological complexity relates to the evolution of molecular elements is unclear, because features in these cells have been defined mainly at the morphological level. Among these ciliate features are structures resembling clathrin-coated, endocytic pits associated with plasma membrane invaginations called parasomal sacs. The combination of genome-wide sequencing in Tetrahymena thermophila with tools for gene expression and replacement has allowed us to examine this pathway in detail. Here we demonstrate that parasomal sacs are sites of clathrin-dependent endocytosis and that AP-2 localizes to these sites. Unexpectedly, endocytosis in Tetrahymena also involves a protein in the dynamin family, Drp1p (Dynamin-related protein 1. While phylogenetic analysis of AP subunits indicates a primitive origin for clathrin-mediated endocytosis, similar analysis of dynamin-related proteins suggests, strikingly, that the recruitment of dynamin-family proteins to the endocytic pathway occurred independently during the course of the ciliate and metazoan radiations. Consistent with this, our functional analysis suggests that the precise roles of dynamins in endocytosis, as well as the mechanisms of targeting, differ in metazoans and ciliates.

  9. An evolutionarily conserved enhancer regulates Bmp4 expression in developing incisor and limb bud.

    Directory of Open Access Journals (Sweden)

    Dolrudee Jumlongras

    Full Text Available To elucidate the transcriptional regulation of Bmp4 expression during organogenesis, we used phylogenetic footprinting and transgenic reporter analyses to identify Bmp4 cis-regulatory modules (CRMs. These analyses identified a regulatory region located ∼46 kb upstream of the mouse Bmp4 transcription start site that had previously been shown to direct expression in lateral plate mesoderm. We refined this regulatory region to a 396-bp minimal enhancer, and show that it recapitulates features of endogenous Bmp4 expression in developing mandibular arch ectoderm and incisor epithelium during the initiation-stage of tooth development. In addition, this enhancer directs expression in the apical ectodermal ridge (AER of the developing limb and in anterior and posterior limb mesenchyme. Transcript profiling of E11.5 mouse incisor dental lamina, together with protein binding microarray (PBM analyses, allowed identification of a conserved DNA binding motif in the Bmp4 enhancer for Pitx homeoproteins, which are also expressed in the developing mandibular and incisor epithelium. In vitro electrophoretic mobility shift assays (EMSA and in vivo transgenic reporter mutational analyses revealed that this site supports Pitx binding and that the site is necessary to recapitulate aspects of endogenous Bmp4 expression in developing craniofacial and limb tissues. Finally, Pitx2 chromatin immunoprecipitation (ChIP demonstrated direct binding of Pitx2 to this Bmp4 enhancer site in a dental epithelial cell line. These results establish a direct molecular regulatory link between Pitx family members and Bmp4 gene expression in developing incisor epithelium.

  10. Evolutionarily conserved roles of the dicer helicase domain in regulating RNA interference processing.

    Science.gov (United States)

    Kidwell, Mary Anne; Chan, Jessica M; Doudna, Jennifer A

    2014-10-10

    The enzyme Dicer generates 21-25 nucleotide RNAs that target specific mRNAs for silencing during RNA interference and related pathways. Although their active sites and RNA binding regions are functionally conserved, the helicase domains have distinct activities in the context of different Dicer enzymes. To examine the evolutionary origins of Dicer helicase functions, we investigated two related Dicer enzymes from the thermophilic fungus Sporotrichum thermophile. RNA cleavage assays showed that S. thermophile Dicer-1 (StDicer-1) can process hairpin precursor microRNAs, whereas StDicer-2 can only cleave linear double-stranded RNAs. Furthermore, only StDicer-2 possesses robust ATP hydrolytic activity in the presence of double-stranded RNA. Deletion of the StDicer-2 helicase domain increases both StDicer-2 cleavage activity and affinity for hairpin RNA. Notably, both StDicer-1 and StDicer-2 could complement the distantly related yeast Schizosaccharomyces pombe lacking its endogenous Dicer gene but only in their full-length forms, underscoring the importance of the helicase domain. These results suggest an in vivo regulatory function for the helicase domain that may be conserved from fungi to humans. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. WASP and SCAR are evolutionarily conserved in actin-filled pseudopod-based motility.

    Science.gov (United States)

    Fritz-Laylin, Lillian K; Lord, Samuel J; Mullins, R Dyche

    2017-06-05

    Diverse eukaryotic cells crawl through complex environments using distinct modes of migration. To understand the underlying mechanisms and their evolutionary relationships, we must define each mode and identify its phenotypic and molecular markers. In this study, we focus on a widely dispersed migration mode characterized by dynamic actin-filled pseudopods that we call "α-motility." Mining genomic data reveals a clear trend: only organisms with both WASP and SCAR/WAVE-activators of branched actin assembly-make actin-filled pseudopods. Although SCAR has been shown to drive pseudopod formation, WASP's role in this process is controversial. We hypothesize that these genes collectively represent a genetic signature of α-motility because both are used for pseudopod formation. WASP depletion from human neutrophils confirms that both proteins are involved in explosive actin polymerization, pseudopod formation, and cell migration. WASP and WAVE also colocalize to dynamic signaling structures. Moreover, retention of WASP together with SCAR correctly predicts α-motility in disease-causing chytrid fungi, which we show crawl at >30 µm/min with actin-filled pseudopods. By focusing on one migration mode in many eukaryotes, we identify a genetic marker of pseudopod formation, the morphological feature of α-motility, providing evidence for a widely distributed mode of cell crawling with a single evolutionary origin. © 2017 Fritz-Laylin et al.

  12. IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis

    DEFF Research Database (Denmark)

    Gyrd-Hansen, Mads; Darding, Maurice; Miasari, Maria

    2008-01-01

    in cancer and their expression level is implicated in contributing to tumorigenesis, chemoresistance, disease progression and poor patient-survival. Here, we have identified an evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs, which enables them to bind to Lys 63-linked polyubiquitin. We...

  13. Drosophila Ncd reveals an evolutionarily conserved powerstroke mechanism for homodimeric and heterodimeric kinesin-14s.

    Science.gov (United States)

    Zhang, Pengwei; Dai, Wei; Hahn, Juergen; Gilbert, Susan P

    2015-05-19

    Drosophila melanogaster kinesin-14 Ncd cross-links parallel microtubules at the spindle poles and antiparallel microtubules within the spindle midzone to play roles in bipolar spindle assembly and proper chromosome distribution. As observed for Saccharomyces cerevisiae kinesin-14 Kar3Vik1 and Kar3Cik1, Ncd binds adjacent microtubule protofilaments in a novel microtubule binding configuration and uses an ATP-promoted powerstroke mechanism. The hypothesis tested here is that Kar3Vik1 and Kar3Cik1, as well as Ncd, use a common ATPase mechanism for force generation even though the microtubule interactions for both Ncd heads are modulated by nucleotide state. The presteady-state kinetics and computational modeling establish an ATPase mechanism for a powerstroke model of Ncd that is very similar to those determined for Kar3Vik1 and Kar3Cik1, although these heterodimers have one Kar3 catalytic motor domain and a Vik1/Cik1 partner motor homology domain whose interactions with microtubules are not modulated by nucleotide state but by strain. The results indicate that both Ncd motor heads bind the microtubule lattice; two ATP binding and hydrolysis events are required for each powerstroke; and a slow step occurs after microtubule collision and before the ATP-promoted powerstroke. Note that unlike conventional myosin-II or other processive molecular motors, Ncd requires two ATP turnovers rather than one for a single powerstroke-driven displacement or step. These results are significant because all metazoan kinesin-14s are homodimers, and the results presented show that despite their structural and functional differences, the heterodimeric and homodimeric kinesin-14s share a common evolutionary structural and mechanochemical mechanism for force generation.

  14. Drosophila KCNQ channel displays evolutionarily conserved electrophysiology and pharmacology with mammalian KCNQ channels.

    Directory of Open Access Journals (Sweden)

    Sonia Cavaliere

    Full Text Available Of the five human KCNQ (Kv7 channels, KCNQ1 with auxiliary subunit KCNE1 mediates the native cardiac I(Ks current with mutations causing short and long QT cardiac arrhythmias. KCNQ4 mutations cause deafness. KCNQ2/3 channels form the native M-current controlling excitability of most neurons, with mutations causing benign neonatal febrile convulsions. Drosophila contains a single KCNQ (dKCNQ that appears to serve alone the functions of all the duplicated mammalian neuronal and cardiac KCNQ channels sharing roughly 50-60% amino acid identity therefore offering a route to investigate these channels. Current information about the functional properties of dKCNQ is lacking therefore we have investigated these properties here. Using whole cell patch clamp electrophysiology we compare the biophysical and pharmacological properties of dKCNQ with the mammalian neuronal and cardiac KCNQ channels expressed in HEK cells. We show that Drosophila KCNQ (dKCNQ is a slowly activating and slowly-deactivating K(+ current open at sub-threshold potentials that has similar properties to neuronal KCNQ2/3 with some features of the cardiac KCNQ1/KCNE1 accompanied by conserved sensitivity to a number of clinically relevant KCNQ blockers (chromanol 293B, XE991, linopirdine and opener (zinc pyrithione. We also investigate the molecular basis of the differential selectivity of KCNQ channels to the opener retigabine and show a single amino acid substitution (M217W can confer sensitivity to dKCNQ. We show dKCNQ has similar electrophysiological and pharmacological properties as the mammalian KCNQ channels, allowing future study of physiological and pathological roles of KCNQ in Drosophila and whole organism screening for new modulators of KCNQ channelopathies.

  15. Holographic investigations of azobenzene-containing low-molecular-weight compounds in pure materials and binary blends with polystyrene.

    Science.gov (United States)

    Audorff, Hubert; Walker, Roland; Kador, Lothar; Schmidt, Hans-Werner

    2011-11-04

    This paper reports on the synthesis and the thermal and optical properties of photochromic low-molecular-weight compounds, especially with respect to the formation of holographic volume gratings in the pure materials and in binary blends with polystyrene. Its aim is to provide a basic understanding of the holographic response with regard to the molecular structure, and thus to show a way to obtain suitable rewritable materials with high sensitivity for holographic data storage. The photoactive low-molecular-weight compounds consist of a central core with three or four azobenzene-based arms attached through esterification. Four different cores were investigated that influence the glass transition temperature and the glass-forming properties. Additional structural variations were introduced by the polar terminal substituent at the azobenzene chromophore to fine-tune the optical properties and the holographic response. Films of the neat compounds were investigated in holographic experiments, especially with regard to the material sensitivity. In binary blends of the low-molecular-weight compounds with polystyrene, the influence of a polymer matrix on the behavior in holographic experiments was studied. The most promising material combination was also investigated at elevated temperatures, at which the holographic recording sensitivity is even higher. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Identification of evolutionarily conserved exons as regulated targets for the splicing activator tra2β in development.

    Directory of Open Access Journals (Sweden)

    Sushma Grellscheid

    2011-12-01

    Full Text Available Alternative splicing amplifies the information content of the genome, creating multiple mRNA isoforms from single genes. The evolutionarily conserved splicing activator Tra2β (Sfrs10 is essential for mouse embryogenesis and implicated in spermatogenesis. Here we find that Tra2β is up-regulated as the mitotic stem cell containing population of male germ cells differentiate into meiotic and post-meiotic cells. Using CLIP coupled to deep sequencing, we found that Tra2β binds a high frequency of exons and identified specific G/A rich motifs as frequent targets. Significantly, for the first time we have analysed the splicing effect of Sfrs10 depletion in vivo by generating a conditional neuronal-specific Sfrs10 knock-out mouse (Sfrs10(fl/fl; Nestin-Cre(tg/+. This mouse has defects in brain development and allowed correlation of genuine physiologically Tra2β regulated exons. These belonged to a novel class which were longer than average size and importantly needed multiple cooperative Tra2β binding sites for efficient splicing activation, thus explaining the observed splicing defects in the knockout mice. Regulated exons included a cassette exon which produces a meiotic isoform of the Nasp histone chaperone that helps monitor DNA double-strand breaks. We also found a previously uncharacterised poison exon identifying a new pathway of feedback control between vertebrate Tra2 proteins. Both Nasp-T and the Tra2a poison exon are evolutionarily conserved, suggesting they might control fundamental developmental processes. Tra2β protein isoforms lacking the RRM were able to activate specific target exons indicating an additional functional role as a splicing co-activator. Significantly the N-terminal RS1 domain conserved between flies and humans was essential for the splicing activator function of Tra2β. Versions of Tra2β lacking this N-terminal RS1 domain potently repressed the same target exons activated by full-length Tra2β protein.

  17. The Populus ARBORKNOX1 homeodomain transcription factor regulates woody growth through binding to evolutionarily conserved target genes of diverse function.

    Science.gov (United States)

    Liu, Lijun; Zinkgraf, Matthew; Petzold, H Earl; Beers, Eric P; Filkov, Vladimir; Groover, Andrew

    2015-01-01

    The class I KNOX homeodomain transcription factor ARBORKNOX1 (ARK1) is a key regulator of vascular cambium maintenance and cell differentiation in Populus. Currently, basic information is lacking concerning the distribution, functional characteristics, and evolution of ARK1 binding in the Populus genome. Here, we used chromatin immunoprecipitation sequencing (ChIP-seq) technology to identify ARK1 binding loci genome-wide in Populus. Computational analyses evaluated the distribution of ARK1 binding loci, the function of genes associated with bound loci, the effect of ARK1 binding on transcript levels, and evolutionary conservation of ARK1 binding loci. ARK1 binds to thousands of loci which are highly enriched proximal to the transcriptional start sites of genes of diverse functions. ARK1 target genes are significantly enriched in paralogs derived from the whole-genome salicoid duplication event. Both ARK1 and a maize (Zea mays) homolog, KNOTTED1, preferentially target evolutionarily conserved genes. However, only a small portion of ARK1 target genes are significantly differentially expressed in an ARK1 over-expression mutant. This study describes the functional characteristics and evolution of DNA binding by a transcription factor in an undomesticated tree, revealing complexities similar to those shown for transcription factors in model animal species. No claim to original US Government works. New Phytologist © 2014 New Phytologist Trust.

  18. Functional role of phenylacetic acid from metapleural gland secretions in controlling fungal pathogens in evolutionarily derived leaf-cutting ants

    Science.gov (United States)

    Fernández-Marín, Hermógenes; Nash, David R.; Higginbotham, Sarah; Estrada, Catalina; van Zweden, Jelle S.; d'Ettorre, Patrizia; Wcislo, William T.; Boomsma, Jacobus J.

    2015-01-01

    Fungus-farming ant colonies vary four to five orders of magnitude in size. They employ compounds from actinomycete bacteria and exocrine glands as antimicrobial agents. Atta colonies have millions of ants and are particularly relevant for understanding hygienic strategies as they have abandoned their ancestors' prime dependence on antibiotic-based biological control in favour of using metapleural gland (MG) chemical secretions. Atta MGs are unique in synthesizing large quantities of phenylacetic acid (PAA), a known but little investigated antimicrobial agent. We show that particularly the smallest workers greatly reduce germination rates of Escovopsis and Metarhizium spores after actively applying PAA to experimental infection targets in garden fragments and transferring the spores to the ants' infrabuccal cavities. In vitro assays further indicated that Escovopsis strains isolated from evolutionarily derived leaf-cutting ants are less sensitive to PAA than strains from phylogenetically more basal fungus-farming ants, consistent with the dynamics of an evolutionary arms race between virulence and control for Escovopsis, but not Metarhizium. Atta ants form larger colonies with more extreme caste differentiation relative to other attines, in societies characterized by an almost complete absence of reproductive conflicts. We hypothesize that these changes are associated with unique evolutionary innovations in chemical pest management that appear robust against selection pressure for resistance by specialized mycopathogens. PMID:25925100

  19. A nuclear DNA perspective on delineating evolutionarily significant lineages in polyploids: the case of the endangered shortnose sturgeon (Acipenser brevirostrum)

    Science.gov (United States)

    King, Timothy L.; Henderson, Anne P.; Kynard, Boyd E.; Kieffer, Micah C.; Peterson, Douglas L.; Aunins, Aaron W.; Brown, Bonnie L.

    2014-01-01

    The shortnose sturgeon, Acipenser brevirostrum, oft considered a phylogenetic relic, is listed as an “endangered species threatened with extinction” in the US and “Vulnerable” on the IUCN Red List. Effective conservation of A. brevirostrum depends on understanding its diversity and evolutionary processes, yet challenges associated with the polyploid nature of its nuclear genome have heretofore limited population genetic analysis to maternally inherited haploid characters. We developed a suite of polysomic microsatellite DNA markers and characterized a sample of 561 shortnose sturgeon collected from major extant populations along the North American Atlantic coast. The 181 alleles observed at 11 loci were scored as binary loci and the data were subjected to multivariate ordination, Bayesian clustering, hierarchical partitioning of variance, and among-population distance metric tests. The methods uncovered moderately high levels of gene diversity suggesting population structuring across and within three metapopulations (Northeast, Mid-Atlantic, and Southeast) that encompass seven demographically discrete and evolutionarily distinct lineages. The predicted groups are consistent with previously described behavioral patterns, especially dispersal and migration, supporting the interpretation that A. brevirostrum exhibit adaptive differences based on watershed. Combined with results of prior genetic (mitochondrial DNA) and behavioral studies, the current work suggests that dispersal is an important factor in maintaining genetic diversity in A. brevirostrum and that the basic unit for conservation management is arguably the local population.

  20. The molecular basis of high-altitude adaptation in deer mice.

    Directory of Open Access Journals (Sweden)

    Jay F Storz

    2007-03-01

    Full Text Available Elucidating genetic mechanisms of adaptation is a goal of central importance in evolutionary biology, yet few empirical studies have succeeded in documenting causal links between molecular variation and organismal fitness in natural populations. Here we report a population genetic analysis of a two-locus alpha-globin polymorphism that underlies physiological adaptation to high-altitude hypoxia in natural populations of deer mice, Peromyscus maniculatus. This system provides a rare opportunity to examine the molecular underpinnings of fitness-related variation in protein function that can be related to a well-defined selection pressure. We surveyed DNA sequence variation in the duplicated alpha-globin genes of P. maniculatus from high- and low-altitude localities (i to identify the specific mutations that may be responsible for the divergent fine-tuning of hemoglobin function and (ii to test whether the genes exhibit the expected signature of diversifying selection between populations that inhabit different elevational zones. Results demonstrate that functionally distinct protein alleles are maintained as a long-term balanced polymorphism and that adaptive modifications of hemoglobin function are produced by the independent or joint effects of five amino acid mutations that modulate oxygen-binding affinity.

  1. Molecular design and synthesis of self-assembling camptothecin drug amphiphiles.

    Science.gov (United States)

    Cheetham, Andrew G; Lin, Yi-An; Lin, Ran; Cui, Honggang

    2017-06-01

    The conjugation of small molecular hydrophobic anticancer drugs onto a short peptide with overall hydrophilicity to create self-assembling drug amphiphiles offers a new prodrug strategy, producing well-defined, discrete nanostructures with a high and quantitative drug loading. Here we show the detailed synthesis procedure and how the molecular structure can influence the synthesis of the self-assembling prodrugs and the physicochemical properties of their assemblies. A series of camptothecin-based drug amphiphiles were synthesized via combined solid- and solution-phase synthetic techniques, and the physicochemical properties of their self-assembled nanostructures were probed using a number of imaging and spectroscopic techniques. We found that the number of incorporated drug molecules strongly influences the rate at which the drug amphiphiles are formed, exerting a steric hindrance toward any additional drugs to be conjugated and necessitating extended reaction time. The choice of peptide sequence was found to affect the solubility of the conjugates and, by extension, the critical aggregation concentration and contour length of the filamentous nanostructures formed. In the design of self-assembling drug amphiphiles, the number of conjugated drug molecules and the choice of peptide sequence have significant effects on the nanostructures formed. These observations may allow the fine-tuning of the physicochemical properties for specific drug delivery applications, ie systemic vs local delivery.

  2. Evolutionarily divergent spliceosomal snRNAs and a conserved non-coding RNA processing motif in Giardia lamblia

    Science.gov (United States)

    Hudson, Andrew J.; Moore, Ashley N.; Elniski, David; Joseph, Joella; Yee, Janet; Russell, Anthony G.

    2012-01-01

    Non-coding RNAs (ncRNAs) have diverse essential biological functions in all organisms, and in eukaryotes, two such classes of ncRNAs are the small nucleolar (sno) and small nuclear (sn) RNAs. In this study, we have identified and characterized a collection of sno and snRNAs in Giardia lamblia, by exploiting our discovery of a conserved 12 nt RNA processing sequence motif found in the 3′ end regions of a large number of G. lamblia ncRNA genes. RNA end mapping and other experiments indicate the motif serves to mediate ncRNA 3′ end formation from mono- and di-cistronic RNA precursor transcripts. Remarkably, we find the motif is also utilized in the processing pathway of all four previously identified trans-spliced G. lamblia introns, revealing a common RNA processing pathway for ncRNAs and trans-spliced introns in this organism. Motif sequence conservation then allowed for the bioinformatic and experimental identification of additional G. lamblia ncRNAs, including new U1 and U6 spliceosomal snRNA candidates. The U6 snRNA candidate was then used as a tool to identity novel U2 and U4 snRNAs, based on predicted phylogenetically conserved snRNA–snRNA base-pairing interactions, from a set of previously identified G. lamblia ncRNAs without assigned function. The Giardia snRNAs retain the core features of spliceosomal snRNAs but are sufficiently evolutionarily divergent to explain the difficulties in their identification. Most intriguingly, all of these snRNAs show structural features diagnostic of U2-dependent/major and U12-dependent/minor spliceosomal snRNAs. PMID:23019220

  3. H3K23me1 is an evolutionarily conserved histone modification associated with CG DNA methylation in Arabidopsis.

    Science.gov (United States)

    Trejo-Arellano, Minerva S; Mahrez, Walid; Nakamura, Miyuki; Moreno-Romero, Jordi; Nanni, Paolo; Köhler, Claudia; Hennig, Lars

    2017-04-01

    Amino-terminal tails of histones are targets for diverse post-translational modifications whose combinatorial action may constitute a code that will be read and interpreted by cellular proteins to define particular transcriptional states. Here, we describe monomethylation of histone H3 lysine 23 (H3K23me1) as a histone modification not previously described in plants. H3K23me1 is an evolutionarily conserved mark in diverse species of flowering plants. Chromatin immunoprecipitation followed by high-throughput sequencing in Arabidopsis thaliana showed that H3K23me1 was highly enriched in pericentromeric regions and depleted from chromosome arms. In transposable elements it co-localized with CG, CHG and CHH DNA methylation as well as with the heterochromatic histone mark H3K9me2. Transposable elements are often rich in H3K23me1 but different families vary in their enrichment: LTR-Gypsy elements are most enriched and RC/Helitron elements are least enriched. The histone methyltransferase KRYPTONITE and normal DNA methylation were required for normal levels of H3K23me1 on transposable elements. Immunostaining experiments confirmed the pericentromeric localization and also showed mild enrichment in less condensed regions. Accordingly, gene bodies of protein-coding genes had intermediate H3K23me1 levels, which coexisted with CG DNA methylation. Enrichment of H3K23me1 along gene bodies did not correlate with transcription levels. Together, this work establishes H3K23me1 as a so far undescribed component of the plant histone code. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  4. Comparative analysis of evolutionarily conserved motifs of epidermal growth factor receptor 2 (HER2 predicts novel potential therapeutic epitopes.

    Directory of Open Access Journals (Sweden)

    Xiaohong Deng

    Full Text Available Overexpression of human epidermal growth factor receptor 2 (HER2 is associated with tumor aggressiveness and poor prognosis in breast cancer. With the availability of therapeutic antibodies against HER2, great strides have been made in the clinical management of HER2 overexpressing breast cancer. However, de novo and acquired resistance to these antibodies presents a serious limitation to successful HER2 targeting treatment. The identification of novel epitopes of HER2 that can be used for functional/region-specific blockade could represent a central step in the development of new clinically relevant anti-HER2 antibodies. In the present study, we present a novel computational approach as an auxiliary tool for identification of novel HER2 epitopes. We hypothesized that the structurally and linearly evolutionarily conserved motifs of the extracellular domain of HER2 (ECD HER2 contain potential druggable epitopes/targets. We employed the PROSITE Scan to detect structurally conserved motifs and PRINTS to search for linearly conserved motifs of ECD HER2. We found that the epitopes recognized by trastuzumab and pertuzumab are located in the predicted conserved motifs of ECD HER2, supporting our initial hypothesis. Considering that structurally and linearly conserved motifs can provide functional specific configurations, we propose that by comparing the two types of conserved motifs, additional druggable epitopes/targets in the ECD HER2 protein can be identified, which can be further modified for potential therapeutic application. Thus, this novel computational process for predicting or searching for potential epitopes or key target sites may contribute to epitope-based vaccine and function-selected drug design, especially when x-ray crystal structure protein data is not available.

  5. Comparative analysis of evolutionarily conserved motifs of epidermal growth factor receptor 2 (HER2) predicts novel potential therapeutic epitopes.

    Science.gov (United States)

    Deng, Xiaohong; Zheng, Xuxu; Yang, Huanming; Moreira, José Manuel Afonso; Brünner, Nils; Christensen, Henrik

    2014-01-01

    Overexpression of human epidermal growth factor receptor 2 (HER2) is associated with tumor aggressiveness and poor prognosis in breast cancer. With the availability of therapeutic antibodies against HER2, great strides have been made in the clinical management of HER2 overexpressing breast cancer. However, de novo and acquired resistance to these antibodies presents a serious limitation to successful HER2 targeting treatment. The identification of novel epitopes of HER2 that can be used for functional/region-specific blockade could represent a central step in the development of new clinically relevant anti-HER2 antibodies. In the present study, we present a novel computational approach as an auxiliary tool for identification of novel HER2 epitopes. We hypothesized that the structurally and linearly evolutionarily conserved motifs of the extracellular domain of HER2 (ECD HER2) contain potential druggable epitopes/targets. We employed the PROSITE Scan to detect structurally conserved motifs and PRINTS to search for linearly conserved motifs of ECD HER2. We found that the epitopes recognized by trastuzumab and pertuzumab are located in the predicted conserved motifs of ECD HER2, supporting our initial hypothesis. Considering that structurally and linearly conserved motifs can provide functional specific configurations, we propose that by comparing the two types of conserved motifs, additional druggable epitopes/targets in the ECD HER2 protein can be identified, which can be further modified for potential therapeutic application. Thus, this novel computational process for predicting or searching for potential epitopes or key target sites may contribute to epitope-based vaccine and function-selected drug design, especially when x-ray crystal structure protein data is not available.

  6. Is altruism evolutionarily stable ?

    NARCIS (Netherlands)

    Bester, H.; Güth, W.

    1994-01-01

    We develop an evolutionary approach to explain altruistic preferences. Given their preferences, individuals interact rationally with each other. By comparing the success of players with different preferences, we investigate whether evolution favors altruistic or selfish attitudes. The outcome

  7. Using molecular mechanics to predict bulk material properties of fibronectin fibers.

    Directory of Open Access Journals (Sweden)

    Mark J Bradshaw

    Full Text Available The structural proteins of the extracellular matrix (ECM form fibers with finely tuned mechanical properties matched to the time scales of cell traction forces. Several proteins such as fibronectin (Fn and fibrin undergo molecular conformational changes that extend the proteins and are believed to be a major contributor to the extensibility of bulk fibers. The dynamics of these conformational changes have been thoroughly explored since the advent of single molecule force spectroscopy and molecular dynamics simulations but remarkably, these data have not been rigorously applied to the understanding of the time dependent mechanics of bulk ECM fibers. Using measurements of protein density within fibers, we have examined the influence of dynamic molecular conformational changes and the intermolecular arrangement of Fn within fibers on the bulk mechanical properties of Fn fibers. Fibers were simulated as molecular strands with architectures that promote either equal or disparate molecular loading under conditions of constant extension rate. Measurements of protein concentration within micron scale fibers using deep ultraviolet transmission microscopy allowed the simulations to be scaled appropriately for comparison to in vitro measurements of fiber mechanics as well as providing estimates of fiber porosity and water content, suggesting Fn fibers are approximately 75% solute. Comparing the properties predicted by single molecule measurements to in vitro measurements of Fn fibers showed that domain unfolding is sufficient to predict the high extensibility and nonlinear stiffness of Fn fibers with surprising accuracy, with disparately loaded fibers providing the best fit to experiment. This work shows the promise of this microstructural modeling approach for understanding Fn fiber properties, which is generally applicable to other ECM fibers, and could be further expanded to tissue scale by incorporating these simulated fibers into three dimensional

  8. A Molecular Titration System Coordinates Ribosomal Protein Gene Transcription with Ribosomal RNA Synthesis.

    Science.gov (United States)

    Albert, Benjamin; Knight, Britta; Merwin, Jason; Martin, Victoria; Ottoz, Diana; Gloor, Yvonne; Bruzzone, Maria Jessica; Rudner, Adam; Shore, David

    2016-11-17

    Cell growth potential is determined by the rate of ribosome biogenesis, a complex process that requires massive and coordinated transcriptional output. In the yeast Saccharomyces cerevisiae, ribosome biogenesis is highly regulated at the transcriptional level. Although evidence for a system that coordinates ribosomal RNA (rRNA) and ribosomal protein gene (RPG) transcription has been described, the molecular mechanisms remain poorly understood. Here we show that an interaction between the RPG transcriptional activator Ifh1 and the rRNA processing factor Utp22 serves to coordinate RPG transcription with that of rRNA. We demonstrate that Ifh1 is rapidly released from RPG promoters by a Utp22-independent mechanism following growth inhibition, but that its long-term dissociation requires Utp22. We present evidence that RNA polymerase I activity inhibits the ability of Utp22 to titrate Ifh1 from RPG promoters and propose that a dynamic Ifh1-Utp22 interaction fine-tunes RPG expression to coordinate RPG and rRNA transcription. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Evolutionarily stable strategy of carbon and nitrogen investments in forest leaves and its application in vegetation dynamic modeling

    Science.gov (United States)

    Weng, E.; Farrior, C.; Dybzinski, R.; Pacala, S. W.

    2015-12-01

    Leaf mass per area (LMA) and leaf lifespan (LL) are two highly correlated plant traits that are key to plant physiological and ecological properties. Usually, low LMA means short LL, high nitrogen (N) content per unit mass, and fast turnover rates of nutrients; high LMA leads to long LL, low N content, and slow turnover rates. Deciduous trees with low LMA and short lifespan leaves have low carbon cost but high nitrogen demand; and evergreen trees, with high LMA and long lifespan leaves, have high carbon cost but low nitrogen demand. These relationships lead to: 1) evergreen trees have higher leaf area index than deciduous trees; 2) evergreen trees' carbon use efficiency is lower than the deciduous trees' because of their thick leaves and therefore high maintenance respiration; 3) the advantage of evergreens trees brought by their extra leaves over deciduous trees diminishes with increase N in ecosystem. These facts determine who will win when trees compete with each other in a N-limited ecosystem. In this study, we formulate a mathematical model according to the relationships between LMA, LL, leaf nitrogen, and leaf building and maintenance cost, where LMA is the fundamental variable determining the other three. We analyze the evolutionarily stable strategies (ESSs) of LMA with this mathematical model by examining the benefits of carbon and nitrogen investments to leaves in ecosystems with different N. The model shows the ESS converges to low LMA at high N and high LMA at low N. At intermediate N, there are two ESSs at low and high ends of LMA, respectively. The ESS also leads to low forest productivity by outcompeting the possible high productive strategies. We design a simulation scheme in an individual-based competition model (LM3-PPA) to simulate forest dynamics as results of the competition between deciduous and evergreen trees in three different biomes, which are temperate deciduous forest, deciduous-evergreen mixed forest, and boreal evergreen forest. The

  10. The wing-patterning network in the wingless castes of Myrmicine and Formicine ant species is a mix of evolutionarily labile and non-labile genes.

    Science.gov (United States)

    Shbailat, Seba Jamal; Abouheif, Ehab

    2013-03-01

    Wing polyphenism in ants is the ability of a single genome to produce winged or wingless castes in a colony in response to environmental cues. Although wing polyphenism is a universal and homologous feature of ants, the gene network underlying wing polyphenism is conserved in the winged castes, but is labile in the wingless castes, that is, the network is interrupted at different points in the wingless castes of different ant species. Because the expression of all genes sampled so far in this network in the wingless castes is evolutionarily labile across species, an important question is whether all "interruption points" in the network are evolutionarily labile or are there interruption points that are evolutionarily non-labile. Here we show that in the wingless castes, the expression of the gene brinker (brk), which mediates growth, patterning, and apoptosis in the Drosophila wing disc, is non-labile; it is absent in vestigial wing discs of four ants species. In contrast, the expression of engrailed (en), a gene upstream of brk is labile; it is present in some species but absent in others. In the winged castes, both brk and en expression are conserved relative to their expression in Drosophila wing discs. The differential lability of genes in the network in wingless castes may be a general feature of networks underlying polyphenic traits. This raises the possibility that some genes, like brk, may be under stabilizing selection while most others, like en, may be evolving via directional selection or neutral drift. Copyright © 2012 Wiley Periodicals, Inc.

  11. Environmental Molecular Sciences Laboratory Operations System: Version 4.0 - system requirements specification

    Energy Technology Data Exchange (ETDEWEB)

    Kashporenko, D.

    1996-07-01

    This document is intended to provide an operations standard for the Environmental Molecular Sciences Laboratory OPerations System (EMSL OPS). It is directed toward three primary audiences: (1) Environmental Molecular Sciences Laboratory (EMSL) facility and operations personnel; (2) laboratory line managers and staff; and (3) researchers, equipment operators, and laboratory users. It is also a statement of system requirements for software developers of EMSL OPS. The need for a finely tuned, superior research environment as provided by the US Department of Energy`s (DOE) Environmental Molecular Sciences Laboratory has never been greater. The abrupt end of the Cold War and the realignment of national priorities caused major US and competing overseas laboratories to reposition themselves in a highly competitive research marketplace. For a new laboratory such as the EMSL, this means coming into existence in a rapidly changing external environment. For any major laboratory, these changes create funding uncertainties and increasing global competition along with concomitant demands for higher standards of research product quality and innovation. While more laboratories are chasing fewer funding dollars, research ideas and proposals, especially for molecular-level research in the materials and biological sciences, are burgeoning. In such an economically constrained atmosphere, reduced costs, improved productivity, and strategic research project portfolio building become essential to establish and maintain any distinct competitive advantage. For EMSL, this environment and these demands require clear operational objectives, specific goals, and a well-crafted strategy. Specific goals will evolve and change with the evolution of the nature and definition of DOE`s environmental research needs. Hence, EMSL OPS is designed to facilitate migration of these changes with ease into every pertinent job function, creating a facile {open_quotes}learning organization.{close_quotes}

  12. Structural organization of essential iron-sulfur clusters in the evolutionarily highly conserved ATP-binding cassette protein ABCE1

    NARCIS (Netherlands)

    Barthelme, Dominik; Scheele, Urte; Dinkelaker, Stephanie; Janoschka, Adam; MacMillan, Fraser; Albers, Sonja-Verena; Driessen, Arnold J. M.; Stagni, Marco Salamone; Bill, Eckhard; Meyer-Klaucke, Wolfram; Schuenemann, Volker; Tampe, Robert; Schünemann, Volker

    2007-01-01

    The ABC protein ABCE1, formerly named RNase L inhibitor RLI1, is one of the most conserved proteins in evolution and is expressed in all organisms except eubacteria. Because of its fundamental role in translation initiation and/or ribosome biosynthesis, ABCE1 is essential for life. Its molecular

  13. Positive selection drives rapid evolution of certain amino acid residues in an evolutionarily highly conserved interferon-inducible antiviral protein of fishes.

    Science.gov (United States)

    Padhi, Abinash

    2013-01-01

    Viperin, an evolutionarily highly conserved interferon-inducible multifunctional protein, has previously been reported to exhibit antiviral activity against a wide range of DNA and RNA viruses. Utilizing the complete nucleotide coding sequence data of fish viperin antiviral genes, and employing the maximum likelihood-based codon substitution models, the present study reports the pervasive role of positive selection in the evolution of viperin antiviral protein in fishes. The overall rate of nonsynonymous (dN) to synonymous (dS) substitutions (dN/dS) for the three functional domains of viperin (N-terminal, central domain and C-terminal) were 1.1, 0.12, and 0.24, respectively. Codon-by-codon substitution analyses have revealed that while most of the positively selected sites were located at the N-terminal amphipathic α-helix domain, few amino acid residues at the C-terminal domain were under positive selection. However, none of the sites in the central domain were under positive selection. These results indicate that, although viperin is evolutionarily highly conserved, the three functional domains experienced differential selection pressures. Taken together with the results of previous studies, the present study suggests that the persistent antagonistic nature of surrounding infectious viral pathogens might be the likely cause for such adaptive evolutionary changes of certain amino acids in fish viperin antiviral protein.

  14. MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia

    NARCIS (Netherlands)

    B. Gentner (Bernhard); N. Pochert (Nicole); A. Rouhi (Arefeh); F. Boccalatte (Francesco); T. Plati (Tiziana); T. Berg (Tobias); S.M. Sun; S.M. Mah (Sarah M.); M. Mirkovic-Hösle (Milijana); J. Ruschmann (Jens); A. Muranyi (Andrew); S. Leierseder (Simon); B. Argiropoulos (Bob); D.T. Starczynowski (Daniel T.); A. Karsan (Aly); M. Heuser (Michael); D. Hogge (Donna); F.D. Camargo (Fernando D.); S. Engelhardt (Stefan); H. Döhner (Hartmut); C. Buske (Christian); M. Jongen-Lavrencic (Mojca); L. Naldini (Luigi); R.K. Humphries (R. Keith); F. Kuchenbauer (Florian)

    2015-01-01

    textabstractA precise understanding of the role of miR-223 in human hematopoiesis and in the pathogenesis of acute myeloid leukemia (AML) is still lacking. By measuring miR-223 expression in blasts from 115 AML patients, we found significantly higher miR-223 levels in patients with favorable

  15. Constitutive activity of the A2A adenosine receptor and compartmentalised cyclic AMP signalling fine-tune noradrenaline release.

    Science.gov (United States)

    Ibrisimovic, Edin; Drobny, Helmut; Yang, Qiong; Höfer, Thomas; Boehm, Stefan; Nanoff, Christian; Schicker, Klaus

    2012-12-01

    Neuroblastoma SH-SY5Y (SH) cells endogenously express A(2A) adenosine receptors and can be differentiated into a sympathetic neuronal phenotype, capable of depolarisation-dependent noradrenaline release. Using differentiated SH culture, we here explored the link between A(2A)-receptor signalling and neurotransmitter release. In response to the receptor agonist CGS21680, the cells produced cyclic AMP (cAMP), and when depolarised, they released increased amounts of noradrenaline. An A(2A)-receptor antagonist, XAC, as well as an inhibitor of cAMP-dependent protein kinase A (PKA), H89, depressed agonist-dependent release. In the presence of XAC or H89, noradrenaline release was found to be below basal values. This suggested that release facilitation also owes to constitutive receptor activity. We demonstrate that even in the absence of an agonist, the native A(2A)-receptor stimulated cAMP production, leading to the activation of PKA and enhanced noradrenaline release. Ancillary, non-cAMP-dependent effects of the receptor (i.e. phosphorylation of CREB, of Rabphilin3A) were refractory to constitutive activation. PKA-dependent facilitation of noradrenaline release was recapitulated with membrane-permeable 8-Br-cAMP; in addition to facilitation, 8-Br-cAMP caused marked inhibition of release, an effect not observed upon receptor activation. Inhibition by receptor-independent cAMP was likely due to suppression of voltage-dependent calcium current (VDCC) and increased activity of Src-family kinases. Receptor-mediated release facilitation was reproduced in the presence of tetrodotoxin (blocking action potentials); hence, the signalling occurred at the active zone comprising release sites. Our findings thus support (1) presynaptic localisation of the A(2A)-receptor and (2) suggest that compartmentalised pathways transmit cAMP signalling in order to facilitate depolarisation-dependent neurotransmitter release.

  16. [Fine-tuning of antithrombotic therapy in patients with non-valvular atrial fibrillation. The AFINVA register].

    Science.gov (United States)

    Dubois Marques, Daniela; Mora Llabata, Vicente; Pacheco Arroyo, Julián; Gasull Insertis, Salvador; Vicente Cañizares, Manuela; Roldán Torres, Ildefonso

    2017-08-31

    To determine whether antithrombotic treatment (ATT) in patients with non-valvular atrial fibrillation in a health area complies with the recommendations of current clinical guidelines. Prospective observational study. Primary Health Care Centres and Cardiology Department of a Health Department of the Valencian Community, Spain. A total of 505 patients with nonvalvular atrial fibrillation were included in the study. ATT was deemed to be inappropriate in patients with a CHA2DS2-VASc score ≥1 and who were not under oral anticoagulation, in patients treated with antivitaminK drugs, and poor control of oral anticoagulation, or with antiplatelet therapy inappropriately associated with anticoagulation, and in patients on ATT with a CHA2DS2-VASc score=0. The median age was 77.4±10years. The ATT was considered inadequate in 58% of cases. Factors independently associated with inadequate ATT were age (OR: 1.02 [1-1.04]; P=.029), hypothyroidism (OR: 1.98 [1.14-3.43]; P=.015), ischaemic heart disease (OR: 1.3 [1.15-2.59]; P=.008) and paroxysmal non-valvular AF (OR: 2.11 [1.41-3.17]; P<.0001). These data underline the high prevalence of inadequate ATT in daily practice, as well its different causes. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  17. Localized adenosine signaling provides fine-tuned negative feedback over a wide dynamic range of neocortical network activities

    Science.gov (United States)

    Richardson, Magnus J. E.

    2014-01-01

    Although the patterns of activity produced by neocortical networks are now better understood, how these states are activated, sustained, and terminated still remains unclear. Negative feedback by the endogenous neuromodulator adenosine may potentially play an important role, as it can be released by activity and there is dense A1 receptor expression in the neocortex. Using electrophysiology, biosensors, and modeling, we have investigated the properties of adenosine signaling during physiological and pathological network activity in rat neocortical slices. Both low- and high-rate network activities were reduced by A1 receptor activation and enhanced by block of A1 receptors, consistent with activity-dependent adenosine release. Since the A1 receptors were neither saturated nor completely unoccupied during either low- or high-rate activity, adenosine signaling provides a negative-feedback mechanism with a wide dynamic range. Modeling and biosensor experiments show that during high-rate activity increases in extracellular adenosine concentration are highly localized and are uncorrelated over short distances that are certainly adenosine release during low-rate activity, although it is present, is probably a consequence of small localized increases in adenosine concentration that are rapidly diminished by diffusion and active removal mechanisms. Saturation of such removal mechanisms when higher concentrations of adenosine are released results in the accumulation of inosine, explaining the strong purine signal during high-rate activity. PMID:25392170

  18. SpoVT : From Fine-Tuning Regulator in Bacillus subtilis to Essential Sporulation Protein in Bacillus

    NARCIS (Netherlands)

    Eijlander, Robyn T.; Holsappel, Siger; de Jong, Anne; Ghosh, Abhinaba; Christie, Graham; Kuipers, Oscar

    2016-01-01

    Sporulation is a highly sophisticated developmental process adopted by most Bacilli as a survival strategy to withstand extreme conditions that normally do not support microbial growth. A complicated regulatory cascade, divided into various stages and taking place in two different compartments of

  19. A fine-tuned fluorinated MOF addresses the needs for trace CO2 removal and air capture using physisorption.

    KAUST Repository

    Bhatt, Prashant

    2016-07-08

    The development of functional solid-state materials for carbon capture at low carbon dioxide (CO2) concentrations, from con-fined spaces (<0.5 %) and particularly from air (400 ppm), is of prime importance with respect to energy and environment sustainability. Herein, we report the deliberate construction of a hydrolytically stable fluorinated metal-organic framework (MOF), NbOFFIVE-1-Ni, with the proper pore system (size, shape and functionality), ideal for efficient and effective traces carbon dioxide removal. Markedly, the CO2-selective NbOFFIVE-1-Ni exhibits the highest CO2 gravimetric and volumetric uptake (ca. 1.3 mmol/g and 51.4 cm3.cm-3) for physical adsorbents at 400 ppm CO2 and 298 K. Practically, the NbOFFIVE-1-Ni affords the complete CO2 desorption at 328 K under vacuum with an associated moderate energy input of 54 kJ/mol, typical for the full CO2 desorption in reference physical adsorbents but considerably lower than the conventional chemical sorbents. Noticeably, the contracted square-like channels, affording the close proximity of the fluorine centers, permitted the enhancement of the CO2-framework interactions and subsequently the attainment of an unprecedented CO2-selectivity at very low CO2 concentrations. The precise localization of the adsorbed CO2 at the vicinity of the periodically aligned fluorine centers, promoting the selective adsorption of CO2, is evidenced by the single-crystal X-ray diffraction study on the NbOFFIVE-1-Ni hosting CO2 molecules. Cyclic CO2/N2 mixed-gas column breakthrough experiments under dry and humid conditions corroborate the excellent CO2-selectivity under practical carbon capture conditions. Pertinently, the no-table hydrolytic stability positions the NbOFFIVE-1-Ni as the new benchmark adsorbent for direct air capture and CO2 removal from confined spaces.

  20. The Yaa locus and IFN-α fine-tune germinal center B cell selection in murine systemic lupus erythematosus.

    Science.gov (United States)

    Moisini, Ioana; Huang, Weiqing; Bethunaickan, Ramalingam; Sahu, Ranjit; Ricketts, Peta-Gay; Akerman, Meredith; Marion, Tony; Lesser, Martin; Davidson, Anne

    2012-11-01

    Male NZW/BXSB.Yaa (W/B) mice express two copies of TLR7 and develop pathogenic autoantibodies, whereas females with only one copy of TLR7 have attenuated disease. Our goal was to analyze the regulation of the autoantibody response in male and female W/B mice bearing the autoreactive site-directed H chain transgene 3H9. Serum anti-dsDNA Abs appeared in males at 12 wk, and most had high-titer IgG anti-dsDNA and anti-cardiolipin Abs and developed >300 mg/dl proteinuria by 8 mo. Females had only low-titer IgG anti-cardiolipin Abs, and none developed proteinuria by 1 y. Males had a smaller marginal zone than females with a repertoire that was distinct from the follicular repertoire, indicating that the loss of marginal zone B cells was not due to diversion to the follicular compartment. Vk5-43 and Vk5-48, which were rare in the naive repertoire, were markedly overrepresented in the germinal center repertoire of both males and females, but the VJ junctions differed between males and females with higher-affinity autoreactive B cells being selected into the germinal centers of males. Administration of IFN-α to females induced anti-cardiolipin and anti-DNA autoantibodies and proteinuria and was associated with a male pattern of junctional diversity in Vk5-43 and Vk5-48. Our studies are consistent with the hypothesis that presence of the Yaa locus, which includes an extra copy of Tlr7, or administration of exogenous IFN-α relaxes the stringency for selection in the germinal centers resulting in increased autoreactivity of the Ag-driven B cell repertoire.

  1. A Coordination Chemistry Approach to Fine-Tune the Physicochemical Parameters of Lanthanide Complexes Relevant to Medical Applications.

    Science.gov (United States)

    Le Fur, Mariane; Molnár, Enikő; Beyler, Maryline; Kálmán, Ferenc K; Fougère, Olivier; Esteban-Gómez, David; Rousseaux, Olivier; Tripier, Raphaël; Tircsó, Gyula; Platas-Iglesias, Carlos

    2017-12-15

    The geometric features of two pyclen-based ligands possessing identical donor atoms but different site organization have a profound impact in their complexation properties toward lanthanide ions. The ligand containing two acetate groups and a picolinate arm arranged in a symmetrical fashion (L1) forms a Gd 3+ complex being two orders of magnitude less stable than its dissymmetric analogue GdL2. Besides, GdL1 experiences a much faster dissociation following the acid-catalyzed mechanism than GdL2. On the contrary, GdL1 exhibits a lower exchange rate of the coordinated water molecule compared to GdL2. These very different properties are related to different strengths of the Gd-ligand bonds associated to steric effects, which hinder the coordination of a water molecule in GdL2 and the binding of acetate groups in GdL1. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. A novel mechanism for fine-tuning open-state stability in a voltage-gated potassium channel

    DEFF Research Database (Denmark)

    Pless, Stephan Alexander; Niciforovic, Ana P; Galpin, Jason D

    2013-01-01

    stabilization is the consequence of the amelioration of an inherently repulsive open-state interaction between the partial negative charge on the face of Phe481 and a highly co-evolved acidic side chain, Glu395, and this interaction is potentially modulated through the Tyr485 hydroxyl. We propose...

  3. Fine-tuning the Predictive Model for Proximal Junctional Failure in Surgically Treated Patients With Adult Spinal Deformity.

    Science.gov (United States)

    Yagi, Mitsuru; Fujita, Nobuyuki; Okada, Eijiro; Tsuji, Osahiko; Nagoshi, Narihito; Asazuma, Takashi; Ishii, Ken; Nakamura, Masaya; Matsumoto, Morio; Watanabe, Kota

    2017-09-08

    Multi-center retrospective study. To validate and improve the predictive model for proximal junctional failure (PJF) with or without the bone mineral density (BMD) score. PJF is a serious complication of surgery for adult spinal deformity (ADS). A predictive model for PJF was recently reported that has good accuracy, but does not include BMD, a known PJF risk factor, as a variable. We included 145 surgically treated ASD patients who were older than 50 at the time of surgery and had been followed up for at least 2 years. Variables included age, gender, body mass index (BMI), fusion level, upper and lower instrumented vertebral (UIV and LIV) level, primary or revision surgery, pedicle subtraction osteotomy (PSO), Schwab-SRS type, and BMD. PJF was defined as a ≥ 20° increase from baseline (immediately postoperative) of the proximal junctional angle with concomitant deterioration of at least 1 SRS-Schwab sagittal modifier grade, or any proximal junctional kyphosis requiring revision. Decision-making trees were constructed using the C5.0 algorithm with 10 different bootstrapped models, and validated by a 7:3 data split for training and testing; 112 patients were categorized as training and 33 as testing samples. PJF incidence was 20% in the training samples. Univariate analyses showed that BMD, BMI, pelvic tilt (PT), UIV level, and LIV level were PJF risk factors. Our predictive model was 100% accurate in the testing samples with an AUC of 1.0, indicating excellent fit. The best predictors were (strongest to weakest): PT, BMD, LIV level (pelvis), UIV level (lower thoracic), PSO, global alignment, BMI, pelvic incidence minus lumbar lordosis, and age. A successful model was developed for predicting PJF that included BMD. Our model could inform physicians about patients with a high risk of developing PJF in the peri-operative period. 4.

  4. “Fifty Shades” of Black and Red or How Carboxyl Groups Fine Tune Eumelanin and Pheomelanin Properties

    Directory of Open Access Journals (Sweden)

    Raffaella Micillo

    2016-05-01

    Full Text Available Recent advances in the chemistry of melanins have begun to disclose a number of important structure-property-function relationships of crucial relevance to the biological role of human pigments, including skin (photo protection and UV-susceptibility. Even slight variations in the monomer composition of black eumelanins and red pheomelanins have been shown to determine significant differences in light absorption, antioxidant, paramagnetic and redox behavior, particle morphology, surface properties, metal chelation and resistance to photo-oxidative wear-and-tear. These variations are primarily governed by the extent of decarboxylation at critical branching points of the eumelanin and pheomelanin pathways, namely the rearrangement of dopachrome to 5,6-dihydroxyindole (DHI and 5,6-dihydroxyindole-2-carboxylic acid (DHICA, and the rearrangement of 5-S-cysteinyldopa o-quinoneimine to 1,4-benzothiazine (BTZ and its 3-carboxylic acid (BTZCA. In eumelanins, the DHICA-to-DHI ratio markedly affects the overall antioxidant and paramagnetic properties of the resulting pigments. In particular, a higher content in DHICA decreases visible light absorption and paramagnetic response relative to DHI-based melanins, but markedly enhances antioxidant properties. In pheomelanins, likewise, BTZCA-related units, prevalently formed in the presence of zinc ions, appear to confer pronounced visible and ultraviolet A (UVA absorption features, accounting for light-dependent reactive oxygen species (ROS production, whereas non-carboxylated benzothiazine intermediates seem to be more effective in inducing ROS production by redox cycling mechanisms in the dark. The possible biological and functional significance of carboxyl retention in the eumelanin and pheomelanin pathways is discussed.

  5. Triggering receptor expressed on myeloid cells-2 fine-tunes inflammatory responses in murine Gram-negative sepsis

    DEFF Research Database (Denmark)

    Schmidt Thøgersen, Mariane; Gawish, Riem; Martins, Rui

    2015-01-01

    in bacterial phagocytosis. In line with this, TREM-2(-/-) peritoneal macrophages (PMs) exhibited augmented inflammation following TLR4 stimulation, demonstrating the presence and negative regulatory functionality of TREM-2 on primary PMs. Significantly, we identified a high turnover rate because TREM-2 RNA......During infections, TLR-mediated responses require tight regulation to allow for pathogen removal, while preventing overwhelming inflammation and immunopathology. The triggering receptor expressed on myeloid cells (TREM)-2 negatively regulates inflammation by macrophages and impacts on phagocytosis...

  6. Floral Sonication is an Innate Behaviour in Bumblebees that can be Fine-Tuned with Experience in Manipulating Flowers.

    Science.gov (United States)

    Morgan, Tan; Whitehorn, Penelope; Lye, Gillian C; Vallejo-Marín, Mario

    Bumblebees demonstrate an extensive capacity for learning complex motor skills to maximise exploitation of floral rewards. This ability is well studied in nectar collection but its role in pollen foraging is less well understood. Floral sonication is used by bees to extract pollen from some plant species with anthers which must be vibrated (buzzed) to release pollen. Pollen removal is determined by sonication characteristics including frequency and amplitude, and thus the ability to optimise sonication should allow bees to maximise the pollen collection. We investigated the ability of the buff-tailed bumblebee (Bombus terrestris) to modify the frequency and amplitude of their buzzes with increasing experience manipulating flowers of the buzz-pollinated plant Solanum rostratum. We analysed flight and feeding vibrations generated by naïve workers across feeding bouts. Feeding buzzes were of a higher frequency and a lower amplitude than flight buzzes. Both flight and feeding buzzes had reduced amplitudes with increasing number of foraging trips. However, the frequency of their feeding buzzes was reduced significantly more than their flight buzzes as bumblebee workers gained experience manipulating flowers. These results suggest that bumblebees are able to modify the characteristics of their buzzes with experience manipulating buzz-pollinated flowers. We discuss our findings in the context of bumblebee learning, and the current understanding of the optimal sonication characteristics for releasing pollen in buzz-pollinated species. Our results present a tantalising insight into the potential role of learning in floral sonication, paving the way for future research in this area.

  7. Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle.

    Science.gov (United States)

    Laurens, Claire; Bourlier, Virginie; Mairal, Aline; Louche, Katie; Badin, Pierre-Marie; Mouisel, Etienne; Montagner, Alexandra; Marette, André; Tremblay, Angelo; Weisnagel, John S; Guillou, Hervé; Langin, Dominique; Joanisse, Denis R; Moro, Cedric

    2016-12-06

    Lipid droplets (LD) play a central role in lipid homeostasis by controlling transient fatty acid (FA) storage and release from triacylglycerols stores, while preventing high levels of cellular toxic lipids. This crucial function in oxidative tissues is altered in obesity and type 2 diabetes. Perilipin 5 (PLIN5) is a LD protein whose mechanistic and causal link with lipotoxicity and insulin resistance has raised controversies. We investigated here the physiological role of PLIN5 in skeletal muscle upon various metabolic challenges. We show that PLIN5 protein is elevated in endurance-trained (ET) subjects and correlates with muscle oxidative capacity and whole-body insulin sensitivity. When overexpressed in human skeletal muscle cells to recapitulate the ET phenotype, PLIN5 diminishes lipolysis and FA oxidation under basal condition, but paradoxically enhances FA oxidation during forskolin- and contraction- mediated lipolysis. Moreover, PLIN5 partly protects muscle cells against lipid-induced lipotoxicity. In addition, we demonstrate that down-regulation of PLIN5 in skeletal muscle inhibits insulin-mediated glucose uptake under normal chow feeding condition, while paradoxically improving insulin sensitivity upon high-fat feeding. These data highlight a key role of PLIN5 in LD function, first by finely adjusting LD FA supply to mitochondrial oxidation, and second acting as a protective factor against lipotoxicity in skeletal muscle.

  8. Hydrogen Oxidation-Selective Electrocatalysis by Fine Tuning of Pt Ensemble Sites to Enhance the Durability of Automotive Fuel Cells.

    Science.gov (United States)

    Yun, Su-Won; Park, Shin-Ae; Kim, Tae-June; Kim, Jun-Hyuk; Pak, Gi-Woong; Kim, Yong-Tae

    2017-02-08

    A simple, inexpensive approach is proposed for enhancing the durability of automotive proton exchange membrane fuel cells by selective promotion of the hydrogen oxidation reaction (HOR) and suppression of the oxygen reduction reaction (ORR) at the anode in startup/shutdown events. Dodecanethiol forms a self-assembled monolayer (SAM) on the surface of Pt particles, thus decreasing the number of Pt ensemble sites. Interestingly, by controlling the dodecanethiol concentration during SAM formation, the number of ensemble sites can be precisely optimized such that it is sufficient for the HOR but insufficient for the ORR. Thus, a Pt surface with an SAM of dodecanethiol clearly effects HOR-selective electrocatalysis. Clear HOR selectivity is demonstrated in unit cell tests with the actual membrane electrode assembly, as well as in an electrochemical three-electrode setup with a thin-film rotating disk electrode configuration. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. CνB Damping of Primordial Gravitational Waves and the Fine-Tuning of the CγB Temperature Anisotropy

    Directory of Open Access Journals (Sweden)

    A. E. Bernardini

    2014-01-01

    Full Text Available Damping of primordial gravitational waves due to the anisotropic stress contribution owing to the cosmological neutrino background (CνB is investigated in the context of a radiation-to-matter dominated universe. Besides its inherent effects on the gravitational wave propagation, the inclusion of the CνB anisotropic stress into the dynamical equations also affects the tensor mode contribution to the anisotropy of the cosmological microwave background (CγB temperature. The mutual effects on the gravitational waves and on the CγB are obtained through a unified prescription for a radiation-to-matter dominated scenario. The results are confronted with some preliminary results for the radiation dominated scenario. Both scenarios are supported by a simplified analytical framework, in terms of a scale independent dynamical variable, kη, that relates cosmological scales, k, and the conformal time, η. The background relativistic (hot dark matter essentially works as an effective dispersive medium for the gravitational waves such that the damping effect is intensified for the universe evolving to the matter dominated era. Changes on the temperature variance owing to the inclusion of neutrino collision terms into the dynamical equations result in spectral features that ratify that the multipole expansion coefficients ClT’s die out for l~100.

  10. A novel generation of hybrid photochromic vinylidene-naphthofuran silica nanoparticles through fine-tuning of surface chemistry.

    Science.gov (United States)

    Pinto, Tânia V; Sousa, Céu M; Sousa, Carlos A D; Aboelhassan, Mohamed M; Peixoto, Andreia F; Pereira, Clara; Coelho, Paulo J; Freire, Cristina

    2017-07-18

    Novel photochromic 1-vinylidene-naphtho[2,1-b]furan derivatives (VNF-1 and VNF-2) were successfully anchored onto silica nanoparticles (SiO2 NPs) through direct adsorption (SiO2@VNF-1) and covalent post-grafting (SiO2@VNF-2). SiO2 NPs with different sizes (15 ± 3 and 123 ± 7 nm) and surface chemistry (pHpzc in the range of 5-9) were used, offering a wide range of possibilities to fabricate tailor-made photochromic materials. The characterization of VNF-based SiO2 NPs confirmed the efficient VNF immobilization and the integrity of both organic and inorganic components. The photochromic behavior of these new nanoparticles indicates that silica surface acidity and the type of VNF immobilization strategy (adsorption vs. covalent grafting) were crucial factors for the occurrence of photochromism in the VNF-based SiO2 NPs. Upon UV (λ = 365 nm) or sunlight exposure for 1 min, only the SiO2@VNF-1 nanomaterials prepared by direct VNF adsorption onto SiO2 NPs with pHpzc ≈ 6.0 showed direct and reversible photochromic properties, developing fast (in seconds) and intense salmon and violet coloration, with high values of total color difference () and optical densities (ΔOD = 0.14-0.25). In contrast, all nanomaterials prepared by covalent grafting of VNF-2 onto SiO2 NPs (SiO2@VNF-2) did not exhibit photochromism. In the case of the photochromic SiO2@VNF-1 NPs, the decoloration process followed a bi-exponential decay with fast rate constants (k1 = 1.6 × 10-1-1.6 min-1 and k2 = 9.1 × 10-3-1.3 × 10-1 min-1), which were responsible for the loss of coloration in less than 10 min. Furthermore, they presented very good resistance to fatigue, showing reversibility between the colored/uncolored states without significant loss of their performance for at least 8 successive UV/dark cycles.

  11. Children's Problem-Solving in Serious Games: The "Fine-Tuning System (FTS)" Elaborated

    Science.gov (United States)

    Obikwelu, Chinedu; Read, Janet; Sim, Gavin

    2013-01-01

    For a child to learn through Problem-Solving in Serious games, the game scaffolding mechanism has to be effective. Scaffolding is based on the Vygotzkian Zone of Proximal Development (ZPD) concept which refers to the distance between the actual development level as determined by independent problem solving and the level of potential development as…

  12. Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production

    NARCIS (Netherlands)

    Metghalchi, Sarvenaz; Ponnuswamy, Padmapriya; Simon, Tabassome; Haddad, Yacine; Laurans, Ludivine; Clement, Marc; Dalloz, Marion; Romain, Melissa; Esposito, Bruno; Koropoulis, Vincent; Lamas, Bruno; Paul, Jean-Louis; Cottin, Yves; Kotti, Salma; Bruneval, Patrick; Callebert, Jacques; den Ruijter, Hester; Launay, Jean-Marie; Danchin, Nicolas; Sokol, Harry; Tedgui, Alain; Taleb, Soraya; Mallat, Ziad

    2015-01-01

    Indoleamine 2,3-dioxygenase 1 (Ido1) is a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway. Here, we show that Ido1 activity sustains an immunostimulatory potential through inhibition of interleukin (Il)10. In atherosclerosis, Ido1-dependent inhibition

  13. Single-Crystalline, Nanoporous Gallium Nitride Films With Fine Tuning of Pore Size for Stem Cell Engineering.

    Science.gov (United States)

    Han, Lin; Zhou, Jing; Sun, Yubing; Zhang, Yu; Han, Jung; Fu, Jianping; Fan, Rong

    2014-11-01

    Single-crystalline nanoporous gallium nitride (GaN) thin films were fabricated with the pore size readily tunable in 20-100 nm. Uniform adhesion and spreading of human mesenchymal stem cells (hMSCs) seeded on these thin films peak on the surface with pore size of 30 nm. Substantial cell elongation emerges as pore size increases to ∼80 nm. The osteogenic differentiation of hMSCs occurs preferentially on the films with 30 nm sized nanopores, which is correlated with the optimum condition for cell spreading, which suggests that adhesion, spreading, and stem cell differentiation are interlinked and might be coregulated by nanotopography.

  14. High Thermoelectric Power Factor of a Diketopyrrolopyrrole-Based Low Bandgap Polymer via Finely Tuned Doping Engineering

    Science.gov (United States)

    Jung, In Hwan; Hong, Cheon Taek; Lee, Un-Hak; Kang, Young Hun; Jang, Kwang-Suk; Cho, Song Yun

    2017-03-01

    We studied the thermoelectric properties of a diketopyrrolopyrrole-based semiconductor (PDPP3T) via a precisely tuned doping process using Iron (III) chloride. In particular, the doping states of PDPP3T film were linearly controlled depending on the dopant concentration. The outstanding Seebeck coefficient of PDPP3T assisted the excellent power factors (PFs) over 200 μW m-1K-2 at the broad range of doping concentration (3-8 mM) and the maximum PF reached up to 276 μW m-1K-2, which is much higher than that of poly(3-hexylthiophene), 56 μW m-1K-2. The high-mobility of PDPP3T was beneficial to enhance the electrical conductivity and the low level of total dopant volume was important to maintain high Seebeck coefficients. In addition, the low bandgap PDPP3T polymer effiectively shifted its absorption into near infra-red area and became more colorless after doping, which is great advantage to realize transparent electronic devices. Our results give importance guidance to develop thermoelectric semiconducting polymers and we suggest that the use of low bandgap and high-mobility polymers, and the accurate control of the doping levels are key factors for obtaining the high thermoelectric PF.

  15. Cx47 fine-tunes the handling of serum lipids but is dispensable for lymphatic vascular function.

    Science.gov (United States)

    Meens, Merlijn J; Kutkut, Issa; Rochemont, Viviane; Dubrot, Juan; Kaladji, Fouad R; Sabine, Amélie; Lyons, Oliver; Hendrikx, Stefanie; Bernier-Latmani, Jeremiah; Kiefer, Friedemann; Smith, Alberto; Hugues, Stéphanie; Petrova, Tatiana V; Kwak, Brenda R

    2017-01-01

    Mutations in the gap junction protein connexin47 (Cx47) are associated with lymphedema. However, the role of Cx47 in lymphatic pathophysiology is unknown. We demonstrate that Cx47 is expressed in lymphatic endothelial cells by whole-mount immunostaining and qPCR. To determine if Cx47 plays a role in lymphatic vessel function we analysed Cx47-/- mice. Cx47-deficiency did not affect lymphatic contractility (contractile amplitude or frequency) or lymphatic morphology (vessel diameter or number of valves). Interstitial fluid drainage or dendritic cell migration through lymphatic vessels was also not affected by Cx47-deficiency. Cx47 is dispensable for long-chain fatty acid absorption from the gut but rather promotes serum lipid handling as prolonged elevated triglyceride levels were observed in Cx47-deficient mice after oral lipid tolerance tests. When crossed with Apolipoprotein E-deficient (Apoe-/-) mice, LDL-cholesterol was decreased in young Cx47-/-Apoe-/- adults as compared to Apoe-/- mice, which was inverted later in life. Finally, advanced atherosclerotic plaques in thoracic-abdominal aortas of 15 months-old mice tended to be larger in Cx47-/-Apoe-/- mice. These plaques contained fewer macrophages but similar amounts of T lymphocytes, collagen and lipids than plaques of Apoe-/- mice. In conclusion, Cx47 is expressed in lymphatic endothelium and seems modestly implicated in multiple aspects of lymphatic pathophysiology.

  16. A Fine-Tuned Fluorinated MOF Addresses the Needs for Trace CO2 Removal and Air Capture Using Physisorption.

    Science.gov (United States)

    Bhatt, Prashant M; Belmabkhout, Youssef; Cadiau, Amandine; Adil, Karim; Shekhah, Osama; Shkurenko, Aleksander; Barbour, Leonard J; Eddaoudi, Mohamed

    2016-07-27

    The development of functional solid-state materials for carbon capture at low carbon dioxide (CO2) concentrations, namely, from confined spaces (MOF), NbOFFIVE-1-Ni, with the appropriate pore system (size, shape, and functionality), ideal for the effective and energy-efficient removal of trace carbon dioxide. Markedly, the CO2-selective NbOFFIVE-1-Ni exhibits the highest CO2 gravimetric and volumetric uptake (ca. 1.3 mmol/g and 51.4 cm(3) (STP) cm(-3)) for a physical adsorbent at 400 ppm of CO2 and 298 K. Practically, NbOFFIVE-1-Ni offers the complete CO2 desorption at 328 K under vacuum with an associated moderate energy input of 54 kJ/mol, typical for the full CO2 desorption in conventional physical adsorbents but considerably lower than chemical sorbents. Noticeably, the contracted square-like channels, affording the close proximity of the fluorine centers, permitted the enhancement of the CO2-framework interactions and subsequently the attainment of an unprecedented CO2 selectivity at very low CO2 concentrations. The precise localization of the adsorbed CO2 at the vicinity of the periodically aligned fluorine centers, promoting the selective adsorption of CO2, is evidenced by the single-crystal X-ray diffraction study on NbOFFIVE-1-Ni hosting CO2 molecules. Cyclic CO2/N2 mixed-gas column breakthrough experiments under dry and humid conditions corroborate the excellent CO2 selectivity under practical carbon capture conditions. Pertinently, the notable hydrolytic stability positions NbOFFIVE-1-Ni as the new benchmark adsorbent for direct air capture and CO2 removal from confined spaces.

  17. Fine tuning of fluorene-based dye structures for high-efficiency p-type dye-sensitized solar cells.

    Science.gov (United States)

    Liu, Zonghao; Li, Wenhui; Topa, Sanjida; Xu, Xiaobao; Zeng, Xianwei; Zhao, Zhixin; Wang, Mingkui; Chen, Wei; Wang, Feng; Cheng, Yi-Bing; He, Hongshan

    2014-07-09

    We report on an experimental study of three organic push-pull dyes (coded as zzx-op1, zzx-op1-2, and zzx-op1-3) featuring one, two, and three fluorene units as spacers between donors and acceptors for p-type dye-sensitized solar cells (p-DSSC). The results show increasing the number of spacer units leads to obvious increases of the absorption intensity between 300 nm and 420 nm, a subtle increase in hole driving force, and almost the same hole injection rate from dyes to NiO nanoparticles. Under optimized conditions, the zzx-op1-2 dye with two fluorene spacer units outperforms other two dyes in p-DSSC. It exhibits an unprecedented photocurrent density of 7.57 mA cm(-2) under full sun illumination (simulated AM 1.5G light illumination, 100 mW cm(-2)) when the I(-)/I3(-) redox couple and commercial NiO nanoparticles were used as an electrolyte and a semiconductor, respectively. The cells exhibited excellent long-term stability. Theoretical calculations, impedance spectroscopy, and transient photovoltage decay measurements reveal that the zzx-op1-2 exhibits lower photocurrent losses, longer hole lifetime, and higher photogenerated hole density than zzx-op1 and zzx-op1-3. A dye packing model was proposed to reveal the impact of dye aggregation on the overall photovoltaic performance. Our results suggest that the structural engineering of organic dyes is important to enhance the photovoltaic performance of p-DSSC.

  18. To eat or not to eat : egg-based assessment of paternity triggers fine-tuned decisions about filial cannibalism

    NARCIS (Netherlands)

    Mehlis, Marion; Bakker, Theo C. M.; Engqvist, Leif; Frommen, Joachim G.

    2010-01-01

    Filial cannibalism occurs in many animal species ranging from insects to mammals, and is especially well described in teleost fishes. Numerous causes may lead to this behaviour, e. g. certainty of paternity. However, the cues males use to assess their paternity often remain unknown. One possible way

  19. To eat or not to eat: egg-based assessment of paternity triggers fine-tuned decisions about filial cannibalism

    OpenAIRE

    Mehlis, Marion; Bakker, Theo C.M; Engqvist, Leif; Frommen, Joachim G.

    2010-01-01

    Filial cannibalism occurs in many animal species ranging from insects to mammals, and is especially well described in teleost fishes. Numerous causes may lead to this behaviour, e. g. certainty of paternity. However, the cues males use to assess their paternity often remain unknown. One possible way to differentiate between own and foreign offspring is by using egg cues. Nevertheless, in egg-laying species, evidence for this is still scarce. In this study, male three-spined sticklebacks (Gast...

  20. To eat or not to eat: egg-based assessment of paternity triggers fine-tuned decisions about filial cannibalism.

    Science.gov (United States)

    Mehlis, Marion; Bakker, Theo C M; Engqvist, Leif; Frommen, Joachim G

    2010-09-07

    Filial cannibalism occurs in many animal species ranging from insects to mammals, and is especially well described in teleost fishes. Numerous causes may lead to this behaviour, e.g. certainty of paternity. However, the cues males use to assess their paternity often remain unknown. One possible way to differentiate between own and foreign offspring is by using egg cues. Nevertheless, in egg-laying species, evidence for this is still scarce. In this study, male three-spined sticklebacks (Gasterosteus aculeatus), a fish with paternal care in which sneaking as well as filial cannibalism is common, were allowed to care for manipulated nests that contained different percentages of own fertilized eggs. After 7 days, embryo survival was determined. Furthermore, brood-caring as well as aggressive behaviour was measured daily. Clutches containing a higher proportion of foreign eggs were more likely to be completely cannibalized than clutches containing a lower proportion of foreign eggs, particularly when the clutch was laid early in the breeding season. However, the behavioural observations revealed no influence of paternity. The results show that paternity triggers filial cannibalism in sticklebacks and that males are able to evaluate their paternity using egg cues alone.

  1. Fine-Tuned and Cell-Cycle-Restricted Expression of Fusogenic Protein Syncytin-2 Maintains Functional Placental Syncytia

    Directory of Open Access Journals (Sweden)

    Xiaoyin Lu

    2017-10-01

    Full Text Available Summary: Many types of multinucleated cells (syncytia generated by cell-cell fusion are post-mitotic, but it remains unclear how this state is maintained and why. Here, we utilized the fluorescent ubiquitination-based cell-cycle indicator (Fucci reporter system to show that human placental trophoblast cells were all in the G0 phase before they fuse. Expression of the fusogenic protein (fusogen Syncytin-2 was confined to G0 cells. Overexpression of Syncytin-2 in cycling cells overrode the cell-cycle restriction and enabled fusion of cells in the S/G2/M phases but resulted in the unstable syncytia retaining mitotic features. The Syncytin-2-induced syncytia were functionally compromised with respect to pathogen defense and hormone secretion. We found that, during trophoblast fusion, the cell-cycle inhibitor p21 interacted with the GCM1 transcription factor, and this complex bound to the promoter of Syncytin-2 and promoted its transcription. These findings demonstrate that G0-restricted Syncytin-2 expression is a prerequisite for development of functional post-mitotic syncytia. : Lu et al. demonstrate that G0-phase-restricted fusogenic protein Syncytin-2 is essential for maintenance of functional human placental syncytia. Overexpression of Syncytin-2 overrides cell-cycle restriction and results in functionally compromised syncytia carrying mitotic features. p21 coordinates with transcription factor GCM1 to regulate Syncytin-2 transcription to guarantee appropriate human trophoblast fusion. Keywords: cell fusion, fusogenic protein, syncytin, cell cycle, p21, placenta

  2. Fine-tuning for the tropics: application of eDNA technology for invasive fish detection in tropical freshwater ecosystems.

    Science.gov (United States)

    Robson, Heather L A; Noble, Tansyn H; Saunders, Richard J; Robson, Simon K A; Burrows, Damien W; Jerry, Dean R

    2016-07-01

    Invasive species pose a major threat to aquatic ecosystems. Their impact can be particularly severe in tropical regions, like those in northern Australia, where >20 invasive fish species are recorded. In temperate regions, environmental DNA (eDNA) technology is gaining momentum as a tool to detect aquatic pests, but the technology's effectiveness has not been fully explored in tropical systems with their unique climatic challenges (i.e. high turbidity, temperatures and ultraviolet light). In this study, we modified conventional eDNA protocols for use in tropical environments using the invasive fish, Mozambique tilapia (Oreochromis mossambicus) as a detection model. We evaluated the effects of high water temperatures and fish density on the detection of tilapia eDNA, using filters with larger pores to facilitate filtration. Large-pore filters (20 μm) were effective in filtering turbid waters and retaining sufficient eDNA, whilst achieving filtration times of 2-3 min per 2-L sample. High water temperatures, often experienced in the tropics (23, 29, 35 °C), did not affect eDNA degradation rates, although high temperatures (35 °C) did significantly increase fish eDNA shedding rates. We established a minimum detection limit for tilapia (1 fish/0.4 megalitres/after 4 days) and found that low water flow (3.17 L/s) into ponds with high fish density (>16 fish/0.4 megalitres) did not affect eDNA detection. These results demonstrate that eDNA technology can be effectively used in tropical ecosystems to detect invasive fish species. © 2016 John Wiley & Sons Ltd.

  3. Give Me a Hand... As We Dance With the Dragon: Fine Tuning the Asia-Pacific Hands Concept

    Science.gov (United States)

    2015-06-01

    from Africa Command (Comoros, Madagascar , and Mauritius), two from Northern Command (U.S. and Canada), two from Southern Command (Chile and Peru...two small island nations governed by New Zealand (Cook Islands and Niue), one from European Command (Russia), and one from Central Command (Pakistan...subtropical islands .20 Both the climate and the terrain create the home for 56 officially recognized ethnic groups that use a dialect or language

  4. Fine-Tuning of iPSC Derivation by an Inducible Reprogramming System at the Protein Level

    Directory of Open Access Journals (Sweden)

    Dandan Sui

    2014-05-01

    Full Text Available Induced pluripotent stem cells (iPSCs generated from somatic cells by ectopic expression of reprogramming factors, e.g., POU5F1 (OCT4, KLF4, and SOX2, have great potential for regenerative medicine. However, before they can be used in a clinical setting, the mechanism of reprogramming needs to be better understood. Here, by engineering reprogramming factors to a destabilizing protein domain, we achieved inducible generation of mouse and pig iPSCs. Stability of the fusion protein was precisely regulated by the addition of the cell-permeable small molecule trimethoprim (TMP in a dose-dependent manner. With these tools, we found that during the early and middle stages of reprogramming, exogenous OCT4 or KLF4 could be omitted, whereas exogenous SOX2 expression at early and middle stages was required for successful reprogramming. Our TMP reprogramming system is useful for defining the stoichiometry and temporal requirements of transcription factors for reprogramming.

  5. The fine-tuning of thermosensitive and degradable polymer micelles for enhancing intracellular uptake and drug release in tumors.

    Science.gov (United States)

    Li, Wei; Li, Jinfeng; Gao, Jie; Li, Bohua; Xia, Yu; Meng, Yanchun; Yu, Yongsheng; Chen, Huaiwen; Dai, Jianxin; Wang, Hao; Guo, Yajun

    2011-05-01

    Focusing on high temperature and low pH of tumor tissue, we prepared temperature and pH responsive poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide-b-lacitde) (PID(118)-b-PLA(59)) and poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide-b-ε-caprolactone) (PID(118)-b-PCL(60)) diblock copolymers with symmetric hydrophobic blocks by the reversible addition-fragmentation chain transfer (RAFT). The corresponding dual functional polymeric micelles were fabricated by dialysis methods. Their well-defined core-shell structure was characterized by (1)H NMR in D(2)O and further confirmed by TEM. Their structural and physical chemistry properties such as diameters (D), core corona dimension (R(core), R(shell)), distribution (PDI), M(w), aggregation number (N(agg)), second virial coefficient (A(2)), critical micellization concentration (CMC) and z-potential were firstly systemically investigated by dynamic and static laser light scattering. The volume phase transition temperature (VPTT) was around 40 °C above which the intracellular uptake of adriamycin (ADR) was significantly enhanced. Both flow cytometry and fluorescent microscopy showed that the ADR transported by these micelles was about 4 times higher than that by the commercial ADR formulation Taxotere®. In vitro cytotoxicity assay against N-87 cancer cell and confocal laser scanning microscopy (CLSM) also confirmed such promoting efficiency. In addition, it was interesting to find that cell surviving bounced back as T = 42 °C due to the inter-micellar aggregation. The well clarified mechanism strongly support that our finely tailored dual functional core-shell micelles are potent in enhancing cellular uptake and drug release. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. Fine-Tuning the Surface of Forward Osmosis Membranes via Grafting Graphene Oxide: Performance Patterns and Biofouling Propensity.

    Science.gov (United States)

    Hegab, Hanaa M; ElMekawy, Ahmed; Barclay, Thomas G; Michelmore, Andrew; Zou, Linda; Saint, Christopher P; Ginic-Markovic, Milena

    2015-08-19

    Graphene oxide (GO) nanosheets were attached to the polyamide selective layer of thin film composite (TFC) forward osmosis (FO) membranes through a poly L-Lysine (PLL) intermediary using either layer-by-layer or hybrid (H) grafting strategies. Fourier transform infrared spectroscopy, zeta potential, and thermogravimetric analysis confirmed the successful attachment of GO/PLL, the surface modification enhancing both the hydrophilicity and smoothness of the membrane's surface demonstrated by water contact angle, atomic force microscopy, and transmission electron microscopy. The biofouling resistance of the FO membranes determined using an adenosine triphosphate bioluminescence test showed a 99% reduction in surviving bacteria for GO/PLL-H modified membranes compared to pristine membrane. This antibiofouling property of the GO/PLL-H modified membrane was reflected in reduced flux decline compared to all other samples when filtering brackish water under biofouling conditions. Further, the high density and tightly bound GO nanosheets using the hybrid modification reduced the reverse solute flux compared to the pristine, which reflects improved membrane selectivity. These results illustrate that the GO/PLL-H modification is a valuable addition to improve the performance of FO TFC membranes.

  7. Fine-tuning and autoregulation of the intestinal determinant and tumor suppressor homeobox gene CDX2 by alternative splicing

    NARCIS (Netherlands)

    Balbinot, Camille; Vanier, Marie; Armant, Olivier; Nair, Asmaa; Penichon, Julien; Soret, Christine; Martin, Elisabeth; Saandi, Thoueiba; Reimund, Jean-Marie; Deschamps, Jacqueline; Beck, Felix; Domon-Dell, Claire; Gross, Isabelle; Duluc, Isabelle; Freund, Jean-Noël

    2017-01-01

    On the basis of phylogenetic analyses, we uncovered a variant of the CDX2 homeobox gene, a major regulator of the development and homeostasis of the gut epithelium, also involved in cancer. This variant, miniCDX2, is generated by alternative splicing coupled to alternative translation initiation,

  8. All-atom molecular dynamics simulations of lung surfactant protein B: Structural features of SP-B promote lipid reorganization.

    Science.gov (United States)

    Khatami, Mohammad Hassan; Saika-Voivod, Ivan; Booth, Valerie

    2016-12-01

    Lung surfactant protein B (SP-B), a 79 residue, hydrophobic protein from the saposin superfamily, plays an essential role in breathing. Because of the extreme hydrophobicity of SP-B, the experimental structure of this protein has not yet been determined. Here, we run all-atom molecular dynamics simulations using the OPLS-AA force field in GROMACS to study SP-B's structure and mechanisms for promoting lipid reorganization. Firstly, we find that the final structures indicate the need for some fine-tuning of the homology-based secondary structure predictions. Secondly, we find energetically feasible structures 1) with SP-B's helices in the plane of the bilayer, 2) with SP-B's helices inclined with respect to the bilayer, and 3) with SP-B in a closed structure interacting peripherally with the bilayer. Interestingly, SP-B structures that were bent at the hinge region between the pairs of helices promoted and/or stabilized defects in the lipid bilayer. Finally, particular salt bridge patterns and structural plasticity in the central loop and adjacent region of SP-B appeared to be involved in SP-B's lipid reorganization abilities. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Molecular basis for the wide range of affinity found in Csr/Rsm protein-RNA recognition.

    Science.gov (United States)

    Duss, Olivier; Michel, Erich; Diarra dit Konté, Nana; Schubert, Mario; Allain, Frédéric H-T

    2014-04-01

    The carbon storage regulator/regulator of secondary metabolism (Csr/Rsm) type of small non-coding RNAs (sRNAs) is widespread throughout bacteria and acts by sequestering the global translation repressor protein CsrA/RsmE from the ribosome binding site of a subset of mRNAs. Although we have previously described the molecular basis of a high affinity RNA target bound to RsmE, it remains unknown how other lower affinity targets are recognized by the same protein. Here, we have determined the nuclear magnetic resonance solution structures of five separate GGA binding motifs of the sRNA RsmZ of Pseudomonas fluorescens in complex with RsmE. The structures explain how the variation of sequence and structural context of the GGA binding motifs modulate the binding affinity for RsmE by five orders of magnitude (∼10 nM to ∼3 mM, Kd). Furthermore, we see that conformational adaptation of protein side-chains and RNA enable recognition of different RNA sequences by the same protein contributing to binding affinity without conferring specificity. Overall, our findings illustrate how the variability in the Csr/Rsm protein-RNA recognition allows a fine-tuning of the competition between mRNAs and sRNAs for the CsrA/RsmE protein.

  10. Ethylene/ethane permeation, diffusion and gas sorption properties of carbon molecular sieve membranes derived from the prototype ladder polymer of intrinsic microporosity (PIM-1)

    KAUST Repository

    Salinas, Octavio

    2016-01-05

    Fine-tuning the microporosity of PIM-1 by heat treatment was applied to develop a suitable carbon molecular sieve membrane for ethylene/ethane separation. Pristine PIM-1 films were heated from 400 to 800 °C under inert N2 atmosphere (< 2 ppm O2). At 400 °C, PIM-1 self-cross-linked and developed polar carbonyl and hydroxyl groups due to partial dioxane splitting in the polymer backbone. Significant degradation occurred at 600 °C due to carbonization of PIM-1 and resulted in 30% increase in cumulative surface area compared to its cross-linked predecessor. In addition, PIM-1-based CMS developed smaller ultramicropores with increasing pyrolysis temperature, which enhanced their molecular sieving capability by restricted diffusion of ethylene and ethane through the matrix due to microstructural carbon densification. Consequently, the pure-gas ethylene permeability (measured at 35 °C and 2 bar) decreased from 1600 Barrer for the pristine PIM-1 to 1.3 Barrer for the amorphous carbon generated at 800 °C, whereas the ethylene/ethane pure-gas selectivity increased significantly from 1.8 to 13.

  11. Non-conservative surface decoration of hemoglobin: influence of neutralization of positive charges at PEGylation sites on molecular and functional properties of PEGylated hemoglobin.

    Science.gov (United States)

    Li, Dongxia; Hu, Tao; Manjula, Belur N; Acharya, Seetharama A

    2008-10-01

    High hydrodynamic volume, high viscosity and high colloidal osmotic pressure (COP) of PEGylated hemoglobin (Hb) have been suggested to neutralize the vasoactivity of acellular Hb. Consequences of non-conservative PEGylation (positive charge of the amino groups at the PEGylation sites is neutralized) using succinimidyl-ester of propionic acid PEG5K on the properties of PEGylated Hb have now been investigated. Non-conservative PEGylation of Hb leads to a much higher increase in the COP and viscosity of Hb than conservative extension arm facilitated (EAF) PEGylation of Hb. Introduction of alphaalpha-fumaryl crosslinking decreased the COP of non-conservative PEGylated Hb by stabilization of interdimeric interactions. Compared to the EAF-PEGylated alphaalpha-fumaryl Hb, non-conservative PEGylated product shows a comparable COP and higher viscosity. Conservative PEGylation of alphaalpha-fumaryl Hb by reductive alkylation chemistry does not increase the COP to this level, but enhanced the molecular volume and viscosity comparable to EAF-PEGylated product. Thus, the molecular properties of PEGylated Hb can be fine tuned using different PEGylation platforms and provide a unique opportunity for the design of second generation PEGylated Hbs.

  12. Molecular Tension Probes for Imaging Forces at the Cell Surface.

    Science.gov (United States)

    Liu, Yang; Galior, Kornelia; Ma, Victor Pui-Yan; Salaita, Khalid

    2017-11-21

    Mechanical forces are essential for a variety of biological processes ranging from transcription and translation to cell adhesion, migration, and differentiation. Through the activation of mechanosensitive signaling pathways, cells sense and respond to physical stimuli from the surrounding environment, a process widely known as mechanotransduction. At the cell membrane, many signaling receptors, such as integrins, cadherins and T- or B-cell receptors, bind to their ligands on the surface of adjacent cells or the extracellular matrix (ECM) to mediate mechanotransduction. Upon ligation, these receptor-ligand bonds transmit piconewton (pN) mechanical forces that are generated, in part, by the cytoskeleton. Importantly, these forces expose cryptic sites within mechanosensitive proteins and modulate the binding kinetics (on/off rate) of receptor-ligand complexes to further fine-tune mechanotransduction and the corresponding cell behavior. Over the past three decades, two categories of methods have been developed to measure cell receptor forces. The first class is traction force microscopy (TFM) and micropost array detectors (mPADs). In these methods, cells are cultured on elastic polymers or microstructures that deform under mechanical forces. The second category of techniques is single molecule force spectroscopy (SMFS) including atomic force microscopy (AFM), optical or magnetic tweezers, and biomembrane force probe (BFP). In SMFS, the experimenter applies external forces to probe the mechanics of individual cells or single receptor-ligand complexes, serially, one bond at a time. Although these techniques are powerful, the limited throughput of SMFS and the nN force sensitivity of TFM have hindered further elucidation of the molecular mechanisms of mechanotransduction. In this Account, we introduce the recent advent of molecular tension fluorescence microscopy (MTFM) as an emerging tool for molecular imaging of receptor mechanics in living cells. MTFM probes are

  13. Novel photoresist thin films with in-situ photoacid generator by molecular layer deposition

    Science.gov (United States)

    Zhou, Han; Bent, Stacey F.

    2013-03-01

    Current photoresist materials are facing many challenges introduced by advanced lithographies, particularly the need for excellent compositional homogeneity and ultrathin film thickness. Traditional spin-on polymeric resists have inherent limitations in achieving a high level of control over the chemical composition, leading to interest in development of alternative methods for making photoresists. In this work, we demonstrate that molecular layer deposition (MLD) is a potential method for synthesizing photoresists because it allows for precise control over organic film thickness and composition. MLD utilizes sequential, self-limiting reactions of organic precursors to build a thin film directly on a substrate surface and grows organic films by depositing only one molecular layer at each precursor dose, which in turn allows for fine-tuning of the position and concentration of various functionalities in the deposited film. In this study, we use bifunctional precursors, diamine and diisocyanate, to build polyurea resist films via urea coupling reaction between the amine and isocyanate groups. Acid-labile groups and photoacid generators (PAGs) are embedded in the backbone of the resist films with a highly uniform distribution. The resist films were successfully deposited and characterized for both materials properties and resist response. E-beam patterning was achieved with the resist films. Cross-linking behavior of the resist films was observed, likely due to the aromatic rings in the films, which is undesirable for application as a positive-tone photoresist. Moreover, the in-situ polymer-bound PAGs had low sensitivity. It is suggested that this effect may arise because the PAG is cation-bound, leading to lower efficiency of sulfur-carbon bond cleavage in the sulfonium cation, which is needed to produce the photoacid, and consequently a lower photoacid yield. Further work is needed to improve the performance of the MLD resist films.

  14. TRACING EMBEDDED STELLAR POPULATIONS IN CLUSTERS AND GALAXIES USING MOLECULAR EMISSION: METHANOL AS A SIGNATURE OF THE LOW-MASS END OF THE IMF

    Energy Technology Data Exchange (ETDEWEB)

    Kristensen, Lars E. [Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States); Bergin, Edwin A., E-mail: lkristensen@cfa.harvard.edu [Department of Astronomy, University of Michigan, 500 Church Street, Ann Arbor, MI 48109 (United States)

    2015-07-10

    Most low-mass protostars form in clusters, in particular high-mass clusters; however, how low-mass stars form in high-mass clusters and what the mass distribution is are still open questions both in our own Galaxy and elsewhere. To access the population of forming embedded low-mass protostars observationally, we propose using molecular outflows as tracers. Because the outflow emission scales with mass, the effective contrast between low-mass protostars and their high-mass cousins is greatly lowered. In particular, maps of methanol emission at 338.4 GHz (J = 7{sub 0}–6{sub 0} A{sup +}) in low-mass clusters illustrate that this transition is an excellent probe of the low-mass population. We present here a model of a forming cluster where methanol emission is assigned to every embedded low-mass protostar. The resulting model image of methanol emission is compared to recent ALMA observations toward a high-mass cluster and the similarity is striking: the toy model reproduces observations to better than a factor of two and suggests that approximately 50% of the total flux originates in low-mass outflows. Future fine-tuning of the model will eventually make it a tool for interpreting the embedded low-mass population of distant regions within our own Galaxy and ultimately higher-redshift starburst galaxies, not just for methanol emission but also water and high-J CO.

  15. Tracing Embedded Stellar Populations in Clusters and Galaxies Using Molecular Emission: Methanol as a Signature of the Low-mass End of the IMF

    Science.gov (United States)

    Kristensen, Lars E.; Bergin, Edwin A.

    2015-07-01

    Most low-mass protostars form in clusters, in particular high-mass clusters; however, how low-mass stars form in high-mass clusters and what the mass distribution is are still open questions both in our own Galaxy and elsewhere. To access the population of forming embedded low-mass protostars observationally, we propose using molecular outflows as tracers. Because the outflow emission scales with mass, the effective contrast between low-mass protostars and their high-mass cousins is greatly lowered. In particular, maps of methanol emission at 338.4 GHz (J = 70-60 A+) in low-mass clusters illustrate that this transition is an excellent probe of the low-mass population. We present here a model of a forming cluster where methanol emission is assigned to every embedded low-mass protostar. The resulting model image of methanol emission is compared to recent ALMA observations toward a high-mass cluster and the similarity is striking: the toy model reproduces observations to better than a factor of two and suggests that approximately 50% of the total flux originates in low-mass outflows. Future fine-tuning of the model will eventually make it a tool for interpreting the embedded low-mass population of distant regions within our own Galaxy and ultimately higher-redshift starburst galaxies, not just for methanol emission but also water and high-J CO.

  16. A Functional Genomic Screen for Evolutionarily Conserved Genes Required for Lifespan and Immunity in Germline-Deficient C. elegans

    Science.gov (United States)

    Sinha, Amit; Rae, Robbie

    2014-01-01

    The reproductive system regulates lifespan in insects, nematodes and vertebrates. In Caenorhabditis elegans removal of germline increases lifespan by 60% which is dependent upon insulin signaling, nuclear hormone signaling, autophagy and fat metabolism and their microRNA-regulators. Germline-deficient C. elegans are also more resistant to various bacterial pathogens but the underlying molecular mechanisms are largely unknown. Firstly, we demonstrate that previously identified genes that regulate the extended lifespan of germline-deficient C. elegans (daf-2, daf-16, daf-12, tcer-1, mir-7.1 and nhr-80) are also essential for resistance to the pathogenic bacterium Xenorhabdus nematophila. We then use a novel unbiased approach combining laser cell ablation, whole genome microarrays, RNAi screening and exposure to X. nematophila to generate a comprehensive genome-wide catalog of genes potentially required for increased lifespan and innate immunity in germline-deficient C. elegans. We find 3,440 genes to be upregulated in C. elegans germline-deficient animals in a gonad dependent manner, which are significantly enriched for genes involved in insulin signaling, fatty acid desaturation, translation elongation and proteasome complex function. Using RNAi against a subset of 150 candidate genes selected from the microarray results, we show that the upregulated genes such as transcription factor DAF-16/FOXO, the PTEN homolog lipid phosphatase DAF-18 and several components of the proteasome complex (rpn-6.1, rpn-7, rpn-9, rpn-10, rpt-6, pbs-3 and pbs-6) are essential for both lifespan and immunity of germline deficient animals. We also identify a novel role for genes including par-5 and T12G3.6 in both lifespan-extension and increased survival on X. nematophila. From an evolutionary perspective, most of the genes differentially expressed in germline deficient C. elegans also show a conserved expression pattern in germline deficient Pristionchus pacificus, a nematode species

  17. Gene Regulatory Enhancers with Evolutionarily Conserved Activity Are More Pleiotropic than Those with Species-Specific Activity.

    Science.gov (United States)

    Fish, Alexandra; Chen, Ling; Capra, John A

    2017-10-01

    Press on behalf of the Society for Molecular Biology and Evolution.

  18. H2B ubiquitination: Conserved molecular mechanism, diverse physiologic functions of the E3 ligase during meiosis.

    Science.gov (United States)

    Wang, Liying; Cao, Chunwei; Wang, Fang; Zhao, Jianguo; Li, Wei

    2017-09-03

    RNF20/Bre1 mediated H2B ubiquitination (H2Bub) has various physiologic functions. Recently, we found that H2Bub participates in meiotic recombination by promoting chromatin relaxation during meiosis. We then analyzed the phylogenetic relationships among the E3 ligase for H2Bub, its E2 Rad6 and their partner WW domain-containing adaptor with a coiled-coil (WAC) or Lge1, and found that the molecular mechanism underlying H2Bub is evolutionarily conserved from yeast to mammals. However, RNF20 has diverse physiologic functions in different organisms, which might be caused by the evolutionary divergency of their domain/motif architectures. In the current extra view, we not only elucidate the evolutionarily conserved molecular mechanism underlying H2Bub, but also discuss the diverse physiologic functions of RNF20 during meiosis.

  19. Fourier transform photoelectron diffraction and its application to molecular orbitals and surface structure

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Xin [Pennsylvania State Univ., University Park, PA (United States)

    1998-11-30

    Photoemission intensities from the molecular orbitals of c(2x2)CO/Pt(111) over a wide photon energy range were measured and analyzed by the same methods developed for structural studies using core levels. The 4{sigma} orbital center of gravity is found to be concentrated between the C and O atoms, while that of the 5{sigma} orbital lies between the C atom and the Pt surface. The C 1s photoelectron diffraction was used to determine the adsorption geometry. The earlier ambiguity that multiple scattering is needed to correctly model a {chi} curve while single scattering is sufficient for understanding major peaks in the ARPEFS-FTS is clarified by studying the clean Ni(111) surface. In the normal emission case, several different combinations of scattering events have similar path length differences (PLDs), and can either cancel each other or enhance the corresponding FT peak. In the off-normal case the degeneracy is greatly reduced due to the lower degree of symmetry. In normal emission AR PEFS, up to third order multiple scattering is needed to describe fully both the {chi} curve and its FT spectrum. To improve the spectral resolution in the ARPEFS-FT analysis, several new spectral analysis methods are introduced. With both autocorrelation autoregression (ACAR) and autocorrelation eigenvector (ACE), we can produce a reliable power spectrum by following the order-closing procedure. The best spectra are usually obtained when the autocorrelation sequence is computed with lags up to half the data range. A simple way of determining surface adsorption sites is proposed as follows: First use a single scattering cluster for possible adsorption sites to construct the geometrical PLDs from the strong backscattering events; then compare these PLDs with those obtained from the ARPEFS-FT analysis of the experimental data. After the preferred adsorption site is determined, fine tune the interlayer distances according to the positional R-factor.

  20. Reactive Center Loop Insertion in α-1-Antitrypsin Captured by Accelerated Molecular Dynamics Simulation.

    Science.gov (United States)

    Andersen, Ole Juul; Risør, Michael Wulff; Poulsen, Emil Christian; Nielsen, Niels Chr; Miao, Yinglong; Enghild, Jan J; Schiøtt, Birgit

    2017-01-31

    Protease inhibition by metastable serine protease inhibitors (serpins) is mediated by one of the largest functional intradomain conformational changes known in biology. In this extensive structural rearrangement, protease-serpin complex formation triggers cleavage of the serpin reactive center loop (RCL), its subsequent insertion into central β-sheet A, and covalent trapping of the target protease. In this study, we present the first detailed accelerated molecular dynamics simulation of the insertion of the fully cleaved RCL in α-1-antitrypsin (α1AT), the archetypal member of the family of human serpins. Our results reveal internal water pathways that allow the initial incorporation of side chains of RCL residues into the protein interior. We observed structural plasticity of the helix F (hF) element that blocks the RCL path in the native state, which is in excellent agreement with previous experimental reports. Furthermore, the simulation suggested a novel role of hF and the connected turn (thFs3A) as chaperones that support the insertion process by reducing the conformational space available to the RCL. Transient electrostatic interactions of RCL residues potentially fine-tune the serpin inhibitory activity. On the basis of our simulation, we generated the α1AT mutants K168E, E346K, and K168E/E346K and analyzed their inhibitory activity along with their intrinsic stability and heat-induced polymerization. Remarkably, the E346K mutation exhibited enhanced inhibitory activity along with an increased rate of premature structural collapse (polymerization), suggesting a significant role of E346 in the gatekeeping of the strain in the metastable native state.

  1. “The Environment is Everything That Isn't Me”: Molecular Mechanisms and Evolutionary Dynamics of Insect Clocks in Variable Surroundings

    Science.gov (United States)

    Rivas, Gustavo B. S.; Bauzer, Luiz G. S. da R.; Meireles-Filho, Antonio C. A.

    2016-01-01

    Circadian rhythms are oscillations in behavior, metabolism and physiology that have a period close to 24 h. These rhythms are controlled by an internal pacemaker that evolved under strong selective pressures imposed by environmental cyclical changes, mainly of light and temperature. The molecular nature of the circadian pacemaker was extensively studied in a number of organisms under controlled laboratory conditions. But although these studies were fundamental to our understanding of the circadian clock, most of the environmental conditions used resembled rather crudely the relatively constant situation at lower latitudes. At higher latitudes light-dark and temperature cycles vary considerably across different seasons, with summers having long and hot days and winters short and cold ones. Considering these differences and other external cues, such as moonlight, recent studies in more natural and semi-natural situations revealed unexpected features at both molecular and behavioral levels, highlighting the dramatic influence of multiple environmental variables in the molecular clockwork. This emphasizes the importance of studying the circadian clock in the wild, where seasonal environmental changes fine-tune the underlying circadian mechanism, affecting population dynamics and impacting the geographical variation in clock genes. Indeed, latitudinal clines in clock gene frequencies suggest that natural selection and demography shape the circadian clock over wide geographical ranges. In this review we will discuss the recent advances in understanding the molecular underpinnings of the circadian clock, how it resonates with the surrounding variables (both in the laboratory and in semi-natural conditions) and its impact on population dynamics and evolution. In addition, we will elaborate on how next-generation sequencing technologies will complement classical reductionist approaches by identifying causal variants in natural populations that will link genetic variation to

  2. In Silico Analysis of Gene Expression Network Components Underlying Pigmentation Phenotypes in the Python Identified Evolutionarily Conserved Clusters of Transcription Factor Binding Sites

    Directory of Open Access Journals (Sweden)

    Kristopher J. L. Irizarry

    2016-01-01

    Full Text Available Color variation provides the opportunity to investigate the genetic basis of evolution and selection. Reptiles are less studied than mammals. Comparative genomics approaches allow for knowledge gained in one species to be leveraged for use in another species. We describe a comparative vertebrate analysis of conserved regulatory modules in pythons aimed at assessing bioinformatics evidence that transcription factors important in mammalian pigmentation phenotypes may also be important in python pigmentation phenotypes. We identified 23 python orthologs of mammalian genes associated with variation in coat color phenotypes for which we assessed the extent of pairwise protein sequence identity between pythons and mouse, dog, horse, cow, chicken, anole lizard, and garter snake. We next identified a set of melanocyte/pigment associated transcription factors (CREB, FOXD3, LEF-1, MITF, POU3F2, and USF-1 that exhibit relatively conserved sequence similarity within their DNA binding regions across species based on orthologous alignments across multiple species. Finally, we identified 27 evolutionarily conserved clusters of transcription factor binding sites within ~200-nucleotide intervals of the 1500-nucleotide upstream regions of AIM1, DCT, MC1R, MITF, MLANA, OA1, PMEL, RAB27A, and TYR from Python bivittatus. Our results provide insight into pigment phenotypes in pythons.

  3. Genetic diversity and population structure of the pelagic thresher shark (Alopias pelagicus) in the Pacific Ocean: evidence for two evolutionarily significant units.

    Science.gov (United States)

    Cardeñosa, Diego; Hyde, John; Caballero, Susana

    2014-01-01

    There has been an increasing concern about shark overexploitation in the last decade, especially for open ocean shark species, where there is a paucity of data about their life histories and population dynamics. Little is known regarding the population structure of the pelagic thresher shark, Alopias pelagicus. Though an earlier study using mtDNA control region data, showed evidence for differences between eastern and western Pacific populations, the study was hampered by low sample size and sparse geographic coverage, particularly a lack of samples from the central Pacific. Here, we present the population structure of Alopias pelagicus analyzing 351 samples from six different locations across the Pacific Ocean. Using data from mitochondrial DNA COI sequences and seven microsatellite loci we found evidence of strong population differentiation between western and eastern Pacific populations and evidence for reciprocally monophyly for organelle haplotypes and significant divergence of allele frequencies at nuclear loci, suggesting the existence of two Evolutionarily Significant Units (ESU) in the Pacific Ocean. Interestingly, the population in Hawaii appears to be composed of both ESUs in what seems to be clear sympatry with reproductive isolation. These results may indicate the existence of a new cryptic species in the Pacific Ocean. The presence of these distinct ESUs highlights the need for revised management plans for this highly exploited shark throughout its range.

  4. Genetic diversity and population structure of the pelagic thresher shark (Alopias pelagicus in the Pacific Ocean: evidence for two evolutionarily significant units.

    Directory of Open Access Journals (Sweden)

    Diego Cardeñosa

    Full Text Available There has been an increasing concern about shark overexploitation in the last decade, especially for open ocean shark species, where there is a paucity of data about their life histories and population dynamics. Little is known regarding the population structure of the pelagic thresher shark, Alopias pelagicus. Though an earlier study using mtDNA control region data, showed evidence for differences between eastern and western Pacific populations, the study was hampered by low sample size and sparse geographic coverage, particularly a lack of samples from the central Pacific. Here, we present the population structure of Alopias pelagicus analyzing 351 samples from six different locations across the Pacific Ocean. Using data from mitochondrial DNA COI sequences and seven microsatellite loci we found evidence of strong population differentiation between western and eastern Pacific populations and evidence for reciprocally monophyly for organelle haplotypes and significant divergence of allele frequencies at nuclear loci, suggesting the existence of two Evolutionarily Significant Units (ESU in the Pacific Ocean. Interestingly, the population in Hawaii appears to be composed of both ESUs in what seems to be clear sympatry with reproductive isolation. These results may indicate the existence of a new cryptic species in the Pacific Ocean. The presence of these distinct ESUs highlights the need for revised management plans for this highly exploited shark throughout its range.

  5. CRISPR-based gene replacement reveals evolutionarily conserved axon guidance functions of Drosophila Robo3 and Tribolium Robo2/3.

    Science.gov (United States)

    Evans, Timothy A

    2017-01-01

    Axon guidance receptors of the Roundabout (Robo) family regulate a number of axon guidance outcomes in bilaterian animals in addition to their canonical role in Slit-dependent midline repulsion. In the fruit fly Drosophila melanogaster, three Robo paralogs (Robo1, Robo2, and Robo3) each have specialized roles in regulating midline crossing and the formation of longitudinal axon pathways in the embryonic ventral nerve cord. The number of robo genes differs in other insects, and it is unknown whether the roles and/or signaling mechanisms of Drosophila Robos are shared in other insect species. To directly compare the axon guidance activities of Robo receptors in Drosophila and the flour beetle Tribolium castaneum, I have used a CRISPR/Cas9-based approach to replace Drosophila robo3 with Tribolium robo2/3. I show that when expressed from the robo3 locus in Drosophila embryos, Tribolium Robo2/3 (TcRobo2/3) protein is properly translated and localized to axons, where it reproduces the normal expression pattern of Drosophila Robo3. In embryos expressing TcRobo2/3 in place of robo3, two distinct subsets of longitudinal axons are guided properly to their normal positions in the intermediate neuropile, indicating that TcRobo2/3 can promote Robo3-dependent axon guidance decisions in developing Drosophila neurons. These observations suggest that the mechanism by which Drosophila Robo3 promotes longitudinal pathway formation is evolutionarily conserved in Tribolium, where it is performed by TcRobo2/3. The CRISPR/Cas9-based gene replacement approach described here can be applied to comparative evolutionary developmental studies of other Drosophila genes and their orthologs in other species.

  6. CRISPR-based gene replacement reveals evolutionarily conserved axon guidance functions of Drosophila Robo3 and Tribolium Robo2/3

    Directory of Open Access Journals (Sweden)

    Timothy A. Evans

    2017-06-01

    Full Text Available Abstract Background Axon guidance receptors of the Roundabout (Robo family regulate a number of axon guidance outcomes in bilaterian animals in addition to their canonical role in Slit-dependent midline repulsion. In the fruit fly Drosophila melanogaster, three Robo paralogs (Robo1, Robo2, and Robo3 each have specialized roles in regulating midline crossing and the formation of longitudinal axon pathways in the embryonic ventral nerve cord. The number of robo genes differs in other insects, and it is unknown whether the roles and/or signaling mechanisms of Drosophila Robos are shared in other insect species. To directly compare the axon guidance activities of Robo receptors in Drosophila and the flour beetle Tribolium castaneum, I have used a CRISPR/Cas9-based approach to replace Drosophila robo3 with Tribolium robo2/3. Results I show that when expressed from the robo3 locus in Drosophila embryos, Tribolium Robo2/3 (TcRobo2/3 protein is properly translated and localized to axons, where it reproduces the normal expression pattern of Drosophila Robo3. In embryos expressing TcRobo2/3 in place of robo3, two distinct subsets of longitudinal axons are guided properly to their normal positions in the intermediate neuropile, indicating that TcRobo2/3 can promote Robo3-dependent axon guidance decisions in developing Drosophila neurons. Conclusions These observations suggest that the mechanism by which Drosophila Robo3 promotes longitudinal pathway formation is evolutionarily conserved in Tribolium, where it is performed by TcRobo2/3. The CRISPR/Cas9-based gene replacement approach described here can be applied to comparative evolutionary developmental studies of other Drosophila genes and their orthologs in other species.

  7. Deep sequencing of organ- and stage-specific microRNAs in the evolutionarily basal insect Blattella germanica (L. (Dictyoptera, Blattellidae.

    Directory of Open Access Journals (Sweden)

    Alexandre S Cristino

    Full Text Available BACKGROUND: microRNAs (miRNAs have been reported as key regulators at post-transcriptional level in eukaryotic cells. In insects, most of the studies have focused in holometabolans while only recently two hemimetabolans (Locusta migratoria and Acyrthosiphon pisum have had their miRNAs identified. Therefore, the study of the miRNAs of the evolutionarily basal hemimetabolan Blattella germanica may provide valuable insights on the structural and functional evolution of miRNAs. METHODOLOGY/PRINCIPAL FINDINGS: Small RNA libraries of the cockroach B. germanica were built from the whole body of the last instar nymph, and the adult ovaries. The high throughput Solexa sequencing resulted in approximately 11 and 8 million reads for the whole-body and ovaries, respectively. Bioinformatic analyses identified 38 known miRNAs as well as 11 known miRNA*s. We also found 70 miRNA candidates conserved in other insects and 170 candidates specific to B. germanica. The positive correlation between Solexa data and real-time quantitative PCR showed that number of reads can be used as a quantitative approach. Five novel miRNA precursors were identified and validated by PCR and sequencing. Known miRNAs and novel candidates were also validated by decreasing levels of their expression in dicer-1 RNAi knockdown individuals. The comparison of the two libraries indicates that whole-body nymph contain more known miRNAs than ovaries, whereas the adult ovaries are enriched with novel miRNA candidates. CONCLUSIONS/SIGNIFICANCE: Our study has identified many known miRNAs and novel miRNA candidates in the basal hemimetabolan insect B. germanica, and most of the specific sequences were found in ovaries. Deep sequencing data reflect miRNA abundance and dicer-1 RNAi assay is shown to be a reliable method for validation of novel miRNAs.

  8. Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies.

    Directory of Open Access Journals (Sweden)

    Aaron Silva-Sanchez

    Full Text Available Variability in the developing antibody repertoire is focused on the third complementarity determining region of the H chain (CDR-H3, which lies at the center of the antigen binding site where it often plays a decisive role in antigen binding. The power of VDJ recombination and N nucleotide addition has led to the common conception that the sequence of CDR-H3 is unrestricted in its variability and random in its composition. Under this view, the immune response is solely controlled by somatic positive and negative clonal selection mechanisms that act on individual B cells to promote production of protective antibodies and prevent the production of self-reactive antibodies. This concept of a repertoire of random antigen binding sites is inconsistent with the observation that diversity (DH gene segment sequence content by reading frame (RF is evolutionarily conserved, creating biases in the prevalence and distribution of individual amino acids in CDR-H3. For example, arginine, which is often found in the CDR-H3 of dsDNA binding autoantibodies, is under-represented in the commonly used DH RFs rearranged by deletion, but is a frequent component of rarely used inverted RF1 (iRF1, which is rearranged by inversion. To determine the effect of altering this germline bias in DH gene segment sequence on autoantibody production, we generated mice that by genetic manipulation are forced to utilize an iRF1 sequence encoding two arginines. Over a one year period we collected serial serum samples from these unimmunized, specific pathogen-free mice and found that more than one-fifth of them contained elevated levels of dsDNA-binding IgG, but not IgM; whereas mice with a wild type DH sequence did not. Thus, germline bias against the use of arginine enriched DH sequence helps to reduce the likelihood of producing self-reactive antibodies.

  9. IAA-Ala Resistant3, an evolutionarily conserved target of miR167, mediates Arabidopsis root architecture changes during high osmotic stress

    KAUST Repository

    Kinoshita, Natsuko

    2012-09-01

    The functions of microRNAs and their target mRNAs in Arabidopsis thaliana development have been widely documented; however, roles of stress-responsive microRNAs and their targets are not as well understood. Using small RNA deep sequencing and ATH1 microarrays to profile mRNAs, we identified IAA-Ala Resistant3 (IAR3) as a new target of miR167a. As expected, IAR3 mRNA was cleaved at the miR167a complementary site and under high osmotic stress miR167a levels decreased, whereas IAR3 mRNA levels increased. IAR3 hydrolyzes an inactive form of auxin (indole-3-acetic acid [IAA]-alanine) and releases bioactive auxin (IAA), a central phytohormone for root development. In contrast with the wild type, iar3 mutants accumulated reduced IAA levels and did not display high osmotic stress-induced root architecture changes. Transgenic plants expressing a cleavage-resistant form of IAR3 mRNA accumulated high levels of IAR3 mRNAs and showed increased lateral root development compared with transgenic plants expressing wild-type IAR3. Expression of an inducible noncoding RNA to sequester miR167a by target mimicry led to an increase in IAR3 mRNA levels, further confirming the inverse relationship between the two partners. Sequence comparison revealed the miR167 target site on IAR3 mRNA is conserved in evolutionarily distant plant species. Finally, we showed that IAR3 is required for drought tolerance. © 2012 American Society of Plant Biologists. All rights reserved.

  10. Magnetismo Molecular (Molecular Magentism)

    Energy Technology Data Exchange (ETDEWEB)

    Reis, Mario S [Universidade Federal Fluminense, Brasil; Moreira Dos Santos, Antonio F [ORNL

    2010-07-01

    The new synthesis processes in chemistry open a new world of research, new and surprising materials never before found in nature can now be synthesized and, as a wonderful result, observed a series of physical phenomena never before imagined. Among these are many new materials the molecular magnets, the subject of this book and magnetic properties that are often reflections of the quantum behavior of these materials. Aside from the wonderful experience of exploring something new, the theoretical models that describe the behavior these magnetic materials are, in most cases, soluble analytically, which allows us to know in detail the physical mechanisms governing these materials. Still, the academic interest in parallel this subject, these materials have a number of properties that are promising to be used in technological devices, such as in computers quantum magnetic recording, magnetocaloric effect, spintronics and many other devices. This volume will journey through the world of molecular magnets, from the structural description of these materials to state of the art research.

  11. Physiological and molecular aspects of degradation of plant polysaccharides by fungi: What have we learned from Aspergillus?

    NARCIS (Netherlands)

    Culleton, H.; McKie, V.; de Vries, R.P.

    2013-01-01

    Plant biomass is the most abundant and usable carbon source for many fungal species. Due to its diverse and complex structure, fungi need to produce a large range of enzymes to degrade these polysaccharides into monomeric components. The fine-tuned production of such diverse enzyme sets requires

  12. Molecular hematology

    National Research Council Canada - National Science Library

    Provan, Drew; Gribben, John

    2010-01-01

    ... The molecular basis of hemophilia, 219 Paul LF Giangrande 4 The genetics of acute myeloid leukemias, 42 Carolyn J Owen & Jude Fitzgibbon 19 The molecular basis of von Willebrand disease, 233 Luciano Baronc...

  13. Molecular evolution of B6 enzymes: Binding of pyridoxal-5'-phosphate and Lys41Arg substitution turn ribonuclease A into a model B6 protoenzyme

    OpenAIRE

    Marra Ersilia; Capitani Guido; Giannattasio Sergio; Vacca Rosa A; Christen Philipp

    2008-01-01

    Abstract Background The pyridoxal-5'-phosphate (PLP)-dependent or vitamin B6-dependent enzymes that catalyze manifold reactions in the metabolism of amino acids belong to no fewer than four evolutionarily independent protein families. The multiple evolutionary origin and the essential mechanistic role of PLP in these enzymes argue for the cofactor having arrived on the evolutionary scene before the emergence of the respective apoenzymes and having played a dominant role in the molecular evolu...

  14. Structural, biochemical, and phylogenetic analyses suggest that indole-3-acetic acid methyltransferase is an evolutionarily ancient member of the SABATH family.

    Science.gov (United States)

    Zhao, Nan; Ferrer, Jean-Luc; Ross, Jeannine; Guan, Ju; Yang, Yue; Pichersky, Eran; Noel, Joseph P; Chen, Feng

    2008-02-01

    The plant SABATH protein family encompasses a group of related small-molecule methyltransferases (MTs) that catalyze the S-adenosyl-L-methionine-dependent methylation of natural chemicals encompassing widely divergent structures. Indole-3-acetic acid (IAA) methyltransferase (IAMT) is a member of the SABATH family that modulates IAA homeostasis in plant tissues through methylation of IAA's free carboxyl group. The crystal structure of Arabidopsis (Arabidopsis thaliana) IAMT (AtIAMT1) was determined and refined to 2.75 A resolution. The overall tertiary and quaternary structures closely resemble the two-domain bilobed monomer and the dimeric arrangement, respectively, previously observed for the related salicylic acid carboxyl methyltransferase from Clarkia breweri (CbSAMT). To further our understanding of the biological function and evolution of SABATHs, especially of IAMT, we analyzed the SABATH gene family in the rice (Oryza sativa) genome. Forty-one OsSABATH genes were identified. Expression analysis showed that more than one-half of the OsSABATH genes were transcribed in one or multiple organs. The OsSABATH gene most similar to AtIAMT1 is OsSABATH4. Escherichia coli-expressed OsSABATH4 protein displayed the highest level of catalytic activity toward IAA and was therefore named OsIAMT1. OsIAMT1 exhibited kinetic properties similar to AtIAMT1 and poplar IAMT (PtIAMT1). Structural modeling of OsIAMT1 and PtIAMT1 using the experimentally determined structure of AtIAMT1 reported here as a template revealed conserved structural features of IAMTs within the active-site cavity that are divergent from functionally distinct members of the SABATH family, such as CbSAMT. Phylogenetic analysis revealed that IAMTs from Arabidopsis, rice, and poplar (Populus spp.) form a monophyletic group. Thus, structural, biochemical, and phylogenetic evidence supports the hypothesis that IAMT is an evolutionarily ancient member of the SABATH family likely to play a critical role in IAA

  15. Molecular pharmacognosy.

    Science.gov (United States)

    Huang, LuQi; Xiao, PeiGen; Guo, LanPing; Gao, WenYuan

    2010-06-01

    This article analyzes the background and significance of molecular pharmacognosy, including the molecular identification of medicinal raw materials, phylogenetic evolution of medicinal plants and animals, evaluation and preservation of germplasm resources for medicinal plants and animals, etiology of endangerment and protection of endangered medicinal plants and animals, biosynthesis and bioregulation of active components in medicinal plants, and characteristics and the molecular bases of top-geoherbs.

  16. Molecular Gastronomy

    OpenAIRE

    Burke, Roisin; This, Herve; Kelly, Alan

    2016-01-01

    Molecular gastronomy may be defined as the scientific discipline that explores the phenomena occurring during culinary transformations. In contrast with traditional approaches of food science and technology, which considered mostly the chemistry, physics, or biology of food ingredients and industrial transformations, the focus is on phenomena occurring during the preparation of dishes. Applications building on the principles of molecular gastronomy, such as ‘Molecular Cooking’ and ‘Note-by-No...

  17. Molecular dynamics

    NARCIS (Netherlands)

    Bergstra, J.A.; Bethke, I.

    2002-01-01

    Molecular dynamics is a model for the structure and meaning of object based programming systems. In molecular dynamics the memory state of a system is modeled as a fluid consisting of a collection of molecules. Each molecule is a collection of atoms with bindings between them. A computation is

  18. Molecular motors

    Science.gov (United States)

    Allemand, Jean François Desbiolles, Pierre

    2015-10-01

    How do we move? More precisely, what are the molecular mechanisms that can explain that our muscles, made of very small components can move at a osopic scale? To answer these questions we must introduce molecular motors. Those motors are proteins, or small protein assemblies that, in our cells, transform chemical energy into mechanical work. Then, like we could do for a oscopic motor, used in a car or in a fan, we are going to study the basic behavior of these molecular machines, present what are their energy sources, calculate their power, their yield. If molecular motors are crucial for our oscopic movements, we are going to see that they are also essential to cellular transport and that considering the activity of some enzymes as molecular motors bring some interesting new insights on their activity.

  19. Molecular geometry

    CERN Document Server

    Rodger, Alison

    1995-01-01

    Molecular Geometry discusses topics relevant to the arrangement of atoms. The book is comprised of seven chapters that tackle several areas of molecular geometry. Chapter 1 reviews the definition and determination of molecular geometry, while Chapter 2 discusses the unified view of stereochemistry and stereochemical changes. Chapter 3 covers the geometry of molecules of second row atoms, and Chapter 4 deals with the main group elements beyond the second row. The book also talks about the complexes of transition metals and f-block elements, and then covers the organometallic compounds and trans

  20. Molecular Haeckel.

    Science.gov (United States)

    Elinson, Richard P; Kezmoh, Lorren

    2010-07-01

    More than a century ago, Ernst Haeckel created embryo drawings to illustrate the morphological similarity of vertebrate early embryos. These drawings have been both widely presented and frequently criticized. At the same time that the idea of morphological similarity was recently attacked, there has been a growing realization of molecular similarities in the development of tissues and organs. We have surveyed genes expressed in vertebrate embryos, and we have used them to construct drawings that we call Molecular Haeckels. The Molecular Haeckels emphasize that, based on gene expression, there is a greater similarity among vertebrate embryos than even Haeckel might have imagined. (c) 2010 Wiley-Liss, Inc.

  1. Widespread purifying selection on RNA structure in mammals.

    Science.gov (United States)

    Smith, Martin A; Gesell, Tanja; Stadler, Peter F; Mattick, John S

    2013-09-01

    Evolutionarily conserved RNA secondary structures are a robust indicator of purifying selection and, consequently, molecular function. Evaluating their genome-wide occurrence through comparative genomics has consistently been plagued by high false-positive rates and divergent predictions. We present a novel benchmarking pipeline aimed at calibrating the precision of genome-wide scans for consensus RNA structure prediction. The benchmarking data obtained from two refined structure prediction algorithms, RNAz and SISSIz, were then analyzed to fine-tune the parameters of an optimized workflow for genomic sliding window screens. When applied to consistency-based multiple genome alignments of 35 mammals, our approach confidently identifies >4 million evolutionarily constrained RNA structures using a conservative sensitivity threshold that entails historically low false discovery rates for such analyses (5-22%). These predictions comprise 13.6% of the human genome, 88% of which fall outside any known sequence-constrained element, suggesting that a large proportion of the mammalian genome is functional. As an example, our findings identify both known and novel conserved RNA structure motifs in the long noncoding RNA MALAT1. This study provides an extensive set of functional transcriptomic annotations that will assist researchers in uncovering the precise mechanisms underlying the developmental ontologies of higher eukaryotes.

  2. Molecular Origami

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 5; Issue 9. Molecular Origami - Modular Construction of Platonic Solids as Models for Reversible Assemblies. Subramania Ranganathan. General Article Volume 5 Issue 9 September 2000 pp 82-91 ...

  3. Molecular identification of the insect adipokinetic hormone receptors

    DEFF Research Database (Denmark)

    Staubli, Frank; Jørgensen, Thomas J D; Cazzamali, Giuseppe

    2002-01-01

    The insect adipokinetic hormones (AKHs) are a large family of peptide hormones that are involved in the mobilization of sugar and lipids from the insect fat body during energy-requiring activities such as flight and locomotion, but that also contribute to hemolymph sugar homeostasis. Here, we have...... identified the first insect AKH receptors, namely those from the fruitfly Drosophila melanogaster and the silkworm Bombyx mori. These results represent a breakthrough for insect molecular endocrinology, because it will lead to the cloning of all AKH receptors from all model insects used in AKH research, and......, therefore, to a better understanding of AKH heterogeneity and actions. Interestingly, the insect AKH receptors are structurally and evolutionarily related to the gonadotropin-releasing hormone receptors from vertebrates....

  4. Molecular aging and rejuvenation of human muscle stem cells

    DEFF Research Database (Denmark)

    Carlson, Morgan E; Suetta, Charlotte; Conboy, Michael J

    2009-01-01

    Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans....... Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth...... factor beta (TGF-beta)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular...

  5. Conserved Molecular Mechanisms Underlying Homeostasis of the Golgi Complex

    Directory of Open Access Journals (Sweden)

    Cathal Wilson

    2010-01-01

    Full Text Available The Golgi complex performs a central function in the secretory pathway in the sorting and sequential processing of a large number of proteins destined for other endomembrane organelles, the plasma membrane, or secretion from the cell, in addition to lipid metabolism and signaling. The Golgi apparatus can be regarded as a self-organizing system that maintains a relatively stable morphofunctional organization in the face of an enormous flux of lipids and proteins. A large number of the molecular players that operate in these processes have been identified, their functions and interactions defined, but there is still debate about many aspects that regulate protein trafficking and, in particular, the maintenance of these highly dynamic structures and processes. Here, we consider how an evolutionarily conserved underlying mechanism based on retrograde trafficking that uses lipids, COPI, SNAREs, and tethers could maintain such a homeodynamic system.

  6. Is there a "molecular Nirvana Principle"? Towards a unified resolutional model of the biological symbol-matter dichotomy.

    Science.gov (United States)

    Balázs, András

    2004-11-01

    In the present paper, the metapsychological "Nirvana Principle" is investigated evolutionarily at the earliest forms of life in a highly tentative way. A corresponding "molecular Nirvana Principle" is proposed, where the recent suggestions of the "internal measurement" biophysical quantum-molecular research programme of modern quantum biology are introduced, in relation to the former metapsychological theory, conceived to be valid in the entire realm of living systems (just as it was intended by the original author). By an appropriate introduction of a special primordeal dynamical time inversion symmetry breaking, originating in a premeval self-measurement in a composite nucleic acid-protein system, a special internal symmetry restoration time series is defined. In this way, a strictly physically defined self-identity ("molecular Nirvana," special physical symmetry restored) is derived, which is put equal to the quantum physical equivalent and root of the goals of evolutionarily higher level fundamental drives (the "Nirvana Principle"). It is shown that it is a natural requirement that the following internal regressive time (-reversal) physical molecular relations (and so the ultimate time symmetry) is mapped onto space, as is also suggested by some symbol-theoretical propositions.

  7. Molecular Regulators of Metabolism and Cardiometabolic Disease

    Directory of Open Access Journals (Sweden)

    Indriyanti Rafi Sukmawati

    2012-12-01

    Full Text Available BACKGROUND: The mechanisms that are responsible for energy management in cells in an organism require a complex network of transcription of factors and cofactors. CONTENT: All living system must maintain a tight equilibrium between energy intake, storage and expenditure for optimal performance. This  tight equilibrium must be both robust and flexible to allow for adaptation to every situation such as exercise or rest and famine or feast. Organisms rely on finely tuned and complex signaling network to confront with all possibilities. Metabolic imbalance can cause dysfunction and pertubation of these networks, which if uncorrected will induce disease such as obesity and diabetes mellitus. SUMMARY: During the last decades the understanding of the transcriptional regulation of diverse metabolic pathways has contributed to the elucidation of mechanisms of metabolic control and to a better knowledge of the pathogenesis of metabolic diseases. KEYWORDS: AMPK, SIRT1, PGC-1α;, FGF21, mTORC1.

  8. Fine-tuning key parameters of an integrated reactor system for the simultaneous removal of COD, sulfate and ammonium and elemental sulfur reclamation

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Ye, E-mail: yuanye_19840915@163.com [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Chen, Chuan, E-mail: echo110244@126.com [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Liang, Bin, E-mail: liangbin1214@163.com [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Huang, Cong, E-mail: hengyue5257@163.com [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Zhao, Youkang, E-mail: zhaoyoukang@gmail.com [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Xu, Xijun, E-mail: xuxijun3220@sina.com [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Tan, Wenbo, E-mail: tanwenbo1@163.com [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Zhou, Xu, E-mail: x.zhou@awmc.uq.edu.au [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Gao, Shuang, E-mail: localinna.1990@163.com [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Sun, Dezhi, E-mail: sundezhi@bjfu.edu.cn [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Lee, DuuJong, E-mail: djlee@ntu.edu.tw [State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China); Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei 106, Taiwan (China); and others

    2014-03-01

    Graphical abstract: - Highlights: • The system achieved simultaneous removal of 98% COD, 98% sulfate and 78% nitrogen. • The HRTs and reflux ratios were key parameters for performance and S{sup 0} recovery. • 60% S{sup 0} reclaimed from effluent, 30% deposited in reactor S{sup 0} (S{sup 0} production ≈ 90%). • Characteristics of bio-S{sup 0} were targeted to acquire high-rate S{sup 0} recovery. • Microbial community succession and function were discussed at different stage. - Abstract: In this paper, we proposed an integrated reactor system for simultaneous removal of COD, sulfate and ammonium (integrated C-S-N removal system) and investigated the key parameters of the system for a high level of elemental sulfur (S{sup 0}) production. The system consisted of 4 main units: sulfate reduction and organic carbon removal (SR-CR), autotrophic and heterotrophic denitrifying sulfide removal (A and H-DSR), sulfur reclamation (SR), and aerated filter for aerobic nitrification (AN). In the system, the effects of key operational parameters on production of elemental sulfur were investigated, including hydraulic retention time (HRT) of each unit, sulfide/nitrate (S{sup 2−}-S/NO{sub 3}{sup −}-N) ratios, reflux ratios between the A and H-DSR and AN units, and loading rates of chemical oxygen demand (COD), sulfate and ammonium. Physico-chemical characteristics of biosulfur were studied for acquiring efficient S{sup 0} recovery. The experiments successfully explored the optimum parameters for each unit and demonstrated 98% COD, 98% sulfate and 78% nitrogen removal efficiency. The optimum HRTs for SR-CR, A and H-DSR and AN were 12 h, 3 h and 3 h, respectively. The reflux ratio of 3 could provide adequate S{sup 2−}-S/NO{sub 3}{sup −}-N ratio (approximately 1:1) to the A and H-DSR unit for obtaining maximum sulfur production. In this system, the maximum production of S{sup 0} reached 90%, but only 60% S{sup 0} was reclaimed from effluent. The S{sup 0} that adhered to the outer layer of granules was deposited in the bottom of the A and H-DSR unit. Finally, the microbial community structure of the corresponding unit at different operational stage were analyzed by 16S rRNA gene based high throughput Illumina MiSeq sequencing and the potential function of dominant species were discussed.

  9. Large scale comparative codon-pair context analysis unveils general rules that fine-tune evolution of mRNA primary structure.

    Directory of Open Access Journals (Sweden)

    Gabriela Moura

    Full Text Available BACKGROUND: Codon usage and codon-pair context are important gene primary structure features that influence mRNA decoding fidelity. In order to identify general rules that shape codon-pair context and minimize mRNA decoding error, we have carried out a large scale comparative codon-pair context analysis of 119 fully sequenced genomes. METHODOLOGIES/PRINCIPAL FINDINGS: We have developed mathematical and software tools for large scale comparative codon-pair context analysis. These methodologies unveiled general and species specific codon-pair context rules that govern evolution of mRNAs in the 3 domains of life. We show that evolution of bacterial and archeal mRNA primary structure is mainly dependent on constraints imposed by the translational machinery, while in eukaryotes DNA methylation and tri-nucleotide repeats impose strong biases on codon-pair context. CONCLUSIONS: The data highlight fundamental differences between prokaryotic and eukaryotic mRNA decoding rules, which are partially independent of codon usage.

  10. Impact of {Os(pap)2} in fine-tuning the binding modes and non-innocent potential of deprotonated 2,2'-bipyridine-3,3'-diol.

    Science.gov (United States)

    Ghosh, Prabir; Lahiri, Goutam Kumar

    2016-03-28

    The reaction of ctc-Os(II)(pap)2Cl2 (pap = 2-phenylazopyridine, ctc = cis-trans-cis with respect to chlorides and pyridine/azo nitrogens of pap, respectively) and ambidentate 2,2'-bipyridine-3,3'-diol (H2L) leads to the simultaneous formation of isomeric [Os(II)(pap)2(HL(-))](+) ((2+)/(3+)), seven-membered chelate containing Os(II)(pap)2(L(2-)) (4) and diastereomeric [{Os(II)(pap)2}2(μ-L(2-))](2+) (5a(2+) (meso, ΔΛ)/5b(2+) (rac, ΔΔ/ΛΛ)). The reaction of 2,2'-biphenol (H2L') and ctc-Os(II)(pap)2Cl2 yields Os(II)(pap)2(L'(2-)) (6), an analogue of 4. The identities of the newly designed complexes have been established by different analytical, spectroscopic and X-ray diffraction techniques. (1)H-NMR spectra of the complexes and single crystal X-ray structures of selective derivatives [2]ClO4, [3]ClO4, [5a](ClO4)2, and 6 establish the retention of the tc-configuration of the precursor {Os(pap)2}. In isomeric 2(+) and 3(+), monodeprotonated HL(-) is linked to the {Os(II)(pap)2} fragment through N,N and N,O(-) donors, resulting in nearly planar five- and six-membered chelates with O-HO(-) and O-HN hydrogen bonds at its back face, respectively. The O(-),O(-) donating L'(2-) extends a severely twisted seven-membered chelate with the {Os(pap)2} unit in 6. The N,O(-)/O(-),N donors of deprotonated L(2-) bridge the two {Os(II)(pap)2} units in a symmetric fashion in 5a(2+), forming two moderately twisted six-membered chelates. Though the deprotonation of the O-HN hydrogen bond in (+) by another unit of {Os(II)(pap)2} generates a diastereomeric mixture of 5a(2+) and 5b(2+), attempts to deprotonate the relatively stronger O-H···O(-) hydrogen bond in 2(+) have failed. The isomeric 2(+)/3(+), seven-membered chelate containing 4/6 and diastereomeric 5a(2+)/5b(2+) exhibit distinctive (1)H-NMR and absorption spectra as well as electrochemical responses. The pap (N[double bond, length as m-dash]N) based two successive reductions and the participation of HL(-), L(2-), L'(2-) in the oxidation processes of the respective complexes have been revealed using EPR and DFT calculated MOs and Mulliken spin density plots at the intermediate paramagnetic states.

  11. Fine tuning of spatial arrangement of enzymes in a PCNA-mediated multienzyme complex using a rigid poly-L-proline linker.

    Directory of Open Access Journals (Sweden)

    Tomoaki Haga

    Full Text Available Inspired by natural multienzyme complexes, many types of artificial multienzyme complexes have recently been constructed. We previously constructed a self-assembled complex of a bacterial cytochrome P450 and its ferredoxin and ferredoxin reductase partners using heterotrimerization of proliferating cell nuclear antigen (PCNA from Sulfolobus solfataricus. In this study, we inserted different peptide linkers between ferredoxin and the PCNA subunit, and examined the effect on activity of the self-assembled multienzyme complex. Although the activity was affected by the lengths of both the rigid poly-L-proline-rich linkers and the flexible Gly4-Ser repeating linkers, the poly-L-proline-rich linkers provided the greatest activity enhancement. The optimized poly-L-proline-rich linker enhanced the activity 1.9-fold compared with the GGGGSLVPRGSGGGGS linker used in the previously reported complex, while the Gly4-Ser repeating linkers, (G4Sn (n = 1-6, did not yield higher activity than the maximum activity by the optimized poly-L-proline linker. Both the rigidity/flexibility and length of the peptide linker were found to be important for enhancing the overall activity of the multienzyme complex.

  12. Fine tuning of dwelling time in friction stir welding for preventing material overheating, weld tensile strength increase and weld nugget size decrease

    Directory of Open Access Journals (Sweden)

    Mijajlović Miroslav M.

    2016-01-01

    Full Text Available After successful welding, destructive testing into test samples from Al 2024-T351 friction stir butt welds showed that tensile strength of the weld improve along the joint line, while dimensions of the weld nugget decrease. For those welds, both the base material and the welding tool constantly cool down during the welding phase. Obviously, the base material became overheated during the long dwelling phase what made conditions for creation of joints with the reduced mechanical properties. Preserving all process parameters but varying the dwelling time from 5-27 seconds a new set of welding is done to reach maximal achievable tensile strength. An analytical-numerical-experimental model is used for optimising the duration of the dwelling time while searching for the maximal tensile strength of the welds

  13. Fine-tuning of Smad protein function by poly(ADP-ribose polymerases and poly(ADP-ribose glycohydrolase during transforming growth factor β signaling.

    Directory of Open Access Journals (Sweden)

    Markus Dahl

    Full Text Available Initiation, amplitude, duration and termination of transforming growth factor β (TGFβ signaling via Smad proteins is regulated by post-translational modifications, including phosphorylation, ubiquitination and acetylation. We previously reported that ADP-ribosylation of Smads by poly(ADP-ribose polymerase 1 (PARP-1 negatively influences Smad-mediated transcription. PARP-1 is known to functionally interact with PARP-2 in the nucleus and the enzyme poly(ADP-ribose glycohydrolase (PARG can remove poly(ADP-ribose chains from target proteins. Here we aimed at analyzing possible cooperation between PARP-1, PARP-2 and PARG in regulation of TGFβ signaling.A robust cell model of TGFβ signaling, i.e. human HaCaT keratinocytes, was used. Endogenous Smad3 ADP-ribosylation and protein complexes between Smads and PARPs were studied using proximity ligation assays and co-immunoprecipitation assays, which were complemented by in vitro ADP-ribosylation assays using recombinant proteins. Real-time RT-PCR analysis of mRNA levels and promoter-reporter assays provided quantitative analysis of gene expression in response to TGFβ stimulation and after genetic perturbations of PARP-1/-2 and PARG based on RNA interference.TGFβ signaling rapidly induces nuclear ADP-ribosylation of Smad3 that coincides with a relative enhancement of nuclear complexes of Smads with PARP-1 and PARP-2. Inversely, PARG interacts with Smads and can de-ADP-ribosylate Smad3 in vitro. PARP-1 and PARP-2 also form complexes with each other, and Smads interact and activate auto-ADP-ribosylation of both PARP-1 and PARP-2. PARP-2, similar to PARP-1, negatively regulates specific TGFβ target genes (fibronectin, Smad7 and Smad transcriptional responses, and PARG positively regulates these genes. Accordingly, inhibition of TGFβ-mediated transcription caused by silencing endogenous PARG expression could be relieved after simultaneous depletion of PARP-1.Nuclear Smad function is negatively regulated by PARP-1 that is assisted by PARP-2 and positively regulated by PARG during the course of TGFβ signaling.

  14. Fine-tuning alkyne cycloadditions: Insights into photochemistry responsible for the double-strand DNA cleavage via structural perturbations in diaryl alkyne conjugates

    Directory of Open Access Journals (Sweden)

    Igor V. Alabugin

    2011-06-01

    Full Text Available Hybrid molecules combining photoactivated aryl acetylenes and a dicationic lysine moiety cause the most efficient double-strand (ds DNA cleavage known to date for a small molecule. In order to test the connection between the alkylating ability and the DNA-damaging properties of these compounds, we investigated the photoreactivity of three isomeric aryl–tetrafluoropyridinyl (TFP alkynes with amide substituents in different positions (o-, m-, and p- toward a model π-system. Reactions with 1,4-cyclohexadiene (1,4-CHD were used to probe the alkylating properties of the triplet excited states in these three isomers whilst Stern–Volmer quenching experiments were used to investigate the kinetics of photoinduced electron transfer (PET. The three analogous isomeric lysine conjugates cleaved DNA with different efficiencies (34, 15, and 0% of ds DNA cleavage for p-, m-, and o-substituted lysine conjugates, respectively consistent with the alkylating ability of the respective acetamides. The significant protecting effect of the hydroxyl radical and singlet oxygen scavengers to DNA cleavage was shown only with m-lysine conjugate. All three isomeric lysine conjugates inhibited human melanoma cell growth under photoactivation: The p-conjugate had the lowest CC50 (50% cell cytotoxicity value of 1.49 × 10−7 M.

  15. Fine-tuning of T-cell development by the CD3γ di-leucine-based TCR-sorting motif

    DEFF Research Database (Denmark)

    Lauritsen, Jens Peter Holst; Boding, Lasse; Buus, Terkild B

    2015-01-01

    The CD3γ di-leucine-based (diL) receptor-sorting motif plays a central role in TCR down-regulation and in clonal expansion of virus-specific T cells. However, the role of the CD3γ diL motif in T-cell development is not known. In this study, we show that protein kinase C-induced TCR down......-regulation is abolished in thymocytes from CD3γLLAA mice with a mutated CD3γ diL motif, and that CD3γLLAA mice have reduced numbers of thymocytes compared with aged-matched wild-type mice. We found that early thymocyte development at the β-selection checkpoint is impaired resulting in reduced numbers of double negative...... (DN) 4 cells in CD3γLLAA mice. This was not caused by reduced proliferation but most probably by increased down-regulation of the antiapoptotic molecule Bcl-2 causing enhanced apoptosis during the transition from the DN3 to the DN4 stage. In contrast, proliferation of immature CD8 single positive (ISP...

  16. Acetylations of Ftz-F1 and histone H4K5 are required for the fine-tuning of ecdysone biosynthesis during Drosophila metamorphosis.

    Science.gov (United States)

    Borsos, Barbara N; Pankotai, Tibor; Kovács, Dávid; Popescu, Christina; Páhi, Zoltán; Boros, Imre M

    2015-08-01

    The molting during Drosophila development is tightly regulated by the ecdysone hormone. Several steps of the ecdysone biosynthesis have been already identified but the regulation of the entire process has not been clarified yet. We have previously reported that dATAC histone acetyltransferase complex is necessary for the steroid hormone biosynthesis process. To reveal possible mechanisms controlled by dATAC we made assumptions that either dATAC may influence directly the transcription of Halloween genes involved in steroid hormone biosynthesis or it may exert an indirect effect on it by acetylating the Ftz-F1 transcription factor which regulates the transcription of steroid converting genes. Here we show that the lack of dATAC complex results in increased mRNA level and decreased protein level of Ftz-F1. In this context, decreased mRNA and increased protein levels of Ftz-F1 were detected upon treatment of Drosophila S2 cells with histone deacetylase inhibitor trichostatin A. We showed that Ftz-F1, the transcriptional activator of Halloween genes, is acetylated in S2 cells. In addition, we found that ecdysone biosynthetic Halloween genes are transcribed in S2 cells and their expression can be influenced by deacetylase inhibitors. Furthermore, we could detect H4K5 acetylation at the regulatory regions of disembodied and shade Halloween genes, while H3K9 acetylation is absent on these genes. Based on our findings we conclude that the dATAC HAT complex might play a dual regulatory role in Drosophila steroid hormone biosynthesis through the acetylation of Ftz-F1 protein and the regulation of the H4K5 acetylation at the promoters of Halloween genes. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Adamantane-bearing benzylamines and benzylamides: novel building blocks for supramolecular systems with finely tuned binding properties towards β-cyclodextrin

    Czech Academy of Sciences Publication Activity Database

    Rouchal, M.; Matelová, A.; de Carvalho, F. P.; Bernat, R.; Grbić, D.; Kuřitka, I.; Babinský, M.; Marek, R.; Čmelík, Richard; Vícha, R.

    2013-01-01

    Roč. 25, č. 6 (2013), s. 349-361 ISSN 1061-0278 Institutional support: RVO:68081715 Keywords : host-guest system * cyclodextrin s * adamantane Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 2.132, year: 2013

  18. Fine-tuning of root elongation by ethylene: a tool to study dynamic structure-function relationships between root architecture and nitrate absorption.

    Science.gov (United States)

    Le Deunff, Erwan; Lecourt, Julien; Malagoli, Philippe

    2016-07-12

    Recently developed genetic and pharmacological approaches have been used to explore [Formula: see text]/ethylene signalling interactions and how the modifications in root architecture by pharmacological modulation of ethylene biosynthesis affect nitrate uptake. Structure-function studies combined with recent approaches to chemical genomics highlight the non-specificity of commonly used inhibitors of ethylene biosynthesis such as AVG (l-aminoethoxyvinylglycine). Indeed, AVG inhibits aminotransferases such as ACC synthase (ACS) and tryptophan aminotransferase (TAA) involved in ethylene and auxin biosynthesis but also some aminotransferases implied in nitrogen (N) metabolism. In this framework, it can be assumed that the products of nitrate assimilation and hormones may interact through a hub in carbon (C) and N metabolism to drive the root morphogenetic programme (RMP). Although ethylene/auxin interactions play a major role in cell division and elongation in root meristems, shaping of the root system depends also on energetic considerations. Based on this finding, the analysis is extended to nutrient ion-hormone interactions assuming a fractal or constructal model for root development. Therefore, the tight control of root structure-function in the RMP may explain why over-expressing nitrate transporter genes to decouple structure-function relationships and improve nitrogen use efficiency (NUE) has been unsuccessful. © The Author 2016. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. A way to inhibit SO[sub 2] poisoning of SCR catalysts by fine tuning of the composition and the preparation method of the support

    Energy Technology Data Exchange (ETDEWEB)

    Matralis, H.; Fiasse, S.; Bastians, Ph.; Ruwet, M.; Grange, P.; Delmon, B. (Unite de Catalyse et Chimie des Materiaux Divise, Louvain-la-Neuve (Belgium)); Castillo, R. (Monomeros Colombo Venezolanos (EMA), Las Flores Barranquilla (Colombia))

    1993-05-26

    Two series of mixed SiO[sub 2]-TiO[sub 2] and Al[sub 2]O[sub 3]-TiO[sub 2] supports were prepared by the following methods: precipitation from TiCl[sub 4] solution with aqueous ammonia, impregnation with titanium isopropoxide solution in isopropanol, and grafting by reaction of TiCl[sub 4] with the hydroxyl groups of the main carrier (SiO[sub 2] or Al[sub 2]O[sub 3]). The vanadia catalysts, resulting from the impregnation of these mixed supports with an aqueous solution of vanadium oxalate, were tested in the selective catalytic reduction-(SCR) of NO with NH[sub 3] in the presence of O[sub 2]. BET, XRD and XPS were used to characterise the samples. All these catalysts were less active than a standard TiO[sub 2]-V[sub 2]O[sub 5] catalyst when tested with a SO[sub 2]-free feed. However, in the presence of 4000 ppm SO[sub 2] in the feed they were more resistant and more active than the TiO[sub 2]-V[sub 2]O[sub 5] catalyst. Our results indicate that the dispersion of TiO[sub 2] on the main carrier is a key factor for preparing a performant SCR-catalyst. The grafting and impregnation methods for the Al[sub 2]O[sub 3]-TiO[sub 2] and the impregnation for the SiO[sub 2]-TiO[sub 2] supports were found to be the most effective preparation techniques for dispersing TiO[sub 2], and for giving the most performant and resistant, towards SO[sub 2] poisoning, catalysts.

  20. Fine tuning of magnetite nanoparticle size distribution using dissymmetric potential pulses in the presence of biocompatible surfactants and the electrochemical characterization of the nanoparticles.

    Science.gov (United States)

    Rodríguez-López, A; Cruz-Rivera, J J; Elías-Alfaro, C G; Betancourt, I; Ruiz-Silva, H; Antaño-López, R

    2015-01-01

    The effects of varying the surfactant concentration and the anodic pulse potential on the properties and electrochemical behaviors of magnetite nanoparticles were investigated. The nanoparticles were synthesized with an electrochemical method based on applying dissymmetric potential pulses, which offers the advantage that can be used to tune the particle size distribution very precisely in the range of 10 to 50 nm. Under the conditions studied, the surfactant concentration directly affects the size distribution, with higher concentrations producing narrower distributions. Linear voltammetry was used to characterize the electrochemical behavior of the synthesized nanoparticles in both the anodic and cathodic regions, which are attributed to the oxidation of Fe(2+) and the reduction of Fe(3+); these species are part of the spinel structure of magnetite. Electrochemical impedance spectroscopy data indicated that the reduction and oxidation reactions of the nanoparticles are not controlled by the mass transport step, but by the charge transfer step. The sample with the highest saturation magnetization was that synthesized in the presence of polyethylene glycol. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Fine tuning of cascaded d-q axis controller for AC-DC-AC converter without DC link capacitor using artificial neural network

    Directory of Open Access Journals (Sweden)

    Padmanaban Sanjeevikumar

    2008-01-01

    Full Text Available This paper presents an artificial neural network (ANN based approach to tune the parameters of the cascaded d-q axis controller for an AC-DC-AC converter without dc link capacitor. The proposed converter uses the cascaded d-q axis controller on the rectifier side and space vector pulse width modulation on the inverter side. The feed-forward ANN with the error back-propagation training is employed to tune the parameters of the cascaded d-q axis controller. The converter topology provides simple commutation procedure with reduced number of switches and has additional advantages such as good voltage transfer ratio, four quadrant operation, unity power factor, no DC link capacitor and less THD in both the line and load sides. Simulation results closely match with theoretical analysis.

  2. Fine-tuning levels of heterologous gene expression in plants by orthogonal variation of the untranslated regions of a nonreplicating transient expression system.

    Science.gov (United States)

    Meshcheriakova, Yulia A; Saxena, Pooja; Lomonossoff, George P

    2014-08-01

    A transient expression system based on a deleted version of Cowpea mosaic virus (CPMV) RNA-2, termed CPMV-HT, in which the sequence to be expressed is positioned between a modified 5' UTR and the 3' UTR has been successfully used for the plant-based expression of a wide range of proteins, including heteromultimeric complexes. While previous work has demonstrated that alterations to the sequence of the 5' UTR can dramatically influence expression levels, the role of the 3' UTR in enhancing expression has not been determined. In this work, we have examined the effect of different mutations in the 3'UTR of CPMV RNA-2 on expression levels using the reporter protein GFP encoded by the expression vector, pEAQexpress-HT-GFP. The results showed that the presence of a 3' UTR in the CPMV-HT system is important for achieving maximal expression levels. Removal of the entire 3' UTR reduced expression to approximately 30% of that obtained in its presence. It was found that the Y-shaped secondary structure formed by nucleotides 125-165 of the 3' UTR plays a key role in its function; mutations that disrupt this Y-shaped structure have an effect equivalent to the deletion of the entire 3' UTR. Our results suggest that the Y-shaped secondary structure acts by enhancing mRNA accumulation rather than by having a direct effect on RNA translation. The work described in this paper shows that the 5' and 3' UTRs in CPMV-HT act orthogonally and that mutations introduced into them allow fine modulation of protein expression levels. © 2014 John Innes Centre. Plant Biotechnology Journal published by Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

  3. Nanochitosan enriched poly ε-caprolactone electrospun wound dressing membranes: A fine tuning of physicochemical properties, hemocompatibility and curcumin release profile.

    Science.gov (United States)

    Cr, Reshmi; Ps, Suja; O, Manaf; Pp, Sanu; A, Sujith

    2017-11-08

    Nanochitosan (NC) enriched Poly (ε-caprolactone) (PCL) nanofibrous membranes were fabricated for controlled curcumin delivery and wound dressing. A significant increase in hydrophilicity, PBS sorption, and vapour transmission were observed by incorporation of NC in PCL. Hemolysis assay, blood clot kinetics and platelet adhesion studies on PCL/NC membranes confirmed the hemocompatibility of the scaffold. NC also imparts appropriate antibacterial activity and biocompatibility promising for a wound dressing material. 15% NC (PCL/15NC) loaded membrane exhibits excellent bioavailability and sustained release behaviour of curcumin at different pH of 7.4, 5.8 and 1.2 with pH sensitive nature. Thus, it can be concluded that PCL/15NC nanofibrous membrane is a promising material for wound dressings and transdermal patches with tunable drug releasing properties with pH stimulus. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Synthesis of 7,9-diazabicyclo[4.2.2]decanes as conformationally restricted κ receptor agonists: fine tuning of the dihedral angle of the ethylenediamine pharmacophore.

    Science.gov (United States)

    Sunnam, Sunil K; Rack, Elisabeth; Schepmann, Dirk; Wünsch, Bernhard

    2011-06-01

    In order to slightly modify the orientation of the pharmacophoric structural elements of the potent κ agonists 7 and 8, the three-membered bridge of these compounds was enlarged to four carbon atoms. Reductive amination of the bicyclic ketone 11 with pyrrolidine and NaBH(OAc)3 provided the pyrrolidine 12 with excellent diastereoselectivity (>99:1). The diastereomeric pyrrolidine 24 was established by a stepwise strategy, involving an unselective nucleophilic substitution of the triflate 20 with NaN3 as key step. The synthesis of 9 and 10 was completed by LiAlH4 reduction, replacement of the PMB group at N-9 with a (3,4-dichlorophenyl)acetyl residue and the N-7-benzyl group with the methoxycarbonyl moiety. The κ receptor affinity of the new compounds is strongly dependent on the stereochemistry and the N-7-substituent. The (1RS,2SR,6SR)-configured pyrrolidine 9 with a methoxycarbonyl moiety at N-7 represents the most potent κ ligand (Ki=65 nM) of this series. The 65fold lower κ affinity of 9 compared with its smaller homologue 7 is partly explained by 9 being a racemic mixture, and the slightly modified dihedral angle of the pharmacophoric N(pyrrolidine)-C-C-N(dichlorophenylacetyl) substructure. However, the additional methylene moiety, which enlarges the size of the bridge, is assumed to be responsible for the reduced κ affinity. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  5. Molecular fountain.

    Energy Technology Data Exchange (ETDEWEB)

    Strecker, Kevin E.; Chandler, David W.

    2009-09-01

    A molecular fountain directs slowly moving molecules against gravity to further slow them to translational energies that they can be trapped and studied. If the molecules are initially slow enough they will return some time later to the position from which they were launched. Because this round trip time can be on the order of a second a single molecule can be observed for times sufficient to perform Hz level spectroscopy. The goal of this LDRD proposal was to construct a novel Molecular Fountain apparatus capable of producing dilute samples of molecules at near zero temperatures in well-defined user-selectable, quantum states. The slowly moving molecules used in this research are produced by the previously developed Kinematic Cooling technique, which uses a crossed atomic and molecular beam apparatus to generate single rotational level molecular samples moving slowly in the laboratory reference frame. The Kinematic Cooling technique produces cold molecules from a supersonic molecular beam via single collisions with a supersonic atomic beam. A single collision of an atom with a molecule occurring at the correct energy and relative velocity can cause a small fraction of the molecules to move very slowly vertically against gravity in the laboratory. These slowly moving molecules are captured by an electrostatic hexapole guiding field that both orients and focuses the molecules. The molecules are focused into the ionization region of a time-of-flight mass spectrometer and are ionized by laser radiation. The new molecular fountain apparatus was built utilizing a new design for molecular beam apparatus that has allowed us to miniaturize the apparatus. This new design minimizes the volumes and surface area of the machine allowing smaller pumps to maintain the necessary background pressures needed for these experiments.

  6. Molecular rheology of branched polymers: Decoding and exploring the role of architectural dispersity through a synergy of anionic synthesis, interaction chromatography, rheometry and modeling

    KAUST Repository

    Van Ruymbeke, Evelyne

    2014-01-01

    polymers. It is important to appreciate that, even optimal model systems, i.e., those synthesized with high-vacuum anionic methods, need thorough characterization via a combination of techniques. Besides helping to improve synthetic techniques, this methodology will be significant in fine-tuning mesoscopic tube-based models and addressing outstanding issues such as the quantitative description of the constraint release mechanism. © 2014 the Partner Organisations.

  7. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns

    LENUS (Irish Health Repository)

    Sen, Lin

    2011-06-03

    Abstract Background The chloroplast-localized ribulose-1, 5-biphosphate carboxylase\\/oxygenase (Rubisco), the primary enzyme responsible for autotrophy, is instrumental in the continual adaptation of plants to variations in the concentrations of CO2. The large subunit (LSU) of Rubisco is encoded by the chloroplast rbcL gene. Although adaptive processes have been previously identified at this gene, characterizing the relationships between the mutational dynamics at the protein level may yield clues on the biological meaning of such adaptive processes. The role of such coevolutionary dynamics in the continual fine-tuning of RbcL remains obscure. Results We used the timescale and phylogenetic analyses to investigate and search for processes of adaptive evolution in rbcL gene in three gymnosperm families, namely Podocarpaceae, Taxaceae and Cephalotaxaceae. To understand the relationships between regions identified as having evolved under adaptive evolution, we performed coevolutionary analyses using the software CAPS. Importantly, adaptive processes were identified at amino acid sites located on the contact regions among the Rubisco subunits and on the interface between Rubisco and its activase. Adaptive amino acid replacements at these regions may have optimized the holoenzyme activity. This hypothesis was pinpointed by evidence originated from our analysis of coevolution that supported the correlated evolution between Rubisco and its activase. Interestingly, the correlated adaptive processes between both these proteins have paralleled the geological variation history of the concentration of atmospheric CO2. Conclusions The gene rbcL has experienced bursts of adaptations in response to the changing concentration of CO2 in the atmosphere. These adaptations have emerged as a result of a continuous dynamic of mutations, many of which may have involved innovation of functional Rubisco features. Analysis of the protein structure and the functional implications of such

  8. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns.

    Science.gov (United States)

    Sen, Lin; Fares, Mario A; Liang, Bo; Gao, Lei; Wang, Bo; Wang, Ting; Su, Ying-Juan

    2011-06-03

    The chloroplast-localized ribulose-1, 5-biphosphate carboxylase/oxygenase (Rubisco), the primary enzyme responsible for autotrophy, is instrumental in the continual adaptation of plants to variations in the concentrations of CO2. The large subunit (LSU) of Rubisco is encoded by the chloroplast rbcL gene. Although adaptive processes have been previously identified at this gene, characterizing the relationships between the mutational dynamics at the protein level may yield clues on the biological meaning of such adaptive processes. The role of such coevolutionary dynamics in the continual fine-tuning of RbcL remains obscure. We used the timescale and phylogenetic analyses to investigate and search for processes of adaptive evolution in rbcL gene in three gymnosperm families, namely Podocarpaceae, Taxaceae and Cephalotaxaceae. To understand the relationships between regions identified as having evolved under adaptive evolution, we performed coevolutionary analyses using the software CAPS. Importantly, adaptive processes were identified at amino acid sites located on the contact regions among the Rubisco subunits and on the interface between Rubisco and its activase. Adaptive amino acid replacements at these regions may have optimized the holoenzyme activity. This hypothesis was pinpointed by evidence originated from our analysis of coevolution that supported the correlated evolution between Rubisco and its activase. Interestingly, the correlated adaptive processes between both these proteins have paralleled the geological variation history of the concentration of atmospheric CO2. The gene rbcL has experienced bursts of adaptations in response to the changing concentration of CO2 in the atmosphere. These adaptations have emerged as a result of a continuous dynamic of mutations, many of which may have involved innovation of functional Rubisco features. Analysis of the protein structure and the functional implications of such mutations put forward the conclusion that

  9. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns

    Directory of Open Access Journals (Sweden)

    Gao Lei

    2011-06-01

    Full Text Available Abstract Background The chloroplast-localized ribulose-1, 5-biphosphate carboxylase/oxygenase (Rubisco, the primary enzyme responsible for autotrophy, is instrumental in the continual adaptation of plants to variations in the concentrations of CO2. The large subunit (LSU of Rubisco is encoded by the chloroplast rbcL gene. Although adaptive processes have been previously identified at this gene, characterizing the relationships between the mutational dynamics at the protein level may yield clues on the biological meaning of such adaptive processes. The role of such coevolutionary dynamics in the continual fine-tuning of RbcL remains obscure. Results We used the timescale and phylogenetic analyses to investigate and search for processes of adaptive evolution in rbcL gene in three gymnosperm families, namely Podocarpaceae, Taxaceae and Cephalotaxaceae. To understand the relationships between regions identified as having evolved under adaptive evolution, we performed coevolutionary analyses using the software CAPS. Importantly, adaptive processes were identified at amino acid sites located on the contact regions among the Rubisco subunits and on the interface between Rubisco and its activase. Adaptive amino acid replacements at these regions may have optimized the holoenzyme activity. This hypothesis was pinpointed by evidence originated from our analysis of coevolution that supported the correlated evolution between Rubisco and its activase. Interestingly, the correlated adaptive processes between both these proteins have paralleled the geological variation history of the concentration of atmospheric CO2. Conclusions The gene rbcL has experienced bursts of adaptations in response to the changing concentration of CO2 in the atmosphere. These adaptations have emerged as a result of a continuous dynamic of mutations, many of which may have involved innovation of functional Rubisco features. Analysis of the protein structure and the functional

  10. Molecular Electronics

    DEFF Research Database (Denmark)

    Jennum, Karsten Stein

    This thesis includes the synthesis and characterisation of organic compounds designed for molecular electronics. The synthesised organic molecules are mainly based on two motifs, the obigo(phenyleneethynylenes) (OPE)s and tetrathiafulvalene (TTF) as shown below. These two scaffolds (OPE and TTF...... transistors (Part 2). The synthetic protocols rely on stepwise Sonogashira coupling reactions. Conductivity studies on various OPE-based molecular wires reveal that mere OPE compounds have a higher electrical resistance compared to the cruciform based wires (up to 9 times higher). The most spectacular result...... be potential candidates for future molecular electronics Synthesis of a new donor-acceptor chromophore based on a benzoquinone- TTF motif (QuinoneDTF) is also described herein (Part 2). Reaction of this molecule with acid induces a colour change from purple to orange. The purple colour can be restored...

  11. Molecular pathways

    DEFF Research Database (Denmark)

    Cox, Thomas R; Erler, Janine Terra

    2014-01-01

    that 45% of deaths in the developed world are linked to fibrotic disease. Fibrosis and cancer are known to be inextricably linked; however, we are only just beginning to understand the common and overlapping molecular pathways between the two. Here, we discuss what is known about the intersection...... of fibrosis and cancer, with a focus on cancer metastasis, and highlight some of the exciting new potential clinical targets that are emerging from analysis of the molecular pathways associated with these two devastating diseases. Clin Cancer Res; 20(14); 3637-43. ©2014 AACR....

  12. Molecular modeling

    Directory of Open Access Journals (Sweden)

    Aarti Sharma

    2009-01-01

    Full Text Available The use of computational chemistry in the development of novel pharmaceuticals is becoming an increasingly important tool. In the past, drugs were simply screened for effectiveness. The recent advances in computing power and the exponential growth of the knowledge of protein structures have made it possible for organic compounds to be tailored to decrease the harmful side effects and increase the potency. This article provides a detailed description of the techniques employed in molecular modeling. Molecular modeling is a rapidly developing discipline, and has been supported by the dramatic improvements in computer hardware and software in recent years.

  13. Large-scale nucleotide sequence alignment and sequence variability assessment to identify the evolutionarily highly conserved regions for universal screening PCR assay design: an example of influenza A virus.

    Science.gov (United States)

    Nagy, Alexander; Jiřinec, Tomáš; Černíková, Lenka; Jiřincová, Helena; Havlíčková, Martina

    2015-01-01

    The development of a diagnostic polymerase chain reaction (PCR) or quantitative PCR (qPCR) assay for universal detection of highly variable viral genomes is always a difficult task. The purpose of this chapter is to provide a guideline on how to align, process, and evaluate a huge set of homologous nucleotide sequences in order to reveal the evolutionarily most conserved positions suitable for universal qPCR primer and hybridization probe design. Attention is paid to the quantification and clear graphical visualization of the sequence variability at each position of the alignment. In addition, specific problems related to the processing of the extremely large sequence pool are highlighted. All of these steps are performed using an ordinary desktop computer without the need for extensive mathematical or computational skills.

  14. Molecular gastronomy

    Science.gov (United States)

    This, Hervé

    2005-01-01

    For centuries, cooks have been applying recipes without looking for the mechanisms of the culinary transformations. A scientific discipline that explores these changes from raw ingredients to eating the final dish, is developing into its own field, termed molecular gastronomy. Here, one of the founders of the discipline discusses its aims and importance.

  15. Molecular farming

    NARCIS (Netherlands)

    Merck, K.B.; Vereijken, J.M.

    2006-01-01

    Molecular Farming is a new and emerging technology that promises relatively cheap and flexible production of large quantities of pharmaceuticals in genetically modified plants. Many stakeholders are involved in the production of pharmaceuticals in plants, which complicates the discussion on the

  16. An evolutionarily conserved mitochondrial orf108 is associated with cytoplasmic male sterility in different alloplasmic lines of Brassica juncea and induces male sterility in transgenic Arabidopsis thaliana.

    Science.gov (United States)

    Kumar, Pankaj; Vasupalli, Naresh; Srinivasan, R; Bhat, Shripad R

    2012-05-01

    Nuclear-mitochondrial gene interactions governing cytoplasmic male sterility (CMS) in angiosperms have been found to be unique to each system. Fertility restoration of three diverse alloplasmic CMS lines of Brassica juncea by a line carrying the fertility-restorer gene introgressed from Moricandia arvensis prompted this investigation to examine the molecular basis of CMS in these lines. Since previous studies had found altered atpA transcription associated with CMS in these lines, the atpA genes and transcripts of CMS, fertility-restored, and euplasmic lines were cloned and compared. atpA coding and downstream sequences were conserved among CMS and euplasmic lines but major differences were found in the 5' flanking sequences of atpA. A unique open reading frame (ORF), orf108, co-transcribed with atpA, was found in male sterile flowers of CMS lines carrying mitochondrial genomes of Diplotaxis berthautii, D. catholica, or D. erucoides. In presence of the restorer gene, the bicistronic orf108-atpA transcript was cleaved within orf108 to yield a monocistronic atpA transcript. Transgenic expression of orf108 with anther-specific Atprx18 promoter in Arabidopsis thaliana gave 50% pollen sterility, indicating that Orf108 is lethal at the gametophytic stage. Further, lack of transmission of orf108 to the progeny showed for the first time that mitochondrial ORFs could also cause female sterility. orf108 was found to be widely distributed among wild relatives of Brassica, indicating its ancient origin. This is the first report that shows that CMS lines of different origin and morphology could share common molecular basis. The gametic lethality of Orf108 offers a novel opportunity for transgene containment.

  17. Molecular cytogenetics.

    Science.gov (United States)

    Carpenter, N J

    2001-09-01

    In the past decade, clinical cytogenetics has undergone remarkable advancement as molecular biology techniques have been applied to conventional chromosome analysis. The limitations of conventional banding analysis in the accurate diagnosis and interpretation of certain chromosome abnormalities have largely been overcome by these new technologies, which include fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), and multicolor FISH (M-FISH, SKY, and Rx-FISH). Clinical applications include diagnosis of microdeletion and microduplication syndromes, detection of subtelomeric rearrangements in idiopathic mental retardation, identification of marker and derivative chromosomes, prenatal diagnosis of trisomy syndromes, and gene rearrangements and gene amplification in tumors. Molecular cytogenetic methods have expanded the possibilities for precise genetic diagnoses, which are extremely important for clinical management of patients and appropriate counseling of their families.

  18. Molecular Modelling

    Directory of Open Access Journals (Sweden)

    Aarti Sharma

    2009-12-01

    Full Text Available

    The use of computational chemistry in the development of novel pharmaceuticals is becoming an increasingly important
    tool. In the past, drugs were simply screened for effectiveness. The recent advances in computing power and
    the exponential growth of the knowledge of protein structures have made it possible for organic compounds to tailored to
    decrease harmful side effects and increase the potency. This article provides a detailed description of the techniques
    employed in molecular modeling. Molecular modelling is a rapidly developing discipline, and has been supported from
    the dramatic improvements in computer hardware and software in recent years.

  19. Molecular belts.

    Science.gov (United States)

    Evans, Paul J; Jasti, Ramesh

    2014-01-01

    Rigid hydrocarbon macrocycles with radially-oriented π-systems and continuous conjugation have attracted great interest in recent years. These molecular belts have novel optoelectronic properties and host-guest behavior. Certain belts may also ultimately lead to a rational synthesis of carbon nanotubes. The high strain associated with the nonplanar, conjugated backbones requires the development of new synthetic methods, and clever synthetic design. Herein we describe the synthetic history and properties of these structurally simple but synthetically challenging molecules.

  20. Molecular Imprinting

    Science.gov (United States)

    Dufaud, V.; Bonneviot, L.

    Our senses of smell and taste are able to recognise molecules selectively, to the point where they can even discriminate between different chiral states. This property, called molecular recognition, is essential to all forms of life [1]. It is based on the principle of a specific interaction between a receptor or host and a target molecule, which will be identified among a multitude of others, then selectively adsorbed. If the host is endowed with reactive functions, the attached molecule may be transported or transformed. Enzymes are the archetypal host molecules exploiting the idea of molecular recognition. Their complexation sites comprise a hydrophobic pocket with definite shape within which amino acid residues are located in a precisely defined way. The combined effect of these different characteristics underlies not only the affinity for some specific substrate, but also the transformation of this substrate into the desired product [2]. In fact, the phenomena actually brought into play are much more involved, being made up of an ensemble of physicochemical events that act together in a cooperative way, either simultaneously or sequentially, and in which the molecular processes are difficult to follow in detail.

  1. Molecular Modeling

    Science.gov (United States)

    Holmes, Jon L.

    1999-06-01

    Molecular modeling has trickled down from the realm of pharmaceutical and research laboratories into the realm of undergraduate chemistry instruction. It has opened avenues for the visualization of chemical concepts that previously were difficult or impossible to convey. I am sure that many of you have developed exercises using the various molecular modeling tools. It is the desire of this Journal to become an avenue for you to share these exercises among your colleagues. It is to this end that Ron Starkey has agreed to edit such a column and to publish not only the description of such exercises, but also the software documents they use. The WWW is the obvious medium to distribute this combination and so accepted submissions will appear online as a feature of JCE Internet. Typical molecular modeling exercise: finding conformation energies. Molecular Modeling Exercises and Experiments is the latest feature column of JCE Internet, joining Conceptual Questions and Challenge Problems, Hal's Picks, and Mathcad in the Chemistry Curriculum. JCE Internet continues to seek submissions in these areas of interest and submissions of general interest. If you have developed materials and would like to submit them, please see our Guide to Submissions for more information. The Chemical Education Resource Shelf, Equipment Buyers Guide, and WWW Site Review would also like to hear about chemistry textbooks and software, equipment, and WWW sites, respectively. Please consult JCE Internet Features to learn more about these resources at JCE Online. Email Announcements Would you like to be informed by email when the latest issue of the Journal is available online? when a new JCE Software title is shipping? when a new JCE Internet article has been published or is available for Open Review? when your subscription is about to expire? A new feature of JCE Online makes this possible. Visit our Guestbook to learn how. When you submit the form on this page, which includes your email address

  2. GMF is an evolutionarily developed Adf/cofilin-super family protein involved in the Arp2/3 complex-mediated organization of the actin cytoskeleton.

    Science.gov (United States)

    Nakano, Kentaro; Kuwayama, Hidekazu; Kawasaki, Masato; Numata, Osamu; Takaine, Masak

    2010-06-01

    Actin-depolymerizing factor (ADF)/cofilin is widely expressed in eukaryotes and plays a central role in reorganizing the actin cytoskeleton by disassembling actin filaments. The ADF-homologous domain (ADF-H) is conserved in several other actin-modulating proteins such as twinfilin, Abp1/drebrin, and coactosin. Although these proteins interact with actin via ADF-H, their effects on actin are not identical to each other. Here, we report a novel ADF/cofilin-super family protein, Gmf1 (Glia maturation factor-like protein 1), from the fission yeast Schizosaccharomyces pombe. Gmf1 is a component of actin patches, which are located on the cell cortex and required for endocytosis, and may be involved in the control of the disassembly of actin patches since its overexpression diminishes them. We provide evidence that Gmf1 binds weakly if at all to actin, but it associates with actin-related protein (Arp) 2/3 complex and suppresses its functions such as the promotion of actin polymerization and branching filaments. Importantly, Arp2/3 complex-suppressing activity is conserved among GMF-family proteins from other organisms. Given the functional plasticity of ADF-H, GMF-family proteins possibly have changed their target from conventional actin to Arps through molecular evolution.

  3. Evolutionarily Dynamic, but Robust, Targeting of Resistance Genes by the miR482/2118 Gene Family in the Solanaceae.

    Science.gov (United States)

    de Vries, Sophie; Kloesges, Thorsten; Rose, Laura E

    2015-11-19

    Plants are exposed to pathogens around the clock. A common resistance response in plants upon pathogen detection is localized cell death. Given the irreversible nature of this response, multiple layers of negative regulation are present to prevent the untimely or misexpression of resistance genes. One layer of negative regulation is provided by a recently discovered microRNA (miRNA) gene family, miR482/2118. This family targets the transcripts of resistance genes in plants. We investigated the evolutionary history and specificity of this miRNA gene family within the Solanaceae. This plant family includes many important crop species, providing a set of well-defined resistance gene repertoires. Across 14 species from the Solanaceae, we identified eight distinct miR482/2118 gene family members. Our studies show conservation of miRNA type and number in the group of wild tomatoes and, to a lesser extent, throughout the Solanaceae. The eight orthologous miRNA gene clusters evolved under different evolutionary constraints, allowing for individual subfunctionalization of the miRNAs. Despite differences in the predicted targeting behavior of each miRNA, the miRNA-R-gene network is robust due to its high degree of interconnectivity and redundant targeting. Our data suggest that the miR482/2118 gene family acts as an evolutionary buffer for R-gene sequence diversity. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  4. Molecular nanomagnets

    CERN Document Server

    Gatteschi, Dante; Villain, Jacques

    2006-01-01

    Nanomagnetism is a rapidly expanding area of research which appears to be able to provide novel applications. Magnetic molecules are at the very bottom of the possible size of nanomagnets and they provide a unique opportunity to observe the coexistence of classical and quantum properties. The discovery in the early 90's that a cluster comprising twelve manganese ions shows hysteresis of molecular origin, and later proved evidence of quantum effects, opened a new research area whichis still flourishing through the collaboration of chemists and physicists. This book is the first attempt to cover

  5. Molecular plasmonics

    CERN Document Server

    Fritzsche, Wolfgang

    2014-01-01

    Adopting a novel approach, this book provides a unique ""molecular perspective"" on plasmonics, concisely presenting the fundamentals and applications in a way suitable for beginners entering this hot field as well as for experienced researchers and practitioners. It begins by introducing readers to the optical effects that occur at the nanoscale and particularly their modification in the presence of biomolecules, followed by a concise yet thorough overview of the different methods for the actual fabrication of nanooptical materials. Further chapters address the relevant nanooptics, as well as

  6. Impact of molecular solvophobicity vs. solvophilicity on device performances of dimeric perylene diimide based solution-processed non-fullerene organic solar cells.

    Science.gov (United States)

    Lu, Zhenhuan; Zhang, Xin; Zhan, Chuanlang; Jiang, Bo; Zhang, Xinliang; Chen, Lili; Yao, Jiannian

    2013-07-21

    Because of their outstanding molecular optoelectronic properties, perylene diimides (PDIs) are promising alternatives to the commonly used PCBM. However, the overly strong aggregation ability, poor solution-processability and compatibility of PDIs severely limit their photovoltaic applications. We turned to borrowing the amphiphile concept to improve these supramolecular properties. Practically, we fine-tuned the molecular solvophobicity with respect to the molecular solvophilicity, e.g. F(solvophob/solvophil), by changing the number of the weakly solvophobic 2-methoxyethoxyl (EG) groups in the bay-region of the thienyl-bridged dimeric PDI backbone, forming three PDI dimers of Bis-PDI-T (0 EG), Bis-PDI-T-EG (2 EG) and Bis-PDI-T-di-EG (4 EG) (Scheme 1). The photovoltaic properties using these dimers as the solution-processed non-fullerene electron-acceptor and P3HT as the electron-donor were investigated via the device configuration of ITO/PEDOT:PSS/P3HT:PDI dimer/Ca/Al. Bis-PDI-T exhibited overly strong aggregation ability and very poor solution-processability, which severely limited compatibility, giving a very poor power conversion efficiency (PCE) of 0.007%. When two EG groups were attached at the 1,1'-positions, the resulted Bis-PDI-T-EG showed dramatically reduced aggregation ability, improved solution-processability, compatibility and proper phase separation. Small sized phases (∼20 nm) dominated in the active layer and the best PCE was increased to 0.39%. When four solvophobic EG functions were introduced, affording Bis-PDI-T-di-EG with excellent supramolecular properties, particularly, the improvement of the phase separation with an increased phase size of 24 nm and the enhanced electron and hole mobilities, by 2-4 times, with respect to that of Bis-PDI-T-EG. The best PCE was further enhanced to 0.88%. After using 1-chloronaphthalene as the co-solvent of 1,2-dichlorobenzene to further improve the compatibility, the PCE was improved further up to 0.41% for

  7. Molecular control of seasonal flowering in rice, arabidopsis and temperate cereals.

    Science.gov (United States)

    Shrestha, Roshi; Gómez-Ariza, Jorge; Brambilla, Vittoria; Fornara, Fabio

    2014-11-01

    Rice (Oryza sativa) and Arabidopsis thaliana have been widely used as model systems to understand how plants control flowering time in response to photoperiod and cold exposure. Extensive research has resulted in the isolation of several regulatory genes involved in flowering and for them to be organized into a molecular network responsive to environmental cues. When plants are exposed to favourable conditions, the network activates expression of florigenic proteins that are transported to the shoot apical meristem where they drive developmental reprogramming of a population of meristematic cells. Several regulatory factors are evolutionarily conserved between rice and arabidopsis. However, other pathways have evolved independently and confer specific characteristics to flowering responses. This review summarizes recent knowledge on the molecular mechanisms regulating daylength perception and flowering time control in arabidopsis and rice. Similarities and differences are discussed between the regulatory networks of the two species and they are compared with the regulatory networks of temperate cereals, which are evolutionarily more similar to rice but have evolved in regions where exposure to low temperatures is crucial to confer competence to flower. Finally, the role of flowering time genes in expansion of rice cultivation to Northern latitudes is discussed. Understanding the mechanisms involved in photoperiodic flowering and comparing the regulatory networks of dicots and monocots has revealed how plants respond to environmental cues and adapt to seasonal changes. The molecular architecture of such regulation shows striking similarities across diverse species. However, integration of specific pathways on a basal scheme is essential for adaptation to different environments. Artificial manipulation of flowering time by means of natural genetic resources is essential for expanding the cultivation of cereals across different environments. © The Author 2014

  8. Controlling stereochemical outcomes of asymmetric processes by catalyst remote molecular functionalizations: chiral diamino-oligothiophenes (DATs) as ligands in asymmetric catalysis.

    Science.gov (United States)

    Albano, Vincenzo Giulio; Bandini, Marco; Barbarella, Giovanna; Melucci, Manuela; Monari, Magda; Piccinelli, Fabio; Tommasi, Simona; Umani-Ronchi, Achille

    2006-01-11

    The synthesis, characterization, and structure-guided application of a new class of highly versatile chiral C(2)-symmetric diamine-oligothiophene ligands in Pd-catalyzed asymmetric transformations are presented. Experimental investigations of the intimate role of pendant pi-conjugate oligothiophenes in determining the catalytic activity of the corresponding chiral Pd complexes are described. Their unusual behavior opens up new routes toward the logical design of finely tuned organometallic catalysts by remote structural functionalizations.

  9. Structures of Human Pumilio with Noncognate RNAs Reveal Molecular Mechanisms for Binding Promiscuity

    Energy Technology Data Exchange (ETDEWEB)

    Gupta,Y.; Nair, D.; Wharton, R.; Aggarwal, A.

    2008-01-01

    Pumilio is a founder member of the evolutionarily conserved Puf family of RNA-binding proteins that control a number of physiological processes in eukaryotes. A structure of human Pumilio (hPum) Puf domain bound to a Drosophila regulatory sequence showed that each Puf repeat recognizes a single nucleotide. Puf domains in general bind promiscuously to a large set of degenerate sequences, but the structural basis for this promiscuity has been unclear. Here, we describe the structures of hPum Puf domain complexed to two noncognate RNAs, CycBreverse and Puf5. In each complex, one of the nucleotides is ejected from the binding surface, in effect, acting as a 'spacer.' The complexes also reveal the plasticity of several Puf repeats, which recognize noncanonical nucleotides. Together, these complexes provide a molecular basis for recognition of degenerate binding sites, which significantly increases the number of mRNAs targeted for regulation by Puf proteins in vivo.

  10. Evolutionarily conserved phenylpropanoid pattern on angiosperm pollen.

    Science.gov (United States)

    Fellenberg, Christin; Vogt, Thomas

    2015-04-01

    The male gametophyte of higher plants appears as a solid box containing the essentials to transmit genetic material to the next generation. These consist of haploid generative cells that are required for reproduction, and an invasive vegetative cell producing the pollen tube, both mechanically protected by a rigid polymer, the pollen wall, and surrounded by a hydrophobic pollen coat. This coat mediates the direct contact to the biotic and abiotic environments. It contains a mixture of compounds required not only for fertilization but also for protection against biotic and abiotic stressors. Among its metabolites, the structural characteristics of two types of phenylpropanoids, hydroxycinnamic acid amides and flavonol glycosides, are highly conserved in Angiosperm pollen. Structural and functional aspects of these compounds will be discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Evolutionarily conserved herpesviral protein interaction networks.

    Directory of Open Access Journals (Sweden)

    Even Fossum

    2009-09-01

    Full Text Available Herpesviruses constitute a family of large DNA viruses widely spread in vertebrates and causing a variety of different diseases. They possess dsDNA genomes ranging from 120 to 240 kbp encoding between 70 to 170 open reading frames. We previously reported the protein interaction networks of two herpesviruses, varicella-zoster virus (VZV and Kaposi's sarcoma-associated herpesvirus (KSHV. In this study, we systematically tested three additional herpesvirus species, herpes simplex virus 1 (HSV-1, murine cytomegalovirus and Epstein-Barr virus, for protein interactions in order to be able to perform a comparative analysis of all three herpesvirus subfamilies. We identified 735 interactions by genome-wide yeast-two-hybrid screens (Y2H, and, together with the interactomes of VZV and KSHV, included a total of 1,007 intraviral protein interactions in the analysis. Whereas a large number of interactions have not been reported previously, we were able to identify a core set of highly conserved protein interactions, like the interaction between HSV-1 UL33 with the nuclear egress proteins UL31/UL34. Interactions were conserved between orthologous proteins despite generally low sequence similarity, suggesting that function may be more conserved than sequence. By combining interactomes of different species we were able to systematically address the low coverage of the Y2H system and to extract biologically relevant interactions which were not evident from single species.

  12. Cellular and molecular mechanisms of HIV-1 integration targeting.

    Science.gov (United States)

    Engelman, Alan N; Singh, Parmit K

    2018-02-07

    Integration is central to HIV-1 replication and helps mold the reservoir of cells that persists in AIDS patients. HIV-1 interacts with specific cellular factors to target integration to interior regions of transcriptionally active genes within gene-dense regions of chromatin. The viral capsid interacts with several proteins that are additionally implicated in virus nuclear import, including cleavage and polyadenylation specificity factor 6, to suppress integration into heterochromatin. The viral integrase protein interacts with transcriptional co-activator lens epithelium-derived growth factor p75 to principally position integration within gene bodies. The integrase additionally senses target DNA distortion and nucleotide sequence to help fine-tune the specific phosphodiester bonds that are cleaved at integration sites. Research into virus-host interactions that underlie HIV-1 integration targeting has aided the development of a novel class of integrase inhibitors and may help to improve the safety of viral-based gene therapy vectors.

  13. Origin of the Eumetazoa: testing ecological predictions of molecular clocks against the Proterozoic fossil record

    Science.gov (United States)

    Peterson, Kevin J.; Butterfield, Nicholas J.

    2005-01-01

    Molecular clocks have the potential to shed light on the timing of early metazoan divergences, but differing algorithms and calibration points yield conspicuously discordant results. We argue here that competing molecular clock hypotheses should be testable in the fossil record, on the principle that fundamentally new grades of animal organization will have ecosystem-wide impacts. Using a set of seven nuclear-encoded protein sequences, we demonstrate the paraphyly of Porifera and calculate sponge/eumetazoan and cnidarian/bilaterian divergence times by using both distance [minimum evolution (ME)] and maximum likelihood (ML) molecular clocks; ME brackets the appearance of Eumetazoa between 634 and 604 Ma, whereas ML suggests it was between 867 and 748 Ma. Significantly, the ME, but not the ML, estimate is coincident with a major regime change in the Proterozoic acritarch record, including: (i) disappearance of low-diversity, evolutionarily static, pre-Ediacaran acanthomorphs; (ii) radiation of the high-diversity, short-lived Doushantuo-Pertatataka microbiota; and (iii) an order-of-magnitude increase in evolutionary turnover rate. We interpret this turnover as a consequence of the novel ecological challenges accompanying the evolution of the eumetazoan nervous system and gut. Thus, the more readily preserved microfossil record provides positive evidence for the absence of pre-Ediacaran eumetazoans and strongly supports the veracity, and therefore more general application, of the ME molecular clock.

  14. Expression profiling of the wheat pathogen Zymoseptoria tritici reveals genomic patterns of transcription and host-specific regulatory programs.

    Science.gov (United States)

    Kellner, Ronny; Bhattacharyya, Amitava; Poppe, Stephan; Hsu, Tiffany Y; Brem, Rachel B; Stukenbrock, Eva H

    2014-05-14

    Host specialization by pathogens requires a repertoire of virulence factors as well as fine-tuned regulation of gene expression. The fungal wheat pathogen Zymoseptoria tritici (synonym Mycosphaerella graminicola) is a powerful model system for the discovery of genetic elements that underlie virulence and host specialization. We transcriptionally profiled the early stages of Z. tritici infection of a compatible host (wheat) and a noncompatible host (Brachypodium distachyon). The results revealed infection regulatory programs common to both hosts and genes with striking wheat-specific expression, with many of the latter showing sequence signatures of positive selection along the Z. tritici lineage. Genes specifically regulated during infection of wheat populated two large clusters of coregulated genes that may represent candidate pathogenicity islands. On evolutionarily labile, repeat-rich accessory chromosomes (ACs), we identified hundreds of highly expressed genes with signatures of evolutionary constraint and putative biological function. Phylogenetic analyses suggested that gene duplication events on these ACs were rare and largely preceded the diversification of Zymoseptoria species. Together, our data highlight the likely relevance for fungal growth and virulence of hundreds of Z. tritici genes, deepening the annotation and functional inference of the genes of this model pathogen. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  15. Hippo Pathway: An Emerging Regulator of Craniofacial and Dental Development.

    Science.gov (United States)

    Wang, J; Martin, J F

    2017-10-01

    The evolutionarily conserved Hippo signaling pathway is a vital regulator of organ size that fine-tunes cell proliferation, apoptosis, and differentiation. A number of important studies have revealed critical roles of Hippo signaling and its effectors Yap (Yes-associated protein) and Taz (transcriptional coactivator with PDZ binding motif) in tissue development, homeostasis, and regeneration, as well as in tumorigenesis. In addition, recent studies have shown evidence of crosstalk between the Hippo pathway and other key signaling pathways, such as Wnt signaling, that not only regulates developmental processes but also contributes to disease pathogenesis. In this review, we summarize the major discoveries in the field of Hippo signaling and what has been learned about its regulation and crosstalk with other signaling pathways, with a particular focus on recent findings involving the Hippo-Yap pathway in craniofacial and tooth development. New and exciting studies of the Hippo pathway are anticipated that will significantly improve our understanding of the molecular mechanisms of human craniofacial and tooth development and disease and will ultimately lead to the development of new therapies.

  16. Understanding molecular structure from molecular mechanics.

    Science.gov (United States)

    Allinger, Norman L

    2011-04-01

    Molecular mechanics gives us a well known model of molecular structure. It is less widely recognized that valence bond theory gives us structures which offer a direct interpretation of molecular mechanics formulations and parameters. The electronic effects well-known in physical organic chemistry can be directly interpreted in terms of valence bond structures, and hence quantitatively calculated and understood. The basic theory is outlined in this paper, and examples of the effects, and their interpretation in illustrative examples is presented.

  17. Distance-dependent patterns of molecular divergences in Tuatara mitogenomes.

    Science.gov (United States)

    Subramanian, Sankar; Mohandesan, Elmira; Millar, Craig D; Lambert, David M

    2015-03-03

    Population genetic models predict that populations that are geographically close to each other are expected to be genetically more similar to each other compared to those that are widely separate. However the patterns of relationships between geographic distance and molecular divergences at neutral and constrained regions of the genome are unclear. We attempted to clarify this relationship by sequencing complete mitochondrial genomes of the relic species Tuatara (Sphenodon punctatus) from ten offshore islands of New Zealand. We observed a positive relationship that showed a proportional increase in the neutral diversity at synonymous sites (dS), with increasing geographical distance. In contrast we showed that diversity at evolutionarily constrained sites (dC) was elevated in the case of comparisons involving closely located populations. Conversely diversity was reduced in the case of comparisons between distantly located populations. These patterns were confirmed by a significant negative relationship between the ratio of dC/dS and geographic distance. The observed high dC/dS could be explained by the abundance of deleterious mutations in comparisons involving closely located populations, due to the recent population divergence times. Since distantly related populations were separated over long periods of time, deleterious mutations might have been removed by purifying selection.

  18. Identification of a molecular pH sensor in coral.

    Science.gov (United States)

    Barott, Katie L; Barron, Megan E; Tresguerres, Martin

    2017-11-15

    Maintaining stable intracellular pH (pHi) is essential for homeostasis, and requires the ability to both sense pH changes that may result from internal and external sources, and to regulate downstream compensatory pH pathways. Here we identified the cAMP-producing enzyme soluble adenylyl cyclase (sAC) as the first molecular pH sensor in corals. sAC protein was detected throughout coral tissues, including those involved in symbiosis and calcification. Application of a sAC-specific inhibitor caused significant and reversible pHi acidosis in isolated coral cells under both dark and light conditions, indicating sAC is essential for sensing and regulating pHi perturbations caused by respiration and photosynthesis. Furthermore, pHi regulation during external acidification was also dependent on sAC activity. Thus, sAC is a sensor and regulator of pH disturbances from both metabolic and external origin in corals. Since sAC is present in all coral cell types, and the cAMP pathway can regulate virtually every aspect of cell physiology through post-translational modifications of proteins, sAC is likely to trigger multiple homeostatic mechanisms in response to pH disturbances. This is also the first evidence that sAC modulates pHi in any non-mammalian animal. Since corals are basal metazoans, our results indicate this function is evolutionarily conserved across animals. © 2017 The Author(s).

  19. Basic molecular spectroscopy

    CERN Document Server

    Gorry, PA

    1985-01-01

    BASIC Molecular Spectroscopy discusses the utilization of the Beginner's All-purpose Symbolic Instruction Code (BASIC) programming language in molecular spectroscopy. The book is comprised of five chapters that provide an introduction to molecular spectroscopy through programs written in BASIC. The coverage of the text includes rotational spectra, vibrational spectra, and Raman and electronic spectra. The book will be of great use to students who are currently taking a course in molecular spectroscopy.

  20. Artificial molecular motors

    NARCIS (Netherlands)

    Kassem, Salma; van Leeuwen, Thomas; Lubbe, Anouk S.; Wilson, Miriam R.; Feringa, Ben L.; Leigh, David A.

    2017-01-01

    Motor proteins are nature's solution for directing movement at the molecular level. The field of artificial molecular motors takes inspiration from these tiny but powerful machines. Although directional motion on the nanoscale performed by synthetic molecular machines is a relatively new

  1. Molecular mechanisms of photosynthesis

    Energy Technology Data Exchange (ETDEWEB)

    Youvan, D.C.; Marrs, B.L.

    1987-06-01

    Knowledge of the molecular interactions, structure and genetic basis of the photosynthetic reaction center makes it possible to ask more detailed questions about its function. Spectroscopy, X-ray crystallography and molecular genetics combine to give a detailed picture of events in photosynthesis and shown how particular molecules contribute to the process. The molecular biology of the photosynthesis center of Rhodopseudomonas is investigated.

  2. Molecular computing origins and promises

    CERN Document Server

    Rambidi, Nicholas G

    2014-01-01

    Molecular Computing explores whether molecular primitives can prove to be real alternatives to contemporary semiconductor means. The text discusses molecular primitives and circuitry for information processing devices.

  3. Molecular Population Genetics

    OpenAIRE

    Casillas, S?nia; Barbadilla, Antonio

    2017-01-01

    Molecular population genetics aims to explain genetic variation and molecular evolution from population genetics principles. The field was born 50 years ago with the first measures of genetic variation in allozyme loci, continued with the nucleotide sequencing era, and is currently in the era of population genomics. During this period, molecular population genetics has been revolutionized by progress in data acquisition and theoretical developments. The conceptual elegance of the neutral theo...

  4. [Molecular diagnostics in melanoma].

    Science.gov (United States)

    Lang, R; Bauer, J W; Laimer, M

    2015-04-01

    The molecular landscape of melanoma is changing more rapidly than ever since new molecular technology approaches have made it possible to examine human melanoma for genetic alterations underlying the disease. In recent years, these approaches have identified new familial melanoma susceptibility genes, most of them also conferring risk to other cancers. This has implications for clinical testing and surveillance. Furthermore, molecular testing of melanoma to determine therapeutic eligibility for targeted therapies is now standard of care and should be familiar to the dermatologist.

  5. Molecular heat pump

    OpenAIRE

    Segal, Dvira; Nitzan, Abraham

    2005-01-01

    We propose a novel molecular device that pumps heat against a thermal gradient. The system consists of a molecular element connecting two thermal reservoirs that are characterized by different spectral properties. The pumping action is achieved by applying an external force that periodically modulates molecular levels. This modulation affects periodic oscillations of the internal temperature of the molecule and the strength of its coupling to each reservoir resulting in a net heat flow in the...

  6. Translational Molecular Nuclear Cardiology.

    Science.gov (United States)

    Thackeray, James T; Bengel, Frank M

    2016-02-01

    Increased rollout and availability of preclinical imaging provides a foundation for development of novel molecular nuclear imaging agents. The current armamentarium of radiotracers available for nuclear cardiology allows for the interrogation of critical molecular processes involved in a myriad of cardiovascular disorders, including altered metabolism, ventricular remodeling, sympathetic neuronal activation, and systemic inflammation. Effective translational molecular imaging requires coordination of clinical need with tracer development and molecular biology, leading to the identification of ideal translational imaging compounds. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. The modern molecular clock.

    Science.gov (United States)

    Bromham, Lindell; Penny, David

    2003-03-01

    The discovery of the molecular clock--a relatively constant rate of molecular evolution--provided an insight into the mechanisms of molecular evolution, and created one of the most useful new tools in biology. The unexpected constancy of rate was explained by assuming that most changes to genes are effectively neutral. Theory predicts several sources of variation in the rate of molecular evolution. However, even an approximate clock allows time estimates of events in evolutionary history, which provides a method for testing a wide range of biological hypotheses ranging from the origins of the animal kingdom to the emergence of new viral epidemics.

  8. Polymer friction Molecular Dynamics

    DEFF Research Database (Denmark)

    Sivebæk, Ion Marius; Samoilov, Vladimir N.; Persson, Bo N. J.

    We present molecular dynamics friction calculations for confined hydrocarbon solids with molecular lengths from 20 to 1400 carbon atoms. Two cases are considered: a) polymer sliding against a hard substrate, and b) polymer sliding on polymer. In the first setup the shear stresses are relatively...... independent of molecular length. For polymer sliding on polymer the friction is significantly larger, and dependent on the molecular chain length. In both cases, the shear stresses are proportional to the squeezing pressure and finite at zero load, indicating an adhesional contribution to the friction force....

  9. Densities and Excess Molar Volume for the Ternary Systems (1 ...

    African Journals Online (AJOL)

    NICO

    2012-09-10

    Sep 10, 2012 ... catalyst to extend its life span, and as reagents for nanomaterials.2,3. The physical properties of ILs such as density, viscosity, melting point, polarity and miscibility with water or molecular solvents, can be finely tuned by changing either the anion or the cation.2–6. ILs have other properties such as very low ...

  10. Effect of zeatin on the infection process and expression of MAPK-4 ...

    African Journals Online (AJOL)

    HP

    2013-04-24

    Apr 24, 2013 ... Molecular Biology and Genetic Engineering, College of Basic Science and Humanities, G.B. Pant University of. Agriculture and ... crosstalk between zeatin and MAPK signaling pathway may help plants fine-tune defense responses against A. ... Interestingly, A. brassicae toxin mediated signal transduction ...

  11. Sweet business: Spot42 RNA networks with CRP to modulate catabolite repression.

    Science.gov (United States)

    Papenfort, Kai; Vogel, Jörg

    2011-02-04

    Spot42 is a paradigm for small RNAs that fine-tune carbon metabolism. In this issue of Molecular Cell, Beisel and Storz (2011) reveal that this conserved RNA acts through a multioutput feedforward loop to modulate the global dynamics of sugar consumption. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

    Science.gov (United States)

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

  13. Molecular Stirrers in Action

    NARCIS (Netherlands)

    Chen, Jiawen; Kistemaker, Jos C. M.; Robertus, Jort; Feringa, Ben L.

    2014-01-01

    A series of first-generation light-driven molecular motors with rigid substituents of varying length was synthesized to act as "molecular stirrers". Their rotary motion was studied by H-1 NMR and UV-vis absorption spectroscopy in a variety of solvents with different polarity and viscosity.

  14. Molecular microbial ecology manual

    NARCIS (Netherlands)

    Kowalchuk, G.A.; Bruijn, de F.J.; Head, I.M.; Akkermans, A.D.L.

    2004-01-01

    The field of microbial ecology has been revolutionized in the past two decades by the introduction of molecular methods into the toolbox of the microbial ecologist. This molecular arsenal has helped to unveil the enormity of microbial diversity across the breadth of the earth's ecosystems, and has

  15. Ionic and Molecular Liquids

    DEFF Research Database (Denmark)

    Chaban, Vitaly V.; Prezhdo, Oleg

    2013-01-01

    applications of RTILs in combination with molecular liquids, concentrating on three significant areas: (1) the use of molecular liquids to decrease the viscosity of RTILs; (2) the role of RTIL micelle formation in water and organic solvents; and (3) the ability of RTILs to adsorb pollutant gases. Current...

  16. Molecular phosphates and siloxanes

    Indian Academy of Sciences (India)

    Administrator

    There has been immense interest and enthusiasm recently among chemists to develop materials at low temperatures through molecular routes. Especially interesting are the studies carried out on molecular phosphonates 1 and siloxanes 2,3 by Roesky, Tilley,. Mason, Feher and others. This presentation focuses on the ...

  17. Principles of molecular oncology

    National Research Council Canada - National Science Library

    Bronchud, Miguel H

    2008-01-01

    ...-threatening diseases. Many new molecularly targeted diagnostics and therapeutics described in this text, developed based on the rapid growth in our understanding of the molecular basis of cancer, already substantially improve survival of patients with previously lethal malignancies, and also improve quality of life because of fewer toxicities. Clearly re...

  18. Making molecular machines work

    NARCIS (Netherlands)

    Browne, Wesley R.; Feringa, Ben L.

    2006-01-01

    In this review we chart recent advances in what is at once an old and very new field of endeavour the achievement of control of motion at the molecular level including solid-state and surface-mounted rotors, and its natural progression to the development of synthetic molecular machines. Besides a

  19. Structure determination of an 11-subunit exosome in complex with RNA by molecular replacement

    Energy Technology Data Exchange (ETDEWEB)

    Makino, Debora Lika, E-mail: dmakino@biochem.mpg.de; Conti, Elena [Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried (Germany)

    2013-11-01

    The crystallographic steps towards the structure determination of a complete eukaryotic exosome complex bound to RNA are presented. Phasing of this 11-protein subunit complex was carried out via molecular replacement. The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3′ degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. Several structures of subcomplexes of eukaryotic exosomes or related prokaryotic exosome-like complexes are known, but how the complete assembly is organized to fulfil processive RNA degradation has been unclear. An atomic snapshot of a Saccharomyces cerevisiae 420 kDa exosome complex bound to an RNA substrate in the pre-cleavage state of a hydrolytic reaction has been determined. Here, the crystallographic steps towards the structural elucidation, which was carried out by molecular replacement, are presented.

  20. Molecular Dynamics Information Improves cis-Peptide-Based Function Annotation of Proteins.

    Science.gov (United States)

    Das, Sreetama; Bhadra, Pratiti; Ramakumar, Suryanarayanarao; Pal, Debnath

    2017-08-04

    cis-Peptide bonds, whose occurrence in proteins is rare but evolutionarily conserved, are implicated to play an important role in protein function. This has led to their previous use in a homology-independent, fragment-match-based protein function annotation method. However, proteins are not static molecules; dynamics is integral to their activity. This is nicely epitomized by the geometric isomerization of cis-peptide to trans form for molecular activity. Hence we have incorporated both static (cis-peptide) and dynamics information to improve the prediction of protein molecular function. Our results show that cis-peptide information alone cannot detect functional matches in cases where cis-trans isomerization exists but 3D coordinates have been obtained for only the trans isomer or when the cis-peptide bond is incorrectly assigned as trans. On the contrary, use of dynamics information alone includes false-positive matches for cases where fragments with similar secondary structure show similar dynamics, but the proteins do not share a common function. Combining the two methods reduces errors while detecting the true matches, thereby enhancing the utility of our method in function annotation. A combined approach, therefore, opens up new avenues of improving existing automated function annotation methodologies.

  1. Theoretical molecular biophysics

    CERN Document Server

    Scherer, Philipp O J

    2017-01-01

    This book gives an introduction to molecular biophysics. It starts from material properties at equilibrium related to polymers, dielectrics and membranes. Electronic spectra are developed for the understanding of elementary dynamic processes in photosynthesis including proton transfer and dynamics of molecular motors. Since the molecular structures of functional groups of bio-systems were resolved, it has become feasible to develop a theory based on the quantum theory and statistical physics with emphasis on the specifics of the high complexity of bio-systems. This introduction to molecular aspects of the field focuses on solvable models. Elementary biological processes provide as special challenge the presence of partial disorder in the structure which does not destroy the basic reproducibility of the processes. Apparently the elementary molecular processes are organized in a way to optimize the efficiency. Learning from nature by means exploring the relation between structure and function may even help to b...

  2. Molecular Programming with DNA

    Science.gov (United States)

    Winfree, Erik

    2009-05-01

    Information can be stored in molecules and processed by molecular reactions. Molecular information processing is at the heart of all biological systems; might it soon also be at the heart of non-biological synthetic chemical systems? Perhaps yes. One technological approach comes from DNA nanotechnology and DNA computing, where DNA is used as a non-biological informational polymer that can be rationally designed to create a rich class of molecular systems -- for example, DNA molecules that self-assemble precisely, that fold into complex nanoscale objects, that act as mechanical actuators and molecular motors, and that make decisions based on digital and analog logic. I will argue that to fully exploit their design potential, we will need to invent programming languages for specifying the behavior of information-based molecular systems, to create theoretical tools for understanding and analyzing the behavior of molecular programs, to develop compilers that automate the design of molecules with the desired behaviors, and to expand experimental techniques so that the implementation and debugging of complex molecular systems becomes as commonplace and practical as computer programming.

  3. Molecular markers in melanoma.

    Science.gov (United States)

    Kashani-Sabet, M

    2014-01-01

    The last few years have witnessed the dawn of the molecular era in melanoma treatment. With the advent of successful therapy targeting mutant BRAF, melanoma is leading the field of cancer research in the molecular approach to therapy of advanced disease. Attempting to keep pace with advances in therapy are advances in the molecular assessment of melanoma progression, facilitated by the availability of genome-wide approaches to interrogate the malignant phenotype. At the DNA level, this has included approaches such as comparative genomic hybridization. At the RNA level, this has consisted of gene expression profiling using various assay methodologies. In certain instances, markers identified using these platforms have been further examined and developed using fluorescence in situ hybridization and immunohistochemical analysis. In this article, we will review recent progress in the development of novel molecular markers for melanoma that are nearing clinical application. We will review developments in the molecular classification of melanoma, in the molecular diagnosis of melanoma, and in the molecular assessment of melanoma prognosis. © 2013 British Association of Dermatologists.

  4. Molecular Population Genetics.

    Science.gov (United States)

    Casillas, Sònia; Barbadilla, Antonio

    2017-03-01

    Molecular population genetics aims to explain genetic variation and molecular evolution from population genetics principles. The field was born 50 years ago with the first measures of genetic variation in allozyme loci, continued with the nucleotide sequencing era, and is currently in the era of population genomics. During this period, molecular population genetics has been revolutionized by progress in data acquisition and theoretical developments. The conceptual elegance of the neutral theory of molecular evolution or the footprint carved by natural selection on the patterns of genetic variation are two examples of the vast number of inspiring findings of population genetics research. Since the inception of the field, Drosophila has been the prominent model species: molecular variation in populations was first described in Drosophila and most of the population genetics hypotheses were tested in Drosophila species. In this review, we describe the main concepts, methods, and landmarks of molecular population genetics, using the Drosophila model as a reference. We describe the different genetic data sets made available by advances in molecular technologies, and the theoretical developments fostered by these data. Finally, we review the results and new insights provided by the population genomics approach, and conclude by enumerating challenges and new lines of inquiry posed by increasingly large population scale sequence data. Copyright © 2017 Casillas and Barbadilla.

  5. Proteomic Insight into the Molecular Function of the Vitreous

    Science.gov (United States)

    Skeie, Jessica M.; Roybal, C. Nathaniel; Mahajan, Vinit B.

    2015-01-01

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

  6. Molecular heat pump.

    Science.gov (United States)

    Segal, Dvira; Nitzan, Abraham

    2006-02-01

    We propose a molecular device that pumps heat against a thermal gradient. The system consists of a molecular element connecting two thermal reservoirs that are characterized by different spectral properties. The pumping action is achieved by applying an external force that periodically modulates molecular levels. This modulation affects periodic oscillations of the internal temperature of the molecule and the strength of its coupling to each reservoir resulting in a net heat flow in the desired direction. The heat flow is examined in the slow and fast modulation limits and for different modulation wave forms, thus making it possible to optimize the device performance.

  7. Molecularly Imprinted Membranes

    Science.gov (United States)

    Trotta, Francesco; Biasizzo, Miriam; Caldera, Fabrizio

    2012-01-01

    Although the roots of molecularly imprinted polymers lie in the beginning of 1930s in the past century, they have had an exponential growth only 40–50 years later by the works of Wulff and especially by Mosbach. More recently, it was also proved that molecular imprinted membranes (i.e., polymer thin films) that show recognition properties at molecular level of the template molecule are used in their formation. Different procedures and potential application in separation processes and catalysis are reported. The influences of different parameters on the discrimination abilities are also discussed. PMID:24958291

  8. Molecular regionalization in the compact brain of the meiofaunal annelid Dinophilus gyrociliatus (Dinophilidae

    Directory of Open Access Journals (Sweden)

    Alexandra Kerbl

    2016-08-01

    Full Text Available Abstract Background Annelida is a morphologically diverse animal group that exhibits a remarkable variety in nervous system architecture (e.g., number and location of longitudinal cords, architecture of the brain. Despite this heterogeneity of neural arrangements, the molecular profiles related to central nervous system patterning seem to be conserved even between distantly related annelids. In particular, comparative molecular studies on brain and anterior neural region patterning genes have focused so far mainly on indirect-developing macrofaunal taxa. Therefore, analyses on microscopic, direct-developing annelids are important to attain a general picture of the evolutionary events underlying the vast diversity of annelid neuroanatomy. Results We have analyzed the expression domains of 11 evolutionarily conserved genes involved in brain and anterior neural patterning in adult females of the direct-developing meiofaunal annelid Dinophilus gyrociliatus. The small, compact brain shows expression of dimmed, foxg, goosecoid, homeobrain, nk2.1, orthodenticle, orthopedia, pax6, six3/6 and synaptotagmin-1. Although most of the studied markers localize to specific brain areas, the genes six3/6 and synaptotagmin-1 are expressed in nearly all perikarya of the brain. All genes except for goosecoid, pax6 and nk2.2 overlap in the anterior brain region, while the respective expression domains are more separated in the posterior brain. Conclusions Our findings reveal that the expression patterns of the genes foxg, orthodenticle, orthopedia and six3/6 correlate with those described in Platynereis dumerilii larvae, and homeobrain, nk2.1, orthodenticle and synaptotagmin-1 resemble the pattern of late larvae of Capitella teleta. Although data on other annelids are limited, molecular similarities between adult Dinophilus and larval Platynereis and Capitella suggest an overall conservation of molecular mechanisms patterning the anterior neural regions, independent

  9. Fine-tuned regulation by oxygen and nitric oxide of the activity of a semi-synthetic FNR-dependent promoter and expression of denitrification enzymes in Paracoccus denitrificans

    NARCIS (Netherlands)

    Mazoch, Jirí; Kunák, Michal; Kucera, Igor; Van Spanning, Rob J M

    2003-01-01

    In Paracoccus denitrificans at least three fumarate and nitrate reductase regulator (FNR)-like proteins [FnrP, nitrite and nitric oxide reductases regulator (NNR) and NarR] control the expression of several genes necessary for denitrifying growth. To gain more insight into this regulation,

  10. Use of additives to fine-tune the composition of carbonate units in the polymer formed by copolymerization of co2 with epoxide: application to the synthesis of polycarbonate-based block copolymers and of telechelics

    KAUST Repository

    Feng, Xiaoshuang

    2016-12-22

    Embodiments of the present disclosure describe a method of making a polycarbonate, comprising contacting one or more cyclic monomers and carbon dioxide in the presence of one or more of a Lewis acid catalyst, an initiator, and an ionic liquid; and agitating, sufficient to copolymerize the one or more cyclic monomers and carbon dioxide to create a polycarbonate. Embodiments of the present disclosure further describe a method of controlling a polymer composition, comprising contacting one or more cyclic monomers and carbon dioxide; adjusting an amount of one or more of a Lewis acid catalyst, an ionic liquid, and an initiator in the presence of the one or more cyclic monomers and carbon dioxide, sufficient to selectively modify a resulting polycarbonate; and agitating, sufficient to copolymerize the one or more cyclic monomers and carbon dioxide to create the polycarbonate.

  11. Fine-tuning the sodium hypochlorite injection system on platforms in the Campos basin - a proposal; Otimizacao do sistema de injecao de hipoclorito de sodio nas plataformas da Bacia de Campos - uma proposta

    Energy Technology Data Exchange (ETDEWEB)

    Borges Filho, Alvaro de Miranda; Motomura, Tsukasa [PETROBRAS, Rio de Janeiro, RJ (Brazil)

    2001-07-01

    Sea water serves as an important utility on the Campos Basin platforms. It is used as process cold source and is injected into the reservoir for pressure keeping porpoise. Among the many treatments suffered by the sea water, one is the disinfection by sodium hypochlorite. The sodium hypochlorite kills organic material, minimizing the threat or fouling and microbiological corrosion of the installation. Nowadays the hypochlorite injection system is based on electrically driven reciprocating dosing pumps. The systems performance is acquired by redox potential monitors or by chemical analysis kits, that measure the hypochlorite residual in the sea water system. Whenever a low residual value is identified a manual action for change the injection rate of the dosing pumps is developed. This paper proposes a new configuration that inputs automated online actions for monitoring residual and injecting sodium hypochlorite, using variable speed electric drivers and the control function of the modern redox potential monitors. The mean advantages of the new system are: man work reduction, effective sea water system protection, and chemical injection rate optimization. The expenditure on the new system is low because it is based on vendors standard equipment, that reduces its implementation time, too. (author)

  12. Atomic & Molecular Interactions

    Energy Technology Data Exchange (ETDEWEB)

    None

    2002-07-12

    The Gordon Research Conference (GRC) on Atomic & Molecular Interactions was held at Roger Williams University, Bristol, RI. Emphasis was placed on current unpublished research and discussion of the future target areas in this field.

  13. Appendix II. Molecular Analysis

    Science.gov (United States)

    The study of crop evolution, origins, and conservation entails the assessment of genetic variability with and between populations and species at different genetic, evolutionary, and taxonomic hierarchical levels. Molecular biology has greatly increased the amount of data and computational intensity...

  14. Natural Product Molecular Fossils.

    Science.gov (United States)

    Falk, Heinz; Wolkenstein, Klaus

    The natural products synthesized by organisms that were living a long time ago gave rise to their molecular fossils. These can consist of either the original unchanged compounds or they may undergo peripheral transformations in which their skeletons remain intact. In cases when molecular fossils can be traced to their organismic source, they are termed "geological biomarkers".This contribution describes apolar and polar molecular fossils and, in particular biomarkers, along the lines usually followed in organic chemistry textbooks, and points to their bioprecursors when available. Thus, the apolar compounds are divided in linear and branched alkanes followed by alicyclic compounds and aromatic and heterocyclic molecules, and, in particular, the geoporphyrins. The polar molecular fossils contain as functional groups or constituent units ethers, alcohols, phenols, carbonyl groups, flavonoids, quinones, and acids, or are polymers like kerogen, amber, melanin, proteins, or nucleic acids. The final sections discuss the methodology used and the fundamental processes encountered by the biomolecules described, including diagenesis, catagenesis, and metagenesis.

  15. Molecular Machines: Nanoscale gadgets

    Science.gov (United States)

    Garcia-Garibay, Miguel A.

    2008-06-01

    Meeting their biological counterparts halfway, artificial molecular machines embedded in liquid crystals, crystalline solids and mesoporous materials are poised to meet the demands of the next generation of functional materials.

  16. Are there molecular signatures?

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, W.P.

    1995-10-01

    This report describes molecular signatures and mutational spectrum analysis. The mutation spectrum is defined as the type and location of DNA base change. There are currently about five well documented cases. Mutations and radon-associated tumors are discussed.

  17. The Molecular Foundry (TMF)

    Data.gov (United States)

    Federal Laboratory Consortium — Founded in 2006 by the Department of Energy (DOE), the Molecular Foundry is a critical part of the DOE's National Nanotechnology Initiative, a multi-agency framework...

  18. Human papillomavirus molecular biology.

    Science.gov (United States)

    Harden, Mallory E; Munger, Karl

    Human papillomaviruses are small DNA viruses with a tropism for squamous epithelia. A unique aspect of human papillomavirus molecular biology involves dependence on the differentiation status of the host epithelial cell to complete the viral lifecycle. A small group of these viruses are the etiologic agents of several types of human cancers, including oral and anogenital tract carcinomas. This review focuses on the basic molecular biology of human papillomaviruses. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Molecular electronic junction transport

    DEFF Research Database (Denmark)

    Solomon, Gemma C.; Herrmann, Carmen; Ratner, Mark

    2012-01-01

    Whenasinglemolecule,oracollectionofmolecules,isplacedbetween two electrodes and voltage is applied, one has a molecular transport junction. We discuss such junctions, their properties, their description, and some of their applications. The discussion is qualitative rather than quantitative......, and focuses on mechanism, structure/function relations, regimes and mechanisms of transport, some molecular regularities, and some substantial challenges facing the field. Because there are many regimes and mechanisms in transport junctions, we will discuss time scales, geometries, and inelastic scattering...

  20. Molecular imaging in oncology

    Energy Technology Data Exchange (ETDEWEB)

    Schober, Otmar; Riemann, Burkhard (eds.) [Universitaetsklinikum Muenster (Germany). Klinik fuer Nuklearmedizin

    2013-02-01

    Considers in detail all aspects of molecular imaging in oncology, ranging from basic research to clinical applications in the era of evidence-based medicine. Examines technological issues and probe design. Discusses preclinical studies in detail, with particular attention to multimodality imaging. Presents current clinical use of PET/CT, SPECT/CT, and optical imagingWritten by acknowledged experts. The impact of molecular imaging on diagnostics, therapy, and follow-up in oncology is increasing significantly. The process of molecular imaging includes key biotarget identification, design of specific molecular imaging probes, and their preclinical evaluation, e.g., in vivo using small animal studies. A multitude of such innovative molecular imaging probes have already entered clinical diagnostics in oncology. There is no doubt that in future the emphasis will be on multimodality imaging in which morphological, functional, and molecular imaging techniques are combined in a single clinical investigation that will optimize diagnostic processes. This handbook addresses all aspects of molecular imaging in oncology, ranging from basic research to clinical applications in the era of evidence-based medicine. The first section is devoted to technology and probe design, and examines a variety of PET and SPECT tracers as well as multimodality probes. Preclinical studies are then discussed in detail, with particular attention to multimodality imaging. In the third section, diverse clinical applications are presented, and the book closes by looking at future challenges. This handbook will be of value to all who are interested in the revolution in diagnostic oncology that is being brought about by molecular imaging.

  1. Molecular toxicity of nanomaterials.

    Science.gov (United States)

    Chang, Xue-Ling; Yang, Sheng-Tao; Xing, Gengmei

    2014-10-01

    With the rapid developments in the fields of nanoscience and nanotechnlogy, more and more nanomaterials and their based consumer products have been used into our daily life. The safety concerns of nanomaterials have been well recognized by the scientific community and the public. Molecular mechanism of interactions between nanomaterials and biosystems is the most essential topic and final core of the biosafety. In the last two decades, nanotoxicology developed very fast and toxicity phenomena of nanomaterials have been reported. To achieve better understanding and detoxication of nanomaterials, thorough studies of nanotoxicity at molecular level are important. The interactions between nanomaterials and biomolecules have been widely investigated as the first step toward the molecular nanotoxicology. The consequences of such interactions have been discussed in the literature. Besides this, the chemical mechanism of nanotoxicology is gaining more attention, which would lead to a better design of nontoxic nanomaterials. In this review, we focus on the molecular nanotoxicology and explore the toxicity of nanomaterials at molecular level. The molecular level studies of nanotoxicology are summarized and the published nanotoxicological data are revisited.

  2. Nanoplatform-based molecular imaging

    National Research Council Canada - National Science Library

    Chen, Xiaoyuan

    2011-01-01

    "Nanoplathform-Based Molecular Imaging provides rationale for using nanoparticle-based probes for molecular imaging, then discusses general strategies for this underutilized, yet promising, technology...

  3. Multilayered proteomics reveals molecular switches dictating ligand-dependent EGFR trafficking

    DEFF Research Database (Denmark)

    Francavilla, Chiara; Papetti, Moreno; Rigbolt, Kristoffer T G

    2016-01-01

    , we devised an integrated multilayered proteomics approach (IMPA). We analyzed dynamic changes in the receptor interactome, ubiquitinome, phosphoproteome, and late proteome in response to both ligands in human cells by quantitative MS and identified 67 proteins regulated at multiple levels. We...... identified RAB7 phosphorylation and RCP recruitment to EGFR as switches for EGF and TGF-α outputs, controlling receptor trafficking, signaling duration, proliferation, and migration. By manipulating RCP levels or phosphorylation of RAB7 in EGFR-positive cancer cells, we were able to switch a TGF......-α-mediated response to an EGF-like response or vice versa as EGFR trafficking was rerouted. We propose IMPA as an approach to uncover fine-tuned regulatory mechanisms in cell signaling....

  4. Artificial Molecular Machines.

    Science.gov (United States)

    Balzani; Credi; Raymo; Stoddart

    2000-10-02

    The miniaturization of components used in the construction of working devices is being pursued currently by the large-downward (top-down) fabrication. This approach, however, which obliges solid-state physicists and electronic engineers to manipulate progressively smaller and smaller pieces of matter, has its intrinsic limitations. An alternative approach is a small-upward (bottom-up) one, starting from the smallest compositions of matter that have distinct shapes and unique properties-namely molecules. In the context of this particular challenge, chemists have been extending the concept of a macroscopic machine to the molecular level. A molecular-level machine can be defined as an assembly of a distinct number of molecular components that are designed to perform machinelike movements (output) as a result of an appropriate external stimulation (input). In common with their macroscopic counterparts, a molecular machine is characterized by 1) the kind of energy input supplied to make it work, 2) the nature of the movements of its component parts, 3) the way in which its operation can be monitored and controlled, 4) the ability to make it repeat its operation in a cyclic fashion, 5) the timescale needed to complete a full cycle of movements, and 6) the purpose of its operation. Undoubtedly, the best energy inputs to make molecular machines work are photons or electrons. Indeed, with appropriately chosen photochemically and electrochemically driven reactions, it is possible to design and synthesize molecular machines that do work. Moreover, the dramatic increase in our fundamental understanding of self-assembly and self-organizational processes in chemical synthesis has aided and abetted the construction of artificial molecular machines through the development of new methods of noncovalent synthesis and the emergence of supramolecular assistance to covalent synthesis as a uniquely powerful synthetic tool. The aim of this review is to present a unified view of the field

  5. The Dark Molecular Gas

    Science.gov (United States)

    Wolfire, Mark G.; Hollenbach, David; McKee, Christopher F.

    2010-06-01

    The mass of molecular gas in an interstellar cloud is often measured using line emission from low rotational levels of CO, which are sensitive to the CO mass, and then scaling to the assumed molecular hydrogen H2 mass. However, a significant H2 mass may lie outside the CO region, in the outer regions of the molecular cloud where the gas-phase carbon resides in C or C+. Here, H2 self-shields or is shielded by dust from UV photodissociation, whereas CO is photodissociated. This H2 gas is "dark" in molecular transitions because of the absence of CO and other trace molecules, and because H2 emits so weakly at temperatures 10 K mass such as gamma rays produced in cosmic-ray collisions with the gas and far-infrared/submillimeter wavelength dust continuum radiation. In this paper, we theoretically model this dark mass and find that the fraction of the molecular mass in this dark component is remarkably constant (~0.3 for average visual extinction through the cloud \\bar{A}_V ≃ 8) and insensitive to the incident ultraviolet radiation field strength, the internal density distribution, and the mass of the molecular cloud as long as \\bar{A}_V, or equivalently, the product of the average hydrogen nucleus column and the metallicity through the cloud, is constant. We also find that the dark mass fraction increases with decreasing \\bar{A}_V, since relatively more molecular H2 material lies outside the CO region in this case.

  6. Molecular regulation of steroidogenesis in endocrine Leydig cells.

    Science.gov (United States)

    Tremblay, Jacques J

    2015-11-01

    Steroid hormones regulate essential physiological processes and inadequate levels are associated with various pathological conditions. Consequently, the process of steroid hormone biosynthesis is finely regulated. In the testis, the main steroidogenic cells are the Leydig cells. There are two distinct populations of Leydig cells that arise during development: fetal and adult Leydig cells. Fetal Leydig cells are responsible for masculinizing the male urogenital tract and inducing testis descent. These cells atrophy shortly after birth and do not contribute to the adult Leydig cell population. Adult Leydig cells derive from undifferentiated precursors present after birth and become fully steroidogenic at puberty. The differentiation of both Leydig cell populations is controlled by locally produced paracrine factors and by endocrine hormones. In fully differentially and steroidogenically active Leydig cells, androgen production and hormone-responsiveness involve various signaling pathways and downstream transcription factors. This review article focuses on recent developments regarding the origin and function of Leydig cells, the regulation of their differentiation by signaling molecules, hormones, and structural changes, the signaling pathways, kinases, and transcription factors involved in their differentiation and in mediating LH-responsiveness, as well as the fine-tuning mechanisms that ensure adequate production steroid hormones. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Molecular regulation of mitochondrial dynamics in cardiac disease.

    Science.gov (United States)

    Nan, Jinliang; Zhu, Wei; Rahman, M S; Liu, Mingfei; Li, Dan; Su, Shengan; Zhang, Na; Hu, Xinyang; Yu, Hong; Gupta, Mahesh P; Wang, Jian'an

    2017-07-01

    Mitochondrial homeostasis is critical for keeping functional heart in response to metabolic or environmental stresses. Mitochondrial fission and fusion (mitochondrial dynamics) play essential roles in maintaining mitochondrial homeostasis, defects in mitochondrial dynamics lead to cardiac diseases such as ischemia-reperfusion injury (IRI), heart failure and diabetic cardiomyopathy. Mitochondrial dynamics is determined by mitochondrial fission and fusion proteins, including OPA1, mitofusins and Drp1. These proteins are tightly regulated by a series of signaling pathways through different aspects such as transcription, post translation modifications (PTMs) and proteasome-dependent protein degradation. By modulating these mitochondrial fission and fusion proteins, mitochondria fine-tune their metabolic status to meet the energy demands of the heart. Moreover, these mitochondrial fission and fusion proteins are essential for mediating mitochondrial autophagy (mitophagy), leading to clearance of damaged mitochondria to maintain a healthy population of mitochondria in heart under stressed conditions. Mitochondrial dynamics dependent improvement in mitochondrial metabolism and quality could partially reverse the pathological conditions of heart. This review describes an overview of mechanisms on mitochondrial dynamics regulation and provides potential therapeutic targets for treating cardiovascular diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Molecular genetics in aquaculture

    Directory of Open Access Journals (Sweden)

    Liliana Di Stasio

    2010-01-01

    Full Text Available Great advances in molecular genetics have deeply changed the way of doing research in aquaculture, as it has already done in other fields. The molecular revolution started in the 1980’s, thanks to the widespread use of restriction enzymes and Polymerase Chain Reaction technology, which makes it possible to easily detect the genetic variability directly at the DNA level. In aquaculture, the molecular data are used for several purposes, which can be clustered into two main groups. The first one, focused on individuals, includes the sex identification and parentage assignment, while the second one, focused on populations, includes the wide area of the genetic characterization, aimed at solving taxonomic uncertainties, preserving genetic biodiversity and detecting genetic tags. For the future, the increase in the number of molecular markers and the construction of high density genetic maps, as well as the implementation of genomic resources (including genome sequencing, are expected to provide tools for the genetic improvement of aquaculture species through Marked Assisted Selection. In this review the characteristics of different types of molecular markers, along with their applications to a variety of aquaculture issues are presented.

  9. Mesoporous molecular sieve catalysts

    DEFF Research Database (Denmark)

    Højholt, Karen Thrane

    This thesis deals with a very specific class of molecular sieves known as zeolites. Zeolites are a class of crystalline aluminosilicates characterised by pores or cavities of molecular dimensions as part of their crystal structure. In this work zeolites were modified for the use and understanding...... of different catalytic applications. Primarily the zeolites were modified regarding the porosity and the introduction of metals to the framework. The obtained materials were used as solid acid catalysts, as an inert matrix for stabilising metal nanoparticles and as an anchoring material for molecular metal...... be used as solid acid catalysts but can also be used as a size-selective matrix. It was shown that it is possible to encapsulate 1-2 nm sized gold nanoparticles by silicalite-1 or ZSM-5 zeolite crystals thereby forming a sintering-stable and substrate size-selective oxidation catalyst. After carrying out...

  10. [Molecular techniques in mycology].

    Science.gov (United States)

    Rodríguez-Tudela, Juan Luis; Cuesta, Isabel; Gómez-López, Alicia; Alastruey-Izquierdo, Ana; Bernal-Martínez, Leticia; Cuenca-Estrella, Manuel

    2008-11-01

    An increasing number of molecular techniques for the diagnosis of fungal infections have been developed in the last few years, due to the growing prevalence of mycoses and the length of time required for diagnosis when classical microbiological methods are used. These methods are designed to resolve the following aspects of mycological diagnosis: a) Identification of fungi to species level by means of sequencing relevant taxonomic targets; b) early clinical diagnosis of invasive fungal infections; c) detection of molecular mechanisms of resistance to antifungal agents; and d) molecular typing of fungi. Currently, these methods are restricted to highly developed laboratories. However, some of these techniques will probably be available in daily clinical practice in the near future.

  11. Evolutionary molecular medicine.

    Science.gov (United States)

    Nesse, Randolph M; Ganten, Detlev; Gregory, T Ryan; Omenn, Gilbert S

    2012-05-01

    Evolution has long provided a foundation for population genetics, but some major advances in evolutionary biology from the twentieth century that provide foundations for evolutionary medicine are only now being applied in molecular medicine. They include the need for both proximate and evolutionary explanations, kin selection, evolutionary models for cooperation, competition between alleles, co-evolution, and new strategies for tracing phylogenies and identifying signals of selection. Recent advances in genomics are transforming evolutionary biology in ways that create even more opportunities for progress at its interfaces with genetics, medicine, and public health. This article reviews 15 evolutionary principles and their applications in molecular medicine in hopes that readers will use them and related principles to speed the development of evolutionary molecular medicine.

  12. Theoretical Molecular Biophysics

    CERN Document Server

    Scherer, Philipp

    2010-01-01

    "Theoretical Molecular Biophysics" is an advanced study book for students, shortly before or after completing undergraduate studies, in physics, chemistry or biology. It provides the tools for an understanding of elementary processes in biology, such as photosynthesis on a molecular level. A basic knowledge in mechanics, electrostatics, quantum theory and statistical physics is desirable. The reader will be exposed to basic concepts in modern biophysics such as entropic forces, phase separation, potentials of mean force, proton and electron transfer, heterogeneous reactions coherent and incoherent energy transfer as well as molecular motors. Basic concepts such as phase transitions of biopolymers, electrostatics, protonation equilibria, ion transport, radiationless transitions as well as energy- and electron transfer are discussed within the frame of simple models.

  13. Substructured multibody molecular dynamics.

    Energy Technology Data Exchange (ETDEWEB)

    Grest, Gary Stephen; Stevens, Mark Jackson; Plimpton, Steven James; Woolf, Thomas B. (Johns Hopkins University, Baltimore, MD); Lehoucq, Richard B.; Crozier, Paul Stewart; Ismail, Ahmed E.; Mukherjee, Rudranarayan M. (Rensselaer Polytechnic Institute, Troy, NY); Draganescu, Andrei I.

    2006-11-01

    We have enhanced our parallel molecular dynamics (MD) simulation software LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator, lammps.sandia.gov) to include many new features for accelerated simulation including articulated rigid body dynamics via coupling to the Rensselaer Polytechnic Institute code POEMS (Parallelizable Open-source Efficient Multibody Software). We use new features of the LAMMPS software package to investigate rhodopsin photoisomerization, and water model surface tension and capillary waves at the vapor-liquid interface. Finally, we motivate the recipes of MD for practitioners and researchers in numerical analysis and computational mechanics.

  14. Valency and molecular structure

    CERN Document Server

    Cartmell, E

    1977-01-01

    Valency and Molecular Structure, Fourth Edition provides a comprehensive historical background and experimental foundations of theories and methods relating to valency and molecular structures. In this edition, the chapter on Bohr theory has been removed while some sections, such as structures of crystalline solids, have been expanded. Details of structures have also been revised and extended using the best available values for bond lengths and bond angles. Recent developments are mostly noted in the chapter on complex compounds, while a new chapter has been added to serve as an introduction t

  15. Molecular beam epitaxy

    CERN Document Server

    Pamplin, Brian R

    1980-01-01

    Molecular Beam Epitaxy introduces the reader to the use of molecular beam epitaxy (MBE) in the generation of III-V and IV-VI compounds and alloys and describes the semiconductor and integrated optics reasons for using the technique. Topics covered include semiconductor superlattices by MBE; design considerations for MBE systems; periodic doping structure in gallium arsenide (GaAs); nonstoichiometry and carrier concentration control in MBE of compound semiconductors; and MBE techniques for IV-VI optoelectronic devices. The use of MBE to fabricate integrated optical devices and to study semicond

  16. Open source molecular modeling.

    Science.gov (United States)

    Pirhadi, Somayeh; Sunseri, Jocelyn; Koes, David Ryan

    2016-09-01

    The success of molecular modeling and computational chemistry efforts are, by definition, dependent on quality software applications. Open source software development provides many advantages to users of modeling applications, not the least of which is that the software is free and completely extendable. In this review we categorize, enumerate, and describe available open source software packages for molecular modeling and computational chemistry. An updated online version of this catalog can be found at https://opensourcemolecularmodeling.github.io. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. Molecular subgroups of medulloblastoma

    Science.gov (United States)

    Northcott, Paul A; Dubuc, Adrian M; Pfister, Stefan; Taylor, Michael D

    2014-01-01

    Recent efforts at stratifying medulloblastomas based on their molecular features have revolutionized our understanding of this morbidity. Collective efforts by multiple independent groups have subdivided medulloblastoma from a single disease into four distinct molecular subgroups characterized by disparate transcriptional signatures, mutational spectra, copy number profiles and, most importantly, clinical features. We present a summary of recent studies that have contributed to our understanding of the core medulloblastoma subgroups, focusing largely on clinically relevant discoveries that have already, and will continue to, shape research. PMID:22853794

  18. Synergetics of molecular systems

    CERN Document Server

    Lupichev, Lev N; Kadantsev, Vasiliy N

    2014-01-01

    Synergetics is the quantitative study of multicomponent systems that exhibit nonlinear dynamics and cooperativity. This book specifically considers basic models of the nonlinear dynamics of molecular systems and discusses relevant applications in biological physics and the polymer sciences.Emphasis is placed on specific solutions to the dynamical equations that correspond to the coherent formation of spatial-temporal structures, such as solitons, kinks and breathers, in particular. The emergence of these patterns in molecular structures provides a variety of information on their structural pro

  19. Molecular epidemiology of Blastocystis

    Directory of Open Access Journals (Sweden)

    Fadime Eroğlu

    2015-12-01

    Full Text Available Blastocystis pathogenicity and classification was newly illuminated with molecular genetic studies and recently the parasite was found in the focus of many researchers. Several molecular methods such as; polymerase chain reaction (PCR, PCR-restriction fragment length polymorphism, random amplified polymorphic DNA, real-time polymerase chain reaction and DNA sequencing analyses can be used in genotyping of Blastocystis. Blastocystis parasites may cause diarrhea, abdominal pain, bloating, gas, irritability, anorexia, cramps, vomiting, dehydration, insomnia, nausea, loss of appetite, weight loss, fatigue symptoms and also could be asymptomatic cases. In this review, it was aimed to summarize the associations between Blastocystis subtypes and pathogenicity.

  20. A time-resolved molecular map of the macrophage response to VSV infection.

    Science.gov (United States)

    Kandasamy, Richard K; Vladimer, Gregory I; Snijder, Berend; Müller, André C; Rebsamen, Manuele; Bigenzahn, Johannes W; Moskovskich, Anna; Sabler, Monika; Stefanovic, Adrijana; Scorzoni, Stefania; Brückner, Manuela; Penz, Thomas; Cleary, Ciara; Kralovics, Robert; Colinge, Jacques; Bennett, Keiryn L; Superti-Furga, Giulio

    2016-01-01

    Studying the relationship between virus infection and cellular response is paradigmatic for our understanding of how perturbation changes biological systems. Immune response, in this context is a complex yet evolutionarily adapted and robust cellular change, and is experimentally amenable to molecular analysis. To visualize the full cellular response to virus infection, we performed temporal transcriptomics, proteomics, and phosphoproteomics analysis of vesicular stomatitis virus (VSV)-infected mouse macrophages. This enabled the understanding of how infection-induced changes in host gene and protein expression are coordinated with post-translational modifications by cells in time to best measure and control the infection process. The vast and complex molecular changes measured could be decomposed in a limited number of clusters within each category (transcripts, proteins, and protein phosphorylation) each with own kinetic parameter and characteristic pathways/processes, suggesting multiple regulatory options in the overall sensing and homeostatic program. Altogether, the data underscored a prevalent executive function to phosphorylation. Resolution of the molecular events affecting the RIG-I pathway, central to viral recognition, reveals that phosphorylation of the key innate immunity adaptor mitochondrial antiviral-signaling protein (MAVS) on S328/S330 is necessary for activation of type-I interferon and nuclear factor κ B (NFκB) pathways. To further understand the hierarchical relationships, we analyzed kinase-substrate relationships and found RAF1 and, to a lesser extent, ARAF to be inhibiting VSV replication and necessary for NFκB activation, and AKT2, but not AKT1, to be supporting VSV replication. Integrated analysis using the omics data revealed co-regulation of transmembrane transporters including SLC7A11, which was subsequently validated as a host factor in the VSV replication. The data sets are predicted to greatly empower future studies on the