WorldWideScience

Sample records for regulators molecular switches

  1. EDITORIAL: Molecular switches at surfaces Molecular switches at surfaces

    Science.gov (United States)

    Weinelt, Martin; von Oppen, Felix

    2012-10-01

    electron-vibration coupling in transport through single moleculesKatharina J Franke and Jose Ignacio Pascual Vibrational heating in single-molecule switches: an energy-dependent density-of-states approachT Brumme, R Gutierrez and G Cuniberti Reversible switching of single tin phthalocyanine molecules on the InAs(111)A surfaceC Nacci, K Kanisawa and S Fölsch Tuning the interaction between carbon nanotubes and dipole switches: the influence of the change of the nanotube-spiropyran distanceP Bluemmel, A Setaro, C Maity, S Hecht and S Reich Carbon nanotubes as substrates for molecular spiropyran-based switchesE Malic, A Setaro, P Bluemmel, Carlos F Sanz-Navarro, Pablo Ordejón, S Reich and A Knorr Ultrafast dynamics of dithienylethenes differently linked to the surface of TiO2 nanoparticlesLars Dworak, Marc Zastrow, Gehad Zeyat, Karola Rück-Braun and Josef Wachtveitl Switching the electronic properties of Co-octaethylporphyrin molecules on oxygen-covered Ni films by NO adsorptionC F Hermanns, M Bernien, A Krüger, J Miguel and W Kuch STM-switching of organic molecules on semiconductor surfaces: an above threshold density matrix model for 1,5 cyclooctadiene on Si(100)K Zenichowski, Ch Nacci, S Fölsch, J Dokić, T Klamroth and P Saalfrank A switch based on self-assembled thymineFatih Kalkan, Michael Mehlhorn and Karina Morgenstern The growth and electronic structure of azobenzene-based functional molecules on layered crystalsJ Iwicki, E Ludwig, J Buck, M Kalläne, F Köhler, R Herges, L Kipp and K Rossnagel Voltage-dependent conductance states of a single-molecule junctionY F Wang, N Néel, J Kröger, H Vázquez, M Brandbyge, B Wang and R Berndt Molecules with multiple switching units on a Au(111) surface: self-organization and single-molecule manipulationJohannes Mielke, Sofia Selvanathan, Maike Peters, Jutta Schwarz, Stefan Hecht and Leonhard Grill Preparing and regulating a bi-stable molecular switch by atomic manipulationS Sakulsermsuk, R E Palmer and P A Sloan Mixed self

  2. Identification of the molecular switch that regulates access of 5alpha-DHT to the androgen receptor.

    Science.gov (United States)

    Penning, Trevor M; Bauman, David R; Jin, Yi; Rizner, Tea Lanisik

    2007-02-01

    Pairs of hydroxysteroid dehydrogenases (HSDs) govern ligand access to steroid receptors in target tissues and act as molecular switches. By acting as reductases or oxidases, HSDs convert potent ligands into their cognate inactive metabolites or vice versa. This pre-receptor regulation of steroid hormone action may have profound effects on hormonal response. We have identified the HSDs responsible for regulating ligand access to the androgen receptor (AR) in human prostate. Type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) acts solely as a reductase to convert 5alpha-dihydrotestosterone (DHT), a potent ligand for the AR (K(d)=10(-11)M for the AR), to the inactive androgen 3alpha-androstanediol (K(d)=10(-6)M for the AR); while RoDH like 3alpha-HSD (a short-chain dehydrogenase/reductase (SDR)) acts solely as an oxidase to convert 3alpha-androstanediol back to 5alpha-DHT. Our studies suggest that aldo-keto reductase (AKRs) and SDRs function as reductases and oxidases, respectively, to control ligand access to nuclear receptors.

  3. Structures of the NLRP14 pyrin domain reveal a conformational switch mechanism regulating its molecular interactions

    International Nuclear Information System (INIS)

    Eibl, Clarissa; Hessenberger, Manuel; Wenger, Julia; Brandstetter, Hans

    2014-01-01

    Pyrin domains (PYDs) recruit downstream effector molecules in NLR signalling. A specific charge-relay system suggests a the formation of a signalling complex involving a PYD dimer. The cytosolic tripartite NLR receptors serve as important signalling platforms in innate immunity. While the C-terminal domains act as sensor and activation modules, the N-terminal death-like domain, e.g. the CARD or pyrin domain, is thought to recruit downstream effector molecules by homotypic interactions. Such homotypic complexes have been determined for all members of the death-domain superfamily except for pyrin domains. Here, crystal structures of human NLRP14 pyrin-domain variants are reported. The wild-type protein as well as the clinical D86V mutant reveal an unexpected rearrangement of the C-terminal helix α6, resulting in an extended α5/6 stem-helix. This reordering mediates a novel symmetric pyrin-domain dimerization mode. The conformational switching is controlled by a charge-relay system with a drastic impact on protein stability. How the identified charge relay allows classification of NLRP receptors with respect to distinct recruitment mechanisms is discussed

  4. Charge transport through molecular switches

    International Nuclear Information System (INIS)

    Jan van der Molen, Sense; Liljeroth, Peter

    2010-01-01

    We review the fascinating research on charge transport through switchable molecules. In the past decade, detailed investigations have been performed on a great variety of molecular switches, including mechanically interlocked switches (rotaxanes and catenanes), redox-active molecules and photochromic switches (e.g. azobenzenes and diarylethenes). To probe these molecules, both individually and in self-assembled monolayers (SAMs), a broad set of methods have been developed. These range from low temperature scanning tunneling microscopy (STM) via two-terminal break junctions to larger scale SAM-based devices. It is generally found that the electronic coupling between molecules and electrodes has a profound influence on the properties of such molecular junctions. For example, an intrinsically switchable molecule may lose its functionality after it is contacted. Vice versa, switchable two-terminal devices may be created using passive molecules ('extrinsic switching'). Developing a detailed understanding of the relation between coupling and switchability will be of key importance for both future research and technology. (topical review)

  5. Charge transport through molecular switches

    Energy Technology Data Exchange (ETDEWEB)

    Jan van der Molen, Sense [Kamerlingh Onnes Laboratorium, Leiden University, Niels Bohrweg 2, 2333 CA Leiden (Netherlands); Liljeroth, Peter, E-mail: molen@physics.leidenuniv.n [Condensed Matter and Interfaces, Debye Institute for Nanomaterials Science, University of Utrecht, PO Box 80000, 3508 TA Utrecht (Netherlands)

    2010-04-07

    We review the fascinating research on charge transport through switchable molecules. In the past decade, detailed investigations have been performed on a great variety of molecular switches, including mechanically interlocked switches (rotaxanes and catenanes), redox-active molecules and photochromic switches (e.g. azobenzenes and diarylethenes). To probe these molecules, both individually and in self-assembled monolayers (SAMs), a broad set of methods have been developed. These range from low temperature scanning tunneling microscopy (STM) via two-terminal break junctions to larger scale SAM-based devices. It is generally found that the electronic coupling between molecules and electrodes has a profound influence on the properties of such molecular junctions. For example, an intrinsically switchable molecule may lose its functionality after it is contacted. Vice versa, switchable two-terminal devices may be created using passive molecules ('extrinsic switching'). Developing a detailed understanding of the relation between coupling and switchability will be of key importance for both future research and technology. (topical review)

  6. Chiroptical Molecular Switches 1; Principles and Syntheses.

    NARCIS (Netherlands)

    Lange, Ben de; Jager, Wolter F.; Feringa, Bernard

    1992-01-01

    The concept and the synthesis of the basic molecules for a chiroptical molecular switch are described. This molecular switch is based on photochemical interconversion of two bistable forms of chiral sterically overcrowded olefins. A large variety of these alkenes with different properties have been

  7. Unity power factor switching regulator

    Science.gov (United States)

    Rippel, Wally E. (Inventor)

    1983-01-01

    A single or multiphase boost chopper regulator operating with unity power factor, for use such as to charge a battery is comprised of a power section for converting single or multiphase line energy into recharge energy including a rectifier (10), one inductor (L.sub.1) and one chopper (Q.sub.1) for each chopper phase for presenting a load (battery) with a current output, and duty cycle control means (16) for each chopper to control the average inductor current over each period of the chopper, and a sensing and control section including means (20) for sensing at least one load parameter, means (22) for producing a current command signal as a function of said parameter, means (26) for producing a feedback signal as a function of said current command signal and the average rectifier voltage output over each period of the chopper, means (28) for sensing current through said inductor, means (18) for comparing said feedback signal with said sensed current to produce, in response to a difference, a control signal applied to the duty cycle control means, whereby the average inductor current is proportionate to the average rectifier voltage output over each period of the chopper, and instantaneous line current is thereby maintained proportionate to the instantaneous line voltage, thus achieving a unity power factor. The boost chopper is comprised of a plurality of converters connected in parallel and operated in staggered phase. For optimal harmonic suppression, the duty cycles of the switching converters are evenly spaced, and by negative coupling between pairs 180.degree. out-of-phase, peak currents through the switches can be reduced while reducing the inductor size and mass.

  8. A nanoplasmonic switch based on molecular machines

    KAUST Repository

    Zheng, Yue Bing; Yang, Ying-Wei; Jensen, Lasse; Fang, Lei; Juluri, Bala Krishna; Weiss, Paul S.; Stoddart, J. Fraser; Huang, Tony Jun

    2009-01-01

    We aim to develop a molecular-machine-driven nanoplasmonic switch for its use in future nanophotonic integrated circuits (ICs) that have applications in optical communication, information processing, biological and chemical sensing. Experimental

  9. Know-How on design of switching regulator

    International Nuclear Information System (INIS)

    1985-08-01

    This book introduces switching regulator from base to application, which deals with fundamentals of switching regulator such as the reason of boom about switching regulator, understanding simple circuit without electric transformer and decision of circuit type with input voltage and output voltage, configuration and characteristic of switching regulator, a concrete design of switching regulator, pulse width control circuit and protection circuit, concrete circuit examples of switching power and the point of switching regulator.

  10. Molecular mechanism of the Syk activation switch.

    Science.gov (United States)

    Tsang, Emily; Giannetti, Anthony M; Shaw, David; Dinh, Marie; Tse, Joyce K Y; Gandhi, Shaan; Ho, Hoangdung; Wang, Sandra; Papp, Eva; Bradshaw, J Michael

    2008-11-21

    Many immune signaling pathways require activation of the Syk tyrosine kinase to link ligation of surface receptors to changes in gene expression. Despite the central role of Syk in these pathways, the Syk activation process remains poorly understood. In this work we quantitatively characterized the molecular mechanism of Syk activation in vitro using a real time fluorescence kinase assay, mutagenesis, and other biochemical techniques. We found that dephosphorylated full-length Syk demonstrates a low initial rate of substrate phosphorylation that increases during the kinase reaction due to autophosphorylation. The initial rate of Syk activity was strongly increased by either pre-autophosphorylation or binding of phosphorylated immune tyrosine activation motif peptides, and each of these factors independently fully activated Syk. Deletion mutagenesis was used to identify regions of Syk important for regulation, and residues 340-356 of the SH2 kinase linker region were identified to be important for suppression of activity before activation. Comparison of the activation processes of Syk and Zap-70 revealed that Syk is more readily activated by autophosphorylation than Zap-70, although both kinases are rapidly activated by Src family kinases. We also studied Syk activity in B cell lysates and found endogenous Syk is also activated by phosphorylation and immune tyrosine activation motif binding. Together these experiments show that Syk functions as an "OR-gate" type of molecular switch. This mechanism of switch-like activation helps explain how Syk is both rapidly activated after receptor binding but also sustains activity over time to facilitate longer term changes in gene expression.

  11. MicroRNA-326 acts as a molecular switch in the regulation of midbrain urocortin 1 expression

    Science.gov (United States)

    Aschrafi, Armaz; Verheijen, Jan M.; Gordebeke, Peter M.; Olde Loohuis, Nikkie F.; Menting, Kelly; Jager, Amanda; Palkovits, Miklos; Geenen, Bram; Kos, Aron; Martens, Gerard J.M.; Glennon, Jeffrey C.; Kaplan, Barry B.; Gaszner, Balázs; Kozicz, Tamas

    2016-01-01

    Background Altered levels of urocortin 1 (Ucn1) in the centrally projecting Edinger–Westphal nucleus (EWcp) of depressed suicide attempters or completers mediate the brain’s response to stress, while the mechanism regulating Ucn1 expression is unknown. We tested the hypothesis that microRNAs (miRNAs), which are vital fine-tuners of gene expression during the brain’s response to stress, have the capacity to modulate Ucn1 expression. Methods Computational analysis revealed that the Ucn1 3′ untranslated region contained a conserved binding site for miR-326. We examined miR-326 and Ucn1 levels in the EWcp of depressed suicide completers. In addition, we evaluated miR-326 and Ucn1 levels in the serum and the EWcp of a chronic variable mild stress (CVMS) rat model of behavioural despair and after recovery from CVMS, respectively. Gain and loss of miR-326 function experiments examined the regulation of Ucn1 by this miRNA in cultured midbrain neurons. Results We found reduced miR-326 levels concomitant with elevated Ucn1 levels in the EWcp of depressed suicide completers as well as in the EWcp of CVMS rats. In CVMS rats fully recovered from stress, both serum and EWcp miR-326 levels rebounded to nonstressed levels. While downregulation of miR-326 levels in primary midbrain neurons enhanced Ucn1 expression levels, miR-326 overexpression selectively reduced the levels of this neuropeptide. Limitations This study lacked experiments showing that in vivo alteration of miR-326 levels alleviate depression-like behaviours. We show only correlative data for miR-325 and cocaine- and amphetamine-regulated transcript levels in the EWcp. Conclusion We identified miR-326 dysregulation in depressed suicide completers and characterized this miRNA as an upstream regulator of the Ucn1 neuropeptide expression in midbrain neurons. PMID:27045550

  12. A nanoplasmonic switch based on molecular machines

    KAUST Repository

    Zheng, Yue Bing

    2009-06-01

    We aim to develop a molecular-machine-driven nanoplasmonic switch for its use in future nanophotonic integrated circuits (ICs) that have applications in optical communication, information processing, biological and chemical sensing. Experimental data show that an Au nanodisk array, coated with rotaxane molecular machines, switches its localized surface plasmon resonances (LSPR) reversibly when it is exposed to chemical oxidants and reductants. Conversely, bare Au nanodisks and disks coated with mechanically inert control compounds, do not display the same switching behavior. Along with calculations based on time-dependent density functional theory (TDDFT), these observations suggest that the nanoscale movements within surface-bound "molecular machines" can be used as the active components in plasmonic devices. ©2009 IEEE.

  13. Reducing Ripple In A Switching Voltage Regulator

    Science.gov (United States)

    Paulkovich, John; Rodriguez, G. Ernest

    1994-01-01

    Ripple voltage in output of switching voltage regulator reduced substantially by simple additional circuitry adding little to overall weight and size of regulator. Heretofore, additional filtering circuitry needed to obtain comparable reductions in ripple typically as large and heavy as original regulator. Current opposing ripple current injected into filter capacitor.

  14. Light-driven molecular current switch

    Czech Academy of Sciences Publication Activity Database

    Nešpůrek, Stanislav; Toman, Petr; Sworakowski, J.; Lipinski, J.

    2002-01-01

    Roč. 2, č. 4 (2002), s. 299-304 ISSN 1567-1739. [Multilateral Symposium between the Korean Academy of Science and Technology and the Foreign Academies. Seoul, 08.05.2002-10.05.2002] R&D Projects: GA AV ČR IAA1050901 Grant - others:GA-(PL) 4T09A 13222 Institutional research plan: CEZ:AV0Z4050913 Keywords : molecular switch * molecular electronics * charge transport Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders Impact factor: 1.117, year: 2002

  15. Quinonoid metal complexes: toward molecular switches.

    Science.gov (United States)

    Dei, Andrea; Gatteschi, Dante; Sangregorio, Claudio; Sorace, Lorenzo

    2004-11-01

    The peculiar redox-active character of quinonoid metal complexes makes them extremely appealing to design materials of potential technological interest. We show here how the tuning of the properties of these systems can be pursued by using appropriate molecular synthetic techniques. In particular, we focus our attention on metal polyoxolene complexes exhibiting intramolecular electron transfer processes involving either the ligand and the metal ion or the two dioxolene moieties of a properly designed ligand thus inducing electronic bistability. The transition between the two metastable electronic states can be induced by different external stimuli such as temperature, pressure, light, or pH suggesting the use of these systems for molecular switches.

  16. Active Molecular Plasmonics: Controlling Plasmon Resonances with Molecular Switches

    KAUST Repository

    Zheng, Yue Bing

    2009-02-11

    A gold nanodisk array, coated with bistable, redox-controllable [2]rotaxane molecules, when exposed to chemical oxidants and reductants, undergoes switching of its plasmonic properties reversibly. By contrast, (i) bare gold nanodisks and (ii) disks coated with a redox-active, but mechanically inert, control compound do not display surface-plasmon-based switching. Along with calculations based on time-dependent density functional theory, these experimental observations suggest that the nanoscale movements within surface-bound “molecular machines” can be used as the active components in plasmonic devices.

  17. Active Molecular Plasmonics: Controlling Plasmon Resonances with Molecular Switches

    KAUST Repository

    Zheng, Yue Bing; Yang, Ying-Wei; Jensen, Lasse; Fang, Lei; Juluri, Bala Krishna; Flood, Amar H.; Weiss, Paul S.; Stoddart, J. Fraser; Huang, Tony Jun

    2009-01-01

    A gold nanodisk array, coated with bistable, redox-controllable [2]rotaxane molecules, when exposed to chemical oxidants and reductants, undergoes switching of its plasmonic properties reversibly. By contrast, (i) bare gold nanodisks and (ii) disks coated with a redox-active, but mechanically inert, control compound do not display surface-plasmon-based switching. Along with calculations based on time-dependent density functional theory, these experimental observations suggest that the nanoscale movements within surface-bound “molecular machines” can be used as the active components in plasmonic devices.

  18. Regulated phosphorylation of the K-Cl cotransporter KCC3 is a molecular switch of intracellular potassium content and cell volume homeostasis.

    Science.gov (United States)

    Adragna, Norma C; Ravilla, Nagendra B; Lauf, Peter K; Begum, Gulnaz; Khanna, Arjun R; Sun, Dandan; Kahle, Kristopher T

    2015-01-01

    The defense of cell volume against excessive shrinkage or swelling is a requirement for cell function and organismal survival. Cell swelling triggers a coordinated homeostatic response termed regulatory volume decrease (RVD), resulting in K(+) and Cl(-) efflux via activation of K(+) channels, volume-regulated anion channels (VRACs), and the K(+)-Cl(-) cotransporters, including KCC3. Here, we show genetic alanine (Ala) substitution at threonines (Thr) 991 and 1048 in the KCC3a isoform carboxyl-terminus, preventing inhibitory phosphorylation at these sites, not only significantly up-regulates KCC3a activity up to 25-fold in normally inhibitory isotonic conditions, but is also accompanied by reversal of activity of the related bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter isoform 1 (NKCC1). This results in a rapid (90%) reduction in intracellular K(+) content (Ki) via both Cl-dependent (KCC3a + NKCC1) and Cl-independent [DCPIB (VRAC inhibitor)-sensitive] pathways, which collectively renders cells less prone to acute swelling in hypotonic osmotic stress. Together, these data demonstrate the phosphorylation state of Thr991/Thr1048 in KCC3a encodes a potent switch of transporter activity, Ki homeostasis, and cell volume regulation, and reveal novel observations into the functional interaction among ion transport molecules involved in RVD.

  19. Organic-based molecular switches for molecular electronics.

    Science.gov (United States)

    Fuentes, Noelia; Martín-Lasanta, Ana; Alvarez de Cienfuegos, Luis; Ribagorda, Maria; Parra, Andres; Cuerva, Juan M

    2011-10-05

    In a general sense, molecular electronics (ME) is the branch of nanotechnology which studies the application of molecular building blocks for the fabrication of electronic components. Among the different types of molecules, organic compounds have been revealed as promising candidates for ME, due to the easy access, great structural diversity and suitable electronic and mechanical properties. Thanks to these useful capabilities, organic molecules have been used to emulate electronic devices at the nanoscopic scale. In this feature article, we present the diverse strategies used to develop organic switches towards ME with special attention to non-volatile systems.

  20. Incremental passivity and output regulation for switched nonlinear systems

    Science.gov (United States)

    Pang, Hongbo; Zhao, Jun

    2017-10-01

    This paper studies incremental passivity and global output regulation for switched nonlinear systems, whose subsystems are not required to be incrementally passive. A concept of incremental passivity for switched systems is put forward. First, a switched system is rendered incrementally passive by the design of a state-dependent switching law. Second, the feedback incremental passification is achieved by the design of a state-dependent switching law and a set of state feedback controllers. Finally, we show that once the incremental passivity for switched nonlinear systems is assured, the output regulation problem is solved by the design of global nonlinear regulator controllers comprising two components: the steady-state control and the linear output feedback stabilising controllers, even though the problem for none of subsystems is solvable. Two examples are presented to illustrate the effectiveness of the proposed approach.

  1. Necroptosis: Modules and molecular switches with therapeutic implications.

    Science.gov (United States)

    Arora, Deepika; Sharma, Pradeep Kumar; Siddiqui, Mohammed Haris; Shukla, Yogeshwer

    2017-06-01

    Among the various programmed cell death (PCD) pathways, "Necroptosis" has gained much importance as a novel paradigm of cell death. This pathway has emerged as a backup mechanism when physiologically conserved PCD (apoptosis) is non-functional either genetically or pathogenically. The expanding spectrum of necroptosis from physiological development to diverse patho-physiological disorders, including xenobiotics-mediated toxicity has now grabbed the attention worldwide. The efficient role of necroptosis regulators in disease development and management are under constant examination. In fact, few regulators (e.g. MLKL) have already paved their way towards clinical trials and others are in queue. In this review, emphasis has been paid to the various contributing factors and molecular switches that can regulate necroptosis. Here we linked the overview of current knowledge of this enigmatic signaling with magnitude of therapeutics that may underpin the opportunities for novel therapeutic approaches to suppress the pathogenesis of necroptosis-driven disorders. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  2. DC switching regulated power supply for driving an inductive load

    Science.gov (United States)

    Dyer, George R.

    1986-01-01

    A power supply for driving an inductive load current from a dc power supply hrough a regulator circuit including a bridge arrangement of diodes and switching transistors controlled by a servo controller which regulates switching in response to the load current to maintain a selected load current. First and second opposite legs of the bridge are formed by first and second parallel-connected transistor arrays, respectively, while the third and fourth legs of the bridge are formed by appropriately connected first and second parallel connected diode arrays, respectively. The regulator may be operated in three "stages" or modes: (1) For current runup in the load, both first and second transistor switch arrays are turned "on" and current is supplied to the load through both transistor arrays. (2) When load current reaches the desired level, the first switch is turned "off", and load current "flywheels" through the second switch array and the fourth leg diode array connecting the second switch array in series with the load. Current is maintained by alternating between modes 1 and 2 at a suitable duty cycle and switching rate set by the controller. (3) Rapid current rundown is accomplished by turning both switch arrays "off", allowing load current to be dumped back into the source through the third and fourth diode arrays connecting the source in series opposition with the load to recover energy from the inductive load. The three operating states are controlled automatically by the controller.

  3. Anti-sigma factor YlaD regulates transcriptional activity of sigma factor YlaC and sporulation via manganese-dependent redox-sensing molecular switch in Bacillus subtilis.

    Science.gov (United States)

    Kwak, Min-Kyu; Ryu, Han-Bong; Song, Sung-Hyun; Lee, Jin-Won; Kang, Sa-Ouk

    2018-05-14

    YlaD, a membrane-anchored anti-sigma factor of Bacillus subtilis , contains a HX 3 CXXC motif that functions as a redox-sensing domain and belongs to one of the zinc-coordinated anti-sigma factor families. Despite previously showing that the YlaC transcription is controlled by YlaD, experimental evidence of how the YlaC-YlaD interaction is affected by active cysteines and/or metal ions is lacking. Here, we showed that the P yla promoter is autoregulated solely by YlaC. Moreover, reduced YlaD contained zinc and iron, while oxidized YlaD did not. Cysteine substitution in YlaD led to changes in its secondary structure; Cys3 had important structural functions in YlaD, and its mutation caused dissociation from YlaC, indicating the essential requirement of a HX 3 CXXC motif for regulating interactions of YlaC with YlaD. Analyses of the far-UV CD spectrum and metal content revealed that the addition of Mn ions to Zn-YlaD changed its secondary structure and that iron was substituted for manganese. The ylaC gene expression using βGlu activity from P yla : gusA was observed at the late-exponential and early-stationary phase and the ylaC -overexpressing mutant constitutively expressed gene transcripts of clpP and sigH , an important alternative sigma factor regulated by ClpXP. Collectively, our data demonstrated that YlaD senses redox changes and elicits increase in manganese ion concentrations and that, in turn, YlaD-mediated transcriptional activity of YlaC regulates sporulation initiation under oxidative stress and manganese-substituted conditions by regulating clpP gene transcripts. This is the first report of the involvement of oxidative stress-responsive B. subtilis extracytoplasmic function sigma factors during sporulation via a manganese-dependent redox-sensing molecular switch. ©2018 The Author(s).

  4. A pH-responsive molecular switch with tricolor luminescence.

    Science.gov (United States)

    Ahn, Hyungmin; Hong, Jaewan; Kim, Sung Yeon; Choi, Ilyoung; Park, Moon Jeong

    2015-01-14

    We developed a new ratiometric pH sensor based on poly(N-phenylmaleimide) (PPMI)-containing block copolymer that emits three different fluorescent colors depending on the pH. The strong solvatochromism and tautomerism of the PPMI derivatives enabled precise pH sensing for almost the entire range of the pH scale. Theoretical calculations have predicted largely dissimilar band gaps for the keto, enol, and enolate tautomers of PPMI owing to low-dimensional conjugation effects. The tunable emission wavelength and intensity of our sensors, as well as the reversible color switching with high-luminescent contrast, were achieved using rational molecular design of PPMI analogues as an innovative platform for accurate H(+) detection. The self-assembly of block copolymers on the nanometer length scale was particularly highlighted as a novel prospective means of regulating fluorescence properties while avoiding the self-quenching phenomenon, and this system can be used as a fast responsive pH sensor in versatile device forms.

  5. Action of Molecular Switches in GPCRs - Theoretical and Experimental Studies

    Science.gov (United States)

    Trzaskowski, B; Latek, D; Yuan, S; Ghoshdastider, U; Debinski, A; Filipek, S

    2012-01-01

    G protein coupled receptors (GPCRs), also called 7TM receptors, form a huge superfamily of membrane proteins that, upon activation by extracellular agonists, pass the signal to the cell interior. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed. Biochemical and crystallographic methods together with molecular dynamics simulations and other theoretical techniques provided models of the receptor activation based on the action of so-called “molecular switches” buried in the receptor structure. They are changed by agonists but also by inverse agonists evoking an ensemble of activation states leading toward different activation pathways. Switches discovered so far include the ionic lock switch, the 3-7 lock switch, the tyrosine toggle switch linked with the nPxxy motif in TM7, and the transmission switch. The latter one was proposed instead of the tryptophan rotamer toggle switch because no change of the rotamer was observed in structures of activated receptors. The global toggle switch suggested earlier consisting of a vertical rigid motion of TM6, seems also to be implausible based on the recent crystal structures of GPCRs with agonists. Theoretical and experimental methods (crystallography, NMR, specific spectroscopic methods like FRET/BRET but also single-molecule-force-spectroscopy) are currently used to study the effect of ligands on the receptor structure, location of stable structural segments/domains of GPCRs, and to answer the still open question on how ligands are binding: either via ensemble of conformational receptor states or rather via induced fit mechanisms. On the other hand the structural investigations of homo- and heterodimers and higher oligomers revealed the mechanism of allosteric signal transmission and receptor

  6. Output regulation control for switched stochastic delay systems with dissipative property under error-dependent switching

    Science.gov (United States)

    Li, L. L.; Jin, C. L.; Ge, X.

    2018-01-01

    In this paper, the output regulation problem with dissipative property for a class of switched stochastic delay systems is investigated, based on an error-dependent switching law. Under the assumption that none subsystem is solvable for the problem, a sufficient condition is derived by structuring multiple Lyapunov-Krasovskii functionals with respect to multiple supply rates, via designing error feedback regulators. The condition is also established when dissipative property reduces to passive property. Finally, two numerical examples are given to demonstrate the feasibility and efficiency of the present method.

  7. Dissipation enhanced vibrational sensing in an olfactory molecular switch

    International Nuclear Information System (INIS)

    Chęcińska, Agata; Heaney, Libby; Pollock, Felix A.; Nazir, Ahsan

    2015-01-01

    Motivated by a proposed olfactory mechanism based on a vibrationally activated molecular switch, we study electron transport within a donor-acceptor pair that is coupled to a vibrational mode and embedded in a surrounding environment. We derive a polaron master equation with which we study the dynamics of both the electronic and vibrational degrees of freedom beyond previously employed semiclassical (Marcus-Jortner) rate analyses. We show (i) that in the absence of explicit dissipation of the vibrational mode, the semiclassical approach is generally unable to capture the dynamics predicted by our master equation due to both its assumption of one-way (exponential) electron transfer from donor to acceptor and its neglect of the spectral details of the environment; (ii) that by additionally allowing strong dissipation to act on the odorant vibrational mode, we can recover exponential electron transfer, though typically at a rate that differs from that given by the Marcus-Jortner expression; (iii) that the ability of the molecular switch to discriminate between the presence and absence of the odorant, and its sensitivity to the odorant vibrational frequency, is enhanced significantly in this strong dissipation regime, when compared to the case without mode dissipation; and (iv) that details of the environment absent from previous Marcus-Jortner analyses can also dramatically alter the sensitivity of the molecular switch, in particular, allowing its frequency resolution to be improved. Our results thus demonstrate the constructive role dissipation can play in facilitating sensitive and selective operation in molecular switch devices, as well as the inadequacy of semiclassical rate equations in analysing such behaviour over a wide range of parameters

  8. Automatic Time Regulator for Switching on an Aeration Device for ...

    African Journals Online (AJOL)

    The need to aerate the pond at odd hours due to diurnal limit, save cost and human labor, necessitated the design of an automatic time regulator circuit, which controls the switching on and o of an aeration device at a pre determined and selected time interval (5mins., 10mins., 20mins., 30mins., and 40mins.) This design ...

  9. Insight into the molecular switch mechanism of human Rab5a from molecular dynamics simulations

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jing-Fang, E-mail: jfwang@gordonlifescience.org [Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China); Shanghai Center for Bioinformation Technology, 100 Qinzhou Road, Shanghai 200235 (China); Gordon Life Science Institute, 13784 Torrey Del Mar Drive, San Diego, CA 92130 (United States); Chou, Kuo-Chen [Gordon Life Science Institute, 13784 Torrey Del Mar Drive, San Diego, CA 92130 (United States)

    2009-12-18

    Rab5a is currently a most interesting target because it is responsible for regulating the early endosome fusion in endocytosis and possibly the budding process. We utilized longtime-scale molecular dynamics simulations to investigate the internal motion of the wild-type Rab5a and its A30P mutant. It was observed that, after binding with GTP, the global flexibility of the two proteins is increasing, while the local flexibility in their sensitive sites (P-loop, switch I and II regions) is decreasing. Also, the mutation of Ala30 to Pro30 can cause notable flexibility variations in the sensitive sites. However, this kind of variations is dramatically reduced after binding with GTP. Such a remarkable feature is mainly caused by the water network rearrangements in the sensitive sites. These findings might be of use for revealing the profound mechanism of the displacements of Rab5a switch regions, as well as the mechanism of the GDP dissociation and GTP association.

  10. Input filter compensation for switching regulators

    Science.gov (United States)

    Lee, F. C.; Kelkar, S. S.

    1982-01-01

    The problems caused by the interaction between the input filter, output filter, and the control loop are discussed. The input filter design is made more complicated because of the need to avoid performance degradation and also stay within the weight and loss limitations. Conventional input filter design techniques are then dicussed. The concept of pole zero cancellation is reviewed; this concept is the basis for an approach to control the peaking of the output impedance of the input filter and thus mitigate some of the problems caused by the input filter. The proposed approach for control of the peaking of the output impedance of the input filter is to use a feedforward loop working in conjunction with feedback loops, thus forming a total state control scheme. The design of the feedforward loop for a buck regulator is described. A possible implementation of the feedforward loop design is suggested.

  11. Molecular Regulation of Histamine Synthesis

    Directory of Open Access Journals (Sweden)

    Hua Huang

    2018-06-01

    Full Text Available Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis, a neurotransmitter and a regulator of gastric acid secretion. Histamine is a monoamine synthesized from the amino acid histidine through a reaction catalyzed by the enzyme histidine decarboxylase (HDC, which removes carboxyl group from histidine. Despite the importance of histamine, transcriptional regulation of HDC gene expression in mammals is still poorly understood. In this review, we focus on discussing advances in the understanding of molecular regulation of mammalian histamine synthesis.

  12. Molecular switches at the synapse emerge from receptor and kinase traffic.

    Directory of Open Access Journals (Sweden)

    2005-07-01

    Full Text Available Changes in the synaptic connection strengths between neurons are believed to play a role in memory formation. An important mechanism for changing synaptic strength is through movement of neurotransmitter receptors and regulatory proteins to and from the synapse. Several activity-triggered biochemical events control these movements. Here we use computer models to explore how these putative memory-related changes can be stabilised long after the initial trigger, and beyond the lifetime of synaptic molecules. We base our models on published biochemical data and experiments on the activity-dependent movement of a glutamate receptor, AMPAR, and a calcium-dependent kinase, CaMKII. We find that both of these molecules participate in distinct bistable switches. These simulated switches are effective for long periods despite molecular turnover and biochemical fluctuations arising from the small numbers of molecules in the synapse. The AMPAR switch arises from a novel self-recruitment process where the presence of sufficient receptors biases the receptor movement cycle to insert still more receptors into the synapse. The CaMKII switch arises from autophosphorylation of the kinase. The switches may function in a tightly coupled manner, or relatively independently. The latter case leads to multiple stable states of the synapse. We propose that similar self-recruitment cycles may be important for maintaining levels of many molecules that undergo regulated movement, and that these may lead to combinatorial possible stable states of systems like the synapse.

  13. 'Molecular switch' vectors for hypoxia- and radiation-mediated gene therapy of cancer

    International Nuclear Information System (INIS)

    Greco, O.; Marples, B.; Joiner, M.C.; Scott, S.D.

    2003-01-01

    Intratumoral areas of low oxygen concentration are known to be refractive to radiotherapy treatment. However, this physiological condition can be exploited for selective cancer gene therapy. We have developed a series of synthetic promoters selectively responsive to both hypoxia and ionizing radiation (IR). These promoters contain hypoxia regulatory elements (HREs) from the erythropoietin (Epo), the phosphoglycerate kinase1(PGK1) and vascular endothelial growth factor (VEGF) genes, and/or IR-responsive CArG elements from the Early Growth Response 1 (Egr1) gene. The HRE and CArG promoters were able to regulate expression of reporter and suicide genes in human tumor cells, following corresponding stimulation with hypoxia (0.1% O2) or X-irradiation (5Gy) [Greco et al, 2002, Gene Therapy 9:1403]. Furthermore, the chimeric HRE + CArG promoters could be activated by these stimuli independently or even more significantly when given in combination, with the Epo HRE/CArG promoter proving to be the most responsive and robust. In order to amplify and maintain transgene expression even following withdrawal of the triggering stimuli, we have developed a 'molecular switch' system [Scott et al, 2000, Gene Therapy 7:1121]. This 'switch' system has now been engineered as a single vector molecule, containing HRE and CArG promoters. This new series of HRE/CArG switch vectors have been tested in a herpes simplex thymidine kinase (HSVtk)/ganciclovir (GCV) suicide gene assay. Results indicate that a) higher and more selective tumor cell kill is achieved with the switch when compared with the HRE and CArG promoters directly driving HSVtk expression and b) the Epo HRE/CArG switch vectors appear to function as efficiently as the strong constitutive cytomegalovirus (CMV) promoter construct

  14. Switching dynamics in reaction networks induced by molecular discreteness

    International Nuclear Information System (INIS)

    Togashi, Yuichi; Kaneko, Kunihiko

    2007-01-01

    To study the fluctuations and dynamics in chemical reaction processes, stochastic differential equations based on the rate equation involving chemical concentrations are often adopted. When the number of molecules is very small, however, the discreteness in the number of molecules cannot be neglected since the number of molecules must be an integer. This discreteness can be important in biochemical reactions, where the total number of molecules is not significantly larger than the number of chemical species. To elucidate the effects of such discreteness, we study autocatalytic reaction systems comprising several chemical species through stochastic particle simulations. The generation of novel states is observed; it is caused by the extinction of some molecular species due to the discreteness in their number. We demonstrate that the reaction dynamics are switched by a single molecule, which leads to the reconstruction of the acting network structure. We also show the strong dependence of the chemical concentrations on the system size, which is caused by transitions to discreteness-induced novel states

  15. Communication over the network of binary switches regulates the activation of A2A adenosine receptor.

    Directory of Open Access Journals (Sweden)

    Yoonji Lee

    2015-02-01

    Full Text Available Dynamics and functions of G-protein coupled receptors (GPCRs are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ~ 5 μsec molecular dynamics simulations of A2A adenosine receptor (A2AAR in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs "binary switches" as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield 2(10 microstates, we show that (i the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii among the three receptor states the apo state explores the broadest range of microstates; (iii in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation. Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.

  16. Light-Triggered Control of Plasmonic Refraction and Group Delay by Photochromic Molecular Switches

    DEFF Research Database (Denmark)

    Großmann, Malte; Klick, Alwin; Lemke, Christoph

    2015-01-01

    An interface supporting plasmonic switching is prepared from a gold substrate coated with a polymerfilm doped with photochromic molecular switches. A reversible light-induced change in the surface plasmon polariton dispersion curve of the interface is experimentally demonstrated, evidencing...... complex functionalities based on surface plasmon refraction and group delay....

  17. Molecular imaging of transcriptional regulation during inflammation

    Directory of Open Access Journals (Sweden)

    Carlsen Harald

    2010-04-01

    Full Text Available Abstract Molecular imaging enables non-invasive visualization of the dynamics of molecular processes within living organisms in vivo. Different imaging modalities as MRI, SPECT, PET and optic imaging are used together with molecular probes specific for the biological process of interest. Molecular imaging of transcription factor activity is done in animal models and mostly in transgenic reporter mice, where the transgene essentially consists of a promoter that regulates a reporter gene. During inflammation, the transcription factor NF-κB is widely involved in orchestration and regulation of the immune system and almost all imaging studies in this field has revolved around the role and regulation of NF-κB. We here present a brief introduction to experimental use and design of transgenic reporter mice and a more extensive review of the various studies where molecular imaging of transcriptional regulation has been applied during inflammation.

  18. Ab initio investigation of the switching behavior of the dithiole-benzene nano-molecular wire

    International Nuclear Information System (INIS)

    Darvish Ganji, M.; Rungger, I.

    2008-01-01

    We report a first-principle study of electrical transport and switching behavior in a single molecular conductor consisting of a dithiole-benzene sandwiched between two Au( 100) electrodes. Ab initio total energy calculations reveal dithiole-benzene molecules on a gold surface, contacted by a monoatomic gold scanning tunneling microscope tip to have two classes of low energy conformations with differing symmetries. Lateral motion of the tip or excitation of the molecule cause it 10 change from one conformation class to the other and to switch between a strongly and a weakly conducting state. Thus, surprisingly. despite their apparent simplicity, these Au-dithiole-benzene -Au nano wires are shown to be electrically bi-stable switches, the smallest two-terminal molecular switches to date. The projected density of states and transmission coefficients are analyzed, and it suggests that the variation of the coupling between the molecule and the electrodes with external bias leads to switching behavior

  19. First-principles study of the electronic transport properties of the anthraquinone-based molecular switch

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, P., E-mail: ss_zhaop@ujn.edu.c [School of Science, University of Jinan, Jinan 250022 (China); Liu, D.S. [School of Physics, State Key Laboratory of Crystal Materials, Shandong University, Jinan 250100 (China); Department of Physics, Jining University, Qufu 273155 (China); Wang, P.J.; Zhang, Z. [School of Science, University of Jinan, Jinan 250022 (China); Fang, C.F.; Ji, G.M. [School of Physics, State Key Laboratory of Crystal Materials, Shandong University, Jinan 250100 (China)

    2011-02-15

    By applying non-equilibrium Green's function (NEGF) formalism combined with first-principles density functional theory (DFT), we have investigated the electronic transport properties of the anthraquinone-based molecular switch. The molecule that comprises the switch can be converted between the hydroquinone (HQ) and anthraquinone (AQ) forms via redox reactions. The transmission spectra of these two forms are remarkably distinctive. Our results show that the current through the HQ form is significantly larger than that through the AQ form, which suggests that this system has attractive potential application in future molecular switch technology.

  20. First-principles study of the electronic transport properties of the anthraquinone-based molecular switch

    International Nuclear Information System (INIS)

    Zhao, P.; Liu, D.S.; Wang, P.J.; Zhang, Z.; Fang, C.F.; Ji, G.M.

    2011-01-01

    By applying non-equilibrium Green's function (NEGF) formalism combined with first-principles density functional theory (DFT), we have investigated the electronic transport properties of the anthraquinone-based molecular switch. The molecule that comprises the switch can be converted between the hydroquinone (HQ) and anthraquinone (AQ) forms via redox reactions. The transmission spectra of these two forms are remarkably distinctive. Our results show that the current through the HQ form is significantly larger than that through the AQ form, which suggests that this system has attractive potential application in future molecular switch technology.

  1. Tlx acts as a proangiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes.

    Science.gov (United States)

    Uemura, Akiyoshi; Kusuhara, Sentaro; Wiegand, Stanley J; Yu, Ruth T; Nishikawa, Shin-ichi

    2006-02-01

    In response to hypoxia, hypoxia-inducible factors act as the primary proangiogenic triggers by regulating transcription levels of target genes, including VEGF. However, little is known about the specific factors that control other components of the angiogenic process, particularly formation of matrix scaffolds that promote adhesion and migration of endothelial cells. We show that in the postnatal mouse retina, the orphan nuclear receptor tailless (Tlx) is strongly expressed in the proangiogenic astrocytes, which secrete VEGF and fibronectin. Tlx expression by retinal astrocytes is controlled by oxygen concentration and rapidly downregulated upon contact with blood vessels. In mice null for Tlx, retinal astrocytes maintain VEGF expression; however, the extracellular assembly of fibronectin matrices by astrocytes is severely impaired, leading to defective scaffold formation and a complete failure of normal retinal vascular development. This work identifies Tlx as an essential component of the molecular network involved in the hypoxia-inducible proangiogenic switch in retinal astrocytes.

  2. Pension Funds and the Impact of Switching Regulation on Long-Term Investment

    OpenAIRE

    Pedraza Morales, Alvaro Enrique; Fuentes, Olga; Searle, Pamela; Stewart, Fiona

    2017-01-01

    This paper looks at the impact of members' ability to switch pension fund provider and /or portfolio on the allocation of pension funds to long-term investments. The level of annual turnover in pension fund portfolios was compared with the amount of short-term investments (using government treasury bills and bank deposits as proxy). The investment regulations around switching and other mar...

  3. The stochastic behavior of a molecular switching circuit with feedback

    Directory of Open Access Journals (Sweden)

    Smith Eric

    2007-05-01

    Full Text Available Abstract Background Using a statistical physics approach, we study the stochastic switching behavior of a model circuit of multisite phosphorylation and dephosphorylation with feedback. The circuit consists of a kinase and phosphatase acting on multiple sites of a substrate that, contingent on its modification state, catalyzes its own phosphorylation and, in a symmetric scenario, dephosphorylation. The symmetric case is viewed as a cartoon of conflicting feedback that could result from antagonistic pathways impinging on the state of a shared component. Results Multisite phosphorylation is sufficient for bistable behavior under feedback even when catalysis is linear in substrate concentration, which is the case we consider. We compute the phase diagram, fluctuation spectrum and large-deviation properties related to switch memory within a statistical mechanics framework. Bistability occurs as either a first-order or second-order non-equilibrium phase transition, depending on the network symmetries and the ratio of phosphatase to kinase numbers. In the second-order case, the circuit never leaves the bistable regime upon increasing the number of substrate molecules at constant kinase to phosphatase ratio. Conclusion The number of substrate molecules is a key parameter controlling both the onset of the bistable regime, fluctuation intensity, and the residence time in a switched state. The relevance of the concept of memory depends on the degree of switch symmetry, as memory presupposes information to be remembered, which is highest for equal residence times in the switched states. Reviewers This article was reviewed by Artem Novozhilov (nominated by Eugene Koonin, Sergei Maslov, and Ned Wingreen.

  4. Building muscle: molecular regulation of myogenesis.

    Science.gov (United States)

    Bentzinger, C Florian; Wang, Yu Xin; Rudnicki, Michael A

    2012-02-01

    The genesis of skeletal muscle during embryonic development and postnatal life serves as a paradigm for stem and progenitor cell maintenance, lineage specification, and terminal differentiation. An elaborate interplay of extrinsic and intrinsic regulatory mechanisms controls myogenesis at all stages of development. Many aspects of adult myogenesis resemble or reiterate embryonic morphogenetic episodes, and related signaling mechanisms control the genetic networks that determine cell fate during these processes. An integrative view of all aspects of myogenesis is imperative for a comprehensive understanding of muscle formation. This article provides a holistic overview of the different stages and modes of myogenesis with an emphasis on the underlying signals, molecular switches, and genetic networks.

  5. Molecular Mechanisms of Appetite Regulation

    Directory of Open Access Journals (Sweden)

    Ji Hee Yu

    2012-12-01

    Full Text Available The prevalence of obesity has been rapidly increasing worldwide over the last several decades and has become a major health problem in developed countries. The brain, especially the hypothalamus, plays a key role in the control of food intake by sensing metabolic signals from peripheral organs and modulating feeding behaviors. To accomplish these important roles, the hypothalamus communicates with other brain areas such as the brainstem and reward-related limbic pathways. The adipocyte-derived hormone leptin and pancreatic β-cell-derived insulin inform adiposity to the hypothalamus. Gut hormones such as cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1, and oxyntomodulin transfer satiety signals to the brain and ghrelin relays hunger signals. The endocannabinoid system and nutrients are also involved in the physiological regulation of food intake. In this article, we briefly review physiological mechanisms of appetite regulation.

  6. Immobilizing Organic-Based Molecular Switches into Metal-Organic Frameworks: A Promising Strategy for Switching in Solid State.

    Science.gov (United States)

    Gui, Bo; Meng, Yi; Xie, Yang; Du, Ke; Sue, Andrew C-H; Wang, Cheng

    2018-01-01

    Organic-based molecular switches (OMS) are essential components for the ultimate miniaturization of nanoscale electronics and devices. For practical applications, it is often necessary for OMS to be incorporated into functional solid-state materials. However, the switching characteristics of OMS in solution are usually not transferrable to the solid state, presumably because of spatial confinement or inefficient conversion in densely packed solid phase. A promising way to circumvent this issue is harboring the functional OMS within the robust and porous environment of metal-organic frameworks (MOFs) as their organic components. In this feature article, recent research progress of OMS-based MOFs is briefly summarized. The switching behaviors of OMS under different stimuli (e.g., light, redox, pH, etc.) in the MOF state are first introduced. After that, the technological applications of these OMS-based MOFs in different areas, including CO 2 adsorption, gas separation, drug delivery, photodynamic therapy, and sensing, are outlined. Finally, perspectives and future challenges are discussed in the conclusion. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Engineered elastomeric proteins with dual elasticity can be controlled by a molecular regulator.

    Science.gov (United States)

    Cao, Yi; Li, Hongbin

    2008-08-01

    Elastomeric proteins are molecular springs that confer excellent mechanical properties to many biological tissues and biomaterials. Depending on the role performed by the tissue or biomaterial, elastomeric proteins can behave as molecular springs or shock absorbers. Here we combine single-molecule atomic force microscopy and protein engineering techniques to create elastomeric proteins that can switch between two distinct types of mechanical behaviour in response to the binding of a molecular regulator. The proteins are mechanically labile by design and behave as entropic springs with an elasticity that is governed by their configurational entropy. However, when a molecular regulator binds to the protein, it switches into a mechanically stable state and can act as a shock absorber. These engineered proteins effectively mimic and combine the two extreme forms of elastic behaviour found in natural elastomeric proteins, and thus represent a new type of smart nanomaterial that will find potential applications in nanomechanics and material sciences.

  8. Identification and Characterization of Wor4, a New Transcriptional Regulator of White-Opaque Switching

    Directory of Open Access Journals (Sweden)

    Matthew B. Lohse

    2016-03-01

    Full Text Available The human fungal pathogen Candida albicans can switch between two cell types, “white” and “opaque,” each of which is heritable through many cell divisions. Switching between these two cell types is regulated by six transcriptional regulators that form a highly interconnected circuit with multiple feedback loops. Here, we identify a seventh regulator of white-opaque switching, which we have named Wor4. We show that ectopic expression of Wor4 is sufficient to drive switching from the white to the opaque cell type, and that deletion of Wor4 blocks switching from the white to the opaque cell type. A combination of ectopic expression and deletion experiments indicates that Wor4 is positioned upstream of Wor1, and that it is formally an activator of the opaque cell type. The combination of ectopic expression and deletion phenotypes for Wor4 is unique; none of the other six white-opaque regulators show this pattern. We determined the pattern of Wor4 binding across the genome by ChIP-seq and found it is highly correlated with that of Wor1 and Wor2, indicating that Wor4 is tightly integrated into the existing white-opaque regulatory circuit. We previously proposed that white-to-opaque switching relies on the activation of a complex circuit of feedback loops that remains excited through many cell divisions. The identification of a new, central regulator of white-opaque switching supports this idea by indicating that the white-opaque switching mechanism is considerably more complex than those controlling conventional, nonheritable patterns of gene expression.

  9. Hydrochromic molecular switches for water-jet rewritable paper

    Science.gov (United States)

    Sheng, Lan; Li, Minjie; Zhu, Shaoyin; Li, Hao; Xi, Guan; Li, Yong-Gang; Wang, Yi; Li, Quanshun; Liang, Shaojun; Zhong, Ke; Zhang, Sean Xiao-An

    2014-01-01

    The days of rewritable paper are coming, printers of the future will use water-jet paper. Although several kinds of rewritable paper have been reported, practical usage of them is rare. Herein, a new rewritable paper for ink-free printing is proposed and demonstrated successfully by using water as the sole trigger to switch hydrochromic dyes on solid media. Water-jet prints with various colours are achieved with a commercial desktop printer based on these hydrochromic rewritable papers. The prints can be erased and rewritten dozens of times with no significant loss in colour quality. This rewritable paper is promising in that it can serve an eco-friendly information display to meet the increasing global needs for environmental protection.

  10. Temperature control of molecular circuit switch responsible for virulent phenotype expression in uropathogenic Escherichia coli

    Science.gov (United States)

    Samoilov, Michael

    2010-03-01

    The behavior and fate of biological organisms are to a large extent dictated by their environment, which can be often viewed as a collection of features and constraints governed by physics laws. Since biological systems comprise networks of molecular interactions, one such key physical property is temperature, whose variations directly affect the rates of biochemical reactions involved. For instance, temperature is known to control many gene regulatory circuits responsible for pathogenicity in bacteria. One such example is type 1 fimbriae (T1F) -- the foremost virulence factor in uropathogenic E. coli (UPEC), which accounts for 80-90% of all community-acquired urinary tract infections (UTIs). The expression of T1F is randomly `phase variable', i.e. individual cells switch between virulent/fimbriate and avirulent/afimbriate phenotypes, with rates regulated by temperature. Our computational investigation of this process, which is based on FimB/FimE recombinase-mediated inversion of fimS DNA element, offers new insights into its discrete-stochastic kinetics. In particular, it elucidates the logic of T1F control optimization to the host temperature and contributes further understanding toward the development of novel therapeutic approaches to UPEC-caused UTIs.

  11. Adsorption and switching properties of a N-benzylideneaniline based molecular switch on a Au(111) surface

    International Nuclear Information System (INIS)

    Ovari, Laszlo; Luo, Ying; Haag, Rainer; Leyssner, Felix; Tegeder, Petra; Wolf, Martin

    2010-01-01

    High resolution electron energy loss spectroscopy has been employed to analyze the adsorption geometry and the photoisomerization ability of the molecular switch carboxy-benzylideneaniline (CBA) adsorbed on Au(111). CBA on Au(111) adopts a planar (trans) configuration in the first monolayer (ML) as well as for higher coverages (up to 6 ML), in contrast to the strongly nonplanar geometry of the molecule in solution. Illumination with UV light of CBA in direct contact with the Au(111) surface (≤1 ML) caused no changes in the vibrational structure, whereas at higher coverages (>1 ML) pronounced modifications of vibrational features were observed, which we assign to a trans→cis isomerization. Thermal activation induced the back reaction to trans-CBA. We propose that the photoisomerization is driven by a direct (intramolecular) electronic excitation of the adsorbed CBA molecules in the second ML (and above) analogous to CBA in the liquid phase.

  12. Models of charge transport and transfer in molecular switch tunnel junctions of bistable catenanes and rotaxanes

    International Nuclear Information System (INIS)

    Flood, Amar H.; Wong, Eric W.; Stoddart, J. Fraser

    2006-01-01

    The processes by which charge transfer can occur play a foundational role in molecular electronics. Here we consider simplified models of the transfer processes that could be present in bistable molecular switch tunnel junction (MSTJ) devices during one complete cycle of the device from its low- to high- and back to low-conductance state. The bistable molecular switches, which are composed of a monolayer of either switchable catenanes or rotaxanes, exist in either a ground-state co-conformation or a metastable one in which the conduction properties of the two co-conformations, when measured at small biases (+0.1 V), are significantly different irrespective of whether transport is dominated by tunneling or hopping. The voltage-driven generation (±2 V) of molecule-based redox states, which are sufficiently long-lived to allow the relative mechanical movements necessary to switch between the two co-conformations, rely upon unequal charge transfer rates on to and/or off of the molecules. Surface-enhanced Raman spectroscopy has been used to image the ground state of the bistable rotaxane in MSTJ-like devices. Consideration of these models provide new ways of looking at molecular electronic devices that rely, not only on nanoscale charge-transport, but also upon the bustling world of molecular motion in mechanically interlocked bistable molecules

  13. Investigation of a metal-organic interface. Realization and understanding of a molecular switch

    Energy Technology Data Exchange (ETDEWEB)

    Neucheva, Olga [Forschungszentrum Juelich (DE). Institute of Bio- and Nanosystems (IBN), Functional Nanostructures at Surfaces (IBN-3)

    2010-07-01

    The field of molecular organic electronics is an emerging and very dynamic area. The continued trend to miniaturisation, combined with increasing complexity and cost of production in conventional semiconductor electronics, forces companies to turn their attention to alternatives that promise the next levels of scale at significantly lower cost. After consumer electronic devices based on organic transistors, such as TVs and book readers, have already been presented, molecular electronics is expected to offer the next breakthrough in feature size. Unfortunately, most of the organic/metal interfaces contain intrinsic defects that break the homogeneity of the interface properties. In this thesis, the electronic and structural properties of such defects were examined in order to understand the influence of the inhomogeneities on the quality of the interface layer. However, the main focus of this work was the investigation of the local properties of a single molecule. Taking advantage of the Scanning Tunnelling Microscope's (STM's) ability to act as a local probe, a single molecular switch was realized and studied. Moreover, in close collaboration with theory groups, the underlying mechanism driving the switching process was identified and described. Besides the investigation of the switching process, the ability of the STM to build nanostructures of different shapes from large organic molecules was shown. Knowing the parameters for realization and control of the switching process and for building the molecular corrals, the results of this investigation enable the reconstruction of the studied molecular ensemble and its deployment in electric molecular circuits, constituting a next step towards further miniaturization of electronic devices. (orig.)

  14. The g0/g1 switch gene 2 is an important regulator of hepatic triglyceride metabolism.

    Science.gov (United States)

    Wang, Yinfang; Zhang, Yahui; Qian, Hang; Lu, Juan; Zhang, Zhifeng; Min, Xinwen; Lang, Mingjian; Yang, Handong; Wang, Nanping; Zhang, Peng

    2013-01-01

    Nonalcoholic fatty liver disease is associated with obesity and insulin resistance. Factors that regulate the disposal of hepatic triglycerides contribute to the development of hepatic steatosis. G0/G1 switch gene 2 (G0S2) is a target of peroxisome proliferator-activated receptors and plays an important role in regulating lipolysis in adipocytes. Therefore, we investigated whether G0S2 plays a role in hepatic lipid metabolism. Adenovirus-mediated expression of G0S2 (Ad-G0S2) potently induced fatty liver in mice. The liver mass of Ad-G0S2-infected mice was markedly increased with excess triglyceride content compared to the control mice. G0S2 did not change cellular cholesterol levels in hepatocytes. G0S2 was found to be co-localized with adipose triglyceride lipase at the surface of lipid droplets. Hepatic G0S2 overexpression resulted in an increase in plasma Low-density lipoprotein (LDL)/Very-Low-density (VLDL) lipoprotein cholesterol level. Plasma High-density lipoprotein (HDL) cholesterol and ketone body levels were slightly decreased in Ad-G0S2 injected mice. G0S2 also increased the accumulation of neutral lipids in cultured HepG2 and L02 cells. However, G0S2 overexpression in the liver significantly improved glucose tolerance in mice. Livers expressing G0S2 exhibited increased 6-(N-(7-nitrobenz-2-oxa-1-3-diazol-4-yl) amino)-6-deoxyglucose uptake compared with livers transfected with control adenovirus. Taken together, our results provide evidence supporting an important role for G0S2 as a regulator of triglyceride content in the liver and suggest that G0S2 may be a molecular target for the treatment of insulin resistance and other obesity-related metabolic disorders.

  15. Ab initio theory for current-induced molecular switching: Melamine on Cu(001)

    KAUST Repository

    Ohto, Tatsuhiko

    2013-05-28

    Melamine on Cu(001) is mechanically unstable under the current of a scanning tunneling microscope tip and can switch among configurations. However, these are not equally accessible, and the switching critical current depends on the bias polarity. In order to explain such rich phenomenology, we have developed a scheme to evaluate the evolution of the reaction paths and activation barriers as a function of bias, which is rooted in the nonequilibrium Green\\'s function method implemented within density functional theory. This, combined with the calculation of the inelastic electron tunneling spectroscopy signal, allows us to identify the vibrational modes promoting the observed molecular conformational changes. Finally, once our ab initio results are used within a resonance model, we are able to explain the details of the switching behavior, such as its dependence on the bias polarity, and the noninteger power relation between the reaction rate constants and both the bias voltage and the electric current. © 2013 American Physical Society.

  16. The importance of the rotor in hydrazone-based molecular switches

    Directory of Open Access Journals (Sweden)

    Xin Su

    2012-06-01

    Full Text Available The pH-activated E/Z isomerization of a series of hydrazone-based systems having different functional groups as part of the rotor (R = COMe, CN, Me, H, was studied. The switching efficiency of these systems was compared to that of a hydrazone-based molecular switch (R = COOEt whose E/Z isomerization is fully reversible. It was found that the nature of the R group is critical for efficient switching to occur; the R group should be a moderate H-bond acceptor in order to (i provide enough driving force for the rotor to move upon protonation, and (ii stabilize the obtained Z configuration, to achieve full conversion.

  17. Ab initio theory for current-induced molecular switching: Melamine on Cu(001)

    KAUST Repository

    Ohto, Tatsuhiko; Rungger, Ivan; Yamashita, Koichi; Nakamura, Hisao; Sanvito, Stefano

    2013-01-01

    Melamine on Cu(001) is mechanically unstable under the current of a scanning tunneling microscope tip and can switch among configurations. However, these are not equally accessible, and the switching critical current depends on the bias polarity. In order to explain such rich phenomenology, we have developed a scheme to evaluate the evolution of the reaction paths and activation barriers as a function of bias, which is rooted in the nonequilibrium Green's function method implemented within density functional theory. This, combined with the calculation of the inelastic electron tunneling spectroscopy signal, allows us to identify the vibrational modes promoting the observed molecular conformational changes. Finally, once our ab initio results are used within a resonance model, we are able to explain the details of the switching behavior, such as its dependence on the bias polarity, and the noninteger power relation between the reaction rate constants and both the bias voltage and the electric current. © 2013 American Physical Society.

  18. Single molecular switch based on thiol tethered iron(II)clathrochelate on gold

    Energy Technology Data Exchange (ETDEWEB)

    Viswanathan, Subramanian [Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-747 Olsztyn (Poland); Voloshin, Yan Z. [Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences, 119991 Moscow (Russian Federation); Radecka, Hanna [Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-747 Olsztyn (Poland); Radecki, Jerzy [Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-747 Olsztyn (Poland)], E-mail: radecki@pan.olsztyn.pl

    2009-09-30

    Molecular electronics has been associated with high density nano-electronic devices. Developments of molecular electronic devices were based on reversible switching of molecules between the two conductive states. In this paper, self-assembled monolayers of dodecanethiol (DDT) and thiol tethered iron(II)clathrochelate (IC) have been prepared on gold film. The electrochemical and electronic properties of IC molecules inserted into the dodecanethiol monolayer (IC-DDT SAM) were investigated using voltammetric, electrochemical impedance spectroscopy (EIS), scanning tunneling microscopy (STM) and cross-wire tunneling measurements. The voltage triggered switching behaviour of IC molecules on mixed SAM was demonstrated. Deposition of polyaniline on the redox sites of IC-DDT SAM using electrochemical polymerization of aniline was performed in order to confirm that this monolayer acts as nano-patterned semiconducting electrode surface.

  19. Magnetic Switching of a Single Molecular Magnet due to Spin-Polarized Current

    OpenAIRE

    Misiorny, Maciej; Barnas, Józef

    2006-01-01

    Magnetic switching of a single molecular magnet (SMM) due to spin-polarized current flowing between ferromagnetic metallic electrodes is investigated theoretically. Magnetic moments of the electrodes are assumed to be collinear and parallel to the magnetic easy axis of the molecule. Electrons tunneling through a barrier between magnetic leads are coupled to the SMM via exchange interaction. The current flowing through the system as well as the spin relaxation times of the SMM are calculated f...

  20. Electrochemical control of quantum interference in anthraquinone-based molecular switches

    DEFF Research Database (Denmark)

    Markussen, Troels; Schiøtz, Jakob; Thygesen, Kristian Sommer

    2010-01-01

    Using first-principles calculations we analyze the electronic transport properties of a recently proposed anthraquinone-based electrochemical switch. Robust conductance on/off ratios of several orders of magnitude are observed due to destructive quantum interference present in the anthraquinone...... of hopping via the localized orbitals. The topology of the tight-binding model, which is dictated by the symmetries of the molecular orbitals, determines the amount of quantum interference....

  1. Heme-dependent Metabolite Switching Regulates H2S Synthesis in Response to Endoplasmic Reticulum (ER) Stress.

    Science.gov (United States)

    Kabil, Omer; Yadav, Vinita; Banerjee, Ruma

    2016-08-05

    Substrate ambiguity and relaxed reaction specificity underlie the diversity of reactions catalyzed by the transsulfuration pathway enzymes, cystathionine β-synthase (CBS) and γ-cystathionase (CSE). These enzymes either commit sulfur metabolism to cysteine synthesis from homocysteine or utilize cysteine and/or homocysteine for synthesis of H2S, a signaling molecule. We demonstrate that a kinetically controlled heme-dependent metabolite switch in CBS regulates these competing reactions where by cystathionine, the product of CBS, inhibits H2S synthesis by the second enzyme, CSE. Under endoplasmic reticulum stress conditions, induction of CSE and up-regulation of the CBS inhibitor, CO, a product of heme oxygenase-1, flip the operating preference of CSE from cystathionine to cysteine, transiently stimulating H2S production. In contrast, genetic deficiency of CBS leads to chronic stimulation of H2S production. This metabolite switch from cystathionine to cysteine and/or homocysteine renders H2S synthesis by CSE responsive to the known modulators of CBS: S-adenosylmethionine, NO, and CO. Used acutely, it regulates H2S synthesis; used chronically, it might contribute to disease pathology. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Research Update: Molecular electronics: The single-molecule switch and transistor

    Directory of Open Access Journals (Sweden)

    Kai Sotthewes

    2014-01-01

    Full Text Available In order to design and realize single-molecule devices it is essential to have a good understanding of the properties of an individual molecule. For electronic applications, the most important property of a molecule is its conductance. Here we show how a single octanethiol molecule can be connected to macroscopic leads and how the transport properties of the molecule can be measured. Based on this knowledge we have realized two single-molecule devices: a molecular switch and a molecular transistor. The switch can be opened and closed at will by carefully adjusting the separation between the electrical contacts and the voltage drop across the contacts. This single-molecular switch operates in a broad temperature range from cryogenic temperatures all the way up to room temperature. Via mechanical gating, i.e., compressing or stretching of the octanethiol molecule, by varying the contact's interspace, we are able to systematically adjust the conductance of the electrode-octanethiol-electrode junction. This two-terminal single-molecule transistor is very robust, but the amplification factor is rather limited.

  3. The limiting dynamics of a bistable molecular switch with and without noise.

    Science.gov (United States)

    Mackey, Michael C; Tyran-Kamińska, Marta

    2016-08-01

    We consider the dynamics of a population of organisms containing two mutually inhibitory gene regulatory networks, that can result in a bistable switch-like behaviour. We completely characterize their local and global dynamics in the absence of any noise, and then go on to consider the effects of either noise coming from bursting (transcription or translation), or Gaussian noise in molecular degradation rates when there is a dominant slow variable in the system. We show analytically how the steady state distribution in the population can range from a single unimodal distribution through a bimodal distribution and give the explicit analytic form for the invariant stationary density which is globally asymptotically stable. Rather remarkably, the behaviour of the stationary density with respect to the parameters characterizing the molecular behaviour of the bistable switch is qualitatively identical in the presence of noise coming from bursting as well as in the presence of Gaussian noise in the degradation rate. This implies that one cannot distinguish between either the dominant source or nature of noise based on the stationary molecular distribution in a population of cells. We finally show that the switch model with bursting but two dominant slow genes has an asymptotically stable stationary density.

  4. Transient Evolutional Dynamics of Quantum-Dot Molecular Phase Coherence for Sensitive Optical Switching

    Science.gov (United States)

    Shen, Jian Qi; Gu, Jing

    2018-04-01

    Atomic phase coherence (quantum interference) in a multilevel atomic gas exhibits a number of interesting phenomena. Such an atomic quantum coherence effect can be generalized to a quantum-dot molecular dielectric. Two quantum dots form a quantum-dot molecule, which can be described by a three-level Λ-configuration model { |0> ,|1> ,|2> } , i.e., the ground state of the molecule is the lower level |0> and the highly degenerate electronic states in the two quantum dots are the two upper levels |1> ,|2> . The electromagnetic characteristics due to the |0>-|1> transition can be controllably manipulated by a tunable gate voltage (control field) that drives the |2>-|1> transition. When the gate voltage is switched on, the quantum-dot molecular state can evolve from one steady state (i.e., |0>-|1> two-level dressed state) to another steady state (i.e., three-level coherent-population-trapping state). In this process, the electromagnetic characteristics of a quantum-dot molecular dielectric, which is modified by the gate voltage, will also evolve. In this study, the transient evolutional behavior of the susceptibility of a quantum-dot molecular thin film and its reflection spectrum are treated by using the density matrix formulation of the multilevel systems. The present field-tunable and frequency-sensitive electromagnetic characteristics of a quantum-dot molecular thin film, which are sensitive to the applied gate voltage, can be utilized to design optical switching devices.

  5. Magnetic switching of a single molecular magnet due to spin-polarized current

    Science.gov (United States)

    Misiorny, Maciej; Barnaś, Józef

    2007-04-01

    Magnetic switching of a single molecular magnet (SMM) due to spin-polarized current flowing between ferromagnetic metallic leads (electrodes) is investigated theoretically. Magnetic moments of the leads are assumed to be collinear and parallel to the magnetic easy axis of the molecule. Electrons tunneling through the barrier between magnetic leads are coupled to the SMM via exchange interaction. The current flowing through the system, as well as the spin relaxation times of the SMM, are calculated from the Fermi golden rule. It is shown that spin of the SMM can be reversed by applying a certain voltage between the two magnetic electrodes. Moreover, the switching may be visible in the corresponding current-voltage characteristics.

  6. Transient photocurrent in molecular junctions: singlet switching on and triplet blocking.

    Science.gov (United States)

    Petrov, E G; Leonov, V O; Snitsarev, V

    2013-05-14

    The kinetic approach adapted to describe charge transmission in molecular junctions, is used for the analysis of the photocurrent under conditions of moderate light intensity of the photochromic molecule. In the framework of the HOMO-LUMO model for the single electron molecular states, the analytic expressions describing the temporary behavior of the transient and steady state sequential (hopping) as well as direct (tunnel) current components have been derived. The conditions at which the current components achieve their maximal values are indicated. It is shown that if the rates of charge transmission in the unbiased molecular diode are much lower than the intramolecular singlet-singlet excitation/de-excitation rate, and the threefold degenerated triplet excited state of the molecule behaves like a trap blocking the charge transmission, a possibility of a large peak-like transient switch-on photocurrent arises.

  7. Charge carrier transport on molecular wire controlled by dipolar species: towards light-driven molecular switch

    Czech Academy of Sciences Publication Activity Database

    Nešpůrek, Stanislav; Toman, Petr; Sworakowski, J.

    438-439, - (2003), s. 268-278 ISSN 0040-6090. [International Conference on Nano- Molecular Electronics /5./. Kobe, 10.12.2002-12.12.2002] R&D Projects: GA AV ČR KSK4050111 Keywords : molecular electronics * polymers * quantum effects Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 1.598, year: 2003

  8. Molecular regulation of plant cell wall extensibility

    Science.gov (United States)

    Cosgrove, D. J.

    1998-01-01

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

  9. 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....

  10. Committing to coal and gas: Long-term contracts, regulation, and fuel switching in power generation

    Science.gov (United States)

    Rice, Michael

    Fuel switching in the electricity sector has important economic and environmental consequences. In the United States, the increased supply of gas during the last decade has led to substantial switching in the short term. Fuel switching is constrained, however, by the existing infrastructure. The power generation infrastructure, in turn, represents commitments to specific sources of energy over the long term. This dissertation explores fuel contracts as the link between short-term price response and long-term plant investments. Contracting choices enable power plant investments that are relationship-specific, often regulated, and face uncertainty. Many power plants are subject to both hold-up in investment and cost-of-service regulation. I find that capital bias is robust when considering either irreversibility or hold-up due to the uncertain arrival of an outside option. For sunk capital, the rental rate is inappropriate for determining capital bias. Instead, capital bias depends on the regulated rate of return, discount rate, and depreciation schedule. If policies such as emissions regulations increase fuel-switching flexibility, this can lead to capital bias. Cost-of-service regulation can shorten the duration of a long-term contract. From the firm's perspective, the existing literature provides limited guidance when bargaining and writing contracts for fuel procurement. I develop a stochastic programming framework to optimize long-term contracting decisions under both endogenous and exogenous sources of hold-up risk. These typically include policy changes, price shocks, availability of fuel, and volatility in derived demand. For price risks, the optimal contract duration is the moment when the expected benefits of the contract are just outweighed by the expected opportunity costs of remaining in the contract. I prove that imposing early renegotiation costs decreases contract duration. Finally, I provide an empirical approach to show how coal contracts can limit

  11. Analysis and design of a standardized control module for switching regulators

    Science.gov (United States)

    Lee, F. C.; Mahmoud, M. F.; Yu, Y.; Kolecki, J. C.

    1982-07-01

    Three basic switching regulators: buck, boost, and buck/boost, employing a multiloop standardized control module (SCM) were characterized by a common small signal block diagram. Employing the unified model, regulator performances such as stability, audiosusceptibility, output impedance, and step load transient are analyzed and key performance indexes are expressed in simple analytical forms. More importantly, the performance characteristics of all three regulators are shown to enjoy common properties due to the unique SCM control scheme which nullifies the positive zero and provides adaptive compensation to the moving poles of the boost and buck/boost converters. This allows a simple unified design procedure to be devised for selecting the key SCM control parameters for an arbitrarily given power stage configuration and parameter values, such that all regulator performance specifications can be met and optimized concurrently in a single design attempt.

  12. Role of melatonin combined with exercise as a switch-like regulator for circadian behavior in advanced osteoarthritic knee.

    Science.gov (United States)

    Hong, Yunkyung; Kim, Hyunsoo; Lee, Seunghoon; Jin, Yunho; Choi, Jeonghyun; Lee, Sang-Rae; Chang, Kyu-Tae; Hong, Yonggeun

    2017-11-14

    Here, we show the role of melatonin combined with or without exercise as a determinant of multicellular behavior in osteoarthritis. We address the relationship between the molecular components governing local circadian clock and changes in the osteoarthritic musculoskeletal axis. Melatonin was injected subcutaneously in animals with advanced knee osteoarthritis (OA) for 4 weeks. Concurrently, moderate treadmill exercise was applied for 30 min/day. Morphometric, histological, and gene/protein-level analyses were performed in the cartilage, synovium, bone, and gastrocnemius muscle. Primary cultured chondrocytes repeatedly exposed to TNF-α were used in an in vitro study. The symptoms of OA include gait disturbance, osteophyte formation, and abnormal metabolism of the extracellular matrix (ECM) of the cartilage. Low-level expression of clock genes was accompanied by aberrant changes in cartilage specimens. Nanomolar doses of melatonin restored the expression of clock-controlled genes and corrected the abnormal chondrocyte phenotype. Melatonin combined with or without exercise prevented periarticular muscle damage as well as cartilage degeneration. But prolonged melatonin administration promoted the proteolytic cleavage of RANKL protein in the synovium, leading to severe subchondral bone erosion. These musculoskeletal changes apparently occurred via the regulation of molecular clock components, suggesting a role of melatonin as a switch-like regulator for the OA phenotype.

  13. Advanced computational biology methods identify molecular switches for malignancy in an EGF mouse model of liver cancer.

    Directory of Open Access Journals (Sweden)

    Philip Stegmaier

    Full Text Available The molecular causes by which the epidermal growth factor receptor tyrosine kinase induces malignant transformation are largely unknown. To better understand EGFs' transforming capacity whole genome scans were applied to a transgenic mouse model of liver cancer and subjected to advanced methods of computational analysis to construct de novo gene regulatory networks based on a combination of sequence analysis and entrained graph-topological algorithms. Here we identified transcription factors, processes, key nodes and molecules to connect as yet unknown interacting partners at the level of protein-DNA interaction. Many of those could be confirmed by electromobility band shift assay at recognition sites of gene specific promoters and by western blotting of nuclear proteins. A novel cellular regulatory circuitry could therefore be proposed that connects cell cycle regulated genes with components of the EGF signaling pathway. Promoter analysis of differentially expressed genes suggested the majority of regulated transcription factors to display specificity to either the pre-tumor or the tumor state. Subsequent search for signal transduction key nodes upstream of the identified transcription factors and their targets suggested the insulin-like growth factor pathway to render the tumor cells independent of EGF receptor activity. Notably, expression of IGF2 in addition to many components of this pathway was highly upregulated in tumors. Together, we propose a switch in autocrine signaling to foster tumor growth that was initially triggered by EGF and demonstrate the knowledge gain form promoter analysis combined with upstream key node identification.

  14. Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling.

    Directory of Open Access Journals (Sweden)

    Megan Leander

    Full Text Available Peptidergic signaling regulates cardiac contractility; thus, identifying molecular switches, ligand-receptor contacts, and antagonists aids in exploring the underlying mechanisms to influence health. Myosuppressin (MS, a decapeptide, diminishes cardiac contractility and gut motility. Myosuppressin binds to G protein-coupled receptor (GPCR proteins. Two Drosophila melanogaster myosuppressin receptors (DrmMS-Rs exist; however, no mechanism underlying MS-R activation is reported. We predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. Additionally, we believed DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 interactions would reflect our structure-activity relationship (SAR data. We hypothesized agonist- and antagonist-receptor contacts would differ from one another depending on activity. Lastly, we expected our study to apply to other species; we tested this hypothesis in Rhodnius prolixus, the Chagas disease vector. Searching DrmMS-Rs for molecular switches led to the discovery of a unique ionic lock and a novel 3-6 lock, as well as transmission and tyrosine toggle switches. The DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 contacts suggested tissue-specific signaling existed, which was in line with our SAR data. We identified R. prolixus (RhpMS-R and discovered it, too, contained the unique myosuppressin ionic lock and novel 3-6 lock found in DrmMS-Rs as well as transmission and tyrosine toggle switches. Further, these motifs were present in red flour beetle, common water flea, honey bee, domestic silkworm, and termite MS-Rs. RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM. Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions. The active core docking mimicked RhpMS, however, the antagonist did not. Together, these data were consistent with the unique ionic lock, novel 3-6 lock

  15. Molecular-channel driven actuator with considerations for multiple configurations and color switching.

    Science.gov (United States)

    Mu, Jiuke; Wang, Gang; Yan, Hongping; Li, Huayu; Wang, Xuemin; Gao, Enlai; Hou, Chengyi; Pham, Anh Thi Cam; Wu, Lianjun; Zhang, Qinghong; Li, Yaogang; Xu, Zhiping; Guo, Yang; Reichmanis, Elsa; Wang, Hongzhi; Zhu, Meifang

    2018-02-09

    The ability to achieve simultaneous intrinsic deformation with fast response in commercially available materials that can safely contact skin continues to be an unresolved challenge for artificial actuating materials. Rather than using a microporous structure, here we show an ambient-driven actuator that takes advantage of inherent nanoscale molecular channels within a commercial perfluorosulfonic acid ionomer (PFSA) film, fabricated by simple solution processing to realize a rapid response, self-adaptive, and exceptionally stable actuation. Selective patterning of PFSA films on an inert soft substrate (polyethylene terephthalate film) facilitates the formation of a range of different geometries, including a 2D (two-dimensional) roll or 3D (three-dimensional) helical structure in response to vapor stimuli. Chemical modification of the surface allowed the development of a kirigami-inspired single-layer actuator for personal humidity and heat management through macroscale geometric design features, to afford a bilayer stimuli-responsive actuator with multicolor switching capability.

  16. Thermodynamic Molecular Switch in Sequence-Specific Hydrophobic Interaction: Two Computational Models Compared

    Directory of Open Access Journals (Sweden)

    Paul Chun

    2003-01-01

    Full Text Available We have shown in our published work the existence of a thermodynamic switch in biological systems wherein a change of sign in ΔCp°(Treaction leads to a true negative minimum in the Gibbs free energy change of reaction, and hence, a maximum in the related Keq. We have examined 35 pair-wise, sequence-specific hydrophobic interactions over the temperature range of 273–333 K, based on data reported by Nemethy and Scheraga in 1962. A closer look at a single example, the pair-wise hydrophobic interaction of leucine-isoleucine, will demonstrate the significant differences when the data are analyzed using the Nemethy-Scheraga model or treated by the Planck-Benzinger methodology which we have developed. The change in inherent chemical bond energy at 0 K, ΔH°(T0 is 7.53 kcal mol-1 compared with 2.4 kcal mol-1, while ‹ts› is 365 K as compared with 355 K, for the Nemethy-Scheraga and Planck-Benzinger model, respectively. At ‹tm›, the thermal agitation energy is about five times greater than ΔH°(T0 in the Planck-Benzinger model, that is 465 K compared to 497 K in the Nemethy-Scheraga model. The results imply that the negative Gibbs free energy minimum at a well-defined ‹ts›, where TΔS° = 0 at about 355 K, has its origin in the sequence-specific hydrophobic interactions, which are highly dependent on details of molecular structure. The Nemethy-Scheraga model shows no evidence of the thermodynamic molecular switch that we have found to be a universal feature of biological interactions. The Planck-Benzinger method is the best known for evaluating the innate temperature-invariant enthalpy, ΔH°(T0, and provides for better understanding of the heat of reaction for biological molecules.

  17. Efficient L-Alanine Production by a Thermo-Regulated Switch in Escherichia coli.

    Science.gov (United States)

    Zhou, Li; Deng, Can; Cui, Wen-Jing; Liu, Zhong-Mei; Zhou, Zhe-Min

    2016-01-01

    L-Alanine has important applications in food, pharmaceutical and veterinary and is used as a substrate for production of engineered thermoplastics. Microbial fermentation could reduce the production cost and promote the application of L-alanine. However, the presence of L-alanine significantly inhibit cell growth rate and cause a decrease in the ultimate L-alanine productivity. For efficient L-alanine production, a thermo-regulated genetic switch was designed to dynamically control the expression of L-alanine dehydrogenase (alaD) from Geobacillus stearothermophilus on the Escherichia coli B0016-060BC chromosome. The optimal cultivation conditions for the genetically switched alanine production using B0016-060BC were the following: an aerobic growth phase at 33 °C with a 1-h thermo-induction at 42 °C followed by an oxygen-limited phase at 42 °C. In a bioreactor experiment using the scaled-up conditions optimized in a shake flask, B0016-060BC accumulated 50.3 g biomass/100 g glucose during the aerobic growth phase and 96 g alanine/100 g glucose during the oxygen-limited phase, respectively. The L-alanine titer reached 120.8 g/l with higher overall and oxygen-limited volumetric productivities of 3.09 and 4.18 g/l h, respectively, using glucose as the sole carbon source. Efficient cell growth and L-alanine production were reached separately, by switching cultivation temperature. The results revealed the application of a thermo-regulated strategy for heterologous metabolic production and pointed to strategies for improving L-alanine production.

  18. Cell Identity Switching Regulated by Retinoic Acid Signaling Maintains Homogeneous Segments in the Hindbrain.

    Science.gov (United States)

    Addison, Megan; Xu, Qiling; Cayuso, Jordi; Wilkinson, David G

    2018-06-04

    The patterning of tissues to form subdivisions with distinct and homogeneous regional identity is potentially disrupted by cell intermingling. Transplantation studies suggest that homogeneous segmental identity in the hindbrain is maintained by identity switching of cells that intermingle into another segment. We show that switching occurs during normal development and is mediated by feedback between segment identity and the retinoic acid degrading enzymes, cyp26b1 and cyp26c1. egr2, which specifies the segmental identity of rhombomeres r3 and r5, underlies the lower expression level of cyp26b1 and cyp26c1 in r3 and r5 compared with r2, r4, and r6. Consequently, r3 or r5 cells that intermingle into adjacent segments encounter cells with higher cyp26b1/c1 expression, which we find is required for downregulation of egr2b expression. Furthermore, egr2b expression is regulated in r2, r4, and r6 by non-autonomous mechanisms that depend upon the number of neighbors that express egr2b. These findings reveal that a community regulation of retinoid signaling maintains homogeneous segmental identity. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  19. Conformational switching in the coiled-coil domains of a proteasomal ATPase regulates substrate processing.

    Science.gov (United States)

    Snoberger, Aaron; Brettrager, Evan J; Smith, David M

    2018-06-18

    Protein degradation in all domains of life requires ATPases that unfold and inject proteins into compartmentalized proteolytic chambers. Proteasomal ATPases in eukaryotes and archaea contain poorly understood N-terminally conserved coiled-coil domains. In this study, we engineer disulfide crosslinks in the coiled-coils of the archaeal proteasomal ATPase (PAN) and report that its three identical coiled-coil domains can adopt three different conformations: (1) in-register and zipped, (2) in-register and partially unzipped, and (3) out-of-register. This conformational heterogeneity conflicts with PAN's symmetrical OB-coiled-coil crystal structure but resembles the conformational heterogeneity of the 26S proteasomal ATPases' coiled-coils. Furthermore, we find that one coiled-coil can be conformationally constrained even while unfolding substrates, and conformational changes in two of the coiled-coils regulate PAN switching between resting and active states. This switching functionally mimics similar states proposed for the 26S proteasome from cryo-EM. These findings thus build a mechanistic framework to understand regulation of proteasome activity.

  20. Velocity Regulation in Switched Reluctance Motors under Magnetic Flux Saturation Conditions

    Directory of Open Access Journals (Sweden)

    Victor M. Hernández-Guzmán

    2018-01-01

    Full Text Available We propose a controller for velocity regulation in switched reluctance motors under magnetic flux saturation conditions. Both hysteresis and proportional control are employed in the internal electric current loops. A classical PI velocity controller is employed in the external loop. Our control law is the simplest one proposed in the literature but provided with a formal stability proof. We prove that the state is bounded having an ultimate bound which can be rendered arbitrarily small by a suitable selection of controller gains. Furthermore, this result stands when starting from any initial condition within a radius which can be arbitrarily enlarged using suitable controller gains. We present a simulation study where even convergence to zero of velocity error is observed as well as a good performance when regulating velocity in the presence of unknown step changes in external torque disturbances.

  1. Fully on-chip switched capacitor NMOS low dropout voltage regulator

    CERN Document Server

    Camacho, D; Camacho, Daniel; Moreira, Paulo

    2010-01-01

    This paper presents a 1.5 V 50 mA low dropout voltage (LDO) regulator using an NMOS transistor as the output pass element. Continuous time,operation of the LDO is achieved using a new switched floating capacitor scheme that raises the gate voltage of the pass element. The regulator has a 0.2 V dropout at a 50 mA load and is stable for a wide load current range with loading capacitances up to 50 pF. The output variation when a full load step is applied is 300 mV and the recovery time is below 0.3 mu s. it is designed in a 0.13 mu m CMOS process with an area of 0.008 mm(2) and its operation does not require any external component.

  2. Fundamental properties of molecules on surfaces. Molecular switching and interaction of magnetic molecules with superconductors

    Energy Technology Data Exchange (ETDEWEB)

    Hatter, Nino

    2016-12-14

    In this thesis, we investigate individual molecular switches and metal-organic complexes on surfaces with scanning tunneling microscopy (STM) and spectroscopy (STS) at low temperatures. One focus addresses the switching ability and mechanism of diarylethene on Ag(111). The other focus lies on resolving and tuning magnetic interactions of individual molecules with superconductors. 4,4'-(4,4'-(perfluorocyclopent-1-ene-1,2-diyl)bis (5-methylthiophene-4,2-diyl)dip yridine (PDTE) is a prototypical photochromic switch. We can induce a structural change of individual PDTE molecules on Ag(111) with the STM tip. This change is accompanied by a reduction of the energy gap between the occupied and unoccupied molecular orbitals. Density functional theory (DFT) calculations reveal that the induced switching corresponds to a ring-closing reaction from an open isomer in a flat adsorption configuration to a ring-closed isomer with its methyl groups in a cis configuration. The final product is thermodynamically stabilized by strong dispersion interactions with the surface. A linear dependence of the switching threshold with the tip-sample distance with a minimal threshold of 1.4 V is found, which we assign to a combination of an electric-field induced process and a tunneling-electron contribution. DFT calculations suggest a large activation barrier for a ring-closing reaction from the open flat configuration into the closed cis configuration. The interaction of magnetic molecules with superconductors is studied on manganese phthalocyanine (MnPc) adsorbed on Pb(111). We find triplets of Shiba states inside the superconducting gap. Different adsorption sites of MnPc provide a large variety of exchange coupling strengths, which lead to a collective energy shift of the Shiba triplets. We can assign the splitting of the Shiba states to be an effect of magnetic anisotropy in the system. A quantum phase transition from a ''Kondo screened'' to a &apos

  3. G-quadruplex induced chirality of methylazacalix[6]pyridine via unprecedented binding stoichiometry: en route to multiplex controlled molecular switch

    Science.gov (United States)

    Guan, Ai-Jiao; Shen, Meng-Jie; Xiang, Jun-Feng; Zhang, En-Xuan; Li, Qian; Sun, Hong-Xia; Wang, Li-Xia; Xu, Guang-Zhi; Tang, Ya-Lin; Xu, Li-Jin; Gong, Han-Yuan

    2015-05-01

    Nucleic acid based molecular device is a developing research field which attracts great interests in material for building machinelike nanodevices. G-quadruplex, as a new type of DNA secondary structures, can be harnessed to construct molecular device owing to its rich structural polymorphism. Herein, we developed a switching system based on G-quadruplexes and methylazacalix[6]pyridine (MACP6). The induced circular dichroism (CD) signal of MACP6 was used to monitor the switch controlled by temperature or pH value. Furthermore, the CD titration, Job-plot, variable temperature CD and 1H-NMR experiments not only confirmed the binding mode between MACP6 and G-quadruplex, but also explained the difference switching effect of MACP6 and various G-quadruplexes. The established strategy has the potential to be used as the chiral probe for specific G-quadruplex recognition.

  4. Negative differential resistance and switch behavior of T-BxNy (x, y = 5, 6, 11) molecular junctions

    Science.gov (United States)

    Wang, Shi-Liang; Yang, Chuan-Lu; Wang, Mei-Shan; Ma, Xiao-Guang; Xin, Jian-Guo

    2017-05-01

    The electronic transport properties of T-BxNy (x, y = 5, 6, 11) molecular junction are investigated based on first-principle density functional theory and non-equilibrium Green's function method. Strong negative differential resistance (NDR) behavior is observed for T-B5N6 molecule under negative and positive bias voltages, with an obvious switch effect for T-B6N5. However, only small NDR is shown for the complex of the two molecules. The projected device density of states, the spatial distribution of molecular orbitals, and the effect of transmission spectra under various bias voltages on the electronic transport properties are analyzed. The obvious effect of bias voltage on the changes in the electronic distribution of frontier molecular orbitals is responsible for the NDR or switch behavior. Therefore, different functional molecular devices can be obtained with different structures of T-BxNy.

  5. Controlling the color of cholesteric liquid-crystalline films by photoirradiation of a chiroptical molecular switch used as dopant

    NARCIS (Netherlands)

    van Delden, RA; Huck, NPM; Feringa, BL; Delden, Richard A. van; Gelder, Marc B. van; Huck, Nina P.M.

    Using thin films of a cholesteric mixture of acrylates 2 and 3 doped with the chiroptical molecular switch (M)-trans-1, photo-control of the reflection color between red and green is possible. This doped liquid-crystal (LC) film can be used for photoinduced writing, color reading, and photoinduced

  6. Myeloperoxidase serves as a redox switch that regulates apoptosis in epithelial ovarian cancer.

    Science.gov (United States)

    Saed, Ghassan M; Ali-Fehmi, Rouba; Jiang, Zhong L; Fletcher, Nicole M; Diamond, Michael P; Abu-Soud, Husam M; Munkarah, Adnan R

    2010-02-01

    Resistance to apoptosis is a key feature of cancer cells and is believed to be regulated by nitrosonium ion (NO(+))-induced S-nitrosylation of key enzymes. Nitric oxide (NO), produced by inducible nitric oxide synthase (iNOS), is utilized by MPO to generated NO(+). We sought to investigate the expression of myeloperoxidase (MPO) and iNOS in epithelial ovarian cancer (EOC) and determine their effect on S-nitrosylation of caspase-3 and its activity as well as apoptosis. MPO and iNOS expression were determined using immunofluorescence in SKOV-3 and MDAH-2774 and EOC tissue sections. S-nitrosylation of caspase-3 and its activity, levels of MPO and iNOS, as well as apoptosis, were evaluated in the EOC cells before and after silencing MPO or iNOS genes with specific siRNA probes utilizing real-time RT-PCR, ELISA, and TUNEL assays. MPO and iNOS are expressed in EOC cell lines and in over 60% of invasive EOC cases with no expression in normal ovarian epithelium. Indeed, silencing of MPO or iNOS gene expression resulted in decreased S-nitrosylation of caspase-3, increased caspase-3 activity, and increased apoptosis but with a more significant effect when silencing MPO. MPO and iNOS are colocalized to the same cells in EOC but not in the normal ovarian epithelium. Silencing of either MPO or iNOS significantly induced apoptosis, highlighting their role as a redox switch that regulates apoptosis in EOC. Understanding the mechanisms by which MPO functions as a redox switch in regulating apoptosis in EOC may lead to future diagnostic tools and therapeutic interventions. Copyright 2009 Elsevier Inc. All rights reserved.

  7. The structure of Plasmodium falciparum serine hydroxymethyltransferase reveals a novel redox switch that regulates its activities

    Energy Technology Data Exchange (ETDEWEB)

    Chitnumsub, Penchit; Ittarat, Wanwipa; Jaruwat, Aritsara; Noytanom, Krittikar [National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Paholyothin Road, Klong 1, Klong Luang, Pathumthani 12120 (Thailand); Amornwatcharapong, Watcharee [Mahidol University, Bangkok (Thailand); Pornthanakasem, Wichai [National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Paholyothin Road, Klong 1, Klong Luang, Pathumthani 12120 (Thailand); Chaiyen, Pimchai [Mahidol University, Bangkok (Thailand); Yuthavong, Yongyuth; Leartsakulpanich, Ubolsree [National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Paholyothin Road, Klong 1, Klong Luang, Pathumthani 12120 (Thailand)

    2014-06-01

    The crystal structure of P. falciparum SHMT revealed snapshots of an intriguing disulfide/sulfhydryl switch controlling the functional activity. Plasmodium falciparum serine hydroxymethyltransferase (PfSHMT), an enzyme in the dTMP synthesis cycle, is an antimalarial target because inhibition of its expression or function has been shown to be lethal to the parasite. As the wild-type enzyme could not be crystallized, protein engineering of residues on the surface was carried out. The surface-engineered mutant PfSHMT-F292E was successfully crystallized and its structure was determined at 3 Å resolution. The PfSHMT-F292E structure is a good representation of PfSHMT as this variant revealed biochemical properties similar to those of the wild type. Although the overall structure of PfSHMT is similar to those of other SHMTs, unique features including the presence of two loops and a distinctive cysteine pair formed by Cys125 and Cys364 in the tetrahydrofolate (THF) substrate binding pocket were identified. These structural characteristics have never been reported in other SHMTs. Biochemical characterization and mutation analysis of these two residues confirm that they act as a disulfide/sulfhydryl switch to regulate the THF-dependent catalytic function of the enzyme. This redox switch is not present in the human enzyme, in which the cysteine pair is absent. The data reported here can be further exploited as a new strategy to specifically disrupt the activity of the parasite enzyme without interfering with the function of the human enzyme.

  8. The structure of Plasmodium falciparum serine hydroxymethyltransferase reveals a novel redox switch that regulates its activities

    International Nuclear Information System (INIS)

    Chitnumsub, Penchit; Ittarat, Wanwipa; Jaruwat, Aritsara; Noytanom, Krittikar; Amornwatcharapong, Watcharee; Pornthanakasem, Wichai; Chaiyen, Pimchai; Yuthavong, Yongyuth; Leartsakulpanich, Ubolsree

    2014-01-01

    The crystal structure of P. falciparum SHMT revealed snapshots of an intriguing disulfide/sulfhydryl switch controlling the functional activity. Plasmodium falciparum serine hydroxymethyltransferase (PfSHMT), an enzyme in the dTMP synthesis cycle, is an antimalarial target because inhibition of its expression or function has been shown to be lethal to the parasite. As the wild-type enzyme could not be crystallized, protein engineering of residues on the surface was carried out. The surface-engineered mutant PfSHMT-F292E was successfully crystallized and its structure was determined at 3 Å resolution. The PfSHMT-F292E structure is a good representation of PfSHMT as this variant revealed biochemical properties similar to those of the wild type. Although the overall structure of PfSHMT is similar to those of other SHMTs, unique features including the presence of two loops and a distinctive cysteine pair formed by Cys125 and Cys364 in the tetrahydrofolate (THF) substrate binding pocket were identified. These structural characteristics have never been reported in other SHMTs. Biochemical characterization and mutation analysis of these two residues confirm that they act as a disulfide/sulfhydryl switch to regulate the THF-dependent catalytic function of the enzyme. This redox switch is not present in the human enzyme, in which the cysteine pair is absent. The data reported here can be further exploited as a new strategy to specifically disrupt the activity of the parasite enzyme without interfering with the function of the human enzyme

  9. Evaluation of DC/DC switching power regulation with small-scale integrated inductors for PET/MR

    Energy Technology Data Exchange (ETDEWEB)

    Biagi, Laura [IRCCS Fondazione Stella Maris and Fondazione Imago 7, Calambrone, Pisa (Italy); Bisogni, Maria Giuseppina; Camarlinghi, Niccolo [Department of Physics, University of Pisa and INFN, Pisa (Italy); Costagli, Mauro [IRCCS Fondazione Stella Maris and Fondazione Imago 7, Calambrone, Pisa (Italy); Sportelli, Giancarlo [Department of Physics, University of Pisa and INFN, Pisa (Italy); Tosetti, Michela [IRCCS Fondazione Stella Maris and Fondazione Imago 7, Calambrone, Pisa (Italy); Del Guerra, Alberto; Belcari, Nicola [Department of Physics, University of Pisa and INFN, Pisa (Italy)

    2015-05-18

    We present a feasibility study that has been carried out to determine the best power regulation strategy for the PET front-end electronics of the trimodal PET/MRI/EEG TRIMAGE scanner. Conventional power regulation strategies cannot be applied to PET/MRI because standard switching regulators stop working in presence of a high magnetic field. At the state of the art, linear regulators are used instead. However, linear regulators are inefficient and might not allow to fulfill power and thermal constraints if the electronics becomes more power demanding, such as in the case of FPGA based front-ends. Very recently, a new generation of switching power supplies has been introduced for EMI critical applications where the discrete inductor energy buffer is not allowed. These supplies have very small footprint, need few biasing peripherals and they use on-chip integrated inductors for energy storage. These switching power regulators coupled with an adequate EMI shield could be an achievable power solution for our PET front-end electronics. Test procedures for Enpirion. EN2390QI and the Enpirion. EN6347QI switching power regulators are presented. Measurements have been performed at GE 1.5T MRI scanner with the support of IRCCS Fondazione Stella Maris. All the board have been tested in two different configurations: with and without an additional EMI shield. Performance of these two switching power regulators have been compared with a linear power regulator (Enpirion. EY1501DI). Output voltage, output current and temperature have been measured. The stability of these three main characteristic will be presented in different operation conditions and will be discussed (output voltage vs. temperature, output voltage vs. output current and output current vs. temperature).

  10. A dynamic view of molecular switch behavior at serotonin receptors: implications for functional selectivity.

    Directory of Open Access Journals (Sweden)

    Maria Martí-Solano

    Full Text Available Functional selectivity is a property of G protein-coupled receptors that allows them to preferentially couple to particular signaling partners upon binding of biased agonists. Publication of the X-ray crystal structure of serotonergic 5-HT1B and 5-HT2B receptors in complex with ergotamine, a drug capable of activating G protein coupling and β-arrestin signaling at the 5-HT1B receptor but clearly favoring β-arrestin over G protein coupling at the 5-HT2B subtype, has recently provided structural insight into this phenomenon. In particular, these structures highlight the importance of specific residues, also called micro-switches, for differential receptor activation. In our work, we apply classical molecular dynamics simulations and enhanced sampling approaches to analyze the behavior of these micro-switches and their impact on the stabilization of particular receptor conformational states. Our analysis shows that differences in the conformational freedom of helix 6 between both receptors could explain their different G protein-coupling capacity. In particular, as compared to the 5-HT1B receptor, helix 6 movement in the 5-HT2B receptor can be constrained by two different mechanisms. On the one hand, an anchoring effect of ergotamine, which shows an increased capacity to interact with the extracellular part of helices 5 and 6 and stabilize them, hinders activation of a hydrophobic connector region at the center of the receptor. On the other hand, this connector region in an inactive conformation is further stabilized by unconserved contacts extending to the intracellular part of the 5-HT2B receptor, which hamper opening of the G protein binding site. This work highlights the importance of considering receptor capacity to adopt different conformational states from a dynamic perspective in order to underpin the structural basis of functional selectivity.

  11. Building strong bones: molecular regulation of the osteoblast lineage.

    Science.gov (United States)

    Long, Fanxin

    2011-12-22

    The past 15 years have witnessed tremendous progress in the molecular understanding of osteoblasts, the main bone-forming cells in the vertebrate skeleton. In particular, all of the major developmental signals (including WNT and Notch signalling), along with an increasing number of transcription factors (such as RUNX2 and osterix), have been shown to regulate the differentiation and/or function of osteoblasts. As evidence indicates that osteoblasts may also regulate the behaviour of other cell types, a clear understanding of the molecular identity and regulation of osteoblasts is important beyond the field of bone biology.

  12. Molecular biological mechanism II. Molecular mechanisms of cell cycle regulation

    International Nuclear Information System (INIS)

    Jung, T.

    2000-01-01

    The cell cycle in eukaryotes is regulated by central cell cycle controlling protein kinase complexes. These protein kinase complexes consist of a catalytic subunit from the cyclin-dependent protein kinase family (CDK), and a regulatory subunit from the cyclin family. Cyclins are characterised by their periodic cell cycle related synthesis and destruction. Each cell cycle phase is characterised by a specific set of CDKs and cyclins. The activity of CDK/cyclin complexes is mainly regulated on four levels. It is controlled by specific phosphorylation steps, the synthesis and destruction of cyclins, the binding of specific inhibitor proteins, and by active control of their intracellular localisation. At several critical points within the cell cycle, named checkpoints, the integrity of the cellular genome is monitored. If damage to the genome or an unfinished prior cell cycle phase is detected, the cell cycle progression is stopped. These cell cycle blocks are of great importance to secure survival of cells. Their primary importance is to prevent the manifestation and heritable passage of a mutated genome to daughter cells. Damage sensing, DNA repair, cell cycle control and apoptosis are closely linked cellular defence mechanisms to secure genome integrity. Disregulation in one of these defence mechanisms are potentially correlated with an increased cancer risk and therefore in at least some cases with an increased radiation sensitivity. (orig.) [de

  13. Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics.

    Directory of Open Access Journals (Sweden)

    Barry J Grant

    2009-03-01

    Full Text Available Ras mediates signaling pathways controlling cell proliferation and development by cycling between GTP- and GDP-bound active and inactive conformational states. Understanding the complete reaction path of this conformational change and its intermediary structures is critical to understanding Ras signaling. We characterize nucleotide-dependent conformational transition using multiple-barrier-crossing accelerated molecular dynamics (aMD simulations. These transitions, achieved for the first time for wild-type Ras, are impossible to observe with classical molecular dynamics (cMD simulations due to the large energetic barrier between end states. Mapping the reaction path onto a conformer plot describing the distribution of the crystallographic structures enabled identification of highly populated intermediate structures. These structures have unique switch orientations (residues 25-40 and 57-75 intermediate between GTP and GDP states, or distinct loop3 (46-49, loop7 (105-110, and alpha5 C-terminus (159-166 conformations distal from the nucleotide-binding site. In addition, these barrier-crossing trajectories predict novel nucleotide-dependent correlated motions, including correlations of alpha2 (residues 66-74 with alpha3-loop7 (93-110, loop2 (26-37 with loop10 (145-151, and loop3 (46-49 with alpha5 (152-167. The interconversion between newly identified Ras conformations revealed by this study advances our mechanistic understanding of Ras function. In addition, the pattern of correlated motions provides new evidence for a dynamic linkage between the nucleotide-binding site and the membrane interacting C-terminus critical for the signaling function of Ras. Furthermore, normal mode analysis indicates that the dominant collective motion that occurs during nucleotide-dependent conformational exchange, and captured in aMD (but absent in cMD simulations, is a low-frequency motion intrinsic to the structure.

  14. Triple-helix molecular switch-based aptasensors and DNA sensors.

    Science.gov (United States)

    Bagheri, Elnaz; Abnous, Khalil; Alibolandi, Mona; Ramezani, Mohammad; Taghdisi, Seyed Mohammad

    2018-07-15

    Utilization of traditional analytical techniques is limited because they are generally time-consuming and require high consumption of reagents, complicated sample preparation and expensive equipment. Therefore, it is of great interest to achieve sensitive, rapid and simple detection methods. It is believed that nucleic acids assays, especially aptamers, are very important in modern life sciences for target detection and biological analysis. Aptamers and DNA-based sensors have been widely used for the design of various sensors owing to their unique features. In recent years, triple-helix molecular switch (THMS)-based aptasensors and DNA sensors have been broadly utilized for the detection and analysis of different targets. The THMS relies on the formation of DNA triplex via Watson-Crick and Hoogsteen base pairings under optimal conditions. This review focuses on recent progresses in the development and applications of electrochemical, colorimetric, fluorescence and SERS aptasensors and DNA sensors, which are based on THMS. Also, the advantages and drawbacks of these methods are discussed. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Electrospun Nanofibers from a Tricyanofuran-Based Molecular Switch for Colorimetric Recognition of Ammonia Gas.

    Science.gov (United States)

    Khattab, Tawfik A; Abdelmoez, Sherif; Klapötke, Thomas M

    2016-03-14

    A chromophore based on tricyanofuran (TCF) with a hydrazone (H) recognition moiety was developed. Its molecular-switching performance is reversible and has differential sensitivity towards aqueous ammonia at comparable concentrations. Nanofibers were fabricated from the TCF-H chromophore by electrospinning. The film fabricated from these nanofibers functions as a solid-state optical chemosensor for probing ammonia vapor. Recognition of ammonia vapor occurs by proton transfer from the hydrazone fragment of the chromophore to the ammonia nitrogen atom and is facilitated by the strongly electron withdrawing TCF fragment. The TCF-H chromophore was added to a solution of poly(acrylic acid), which was electrospun to obtain a nanofibrous sensor device. The morphology of the nanofibrous sensor was determined by SEM, which showed that nanofibers with a diameter range of 200-450 nm formed a nonwoven mat. The resultant nanofibrous sensor showed very good sensitivity in ammonia-vapor detection. Furthermore, very good reversibility and short response time were also observed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. On the field-induced switching of molecular organization in a biaxial nematic cell and its relaxation

    Science.gov (United States)

    Ricci, Matteo; Berardi, Roberto; Zannoni, Claudio

    2015-08-01

    We investigate the switching of a biaxial nematic filling a flat cell with planar homogeneous anchoring using a coarse-grained molecular dynamics simulation. We have found that an aligning field applied across the film, and acting on specific molecular axes, can drive the reorientation of the secondary biaxial director up to one order of magnitude faster than that for the principal director. While the π/2 switching of the secondary director does not affect the alignment of the long molecular axes, the field-driven reorientation of the principal director proceeds via a concerted rotation of the long and transversal molecular axes. More importantly, while upon switching off a (relatively) weak or intermediate field, the biaxial nematic liquid crystal is always able to relax to the initial surface aligned director state; this is not the case when using fields above a certain threshold. In that case, while the secondary director always recovers the initial state, the principal one remains, occasionally, trapped in a nonuniform director state due to the formation of domain walls.

  17. Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

    Science.gov (United States)

    Liu, Gang; Chandra, Govind; Niu, Guoqing

    2013-01-01

    SUMMARY Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific. Streptomyces coelicolor, the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis in S. coelicolor and other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerous Streptomyces genomes. PMID:23471619

  18. FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP

    Directory of Open Access Journals (Sweden)

    Yuichi Tsuchiya

    2015-12-01

    Full Text Available cFLIP (cellular FLICE-like inhibitory protein is structurally related to caspase-8 but lacks proteolytic activity due to multiple amino acid substitutions of catalytically important residues. cFLIP protein is evolutionarily conserved and expressed as three functionally different isoforms in humans (cFLIPL, cFLIPS, and cFLIPR. cFLIP controls not only the classical death receptor-mediated extrinsic apoptosis pathway, but also the non-conventional pattern recognition receptor-dependent apoptotic pathway. In addition, cFLIP regulates the formation of the death receptor-independent apoptotic platform named the ripoptosome. Moreover, recent studies have revealed that cFLIP is also involved in a non-apoptotic cell death pathway known as programmed necrosis or necroptosis. These functions of cFLIP are strictly controlled in an isoform-, concentration- and tissue-specific manner, and the ubiquitin-proteasome system plays an important role in regulating the stability of cFLIP. In this review, we summarize the current scientific findings from biochemical analyses, cell biological studies, mathematical modeling, and gene-manipulated mice models to illustrate the critical role of cFLIP as a switch to determine the destiny of cells among survival, apoptosis, and necroptosis.

  19. OsWRKY53, a versatile switch in regulating herbivore-induced defense responses in rice

    Science.gov (United States)

    Hu, Lingfei; Ye, Meng; Li, Ran; Lou, Yonggen

    2016-01-01

    ABSTRACT WRKY proteins, which belong to a large family of plant-specific transcription factors, play important roles in plant defenses against pathogens and herbivores by regulating defense-related signaling pathways. Recently, a rice WRKY transcription factor OsWRKY53 has been reported to function as a negative feedback modulator of OsMPK3/OsMPK6 and thereby to control the size of the investment a rice plant makes to defend against a chewing herbivore, the striped stem borer Chilo suppressalis. We investigated the performance of a piecing-sucking herbivore, the brown planthopper (BPH) Nilaparvata lugens, on transgenic plants that silence or overexpress OsWRKY53, and found that OsWRKY53 activates rice defenses against BPH by activating an H2O2 burst and suppressing ethylene biosynthesis. These findings suggest that OsWRKY53 functions not only as a regulator of plants' investment in specific defenses, but also as a switch to initiate new defenses against other stresses, highlighting the versatility and importance of OsWRKY53 in herbivore-induced plant defenses. PMID:27031005

  20. Exploration of Charge Recycling DC-DC Conversion Using a Switched Capacitor Regulator

    Directory of Open Access Journals (Sweden)

    Mircea R. Stan

    2013-07-01

    Full Text Available The increasing popularity of DVFS (dynamic voltage frequency scaling schemes for portable low power applications demands highly efficient on-chip DC-DC converters. The primary aim of this work is to enable increased efficiency of on-chip DC-DC conversion for near-threshold operation of multicore chips. The idea is to supply nominal (high off-chip voltage to the cores which are then “voltage-stacked” to generate the near-threshold (low voltages based on Kirchhoff’s voltage law through charge recycling. However, the effectiveness of this implicit down-conversion is affected by the current imbalance among the cores. The paper presents a design methodology and optimization strategy for highly efficient charge recycling on-chip regulation using a push-pull switched capacitor (SC circuit. A dual-boundary hysteretic feedback control circuit has been designed for stacked loads. A stacked-voltage domain with its self-regulation capability combined with a SC converter has shown average efficiency of 78%–93% for 2:1 down-conversion with ILoad (max of 200 mA and workload imbalance varying from 0–100%.

  1. Molecular analysis of Ku redox regulation

    Directory of Open Access Journals (Sweden)

    Shatilla Andrea

    2009-08-01

    Full Text Available Abstract Background DNA double-strand breaks (DSBs can occur in response to ionizing radiation (IR, radiomimetic agents and from endogenous DNA-damaging reactive oxygen metabolites. Unrepaired or improperly repaired DSBs are potentially the most lethal form of DNA damage and can result in chromosomal translocations and contribute to the development of cancer. The principal mechanism for the repair of DSBs in humans is non-homologous end-joining (NHEJ. Ku is a key member of the NHEJ pathway and plays an important role in the recognition step when it binds to free DNA termini. Ku then stimulates the assembly and activation of other NHEJ components. DNA binding of Ku is regulated by redox conditions and evidence from our laboratory has demonstrated that Ku undergoes structural changes when oxidized that results in a reduction in DNA binding activity. The C-terminal domain and cysteine 493 of Ku80 were investigated for their contribution to redox regulation of Ku. Results We effectively removed the C-terminal domain of Ku80 generating a truncation mutant and co-expressed this variant with wild type Ku70 in an insect cell system to create a Ku70/80ΔC heterodimer. We also generated two single amino acid variants of Cys493, replacing this amino acid with either an alanine (C493A or a serine (C493S, and over-expressed the variant proteins in SF9 insect cells in complex with wild type Ku70. Neither the truncation nor the amino acid substitutions alters protein expression or stability as determined by SDS-PAGE and Western blot analysis. We show that the C493 mutations do not alter the ability of Ku to bind duplex DNA in vitro under reduced conditions while truncation of the Ku80 C-terminus slightly reduced DNA binding affinity. Diamide oxidation of cysteines was shown to inhibit DNA binding similarly for both the wild-type and all variant proteins. Interestingly, differential DNA binding activity following re-reduction was observed for the Ku70/80

  2. Molecular Dynamics of Flexible Polar Cations in a Variable Confined Space: Toward Exceptional Two-Step Nonlinear Optical Switches.

    Science.gov (United States)

    Xu, Wei-Jian; He, Chun-Ting; Ji, Cheng-Min; Chen, Shao-Li; Huang, Rui-Kang; Lin, Rui-Biao; Xue, Wei; Luo, Jun-Hua; Zhang, Wei-Xiong; Chen, Xiao-Ming

    2016-07-01

    The changeable molecular dynamics of flexible polar cations in the variable confined space between inorganic chains brings about a new type of two-step nonlinear optical (NLO) switch with genuine "off-on-off" second harmonic generation (SHG) conversion between one NLO-active state and two NLO-inactive states. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Isomerization of Orthogonal Molecular Switches Encapsulated within Micelles Solubilizing Carbon Nanotubes

    DEFF Research Database (Denmark)

    Kreft, Stefanie K.; Petersen, Michael Åxman; Nielsen, Mogens Brøndsted

    2015-01-01

    We study the effects of the proximity of the orthogonal dipole-switching moiety dihydroazulene/vinylheptafulvene (DHA/VHF) to carbon nanotubes (CNTs). The switches are introduced into a micelle surrounding the CNTs, thereby achieving very close proximity between the molecules and the CNTs...... of the CNTs and the resulting reversible redshift of the nanotubes' emission by the change of the molecules' conformation....

  4. Molecular Mechanisms of Circadian Regulation During Spaceflight

    Science.gov (United States)

    Zanello, S. B.; Boyle, R.

    2012-01-01

    The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ip

  5. CD11b regulates antibody class switching via induction of AID.

    Science.gov (United States)

    Park, Seohyun; Sim, Hyunsub; Kim, Hye-In; Jeong, Daecheol; Wu, Guang; Cho, Soo Young; Lee, Young Seek; Kwon, Hyung-Joo; Lee, Keunwook

    2017-07-01

    The integrin CD11b, which is encoded by the integrin subunit alpha M (ITGAM), is primarily expressed on the surface of innate immune cells. Genetic variations in ITGAM are among the strongest risk factors for systemic lupus erythematosus, an autoimmune disease characterized by the presence of autoantibodies. However, the regulatory function of CD11b in the antibody responses remains unclear. Here, we report the induction of CD11b in activated B2 B cells and define its unexpected role in immunoglobulin heavy chain class switch recombination (CSR). LPS-activated B cells lacking CD11b yielded fewer IgG subtypes such as IgG1 and IgG2a in vitro, and immunization-dependent CSR and affinity maturation of antibodies were severely impaired in CD11b-deficient mice. Notably, we observed the reduced expression of activation-induced cytidine deaminase (AID), an enzyme that initiates CSR and somatic hypermutation, and ectopic expression of AID was sufficient to rescue the defective CSR of CD11b-deficient B cells. LPS-induced phosphorylation of NF-κB p65 and IκBα was attenuated in CD11b-deficient B cells, and hyperactivation of IκB kinase 2 restored the defective AID expression and CSR, which implied that CD11b regulates the NF-κB-dependent induction of AID. Overall, our experimental evidence emphasized the function of CD11b in antibody responses and the role of CD11b as a vital regulator of CSR. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Realization of a four-step molecular switch in scanning tunneling microscope manipulation of single chlorophyll-a molecules

    Science.gov (United States)

    Iancu, Violeta; Hla, Saw-Wai

    2006-01-01

    Single chlorophyll-a molecules, a vital resource for the sustenance of life on Earth, have been investigated by using scanning tunneling microscope manipulation and spectroscopy on a gold substrate at 4.6 K. Chlorophyll-a binds on Au(111) via its porphyrin unit while the phytyl-chain is elevated from the surface by the support of four CH3 groups. By injecting tunneling electrons from the scanning tunneling microscope tip, we are able to bend the phytyl-chain, which enables the switching of four molecular conformations in a controlled manner. Statistical analyses and structural calculations reveal that all reversible switching mechanisms are initiated by a single tunneling-electron energy-transfer process, which induces bond rotation within the phytyl-chain. PMID:16954201

  7. A Phosphorylation Switch on Lon Protease Regulates Bacterial Type III Secretion System in Host

    Directory of Open Access Journals (Sweden)

    Xiaofeng Zhou

    2018-01-01

    Full Text Available Most pathogenic bacteria deliver virulence factors into host cytosol through type III secretion systems (T3SS to perturb host immune responses. The expression of T3SS is often repressed in rich medium but is specifically induced in the host environment. The molecular mechanisms underlying host-specific induction of T3SS expression is not completely understood. Here we demonstrate in Xanthomonas citri that host-induced phosphorylation of the ATP-dependent protease Lon stabilizes HrpG, the master regulator of T3SS, conferring bacterial virulence. Ser/Thr/Tyr phosphoproteome analysis revealed that phosphorylation of Lon at serine 654 occurs in the citrus host. In rich medium, Lon represses T3SS by degradation of HrpG via recognition of its N terminus. Genetic and biochemical data indicate that phosphorylation at serine 654 deactivates Lon proteolytic activity and attenuates HrpG proteolysis. Substitution of alanine for Lon serine 654 resulted in repression of T3SS gene expression in the citrus host through robust degradation of HrpG and reduced bacterial virulence. Our work reveals a novel mechanism for distinct regulation of bacterial T3SS in different environments. Additionally, our data provide new insight into the role of protein posttranslational modification in the regulation of bacterial virulence.

  8. Ionic modulation of QPX stability as a nano-switch regulating gene expression in neurons

    Science.gov (United States)

    Baghaee Ravari, Soodeh

    G-quadruplexes (G-QPX) have been the subject of intense research due to their unique structural configuration and potential applications, particularly their functionality in biological process as a novel type of nano--switch. They have been found in critical regions of the human genome such as telomeres, promoter regions, and untranslated regions of RNA. About 50% of human DNA in promoters has G-rich regions with the potential to form G-QPX structures. A G-QPX might act mechanistically as an ON/OFF switch, regulating gene expression, meaning that the formation of G-QPX in a single strand of DNA disrupts double stranded DNA, prevents the binding of transcription factors (TF) to their recognition sites, resulting in gene down-regulation. Although there are numerous studies on biological roles of G-QPXs in oncogenes, their potential formation in neuronal cells, in particular upstream of transcription start sites, is poorly investigated. The main focus of this research is to identify stable G-QPXs in the 97bp active promoter region of the choline acetyltransferase (ChAT) gene, the terminal enzyme involved in synthesis of the neurotransmitter acetylcholine, and to clarify ionic modulation of G-QPX nanostructures through the mechanism of neural action potentials. Different bioinformatics analyses (in silico), including the QGRS, quadparser and G4-Calculator programs, have been used to predict stable G-QPX in the active promoter region of the human ChAT gene, located 1000bp upstream from the TATA box. The results of computational studies (using those three different algorithms) led to the identification of three consecutive intramolecular G-QPX structures in the negative strand (ChAT G17-2, ChAT G17, and ChAT G29) and one intramolecular G-QPX structure in the positive strand (ChAT G30). Also, the results suggest the possibility that nearby G-runs in opposed DNA strands with a short distance of each other may be able to form a stable intermolecular G-QPX involving two DNA

  9. Theoretical study of a neutral, doubly protonated, and doubly deprotonated porphyrin dithiolate used as a molecular switch

    International Nuclear Information System (INIS)

    Girard, Yvan; Kondo, Masakazu; Yoshizawa, Kazunari

    2006-01-01

    The zero-bias conductance of the neutral, doubly protonated, and doubly deprotonated porphyrin molecules used as molecular junctions between gold electrodes is investigated by using a Green's function formalism combined with density functional theory calculations. The probability for an electron to scatter through the porphyrin is predicted to be significantly increased by the protonation or the deprotonation, and the molecule could be used as a switch controlled by the pH. The shapes and energies of the frontier orbitals are used to rationalize these results

  10. Heat Shock Proteins in Tendinopathy: Novel Molecular Regulators

    Directory of Open Access Journals (Sweden)

    Neal L. Millar

    2012-01-01

    Full Text Available Tendon disorders—tendinopathies—are the primary reason for musculoskeletal consultation in primary care and account for up to 30% of rheumatological consultations. Whilst the molecular pathophysiology of tendinopathy remains difficult to interpret the disease process involving repetitive stress, and cellular load provides important mechanistic insight into the area of heat shock proteins which spans many disease processes in the autoimmune community. Heat shock proteins, also called damage-associated molecular patterns (DAMPs, are rapidly released following nonprogrammed cell death, are key effectors of the innate immune system, and critically restore homeostasis by promoting the reconstruction of the effected tissue. Our investigations have highlighted a key role for HSPs in tendion disease which may ultimately affect tissue rescue mechanisms in tendon pathology. This paper aims to provide an overview of the biology of heat shock proteins in soft tissue and how these mediators may be important regulators of inflammatory mediators and matrix regulation in tendinopathy.

  11. A palmitoylation switch mechanism regulates Rac1 function and membrane organization

    Science.gov (United States)

    Navarro-Lérida, Inmaculada; Sánchez-Perales, Sara; Calvo, María; Rentero, Carles; Zheng, Yi; Enrich, Carlos; Del Pozo, Miguel A

    2012-01-01

    The small GTPase Rac1 plays important roles in many processes, including cytoskeletal reorganization, cell migration, cell-cycle progression and gene expression. The initiation of Rac1 signalling requires at least two mechanisms: GTP loading via the guanosine triphosphate (GTP)/guanosine diphosphate (GDP) cycle, and targeting to cholesterol-rich liquid-ordered plasma membrane microdomains. Little is known about the molecular mechanisms governing this specific compartmentalization. We show that Rac1 can incorporate palmitate at cysteine 178 and that this post-translational modification targets Rac1 for stabilization at actin cytoskeleton-linked ordered membrane regions. Palmitoylation of Rac1 requires its prior prenylation and the intact C-terminal polybasic region and is regulated by the triproline-rich motif. Non-palmitoylated Rac1 shows decreased GTP loading and lower association with detergent-resistant (liquid-ordered) membranes (DRMs). Cells expressing no Rac1 or a palmitoylation-deficient mutant have an increased content of disordered membrane domains, and markers of ordered membranes isolated from Rac1-deficient cells do not correctly partition in DRMs. Importantly, cells lacking Rac1 palmitoylation show spreading and migration defects. These data identify palmitoylation as a mechanism for Rac1 function in actin cytoskeleton remodelling by controlling its membrane partitioning, which in turn regulates membrane organization. PMID:22157745

  12. Translational regulation shapes the molecular landscape of complex disease phenotypes

    Czech Academy of Sciences Publication Activity Database

    Schafer, S.; Adami, E.; Heinig, M.; Rodrigues, K. E. C.; Kreuchwig, F.; Šilhavý, Jan; van Heesch, S.; Simaite, D.; Rajewsky, N.; Cuppen, E.; Pravenec, Michal; Vingron, M.; Cook, S. A.; Hubner, N.

    2015-01-01

    Roč. 6, May 2015 (2015), s. 7200 ISSN 2041-1723 R&D Projects: GA ČR(CZ) GB14-36804G; GA MŠk(CZ) LL1204; GA MŠk(CZ) 7E10067 Institutional support: RVO:67985823 Keywords : translational regulation * RNA sequencing * ribosome profiling * rat Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 11.329, year: 2015

  13. A pentiptycene-derived molecular brake: photochemical E→Z and electrochemical Z→E switching of an enone module.

    Science.gov (United States)

    Chen, Ying-Chen; Sun, Wei-Ting; Lu, Hsiu-Feng; Chao, Ito; Huang, Guan-Jhih; Lin, Ying-Chih; Huang, Shou-Ling; Huang, Hsin-Hau; Lin, Yan-Duo; Yang, Jye-Shane

    2011-01-24

    The synthesis and brakelike performance of a new molecular system (1) consisting of a pentiptycene rotor and a 2-methyleneindanone brake are reported. The rotation kinetics of the rotor was probed by both variable-temperature (1)H and (13)C NMR spectroscopy and DFT calculations, and the switching between the brake-on and brake-off states was conducted by a combination of photochemical and electrochemical isomerization. Because of the greater steric hindrance between the rotor and the brake units in the Z form ((Z)-1) than in the E form ((E)-1), rotation of the rotor is slowed down 500-fold at room temperature (298 K) on going from (E)-1 to (Z)-1, corresponding to the brake-off and brake-on states, respectively. The (E)-1→(Z)-1 photoisomerization in acetonitrile is efficient and reaches an (E)-1/(Z)-1 ratio of 11:89 in the photostationary state upon excitation at 290 nm, attributable to a much larger isomerization quantum efficiency for (E)-1 versus (Z)-1. An efficient (Z)-1→(E)-1 isomerization (96%) was also achieved by electrochemical treatment through the radical anionic intermediates. Consequently, the reversibility of the E-Z switching of 1 is as high as 85%. The repeated E-Z switching of 1 with alternating photochemical and electrochemical treatments is also demonstrated. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell

    Science.gov (United States)

    Sotiropoulou, Georgia; Pampalakis, Georgios; Lianidou, Evi; Mourelatos, Zissimos

    2009-01-01

    Transformation of normal cells into malignant tumors requires the acquisition of six hallmark traits, e.g., self-sufficiency in growth signals, insensitivity to antigrowth signals and self-renewal, evasion of apoptosis, limitless replication potential, angiogenesis, invasion, and metastasis, which are common to all cancers (Hanahan and Weinberg 2000). These new cellular traits evolve from defects in major regulatory microcircuits that are fundamental for normal homeostasis. The discovery of microRNAs (miRNAs) as a new class of small non-protein-coding RNAs that control gene expression post-transcriptionally by binding to various mRNA targets suggests that these tiny RNA molecules likely act as molecular switches in the extensive regulatory web that involves thousands of transcripts. Most importantly, accumulating evidence suggests that numerous microRNAs are aberrantly expressed in human cancers. In this review, we discuss the emergent roles of microRNAs as switches that function to turn on/off known cellular microcircuits. We outline recent compelling evidence that deregulated microRNA-mediated control of cellular microcircuits cooperates with other well-established regulatory mechanisms to confer the hallmark traits of the cancer cell. Furthermore, these exciting insights into aberrant microRNA control in cancer-associated circuits may be exploited for cancer therapies that will target deregulated miRNA switches. PMID:19561119

  15. Adenylyl cyclase-5 in the dorsal striatum function as a molecular switch for the generation of behavioral preferences for cue-directed food choices.

    Science.gov (United States)

    Kim, Hannah; Kim, Tae-Kyung; Kim, Ji-Eun; Park, Jin-Young; Lee, Yunjin; Kang, Minkyung; Kim, Kyoung-Shim; Han, Pyung-Lim

    2014-11-07

    Behavioral choices in habits and innate behaviors occur automatically in the absence of conscious selection. These behaviors are not easily modified by learning. Similar types of behaviors also occur in various mental illnesses including drug addiction, obsessive-compulsive disorder, schizophrenia, and autism. However, underlying mechanisms are not clearly understood. In the present study, we investigated the molecular mechanisms regulating unconditioned preferred behaviors in food-choices. Mice lacking adenylyl cyclase-5 (AC5 KO mice), which is preferentially expressed in the dorsal striatum, consumed food pellets nearly one after another in cages. AC5 KO mice showed aversive behaviors to bitter tasting quinine, but they compulsively chose quinine-containing AC5 KO-pellets over fresh pellets. The unusual food-choice behaviors in AC5 KO mice were due to the gain of behavioral preferences for food pellets containing an olfactory cue, which wild-type mice normally ignored. Such food-choice behaviors in AC5 KO mice disappeared when whiskers were trimmed. Conversely, whisker trimming in wildtype mice induced behavioral preferences for AC5 KO food pellets, indicating that preferred food-choices were not learned through prior experience. Both AC5 KO mice and wildtype mice with trimmed whiskers had increased glutamatergic input from the barrel cortex into the dorsal striatum, resulting in an increase in the mGluR1-dependent signaling cascade. The siRNA-mediated inhibition of mGluR1 in the dorsal striatum in AC5 KO mice and wildtype mice with trimmed whiskers abolished preferred choices for AC5 KO food pellets, whereas siRNA-mediated inhibition of mGluR3 glutamate receptors in the dorsal striatum in wildtype mice induced behavioral preferences for AC5 KO food pellets, thus mimicking AC5 KO phenotypes. Our results show that the gain and loss of behavioral preferences for a specific cue-directed option were regulated by specific cellular factors in the dorsal striatum, such

  16. Cellular Dichotomy Between Anchorage-Independent Growth Responses to bFGF and TA Reflects Molecular Switch in Commitment to Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Waters, Katrina M.; Tan, Ruimin; Opresko, Lee K.; Quesenberry, Ryan D.; Bandyopadhyay, Somnath; Chrisler, William B.; Weber, Thomas J.

    2009-11-01

    We have investigated gene expression patterns underlying reversible and irreversible anchorage-independent growth (AIG) phenotypes to identify more sensitive markers of cell transformation for studies directed at interrogating carcinogenesis responses. In JB6 mouse epidermal cells, basic fibroblast growth factor (bFGF) induces an unusually efficient and reversible AIG response, relative to 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced AIG which is irreversible. The reversible and irreversible AIG phenotypes are characterized by largely non-overlapping global gene expression profiles. However, a subset of differentially expressed genes were identified as common to reversible and irreversible AIG phenotypes, including genes regulated in a reciprocal fashion. Hepatic leukemia factor (HLF) and D-site albumin promoter-binding protein (DBP) were increased in both bFGF and TPA soft agar colonies and selected for functional validation. Ectopic expression of human HLF and DBP in JB6 cells resulted in a marked increase in TPA- and bFGF-regulated AIG responses. HLF and DBP expression were increased in soft agar colonies arising from JB6 cells exposed to gamma radiation and in a human basal cell carcinoma tumor tissue, relative to paired non-tumor tissue. Subsequent biological network analysis suggests that many of the differentially expressed genes that are common to bFGF- and TPA-dependent AIG are regulated by c-Myc, SP-1 and HNF-4 transcription factors. Collectively, we have identified a potential molecular switch that mediates the transition from reversible to irreversible AIG.

  17. The Art of Building Small : From Molecular Switches to Motors (Nobel Lecture)

    NARCIS (Netherlands)

    Feringa, Ben L.

    2017-01-01

    A journey into the nano-world: The ability to design, use and control motor-like functions at the molecular level sets the stage for numerous dynamic molecular systems. In his Nobel Lecture, B. L. Feringa describes the evolution of the field of molecular motors and explains how to program and

  18. Molecular dynamic simulation reveals damaging impact of RAC1 F28L mutation in the switch I region.

    Directory of Open Access Journals (Sweden)

    Ambuj Kumar

    Full Text Available Ras-related C3 botulinum toxin substrate 1 (RAC1 is a plasma membrane-associated small GTPase which cycles between the active GTP-bound and inactive GDP-bound states. There is wide range of evidences indicating its active participation in inducing cancer-associated phenotypes. RAC1 F28L mutation (RAC(F28L is a fast recycling mutation which has been implicated in several cancer associated cases. In this work we have performed molecular docking and molecular dynamics simulation (~0.3 μs to investigate the conformational changes occurring in the mutant protein. The RMSD, RMSF and NHbonds results strongly suggested that the loss of native conformation in the Switch I region in RAC1 mutant protein could be the reason behind its oncogenic transformation. The overall results suggested that the mutant protein attained compact conformation as compared to the native. The major impact of mutation was observed in the Switch I region which might be the crucial reason behind the loss of interaction between the guanine ring and F28 residue.

  19. Molecular Switch for Sub-Diffraction Laser Lithography by Photoenol Intermediate-State Cis-Trans Isomerization.

    Science.gov (United States)

    Mueller, Patrick; Zieger, Markus M; Richter, Benjamin; Quick, Alexander S; Fischer, Joachim; Mueller, Jonathan B; Zhou, Lu; Nienhaus, Gerd Ulrich; Bastmeyer, Martin; Barner-Kowollik, Christopher; Wegener, Martin

    2017-06-27

    Recent developments in stimulated-emission depletion (STED) microscopy have led to a step change in the achievable resolution and allowed breaking the diffraction limit by large factors. The core principle is based on a reversible molecular switch, allowing for light-triggered activation and deactivation in combination with a laser focus that incorporates a point or line of zero intensity. In the past years, the concept has been transferred from microscopy to maskless laser lithography, namely direct laser writing (DLW), in order to overcome the diffraction limit for optical lithography. Herein, we propose and experimentally introduce a system that realizes such a molecular switch for lithography. Specifically, the population of intermediate-state photoenol isomers of α-methyl benzaldehydes generated by two-photon absorption at 700 nm fundamental wavelength can be reversibly depleted by simultaneous irradiation at 440 nm, suppressing the subsequent Diels-Alder cycloaddition reaction which constitutes the chemical core of the writing process. We demonstrate the potential of the proposed mechanism for STED-inspired DLW by covalently functionalizing the surface of glass substrates via the photoenol-driven STED-inspired process exploiting reversible photoenol activation with a polymerization initiator. Subsequently, macromolecules are grown from the functionalized areas and the spatially coded glass slides are characterized by atomic-force microscopy. Our approach allows lines with a full-width-at-half-maximum of down to 60 nm and line gratings with a lateral resolution of 100 nm to be written, both surpassing the diffraction limit.

  20. Azobenzenes as light-controlled molecular electronic switches in nanoscale metal-molecule-metal junctions.

    Science.gov (United States)

    Mativetsky, Jeffrey M; Pace, Giuseppina; Elbing, Mark; Rampi, Maria A; Mayor, Marcel; Samorì, Paolo

    2008-07-23

    Conductance switching associated with the photoisomerization of azobenzene-based (Azo) molecules was observed in nanoscopic metal-molecule-metal junctions. The junctions were formed by using a conducting atomic force microscope (C-AFM) approach, where a metallic AFM tip was used to electrically contact a gold-supported Azo self-assembled monolayer. The measured 30-fold increase in conductance is consistent with the expected decrease in tunneling barrier length resulting from the conformational change of the Azo molecule.

  1. Molecular phylogeny of the bivalve superfamily Galeommatoidea (Heterodonta, Veneroida) reveals dynamic evolution of symbiotic lifestyle and interphylum host switching

    Science.gov (United States)

    2012-01-01

    Background Galeommatoidea is a superfamily of bivalves that exhibits remarkably diverse lifestyles. Many members of this group live attached to the body surface or inside the burrows of other marine invertebrates, including crustaceans, holothurians, echinoids, cnidarians, sipunculans and echiurans. These symbiotic species exhibit high host specificity, commensal interactions with hosts, and extreme morphological and behavioral adaptations to symbiotic life. Host specialization to various animal groups has likely played an important role in the evolution and diversification of this bivalve group. However, the evolutionary pathway that led to their ecological diversity is not well understood, in part because of their reduced and/or highly modified morphologies that have confounded traditional taxonomy. This study elucidates the taxonomy of the Galeommatoidea and their evolutionary history of symbiotic lifestyle based on a molecular phylogenic analysis of 33 galeommatoidean and five putative galeommatoidean species belonging to 27 genera and three families using two nuclear ribosomal genes (18S and 28S ribosomal DNA) and a nuclear (histone H3) and mitochondrial (cytochrome oxidase subunit I) protein-coding genes. Results Molecular phylogeny recovered six well-supported major clades within Galeommatoidea. Symbiotic species were found in all major clades, whereas free-living species were grouped into two major clades. Species symbiotic with crustaceans, holothurians, sipunculans, and echiurans were each found in multiple major clades, suggesting that host specialization to these animal groups occurred repeatedly in Galeommatoidea. Conclusions Our results suggest that the evolutionary history of host association in Galeommatoidea has been remarkably dynamic, involving frequent host switches between different animal phyla. Such an unusual pattern of dynamic host switching is considered to have resulted from their commensalistic lifestyle, in which they maintain filter

  2. Molecular phylogeny of the bivalve superfamily Galeommatoidea (Heterodonta, Veneroida reveals dynamic evolution of symbiotic lifestyle and interphylum host switching

    Directory of Open Access Journals (Sweden)

    Goto Ryutaro

    2012-09-01

    Full Text Available Abstract Background Galeommatoidea is a superfamily of bivalves that exhibits remarkably diverse lifestyles. Many members of this group live attached to the body surface or inside the burrows of other marine invertebrates, including crustaceans, holothurians, echinoids, cnidarians, sipunculans and echiurans. These symbiotic species exhibit high host specificity, commensal interactions with hosts, and extreme morphological and behavioral adaptations to symbiotic life. Host specialization to various animal groups has likely played an important role in the evolution and diversification of this bivalve group. However, the evolutionary pathway that led to their ecological diversity is not well understood, in part because of their reduced and/or highly modified morphologies that have confounded traditional taxonomy. This study elucidates the taxonomy of the Galeommatoidea and their evolutionary history of symbiotic lifestyle based on a molecular phylogenic analysis of 33 galeommatoidean and five putative galeommatoidean species belonging to 27 genera and three families using two nuclear ribosomal genes (18S and 28S ribosomal DNA and a nuclear (histone H3 and mitochondrial (cytochrome oxidase subunit I protein-coding genes. Results Molecular phylogeny recovered six well-supported major clades within Galeommatoidea. Symbiotic species were found in all major clades, whereas free-living species were grouped into two major clades. Species symbiotic with crustaceans, holothurians, sipunculans, and echiurans were each found in multiple major clades, suggesting that host specialization to these animal groups occurred repeatedly in Galeommatoidea. Conclusions Our results suggest that the evolutionary history of host association in Galeommatoidea has been remarkably dynamic, involving frequent host switches between different animal phyla. Such an unusual pattern of dynamic host switching is considered to have resulted from their commensalistic lifestyle, in

  3. A circadian clock-regulated toggle switch explains AtGRP7 and AtGRP8 oscillations in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Christoph Schmal

    Full Text Available The circadian clock controls many physiological processes in higher plants and causes a large fraction of the genome to be expressed with a 24h rhythm. The transcripts encoding the RNA-binding proteins AtGRP7 (Arabidopsis thaliana Glycine Rich Protein 7 and AtGRP8 oscillate with evening peaks. The circadian clock components CCA1 and LHY negatively affect AtGRP7 expression at the level of transcription. AtGRP7 and AtGRP8, in turn, negatively auto-regulate and reciprocally cross-regulate post-transcriptionally: high protein levels promote the generation of an alternative splice form that is rapidly degraded. This clock-regulated feedback loop has been proposed to act as a molecular slave oscillator in clock output. While mathematical models describing the circadian core oscillator in Arabidopsis thaliana were introduced recently, we propose here the first model of a circadian slave oscillator. We define the slave oscillator in terms of ordinary differential equations and identify the model's parameters by an optimization procedure based on experimental results. The model successfully reproduces the pertinent experimental findings such as waveforms, phases, and half-lives of the time-dependent concentrations. Furthermore, we obtain insights into possible mechanisms underlying the observed experimental dynamics: the negative auto-regulation and reciprocal cross-regulation via alternative splicing could be responsible for the sharply peaking waveforms of the AtGRP7 and AtGRP8 mRNA. Moreover, our results suggest that the AtGRP8 transcript oscillations are subordinated to those of AtGRP7 due to a higher impact of AtGRP7 protein on alternative splicing of its own and of the AtGRP8 pre-mRNA compared to the impact of AtGRP8 protein. Importantly, a bifurcation analysis provides theoretical evidence that the slave oscillator could be a toggle switch, arising from the reciprocal cross-regulation at the post-transcriptional level. In view of this

  4. "Plug and play" logic gates based on fluorescence switching regulated by self-assembly of nucleotide and lanthanide ions.

    Science.gov (United States)

    Pu, Fang; Ren, Jinsong; Qu, Xiaogang

    2014-06-25

    Molecular logic gates in response to chemical, biological, or optical input signals at a molecular level have received much interest over the past decade. Herein, we construct "plug and play" logic systems based on the fluorescence switching of guest molecules confined in coordination polymer nanoparticles generated from nucleotide and lanthanide ions. In the system, the addition of new modules directly enables new logic functions. PASS 0, YES, PASS 1, NOT, IMP, OR, and AND gates are successfully constructed in sequence. Moreover, different logic gates (AND, INH, and IMP) can be constructed using different guest molecules and the same input combinations. The work will be beneficial to the future logic design and expand the applications of coordination polymers.

  5. A Redox-Active Bistable Molecular Switch Mounted inside a Metal-Organic Framework.

    Science.gov (United States)

    Chen, Qishui; Sun, Junling; Li, Peng; Hod, Idan; Moghadam, Peyman Z; Kean, Zachary S; Snurr, Randall Q; Hupp, Joseph T; Farha, Omar K; Stoddart, J Fraser

    2016-11-02

    We describe the incorporation of a bistable mechanically interlocked molecule (MIM) into a robust Zr-based metal-organic framework (MOF), NU-1000, by employing a post-synthetic functionalization protocol. On average, close to two bistable [2]catenanes can be incorporated per repeating unit of the hexagonal channels of NU-1000. The reversible redox-switching of the bistable [2]catenanes is retained inside the MOF, as evidenced by solid-state UV-vis-NIR reflectance spectroscopy and cyclic voltammetry. This research demonstrates that bistable MIMs are capable of exhibiting robust dynamics inside the nanopores of a MOF.

  6. Molecular mechanisms of platelet P2Y(12) receptor regulation.

    Science.gov (United States)

    Cunningham, Margaret R; Nisar, Shaista P; Mundell, Stuart J

    2013-02-01

    Platelets are critical for haemostasis, however inappropriate activation can lead to the development of arterial thrombosis, which can result in heart attack and stroke. ADP is a key platelet agonist that exerts its actions via stimulation of two surface GPCRs (G-protein-coupled receptors), P2Y(1) and P2Y(12). Similar to most GPCRs, P2Y receptor activity is tightly regulated by a number of complex mechanisms including receptor desensitization, internalization and recycling. In the present article, we review the molecular mechanisms that underlie P2Y(1) and P2Y(12) receptor regulation, with particular emphasis on the structural motifs within the P2Y(12) receptor, which are required to maintain regulatory protein interaction. The implications of these findings for platelet responsiveness are also discussed.

  7. A complementary switching mechanism for organic memory devices to regulate the conductance of binary states

    Science.gov (United States)

    Vyas, Giriraj; Dagar, Parveen; Sahu, Satyajit

    2016-06-01

    We have fabricated an organic non-volatile memory device wherein the ON/OFF current ratio has been controlled by varying the concentration of a small organic molecule, 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ), in an insulating matrix of a polymer Poly(4-vinylphenol) (PVP). A maximum ON-OFF ratio of 106 is obtained when the concentration of DDQ is half or 10 wt. % of PVP. In this process, the switching direction for the devices has also been altered, indicating the disparity in conduction mechanism. Conduction due to metal filament formation through the active material and the voltage dependent conformational change of the organic molecule seem to be the motivation behind the gradual change in the switching direction.

  8. Behavioral aspects of regulation: A discussion on switching and demand response in Turkish electricity market

    International Nuclear Information System (INIS)

    Sirin, Selahattin Murat; Gonul, Mustafa Sinan

    2016-01-01

    Electricity sector has been transformed from state-owned monopolistic utilities to competitive markets with an aim to promote incentives for improving efficiency, reducing costs and increasing service quality to customers. One of the cardinal assumptions of the liberalized and competitive electricity markets is the rational actor, and decision-makers are assumed to make the best decisions that maximize their utility. However, a vast literature on behavioral economics has shown the weakness of economic theory in explaining and predicting individuals’ decision-making behavior. This issue is quite important for competition in electricity markets in which consumers’ preferences have a significant role. Despite its importance, this issue has almost been neglected in Turkey, which has taken major steps in electricity sector restructuring. Therefore, this paper aims to examine switching and demand response behavior in Turkish electricity market by using multiple correspondence and panel data analysis, and findings are discussed in light of the neoclassical and behavioral economics literature. Analyses’ results show that consumers’ switching and demand response behavior is consistent with the neoclassical literature to some extent; however, behavioral factors are also affecting consumers’ decisions. Furthermore, there are systemic problems that hinder effective functioning of the electricity market and restrict competition. - Highlights: • Behavioral economics can provide insights for consumer’ decisions. • Switching and demand response behavior is examined by econometric methods. • Results is consistent with the neoclassical literature to some extent • However, behavioral factors are also affecting consumers’ decisions.

  9. Molecular current switch: principles and photoelectronic characterization of the model system

    Czech Academy of Sciences Publication Activity Database

    Vala, M.; Weiter, M.; Nešpůrek, Stanislav

    2005-01-01

    Roč. 15, č. 3 (2005), s. 28 ISSN 1210-7409 Institutional research plan: CEZ:AV0Z40500505 Keywords : molecular electronics * photochromism * charge transport Subject RIV: CD - Macromolecular Chemistry

  10. Cytoskeletal Reorganization Drives Mesenchymal Condensation and Regulates Downstream Molecular Signaling.

    Directory of Open Access Journals (Sweden)

    Poulomi Ray

    Full Text Available Skeletal condensation occurs when specified mesenchyme cells self-organize over several days to form a distinctive cartilage template. Here, we determine how and when specified mesenchyme cells integrate mechanical and molecular information from their environment, forming cartilage condensations in the pharyngeal arches of chick embryos. By disrupting cytoskeletal reorganization, we demonstrate that dynamic cell shape changes drive condensation and modulate the response of the condensing cells to Fibroblast Growth Factor (FGF, Bone Morphogenetic Protein (BMP and Transforming Growth Factor beta (TGF-β signaling pathways. Rho Kinase (ROCK-driven actomyosin contractions and Myosin II-generated differential cell cortex tension regulate these cell shape changes. Disruption of the condensation process inhibits the differentiation of the mesenchyme cells into chondrocytes, demonstrating that condensation regulates the fate of the mesenchyme cells. We also find that dorsal and ventral condensations undergo distinct cell shape changes. BMP signaling is instructive for dorsal condensation-specific cell shape changes. Moreover, condensations exhibit ventral characteristics in the absence of BMP signaling, suggesting that in the pharyngeal arches ventral morphology is the ground pattern. Overall, this study characterizes the interplay between cytoskeletal dynamics and molecular signaling in a self-organizing system during tissue morphogenesis.

  11. Current-induced forces: a new mechanism to induce negative differential resistance and current-switching effect in molecular junctions

    Science.gov (United States)

    Gu, Lei; Fu, Hua-Hua

    2015-12-01

    Current-induced forces can excite molecules, polymers and other low-dimensional materials, which in turn leads to an effective gate voltage through Holstein interaction. Here, by taking a short asymmetric DNA junction as an example, and using the Langevin approach, we find that when suppression of charge transport by the effective gate voltage surpasses the current increase from an elevated voltage bias, the current-voltage (I-V) curves display strong negative differential resistance (NDR) and perfect current-switching characteristics. The asymmetric DNA chain differs in mechanical stability under inverse voltages and the I-V curve is asymmetric about inverse biases, which can be used to understand recent transport experiments on DNA chains, and meanwhile provides a new strategy to realize NDR in molecular junctions and other low-dimensional quantum systems.

  12. Current-induced forces: a new mechanism to induce negative differential resistance and current-switching effect in molecular junctions

    International Nuclear Information System (INIS)

    Gu, Lei; Fu, Hua-Hua

    2015-01-01

    Current-induced forces can excite molecules, polymers and other low-dimensional materials, which in turn leads to an effective gate voltage through Holstein interaction. Here, by taking a short asymmetric DNA junction as an example, and using the Langevin approach, we find that when suppression of charge transport by the effective gate voltage surpasses the current increase from an elevated voltage bias, the current-voltage (I–V) curves display strong negative differential resistance (NDR) and perfect current-switching characteristics. The asymmetric DNA chain differs in mechanical stability under inverse voltages and the I–V curve is asymmetric about inverse biases, which can be used to understand recent transport experiments on DNA chains, and meanwhile provides a new strategy to realize NDR in molecular junctions and other low-dimensional quantum systems. (paper)

  13. Conductive polymer/high-TC superconductor sandwich structures: An example of a molecular switch for controlling superconductivity

    International Nuclear Information System (INIS)

    McDevitt, J.T.; Haupt, S.G.; Lo, R.K.

    1994-01-01

    The preparation of a hybrid conducting polymer/high-temperature superconductor device consisting of a polypyrrole coated YBa 2 Cu 3 O 7-x microbridge is reported. Electrochemical techniques are exploited to alter the oxidation state of the polymer and, in doing so, it is found for the first time that superconductivity can be modulated in a controllable and reproducible fashion by a polymer layer. Whereas the neutral (insulating) polypyrrole only slightly influences the electrical properties of the underlying YBa 2 Cu 3 O 7- film, the oxidized (conductive) polymer depresses T c by up to 50K. In a similar fashion, the oxidation state of the polymer is found to modulate reversibly the magnitude of J c , the superconducting critical current. Thus, a new type of molecular switch for controlling superconductivity is demonstrated. Electrochemical, resistance vs. temperature, atomic force microscopy and scanning electron microscopy measurements are utilized to explore the polymer/superconductor interactions

  14. Molecular mechanisms of aging and immune system regulation in Drosophila.

    Science.gov (United States)

    Eleftherianos, Ioannis; Castillo, Julio Cesar

    2012-01-01

    Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span.

  15. On the Role of the SP1 Domain in HIV-1 Particle Assembly: a Molecular Switch?▿

    Science.gov (United States)

    Datta, Siddhartha A. K.; Temeselew, Lakew G.; Crist, Rachael M.; Soheilian, Ferri; Kamata, Anne; Mirro, Jane; Harvin, Demetria; Nagashima, Kunio; Cachau, Raul E.; Rein, Alan

    2011-01-01

    Expression of a retroviral protein, Gag, in mammalian cells is sufficient for assembly of immature virus-like particles (VLPs). VLP assembly is mediated largely by interactions between the capsid (CA) domains of Gag molecules but is facilitated by binding of the nucleocapsid (NC) domain to nucleic acid. We have investigated the role of SP1, a spacer between CA and NC in HIV-1 Gag, in VLP assembly. Mutational analysis showed that even subtle changes in the first 4 residues of SP1 destroy the ability of Gag to assemble correctly, frequently leading to formation of tubes or other misassembled structures rather than proper VLPs. We also studied the conformation of the CA-SP1 junction region in solution, using both molecular dynamics simulations and circular dichroism. Consonant with nuclear magnetic resonance (NMR) studies from other laboratories, we found that SP1 is nearly unstructured in aqueous solution but undergoes a concerted change to an α-helical conformation when the polarity of the environment is reduced by addition of dimethyl sulfoxide (DMSO), trifluoroethanol, or ethanol. Remarkably, such a coil-to-helix transition is also recapitulated in an aqueous medium at high peptide concentrations. The exquisite sensitivity of SP1 to mutational changes and its ability to undergo a concentration-dependent structural transition raise the possibility that SP1 could act as a molecular switch to prime HIV-1 Gag for VLP assembly. We suggest that changes in the local environment of SP1 when Gag oligomerizes on nucleic acid might trigger this switch. PMID:21325421

  16. Dual origin of defect magnetism in graphene and its reversible switching by molecular doping.

    Science.gov (United States)

    Nair, R R; Tsai, I-L; Sepioni, M; Lehtinen, O; Keinonen, J; Krasheninnikov, A V; Castro Neto, A H; Katsnelson, M I; Geim, A K; Grigorieva, I V

    2013-01-01

    Control of magnetism by applied voltage is desirable for spintronics applications. Finding a suitable material remains an elusive goal, with only a few candidates found so far. Graphene is one of them and attracts interest because of its weak spin-orbit interaction, the ability to control electronic properties by the electric field effect and the possibility to introduce paramagnetic centres such as vacancies and adatoms. Here we show that the magnetism of adatoms in graphene is itinerant and can be controlled by doping, so that magnetic moments are switched on and off. The much-discussed vacancy magnetism is found to have a dual origin, with two approximately equal contributions; one from itinerant magnetism and the other from dangling bonds. Our work suggests that graphene's spin transport can be controlled by the field effect, similar to its electronic and optical properties, and that spin diffusion can be significantly enhanced above a certain carrier density.

  17. New concepts in molecular imaging: non-invasive MRI spotting of proteolysis using an Overhauser effect switch.

    Directory of Open Access Journals (Sweden)

    Philippe Mellet

    Full Text Available Proteolysis, involved in many processes in living organisms, is tightly regulated in space and time under physiological conditions. However deregulation can occur with local persistent proteolytic activities, e.g. in inflammation, cystic fibrosis, tumors, or pancreatitis. Furthermore, little is known about the role of many proteases, hence there is a need of new imaging methods to visualize specifically normal or disease-related proteolysis in intact bodies.In this paper, a new concept for non invasive proteolysis imaging is proposed. Overhauser-enhanced Magnetic Resonance Imaging (OMRI at 0.2 Tesla was used to monitor the enzymatic hydrolysis of a nitroxide-labeled protein. In vitro, image intensity switched from 1 to 25 upon proteolysis due to the associated decrease in the motional correlation time of the substrate. The OMRI experimental device used in this study is consistent with protease imaging in mice at 0.2 T without significant heating. Simulations show that this enzymatic-driven OMRI signal switch can be obtained at lower frequencies suitable for larger animals or humans.The method is highly sensitive and makes possible proteolysis imaging in three dimensions with a good spatial resolution. Any protease could be targeted specifically through the use of taylor-made cleavable macromolecules. At short term OMRI of proteolysis may be applied to basic research as well as to evaluate therapeutic treatments in small animal models of experimental diseases.

  18. A Study of Electrocyclic Reactions in a Molecular Junction: Mechanistic and Energetic Requirements for Switching in the Coulomb Blockade Regime.

    Science.gov (United States)

    Olsen, Stine T; Brøndsted Nielsen, Mogens; Hansen, Thorsten; Ratner, Mark A; Mikkelsen, Kurt V

    2017-06-20

    Molecular photoswitches incorporated in molecular junctions yield the possibility of light-controlled switching of conductance due to the electronic difference of the photoisomers. Another isomerization mechanism, dark photoswitching, promoted by a voltage stimulus rather than by light, can be operative in the Coulomb blockade regime for a specific charge state of the molecule. Here we elucidate theoretically the mechanistic and thermodynamic restrictions for this dark photoswitching for donor-acceptor substituted 4n and 4n+2 π-electron open-chain oligoenes (1,3-butadiene and 1,3,5-hexatriene) by considering the molecular energies and orbitals of the molecules placed in a junction. For an electrocyclic ring closure reaction to occur for these compounds, we put forward two requirements: a) the closed stereoisomer (cis or trans form) must be of lower energy than the open form, and b) the reaction pathway must be in accordance to the orbital symmetry rules expressed by the Woodward-Hoffmann rules (when the electrodes do not significantly alter the molecular orbital appearances). We find these two requirements to be valid for the dianion of (1E,3Z,5E)-hexa-1,3,5-triene-1,6-diamine, and the Coulomb blockade diamonds were therefore modeled for this compound to elucidate how a dark photoswitching event would manifest itself in the stability plot. From this modeling of conductance as a function of gate and bias potentials, we predict a collapse in Coulomb diamond size, that is, a decrease in the height of the island of zero conductance. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Fast transient current response to switching events in short chains of molecular islands

    Czech Academy of Sciences Publication Activity Database

    Kalvová, Anděla; Špička, Václav; Velický, B.

    2013-01-01

    Roč. 26, č. 4 (2013), s. 773-777 ISSN 1557-1939 R&D Projects: GA ČR GAP204/12/0897 Institutional support: RVO:68378271 Keywords : nonequilibrium * molecular islands * initial correlations * transient currents Subject RIV: BE - Theoretical Physics Impact factor: 0.930, year: 2013

  20. Stress responses during ageing: molecular pathways regulating protein homeostasis.

    Science.gov (United States)

    Kyriakakis, Emmanouil; Princz, Andrea; Tavernarakis, Nektarios

    2015-01-01

    The ageing process is characterized by deterioration of physiological function accompanied by frailty and ageing-associated diseases. The most broadly and well-studied pathways influencing ageing are the insulin/insulin-like growth factor 1 signaling pathway and the dietary restriction pathway. Recent studies in diverse organisms have also delineated emerging pathways, which collectively or independently contribute to ageing. Among them the proteostatic-stress-response networks, inextricably affect normal ageing by maintaining or restoring protein homeostasis to preserve proper cellular and organismal function. In this chapter, we survey the involvement of heat stress and endoplasmic reticulum stress responses in the regulation of longevity, placing emphasis on the cross talk between different response mechanisms and their systemic effects. We further discuss novel insights relevant to the molecular pathways mediating these stress responses that may facilitate the development of innovative interventions targeting age-related pathologies such as diabetes, cancer, cardiovascular and neurodegenerative diseases.

  1. Molecular targets of epigenetic regulation and effectors of environmental influences

    International Nuclear Information System (INIS)

    Choudhuri, Supratim; Cui Yue; Klaassen, Curtis D.

    2010-01-01

    The true understanding of what we currently define as epigenetics evolved over time as our knowledge on DNA methylation and chromatin modifications and their effects on gene expression increased. The current explosion of research on epigenetics and the increasing documentation of the effects of various environmental factors on DNA methylation, chromatin modification, as well as on the expression of small non-coding RNAs (ncRNAs) have expanded the scope of research on the etiology of various diseases including cancer. The current review briefly discusses the molecular mechanisms of epigenetic regulation and expands the discussion with examples on the role of environment, such as the immediate environment during development, in inducing epigenetic changes and modulating gene expression.

  2. Reversible switch between the nanoporous and the nonporous state of amphiphilic block copolymer films regulated by selective swelling.

    Science.gov (United States)

    Yan, Nina; Wang, Yong

    2015-09-21

    Switchable nanoporous films, which can repeatedly alternate their porosities, are of great interest in a diversity of fields. Currently these intelligent materials are mostly based on polyelectrolytes and their porosities can change only in relatively narrow ranges, typically under wet conditions, severely limiting their applications. Here we develop a new system, which is capable of reversibly switching between a highly porous state and a nonporous state dozens of times regulated simply by exposure to selective solvents. In this system nanopores are created or reversibly eliminated in films of a block copolymer, polystyrene-block-poly(2-vinyl pyridine) (PS-b-P2VP), by exposing the films to P2VP-selective or PS-selective solvents, respectively. The mechanism of the switch is based on the selective swelling of the constituent blocks in corresponding solvents, which is a nondestructive and easily controllable process enabling the repeatable and ample switch between the open and the closed state. Systematic microscopic and ellipsometric characterization methods are performed to elucidate the pore-closing course induced by nonsolvents and the cycling between the pore-open and the pore-closed state up to 20 times. The affinity of the solvent for PS blocks is found to play a dominating role in determining the pore-closing process and the porosities of the pore-open films increase with the cycling numbers as a result of loose packing conditions of the polymer chains. We finally demonstrate the potential applications of these films as intelligent antireflection coatings and drug carriers.

  3. Regulation of wheat seed dormancy by after-ripening is mediated by specific transcriptional switches that induce changes in seed hormone metabolism and signaling.

    Directory of Open Access Journals (Sweden)

    Aihua Liu

    Full Text Available Treatments that promote dormancy release are often correlated with changes in seed hormone content and/or sensitivity. To understand the molecular mechanisms underlying the role of after-ripening (seed dry storage in triggering hormone related changes and dormancy decay in wheat (Triticum aestivum, temporal expression patterns of genes related to abscisic acid (ABA, gibberellin (GA, jasmonate and indole acetic acid (IAA metabolism and signaling, and levels of the respective hormones were examined in dormant and after-ripened seeds in both dry and imbibed states. After-ripening mediated developmental switch from dormancy to germination appears to be associated with declines in seed sensitivity to ABA and IAA, which are mediated by transcriptional repressions of PROTEIN PHOSPHATASE 2C, SNF1-RELATED PROTEIN KINASE2, ABA INSENSITIVE5 and LIPID PHOSPHATE PHOSPHTASE2, and AUXIN RESPONSE FACTOR and RELATED TO UBIQUITIN1 genes. Transcriptomic analysis of wheat seed responsiveness to ABA suggests that ABA inhibits the germination of wheat seeds partly by repressing the transcription of genes related to chromatin assembly and cell wall modification, and activating that of GA catabolic genes. After-ripening induced seed dormancy decay in wheat is also associated with the modulation of seed IAA and jasmonate contents. Transcriptional control of members of the ALLENE OXIDE SYNTHASE, 3-KETOACYL COENZYME A THIOLASE, LIPOXYGENASE and 12-OXOPHYTODIENOATE REDUCTASE gene families appears to regulate seed jasmonate levels. Changes in the expression of GA biosynthesis genes, GA 20-OXIDASE and GA 3-OXIDASE, in response to after-ripening implicate this hormone in enhancing dormancy release and germination. These findings have important implications in the dissection of molecular mechanisms underlying regulation of seed dormancy in cereals.

  4. Electron induced conformational changes of an imine-based molecular switch on a Au(111) surface

    Energy Technology Data Exchange (ETDEWEB)

    Lotze, Christian; Henningsen, Nils; Franke, Katharina; Schulze, Gunnar; Pascual, Jose Ignacio [Inst. f. Experimentalphysik, Freie Universitaet Berlin (Germany); Luo, Ying; Haag, Rainer [Inst. f. Organische Chemie, Freie Universitaet Berlin (Germany)

    2009-07-01

    Azobenzene-based molecules exhibit a cis-trans configurational photoisomerisation in solution. Recently, the adsorption properties of azobenzene derivatives have been investigated on different metal surfaces in order to explore the possible changes in the film properties induced by external stimuli. In azobenzene, the diazo-bridge is a key group for the isomerization process. Its interaction with a metal surface is dominated through the N lone-pair electrons, which reduces the efficiency of the conformational change. In order to reduce the molecule-surface interaction, we explore an alternative molecular architecture by substituting the diazo-bridge (-N=N-) of azobenzene by an imine-group (-N=CH-). We have investigated the imine-based compound para-carboxyl-di-benzene-imine (PCI) adsorbed on a Au(111) surface. The carboxylic terminations mediates the formation of strongly bonded molecular dimers, which align in ordered rows preferentially following the fcc regions of the Au(111) herringbone reconstruction. Low temperature scanning tunneling microscopy was used to induce conformational changes between trans and cis state of individual molecules in a molecular monolayer.

  5. LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs.

    Science.gov (United States)

    Hong, Sungki; Freeberg, Mallory A; Han, Ting; Kamath, Avani; Yao, Yao; Fukuda, Tomoko; Suzuki, Tsukasa; Kim, John K; Inoki, Ken

    2017-06-26

    The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5'TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5'TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5' and 3'UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5'UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3'UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis.

  6. Molecular engineering of lanthanide ion chelating phospholipids generating assemblies with a switched magnetic susceptibility.

    Science.gov (United States)

    Isabettini, Stéphane; Massabni, Sarah; Hodzic, Arnel; Durovic, Dzana; Kohlbrecher, Joachim; Ishikawa, Takashi; Fischer, Peter; Windhab, Erich J; Walde, Peter; Kuster, Simon

    2017-08-09

    Lanthanide ion (Ln 3+ ) chelating amphiphiles are powerful molecules for tailoring the magnetic response of polymolecular assemblies. Mixtures of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-ethanolamine-diethylene triaminepentaacetate (DMPE-DTPA) complexed to Ln 3+ deliver highly magnetically responsive bicelles. Their magnetic properties are readily tuned by changing the bicellar size or the magnetic susceptibility Δχ of the bilayer lipids. The former technique is intrinsically bound to the region of the phase diagram guarantying the formation of bicelles. Methods aiming towards manipulating the Δχ of the bilayer are comparatively more robust, flexible and lacking. Herein, we synthesized a new Ln 3+ chelating phospholipid using glutamic acid as a backbone: DMPE-Glu-DTPA. The chelate polyhedron was specifically engineered to alter the Δχ, whilst remaining geometrically similar to DMPE-DTPA. Planar asymmetric assemblies hundreds of nanometers in size were achieved presenting unprecedented magnetic alignments. The DMPE-Glu-DTPA/Ln 3+ complex switched the Δχ, achieving perpendicular alignment of assemblies containing Dy 3+ and parallel alignment of those containing Tm 3+ . Moreover, samples with chelated Yb 3+ were more alignable than the Tm 3+ chelating counterparts. Such a possibility has never been demonstrated for planar Ln 3+ chelating polymolecular assemblies. The physico-chemical properties of these novel assemblies were further studied by monitoring the alignment behavior at different temperatures and by including 16 mol% of cholesterol (Chol-OH) in the phospholipid bilayer. The DMPE-Glu-DTPA/Ln 3+ complex and the resulting assemblies are promising candidates for applications in numerous fields including pharmaceutical technologies, structural characterization of membrane biomolecules by NMR spectroscopy, as contrasting agents for magnetic resonance imaging, and for the development of smart optical gels.

  7. Ecdysone Receptor-based Singular Gene Switches for Regulated Transgene Expression in Cells and Adult Rodent Tissues

    Directory of Open Access Journals (Sweden)

    Seoghyun Lee

    2016-01-01

    Full Text Available Controlled gene expression is an indispensable technique in biomedical research. Here, we report a convenient, straightforward, and reliable way to induce expression of a gene of interest with negligible background expression compared to the most widely used tetracycline (Tet-regulated system. Exploiting a Drosophila ecdysone receptor (EcR-based gene regulatory system, we generated nonviral and adenoviral singular vectors designated as pEUI(+ and pENTR-EUI, respectively, which contain all the required elements to guarantee regulated transgene expression (GAL4-miniVP16-EcR, termed GvEcR hereafter, and 10 tandem repeats of an upstream activation sequence promoter followed by a multiple cloning site. Through the transient and stable transfection of mammalian cell lines with reporter genes, we validated that tebufenozide, an ecdysone agonist, reversibly induced gene expression, in a dose- and time-dependent manner, with negligible background expression. In addition, we created an adenovirus derived from the pENTR-EUI vector that readily infected not only cultured cells but also rodent tissues and was sensitive to tebufenozide treatment for regulated transgene expression. These results suggest that EcR-based singular gene regulatory switches would be convenient tools for the induction of gene expression in cells and tissues in a tightly controlled fashion.

  8. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation

    DEFF Research Database (Denmark)

    Hansen, Jacob B; Jørgensen, Claus; Petersen, Rasmus K

    2004-01-01

    Adipocyte precursor cells give raise to two major cell populations with different physiological roles: white and brown adipocytes. Here we demonstrate that the retinoblastoma protein (pRB) regulates white vs. brown adipocyte differentiation. Functional inactivation of pRB in wild-type mouse embryo...... fibroblasts (MEFs) and white preadipocytes by expression of simian virus 40 large T antigen results in the expression of the brown fat-specific uncoupling protein 1 (UCP-1) in the adipose state. Retinoblastoma gene-deficient (Rb-/-) MEFs and stem cells, but not the corresponding wild-type cells, differentiate...

  9. Dietary-Induced Signals That Activate the Gonadal Longevity Pathway during Development Regulate a Proteostasis Switch in Caenorhabditis elegans Adulthood

    Directory of Open Access Journals (Sweden)

    Netta Shemesh

    2017-08-01

    Full Text Available Cell-non-autonomous signals dictate the functional state of cellular quality control systems, remodeling the ability of cells to cope with stress and maintain protein homeostasis (proteostasis. One highly regulated cell-non-autonomous switch controls proteostatic capacity in Caenorhabditis elegans adulthood. Signals from the reproductive system down-regulate cyto-protective pathways, unless countered by signals reporting on germline proliferation disruption. Here, we utilized dihomo-γ-linolenic acid (DGLA that depletes the C. elegans germline to ask when cell-non-autonomous signals from the reproductive system determine somatic proteostasis and whether such regulation is reversible. We found that diet supplementation of DGLA resulted in the maintenance of somatic proteostasis after the onset of reproduction. DGLA-dependent proteostasis remodeling was only effective if animals were exposed to DGLA during larval development. A short exposure of 16 h during the second to fourth larval stages was sufficient and required to maintain somatic proteostasis in adulthood but not to extend lifespan. The reproductive system was required for DGLA-dependent remodeling of proteostasis in adulthood, likely via DGLA-dependent disruption of germline stem cells. However, arachidonic acid (AA, a somatic regulator of this pathway that does not require the reproductive system, presented similar regulatory timing. Finally, we showed that DGLA- and AA-supplementation led to activation of the gonadal longevity pathway but presented differential regulatory timing. Proteostasis and stress response regulators, including hsf-1 and daf-16, were only activated if exposed to DGLA and AA during development, while other gonadal longevity factors did not show this regulatory timing. We propose that C. elegans determines its proteostatic fate during development and is committed to either reproduction, and thus present restricted proteostasis, or survival, and thus present robust

  10. A p300 and SIRT1 Regulated Acetylation Switch of C/EBPα Controls Mitochondrial Function

    NARCIS (Netherlands)

    Zaini, Mohamad A; Müller, Christine; de Jong, Tristan V; Ackermann, Tobias; Hartleben, Götz; Kortman, Gertrud; Gührs, Karl-Heinz; Fusetti, Fabrizia; Krämer, Oliver H; Guryev, Victor; Calkhoven, Cornelis F

    2018-01-01

    Cellular metabolism is a tightly controlled process in which the cell adapts fluxes through metabolic pathways in response to changes in nutrient supply. Among the transcription factors that regulate gene expression and thereby cause changes in cellular metabolism is the basic leucine-zipper (bZIP)

  11. A molecular switch driving inactivation in the cardiac K+ channel HERG.

    Directory of Open Access Journals (Sweden)

    David A Köpfer

    Full Text Available K(+ channels control transmembrane action potentials by gating open or closed in response to external stimuli. Inactivation gating, involving a conformational change at the K(+ selectivity filter, has recently been recognized as a major K(+ channel regulatory mechanism. In the K(+ channel hERG, inactivation controls the length of the human cardiac action potential. Mutations impairing hERG inactivation cause life-threatening cardiac arrhythmia, which also occur as undesired side effects of drugs. In this paper, we report atomistic molecular dynamics simulations, complemented by mutational and electrophysiological studies, which suggest that the selectivity filter adopts a collapsed conformation in the inactivated state of hERG. The selectivity filter is gated by an intricate hydrogen bond network around residues S620 and N629. Mutations of this hydrogen bond network are shown to cause inactivation deficiency in electrophysiological measurements. In addition, drug-related conformational changes around the central cavity and pore helix provide a functional mechanism for newly discovered hERG activators.

  12. Ion channel density regulates switches between regular and fast spiking in soma but not in axons.

    Directory of Open Access Journals (Sweden)

    Hugo Zeberg

    2010-04-01

    Full Text Available The threshold firing frequency of a neuron is a characterizing feature of its dynamical behaviour, in turn determining its role in the oscillatory activity of the brain. Two main types of dynamics have been identified in brain neurons. Type 1 dynamics (regular spiking shows a continuous relationship between frequency and stimulation current (f-I(stim and, thus, an arbitrarily low frequency at threshold current; Type 2 (fast spiking shows a discontinuous f-I(stim relationship and a minimum threshold frequency. In a previous study of a hippocampal neuron model, we demonstrated that its dynamics could be of both Type 1 and Type 2, depending on ion channel density. In the present study we analyse the effect of varying channel density on threshold firing frequency on two well-studied axon membranes, namely the frog myelinated axon and the squid giant axon. Moreover, we analyse the hippocampal neuron model in more detail. The models are all based on voltage-clamp studies, thus comprising experimentally measurable parameters. The choice of analysing effects of channel density modifications is due to their physiological and pharmacological relevance. We show, using bifurcation analysis, that both axon models display exclusively Type 2 dynamics, independently of ion channel density. Nevertheless, both models have a region in the channel-density plane characterized by an N-shaped steady-state current-voltage relationship (a prerequisite for Type 1 dynamics and associated with this type of dynamics in the hippocampal model. In summary, our results suggest that the hippocampal soma and the two axon membranes represent two distinct kinds of membranes; membranes with a channel-density dependent switching between Type 1 and 2 dynamics, and membranes with a channel-density independent dynamics. The difference between the two membrane types suggests functional differences, compatible with a more flexible role of the soma membrane than that of the axon membrane.

  13. Structural basis of syndecan-4 phosphorylation as a molecular switch to regulate signaling

    DEFF Research Database (Denmark)

    Koo, Bon-Kyung; Jung, Young Sang; Shin, Joon

    2005-01-01

    The syndecan transmembrane proteoglycans are involved in the organization of the actin cytoskeleton and have important roles as cell surface receptors during cell-matrix interactions. We have shown that the syndecan-4 cytoplasmic domain (4L) forms oligomeric complexes that bind to and stimulate...

  14. Redox-switched complexation/decomplexation of K(+) and Cs(+) by molecular cyanometalate boxes.

    Science.gov (United States)

    Boyer, Julie L; Ramesh, Maya; Yao, Haijun; Rauchfuss, Thomas B; Wilson, Scott R

    2007-02-21

    The reaction of [N(PPh(3))(2)][CpCo(CN)(3)] and [Cb*Co(NCMe)(3)]PF(6) (Cb* = C(4)Me(4)) in the presence of K(+) afforded {K subset[CpCo(CN)(3)](4)[Cb*Co](4)}PF(6), [KCo(8)]PF(6). IR, NMR, ESI-MS indicate that [KCo(8)]PF(6) is a high-symmetry molecular box containing a potassium ion at its interior. The analogous heterometallic cage {K subset[Cp*Rh(CN)(3)](4)[Cb*Co](4)}PF(6) ([KRh(4)Co(4)]PF(6)) was prepared similarly via the condensation of K[Cp*Rh(CN)(3)] and [Cb*Co(NCMe)(3)]PF(6). Crystallographic analysis confirmed the structure of [KCo(8)]PF(6). The cyanide ligands are ordered, implying that no Co-CN bonds are broken upon cage formation and ion complexation. Eight Co-CN-Co edges of the box bow inward toward the encapsulated K(+), and the remaining four mu-CN ligands bow outward. MeCN solutions of [KCo(8)](+) and [KRh(4)Co(4)](+) were found to undergo ion exchange with Cs(+) to give [CsCo(8)](+) and [CsRh(4)Co(4)](+), both in quantitative yields. Labeling experiments involving [(MeC5H4)Co(CN)(3)]- demonstrated that Cs(+)-for-K(+) ion exchange is accompanied by significant fragmentation. Ion exchange of NH(4+) with [KCo(8)](+) proceeds to completion in THF solution, but in MeCN solution, the exclusive products were [Cb*Co(NCMe)(3)]PF(6) and the poorly soluble salt NH(4)CpCo(CN)(3). The lability of the NH(4+)-containing cage was also indicated by the rapid exchange of the acidic protons in [NH(4)Co(8)](+). Oxidation of [MCo(8)](+) with 4 equiv of FcPF(6) produced paramagnetic (S = 4/2) [Co(8)](4+), releasing Cs(+) or K(+). The oxidation-induced dissociation of M(+) from the cages is chemically reversed by treatment of [Co(8)](4+) and CsOTf with 4 equiv of Cp(2)Co. Cation recognition by [Co(8)] and [Rh(4)Co(4)] cages was investigated. Electrochemical measurements indicated that E(1/2)(Cs(+))--E(1/2)(K(+)) approximately 0.08 V for [MCo(8)](+).

  15. Chromosomal islands of Streptococcus pyogenes and related streptococci: molecular switches for survival and virulence.

    Science.gov (United States)

    Nguyen, Scott V; McShan, William M

    2014-01-01

    Streptococcus pyogenes is a significant pathogen of humans, annually causing over 700,000,000 infections and 500,000 deaths. Virulence in S. pyogenes is closely linked to mobile genetic elements like phages and chromosomal islands (CI). S. pyogenes phage-like chromosomal islands (SpyCI) confer a complex mutator phenotype on their host. SpyCI integrate into the 5' end of DNA mismatch repair (MMR) gene mutL, which also disrupts downstream operon genes lmrP, ruvA, and tag. During early logarithmic growth, SpyCI excise from the bacterial chromosome and replicate as episomes, relieving the mutator phenotype. As growth slows and the cells enter stationary phase, SpyCI reintegrate into the chromosome, again silencing the MMR operon. This system creates a unique growth-dependent and reversible mutator phenotype. Additional CI using the identical attachment site in mutL have been identified in related species, including Streptococcus dysgalactiae subsp. equisimilis, Streptococcus anginosus, Streptococcus intermedius, Streptococcus parauberis, and Streptococcus canis. These CI have small genomes, which range from 13 to 20 kB, conserved integrase and DNA replication genes, and no identifiable genes encoding capsid proteins. SpyCI may employ a helper phage for packaging and dissemination in a fashion similar to the Staphylococcus aureus pathogenicity islands (SaPI). Outside of the core replication and integration genes, SpyCI and related CI show considerable diversity with the presence of many indels that may contribute to the host cell phenotype or fitness. SpyCI are a subset of a larger family of streptococcal CI who potentially regulate the expression of other host genes. The biological and phylogenetic analysis of streptococcal chromosomal islands provides important clues as to how these chromosomal islands help S. pyogenes and other streptococcal species persist in human populations in spite of antibiotic therapy and immune challenges.

  16. Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

    NARCIS (Netherlands)

    Landor, S.; Mutvei, A.P.; Mamaeva, V.; Jin, S.; Busk, M.; Borra, R.; Grönroos, T.J.; Kronqvist, P.; Lendahl, U.; Sahlgren, C.M.

    2011-01-01

    A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular

  17. ADP-ribosylation factor arf6p may function as a molecular switch of new end take off in fission yeast

    International Nuclear Information System (INIS)

    Fujita, Atsushi

    2008-01-01

    Small GTPases act as molecular switches in a wide variety of cellular processes. In fission yeast Schizosaccharomyces pombe, the directions of cell growth change from a monopolar manner to a bipolar manner, which is known as 'New End Take Off' (NETO). Here I report the identification of a gene, arf6 + , encoding an ADP-ribosylation factor small GTPase, that may be essential for NETO. arf6Δ cells completely fail to undergo NETO. arf6p localizes at both cell ends and presumptive septa in a cell-cycle dependent manner. And its polarized localization is not dependent on microtubules, actin cytoskeletons and some NETO factors (bud6p, for3p, tea1p, tea3p, and tea4p). Notably, overexpression of a fast GDP/GTP-cycling mutant of arf6p can advance the timing of NETO. These findings suggest that arf6p functions as a molecular switch for the activation of NETO in fission yeast

  18. A Multicontrolled Enamine Configurational Switch Undergoing Dynamic Constitutional Exchange.

    Science.gov (United States)

    Ren, Yansong; Svensson, Per H; Ramström, Olof

    2018-05-22

    A multiresponsive enamine-based molecular switch is presented, in which forward/backward configurational rotation around the C=C bond could be precisely controlled by the addition of an acid/base or metal ions. Fluorescence turn-on/off effects and large Stokes shifts were observed while regulating the switching process with Cu II . The enamine functionality furthermore enabled double dynamic regimes, in which configurational switching could operate in conjunction with constitutional enamine exchange of the rotor part. This behavior was used to construct a prototypical dynamic covalent switch system through enamine exchange with primary amines. The dynamic exchange process could be readily turned on/off by regulating the switch status with pH. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. OsWRKY53, a versatile switch in regulating herbivore-induced defense responses in rice

    OpenAIRE

    Hu, Lingfei; Ye, Meng; Li, Ran; Lou, Yonggen

    2016-01-01

    ABSTRACT WRKY proteins, which belong to a large family of plant-specific transcription factors, play important roles in plant defenses against pathogens and herbivores by regulating defense-related signaling pathways. Recently, a rice WRKY transcription factor OsWRKY53 has been reported to function as a negative feedback modulator of OsMPK3/OsMPK6 and thereby to control the size of the investment a rice plant makes to defend against a chewing herbivore, the striped stem borer Chilo suppressal...

  20. A p300 and SIRT1 Regulated Acetylation Switch of C/EBPα Controls Mitochondrial Function

    Directory of Open Access Journals (Sweden)

    Mohamad A. Zaini

    2018-01-01

    Full Text Available Summary: Cellular metabolism is a tightly controlled process in which the cell adapts fluxes through metabolic pathways in response to changes in nutrient supply. Among the transcription factors that regulate gene expression and thereby cause changes in cellular metabolism is the basic leucine-zipper (bZIP transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα. Protein lysine acetylation is a key post-translational modification (PTM that integrates cellular metabolic cues with other physiological processes. Here, we show that C/EBPα is acetylated by the lysine acetyl transferase (KAT p300 and deacetylated by the lysine deacetylase (KDAC sirtuin1 (SIRT1. SIRT1 is activated in times of energy demand by high levels of nicotinamide adenine dinucleotide (NAD+ and controls mitochondrial biogenesis and function. A hypoacetylated mutant of C/EBPα induces the transcription of mitochondrial genes and results in increased mitochondrial respiration. Our study identifies C/EBPα as a key mediator of SIRT1-controlled adaption of energy homeostasis to changes in nutrient supply. : Zaini et al. show that the transcription factor C/EBPα is acetylated by p300 and deacetylated by the lysine deacetylase SIRT1. Hypoacetylated C/EBPα induces the transcription of mitochondrial genes and results in increased mitochondrial respiration. C/EBPα is a key mediator of SIRT1-controlled adaption of energy homeostasis to changes in nutrient supply. Keywords: C/EBPα, SIRT1, p300, lysine acetylation, mitochondrial function, cellular metabolism, NAD+, gene regulation

  1. A Functional Switch of NuRD Chromatin Remodeling Complex Subunits Regulates Mouse Cortical Development

    Directory of Open Access Journals (Sweden)

    Justyna Nitarska

    2016-11-01

    Full Text Available Histone modifications and chromatin remodeling represent universal mechanisms by which cells adapt their transcriptional response to rapidly changing environmental conditions. Extensive chromatin remodeling takes place during neuronal development, allowing the transition of pluripotent cells into differentiated neurons. Here, we report that the NuRD complex, which couples ATP-dependent chromatin remodeling with histone deacetylase activity, regulates mouse brain development. Subunit exchange of CHDs, the core ATPase subunits of the NuRD complex, is required for distinct aspects of cortical development. Whereas CHD4 promotes the early proliferation of progenitors, CHD5 facilitates neuronal migration and CHD3 ensures proper layer specification. Inhibition of each CHD leads to defects of neuronal differentiation and migration, which cannot be rescued by expressing heterologous CHDs. Finally, we demonstrate that NuRD complexes containing specific CHDs are recruited to regulatory elements and modulate the expression of genes essential for brain development.

  2. Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Mahalingan, Krishna K.; Baskaran†, Sulochanadevi; DePaoli-Roach, Anna A.; Roach, Peter J.; Hurley, Thomas D. (Indiana-Med)

    2017-01-10

    Glycogen synthase (GS) is the rate limiting enzyme in the synthesis of glycogen. Eukaryotic GS is negatively regulated by covalent phosphorylation and allosterically activated by glucose-6-phosphate (G-6-P). To gain structural insights into the inhibited state of the enzyme, we solved the crystal structure of yGsy2-R589A/R592A to a resolution of 3.3 Å. The double mutant has an activity ratio similar to the phosphorylated enzyme and also retains the ability to be activated by G-6-P. When compared to the 2.88 Å structure of the wild-type G-6-P activated enzyme, the crystal structure of the low-activity mutant showed that the N-terminal domain of the inhibited state is tightly held against the dimer-related interface thereby hindering acceptor access to the catalytic cleft. On the basis of these two structural observations, we developed a reversible redox regulatory feature in yeast GS by substituting cysteine residues for two highly conserved arginine residues. When oxidized, the cysteine mutant enzyme exhibits activity levels similar to the phosphorylated enzyme but cannot be activated by G-6-P. Upon reduction, the cysteine mutant enzyme regains normal activity levels and regulatory response to G-6-P activation.

  3. Engineering a pH-Regulated Switch in the Major Light-Harvesting Complex of Plants (LHCII): Proof of Principle.

    Science.gov (United States)

    Liguori, Nicoletta; Natali, Alberto; Croce, Roberta

    2016-12-15

    Under excess light, photosynthetic organisms employ feedback mechanisms to avoid photodamage. Photoprotection is triggered by acidification of the lumen of the photosynthetic membrane following saturation of the metabolic activity. A low pH triggers thermal dissipation of excess absorbed energy by the light-harvesting complexes (LHCs). LHCs are not able to sense pH variations, and their switch to a dissipative mode depends on stress-related proteins and allosteric cofactors. In green algae the trigger is the pigment-protein complex LHCSR3. Its C-terminus is responsible for a pH-driven conformational change from a light-harvesting to a quenched state. Here, we show that by replacing the C-terminus of the main LHC of plants with that of LHCSR3, it is possible to regulate its excited-state lifetime solely via protonation, demonstrating that the protein template of LHCs can be modified to activate reversible quenching mechanisms independent of external cofactors and triggers.

  4. Chiroptical molecular switch

    NARCIS (Netherlands)

    Feringa, B.L.; Jager, W.F.; Lange, de B.; Meijer, E.W.

    1991-01-01

    Methyl(methoxythioxanthylidene)phenanthrenes I (R = MeO, R1 = H, R22 = bond; R = H, R1 = MeO, R22 = bond) were prepd. and underwent photochem. cis-trans isomerization. Thus, 2,3-dihydro-7-methylhydrazone-4(1H)-phenanthrene was converted to its diazo compd. which cyclocondensed with

  5. Regulation of the forming process and the set voltage distribution of unipolar resistance switching in spin-coated CoFe2O4 thin films.

    Science.gov (United States)

    Mustaqima, Millaty; Yoo, Pilsun; Huang, Wei; Lee, Bo Wha; Liu, Chunli

    2015-01-01

    We report the preparation of (111) preferentially oriented CoFe2O4 thin films on Pt(111)/TiO2/SiO2/Si substrates using a spin-coating process. The post-annealing conditions and film thickness were varied for cobalt ferrite (CFO) thin films, and Pt/CFO/Pt structures were prepared to investigate the resistance switching behaviors. Our results showed that resistance switching without a forming process is preferred to obtain less fluctuation in the set voltage, which can be regulated directly from the preparation conditions of the CFO thin films. Therefore, instead of thicker film, CFO thin films deposited by two times spin-coating with a thickness about 100 nm gave stable resistance switching with the most stable set voltage. Since the forming process and the large variation in set voltage have been considered as serious obstacles for the practical application of resistance switching for non-volatile memory devices, our results could provide meaningful insights in improving the performance of ferrite material-based resistance switching memory devices.

  6. Reciprocal regulation of ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition

    Science.gov (United States)

    Musante, Veronica; Li, Lu; Kanyo, Jean; Lam, Tukiet T; Colangelo, Christopher M; Cheng, Shuk Kei; Brody, A Harrison; Greengard, Paul; Le Novère, Nicolas; Nairn, Angus C

    2017-01-01

    ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation by MAST3 kinase inhibits PP2A and regulates key components of striatal signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function of PKA phosphorylation is unknown. We find that phosphorylation by PKA or MAST3 mutually suppresses the ability of the other kinase to act on ARPP-16. Phosphorylation by PKA also acts to prevent inhibition of PP2A by ARPP-16 phosphorylated by MAST3. Moreover, PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Mathematical modeling highlights the role of these three regulatory interactions to create a switch-like response to cAMP. Together, the results suggest a complex antagonistic interplay between the control of ARPP-16 by MAST3 and PKA that creates a mechanism whereby cAMP mediates PP2A disinhibition. DOI: http://dx.doi.org/10.7554/eLife.24998.001 PMID:28613156

  7. Reciprocal regulation of ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition.

    Science.gov (United States)

    Musante, Veronica; Li, Lu; Kanyo, Jean; Lam, Tukiet T; Colangelo, Christopher M; Cheng, Shuk Kei; Brody, A Harrison; Greengard, Paul; Le Novère, Nicolas; Nairn, Angus C

    2017-06-14

    ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation by MAST3 kinase inhibits PP2A and regulates key components of striatal signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function of PKA phosphorylation is unknown. We find that phosphorylation by PKA or MAST3 mutually suppresses the ability of the other kinase to act on ARPP-16. Phosphorylation by PKA also acts to prevent inhibition of PP2A by ARPP-16 phosphorylated by MAST3. Moreover, PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Mathematical modeling highlights the role of these three regulatory interactions to create a switch-like response to cAMP. Together, the results suggest a complex antagonistic interplay between the control of ARPP-16 by MAST3 and PKA that creates a mechanism whereby cAMP mediates PP2A disinhibition.

  8. Regulation of Cellular and Molecular Functions by Protein ...

    Indian Academy of Sciences (India)

    ... a high-energy linkage. The free energy of hydrolysis 1 of protein bound tyrosine phosphate ... protein kinases, cdc2 kinase (which regulates cell division cycle) and related cdc ... residues in response to extracellular signals such as hormones or growth factors. ... involved in regulating glycogen metabolism. The activity of.

  9. Effects of molecular chirality on self-assembly and switching in liquid crystals at the cross-over between rod-like and bent shapes.

    Science.gov (United States)

    Ocak, Hale; Poppe, Marco; Bilgin-Eran, Belkız; Karanlık, Gürkan; Prehm, Marko; Tschierske, Carsten

    2016-09-21

    A bent-core compound derived from a 4-cyanoresorcinol core unit with two terephthalate based rod-like wings and carrying chiral 3,7-dimethyloctyloxy side chains has been synthesized in racemic and enantiomerically pure form and characterized by polarizing microscopy, differential scanning calorimetry, X-ray diffraction and electro-optical investigations to study the influence of molecular chirality on the superstructural chirality and polar order in lamellar liquid crystalline phases. Herein we demonstrate that the coupling of molecular chirality with superstructural layer chirality in SmCsPF domain phases (forming energetically distinct diastereomeric pairs) can fix the tilt direction and thus stabilize synpolar order, leading to bistable ferroelectric switching in the SmC* phases of the (S)-enantiomer, whereas tristable modes determine the switching of the racemate. Moreover, the mechanism of electric field induced molecular reorganization changes from a rotation around the molecular long axis in the racemate to a rotation on the tilt-cone for the (S)-enantiomer. At high temperature the enantiomer behaves like a rod-like molecule with a chirality induced ferroelectric SmC* phase and an electroclinic effect in the SmA'* phase. At reduced temperature sterically induced polarization, due to the bent molecular shape, becomes dominating, leading to much higher polarization values, thus providing access to high polarization ferroelectric materials with weakly bent compounds having only "weakly chiral" stereogenic units. Moreover, the field induced alignment of the SmCsPF(()*()) domains gives rise to a special kind of electroclinic effect appearing even in the absence of molecular chirality. Comparison with related compounds indicates that the strongest effects of chirality appear for weakly bent molecules with a relatively short coherence length of polar order, whereas for smectic phases with long range polar order the effects of the interlayer interfaces can override

  10. Molecular basis and regulation of OTULIN-LUBAC interaction

    DEFF Research Database (Denmark)

    Elliott, Paul R.; Al-Saoudi, Sofie Vincents; Marco-Casanova, Paola

    2014-01-01

    Ub. Now, we show that OTULIN binds via a conserved PUB-interacting motif (PIM) to the PUB domain of the LUBAC component HOIP. Crystal structures and nuclear magnetic resonance experiments reveal the molecular basis for the high-affinity interaction and explain why OTULIN binds the HOIP PUB domain...

  11. Biophysics of filament length regulation by molecular motors

    International Nuclear Information System (INIS)

    Kuan, Hui-Shun; Betterton, M D

    2013-01-01

    Regulating physical size is an essential problem that biological organisms must solve from the subcellular to the organismal scales, but it is not well understood what physical principles and mechanisms organisms use to sense and regulate their size. Any biophysical size-regulation scheme operates in a noisy environment and must be robust to other cellular dynamics and fluctuations. This work develops theory of filament length regulation inspired by recent experiments on kinesin-8 motor proteins, which move with directional bias on microtubule filaments and alter microtubule dynamics. Purified kinesin-8 motors can depolymerize chemically-stabilized microtubules. In the length-dependent depolymerization model, the rate of depolymerization tends to increase with filament length, because long filaments accumulate more motors at their tips and therefore shorten more quickly. When balanced with a constant filament growth rate, this mechanism can lead to a fixed polymer length. However, the mechanism by which kinesin-8 motors affect the length of dynamic microtubules in cells is less clear. We study the more biologically realistic problem of microtubule dynamic instability modulated by a motor-dependent increase in the filament catastrophe frequency. This leads to a significant decrease in the mean filament length and a narrowing of the filament length distribution. The results improve our understanding of the biophysics of length regulation in cells. (paper)

  12. Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms

    DEFF Research Database (Denmark)

    Srinivasan, Supriya; Sadegh, Leila; Elle, Ida C

    2008-01-01

    We investigated serotonin signaling in C. elegans as a paradigm for neural regulation of energy balance and found that serotonergic regulation of fat is molecularly distinct from feeding regulation. Serotonergic feeding regulation is mediated by receptors whose functions are not required for fat...... feeding behavior. These findings suggest that, as in mammals, C. elegans feeding behavior is regulated by extrinsic and intrinsic cues. Moreover, obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses...

  13. Inactivation of ferric uptake regulator (Fur) attenuates Helicobacter pylori J99 motility by disturbing the flagellar motor switch and autoinducer-2 production.

    Science.gov (United States)

    Lee, Ai-Yun; Kao, Cheng-Yen; Wang, Yao-Kuan; Lin, Ssu-Yuan; Lai, Tze-Ying; Sheu, Bor-Shyang; Lo, Chien-Jung; Wu, Jiunn-Jong

    2017-08-01

    Flagellar motility of Helicobacter pylori has been shown to be important for the bacteria to establish initial colonization. The ferric uptake regulator (Fur) is a global regulator that has been identified in H. pylori which is involved in the processes of iron uptake and establishing colonization. However, the role of Fur in H. pylori motility is still unclear. Motility of the wild-type, fur mutant, and fur revertant J99 were determined by a soft-agar motility assay and direct video observation. The bacterial shape and flagellar structure were evaluated by transmission electron microscopy. Single bacterial motility and flagellar switching were observed by phase-contrast microscopy. Autoinducer-2 (AI-2) production in bacterial culture supernatant was analyzed by a bioluminescence assay. The fur mutant showed impaired motility in the soft-agar assay compared with the wild-type J99 and fur revertant. The numbers and lengths of flagellar filaments on the fur mutant cells were similar to those of the wild-type and revertant cells. Phenotypic characterization showed similar swimming speed but reduction in switching rate in the fur mutant. The AI-2 production of the fur mutant was dramatically reduced compared with wild-type J99 in log-phase culture medium. These results indicate that Fur positively modulates H. pylori J99 motility through interfering with bacterial flagellar switching. © 2017 John Wiley & Sons Ltd.

  14. A switch from a gradient to a threshold mode in the regulation of a transcriptional cascade promotes robust execution of meiosis in budding yeast.

    Directory of Open Access Journals (Sweden)

    Vyacheslav Gurevich

    Full Text Available Tight regulation of developmental pathways is of critical importance to all organisms, and is achieved by a transcriptional cascade ensuring the coordinated expression of sets of genes. We aimed to explore whether a strong signal is required to enter and complete a developmental pathway, by using meiosis in budding yeast as a model. We demonstrate that meiosis in budding yeast is insensitive to drastic changes in the levels of its consecutive positive regulators (Ime1, Ime2, and Ndt80. Entry into DNA replication is not correlated with the time of transcription of the early genes that regulate this event. Entry into nuclear division is directly regulated by the time of transcription of the middle genes, as premature transcription of their activator NDT80, leads to a premature entry into the first meiotic division, and loss of coordination between DNA replication and nuclear division. We demonstrate that Cdk1/Cln3 functions as a negative regulator of Ime2, and that ectopic expression of Cln3 delays entry into nuclear division as well as NDT80 transcription. Because Ime2 functions as a positive regulator for premeiotic DNA replication and NDT80 transcription, as well as a negative regulator of Cdk/Cln, we suggest that a double negative feedback loop between Ime2 and Cdk1/Cln3 promotes a bistable switch from the cell cycle to meiosis. Moreover, our results suggest a regulatory mode switch that ensures robust meiosis as the transcription of the early meiosis-specific genes responds in a graded mode to Ime1 levels, whereas that of the middle and late genes as well as initiation of DNA replication, are regulated in a threshold mode.

  15. Evolution of cell cycle control: same molecular machines, different regulation

    DEFF Research Database (Denmark)

    de Lichtenberg, Ulrik; Jensen, Thomas Skøt; Brunak, Søren

    2007-01-01

    Decades of research has together with the availability of whole genomes made it clear that many of the core components involved in the cell cycle are conserved across eukaryotes, both functionally and structurally. These proteins are organized in complexes and modules that are activated or deacti......Decades of research has together with the availability of whole genomes made it clear that many of the core components involved in the cell cycle are conserved across eukaryotes, both functionally and structurally. These proteins are organized in complexes and modules that are activated...... for assembling the same molecular machines just in time for action....

  16. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock.

    Science.gov (United States)

    Narasimamurthy, Rajesh; Virshup, David M

    2017-01-01

    An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep-wake cycle, feeding-fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

  17. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

    Directory of Open Access Journals (Sweden)

    David M. Virshup

    2017-04-01

    Full Text Available An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

  18. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

    OpenAIRE

    David M. Virshup; Rajesh Narasimamurthy

    2017-01-01

    An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entr...

  19. Switched capacitor DC-DC converter with switch conductance modulation and Pesudo-fixed frequency control

    DEFF Research Database (Denmark)

    Larsen, Dennis Øland; Vinter, Martin; Jørgensen, Ivan Harald Holger

    A switched capacitor dc-dc converter with frequency-planned control is presented. By splitting the output stage switches in eight segments the output voltage can be regulated with a combination of switching frequency and switch conductance. This allows for switching at predetermined frequencies, 31...

  20. Sexual polyploidization in plants--cytological mechanisms and molecular regulation.

    Science.gov (United States)

    De Storme, Nico; Geelen, Danny

    2013-05-01

    In the plant kingdom, events of whole genome duplication or polyploidization are generally believed to occur via alterations of the sexual reproduction process. Thereby, diploid pollen and eggs are formed that contain the somatic number of chromosomes rather than the gametophytic number. By participating in fertilization, these so-called 2n gametes generate polyploid offspring and therefore constitute the basis for the establishment of polyploidy in plants. In addition, diplogamete formation, through meiotic restitution, is an essential component of apomixis and also serves as an important mechanism for the restoration of F1 hybrid fertility. Characterization of the cytological mechanisms and molecular factors underlying 2n gamete formation is therefore not only relevant for basic plant biology and evolution, but may also provide valuable cues for agricultural and biotechnological applications (e.g. reverse breeding, clonal seeds). Recent data have provided novel insights into the process of 2n pollen and egg formation and have revealed multiple means to the same end. Here, we summarize the cytological mechanisms and molecular regulatory networks underlying 2n gamete formation, and outline important mitotic and meiotic processes involved in the ectopic induction of sexual polyploidization. © 2013 Ghent University. New Phytologist © 2013 New Phytologist Trust.

  1. Molecular mechanism of immunoglobulin V-region diversification regulated by transcription and RNA metabolism in antigen-driven B cells.

    Science.gov (United States)

    Sakaguchi, N; Maeda, K; Kuwahara, K

    2011-06-01

    The immune system produces specific antibodies (Ab) against any antigens (Ag) of exogenous and endogenous origins with a diverse repertoire of V-region specificities. The primary V-region repertoire is created by the rearrangement of immunoglobulin (Ig) V-region, D- and J-segments with the insertion of N- and P-sequences during early B cell differentiation. Recent studies revealed that secondary diversification of the IgV-region generated in the peripheral lymphoid organs plays a critical role in the generation of effective Ab production for protection from various pathogens. Naïve B cells that react with Ags initiate proliferation and differentiation in the follicular region and create the germinal centres (GCs), where activation-induced cytidine deaminase (AID)-dependent IgV-region somatic hypermutation (SHM) and class-switch recombination generate high-affinity and class-switched mature Ag-specific B cells. Our studies have discovered a 210-kDa nuclear protein, named GC-associated nuclear protein (GANP) that is up-regulated in GC B cells during the T cell-dependent (TD) immune responses. By studying mice with mutant forms of the ganp gene, we demonstrated that GANP is essential for the generation of high-affinity B cells against TD-Ag by affecting SHM at the IgV-regions. GANP is associated with AID in the cytoplasm and the GANP/AID complex is recruited to the nucleus, specifically, the chromatin, and targeted selectively to the IgV-region gene in B cells. GANP augments the access of AID towards IgV-regions in B cells. Here, we review the role of GANP in acquired immunity through the detailed analysis of the molecular mechanism generating SHM specifically at IgV-regions in B cells. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.

  2. Regulating Intracellular Calcium in Plants: From Molecular Genetics to Physiology

    International Nuclear Information System (INIS)

    Sze, Heven

    2008-01-01

    To grow, develop, adapt, and reproduce, plants have evolved mechanisms to regulate the uptake, translocation and sorting of calcium ions into different cells and subcellular compartments. Yet how plants accomplish this remarkable feat is still poorly understood. The spatial and temporal changes in intracellular (Ca2+) during growth and during responses to hormonal and environmental stimuli indicate that Ca2+ influx and efflux transporters are diverse and tightly regulated in plants. The specific goals were to determine the biological roles of multiple Ca pumps (ECAs) in the model plant Arabidopsis thaliana. We had pioneered the use of K616 yeast strain to functionally express plant Ca pumps, and demonstrated two distinct types of Ca pumps in plants (Sze et al., 2000. Annu Rev Plant Biol. 51,433). ACA2 represented one type that was auto-inhibited by the N-terminal region and stimulated by calmodulin. ECA1 represented another type that was not sensitive to calmodulin and phylogenetically distinct from ACAs. The goal to determine the biological roles of multiple ECA-type Ca pumps in Arabidopsis has been accomplished. Although we demonstrated ECA1 was a Ca pump by functional expression in yeast, the in vivo roles of ECAs was unclear. A few highlights are described. ECA1 and/or ECA4 are Ca/Mn pumps localized to the ER and are highly expressed in all cell types. Using homozygous T-DNA insertional mutants of eca1, we demonstrated that the ER-bound ECA1 supports growth and confers tolerance of plants growing on medium low in Ca or containing toxic levels of Mn. This is the first genetic study to determine the in vivo function of a Ca pump in plants. A phylogenetically distinct ECA3 is also a Ca/Mn pump that is localized to endosome, such as post-Golgi compartments. Although it is expressed at lower levels than ECA1, eca3 mutants are impaired in Ca-dependent root growth and in pollen tube elongation. Increased secretion of wall proteins in mutants suggests that Ca and Mn

  3. Photoionization-regulated star formation and the structure of molecular clouds

    Science.gov (United States)

    Mckee, Christopher F.

    1989-01-01

    A model for the rate of low-mass star formation in Galactic molecular clouds and for the influence of this star formation on the structure and evolution of the clouds is presented. The rate of energy injection by newly formed stars is estimated, and the effect of this energy injection on the size of the cloud is determined. It is shown that the observed rate of star formation appears adequate to support the observed clouds against gravitational collapse. The rate of photoionization-regulated star formation is estimated and it is shown to be in agreement with estimates of the observed rate of star formation if the observed molecular cloud parameters are used. The mean cloud extinction and the Galactic star formation rate per unit mass of molecular gas are predicted theoretically from the condition that photionization-regulated star formation be in equilibrium. A simple model for the evolution of isolated molecular clouds is developed.

  4. What makes Ras an efficient molecular switch: a computational, biophysical, and structural study of Ras-GDP interactions with mutants of Raf.

    Science.gov (United States)

    Filchtinski, Daniel; Sharabi, Oz; Rüppel, Alma; Vetter, Ingrid R; Herrmann, Christian; Shifman, Julia M

    2010-06-11

    Ras is a small GTP-binding protein that is an essential molecular switch for a wide variety of signaling pathways including the control of cell proliferation, cell cycle progression and apoptosis. In the GTP-bound state, Ras can interact with its effectors, triggering various signaling cascades in the cell. In the GDP-bound state, Ras looses its ability to bind to known effectors. The interaction of the GTP-bound Ras (Ras(GTP)) with its effectors has been studied intensively. However, very little is known about the much weaker interaction between the GDP-bound Ras (Ras(GDP)) and Ras effectors. We investigated the factors underlying the nucleotide-dependent differences in Ras interactions with one of its effectors, Raf kinase. Using computational protein design, we generated mutants of the Ras-binding domain of Raf kinase (Raf) that stabilize the complex with Ras(GDP). Most of our designed mutations narrow the gap between the affinity of Raf for Ras(GTP) and Ras(GDP), producing the desired shift in binding specificity towards Ras(GDP). A combination of our best designed mutation, N71R, with another mutation, A85K, yielded a Raf mutant with a 100-fold improvement in affinity towards Ras(GDP). The Raf A85K and Raf N71R/A85K mutants were used to obtain the first high-resolution structures of Ras(GDP) bound to its effector. Surprisingly, these structures reveal that the loop on Ras previously termed the switch I region in the Ras(GDP).Raf mutant complex is found in a conformation similar to that of Ras(GTP) and not Ras(GDP). Moreover, the structures indicate an increased mobility of the switch I region. This greater flexibility compared to the same loop in Ras(GTP) is likely to explain the natural low affinity of Raf and other Ras effectors to Ras(GDP). Our findings demonstrate that an accurate balance between a rigid, high-affinity conformation and conformational flexibility is required to create an efficient and stringent molecular switch. Copyright 2010 Elsevier Ltd

  5. Photoelectron spectroscopy of self-assembled monolayers of molecular switches on noble metal surfaces; Photoelektronenspektroskopie selbstorganisierter Adsorbatschichten aus molekularen Schaltern auf Edelmetalloberflaechen

    Energy Technology Data Exchange (ETDEWEB)

    Heinemann, Nils

    2012-09-12

    Self-assembled monolayers (SAMs) of butanethiolate (C4) on single crystalline Au(111) surfaces were prepared by adsorption from solution. The thermally activated desorption behaviour of the C4 molecules from the gold substrate was examined by qualitative thermal desorption measurements (TDM), through this a desorption temperature T{sub Des}=473 K could be determined. With this knowledge, it was possible to produce samples of very good surface quality, by thermal treatment T{sub Sample}molecular switch 3-(4-(4-Hexyl-phenylazo)-phenoxy)-propane-1-thiol (ABT), deposited by self-assembly from solution on Au(111), was examined using laser-based photoelectron spectroscopy. Differences in the molecular dipole moment characteristic for the trans and the cis isomer of ABT were observed via changes in the sample work function, accessible by detection of the threshold energy for photoemission. A quantitative

  6. Acid/Base and H2PO4(-) Controllable High-Contrast Optical Molecular Switches with a Novel BODIPY Functionalized [2]Rotaxane.

    Science.gov (United States)

    Arumugaperumal, Reguram; Srinivasadesikan, Venkatesan; Ramakrishnam Raju, Mandapati V; Lin, Ming-Chang; Shukla, Tarun; Singh, Ravinder; Lin, Hong-Cheu

    2015-12-09

    A novel multifunctional mechanically interlocked switchable [2]rotaxane R4 containing two molecular stations and rotaxane arms terminated with boron-dipyrromethene (BODIPY) fluorophores and its derivatives were synthesized for the first time by CuAAC click reaction. The shuttling motion of macrocycle between the dibenzylammonium and triazolium recognition sites and the distance dependent photoinduced electron transfer process of R4 is demonstrated by utilizing external chemical stimuli (acid/base). Interestingly, the reversible self-assembly process of R4 was recognized by the acid-base molecular switch strategy. Notably, two symmetrical triazolium groups acted as molecular stations, H2PO4(-) receptors, and H-bonded donors. Both [2]rotaxane R4 and thread R2 demonstrated excellent optical responses and high selectivity toward H2PO4(-) ion. The specific motion and guest-host interactions of mechanically interlocked machines (MIMs) were also further explored by quantum mechanical calculations. The thread R2 also demonstrated to enable the detection of H2PO4(-) in RAW 264.7 cells successfully.

  7. Exciter switch

    Science.gov (United States)

    Mcpeak, W. L.

    1975-01-01

    A new exciter switch assembly has been installed at the three DSN 64-m deep space stations. This assembly provides for switching Block III and Block IV exciters to either the high-power or 20-kW transmitters in either dual-carrier or single-carrier mode. In the dual-carrier mode, it provides for balancing the two drive signals from a single control panel located in the transmitter local control and remote control consoles. In addition to the improved switching capabilities, extensive monitoring of both the exciter switch assembly and Transmitter Subsystem is provided by the exciter switch monitor and display assemblies.

  8. Molecular system bioenergetics: regulation of substrate supply in response to heart energy demands.

    Science.gov (United States)

    Saks, Valdur; Favier, Roland; Guzun, Rita; Schlattner, Uwe; Wallimann, Theo

    2006-12-15

    This review re-evaluates regulatory aspects of substrate supply in heart. In aerobic heart, the preferred substrates are always free fatty acids, and workload-induced increase in their oxidation is observed at unchanged global levels of ATP, phosphocreatine and AMP. Here, we evaluate the mechanisms of regulation of substrate supply for mitochondrial respiration in muscle cells, and show that a system approach is useful also for revealing mechanisms of feedback signalling within the network of substrate oxidation and particularly for explaining the role of malonyl-CoA in regulation of fatty acid oxidation in cardiac muscle. This approach shows that a key regulator of fatty acid oxidation is the energy demand. Alterations in malonyl-CoA would not be the reason for, but rather the consequence of, the increased fatty acid oxidation at elevated workloads, when the level of acetyl-CoA decreases due to shifts in the kinetics of the Krebs cycle. This would make malonyl-CoA a feedback regulator that allows acyl-CoA entry into mitochondrial matrix space only when it is needed. Regulation of malonyl-CoA levels by AMPK does not seem to work as a master on-off switch, but rather as a modulator of fatty acid import.

  9. A pH Switch Regulates the Inverse Relationship between Membranolytic and Chaperone-like Activities of HSP-1/2, a Major Protein of Horse Seminal Plasma.

    Science.gov (United States)

    Kumar, C Sudheer; Swamy, Musti J

    2016-07-05

    HSP-1/2, a major protein of horse seminal plasma binds to choline phospholipids present on the sperm plasma membrane and perturbs its structure by intercalating into the hydrophobic core, which results in an efflux of choline phospholipids and cholesterol, an important event in sperm capacitation. HSP-1/2 also exhibits chaperone-like activity (CLA) in vitro and protects target proteins against various kinds of stress. In the present study we show that HSP-1/2 exhibits destabilizing activity toward model supported and cell membranes. The membranolytic activity of HSP-1/2 is found to be pH dependent, with lytic activity being high at mildly acidic pH (6.0-6.5) and low at mildly basic pH (8.0-8.5). Interestingly, the CLA is also found to be pH dependent, with high activity at mildly basic pH and low activity at mildly acidic pH. Taken together the present studies demonstrate that the membranolytic and chaperone-like activities of HSP-1/2 have an inverse relationship and are regulated via a pH switch, which is reversible. The higher CLA observed at mildly basic pH could be correlated to an increase in surface hydrophobicity of the protein. To the best of our knowledge, this is the first study reporting regulation of two different activities of a chaperone protein by a pH switch.

  10. pH-regulated metal-ligand switching in the HM loop of ATP7A: a new paradigm for metal transfer chemistry.

    Science.gov (United States)

    Kline, Chelsey D; Gambill, Benjamin F; Mayfield, Mary; Lutsenko, Svetlana; Blackburn, Ninian J

    2016-08-01

    Cuproproteins such as PHM and DBM mature in late endosomal vesicles of the mammalian secretory pathway where changes in vesicle pH are employed for sorting and post-translational processing. Colocation with the P1B-type ATPase ATP7A suggests that the latter is the source of copper and supports a mechanism where selectivity in metal transfer is achieved by spatial colocation of partner proteins in their specific organelles or vesicles. In previous work we have suggested that a lumenal loop sequence located between trans-membrane helices TM1 and TM2 of the ATPase, and containing five histidines and four methionines, acts as an organelle-specific chaperone for metallation of the cuproproteins. The hypothesis posits that the pH of the vesicle regulates copper ligation and loop conformation via a mechanism which involves His to Met ligand switching induced by histidine protonation. Here we report the effect of pH on the HM loop copper coordination using X-ray absorption spectroscopy (XAS), and show via selenium substitution of the Met residues that the HM loop undergoes similar conformational switching to that found earlier for its partner PHM. We hypothesize that in the absence of specific chaperones, HM motifs provide a template for building a flexible, pH-sensitive transfer site whose structure and function can be regulated to accommodate the different active site structural elements and pH environments of its partner proteins.

  11. Practical switching power supply design

    CERN Document Server

    Brown, Martin C

    1990-01-01

    Take the ""black magic"" out of switching power supplies with Practical Switching Power Supply Design! This is a comprehensive ""hands-on"" guide to the theory behind, and design of, PWM and resonant switching supplies. You'll find information on switching supply operation and selecting an appropriate topology for your application. There's extensive coverage of buck, boost, flyback, push-pull, half bridge, and full bridge regulator circuits. Special attention is given to semiconductors used in switching supplies. RFI/EMI reduction, grounding, testing, and safety standards are also deta

  12. Semester-Long Inquiry-Based Molecular Biology Laboratory: Transcriptional Regulation in Yeast

    Science.gov (United States)

    Oelkers, Peter M.

    2017-01-01

    A single semester molecular biology laboratory has been developed in which students design and execute a project examining transcriptional regulation in "Saccharomyces cerevisiae." Three weeks of planning are allocated to developing a hypothesis through literature searches and use of bioinformatics. Common experimental plans address a…

  13. Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation

    Science.gov (United States)

    Niessen, Carien M.; Leckband, Deborah; Yap, Alpha S.

    2013-01-01

    This review addresses the cellular and molecular mechanisms of cadherin-based tissue morphogenesis. Tissue physiology is profoundly influenced by the distinctive organizations of cells in organs and tissues. In metazoa, adhesion receptors of the classical cadherin family play important roles in establishing and maintaining such tissue organization. Indeed, it is apparent that cadherins participate in a range of morphogenetic events that range from support of tissue integrity to dynamic cellular rearrangements. A comprehensive understanding of cadherin-based morphogenesis must then define the molecular and cellular mechanisms that support these distinct cadherin biologies. Here we focus on four key mechanistic elements: the molecular basis for adhesion through cadherin ectodomains; the regulation of cadherin expression at the cell surface; cooperation between cadherins and the actin cytoskeleton; and regulation by cell signaling. We discuss current progress and outline issues for further research in these fields. PMID:21527735

  14. Structure of the Regulator of G Protein Signaling 8 (RGS8)-Gαq Complex: MOLECULAR BASIS FOR Gα SELECTIVITY.

    Science.gov (United States)

    Taylor, Veronica G; Bommarito, Paige A; Tesmer, John J G

    2016-03-04

    Regulator of G protein signaling (RGS) proteins interact with activated Gα subunits via their RGS domains and accelerate the hydrolysis of GTP. Although the R4 subfamily of RGS proteins generally accepts both Gαi/o and Gαq/11 subunits as substrates, the R7 and R12 subfamilies select against Gαq/11. In contrast, only one RGS protein, RGS2, is known to be selective for Gαq/11. The molecular basis for this selectivity is not clear. Previously, the crystal structure of RGS2 in complex with Gαq revealed a non-canonical interaction that could be due to interfacial differences imposed by RGS2, the Gα subunit, or both. To resolve this ambiguity, the 2.6 Å crystal structure of RGS8, an R4 subfamily member, was determined in complex with Gαq. RGS8 adopts the same pose on Gαq as it does when bound to Gαi3, indicating that the non-canonical interaction of RGS2 with Gαq is due to unique features of RGS2. Based on the RGS8-Gαq structure, residues in RGS8 that contact a unique α-helical domain loop of Gαq were converted to those typically found in R12 subfamily members, and the reverse substitutions were introduced into RGS10, an R12 subfamily member. Although these substitutions perturbed their ability to stimulate GTP hydrolysis, they did not reverse selectivity. Instead, selectivity for Gαq seems more likely determined by whether strong contacts can be maintained between α6 of the RGS domain and Switch III of Gαq, regions of high sequence and conformational diversity in both protein families. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Probing molecular mechanisms of the Hsp90 chaperone: biophysical modeling identifies key regulators of functional dynamics.

    Directory of Open Access Journals (Sweden)

    Anshuman Dixit

    Full Text Available Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based "conformational selection" of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected

  16. Molecular Structures and Dynamics of the Stepwise Activation Mechanism of a Matrix Metalloproteinase Zymogen: Challenging the Cysteine Switch Dogma

    International Nuclear Information System (INIS)

    Rosenblum, G.; Meroueh, S.; Toth, M.; Fisher, J.; Fridman, R.; Mobashery, S.; Sagi, I.

    2007-01-01

    Activation of matrix metalloproteinase zymogen (pro-MMP) is a vital homeostatic process, yet its molecular basis remains unresolved. Using stopped-flow X-ray spectroscopy of the active site zinc ion, we determined the temporal sequence of pro-MMP-9 activation catalyzed by tissue kallikrein protease in milliseconds to several minutes. The identity of three intermediates seen by X-ray spectroscopy was corroborated by molecular dynamics simulations and quantum mechanics/molecular mechanics calculations. The cysteine-zinc interaction that maintains enzyme latency is disrupted via active-site proton transfers that mediate transient metal-protein coordination events and eventual binding of water. Unexpectedly, these events ensue as a direct result of complexation of pro-MMP-9 and kallikrein and occur before proteolysis and eventual dissociation of the pro-peptide from the catalytic site. Here we demonstrate the synergism among long-range protein conformational transitions, local structural rearrangements, and fine atomic events in the process of zymogen activation.

  17. Switching of chirality by light

    NARCIS (Netherlands)

    Feringa, B.L.; Schoevaars, A.M; Jager, W.F.; de Lange, B.; Huck, N.P.M.

    1996-01-01

    Optically active photoresponsive molecules are described by which control of chirality is achieved by light. These chiroptical molecular switches are based on inherently dissymmetric overcrowded alkenes and the synthesis, resolution and dynamic stereochemical properties are discussed. Introduction

  18. Role of accelerated segment switch in exons to alter targeting (ASSET in the molecular evolution of snake venom proteins

    Directory of Open Access Journals (Sweden)

    Kini R Manjunatha

    2009-06-01

    Full Text Available Abstract Background Snake venom toxins evolve more rapidly than other proteins through accelerated changes in the protein coding regions. Previously we have shown that accelerated segment switch in exons to alter targeting (ASSET might play an important role in its functional evolution of viperid three-finger toxins. In this phenomenon, short sequences in exons are radically changed to unrelated sequences and hence affect the folding and functional properties of the toxins. Results Here we analyzed other snake venom protein families to elucidate the role of ASSET in their functional evolution. ASSET appears to be involved in the functional evolution of three-finger toxins to a greater extent than in several other venom protein families. ASSET leads to replacement of some of the critical amino acid residues that affect the biological function in three-finger toxins as well as change the conformation of the loop that is involved in binding to specific target sites. Conclusion ASSET could lead to novel functions in snake venom proteins. Among snake venom serine proteases, ASSET contributes to changes in three surface segments. One of these segments near the substrate binding region is known to affect substrate specificity, and its exchange may have significant implications for differences in isoform catalytic activity on specific target protein substrates. ASSET therefore plays an important role in functional diversification of snake venom proteins, in addition to accelerated point mutations in the protein coding regions. Accelerated point mutations lead to fine-tuning of target specificity, whereas ASSET leads to large-scale replacement of multiple functionally important residues, resulting in change or gain of functions.

  19. Pseudospark switches

    International Nuclear Information System (INIS)

    Billault, P.; Riege, H.; Gulik, M. van; Boggasch, E.; Frank, K.

    1987-01-01

    The pseudospark discharge is bound to a geometrical structure which is particularly well suited for switching high currents and voltages at high power levels. This type of discharge offers the potential for improvement in essentially all areas of switching operation: peak current and current density, current rise, stand-off voltage, reverse current capability, cathode life, and forward drop. The first pseudospark switch was built at CERN at 1981. Since then, the basic switching characteristics of pseudospark chambers have been studied in detail. The main feature of a pseudospark switch is the confinement of the discharge plasma to the device axis. The current transition to the hollow electrodes is spread over a rather large surface area. Another essential feature is the easy and precise triggering of the pseudospark switch from the interior of the hollow electrodes, relatively far from the main discharge gap. Nanosecond delay and jitter values can be achieved with trigger energies of less than 0.1 mJ, although cathode heating is not required. Pseudospark gaps may cover a wide range of high-voltage, high-current, and high-pulse-power switching at repetition rates of many kilohertz. This report reviews the basic researh on pseudospark switches which has been going on at CERN. So far, applications have been developed in the range of thyratron-like medium-power switches at typically 20 to 40 kV and 0.5 to 10 kA. High-current pseudospark switches have been built for a high-power 20 kJ pulse generator which is being used for long-term tests of plasma lenses developed for the future CERN Antiproton Collector (ACOL). The high-current switches have operated for several hundred thousand shots, with 20 to 50 ns jitter at 16 kV charging voltage and more than 100 kA peak current amplitude. (orig.)

  20. Lipid bilayer regulation of membrane protein function: gramicidin channels as molecular force probes

    DEFF Research Database (Denmark)

    Lundbæk, Jens August; Collingwood, S.A.; Ingolfsson, H.I.

    2010-01-01

    with collective physical properties (e.g. thickness, intrinsic monolayer curvature or elastic moduli). Studies in physico-chemical model systems have demonstrated that changes in bilayer physical properties can regulate membrane protein function by altering the energetic cost of the bilayer deformation associated...... with a protein conformational change. This type of regulation is well characterized, and its mechanistic elucidation is an interdisciplinary field bordering on physics, chemistry and biology. Changes in lipid composition that alter bilayer physical properties (including cholesterol, polyunsaturated fatty acids...... channels as molecular force probes for studying this mechanism, with a unique ability to discriminate between consequences of changes in monolayer curvature and bilayer elastic moduli....

  1. Sick and tired: how molecular regulators of human sleep schedules and duration impact immune function.

    Science.gov (United States)

    Kurien, Philip A; Chong, S Y Christin; Ptáček, Louis J; Fu, Ying-Hui

    2013-10-01

    Why do we need to sleep? What regulates when we sleep? And what dictates the number of hours we require? These are often viewed as three separate biological questions. Here, we propose they share molecular etiologies, whereby regulators of sleep schedules and sleep duration also govern the physiological purposes of sleep. To support our hypothesis, we review Mendelian human genetic variants sufficient to advance sleep-wake onset (PER2) and shorten sleep length (DEC2), and evaluate their emerging roles in immune responses that may rely on a sound night of slumber. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes

    DEFF Research Database (Denmark)

    Pasini, Diego; Malatesta, Martina; Jung, Hye Ryung

    2010-01-01

    Polycomb group (PcG) proteins are transcriptional repressors, which regulate proliferation and cell fate decisions during development, and their deregulated expression is a frequent event in human tumours. The Polycomb repressive complex 2 (PRC2) catalyzes trimethylation (me3) of histone H3 lysine...... are poorly understood. To gain insight into these mechanisms, we have determined the global changes in histone modifications in embryonic stem (ES) cells lacking the PcG protein Suz12 that is essential for PRC2 activity. We show that loss of PRC2 activity results in a global increase in H3K27 acetylation....... The methylation to acetylation switch correlates with the transcriptional activation of PcG target genes, both during ES cell differentiation and in MLL-AF9-transduced hematopoietic stem cells. Moreover, we provide evidence that the acetylation of H3K27 is catalyzed by the acetyltransferases p300 and CBP. Based...

  3. Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Janky, Rekin’s; Binda, Maria Mercedes; Allemeersch, Joke; Van den broeck, Anke; Govaere, Olivier; Swinnen, Johannes V.; Roskams, Tania; Aerts, Stein; Topal, Baki

    2016-01-01

    Pancreatic cancer is poorly characterized at genetic and non-genetic levels. The current study evaluates in a large cohort of patients the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC). We performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 histologically normal pancreatic tissue samples. Cox regression models were used to study the effect on survival of molecular subtypes and 16 clinicopathological prognostic factors. In order to better understand the biology of PDAC we used iRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes. We confirmed the PDAssign gene signature as classifier of PDAC in molecular subtypes with prognostic relevance. We found molecular subtypes, but not clinicopathological factors, as independent predictors of survival. Regulatory network analysis predicted that HNF1A/B are among thousand TFs the top enriched master regulators of the genes expressed in the normal pancreatic tissue compared to the PDAC regulatory network. On immunohistochemistry staining of PDAC samples, we observed low expression of HNF1B in well differentiated towards no expression in poorly differentiated PDAC samples. We predicted IRF/STAT, AP-1, and ETS-family members as key transcription factors in gene signatures downstream of mutated KRAS. PDAC can be classified in molecular subtypes that independently predict survival. HNF1A/B seem to be good candidates as master regulators of pancreatic differentiation, which at the protein level loses its expression in malignant ductal cells of the pancreas, suggesting its putative role as tumor suppressor in pancreatic cancer. The study was registered at ClinicalTrials.gov under the number NCT01116791 (May 3, 2010). The online version of this article (doi:10.1186/s12885-016-2540-6) contains supplementary material, which is available to authorized users

  4. KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis

    Directory of Open Access Journals (Sweden)

    Ling-Yu Wang

    2016-09-01

    Full Text Available The histone lysine demethylase KDM4A/JMJD2A has been implicated in prostate carcinogenesis through its role in transcriptional regulation. Here, we describe KDM4A as a E2F1 coactivator and demonstrate a functional role for the E2F1-KDM4A complex in the control of tumor metabolism. KDM4A associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity, thereby modulating the transcriptional profile essential for cancer cell proliferation and survival. The pyruvate dehydrogenase kinases (PDKs PDK1 and PDK3 are direct targets of KDM4A and E2F1 and modulate the switch between glycolytic metabolism and mitochondrial oxidation. Downregulation of KDM4A leads to elevated activity of pyruvate dehydrogenase and mitochondrial oxidation, resulting in excessive accumulation of reactive oxygen species. The altered metabolic phenotypes can be partially rescued by ectopic expression of PDK1 and PDK3, indicating a KDM4A-dependent tumor metabolic regulation via PDK. Our results suggest that KDM4A is a key regulator of tumor metabolism and a potential therapeutic target for prostate cancer.

  5. Regulated phosphorylation of the K-Cl cotransporter KCC3 at dual C-terminal threonines is a potent switch of intracellular potassium content and cell volume homeostasis

    Directory of Open Access Journals (Sweden)

    Norma C. Adragna

    2015-07-01

    Full Text Available The defense of cell volume against excessive shrinkage or swelling is a requirement for cell function and organismal survival. Cell swelling triggers a coordinated homeostatic response termed regulatory volume decrease (RVD, resulting in K+ and Cl– efflux via the activation of K+ channels, volume-regulated anion channels (VRACs, and the K+-Cl– cotransporters, including KCC3. Here, we show genetic alanine (Ala substitution at threonines (Thr 991 and 1048 in the KCC3a isoform carboxyl-terminus, preventing inhibitory phosphorylation at these sites, not only significantly up-regulates KCC3a activity up to 25-fold in normally inhibitory isotonic conditions, but is also accompanied by reversal of activity of the related bumetanide-sensitive Na+-K+-2Cl– cotransporter isoform 1 (NKCC1. This results in a rapid (90 % reduction in intracellular K+ content (Ki via both Cl-dependent (KCC3a + NKCC1 and Cl-independent (DCPIB [VRAC inhibitor]-sensitive pathways, which collectively renders cells less prone to acute swelling in hypotonic osmotic stress. Together, these data demonstrate the phosphorylation state of Thr991/Thr1048 in the KCC3a encodes a potent switch of transporter activity, Ki homeostasis, and cell volume regulation, and reveal novel observations into the functional interaction among ion transport molecules involved in RVD.

  6. Consumption-efficient regulation and switching concepts for air conditioners in buses; Verbrauchseffiziente Regelungs- und Verschaltungskonzepte fuer Omnibusklimaanlagen

    Energy Technology Data Exchange (ETDEWEB)

    Kaiser, Christian; Tegethoff, Wilhelm [TLK-Thermo GmbH, Braunschweig (Germany); Koehler, Juergen [TU Braunschweig (Germany). Inst. fuer Thermodynamik; Sonnekalb, Michael [Konvekta AG, Schwalmstadt (Germany)

    2012-07-01

    The reduction of the fuel consumption and the related reduction of CO{sub 2} emissions is one of the most important requirements in the current development of vehicles. This includes the development of fuel-efficient drive systems and the optimization of the so-called auxiliary users such as the air conditioner. The majority of the buses used today have an air conditioner in order to meet the increased demand of passengers for comfort. Since the operation of the air conditioner results in a significant increase in fuel consumption and thus in enhanced emissions of CO{sub 2}, an essential task of the development engineer is to minimize this additional consumption. In order to identify possible optimization potentials, a bus simulation model was developed which investigates not only exclusively compression refrigeration systems, but also is in communication with their relevant systems: heating circuit with engine cooling circuit, vehicle interior, on-board electrical system and vehicle longitudinal dynamics with the drive train. In the contribution under consideration, potentials of energy conservation should be identified that can be achieved due to the use of improved control and switching concepts. For this purpose, both the conventional R-744 (CO{sub 2}) bus air conditioning systems as well as alternative systems such as an ejector cycle were studied by means of a total vehicle simulation of the bus and compared.

  7. A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation.

    Science.gov (United States)

    Wei, Jia; Zhang, Yixiao; Yu, Tai-Yuan; Sadre-Bazzaz, Kianoush; Rudolph, Michael J; Amodeo, Gabriele A; Symington, Lorraine S; Walz, Thomas; Tong, Liang

    2016-01-01

    Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and attractive targets for drug discovery. Eukaryotic acetyl-CoA carboxylases are 250 kDa single-chain, multi-domain enzymes and function as dimers and higher oligomers. Their catalytic activity is tightly regulated by phosphorylation and other means. Here we show that yeast ACC is directly phosphorylated by the protein kinase SNF1 at residue Ser1157, which potently inhibits the enzyme. Crystal structure of three ACC central domains (AC3-AC5) shows that the phosphorylated Ser1157 is recognized by Arg1173, Arg1260, Tyr1113 and Ser1159. The R1173A/R1260A double mutant is insensitive to SNF1, confirming that this binding site is crucial for regulation. Electron microscopic studies reveal dramatic conformational changes in the holoenzyme upon phosphorylation, likely owing to the dissociation of the biotin carboxylase domain dimer. The observations support a unified molecular mechanism for the regulation of ACC by phosphorylation as well as by the natural product soraphen A, a potent inhibitor of eukaryotic ACC. These molecular insights enhance our understanding of acetyl-CoA carboxylase regulation and provide a basis for drug discovery.

  8. Role of melatonin combined with exercise as a switch-like regulator for circadian behavior in advanced osteoarthritic knee

    OpenAIRE

    Hong, Yunkyung; Kim, Hyunsoo; Lee, Seunghoon; Jin, Yunho; Choi, Jeonghyun; Lee, Sang-Rae; Chang, Kyu-Tae; Hong, Yonggeun

    2017-01-01

    Here, we show the role of melatonin combined with or without exercise as a determinant of multicellular behavior in osteoarthritis. We address the relationship between the molecular components governing local circadian clock and changes in the osteoarthritic musculoskeletal axis. Melatonin was injected subcutaneously in animals with advanced knee osteoarthritis (OA) for 4 weeks. Concurrently, moderate treadmill exercise was applied for 30 min/day. Morphometric, histological, and gene/protein-...

  9. Molecular Regulation of Adipogenesis and Potential Anti-Adipogenic Bioactive Molecules

    Directory of Open Access Journals (Sweden)

    Dorothy Moseti

    2016-01-01

    Full Text Available Adipogenesis is the process by which precursor stem cells differentiate into lipid laden adipocytes. Adipogenesis is regulated by a complex and highly orchestrated gene expression program. In mammalian cells, the peroxisome proliferator-activated receptor γ (PPARγ, and the CCAAT/enhancer binding proteins (C/EBPs such as C/EBPα, β and δ are considered the key early regulators of adipogenesis, while fatty acid binding protein 4 (FABP4, adiponectin, and fatty acid synthase (FAS are responsible for the formation of mature adipocytes. Excess accumulation of lipids in the adipose tissue leads to obesity, which is associated with cardiovascular diseases, type II diabetes and other pathologies. Thus, investigating adipose tissue development and the underlying molecular mechanisms is vital to develop therapeutic agents capable of curbing the increasing incidence of obesity and related pathologies. In this review, we address the process of adipogenic differentiation, key transcription factors and proteins involved, adipogenic regulators and potential anti-adipogenic bioactive molecules.

  10. A Quick-responsive DNA Nanotechnology Device for Bio-molecular Homeostasis Regulation.

    Science.gov (United States)

    Wu, Songlin; Wang, Pei; Xiao, Chen; Li, Zheng; Yang, Bing; Fu, Jieyang; Chen, Jing; Wan, Neng; Ma, Cong; Li, Maoteng; Yang, Xiangliang; Zhan, Yi

    2016-08-10

    Physiological processes such as metabolism, cell apoptosis and immune responses, must be strictly regulated to maintain their homeostasis and achieve their normal physiological functions. The speed with which bio-molecular homeostatic regulation occurs directly determines the ability of an organism to adapt to conditional changes. To produce a quick-responsive regulatory system that can be easily utilized for various types of homeostasis, a device called nano-fingers that facilitates the regulation of physiological processes was constructed using DNA origami nanotechnology. This nano-fingers device functioned in linked open and closed phases using two types of DNA tweezers, which were covalently coupled with aptamers that captured specific molecules when the tweezer arms were sufficiently close. Via this specific interaction mechanism, certain physiological processes could be simultaneously regulated from two directions by capturing one biofactor and releasing the other to enhance the regulatory capacity of the device. To validate the universal application of this device, regulation of the homeostasis of the blood coagulant thrombin was attempted using the nano-fingers device. It was successfully demonstrated that this nano-fingers device achieved coagulation buffering upon the input of fuel DNA. This nano-device could also be utilized to regulate the homeostasis of other types of bio-molecules.

  11. Design and implementation of a bidirectional current-controlled voltage-regulated DC-DC switched-mode converter

    CSIR Research Space (South Africa)

    Coetzer, A

    2016-01-01

    Full Text Available The design and implementation of a bidirectional current-controlled voltage-regulated DC-DC converter is presented. The converter is required to connect a battery of electrochemical cells (the battery) to an asynchronous motor-drive unit via a...

  12. G0/G1 switch gene-2 regulates human adipocyte lipolysis by affecting activity and localization of adipose triglyceride lipase

    NARCIS (Netherlands)

    Schweiger, M.; Paar, M.; Eder, C.; Brandis, J.; Moser, E.; Gorkiewisz, G.; Grond, S.; Radner, F.P.W.; Cerk, I.; Cornaciu, I.; Oberer, M.; Kersten, A.H.; Zechner, R.; Zimmermann, M.B.; Lass, A.

    2012-01-01

    The hydrolysis of triglycerides in adipocytes, termed lipolysis, provides free fatty acids as energy fuel. Murine lipolysis largely depends on the activity of adipose triglyceride lipase (ATGL)5, which is regulated by two proteins annotated as comparative gene identification-58 (CGI-58) and G0/G1

  13. The switch from fermentation to respiration in Saccharomyces cerevisiae is regulated by the Ert1 transcriptional activator/repressor.

    Science.gov (United States)

    Gasmi, Najla; Jacques, Pierre-Etienne; Klimova, Natalia; Guo, Xiao; Ricciardi, Alessandra; Robert, François; Turcotte, Bernard

    2014-10-01

    In the yeast Saccharomyces cerevisiae, fermentation is the major pathway for energy production, even under aerobic conditions. However, when glucose becomes scarce, ethanol produced during fermentation is used as a carbon source, requiring a shift to respiration. This adaptation results in massive reprogramming of gene expression. Increased expression of genes for gluconeogenesis and the glyoxylate cycle is observed upon a shift to ethanol and, conversely, expression of some fermentation genes is reduced. The zinc cluster proteins Cat8, Sip4, and Rds2, as well as Adr1, have been shown to mediate this reprogramming of gene expression. In this study, we have characterized the gene YBR239C encoding a putative zinc cluster protein and it was named ERT1 (ethanol regulated transcription factor 1). ChIP-chip analysis showed that Ert1 binds to a limited number of targets in the presence of glucose. The strongest enrichment was observed at the promoter of PCK1 encoding an important gluconeogenic enzyme. With ethanol as the carbon source, enrichment was observed with many additional genes involved in gluconeogenesis and mitochondrial function. Use of lacZ reporters and quantitative RT-PCR analyses demonstrated that Ert1 regulates expression of its target genes in a manner that is highly redundant with other regulators of gluconeogenesis. Interestingly, in the presence of ethanol, Ert1 is a repressor of PDC1 encoding an important enzyme for fermentation. We also show that Ert1 binds directly to the PCK1 and PDC1 promoters. In summary, Ert1 is a novel factor involved in the regulation of gluconeogenesis as well as a key fermentation gene. Copyright © 2014 by the Genetics Society of America.

  14. A molecular switch between the outer and the inner vestibule of the voltage-gated Na+ channel

    International Nuclear Information System (INIS)

    Zarrabi, T.

    2010-01-01

    conformational change of the inner vestibule generates the IUS state. In order to explain the involvement of both the outer and the inner vestibule in ultra-slow inactivation, we proposed a model in which the mutation K1237E produces a conformational change of the outer vestibule which is transmitted to the internal vestibule through the DIV- S6 segment. The resulting conformational change of the internal vestibule gives rise to the extremely stable IUS state. If this molecular mechanism holds true, then mutations at the location of interaction between the selectivity filter and the adjacent S6 segment should substantially modulate the ultra-slow inactivated state. A homology model of the voltage-gated Na+ channel, based on the crystal structure of the KcsA channel places the domain IV-S6 segment in close proximity to the domain III P-loop (containing the site 1237 which is essential for the generation of IUS). In order to search for experimental evidence for an interaction site between the domain III P-loop and the internal vestibule we generated serial alanine and cysteine replacements of amino acids of the domain DIV- S6 segment in the background of the mutation K1237E. We find that mutations only at the site 1575 substantially decrease the likelihood of entry into IUS or significantly accelerate recovery from IUS, suggesting that this residue represents an interaction site between the domain III p-loop and the domain IV- S6 segment. For the first time these functional data confirm a molecular model in which the turn of the domain III P-loop is in close relationship with the domain IV- S6 segment at the level of I1575. (author) [de

  15. Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a "master switch" regulating synaptic gain in neuronal networks.

    Science.gov (United States)

    Arendt, Thomas; Bullmann, Torsten

    2013-09-01

    The present paper provides an overview of adaptive changes in brain structure and learning abilities during hibernation as a behavioral strategy used by several mammalian species to minimize energy expenditure under current or anticipated inhospitable environmental conditions. One cellular mechanism that contributes to the regulated suppression of metabolism and thermogenesis during hibernation is reversible phosphorylation of enzymes and proteins, which limits rates of flux through metabolic pathways. Reversible phosphorylation during hibernation also affects synaptic membrane proteins, a process known to be involved in synaptic plasticity. This mechanism of reversible protein phosphorylation also affects the microtubule-associated protein tau, thereby generating a condition that in the adult human brain is associated with aggregation of tau protein to paired helical filaments (PHFs), as observed in Alzheimer's disease. Here, we put forward the concept that phosphorylation of tau is a neuroprotective mechanism to escape NMDA-mediated hyperexcitability of neurons that would otherwise occur during slow gradual cooling of the brain. Phosphorylation of tau and its subsequent targeting to subsynaptic sites might, thus, work as a kind of "master switch," regulating NMDA receptor-mediated synaptic gain in a wide array of neuronal networks, thereby enabling entry into torpor. If this condition lasts too long, however, it may eventually turn into a pathological trigger, driving a cascade of events leading to neurodegeneration, as in Alzheimer's disease or other "tauopathies".

  16. Semester-long inquiry-based molecular biology laboratory: Transcriptional regulation in yeast.

    Science.gov (United States)

    Oelkers, Peter M

    2017-03-04

    A single semester molecular biology laboratory has been developed in which students design and execute a project examining transcriptional regulation in Saccharomyces cerevisiae. Three weeks of planning are allocated to developing a hypothesis through literature searches and use of bioinformatics. Common experimental plans address a cell process and how three genes that encode for proteins involved in that process are transcriptionally regulated in response to changing environmental conditions. Planning includes designing oligonucleotides to amplify the putative promoters of the three genes of interest. After the PCR, each product is cloned proximal to β-galactosidase in a yeast reporter plasmid. Techniques used include agarose electrophoresis, extraction of DNA from agarose, plasmid purification from bacteria, restriction digestion, ligation, and bacterial transformation. This promoter/reporter plasmid is then transformed into yeast. Transformed yeast are cultured in conditions prescribed in the experimental design, lysed and β-galactosidase activity is measured. The course provides an independent research experience in a group setting. Notebooks are maintained on-line with regular feedback. Projects culminate with the presentation of a poster worth 60% of the grade. Over the last three years, about 65% of students met expectations for experimental design, data acquisition, and analysis. © 2016 by The International Union of Biochemistry and Molecular Biology, 45(2):145-151, 2017. © 2016 The International Union of Biochemistry and Molecular Biology.

  17. Aux/IAA Gene Family in Plants: Molecular Structure, Regulation, and Function

    Directory of Open Access Journals (Sweden)

    Jie Luo

    2018-01-01

    Full Text Available Auxin plays a crucial role in the diverse cellular and developmental responses of plants across their lifespan. Plants can quickly sense and respond to changes in auxin levels, and these responses involve several major classes of auxin-responsive genes, including the Auxin/Indole-3-Acetic Acid (Aux/IAA family, the auxin response factor (ARF family, small auxin upregulated RNA (SAUR, and the auxin-responsive Gretchen Hagen3 (GH3 family. Aux/IAA proteins are short-lived nuclear proteins comprising several highly conserved domains that are encoded by the auxin early response gene family. These proteins have specific domains that interact with ARFs and inhibit the transcription of genes activated by ARFs. Molecular studies have revealed that Aux/IAA family members can form diverse dimers with ARFs to regulate genes in various ways. Functional analyses of Aux/IAA family members have indicated that they have various roles in plant development, such as root development, shoot growth, and fruit ripening. In this review, recently discovered details regarding the molecular characteristics, regulation, and protein–protein interactions of the Aux/IAA proteins are discussed. These details provide new insights into the molecular basis of the Aux/IAA protein functions in plant developmental processes.

  18. Self-regulated growth of LaVO3 thin films by hybrid molecular beam epitaxy

    International Nuclear Information System (INIS)

    Zhang, Hai-Tian; Engel-Herbert, Roman; Dedon, Liv R.; Martin, Lane W.

    2015-01-01

    LaVO 3 thin films were grown on SrTiO 3 (001) by hybrid molecular beam epitaxy. A volatile metalorganic precursor, vanadium oxytriisopropoxide (VTIP), and elemental La were co-supplied in the presence of a molecular oxygen flux. By keeping the La flux fixed and varying the VTIP flux, stoichiometric LaVO 3 films were obtained for a range of cation flux ratios, indicating the presence of a self-regulated growth window. Films grown under stoichiometric conditions were found to have the largest lattice parameter, which decreased monotonically with increasing amounts of excess La or V. Energy dispersive X-ray spectroscopy and Rutherford backscattering measurements were carried out to confirm film compositions. Stoichiometric growth of complex vanadate thin films independent of cation flux ratios expands upon the previously reported self-regulated growth of perovskite titanates using hybrid molecular beam epitaxy, thus demonstrating the general applicability of this growth approach to other complex oxide materials, where a precise control over film stoichiometry is demanded by the application

  19. Multistable decision switches for flexible control of epigenetic differentiation.

    Directory of Open Access Journals (Sweden)

    Raúl Guantes

    2008-11-01

    Full Text Available It is now recognized that molecular circuits with positive feedback can induce two different gene expression states (bistability under the very same cellular conditions. Whether, and how, cells make use of the coexistence of a larger number of stable states (multistability is however largely unknown. Here, we first examine how autoregulation, a common attribute of genetic master regulators, facilitates multistability in two-component circuits. A systematic exploration of these modules' parameter space reveals two classes of molecular switches, involving transitions in bistable (progression switches or multistable (decision switches regimes. We demonstrate the potential of decision switches for multifaceted stimulus processing, including strength, duration, and flexible discrimination. These tasks enhance response specificity, help to store short-term memories of recent signaling events, stabilize transient gene expression, and enable stochastic fate commitment. The relevance of these circuits is further supported by biological data, because we find them in numerous developmental scenarios. Indeed, many of the presented information-processing features of decision switches could ultimately demonstrate a more flexible control of epigenetic differentiation.

  20. Molecular control of brain size: Regulators of neural stem cell life, death and beyond

    International Nuclear Information System (INIS)

    Joseph, Bertrand; Hermanson, Ola

    2010-01-01

    The proper development of the brain and other organs depends on multiple parameters, including strictly controlled expansion of specific progenitor pools. The regulation of such expansion events includes enzymatic activities that govern the correct number of specific cells to be generated via an orchestrated control of cell proliferation, cell cycle exit, differentiation, cell death etc. Certain proteins in turn exert direct control of these enzymatic activities and thus progenitor pool expansion and organ size. The members of the Cip/Kip family (p21Cip1/p27Kip1/p57Kip2) are well-known regulators of cell cycle exit that interact with and inhibit the activity of cyclin-CDK complexes, whereas members of the p53/p63/p73 family are traditionally associated with regulation of cell death. It has however become clear that the roles for these proteins are not as clear-cut as initially thought. In this review, we discuss the roles for proteins of the Cip/Kip and p53/p63/p73 families in the regulation of cell cycle control, differentiation, and death of neural stem cells. We suggest that these proteins act as molecular interfaces, or 'pilots', to assure the correct assembly of protein complexes with enzymatic activities at the right place at the right time, thereby regulating essential decisions in multiple cellular events.

  1. Molecular control of brain size: Regulators of neural stem cell life, death and beyond

    Energy Technology Data Exchange (ETDEWEB)

    Joseph, Bertrand [Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm (Sweden); Hermanson, Ola, E-mail: ola.hermanson@ki.se [Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, Stockholm (Sweden)

    2010-05-01

    The proper development of the brain and other organs depends on multiple parameters, including strictly controlled expansion of specific progenitor pools. The regulation of such expansion events includes enzymatic activities that govern the correct number of specific cells to be generated via an orchestrated control of cell proliferation, cell cycle exit, differentiation, cell death etc. Certain proteins in turn exert direct control of these enzymatic activities and thus progenitor pool expansion and organ size. The members of the Cip/Kip family (p21Cip1/p27Kip1/p57Kip2) are well-known regulators of cell cycle exit that interact with and inhibit the activity of cyclin-CDK complexes, whereas members of the p53/p63/p73 family are traditionally associated with regulation of cell death. It has however become clear that the roles for these proteins are not as clear-cut as initially thought. In this review, we discuss the roles for proteins of the Cip/Kip and p53/p63/p73 families in the regulation of cell cycle control, differentiation, and death of neural stem cells. We suggest that these proteins act as molecular interfaces, or 'pilots', to assure the correct assembly of protein complexes with enzymatic activities at the right place at the right time, thereby regulating essential decisions in multiple cellular events.

  2. Down-regulation of adipose tissue lipoprotein lipase during fasting requires that a gene, separate from the lipase gene, is switched on.

    Science.gov (United States)

    Bergö, Martin; Wu, Gengshu; Ruge, Toralph; Olivecrona, Thomas

    2002-04-05

    During short term fasting, lipoprotein lipase (LPL) activity in rat adipose tissue is rapidly down-regulated. This down-regulation occurs on a posttranslational level; it is not accompanied by changes in LPL mRNA or protein levels. The LPL activity can be restored within 4 h by refeeding. Previously, we showed that during fasting there is a shift in the distribution of lipase protein toward an inactive form with low heparin affinity. To study the nature of the regulatory mechanism, we determined the in vivo turnover of LPL activity, protein mass, and mRNA in rat adipose tissue. When protein synthesis was inhibited with cycloheximide, LPL activity and protein mass decreased rapidly and in parallel with half-lives of around 2 h, and the effect of refeeding was blocked. This indicates that maintaining high levels of LPL activity requires continuous synthesis of new enzyme protein. When transcription was inhibited by actinomycin, LPL mRNA decreased with half-lives of 13.3 and 16.8 h in the fed and fasted states, respectively, demonstrating slow turnover of the LPL transcript. Surprisingly, when actinomycin was given to fed rats, LPL activity was not down-regulated during fasting, indicating that actinomycin interferes with the transcription of a gene that blocks the activation of newly synthesized LPL protein. When actinomycin was given to fasted rats, LPL activity increased 4-fold within 6 h, even in the absence of refeeding. The same effect was seen with alpha-amanitin, another inhibitor of transcription. The response to actinomycin was much less pronounced in aging rats, which are obese and insulin-resistant. These data suggest a default state where LPL protein is synthesized on a relatively stable mRNA and is processed into its active form. During fasting, a gene is switched on whose product prevents the enzyme from becoming active even though synthesis of LPL protein continues unabated.

  3. Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids

    Science.gov (United States)

    Jaeger, Doris; Schoiswohl, Gabriele; Hofer, Peter; Schreiber, Renate; Schweiger, Martina; Eichmann, Thomas O.; Pollak, Nina M.; Poecher, Nadja; Grabner, Gernot F.; Zierler, Kathrin A.; Eder, Sandra; Kolb, Dagmar; Radner, Franz P.W.; Preiss-Landl, Karina; Lass, Achim; Zechner, Rudolf; Kershaw, Erin E.; Haemmerle, Guenter

    2015-01-01

    Background & Aims Adipose tissue (AT)-derived fatty acids (FAs) are utilized for hepatic triacylglycerol (TG) generation upon fasting. However, their potential impact as signaling molecules is not established. Herein we examined the role of exogenous AT-derived FAs in the regulation of hepatic gene expression by investigating mice with a defect in AT-derived FA supply to the liver. Methods Plasma FA levels, tissue TG hydrolytic activities and lipid content were determined in mice lacking the lipase co-activator comparative gene identification-58 (CGI-58) selectively in AT (CGI-58-ATko) applying standard protocols. Hepatic expression of lipases, FA oxidative genes, transcription factors, ER stress markers, hormones and cytokines were determined by qRT-PCR, Western blotting and ELISA. Results Impaired AT-derived FA supply upon fasting of CGI-58-ATko mice causes a marked defect in liver PPARα-signaling and nuclear CREBH translocation. This severely reduced the expression of respective target genes such as the ATGL inhibitor G0/G1 switch gene-2 (G0S2) and the endocrine metabolic regulator FGF21. These changes could be reversed by lipid administration and raising plasma FA levels. Impaired AT-lipolysis failed to induce hepatic G0S2 expression in fasted CGI-58-ATko mice leading to enhanced ATGL-mediated TG-breakdown strongly reducing hepatic TG deposition. On high fat diet, impaired AT-lipolysis counteracts hepatic TG accumulation and liver stress linked to improved systemic insulin sensitivity. Conclusions AT-derived FAs are a critical regulator of hepatic fasting gene expression required for the induction of G0S2-expression in the liver to control hepatic TG-breakdown. Interfering with AT-lipolysis or hepatic G0S2 expression represents an effective strategy for the treatment of hepatic steatosis. PMID:25733154

  4. Shengui Sansheng San extraction is an angiogenic switch via regulations of AKT/mTOR, ERK1/2 and Notch1 signal pathways after ischemic stroke.

    Science.gov (United States)

    Liu, Bowen; Luo, Cheng; Zheng, Zhaoguang; Xia, Zhenyan; Zhang, Qian; Ke, Chienchih; Liu, Renshyan; Zhao, Yonghua

    2018-05-15

    As a traditional Chinese herbal formula, Shengui Sansheng San (SSS) has been employed for stroke treatment more than 300 years. We hypothesize that SSS extraction is an angiogenic switch in penumbra post-stroke, and corresponding mechanisms are investigated. In present study, rats were subjected to permanent middle cerebral artery occlusion model (MCAo) and were treated with low, middle and high doses of SSS extraction. We assessed neurological function and survival rate, and measured infarct volume by 2,3,5-triphenyltetrazolium chloride staining on day 7 after ischemia. von Willebrand factor (vWF), stromal cell-derived factor-1 alpha (SDF-1α) /chemokine (C-X-C motif) receptor 4 (CXCR4) axis, vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) as well as protein kinase B (AKT)/mammalian target of rapamycin (mTOR) /hypoxia-inducible factor-1 alpha (HIF-1α), extracellular signal-regulated kinase 1/2 (ERK1/2) and Notch1 signaling pathways were respectively investigated by immunofluorescence assay or western blotting in vivo and oxygen-glucose-deprived (OGD) brain microvascular endothelial cells (BMECs); simultaneously, wound healing of BMECs and tube formation assay were administrated. Compared to MCAo group, SSS extraction could significantly improve neurological functional scores, survival rate and cerebral infarct volume, enhance vWF + vascular density and perimeter, SDF-1α/CXCR4 axis, VEGF expression, as well as activate AKT/mTOR/HIF-1α and ERK1/2 and inhibit Notch1 pathways in penumbra. In vitro, containing SSS extraction serum increased BMEC migration, capillary formation and VEGF expression via up-regulations of AKT/mTOR and ERK1/2 pathways in OGD BMECs, but ERK inhibitor (U0126) reversed the result of VEGF expression in high dose of SSS group. Additionally, VEGFR2 and Notch1 expressions were suppressed by containing SSS extraction serum. All results were in dose dependent manner. Our study firstly demonstrates that SSS extraction is an

  5. Characterization of pH-sensitive molecular switches that trigger the structural transition of vesicular stomatitis virus glycoprotein from the postfusion state toward the prefusion state.

    Science.gov (United States)

    Ferlin, Anna; Raux, Hélène; Baquero, Eduard; Lepault, Jean; Gaudin, Yves

    2014-11-01

    prefusion state at the viral surface after its transport through the acidic Golgi compartments. We mutated five acidic residues, proposed to be pH-sensitive switches controlling the structural transition back toward the prefusion state. Our results indicate that residue D268 is the major pH sensor, while other acidic residues have additional contributions, and reveal that the propensity of the segment consisting of residues 264 to 273 to adopt a helical conformation is finely regulated. This segment might be a good target for antiviral compounds. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  6. The Central Metabolism Regulator EIIAGlc Switches Salmonella from Growth Arrest to Acute Virulence through Activation of Virulence Factor Secretion

    Directory of Open Access Journals (Sweden)

    Alain Mazé

    2014-06-01

    Full Text Available The ability of Salmonella to cause disease depends on metabolic activities and virulence factors. Here, we show that a key metabolic protein, EIIAGlc, is absolutely essential for acute infection, but not for Salmonella survival, in a mouse typhoid fever model. Surprisingly, phosphorylation-dependent EIIAGlc functions, including carbohydrate transport and activation of adenylate cyclase for global regulation, do not explain this virulence phenotype. Instead, biochemical studies, in vitro secretion and translocation assays, and in vivo genetic epistasis experiments suggest that EIIAGlc binds to the type three secretion system 2 (TTSS-2 involved in systemic virulence, stabilizes its cytoplasmic part including the crucial TTSS-2 ATPase, and activates virulence factor secretion. This unexpected role of EIIAGlc reveals a striking direct link between central Salmonella metabolism and a crucial virulence mechanism.

  7. Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

    Directory of Open Access Journals (Sweden)

    Zhen-Ye Zhang

    2017-09-01

    Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

  8. [Molecular mechanisms of autophagy in regulating renal aging and interventional effects of Chinese herbal medicine].

    Science.gov (United States)

    Tu, Yue; Sun, Wei; Chen, Di-Ping; Wan, Yi-Gang; Wu, Wei; Yao, Jian

    2016-11-01

    Aging is the gradual functional recession of the living tissues or organs caused by a variety of genetic and environmental factors together. Autophagy is a process of degrading cytoplasmic components mediated by lysosomes in eukaryotic cells. Kidney is a typical target organ of aging. Autophagy regulates renal aging. Decrease in autophagy can accelerate renal aging,whereas,increase in autophagy can delay renal aging. During the process of regulating renal aging,the mammalian target of rapamycin (mTOR) and its related signaling pathways including the adenosine monophosphate activated protein kinase (AMPK)/mTOR,the phosphatidylinositol 3-kinase (PI3K)/ serine-threonine kinase(Akt)/mTOR,the AMPK/silent information regulation 1 (Sirt1) and transforming growth factor β (TGF-β) play the important roles in renal aging. Regulating the key signaling molecules in these pathways in vivo can control renal aging. Some Chinese herbal medicine (CHM) and their extracts with the effects of nourishing kidney or activating stasis, such as Cordyceps sinensis, curcumin and resveratrol have the beneficial effects on renal aging and/or autophagy. Therefore,revealing the pharmacological effects of CHM in anti-renal aging based on the molecular mechanisms of autophagy will become one of the development trends in the future study. Copyright© by the Chinese Pharmaceutical Association.

  9. 8-Quinolineboronic acid as a potential phosphorescent molecular switch for the determination of alpha-fetoprotein variant for the prediction of primary hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Liu Jiaming, E-mail: zzsyliujiaming@163.com [Department of Chemistry and Environmental Science, Zhangzhou Normal College, Xianzhiqian Street, 36 Zhangzhou, Fujian 363000 (China); Li Feiming [Department of Chemistry and Environmental Science, Zhangzhou Normal College, Xianzhiqian Street, 36 Zhangzhou, Fujian 363000 (China); Liu Zhenbo [Third Hospital of Xiamen, Xiamen 316000 (China); Lin Changqing [Department of Food and Biological Engineering, Zhangzhou Institute of Technology, Zhangzhou 363000 (China); Lin Shaoqin [Department of Biochemistry, Fujian Education College, Fuzhou 350001 (China); Lin Liping [Department of Chemistry and Environmental Science, Zhangzhou Normal College, Xianzhiqian Street, 36 Zhangzhou, Fujian 363000 (China); Wang Xinxing [Department of Chemistry and Environmental Science, Zhangzhou Normal College, Xianzhiqian Street, 36 Zhangzhou, Fujian 363000 (China); Department of Food and Biological Engineering, Zhangzhou Institute of Technology, Zhangzhou 363000 (China); Li Zhiming [Department of Food and Biological Engineering, Zhangzhou Institute of Technology, Zhangzhou 363000 (China)

    2010-03-24

    8-Quinolineboronic acid phosphorescent molecular switch (8-QBA-PMS) in the 'off' state emitted weak room temperature phosphorescence (RTP) of 8-QBA on the acetylcellulose membrane (ACM) with the perturbation of Pb{sup 2+}. When 8-QBA-PMS was used to label concanavalin agglutinin (Con A) to form 8-QBA-PMS-Con A based on the reaction between -OH of 8-QBA-PMS and -COOH of Con A, 8-QBA-PMS turned 'on' automatically due to its structure change, and RTP of the system increased 2.7 times. Besides, -NH{sub 2} of 8-QBA-PMS-Con A could carry out affinity adsorption (AA) reaction with the -COOH of alpha-fetoprotein variant (AFP-V) to form the product Con A-AFP-V-Con A-8-QBA-PMS containing -NH-CO- bond, causing the RTP of the system to further increase. Moreover, the amount of AFP-V was linear to the {Delta}I{sub p} of the system in the range of 0.012-2.40 (fg spot{sup -1}). Thus, a new affinity sensitive adsorption solid substrate room temperature phosphorimetry using 8-QBA-PMS as labelling reagent (8-QBA-PMS-AASSRTP) for the determination of AFP-V was proposed with the detection limit (LD) of 9 x 10{sup -15} g mL{sup -1}. It had been used to determine AFP-V in human serum with the results agreeing with enzyme-link immunoassay (ELISA), showing promise for the prediction of PHC due to the intimate association between AFP-V and primary hepatocellular carcinoma (PHC). The mechanism of the promethod was also discussed.

  10. 8-Quinolineboronic acid as a potential phosphorescent molecular switch for the determination of alpha-fetoprotein variant for the prediction of primary hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Liu Jiaming; Li Feiming; Liu Zhenbo; Lin Changqing; Lin Shaoqin; Lin Liping; Wang Xinxing; Li Zhiming

    2010-01-01

    8-Quinolineboronic acid phosphorescent molecular switch (8-QBA-PMS) in the 'off' state emitted weak room temperature phosphorescence (RTP) of 8-QBA on the acetylcellulose membrane (ACM) with the perturbation of Pb 2+ . When 8-QBA-PMS was used to label concanavalin agglutinin (Con A) to form 8-QBA-PMS-Con A based on the reaction between -OH of 8-QBA-PMS and -COOH of Con A, 8-QBA-PMS turned 'on' automatically due to its structure change, and RTP of the system increased 2.7 times. Besides, -NH 2 of 8-QBA-PMS-Con A could carry out affinity adsorption (AA) reaction with the -COOH of alpha-fetoprotein variant (AFP-V) to form the product Con A-AFP-V-Con A-8-QBA-PMS containing -NH-CO- bond, causing the RTP of the system to further increase. Moreover, the amount of AFP-V was linear to the ΔI p of the system in the range of 0.012-2.40 (fg spot -1 ). Thus, a new affinity sensitive adsorption solid substrate room temperature phosphorimetry using 8-QBA-PMS as labelling reagent (8-QBA-PMS-AASSRTP) for the determination of AFP-V was proposed with the detection limit (LD) of 9 x 10 -15 g mL -1 . It had been used to determine AFP-V in human serum with the results agreeing with enzyme-link immunoassay (ELISA), showing promise for the prediction of PHC due to the intimate association between AFP-V and primary hepatocellular carcinoma (PHC). The mechanism of the promethod was also discussed.

  11. Ferroelectric switching of elastin

    Science.gov (United States)

    Liu, Yuanming; Cai, Hong-Ling; Zelisko, Matthew; Wang, Yunjie; Sun, Jinglan; Yan, Fei; Ma, Feiyue; Wang, Peiqi; Chen, Qian Nataly; Zheng, Hairong; Meng, Xiangjian; Sharma, Pradeep; Zhang, Yanhang; Li, Jiangyu

    2014-01-01

    Ferroelectricity has long been speculated to have important biological functions, although its very existence in biology has never been firmly established. Here, we present compelling evidence that elastin, the key ECM protein found in connective tissues, is ferroelectric, and we elucidate the molecular mechanism of its switching. Nanoscale piezoresponse force microscopy and macroscopic pyroelectric measurements both show that elastin retains ferroelectricity at 473 K, with polarization on the order of 1 μC/cm2, whereas coarse-grained molecular dynamics simulations predict similar polarization with a Curie temperature of 580 K, which is higher than most synthetic molecular ferroelectrics. The polarization of elastin is found to be intrinsic in tropoelastin at the monomer level, analogous to the unit cell level polarization in classical perovskite ferroelectrics, and it switches via thermally activated cooperative rotation of dipoles. Our study sheds light onto a long-standing question on ferroelectric switching in biology and establishes ferroelectricity as an important biophysical property of proteins. This is a critical first step toward resolving its physiological significance and pathological implications. PMID:24958890

  12. Molecular and Genetic Analysis of Hormone-Regulated Differential Cell Elongation in Arabidopsis

    Energy Technology Data Exchange (ETDEWEB)

    Ecker, Joseph R.

    2002-12-03

    The authors have utilized the response of Arabidopsis seedlings to the plant hormone ethylene to identify new genes involved in the regulation of ethylene biosynthesis, perception, signal transduction and differential cell growth. In building a genetic framework for the action of these genes, they developed a molecular model that has facilitated the understanding of the molecular requirements of ethylene for cell elongation processes. The ethylene response pathway in Arabidopsis appears to be primarily linear and is defined by the genes: ETR1, ETR2, ERS1, ERS2, EIN4, CTR1, EIN2, EIN3, EIN5 EIN6, and EIN. Downstream branches identified by the HLS1, EIR1, and AUX1 genes involve interactions with other hormonal (auxin) signals in the process of differential cell elongation in the hypocotyl hook. Cloning and characterization of HLS1 and three HLS1-LIKE genes in the laboratory has been supported under this award. HLS1 is required for differential elongation of cells in the hypocotyl and may act in the establishment of hormone gradients. Also during the award period, they have identified and begun preliminary characterization of two genes that genetically act upstream of the ethylene receptors. ETO1 and RAN1 encode negative regulators of ethylene biosynthesis and signaling respectively. Progress on the analysis of these genes along with HOOKLESS1 is described.

  13. Molecular and Genetic Analysis of Hormone-Regulated Differential Cell Elongation in Arabidopsis

    Energy Technology Data Exchange (ETDEWEB)

    Ecker, Joseph R.

    2005-09-15

    We have utilized the response of Arabidopsis seedlings to the plant hormone ethylene to identify new genes involved in the regulation of ethylene biosynthesis, perception, signal transduction and differential cell growth. In building a genetic framework for the action of these genes, we have developed a molecular model that has facilitated our understanding of the molecular requirements of ethylene for cell elongation processes. The ethylene response pathway in Arabidopsis appears to be primarily linear and is defined by the genes: ETR1, ETR2, ERS1, ERS2, EIN4, CTR1, EIN2, EIN3, EIN5, EIN6, and EIN. Downstream branches identified by the HLS1, EIR1, and AUX1 genes involve interactions with other hormonal (auxin) signals in the process of differential cell elongation in the hypocotyl hook. Cloning and characterization of HLS1 (and three HLL genes) and ETO1 (and ETOL genes) in my laboratory has been supported under this award. HLS1 is required for differential elongation of cells in the hypocotyl and may act in the establishment of hormone gradients. Also during the previous period, we have identified and characterized a gene that genetically acts upstream of the ethylene receptors. ETO1 encodes negative regulators of ethylene biosynthesis.

  14. The effects of threonine phosphorylation on the stability and dynamics of the central molecular switch region of 18.5-kDa myelin basic protein.

    Directory of Open Access Journals (Sweden)

    Kenrick A Vassall

    global structure of the peptides through altered electrostatic interactions. The results support the hypothesis that the central conserved segment of MBP constitutes a molecular switch in which the conformation and/or intermolecular interactions are mediated by phosphorylation/dephosphorylation at T92 and T95.

  15. Comprehensive mutagenesis of the fimS promoter regulatory switch reveals novel regulation of type 1 pili in uropathogenic Escherichia coli.

    Science.gov (United States)

    Zhang, Huibin; Susanto, Teodorus T; Wan, Yue; Chen, Swaine L

    2016-04-12

    Type 1 pili (T1P) are major virulence factors for uropathogenic Escherichia coli (UPEC), which cause both acute and recurrent urinary tract infections. T1P expression therefore is of direct relevance for disease. T1P are phase variable (both piliated and nonpiliated bacteria exist in a clonal population) and are controlled by an invertible DNA switch (fimS), which contains the promoter for the fim operon encoding T1P. Inversion of fimS is stochastic but may be biased by environmental conditions and other signals that ultimately converge at fimS itself. Previous studies of fimS sequences important for T1P phase variation have focused on laboratory-adapted E coli strains and have been limited in the number of mutations or by alteration of the fimS genomic context. We surmounted these limitations by using saturating genomic mutagenesis of fimS coupled with accurate sequencing to detect both mutations and phase status simultaneously. In addition to the sequences known to be important for biasing fimS inversion, our method also identifies a previously unknown pair of 5' UTR inverted repeats that act by altering the relative fimA levels to control phase variation. Thus we have uncovered an additional layer of T1P regulation potentially impacting virulence and the coordinate expression of multiple pilus systems.

  16. Engineering of a novel Ca2+-regulated kinesin molecular motor using a calmodulin dimer linker

    International Nuclear Information System (INIS)

    Shishido, Hideki; Maruta, Shinsaku

    2012-01-01

    Highlights: ► Engineered kinesin–M13 and calmodulin involving single cysteine were prepared. ► CaM mutant was cross-linked to dimer by bifunctional thiol reactive reagent. ► Kinesin–M13 was dimerized via CaM dimer in the presence of calcium. ► Function of the engineered kinesin was regulated by a Ca 2+ -calmodulin dimer linker. -- Abstract: The kinesin–microtubule system holds great promise as a molecular shuttle device within biochips. However, one current barrier is that such shuttles do not have “on–off” control of their movement. Here we report the development of a novel molecular motor powered by an accelerator and brake system, using a kinesin monomer and a calmodulin (CaM) dimer. The kinesin monomer, K355, was fused with a CaM target peptide (M13 peptide) at the C-terminal part of the neck region (K355–M13). We also prepared CaM dimers using CaM mutants (Q3C), (R86C), or (A147C) and crosslinkers that react with cysteine residues. Following induction of K355–M13 dimerization with CaM dimers, we measured K355–M13 motility and found that it can be reversibly regulated in a Ca 2+ -dependent manner. We also found that velocities of K355–M13 varied depending on the type and crosslink position of the CaM dimer used; crosslink length also had a moderate effect on motility. These results suggest Ca 2+ -dependent dimerization of K355–M13 could be used as a novel molecular shuttle, equipped with an accelerator and brake system, for biochip applications.

  17. Regulation of assimilate import into sink organs: Update on molecular drivers of sink strength

    Directory of Open Access Journals (Sweden)

    Saadia eBihmidine

    2013-06-01

    Full Text Available Recent developments have altered our view of molecular mechanisms that determine sink strength, defined here as the capacity of non-photosynthetic structures to compete for import of photoassimilates. We review new findings from diverse systems, including stems, seeds, flowers, and fruits. An important advance has been the identification of new transporters and facilitators with major roles in the accumulation and equilibration of sugars at a cellular level. Exactly where each exerts its effect varies among systems. Sugarcane and sweet sorghum stems, for example, both accumulate high levels of sucrose, but may do so via different paths. The distinction is central to strategies for targeted manipulation of sink strength using transporter genes, and shows the importance of system-specific analyses. Another major advance has been the identification of deep hypoxia as a feature of normal grain development. This means that molecular drivers of sink strength in endosperm operate in very low oxygen levels, and under metabolic conditions quite different than previously assumed. Successful enhancement of sink strength has nonetheless been achieved in grains by up-regulating genes for starch biosynthesis. Additionally, our understanding of sink strength is enhanced by awareness of the dual roles played by invertases (INV, not only in sucrose metabolism, but also in production of the hexose sugar signals that regulate cell-cycle and cell-division programs. These contributions of INV to cell expansion and division prove to be vital for establishment of young sinks ranging from flowers to fruit. Since INV genes are themselves sugar-responsive feast genes, they can mediate a feed-forward enhancement of sink strength when assimilates are abundant. Greater overall productivity and yield have thus been attained in key instances, indicating that even broader enhancements may be achievable as we discover the detailed molecular mechanisms that drive sink strength

  18. Estrogen Regulates Protein Synthesis and Actin Polymerization in Hippocampal Neurons through Different Molecular Mechanisms

    Science.gov (United States)

    Briz, Victor; Baudry, Michel

    2014-01-01

    Estrogen rapidly modulates hippocampal synaptic plasticity by activating selective membrane-associated receptors. Reorganization of the actin cytoskeleton and stimulation of mammalian target of rapamycin (mTOR)-mediated protein synthesis are two major events required for the consolidation of hippocampal long-term potentiation and memory. Estradiol regulates synaptic plasticity by interacting with both processes, but the underlying molecular mechanisms are not yet fully understood. Here, we used acute rat hippocampal slices to analyze the mechanisms underlying rapid changes in mTOR activity and actin polymerization elicited by estradiol. Estradiol-induced mTOR phosphorylation was preceded by rapid and transient activation of both extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) and by phosphatase and tensin homolog (PTEN) degradation. These effects were prevented by calpain and ERK inhibitors. Estradiol-induced mTOR stimulation did not require activation of classical estrogen receptors (ER), as specific ERα and ERβ agonists (PPT and DPN, respectively) failed to mimic this effect, and ER antagonists could not block it. Estradiol rapidly activated both RhoA and p21-activated kinase (PAK). Furthermore, a specific inhibitor of RhoA kinase (ROCK), H1152, and a potent and specific PAK inhibitor, PF-3758309, blocked estradiol-induced cofilin phosphorylation and actin polymerization. ER antagonists also blocked these effects of estrogen. Consistently, both PPT and DPN stimulated PAK and cofilin phosphorylation as well as actin polymerization. Finally, the effects of estradiol on actin polymerization were insensitive to protein synthesis inhibitors, but its stimulation of mTOR activity was impaired by latrunculin A, a drug that disrupts actin filaments. Taken together, our results indicate that estradiol regulates local protein synthesis and cytoskeletal reorganization via different molecular mechanisms and signaling pathways. PMID:24611062

  19. Molecular regulation of aluminum resistance and sulfur nutrition during root growth.

    Science.gov (United States)

    Alarcón-Poblete, Edith; Inostroza-Blancheteau, Claudio; Alberdi, Miren; Rengel, Zed; Reyes-Díaz, Marjorie

    2018-01-01

    Aluminum toxicity and sulfate deprivation both regulate microRNA395 expression, repressing its low-affinity sulfate transporter ( SULTR2;1 ) target. Sulfate deprivation also induces the high-affinity sulfate transporter gene ( SULTR12 ), allowing enhanced sulfate uptake. Few studies about the relationships between sulfate, a plant nutrient, and aluminum, a toxic ion, are available; hence, the molecular and physiological processes underpinning this interaction are poorly understood. The Al-sulfate interaction occurs in acidic soils, whereby relatively high concentrations of trivalent toxic aluminum (Al 3+ ) may hamper root growth, limiting uptake of nutrients, including sulfur (S). On the other side, Al 3+ may be detoxified by complexation with sulfate in the acid soil solution as well as in the root-cell vacuoles. In this review, we focus on recent insights into the mechanisms governing plant responses to Al toxicity and its relationship with sulfur nutrition, emphasizing the role of phytohormones, microRNAs, and ion transporters in higher plants. It is known that Al 3+ disturbs gene expression and enzymes involved in biosynthesis of S-containing cysteine in root cells. On the other hand, Al 3+ may induce ethylene biosynthesis, enhance reactive oxygen species production, alter phytohormone transport, trigger root growth inhibition and promote sulfate uptake under S deficiency. MicroRNA395, regulated by both Al toxicity and sulfate deprivation, represses its low-affinity Sulfate Transporter 2;1 (SULTR2;1) target. In addition, sulfate deprivation induces High Affinity Sulfate Transporters (HAST; SULTR1;2), improving sulfate uptake from low-sulfate soil solutions. Identification of new microRNAs and cloning of their target genes are necessary for a better understanding of the role of molecular regulation of plant resistance to Al stress and sulfate deprivation.

  20. Switching Phenomena

    Science.gov (United States)

    Stanley, H. E.; Buldyrev, S. V.; Franzese, G.; Havlin, S.; Mallamace, F.; Mazza, M. G.; Kumar, P.; Plerou, V.; Preis, T.; Stokely, K.; Xu, L.

    One challenge of biology, medicine, and economics is that the systems treated by these serious scientific disciplines can suddenly "switch" from one behavior to another, even though they possess no perfect metronome in time. As if by magic, out of nothing but randomness one finds remarkably fine-tuned processes in time. The past century has, philosophically, been concerned with placing aside the human tendency to see the universe as a fine-tuned machine. Here we will address the challenge of uncovering how, through randomness (albeit, as we shall see, strongly correlated randomness), one can arrive at some of the many temporal patterns in physics, economics, and medicine and even begin to characterize the switching phenomena that enable a system to pass from one state to another. We discuss some applications of correlated randomness to understanding switching phenomena in various fields. Specifically, we present evidence from experiments and from computer simulations supporting the hypothesis that water's anomalies are related to a switching point (which is not unlike the "tipping point" immortalized by Malcolm Gladwell), and that the bubbles in economic phenomena that occur on all scales are not "outliers" (another Gladwell immortalization).

  1. Molecular characterization of Quercus suber MYB1, a transcription factor up-regulated in cork tissues.

    Science.gov (United States)

    Almeida, Tânia; Menéndez, Esther; Capote, Tiago; Ribeiro, Teresa; Santos, Conceição; Gonçalves, Sónia

    2013-01-15

    The molecular processes associated with cork development in Quercus suber L. are poorly understood. A previous molecular approach identified a list of genes potentially important for cork formation and differentiation, providing a new basis for further molecular studies. This report is the first molecular characterization of one of these candidate genes, QsMYB1, coding for an R2R3-MYB transcription factor. The R2R3-MYB gene sub-family has been described as being involved in the phenylpropanoid and lignin pathways, both involved in cork biosynthesis. The results showed that the expression of QsMYB1 is putatively mediated by an alternative splicing (AS) mechanism that originates two different transcripts (QsMYB1.1 and QsMYB1.2), differing only in the 5'-untranslated region, due to retention of the first intron in one of the variants. Moreover, within the retained intron, a simple sequence repeat (SSR) was identified. The upstream regulatory region of QsMYB1 was extended by a genome walking approach, which allowed the identification of the putative gene promoter region. The relative expression pattern of QsMYB1 transcripts determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) revealed that both transcripts were up-regulated in cork tissues; the detected expression was several times higher in newly formed cork harvested from trees producing virgin, second or reproduction cork when compared with wood. Moreover, the expression analysis of QsMYB1 in several Q. suber organs showed very low expression in young branches and roots, whereas in leaves, immature acorns or male flowers, no expression was detected. These preliminary results suggest that QsMYB1 may be related to secondary growth and, in particular, with the cork biosynthesis process with a possible alternative splicing mechanism associated with its regulatory function. Copyright © 2012 Elsevier GmbH. All rights reserved.

  2. Molecular regulation of dendritic cell development and function in homeostasis, inflammation, and cancer.

    Science.gov (United States)

    Chrisikos, Taylor T; Zhou, Yifan; Slone, Natalie; Babcock, Rachel; Watowich, Stephanie S; Li, Haiyan S

    2018-03-14

    Dendritic cells (DCs) are the principal antigen-presenting cells of the immune system and play key roles in controlling immune tolerance and activation. As such, DCs are chief mediators of tumor immunity. DCs can regulate tolerogenic immune responses that facilitate unchecked tumor growth. Importantly, however, DCs also mediate immune-stimulatory activity that restrains tumor progression. For instance, emerging evidence indicates the cDC1 subset has important functions in delivering tumor antigens to lymph nodes and inducing antigen-specific lymphocyte responses to tumors. Moreover, DCs control specific therapeutic responses in cancer including those resulting from immune checkpoint blockade. DC generation and function is influenced profoundly by cytokines, as well as their intracellular signaling proteins including STAT transcription factors. Regardless, our understanding of DC regulation in the cytokine-rich tumor microenvironment is still developing and must be better defined to advance cancer treatment. Here, we review literature focused on the molecular control of DCs, with a particular emphasis on cytokine- and STAT-mediated DC regulation. In addition, we highlight recent studies that delineate the importance of DCs in anti-tumor immunity and immune therapy, with the overall goal of improving knowledge of tumor-associated factors and intrinsic DC signaling cascades that influence DC function in cancer. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome.

    Directory of Open Access Journals (Sweden)

    Pavan Kumar P

    2014-03-01

    Full Text Available TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.

  4. TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome.

    Science.gov (United States)

    Kumar P, Pavan; Franklin, Sarah; Emechebe, Uchenna; Hu, Hao; Moore, Barry; Lehman, Chris; Yandell, Mark; Moon, Anne M

    2014-03-01

    TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.

  5. A molecular roadmap of the AGM region reveals BMPER as a novel regulator of HSC maturation

    Science.gov (United States)

    McGarvey, Alison C.; Souilhol, Céline; Rice, Ritva; Hills, David; Rice, David; Tomlinson, Simon R.

    2017-01-01

    In the developing embryo, hematopoietic stem cells (HSCs) emerge from the aorta-gonad-mesonephros (AGM) region, but the molecular regulation of this process is poorly understood. Recently, the progression from E9.5 to E10.5 and polarity along the dorso-ventral axis have been identified as clear demarcations of the supportive HSC niche. To identify novel secreted regulators of HSC maturation, we performed RNA sequencing over these spatiotemporal transitions in the AGM region and supportive OP9 cell line. Screening several proteins through an ex vivo reaggregate culture system, we identify BMPER as a novel positive regulator of HSC development. We demonstrate that BMPER is associated with BMP signaling inhibition, but is transcriptionally induced by BMP4, suggesting that BMPER contributes to the precise control of BMP activity within the AGM region, enabling the maturation of HSCs within a BMP-negative environment. These findings and the availability of our transcriptional data through an accessible interface should provide insight into the maintenance and potential derivation of HSCs in culture. PMID:29093060

  6. A fundamental trade-off in covalent switching and its circumvention by enzyme bifunctionality in glucose homeostasis.

    Science.gov (United States)

    Dasgupta, Tathagata; Croll, David H; Owen, Jeremy A; Vander Heiden, Matthew G; Locasale, Jason W; Alon, Uri; Cantley, Lewis C; Gunawardena, Jeremy

    2014-05-09

    Covalent modification provides a mechanism for modulating molecular state and regulating physiology. A cycle of competing enzymes that add and remove a single modification can act as a molecular switch between "on" and "off" and has been widely studied as a core motif in systems biology. Here, we exploit the recently developed "linear framework" for time scale separation to determine the general principles of such switches. These methods are not limited to Michaelis-Menten assumptions, and our conclusions hold for enzymes whose mechanisms may be arbitrarily complicated. We show that switching efficiency improves with increasing irreversibility of the enzymes and that the on/off transition occurs when the ratio of enzyme levels reaches a value that depends only on the rate constants. Fluctuations in enzyme levels, which habitually occur due to cellular heterogeneity, can cause flipping back and forth between on and off, leading to incoherent mosaic behavior in tissues, that worsens as switching becomes sharper. This trade-off can be circumvented if enzyme levels are correlated. In particular, if the competing catalytic domains are on the same protein but do not influence each other, the resulting bifunctional enzyme can switch sharply while remaining coherent. In the mammalian liver, the switch between glycolysis and gluconeogenesis is regulated by the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). We suggest that bifunctionality of PFK-2/FBPase-2 complements the metabolic zonation of the liver by ensuring coherent switching in response to insulin and glucagon.

  7. Molecular Regulation of Alternative Polyadenylation (APA) within the Drosophila Nervous System.

    Science.gov (United States)

    Vallejos Baier, Raul; Picao-Osorio, Joao; Alonso, Claudio R

    2017-10-27

    Alternative polyadenylation (APA) is a widespread gene regulatory mechanism that generates mRNAs with different 3'-ends, allowing them to interact with different sets of RNA regulators such as microRNAs and RNA-binding proteins. Recent studies have shown that during development, neural tissues produce mRNAs with particularly long 3'UTRs, suggesting that such extensions might be important for neural development and function. Despite this, the mechanisms underlying neural APA are not well understood. Here, we investigate this problem within the Drosophila nervous system, focusing on the roles played by general cleavage and polyadenylation factors (CPA factors). In particular, we examine the model that modulations in CPA factor concentration may affect APA during development. For this, we first analyse the expression of the Drosophila orthologues of all mammalian CPA factors and note that their expression decreases during embryogenesis. In contrast to this global developmental decrease in CPA factor expression, we see that cleavage factor I (CFI) expression is actually elevated in the late embryonic central nervous system, suggesting that CFI might play a special role in neural tissues. To test this, we use the UAS/Gal4 system to deplete CFI proteins from neural tissue and observe that in this condition, multiple genes switch their APA patterns, demonstrating a role of CFI in APA control during Drosophila neural development. Furthermore, analysis of genes with 3'UTR extensions of different length leads us to suggest a novel relation between 3'UTR length and sensitivity to CPA factor expression. Our work thus contributes to the understanding of the mechanisms of APA control within the developing central nervous system. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Regulating Molecular Aggregations of Polymers via Ternary Copolymerization Strategy for Efficient Solar Cells.

    Science.gov (United States)

    Wang, Qian; Wang, Yingying; Zheng, Wei; Shahid, Bilal; Qiu, Meng; Wang, Di; Zhu, Dangqiang; Yang, Renqiang

    2017-09-20

    For many high-performance photovoltaic materials in polymer solar cells (PSCs), the active layers usually need to be spin-coated at high temperature due to the strong intermolecular aggregation of donor polymers, which is unfavorable in device repeatability and large-scale PSC printing. In this work, we adopted a ternary copolymerization strategy to regulate polymer solubility and molecular aggregation. A series of D-A 1 -D-A 2 random polymers based on different acceptors, strong electron-withdrawing unit ester substituted thieno[3,4-b]thiophene (TT-E), and highly planar dithiazole linked TT-E (DTzTT) were constructed to realize the regulation of molecular aggregation and simplification of device fabrication. The results showed that as the relative proportion of TT-E segment in the backbone increased, the absorption evidently red-shifted with a gradually decreased aggregation in solution, eventually leading to the active layers that can be fabricated at low temperature. Furthermore, due to the excellent phase separation and low recombination, the optimized solar cells based on the terpolymer P1 containing 30% of TT-E segment exhibit high power conversion efficiency (PCE) of 9.09% with a significantly enhanced fill factor up to 72.86%. Encouragingly, the photovoltaic performance is insensitive to the fabrication temperature of the active layer, and it still could maintain high PCE of 8.82%, even at room temperature. This work not only develops the highly efficient photovoltaic materials for low temperature processed PSCs through ternary copolymerization strategy but also preliminarily constructs the relationship between aggregation and photovoltaic performance.

  9. Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation.

    Science.gov (United States)

    Curie, Thomas; Mongrain, Valérie; Dorsaz, Stéphane; Mang, Géraldine M; Emmenegger, Yann; Franken, Paul

    2013-03-01

    Besides their well-established role in circadian rhythms, our findings that the forebrain expression of the clock-genes Per2 and Dbp increases and decreases, respectively, in relation to time spent awake suggest they also play a role in the homeostatic aspect of sleep regulation. Here, we determined whether time of day modulates the effects of elevated sleep pressure on clock-gene expression. Time of day effects were assessed also for recognized electrophysiological (EEG delta power) and molecular (Homer1a) markers of sleep homeostasis. EEG and qPCR data were obtained for baseline and recovery from 6-h sleep deprivation starting at ZT0, -6, -12, or -18. Mouse sleep laboratory. Male mice. Sleep deprivation. The sleep-deprivation induced changes in Per2 and Dbp expression importantly varied with time of day, such that Per2 could even decrease during sleep deprivations occurring at the decreasing phase in baseline. Dbp showed similar, albeit opposite dynamics. These unexpected results could be reliably predicted assuming that these transcripts behave according to a driven damped harmonic oscillator. As expected, the sleep-wake distribution accounted for a large degree of the changes in EEG delta power and Homer1a. Nevertheless, the sleep deprivation-induced increase in delta power varied also with time of day with higher than expected levels when recovery sleep started at dark onset. Per2 and delta power are widely used as exclusive state variables of the circadian and homeostatic process, respectively. Our findings demonstrate a considerable cross-talk between these two processes. As Per2 in the brain responds to both sleep loss and time of day, this molecule is well positioned to keep track of and to anticipate homeostatic sleep need. Curie T; Mongrain V; Dorsaz S; Mang GM; Emmenegger Y; Franken P. Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation. SLEEP 2013;36(3):311-323.

  10. Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging.

    Science.gov (United States)

    Zhang, Liang; Thurber, Greg M

    2016-02-01

    Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type 1 diabetes. The glucagon-like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower-clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, down-regulation of the GLP-1 receptor and non-specific background uptake result in a higher target-to-background ratio for fast-clearing agents.

  11. Insights into the Molecular Events That Regulate Heat-Induced Chilling Tolerance in Citrus Fruits.

    Science.gov (United States)

    Lafuente, María T; Establés-Ortíz, Beatriz; González-Candelas, Luis

    2017-01-01

    Low non-freezing temperature may cause chilling injury (CI), which is responsible for external quality deterioration in many chilling-sensitive horticultural crops. Exposure of chilling-sensitive citrus cultivars to non-lethal high-temperature conditioning may increase their chilling tolerance. Very little information is available about the molecular events involved in such tolerance. In this work, the molecular events associated with the low temperature tolerance induced by heating Fortune mandarin, which is very sensitive to chilling, for 3 days at 37°C prior to cold storage is presented. A transcriptomic analysis reveals that heat-conditioning has an important impact favoring the repression of genes in cold-stored fruit, and that long-term heat-induced chilling tolerance is an active process that requires activation of transcription factors involved in transcription initiation and of the WRKY family. The analysis also shows that chilling favors degradation processes, which affect lipids and proteins, and that the protective effect of the heat-conditioning treatment is more likely to be related to the repression of the genes involved in lipid degradation than to the modification of fatty acids unsaturation, which affects membrane permeability. Another major factor associated with the beneficial effect of the heat treatment on reducing CI is the regulation of stress-related proteins. Many of the genes that encoded such proteins are involved in secondary metabolism and in oxidative stress-related processes.

  12. Insights into the Molecular Events That Regulate Heat-Induced Chilling Tolerance in Citrus Fruits

    Directory of Open Access Journals (Sweden)

    María T. Lafuente

    2017-06-01

    Full Text Available Low non-freezing temperature may cause chilling injury (CI, which is responsible for external quality deterioration in many chilling-sensitive horticultural crops. Exposure of chilling-sensitive citrus cultivars to non-lethal high-temperature conditioning may increase their chilling tolerance. Very little information is available about the molecular events involved in such tolerance. In this work, the molecular events associated with the low temperature tolerance induced by heating Fortune mandarin, which is very sensitive to chilling, for 3 days at 37°C prior to cold storage is presented. A transcriptomic analysis reveals that heat-conditioning has an important impact favoring the repression of genes in cold-stored fruit, and that long-term heat-induced chilling tolerance is an active process that requires activation of transcription factors involved in transcription initiation and of the WRKY family. The analysis also shows that chilling favors degradation processes, which affect lipids and proteins, and that the protective effect of the heat-conditioning treatment is more likely to be related to the repression of the genes involved in lipid degradation than to the modification of fatty acids unsaturation, which affects membrane permeability. Another major factor associated with the beneficial effect of the heat treatment on reducing CI is the regulation of stress-related proteins. Many of the genes that encoded such proteins are involved in secondary metabolism and in oxidative stress-related processes.

  13. Molecular machinery of signal transduction and cell cycle regulation in Plasmodium.

    Science.gov (United States)

    Koyama, Fernanda C; Chakrabarti, Debopam; Garcia, Célia R S

    2009-05-01

    The regulation of the Plasmodium cell cycle is not understood. Although the Plasmodium falciparum genome is completely sequenced, about 60% of the predicted proteins share little or no sequence similarity with other eukaryotes. This feature impairs the identification of important proteins participating in the regulation of the cell cycle. There are several open questions that concern cell cycle progression in malaria parasites, including the mechanism by which multiple nuclear divisions is controlled and how the cell cycle is managed in all phases of their complex life cycle. Cell cycle synchrony of the parasite population within the host, as well as the circadian rhythm of proliferation, are striking features of some Plasmodium species, the molecular basis of which remains to be elucidated. In this review we discuss the role of indole-related molecules as signals that modulate the cell cycle in Plasmodium and other eukaryotes, and we also consider the possible role of kinases in the signal transduction and in the responses it triggers.

  14. Cytological, molecular mechanisms and temperature stress regulating production of diploid male gametes in Dianthus caryophyllus L.

    Science.gov (United States)

    Zhou, Xuhong; Mo, Xijun; Gui, Min; Wu, Xuewei; Jiang, Yalian; Ma, Lulin; Shi, Ziming; Luo, Ying; Tang, Wenru

    2015-12-01

    In plant evolution, because of its key role in sexual polyploidization or whole genome duplication events, diploid gamete formation is considered as an important component in diversification and speciation. Environmental stress often triggers unreduced gamete production. However, the molecular, cellular mechanisms and adverse temperature regulating diplogamete production in carnation remain poorly understood. Here, we investigate the cytological basis for 2n male gamete formation and describe the isolation and characterization of the first gene, DcPS1 (Dianthus Caryophyllus Parallel Spindle 1). In addition, we analyze influence of temperature stress on diploid gamete formation and transcript levels of DcPS1. Cytological evidence indicated that 2n male gamete formation is attributable to abnormal spindle orientation at male meiosis II. DcPS1 protein is conserved throughout the plant kingdom and carries domains suggestive of a regulatory function. DcPS1 expression analysis show DcPS1 gene probably have a role in 2n pollen formation. Unreduced pollen formation in various cultivation was sensitive to high or low temperature which was probably regulated by the level of DcPS1 transcripts. In a broader perspective, these findings can have potential applications in fundamental polyploidization research and plant breeding programs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  15. Molecular machines regulating the release probability of synaptic vesicles at the active zone.

    Directory of Open Access Journals (Sweden)

    Christoph eKoerber

    2016-03-01

    Full Text Available The fusion of synaptic vesicles (SVs with the plasma membrane of the active zone (AZ upon arrival of an action potential (AP at the presynaptic compartment is a tightly regulated probabil-istic process crucial for information transfer. The probability of a SV to release its transmitter content in response to an AP, termed release probability (Pr, is highly diverse both at the level of entire synapses and individual SVs at a given synapse. Differences in Pr exist between different types of synapses, between synapses of the same type, synapses originating from the same axon and even between different SV subpopulations within the same presynaptic terminal. The Pr of SVs at the AZ is set by a complex interplay of different presynaptic properties including the availability of release-ready SVs, the location of the SVs relative to the voltage-gated calcium channels (VGCCs at the AZ, the magnitude of calcium influx upon arrival of the AP, the buffer-ing of calcium ions as well as the identity and sensitivity of the calcium sensor. These properties are not only interconnected, but can also be regulated dynamically to match the requirements of activity patterns mediated by the synapse. Here, we review recent advances in identifying mole-cules and molecular machines taking part in the determination of vesicular Pr at the AZ.

  16. The Wnt Transcriptional Switch: TLE Removal or Inactivation?

    Science.gov (United States)

    Ramakrishnan, Aravinda-Bharathi; Sinha, Abhishek; Fan, Vinson B; Cadigan, Ken M

    2018-02-01

    Many targets of the Wnt/β-catenin signaling pathway are regulated by TCF transcription factors, which play important roles in animal development, stem cell biology, and oncogenesis. TCFs can regulate Wnt targets through a "transcriptional switch," repressing gene expression in unstimulated cells and promoting transcription upon Wnt signaling. However, it is not clear whether this switch mechanism is a general feature of Wnt gene regulation or limited to a subset of Wnt targets. Co-repressors of the TLE family are known to contribute to the repression of Wnt targets in the absence of signaling, but how they are inactivated or displaced by Wnt signaling is poorly understood. In this mini-review, we discuss several recent reports that address the prevalence and molecular mechanisms of the Wnt transcription switch, including the finding of Wnt-dependent ubiquitination/inactivation of TLEs. Together, these findings highlight the growing complexity of the regulation of gene expression by the Wnt pathway. © 2017 WILEY Periodicals, Inc.

  17. A Shh-Foxf-Fgf18-Shh Molecular Circuit Regulating Palate Development.

    Directory of Open Access Journals (Sweden)

    Jingyue Xu

    2016-01-01

    Full Text Available Cleft palate is among the most common birth defects in humans. Previous studies have shown that Shh signaling plays critical roles in palate development and regulates expression of several members of the forkhead-box (Fox family transcription factors, including Foxf1 and Foxf2, in the facial primordia. Although cleft palate has been reported in mice deficient in Foxf2, whether Foxf2 plays an intrinsic role in and how Foxf2 regulates palate development remain to be elucidated. Using Cre/loxP-mediated tissue-specific gene inactivation in mice, we show that Foxf2 is required in the neural crest-derived palatal mesenchyme for normal palatogenesis. We found that Foxf2 mutant embryos exhibit altered patterns of expression of Shh, Ptch1, and Shox2 in the developing palatal shelves. Through RNA-seq analysis, we identified over 150 genes whose expression was significantly up- or down-regulated in the palatal mesenchyme in Foxf2-/- mutant embryos in comparison with control littermates. Whole mount in situ hybridization analysis revealed that the Foxf2 mutant embryos exhibit strikingly corresponding patterns of ectopic Fgf18 expression in the palatal mesenchyme and concomitant loss of Shh expression in the palatal epithelium in specific subdomains of the palatal shelves that correlate with where Foxf2, but not Foxf1, is expressed during normal palatogenesis. Furthermore, tissue specific inactivation of both Foxf1 and Foxf2 in the early neural crest cells resulted in ectopic activation of Fgf18 expression throughout the palatal mesenchyme and dramatic loss of Shh expression throughout the palatal epithelium. Addition of exogenous Fgf18 protein to cultured palatal explants inhibited Shh expression in the palatal epithelium. Together, these data reveal a novel Shh-Foxf-Fgf18-Shh circuit in the palate development molecular network, in which Foxf1 and Foxf2 regulate palatal shelf growth downstream of Shh signaling, at least in part, by repressing Fgf18

  18. Regulation of somatic embryo development in Norway spruce (Picea abies). A molecular approach to the characterization of specific developmental stages

    Energy Technology Data Exchange (ETDEWEB)

    Sabala, I. [Swedish Univ. of Agricultural Sciences, Uppsala (Sweden). Dept. of Forest Genetics

    1998-12-31

    Embryo development is a complex process involving a set of strictly regulated events. The regulation of these events is poorly understood especially during the early stages of embryo development. Somatic embryos go through the same developmental stages as zygotic embryos making them an ideal model system for studying the regulation of embryo development. We have used embryogenic cultures of Picea abies to study some aspects of the regulation of embryo development in gymnosperms. The bottle neck during somatic embryogenesis is the switch from the proliferation stage to the maturation stage. This switch is initiated by giving somatic embryos a maturation treatment i.e. the embryos are treated with abscisic acid (ABA). Somatic embryos which respond to ABA by forming mature somatic embryos were stimulated to secret a 70 kDa protein, AF70. The af70 gene was isolated and characterised. The expression of the af70 gene was constitutive in embryos but was highly ABA-induced in seedlings. Moreover, expression of this gene was stimulated during cold acclimation of Picea abies seedlings. A full length Picea abies cDNA clone Pa18, encoding a protein with the characteristics of plant lipid transfer proteins (LTPs), was isolated and characterised. The Pa18 gene is constitutively expressed in embryogenic cultures of Picea abies representing different stages of development as well as in nonembryogenic callus and seedlings. In situ hybridization showed that Pa18 gene is expressed in all embryonic cells of proliferating somatic embryos but the expression of the gene in mature somatic and zygotic embryos is restricted to the outer cell layer. Southern blot analysis at different stringencies was consistent with a single gene. An alteration in expression of Pa18 causes disturbance in the formation of the proper outer cell layer in the maturing somatic embryos. In addition to its influence on embryo development the Pa18 gene product also inhibits growth of Agrobacterium tumefaciens 195

  19. Homeostatic and Circadian Contribution to EEG and Molecular State Variables of Sleep Regulation

    Science.gov (United States)

    Curie, Thomas; Mongrain, Valérie; Dorsaz, Stéphane; Mang, Géraldine M.; Emmenegger, Yann; Franken, Paul

    2013-01-01

    Study Objectives: Besides their well-established role in circadian rhythms, our findings that the forebrain expression of the clock-genes Per2 and Dbp increases and decreases, respectively, in relation to time spent awake suggest they also play a role in the homeostatic aspect of sleep regulation. Here, we determined whether time of day modulates the effects of elevated sleep pressure on clock-gene expression. Time of day effects were assessed also for recognized electrophysiological (EEG delta power) and molecular (Homer1a) markers of sleep homeostasis. Design: EEG and qPCR data were obtained for baseline and recovery from 6-h sleep deprivation starting at ZT0, -6, -12, or -18. Setting: Mouse sleep laboratory. Participants: Male mice. Interventions: Sleep deprivation. Results: The sleep-deprivation induced changes in Per2 and Dbp expression importantly varied with time of day, such that Per2 could even decrease during sleep deprivations occurring at the decreasing phase in baseline. Dbp showed similar, albeit opposite dynamics. These unexpected results could be reliably predicted assuming that these transcripts behave according to a driven damped harmonic oscillator. As expected, the sleep-wake distribution accounted for a large degree of the changes in EEG delta power and Homer1a. Nevertheless, the sleep deprivation-induced increase in delta power varied also with time of day with higher than expected levels when recovery sleep started at dark onset. Conclusions: Per2 and delta power are widely used as exclusive state variables of the circadian and homeostatic process, respectively. Our findings demonstrate a considerable cross-talk between these two processes. As Per2 in the brain responds to both sleep loss and time of day, this molecule is well positioned to keep track of and to anticipate homeostatic sleep need. Citation: Curie T; Mongrain V; Dorsaz S; Mang GM; Emmenegger Y; Franken P. Homeostatic and circadian contribution to EEG and molecular state

  20. Tyrosine phosphorylation switching of a G protein.

    Science.gov (United States)

    Li, Bo; Tunc-Ozdemir, Meral; Urano, Daisuke; Jia, Haiyan; Werth, Emily G; Mowrey, David D; Hicks, Leslie M; Dokholyan, Nikolay V; Torres, Matthew P; Jones, Alan M

    2018-03-30

    Heterotrimeric G protein complexes are molecular switches relaying extracellular signals sensed by G protein-coupled receptors (GPCRs) to downstream targets in the cytoplasm, which effect cellular responses. In the plant heterotrimeric GTPase cycle, GTP hydrolysis, rather than nucleotide exchange, is the rate-limiting reaction and is accelerated by a receptor-like regulator of G signaling (RGS) protein. We hypothesized that posttranslational modification of the Gα subunit in the G protein complex regulates the RGS-dependent GTPase cycle. Our structural analyses identified an invariant phosphorylated tyrosine residue (Tyr 166 in the Arabidopsis Gα subunit AtGPA1) located in the intramolecular domain interface where nucleotide binding and hydrolysis occur. We also identified a receptor-like kinase that phosphorylates AtGPA1 in a Tyr 166 -dependent manner. Discrete molecular dynamics simulations predicted that phosphorylated Tyr 166 forms a salt bridge in this interface and potentially affects the RGS protein-accelerated GTPase cycle. Using a Tyr 166 phosphomimetic substitution, we found that the cognate RGS protein binds more tightly to the GDP-bound Gα substrate, consequently reducing its ability to accelerate GTPase activity. In conclusion, we propose that phosphorylation of Tyr 166 in AtGPA1 changes the binding pattern with AtRGS1 and thereby attenuates the steady-state rate of the GTPase cycle. We coin this newly identified mechanism "substrate phosphoswitching." © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins

    DEFF Research Database (Denmark)

    Rougier, Jean-Sébastien; van Bemmelen, Miguel X; Bruce, M Christine

    2004-01-01

    -ubiquitin ligases of the Nedd4 family. We recently reported that cardiac Na(v)1.5 is regulated by Nedd4-2. In this study, we further investigated the molecular determinants of regulation of Na(v) proteins. When expressed in HEK-293 cells and studied using whole cell voltage clamping, the neuronal Na(v)1.2 and Na...... that Nedd4-dependent ubiquitination of Na(v) channels may represent a general mechanism regulating the excitability of neurons and myocytes via modulation of channel density at the plasma membrane....

  2. PHF13 is a molecular reader and transcriptional co-regulator of H3K4me2/3

    DEFF Research Database (Denmark)

    Chung, Ho-Ryun; Xu, Chao; Fuchs, Alisa

    2016-01-01

    and its molecular chromatin context. Size exclusion chromatography, mass spectrometry, X-ray crystallography and ChIP sequencing demonstrate that PHF13 binds chromatin in a multivalent fashion via direct interactions with H3K4me2/3 and DNA, and indirectly via interactions with PRC2 and RNA Pol......II. Furthermore, PHF13 depletion disrupted the interactions between PRC2, RNA PolII S5P, H3K4me3 and H3K27me3 and resulted in the up and down regulation of genes functionally enriched in transcriptional regulation, DNA binding, cell cycle, differentiation and chromatin organization. Together our findings argue...... that PHF13 is an H3K4me2/3 molecular reader and transcriptional co-regulator, affording it the ability to impact different chromatin processes....

  3. A heteromeric molecular complex regulates the migration of lung alveolar epithelial cells during wound healing.

    Science.gov (United States)

    Ghosh, Manik C; Makena, Patrudu S; Kennedy, Joseph; Teng, Bin; Luellen, Charlean; Sinclair, Scott E; Waters, Christopher M

    2017-05-19

    Alveolar type II epithelial cells (ATII) are instrumental in early wound healing in response to lung injury, restoring epithelial integrity through spreading and migration. We previously reported in separate studies that focal adhesion kinase-1 (FAK) and the chemokine receptor CXCR4 promote epithelial repair mechanisms. However, potential interactions between these two pathways were not previously considered. In the present study, we found that wounding of rat ATII cells promoted increased association between FAK and CXCR4. In addition, protein phosphatase-5 (PP5) increased its association with this heteromeric complex, while apoptosis signal regulating kinase-1 (ASK1) dissociated from the complex. Cell migration following wounding was decreased when PP5 expression was decreased using shRNA, but migration was increased in ATII cells isolated from ASK1 knockout mice. Interactions between FAK and CXCR4 were increased upon depletion of ASK1 using shRNA in MLE-12 cells, but unaffected when PP5 was depleted. Furthermore, we found that wounded rat ATII cells exhibited decreased ASK1 phosphorylation at Serine-966, decreased serine phosphorylation of FAK, and decreased association of phosphorylated ASK1 with FAK. These changes in phosphorylation were dependent upon expression of PP5. These results demonstrate a unique molecular complex comprising CXCR4, FAK, ASK1, and PP5 in ATII cells during wound healing.

  4. Molecular regulation of high muscle mass in developing Blonde d'Aquitaine cattle foetuses

    Directory of Open Access Journals (Sweden)

    Isabelle Cassar-Malek

    2017-10-01

    Full Text Available The Blonde d'Aquitaine (BA is a French cattle breed with enhanced muscularity, partly attributable to a MSTN mutation. The BA m. Semitendinosus has a faster muscle fibre isoform phenotype comprising a higher proportion of fast type IIX fibres compared to age-matched Charolais (CH. To better understand the molecular network of modifications in BA compared to CH muscle, we assayed the transcriptomes of the m. Semitendinosus at 110, 180, 210 and 260 days postconception (dpc. We used a combination of differential expression (DE and regulatory impact factors (RIF to compare and contrast muscle gene expression between the breeds. Prominently developmentally regulated genes in both breeds reflected the replacement of embryonic myosin isoforms (MYL4, MYH3 with adult isoforms (MYH1 and the upregulation of mitochondrial metabolism (CKMT2, AGXT2L1 in preparation for birth. However, the transition to a fast, glycolytic muscle phenotype in the MSTN mutant BA is detectable through downregulation of various slow twitch subunits (TNNC1, MYH7, TPM3, CSRP3 beyond 210 dpc, and a small but consistent genome-wide reduction in mRNA encoding the mitoproteome. Across the breeds, NRIP2 is the regulatory gene possessing a network change most similar to that of MSTN.

  5. Profiling of Human Molecular Pathways Affected by Retrotransposons at the Level of Regulation by Transcription Factor Proteins

    Science.gov (United States)

    Nikitin, Daniil; Penzar, Dmitry; Garazha, Andrew; Sorokin, Maxim; Tkachev, Victor; Borisov, Nicolas; Poltorak, Alexander; Prassolov, Vladimir; Buzdin, Anton A.

    2018-01-01

    Endogenous retroviruses and retrotransposons also termed retroelements (REs) are mobile genetic elements that were active until recently in human genome evolution. REs regulate gene expression by actively reshaping chromatin structure or by directly providing transcription factor binding sites (TFBSs). We aimed to identify molecular processes most deeply impacted by the REs in human cells at the level of TFBS regulation. By using ENCODE data, we identified ~2 million TFBS overlapping with putatively regulation-competent human REs located in 5-kb gene promoter neighborhood (~17% of all TFBS in promoter neighborhoods; ~9% of all RE-linked TFBS). Most of REs hosting TFBS were highly diverged repeats, and for the evolutionary young (0–8% diverged) elements we identified only ~7% of all RE-linked TFBS. The gene-specific distributions of RE-linked TFBS generally correlated with the distributions for all TFBS. However, several groups of molecular processes were highly enriched in the RE-linked TFBS regulation. They were strongly connected with the immunity and response to pathogens, with the negative regulation of gene transcription, ubiquitination, and protein degradation, extracellular matrix organization, regulation of STAT signaling, fatty acids metabolism, regulation of GTPase activity, protein targeting to Golgi, regulation of cell division and differentiation, development and functioning of perception organs and reproductive system. By contrast, the processes most weakly affected by the REs were linked with the conservative aspects of embryo development. We also identified differences in the regulation features by the younger and older fractions of the REs. The regulation by the older fraction of the REs was linked mainly with the immunity, cell adhesion, cAMP, IGF1R, Notch, Wnt, and integrin signaling, neuronal development, chondroitin sulfate and heparin metabolism, and endocytosis. The younger REs regulate other aspects of immunity, cell cycle progression and

  6. Profiling of Human Molecular Pathways Affected by Retrotransposons at the Level of Regulation by Transcription Factor Proteins

    Directory of Open Access Journals (Sweden)

    Daniil Nikitin

    2018-01-01

    Full Text Available Endogenous retroviruses and retrotransposons also termed retroelements (REs are mobile genetic elements that were active until recently in human genome evolution. REs regulate gene expression by actively reshaping chromatin structure or by directly providing transcription factor binding sites (TFBSs. We aimed to identify molecular processes most deeply impacted by the REs in human cells at the level of TFBS regulation. By using ENCODE data, we identified ~2 million TFBS overlapping with putatively regulation-competent human REs located in 5-kb gene promoter neighborhood (~17% of all TFBS in promoter neighborhoods; ~9% of all RE-linked TFBS. Most of REs hosting TFBS were highly diverged repeats, and for the evolutionary young (0–8% diverged elements we identified only ~7% of all RE-linked TFBS. The gene-specific distributions of RE-linked TFBS generally correlated with the distributions for all TFBS. However, several groups of molecular processes were highly enriched in the RE-linked TFBS regulation. They were strongly connected with the immunity and response to pathogens, with the negative regulation of gene transcription, ubiquitination, and protein degradation, extracellular matrix organization, regulation of STAT signaling, fatty acids metabolism, regulation of GTPase activity, protein targeting to Golgi, regulation of cell division and differentiation, development and functioning of perception organs and reproductive system. By contrast, the processes most weakly affected by the REs were linked with the conservative aspects of embryo development. We also identified differences in the regulation features by the younger and older fractions of the REs. The regulation by the older fraction of the REs was linked mainly with the immunity, cell adhesion, cAMP, IGF1R, Notch, Wnt, and integrin signaling, neuronal development, chondroitin sulfate and heparin metabolism, and endocytosis. The younger REs regulate other aspects of immunity, cell cycle

  7. Determination of trace alkaline phosphatase by affinity adsorption solid substrate room temperature phosphorimetry based on wheat germ agglutinin labeled with 8-quinolineboronic acid phosphorescent molecular switch and prediction of diseases

    Science.gov (United States)

    Liu, Jia-Ming; Gao, Hui; Li, Fei-Ming; Shi, Xiu-Mei; Lin, Chang-Qing; Lin, Li-Ping; Wang, Xin-Xing; Li, Zhi-Ming

    2010-09-01

    The 8-quinolineboronic acid phosphorescent molecular switch (abbreviated as PMS-8-QBA. Thereinto, 8-QBA is 8-quinolineboronic acid, and PMS is phosphorescent molecular switch) was found for the first time. PMS-8-QBA, which was in the "off" state, could only emit weak room temperature phosphorescence (RTP) on the acetyl cellulose membrane (ACM). However, PMS-8-QBA turned "on" automatically for its changed structure, causing that the RTP of 8-QBA in the system increased, after PMS-8-QBA-WGA (WGA is wheat germ agglutinin) was formed by reaction between -OH of PMS-8-QBA and -COOH of WGA. More interesting is that the -NH 2 of PMS-8-QBA-WGA could react with the -COOH of alkaline phosphatase (AP) to form the affinity adsorption (AA) product WGA-AP-WGA-8-QBA-PMS (containing -NH-CO- bond), which caused RTP of the system to greatly increase. Thus, affinity adsorption solid substrate room temperature phosphorimetry using PMS-8-QBA as labelling reagent (PMS-8-QBA-AA-SSRTP) for the determination of trace AP was established. The method had many advantages, such as high sensitivity (the detection limit (LD) was 2.5 zg spot -1. For sample volume of 0.40 μl spot -1, corresponding concentration was 6.2 × 10 -18 g ml -1), good selectivity (the allowed concentration of coexisting material was higher, when the relative error was ±5%), high accuracy (applied to detection of AP content in serum samples, the result was coincided with those obtained by enzyme-linked immunoassay), which was suitable for the detection of trace AP content in serum samples and the forecast of human diseases. Meanwhile, the mechanism of PMS-8-QBA-AASSRTP was discussed. The new field of analytical application and clinic diagnosis technique of molecule switch are exploited, based on the phosphorescence characteristic of PMS-8-QBA, the AA reaction between WGA and AP, as well as the relation between AP content and human diseases. The research results promote the development and interpenetrate among molecule

  8. Stochastic switching in biology: from genotype to phenotype

    International Nuclear Information System (INIS)

    Bressloff, Paul C

    2017-01-01

    There has been a resurgence of interest in non-equilibrium stochastic processes in recent years, driven in part by the observation that the number of molecules (genes, mRNA, proteins) involved in gene expression are often of order 1–1000. This means that deterministic mass-action kinetics tends to break down, and one needs to take into account the discrete, stochastic nature of biochemical reactions. One of the major consequences of molecular noise is the occurrence of stochastic biological switching at both the genotypic and phenotypic levels. For example, individual gene regulatory networks can switch between graded and binary responses, exhibit translational/transcriptional bursting, and support metastability (noise-induced switching between states that are stable in the deterministic limit). If random switching persists at the phenotypic level then this can confer certain advantages to cell populations growing in a changing environment, as exemplified by bacterial persistence in response to antibiotics. Gene expression at the single-cell level can also be regulated by changes in cell density at the population level, a process known as quorum sensing. In contrast to noise-driven phenotypic switching, the switching mechanism in quorum sensing is stimulus-driven and thus noise tends to have a detrimental effect. A common approach to modeling stochastic gene expression is to assume a large but finite system and to approximate the discrete processes by continuous processes using a system-size expansion. However, there is a growing need to have some familiarity with the theory of stochastic processes that goes beyond the standard topics of chemical master equations, the system-size expansion, Langevin equations and the Fokker–Planck equation. Examples include stochastic hybrid systems (piecewise deterministic Markov processes), large deviations and the Wentzel–Kramers–Brillouin (WKB) method, adiabatic reductions, and queuing/renewal theory. The major aim of

  9. Human lymphoma mutations reveal CARD11 as the switch between self-antigen–induced B cell death or proliferation and autoantibody production

    Science.gov (United States)

    Jeelall, Yogesh S.; Wang, James Q.; Law, Hsei-Di; Domaschenz, Heather; Fung, Herman K.H.; Kallies, Axel; Nutt, Stephen L.

    2012-01-01

    Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigen-binding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing individual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell–independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo. PMID:23027925

  10. Simplified design of switching power supplies

    CERN Document Server

    Lenk, John

    1995-01-01

    * Describes the operation of each circuit in detail * Examines a wide selection of external components that modify the IC package characteristics * Provides hands-on, essential information for designing a switching power supply Simplified Design of Switching Power Supplies is an all-inclusive, one-stop guide to switching power-supply design. Step-by-step instructions and diagrams render this book essential for the student and the experimenter, as well as the design professional. Simplified Design of Switching Power Supplies concentrates on the use of IC regulators. All popular forms of swit

  11. Switched on!

    CERN Multimedia

    2008-01-01

    Like a star arriving on stage, impatiently followed by each member of CERN personnel and by millions of eyes around the world, the first beam of protons has circulated in the LHC. After years in the making and months of increasing anticipation, today the work of hundreds of people has borne fruit. WELL DONE to all! Successfully steered around the 27 kilometres of the world’s most powerful particle accelerator at 10:28 this morning, this first beam of protons circulating in the ring marks a key moment in the transition from over two decades of preparation to a new era of scientific discovery. "It’s a fantastic moment," said the LHC project leader Lyn Evans, "we can now look forward to a new era of understanding about the origins and evolution of the universe". Starting up a major new particle accelerator takes much more than flipping a switch. Thousands of individual elements have to work in harmony, timings have to be synchronize...

  12. Grass Carp Follisatin: Molecular Cloning, Functional Characterization, Dopamine D1 Regulation at Pituitary Level, and Implication in Growth Hormone Regulation

    Directory of Open Access Journals (Sweden)

    Roger S. K. Fung

    2017-08-01

    Full Text Available Activin is involved in pituitary hormone regulation and its pituitary actions can be nullified by local production of its binding protein follistatin. In our recent study with grass carp, local release of growth hormone (GH was shown to induce activin expression at pituitary level, which in turn could exert an intrapituitary feedback to inhibit GH synthesis and secretion. To further examine the activin/follistatin system in the carp pituitary, grass carp follistatin was cloned and confirmed to be single-copy gene widely expressed at tissue level. At the pituitary level, follistatin signals could be located in carp somatotrophs, gonadotrophs, and lactotrophs. Functional expression also revealed that carp follistatin was effective in neutralizing activin’s action in stimulating target promoter with activin-responsive elements. In grass carp pituitary cells, follistatin co-treatment was found to revert activin inhibition on GH mRNA expression. Meanwhile, follistatin mRNA levels could be up-regulated by local production of activin but the opposite was true for dopaminergic activation with dopamine (DA or its agonist apomorphine. Since GH stimulation by DA via pituitary D1 receptor is well-documented in fish models, the receptor specificity for follistatin regulation by DA was also investigated. Using a pharmacological approach, the inhibitory effect of DA on follistatin gene expression was confirmed to be mediated by pituitary D1 but not D2 receptor. Furthermore, activation of D1 receptor by the D1-specific agonist SKF77434 was also effective in blocking follistatin mRNA expression induced by activin and GH treatment both in carp pituitary cells as well as in carp somatotrophs enriched by density gradient centrifugation. These results, as a whole, suggest that activin can interact with dopaminergic input from the hypothalamus to regulate follistatin expression in carp pituitary, which may contribute to GH regulation by activin/follistatin system

  13. Transcriptomic Profiling Reveals Complex Molecular Regulation in Cotton Genic Male Sterile Mutant Yu98-8A.

    Directory of Open Access Journals (Sweden)

    Weiping Fang

    Full Text Available Although cotton genic male sterility (GMS plays an important role in the utilization of hybrid vigor, its precise molecular mechanism remains unclear. To characterize the molecular events of pollen abortion, transcriptome analysis, combined with histological observations, was conducted in the cotton GMS line, Yu98-8A. A total of 2,412 genes were identified as significant differentially expressed genes (DEGs before and during the critical pollen abortion stages. Bioinformatics and biochemical analysis showed that the DEGs mainly associated with sugars and starch metabolism, oxidative phosphorylation, and plant endogenous hormones play a critical and complicated role in pollen abortion. These findings extend a better understanding of the molecular events involved in the regulation of pollen abortion in genic male sterile cotton, which may provide a foundation for further research studies on cotton heterosis breeding.

  14. Gut-associated lymphoid tissue contains the molecular machinery to support T-cell-dependent and T-cell-independent class switch recombination.

    Science.gov (United States)

    Barone, F; Patel, P; Sanderson, J D; Spencer, J

    2009-11-01

    A PRoliferation-Inducing Ligand (APRIL) is a secreted cytokine member of the tumor necrosis factor family. It is a B-cell survival factor that also induces class switch recombination (CSR) toward immunoglobulin A (IgA), independent of T cells. It is therefore an important contributor to the maintenance of the mucosal immunological barrier, which has been linked to a putative extrafollicular inductive phase of the IgA response in lamina propria. By immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) on microdissected tissue from normal human gut, we observed APRIL expression, together with TACI (transmembrane activator and CAML interactor) and BCMA (B-cell maturation antigen), in gut-associated lymphoid tissue (GALT), lamina propria, and in the epithelium of stomach, small and large intestine, and rectum. However, no activation-induced cytidine deaminase (AID) expression (an absolute requirement for class switching) was detected in lamina propria by IHC or qRT-PCR. APRIL and its receptors were only observed alongside AID in GALT, showing that GALT contains the apparatus to support both T-independent and T-dependent routes to IgA CSR.

  15. CMOS integrated switching power converters

    CERN Document Server

    Villar-Pique, Gerard

    2011-01-01

    This book describes the structured design and optimization of efficient, energy processing integrated circuits. The approach is multidisciplinary, covering the monolithic integration of IC design techniques, power electronics and control theory. In particular, this book enables readers to conceive, synthesize, design and implement integrated circuits with high-density high-efficiency on-chip switching power regulators. Topics covered encompass the structured design of the on-chip power supply, efficiency optimization, IC-compatible power inductors and capacitors, power MOSFET switches and effi

  16. Mating-Type Genes and MAT Switching in Saccharomyces cerevisiae

    Science.gov (United States)

    Haber, James E.

    2012-01-01

    Mating type in Saccharomyces cerevisiae is determined by two nonhomologous alleles, MATa and MATα. These sequences encode regulators of the two different haploid mating types and of the diploids formed by their conjugation. Analysis of the MATa1, MATα1, and MATα2 alleles provided one of the earliest models of cell-type specification by transcriptional activators and repressors. Remarkably, homothallic yeast cells can switch their mating type as often as every generation by a highly choreographed, site-specific homologous recombination event that replaces one MAT allele with different DNA sequences encoding the opposite MAT allele. This replacement process involves the participation of two intact but unexpressed copies of mating-type information at the heterochromatic loci, HMLα and HMRa, which are located at opposite ends of the same chromosome-encoding MAT. The study of MAT switching has yielded important insights into the control of cell lineage, the silencing of gene expression, the formation of heterochromatin, and the regulation of accessibility of the donor sequences. Real-time analysis of MAT switching has provided the most detailed description of the molecular events that occur during the homologous recombinational repair of a programmed double-strand chromosome break. PMID:22555442

  17. Ikaros controls isotype selection during immunoglobulin class switch recombination.

    Science.gov (United States)

    Sellars, MacLean; Reina-San-Martin, Bernardo; Kastner, Philippe; Chan, Susan

    2009-05-11

    Class switch recombination (CSR) allows the humoral immune response to exploit different effector pathways through specific secondary antibody isotypes. However, the molecular mechanisms and factors that control immunoglobulin (Ig) isotype choice for CSR are unclear. We report that deficiency for the Ikaros transcription factor results in increased and ectopic CSR to IgG(2b) and IgG(2a), and reduced CSR to all other isotypes, regardless of stimulation. Ikaros suppresses active chromatin marks, transcription, and activation-induced cytidine deaminase (AID) accessibility at the gamma2b and gamma2a genes to inhibit class switching to these isotypes. Further, Ikaros directly regulates isotype gene transcription as it directly binds the Igh 3' enhancer and interacts with isotype gene promoters. Finally, Ikaros-mediated repression of gamma2b and gamma2a transcription promotes switching to other isotype genes by allowing them to compete for AID-mediated recombination at the single-cell level. Thus, our results reveal transcriptional competition between constant region genes in individual cells to be a critical and general mechanism for isotype specification during CSR. We show that Ikaros is a master regulator of this competition.

  18. The combination of positive and negative feedback loops confers exquisite flexibility to biochemical switches

    International Nuclear Information System (INIS)

    Pfeuty, Benjamin; Kaneko, Kunihiko

    2009-01-01

    A wide range of cellular processes require molecular regulatory pathways to convert a graded signal into a discrete response. One prevalent switching mechanism relies on the coexistence of two stable states (bistability) caused by positive feedback regulations. Intriguingly, positive feedback is often supplemented with negative feedback, raising the question of whether and how these two types of feedback can cooperate to control discrete cellular responses. To address this issue, we formulate a canonical model of a protein–protein interaction network and analyze the dynamics of a prototypical two-component circuit. The appropriate combination of negative and positive feedback loops can bring a bistable circuit close to the oscillatory regime. Notably, sharply activated negative feedback can give rise to a bistable regime wherein two stable fixed points coexist and may collide pairwise with two saddle points. This specific type of bistability is found to allow for separate and flexible control of switch-on and switch-off events, for example (i) to combine fast and reversible transitions, (ii) to enable transient switching responses and (iii) to display tunable noise-induced transition rates. Finally, we discuss the relevance of such bistable switching behavior, and the circuit topologies considered, to specific biological processes such as adaptive metabolic responses, stochastic fate decisions and cell-cycle transitions. Taken together, our results suggest an efficient mechanism by which positive and negative feedback loops cooperate to drive the flexible and multifaceted switching behaviors arising in biological systems

  19. Digital switched hydraulics

    Science.gov (United States)

    Pan, Min; Plummer, Andrew

    2018-06-01

    This paper reviews recent developments in digital switched hydraulics particularly the switched inertance hydraulic systems (SIHSs). The performance of SIHSs is presented in brief with a discussion of several possible configurations and control strategies. The soft switching technology and high-speed switching valve design techniques are discussed. Challenges and recommendations are given based on the current research achievements.

  20. Reverse engineering of an affinity-switchable molecular interaction characterized by atomic force microscopy single-molecule force spectroscopy.

    Science.gov (United States)

    Anselmetti, Dario; Bartels, Frank Wilco; Becker, Anke; Decker, Björn; Eckel, Rainer; McIntosh, Matthew; Mattay, Jochen; Plattner, Patrik; Ros, Robert; Schäfer, Christian; Sewald, Norbert

    2008-02-19

    Tunable and switchable interaction between molecules is a key for regulation and control of cellular processes. The translation of the underlying physicochemical principles to synthetic and switchable functional entities and molecules that can mimic the corresponding molecular functions is called reverse molecular engineering. We quantitatively investigated autoinducer-regulated DNA-protein interaction in bacterial gene regulation processes with single atomic force microscopy (AFM) molecule force spectroscopy in vitro, and developed an artificial bistable molecular host-guest system that can be controlled and regulated by external signals (UV light exposure and thermal energy). The intermolecular binding functionality (affinity) and its reproducible and reversible switching has been proven by AFM force spectroscopy at the single-molecule level. This affinity-tunable optomechanical switch will allow novel applications with respect to molecular manipulation, nanoscale rewritable molecular memories, and/or artificial ion channels, which will serve for the controlled transport and release of ions and neutral compounds in the future.

  1. Effect of crosslinking and grafting by 60Co-γ-ray irradiation on carbon black/polyethylene switching materials and fluoride resin system in self-regulating heating cables

    International Nuclear Information System (INIS)

    Zhang Zhiping; Wu Yiming; Luo Yanling; Wang Jikui

    2000-01-01

    A new kind of PTC (positive temperature coefficient) conductive composite and its appliance switching, self-regulating heating cables, for organic polymer alloy filled with carbon black was studied and developed in this paper. The conductive mechanism and the dependence of resistivity on temperature of this system was shed light on, and a new view on PTC effect was set up. Power adjustion coefficient was proposed as a parameter for representing the self-regulating properties and aging life. The relationship between structure and properties was investigated by using several measurement means such as differential scanning calorimetry (DSC), wide angle X-ray diffraction (WAXD), small angle X-ray scattering (SAXS), dynamic properties, torque analysis and so on, and the experimental results were fully explained. (author)

  2. Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1.

    Science.gov (United States)

    Gaude, H; Aznar, N; Delay, A; Bres, A; Buchet-Poyau, K; Caillat, C; Vigouroux, A; Rogon, C; Woods, A; Vanacker, J-M; Höhfeld, J; Perret, C; Meyer, P; Billaud, M; Forcet, C

    2012-03-22

    LKB1 is a tumor suppressor that is constitutionally mutated in a cancer-prone condition, called Peutz-Jeghers syndrome, as well as somatically inactivated in a sizeable fraction of lung and cervical neoplasms. The LKB1 gene encodes a serine/threonine kinase that associates with the pseudokinase STRAD (STE-20-related pseudokinase) and the scaffolding protein MO25, the formation of this heterotrimeric complex promotes allosteric activation of LKB1. We have previously reported that the molecular chaperone heat shock protein 90 (Hsp90) binds to and stabilizes LKB1. Combining pharmacological studies and RNA interference approaches, we now provide evidence that the co-chaperone Cdc37 participates to the regulation of LKB1 stability. It is known that the Hsp90-Cdc37 complex recognizes a surface within the N-terminal catalytic lobe of client protein kinases. In agreement with this finding, we found that the chaperones Hsp90 and Cdc37 interact with an LKB1 isoform that differs in the C-terminal region, but not with a novel LKB1 variant that lacks a portion of the kinase N-terminal lobe domain. Reconstitution of the two complexes LKB1-STRAD and LKB1-Hsp90-Cdc37 with recombinant proteins revealed that the former is catalytically active whereas the latter is inactive. Furthermore, consistent with a documented repressor function of Hsp90, LKB1 kinase activity was transiently stimulated upon dissociation of Hsp90. Finally, disruption of the LKB1-Hsp90 complex favors the recruitment of both Hsp/Hsc70 and the U-box dependent E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein) that triggers LKB1 degradation. Taken together, our results establish that the Hsp90-Cdc37 complex controls both the stability and activity of the LKB1 kinase. This study further shows that two chaperone complexes with antagonizing activities, Hsp90-Cdc37 and Hsp/Hsc70-CHIP, finely control the cellular level of LKB1 protein.

  3. Temperature control of fimbriation circuit switch in uropathogenic Escherichia coli: quantitative analysis via automated model abstraction.

    Science.gov (United States)

    Kuwahara, Hiroyuki; Myers, Chris J; Samoilov, Michael S

    2010-03-26

    Uropathogenic Escherichia coli (UPEC) represent the predominant cause of urinary tract infections (UTIs). A key UPEC molecular virulence mechanism is type 1 fimbriae, whose expression is controlled by the orientation of an invertible chromosomal DNA element-the fim switch. Temperature has been shown to act as a major regulator of fim switching behavior and is overall an important indicator as well as functional feature of many urologic diseases, including UPEC host-pathogen interaction dynamics. Given this panoptic physiological role of temperature during UTI progression and notable empirical challenges to its direct in vivo studies, in silico modeling of corresponding biochemical and biophysical mechanisms essential to UPEC pathogenicity may significantly aid our understanding of the underlying disease processes. However, rigorous computational analysis of biological systems, such as fim switch temperature control circuit, has hereto presented a notoriously demanding problem due to both the substantial complexity of the gene regulatory networks involved as well as their often characteristically discrete and stochastic dynamics. To address these issues, we have developed an approach that enables automated multiscale abstraction of biological system descriptions based on reaction kinetics. Implemented as a computational tool, this method has allowed us to efficiently analyze the modular organization and behavior of the E. coli fimbriation switch circuit at different temperature settings, thus facilitating new insights into this mode of UPEC molecular virulence regulation. In particular, our results suggest that, with respect to its role in shutting down fimbriae expression, the primary function of FimB recombinase may be to effect a controlled down-regulation (rather than increase) of the ON-to-OFF fim switching rate via temperature-dependent suppression of competing dynamics mediated by recombinase FimE. Our computational analysis further implies that this down-regulation

  4. Temperature control of fimbriation circuit switch in uropathogenic Escherichia coli: quantitative analysis via automated model abstraction.

    Directory of Open Access Journals (Sweden)

    Hiroyuki Kuwahara

    2010-03-01

    Full Text Available Uropathogenic Escherichia coli (UPEC represent the predominant cause of urinary tract infections (UTIs. A key UPEC molecular virulence mechanism is type 1 fimbriae, whose expression is controlled by the orientation of an invertible chromosomal DNA element-the fim switch. Temperature has been shown to act as a major regulator of fim switching behavior and is overall an important indicator as well as functional feature of many urologic diseases, including UPEC host-pathogen interaction dynamics. Given this panoptic physiological role of temperature during UTI progression and notable empirical challenges to its direct in vivo studies, in silico modeling of corresponding biochemical and biophysical mechanisms essential to UPEC pathogenicity may significantly aid our understanding of the underlying disease processes. However, rigorous computational analysis of biological systems, such as fim switch temperature control circuit, has hereto presented a notoriously demanding problem due to both the substantial complexity of the gene regulatory networks involved as well as their often characteristically discrete and stochastic dynamics. To address these issues, we have developed an approach that enables automated multiscale abstraction of biological system descriptions based on reaction kinetics. Implemented as a computational tool, this method has allowed us to efficiently analyze the modular organization and behavior of the E. coli fimbriation switch circuit at different temperature settings, thus facilitating new insights into this mode of UPEC molecular virulence regulation. In particular, our results suggest that, with respect to its role in shutting down fimbriae expression, the primary function of FimB recombinase may be to effect a controlled down-regulation (rather than increase of the ON-to-OFF fim switching rate via temperature-dependent suppression of competing dynamics mediated by recombinase FimE. Our computational analysis further implies

  5. Coupled Reversible and Irreversible Bistable Switches Underlying TGFβ-induced Epithelial to Mesenchymal Transition

    Science.gov (United States)

    Tian, Xiao-Jun; Zhang, Hang; Xing, Jianhua

    2013-01-01

    Epithelial to mesenchymal transition (EMT) plays an important role in embryonic development, tissue regeneration, and cancer metastasis. Whereas several feedback loops have been shown to regulate EMT, it remains elusive how they coordinately modulate EMT response to TGF-β treatment. We construct a mathematical model for the core regulatory network controlling TGF-β-induced EMT. Through deterministic analyses and stochastic simulations, we show that EMT is a sequential two-step program in which an epithelial cell first is converted to partial EMT then to the mesenchymal state, depending on the strength and duration of TGF-β stimulation. Mechanistically the system is governed by coupled reversible and irreversible bistable switches. The SNAIL1/miR-34 double-negative feedback loop is responsible for the reversible switch and regulates the initiation of EMT, whereas the ZEB/miR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-β/miR-200 feedback loop makes the second switch irreversible, modulating the maintenance of EMT. Such coupled bistable switches are robust to parameter variation and molecular noise. We provide a mechanistic explanation on multiple experimental observations. The model makes several explicit predictions on hysteretic dynamic behaviors, system response to pulsed stimulation, and various perturbations, which can be straightforwardly tested. PMID:23972859

  6. Physical Exercise Modulates L-DOPA-Regulated Molecular Pathways in the MPTP Mouse Model of Parkinson's Disease.

    Science.gov (United States)

    Klemann, Cornelius J H M; Xicoy, Helena; Poelmans, Geert; Bloem, Bas R; Martens, Gerard J M; Visser, Jasper E

    2018-07-01

    Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor dysfunction. Physical exercise improves these symptoms in PD patients. To explore the molecular mechanisms underlying the beneficial effects of physical exercise, we exposed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP)-treated mice to a four-week physical exercise regimen, and subsequently explored their motor performance and the transcriptome of multiple PD-linked brain areas. MPTP reduced the number of DA neurons in the SNpc, whereas physical exercise improved beam walking, rotarod performance, and motor behavior in the open field. Further, enrichment analyses of the RNA-sequencing data revealed that in the MPTP-treated mice physical exercise predominantly modulated signaling cascades that are regulated by the top upstream regulators L-DOPA, RICTOR, CREB1, or bicuculline/dalfampridine, associated with movement disorders, mitochondrial dysfunction, and epilepsy-related processes. To elucidate the molecular pathways underlying these cascades, we integrated the proteins encoded by the exercise-induced differentially expressed mRNAs for each of the upstream regulators into a molecular landscape, for multiple key brain areas. Most notable was the opposite effect of physical exercise compared to previously reported effects of L-DOPA on the expression of mRNAs in the SN and the ventromedial striatum that are involved in-among other processes-circadian rhythm and signaling involving DA, neuropeptides, and endocannabinoids. Altogether, our findings suggest that physical exercise can improve motor function in PD and may, at the same time, counteract L-DOPA-mediated molecular mechanisms. Further, we hypothesize that physical exercise has the potential to improve non-motor symptoms of PD, some of which may be the result of (chronic) L-DOPA use.

  7. IGBT: a solid state switch

    International Nuclear Information System (INIS)

    Chatroux, D.; Maury, J.; Hennevin, B.

    1993-01-01

    A Copper Vapour Laser Power Supply has been designed using a solid state switch consisting in eighteen Isolated Gate Bipolar Transistors (IGBT), -1200 volts, 400 Amps, each-in parallel. This paper presents the Isolated Gate Bipolar Transistor (IGBTs) replaced in the Power Electronic components evolution, and describes the IGBT conduction mechanism, presents the parallel association of IGBTs, and studies the application of these components to a Copper Vapour Laser Power Supply. The storage capacitor voltage is 820 volts, the peak current of the solid state switch is 17.000 Amps. The switch is connected on the primary of a step-up transformer, followed by a magnetic modulator. The reset of the magnetic modulator is provided by part of the laser reflected energy with a patented circuit. The charging circuit is a resonant circuit with a charge controlled by an IGBT switch. When the switch is open, the inductance energy is free-wheeled by an additional winding and does not extend the charging phase of the storage capacitor. The design allows the storage capacitor voltage to be very well regulated. This circuit is also patented. The electric pulse in the laser has 30.000 Volt peak voltage, 2000 Amp peak current, and is 200 nanoseconds long, for a 200 Watt optical power Copper Vapour Laser

  8. Molecular analysis of halorespiration in Desulfitobacterium spp. : catalysis and transcriptional regulation

    NARCIS (Netherlands)

    Gabor, K.

    2006-01-01

    Keywords: iron-sulphur proteins, protein-DNA interaction, allosteric regulation, redox regulation, gene redundancy, chlorophenols, bioremediationSoil and ground water contamination by halogenated organic compounds mainly used as biocides in agriculture or solvents and

  9. Light-controlled supramolecular helicity of a liquid crystalline phase using a helical polymer functionalized with a single chiroptical molecular switch

    NARCIS (Netherlands)

    Pijper, Dirk; Jongejan, Mahthild G. M.; Meetsma, Auke; Feringa, Ben L.

    2008-01-01

    Control over the preferred helical sense of a poly(n-hexyl isocyanate) (PHIC) by using a single light-driven molecular motor, covalently attached at the polymer's terminus, has been accomplished in solution via a combination of photochemical and thermal isomerizations. Here, we report that after

  10. Distinct Molecular Signature of Murine Fetal Liver and Adult Hematopoietic Stem Cells Identify Novel Regulators of Hematopoietic Stem Cell Function.

    Science.gov (United States)

    Manesia, Javed K; Franch, Monica; Tabas-Madrid, Daniel; Nogales-Cadenas, Ruben; Vanwelden, Thomas; Van Den Bosch, Elisa; Xu, Zhuofei; Pascual-Montano, Alberto; Khurana, Satish; Verfaillie, Catherine M

    2017-04-15

    During ontogeny, fetal liver (FL) acts as a major site for hematopoietic stem cell (HSC) maturation and expansion, whereas HSCs in the adult bone marrow (ABM) are largely quiescent. HSCs in the FL possess faster repopulation capacity as compared with ABM HSCs. However, the molecular mechanism regulating the greater self-renewal potential of FL HSCs has not yet extensively been assessed. Recently, we published RNA sequencing-based gene expression analysis on FL HSCs from 14.5-day mouse embryo (E14.5) in comparison to the ABM HSCs. We reanalyzed these data to identify key transcriptional regulators that play important roles in the expansion of HSCs during development. The comparison of FL E14.5 with ABM HSCs identified more than 1,400 differentially expressed genes. More than 200 genes were shortlisted based on the gene ontology (GO) annotation term "transcription." By morpholino-based knockdown studies in zebrafish, we assessed the function of 18 of these regulators, previously not associated with HSC proliferation. Our studies identified a previously unknown role for tdg, uhrf1, uchl5, and ncoa1 in the emergence of definitive hematopoiesis in zebrafish. In conclusion, we demonstrate that identification of genes involved in transcriptional regulation differentially expressed between expanding FL HSCs and quiescent ABM HSCs, uncovers novel regulators of HSC function.

  11. Latching micro optical switch

    Science.gov (United States)

    Garcia, Ernest J; Polosky, Marc A

    2013-05-21

    An optical switch reliably maintains its on or off state even when subjected to environments where the switch is bumped or otherwise moved. In addition, the optical switch maintains its on or off state indefinitely without requiring external power. External power is used only to transition the switch from one state to the other. The optical switch is configured with a fixed optical fiber and a movable optical fiber. The movable optical fiber is guided by various actuators in conjunction with a latching mechanism that configure the switch in one position that corresponds to the on state and in another position that corresponds to the off state.

  12. The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch.

    Science.gov (United States)

    Mauney, Christopher H; Rogers, LeAnn C; Harris, Reuben S; Daniel, Larry W; Devarie-Baez, Nelmi O; Wu, Hanzhi; Furdui, Cristina M; Poole, Leslie B; Perrino, Fred W; Hollis, Thomas

    2017-12-01

    Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools. We demonstrate that the redox state of SAMHD1 regulates its catalytic activity. We have identified three cysteine residues that constitute an intrachain disulfide bond "redox switch" that reversibly inhibits protein tetramerization and catalysis. We show that proliferative signals lead to SAMHD1 oxidation in cells and oxidized SAMHD1 is localized outside of the nucleus. Innovation and Conclusions: SAMHD1 catalytic activity is reversibly regulated by protein oxidation. These data identify a previously unknown mechanism for regulation of nucleotide metabolism by SAMHD1. Antioxid. Redox Signal. 27, 1317-1331.

  13. The carboxy-terminal αN helix of the archaeal XerA tyrosine recombinase is a molecular switch to control site-specific recombination.

    Science.gov (United States)

    Serre, Marie-Claude; El Arnaout, Toufic; Brooks, Mark A; Durand, Dominique; Lisboa, Johnny; Lazar, Noureddine; Raynal, Bertrand; van Tilbeurgh, Herman; Quevillon-Cheruel, Sophie

    2013-01-01

    Tyrosine recombinases are conserved in the three kingdoms of life. Here we present the first crystal structure of a full-length archaeal tyrosine recombinase, XerA from Pyrococcus abyssi, at 3.0 Å resolution. In the absence of DNA substrate XerA crystallizes as a dimer where each monomer displays a tertiary structure similar to that of DNA-bound Tyr-recombinases. Active sites are assembled in the absence of dif except for the catalytic Tyr, which is extruded and located equidistant from each active site within the dimer. Using XerA active site mutants we demonstrate that XerA follows the classical cis-cleavage reaction, suggesting rearrangements of the C-terminal domain upon DNA binding. Surprisingly, XerA C-terminal αN helices dock in cis in a groove that, in bacterial tyrosine recombinases, accommodates in trans αN helices of neighbour monomers in the Holliday junction intermediates. Deletion of the XerA C-terminal αN helix does not impair cleavage of suicide substrates but prevents recombination catalysis. We propose that the enzymatic cycle of XerA involves the switch of the αN helix from cis to trans packing, leading to (i) repositioning of the catalytic Tyr in the active site in cis and (ii) dimer stabilisation via αN contacts in trans between monomers.

  14. The carboxy-terminal αN helix of the archaeal XerA tyrosine recombinase is a molecular switch to control site-specific recombination.

    Directory of Open Access Journals (Sweden)

    Marie-Claude Serre

    Full Text Available Tyrosine recombinases are conserved in the three kingdoms of life. Here we present the first crystal structure of a full-length archaeal tyrosine recombinase, XerA from Pyrococcus abyssi, at 3.0 Å resolution. In the absence of DNA substrate XerA crystallizes as a dimer where each monomer displays a tertiary structure similar to that of DNA-bound Tyr-recombinases. Active sites are assembled in the absence of dif except for the catalytic Tyr, which is extruded and located equidistant from each active site within the dimer. Using XerA active site mutants we demonstrate that XerA follows the classical cis-cleavage reaction, suggesting rearrangements of the C-terminal domain upon DNA binding. Surprisingly, XerA C-terminal αN helices dock in cis in a groove that, in bacterial tyrosine recombinases, accommodates in trans αN helices of neighbour monomers in the Holliday junction intermediates. Deletion of the XerA C-terminal αN helix does not impair cleavage of suicide substrates but prevents recombination catalysis. We propose that the enzymatic cycle of XerA involves the switch of the αN helix from cis to trans packing, leading to (i repositioning of the catalytic Tyr in the active site in cis and (ii dimer stabilisation via αN contacts in trans between monomers.

  15. Molecular machinery of signal transduction and cell cycle regulation in Plasmodium

    OpenAIRE

    Koyama, Fernanda C.; Chakrabarti, Debopam; Garcia, Célia R.S.

    2009-01-01

    The regulation of the Plasmodium cell cycle is not understood. Although the Plasmodium falciparum genome is completely sequenced, about 60% of the predicted proteins share little or no sequence similarity with other eukaryotes. This feature impairs the identification of important proteins participating in the regulation of the cell cycle. There are several open questions that concern cell cycle progression in malaria parasites, including the mechanism by which multiple nuclear divisions is co...

  16. Shape memory thermal conduction switch

    Science.gov (United States)

    Vaidyanathan, Rajan (Inventor); Krishnan, Vinu (Inventor); Notardonato, William U. (Inventor)

    2010-01-01

    A thermal conduction switch includes a thermally-conductive first member having a first thermal contacting structure for securing the first member as a stationary member to a thermally regulated body or a body requiring thermal regulation. A movable thermally-conductive second member has a second thermal contacting surface. A thermally conductive coupler is interposed between the first member and the second member for thermally coupling the first member to the second member. At least one control spring is coupled between the first member and the second member. The control spring includes a NiTiFe comprising shape memory (SM) material that provides a phase change temperature <273 K, a transformation range <40 K, and a hysteresis of <10 K. A bias spring is between the first member and the second member. At the phase change the switch provides a distance change (displacement) between first and second member by at least 1 mm, such as 2 to 4 mm.

  17. Switched-capacitor isolated LED driver

    Science.gov (United States)

    Sanders, Seth R.; Kline, Mitchell

    2016-03-22

    A switched-capacitor voltage converter which is particularly well-suited for receiving a line voltage from which to drive current through a series of light emitting diodes (LEDs). Input voltage is rectified in a multi-level rectifier network having switched capacitors in an ascending-bank configuration for passing voltages in uniform steps between zero volts up to full received voltage V.sub.DC. A regulator section, operating on V.sub.DC, comprises switched-capacitor stages of H-bridge switching and flying capacitors. A current controlled oscillator drives the states of the switched-capacitor stages and changes its frequency to maintain a constant current to the load. Embodiments are described for isolating the load from the mains, utilizing an LC tank circuit or a multi-primary-winding transformer.

  18. Insight into the molecular regulation of the epithelial magnesium channel TRPM6.

    NARCIS (Netherlands)

    Cao, G.; Hoenderop, J.G.J.; Bindels, R.J.M.

    2008-01-01

    PURPOSE OF REVIEW: Recent studies have greatly increased our knowledge concerning the molecular mechanisms of renal magnesium handling. This review highlights the functional features of the newly identified transient receptor potential channel melastatin subtype 6 (TRPM6), which forms the gatekeeper

  19. Constant pH Accelerated Molecular Dynamics Investigation of the pH Regulation Mechanism of Dinoflagellate Luciferase.

    Science.gov (United States)

    Donnan, Patrick H; Ngo, Phong D; Mansoorabadi, Steven O

    2018-01-23

    The bioluminescence reaction in dinoflagellates involves the oxidation of an open-chain tetrapyrrole by the enzyme dinoflagellate luciferase (LCF). The activity of LCF is tightly regulated by pH, where the enzyme is essentially inactive at pH ∼8 and optimally active at pH ∼6. Little is known about the mechanism of LCF or the structure of the active form of the enzyme, although it has been proposed that several intramolecularly conserved histidine residues in the N-terminal region are important for the pH regulation mechanism. Here, constant pH accelerated molecular dynamics was employed to gain insight into the conformational activation of LCF induced by acidification.

  20. Functions of NQO1 in Cellular Protection and CoQ10 Metabolism and its Potential Role as a Redox Sensitive Molecular Switch

    Directory of Open Access Journals (Sweden)

    David Ross

    2017-08-01

    Full Text Available NQO1 is one of the two major quinone reductases in mammalian systems. It is highly inducible and plays multiple roles in cellular adaptation to stress. A prevalent polymorphic form of NQO1 results in an absence of NQO1 protein and activity so it is important to elucidate the specific cellular functions of NQO1. Established roles of NQO1 include its ability to prevent certain quinones from one electron redox cycling but its role in quinone detoxification is dependent on the redox stability of the hydroquinone generated by two-electron reduction. Other documented roles of NQO1 include its ability to function as a component of the plasma membrane redox system generating antioxidant forms of ubiquinone and vitamin E and at high levels, as a direct superoxide reductase. Emerging roles of NQO1 include its function as an efficient intracellular generator of NAD+ for enzymes including PARP and sirtuins which has gained particular attention with respect to metabolic syndrome. NQO1 interacts with a growing list of proteins, including intrinsically disordered proteins, protecting them from 20S proteasomal degradation. The interactions of NQO1 also extend to mRNA. Recent identification of NQO1 as a mRNA binding protein have been investigated in more detail using SERPIN1A1 (which encodes the serine protease inhibitor α-1-antitrypsin as a target mRNA and indicate a role of NQO1 in control of translation of α-1-antitrypsin, an important modulator of COPD and obesity related metabolic syndrome. NQO1 undergoes structural changes and alterations in its ability to bind other proteins as a result of the cellular reduced/oxidized pyridine nucleotide ratio. This suggests NQO1 may act as a cellular redox switch potentially altering its interactions with other proteins and mRNA as a result of the prevailing redox environment.

  1. Natural IgM and TLR Agonists Switch Murine Splenic Pan-B to “Regulatory” Cells That Suppress Ischemia-Induced Innate Inflammation via Regulating NKT-1 Cells

    Directory of Open Access Journals (Sweden)

    Peter I. Lobo

    2017-08-01

    Full Text Available Natural IgM anti-leukocyte autoantibodies (IgM-ALAs inhibit inflammation by several mechanisms. Here, we show that pan-B cells and bone marrow-derived dendritic cells (BMDCs are switched to regulatory cells when pretreated ex vivo with IgM. B cells are also switched to regulatory cells when pretreated ex vivo with CpG but not with LPS. Pre-emptive infusion of such ex vivo induced regulatory cells protects C57BL/6 mice from ischemia-induced acute kidney injury (AKI via regulation of in vivo NKT-1 cells, which normally amplify the innate inflammatory response to DAMPS released after reperfusion of the ischemic kidney. Such ex vivo induced regulatory pan-B cells and BMDC express low CD1d and inhibit inflammation by regulating in vivo NKT-1 in the context of low-lipid antigen presentation and by a mechanism that requires costimulatory molecules, CD1d, PDL1/PD1, and IL10. Second, LPS and CpG have opposite effects on induction of regulatory activity in BMDC and B cells. LPS enhances regulatory activity of IgM-pretreated BMDC but negates the IgM-induced regulatory activity in B cells, while CpG, with or without IgM pretreatment, induces regulatory activity in B cells but not in BMDC. Differences in the response of pan-B and dendritic cells to LPS and CpG, especially in the presence of IgM-ALA, may have relevance during infections and inflammatory disorders where there is an increased IgM-ALA and release of TLRs 4 and 9 ligands. Ex vivo induced regulatory pan-B cells could have therapeutic relevance as these easily available cells can be pre-emptively infused to prevent AKI that can occur during open heart surgery or in transplant recipients receiving deceased donor organs.

  2. FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Yusuke Murata

    2011-01-01

    Full Text Available The FGF family comprises twenty-two structurally related proteins with functions in development and metabolism. The Fgf21 gene was generated early in vertebrate evolution. FGF21 acts as an endocrine regulator in lipid metabolism. Hepatic Fgf21 expression is markedly induced in mice by fasting or a ketogenic diet. Experiments with Fgf21 transgenic mice and cultured cells indicate that FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes via cell surface FGF receptors. However, experiments with Fgf21 knockout mice indicate that FGF21 inhibits lipolysis in adipocytes during fasting and attenuates torpor induced by a ketogenic diet but maybe not a physiological regulator for these hepatic functions. These findings suggest the pharmacological effects to be distinct from the physiological roles. Serum FGF21 levels are increased in patients with metabolic diseases having insulin resistance, indicating that FGF21 is a metabolic regulator and a biomarker for these diseases.

  3. The AMPK enzyme-complex: From the regulation of cellular energy homeostasis to a possible new molecular target in the management of chronic inflammatory disorders

    NARCIS (Netherlands)

    Antonioli, Luca; Colucci, Rocchina; Pellegrini, Carolina; Giustarini, Giulio; Sacco, Deborah; Tirotta, Erika; Caputi, Valentina; Marsilio, Ilaria; Giron, Maria Cecilia; Németh, Zoltán H; Blandizzi, Corrado; Fornai, Matteo

    2016-01-01

    Introduction: Adenosine monophosphate-activated protein kinase (AMPK), known as an enzymatic complex that regulates the energetic metabolism, is emerging as a pivotal enzyme and enzymatic pathway involved in the regulation of immune homeostatic networks. It is also involved in the molecular

  4. Molecular Regulation of Photosynthetic Carbon Dioxide Fixation in Nonsulfur Purple Bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Tabita, Fred Robert [The Ohio State Univ., Columbus, OH (United States)

    2015-12-01

    The overall objective of this project is to determine the mechanism by which a transcriptional activator protein affects CO2 fixation (cbb) gene expression in nonsulfur purple photosynthetic bacteria, with special emphasis to Rhodobacter sphaeroides and with comparison to Rhodopseudomonas palustris. These studies culminated in several publications which indicated that additional regulators interact with the master regulator CbbR in both R. sphaeroides and R. palustris. In addition, the interactive control of the carbon and nitrogen assimilatory pathways was studied and unique regulatory signals were discovered.

  5. Molecular regulation and genetic improvement of seed oil content in Brassica napus L.

    Directory of Open Access Journals (Sweden)

    Wei HUA,Jing LIU,Hanzhong WANG

    2016-09-01

    Full Text Available As an important oil crop and a potential bioenergy crop, Brassica napus L. is becoming a model plant for basic research on seed lipid biosynthesis as well as seed oil content, which has always been the key breeding objective. In this review, we present current progress in understanding of the regulation of oil content in B. napus, including genetics, biosynthesis pathway, transcriptional regulation, maternal effects and QTL analysis. Furthermore, the history of breeding for high oil content in B. napus is summarized and the progress in breeding ultra-high oil content lines is described. Finally, prospects for breeding high oil content B. napus cultivars are outlined.

  6. Carbon dioxide-dependent regulation of NF-κB family members RelB and p100 gives molecular insight into CO2-dependent immune regulation.

    Science.gov (United States)

    Keogh, Ciara E; Scholz, Carsten C; Rodriguez, Javier; Selfridge, Andrew C; von Kriegsheim, Alexander; Cummins, Eoin P

    2017-07-07

    CO 2 is a physiological gas normally produced in the body during aerobic respiration. Hypercapnia (elevated blood pCO 2 >≈50 mm Hg) is a feature of several lung pathologies, e.g. chronic obstructive pulmonary disease. Hypercapnia is associated with increased susceptibility to bacterial infections and suppression of inflammatory signaling. The NF-κB pathway has been implicated in these effects; however, the molecular mechanisms underpinning cellular sensitivity of the NF-κB pathway to CO 2 are not fully elucidated. Here, we identify several novel CO 2 -dependent changes in the NF-κB pathway. NF-κB family members p100 and RelB translocate to the nucleus in response to CO 2 A cohort of RelB protein-protein interactions ( e.g. with Raf-1 and IκBα) are altered by CO 2 exposure, although others are maintained ( e.g. with p100). RelB is processed by CO 2 in a manner dependent on a key C-terminal domain located in its transactivation domain. Loss of the RelB transactivation domain alters NF-κB-dependent transcriptional activity, and loss of p100 alters sensitivity of RelB to CO 2 Thus, we provide molecular insight into the CO 2 sensitivity of the NF-κB pathway and implicate altered RelB/p100-dependent signaling in the CO 2 -dependent regulation of inflammatory signaling. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Clumpy molecular clouds: A dynamic model self-consistently regulated by T Tauri star formation

    International Nuclear Information System (INIS)

    Norman, C.; Silk, J.

    1980-01-01

    A new model is proposed which can account for the longevity, energetics, and dynamical structure of dark molecular clouds. It seems clear that the kinetic and gravitational energy in macroscopic cloud motions cannot account for the energetic of many molecular clouds. A stellar energy source must evidently be tapped, and infrared observations indicate that one cannot utilize massive stars in dark clouds. Recent observations of a high space density of T Tauri stars in some dark clouds provide the basis for our assertion that high-velocity winds from these low-mass pre--main-sequence stars provide a continuous dynamic input into molecular clouds. The T Tauri winds sweep up shells of gas, the intersections or collisions of which form dense clumps embedded in a more rarefied interclump medium. Observations constrain the clumps to be ram-pressure confined, but at the relatively low Mach numbers, continuous leakage occurs. This mass input into the interclump medium leads to the existence of two phases; a dense, cold phase (clumps of density approx.10 4 --10 5 cm -3 and temperature approx.10 K) and a warm, more diffuse, interclump medium (ICM, of density approx.10 3 --10 4 cm -3 and temperature approx.30 K). Clump collisions lead to coalescence, and the evolution of the mass spectrum of clumps is studied

  8. Molecular regulation of CCN2 in the intervertebral disc: lessons learned from other connective tissues.

    Science.gov (United States)

    Tran, Cassie M; Shapiro, Irving M; Risbud, Makarand V

    2013-08-08

    Connective tissue growth factor (CCN2/CTGF) plays an important role in extracellular matrix synthesis, especially in skeletal tissues such as cartilage, bone, and the intervertebral disc. As a result there is a growing interest in examining the function and regulation of this important molecule in the disc. This review discusses the regulation of CCN2 by TGF-β and hypoxia, two critical determinants that characterize the disc microenvironment, and discusses known functions of CCN2 in the disc. The almost ubiquitous regulation of CCN2 by TGF-β, including that seen in the disc, emphasizes the importance of the TGF-β-CCN2 relationship, especially in terms of extracellular matrix synthesis. Likewise, the unique cross-talk between CCN2 and HIF-1 in the disc highlights the tissue and niche specific mode of regulation. Taken together the current literature supports an anabolic role for CCN2 in the disc and its involvement in the maintenance of tissue homeostasis during both health and disease. Further studies of CCN2 in this tissue may reveal valuable targets for the biological therapy of disc degeneration. © 2013 Elsevier B.V. All rights reserved.

  9. Identification and regulation of a molecular module for bleb-based cell motility

    NARCIS (Netherlands)

    Goudarzi, M.; Banisch, T.U.; Mobin, M.B.; Maghelli, N.; Tarbashevich, K.; Strate, I.; ter Berg, J.; Blaser, H.; Bandemer, S.; Paluch, E.; Bakkers, J.; Tolic-Norrelykke, I.M.; Raz, E.

    2012-01-01

    Single-cell migration is a key process in development, homeostasis, and disease. Nevertheless, the control over basic cellular mechanisms directing cells into motile behavior in vivo is largely unknown. Here, we report on the identification of a minimal set of parameters the regulation of which

  10. SIRT1 regulates MAPK pathways in vitiligo skin: insight into the molecular pathways of cell survival

    Science.gov (United States)

    Becatti, Matteo; Fiorillo, Claudia; Barygina, Victoria; Cecchi, Cristina; Lotti, Torello; Prignano, Francesca; Silvestro, Agrippino; Nassi, Paolo; Taddei, Niccolò

    2014-01-01

    Vitiligo is an acquired and progressive hypomelanotic disease that manifests as circumscribed depigmented patches on the skin. The aetiology of vitiligo remains unclear, but recent experimental data underline the interactions between melanocytes and other typical skin cells, particularly keratinocytes. Our previous results indicate that keratinocytes from perilesional skin show the features of damaged cells. Sirtuins (silent mating type information regulation 2 homolog) 1, well-known modulators of lifespan in many species, have a role in gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection and healthy ageing. In the literature there is no evidence for SIRT1 signalling in vitiligo and its possible involvement in disease progression. Here, biopsies were taken from the perilesional skin of 16 patients suffering from non-segmental vitiligo and SIRT1 signalling was investigated in these cells. For the first time, a new SIRT1/Akt, also known as Protein Kinase B (PKB)/mitogen-activated protein kinase (MAPK) signalling has been revealed in vitiligo. SIRT1 regulates MAPK pathway via Akt-apoptosis signal-regulating kinase-1 and down-regulates pro-apoptotic molecules, leading to decreased oxidative stress and apoptotic cell death in perilesional vitiligo keratinocytes. We therefore propose SIRT1 activation as a novel way of protecting perilesional vitiligo keratinocytes from damage. PMID:24410795

  11. Resonance Energy Transfer-Based Molecular Switch Designed Using a Systematic Design Process Based on Monte Carlo Methods and Markov Chains

    Science.gov (United States)

    Rallapalli, Arjun

    A RET network consists of a network of photo-active molecules called chromophores that can participate in inter-molecular energy transfer called resonance energy transfer (RET). RET networks are used in a variety of applications including cryptographic devices, storage systems, light harvesting complexes, biological sensors, and molecular rulers. In this dissertation, we focus on creating a RET device called closed-diffusive exciton valve (C-DEV) in which the input to output transfer function is controlled by an external energy source, similar to a semiconductor transistor like the MOSFET. Due to their biocompatibility, molecular devices like the C-DEVs can be used to introduce computing power in biological, organic, and aqueous environments such as living cells. Furthermore, the underlying physics in RET devices are stochastic in nature, making them suitable for stochastic computing in which true random distribution generation is critical. In order to determine a valid configuration of chromophores for the C-DEV, we developed a systematic process based on user-guided design space pruning techniques and built-in simulation tools. We show that our C-DEV is 15x better than C-DEVs designed using ad hoc methods that rely on limited data from prior experiments. We also show ways in which the C-DEV can be improved further and how different varieties of C-DEVs can be combined to form more complex logic circuits. Moreover, the systematic design process can be used to search for valid chromophore network configurations for a variety of RET applications. We also describe a feasibility study for a technique used to control the orientation of chromophores attached to DNA. Being able to control the orientation can expand the design space for RET networks because it provides another parameter to tune their collective behavior. While results showed limited control over orientation, the analysis required the development of a mathematical model that can be used to determine the

  12. Molecular mechanisms underlying the regulation of brain-derived neurotrophic factor (BDNF) translation in dendrites

    OpenAIRE

    Pinheiro, Vera Lúcia Margarido

    2010-01-01

    Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra A especificidade espacial e temporal subjacente à diversidade de processos de plasticidade sináptica que ocorrem no sistema nervoso central está profundamente relacionada com a disponibilidade da proteína brain-derived neurotrophic factor (BDNF) em domínios sub-celulares distintos, especialmente na área pós-sinápti...

  13. Molecular mechanisms regulating oxygen transport and consumption in high altitude and hibernating mammals

    DEFF Research Database (Denmark)

    Revsbech, Inge Grønvall

    2016-01-01

    The aim of this thesis is to broaden the knowledge of molecular mechanisms of adjustment in oxygen (O2) uptake, conduction, delivery and consumption in mammals adapted to extreme conditions. For this end, I have worked with animals living at high altitude as an example of environmental hypoxia...... of the repeatedly found adaptive traits in animals living at high altitude and in hibernating mammals during hibernation compared with the active state. Factors that affect O2 affinity of Hb include temperature, H+/CO2 via the Bohr effect as well as Cl- and organic phosphates, in mammals mainly 2...

  14. RecA: Regulation and Mechanism of a Molecular Search Engine.

    Science.gov (United States)

    Bell, Jason C; Kowalczykowski, Stephen C

    2016-06-01

    Homologous recombination maintains genomic integrity by repairing broken chromosomes. The broken chromosome is partially resected to produce single-stranded DNA (ssDNA) that is used to search for homologous double-stranded DNA (dsDNA). This homology driven 'search and rescue' is catalyzed by a class of DNA strand exchange proteins that are defined in relation to Escherichia coli RecA, which forms a filament on ssDNA. Here, we review the regulation of RecA filament assembly and the mechanism by which RecA quickly and efficiently searches for and identifies a unique homologous sequence among a vast excess of heterologous DNA. Given that RecA is the prototypic DNA strand exchange protein, its behavior affords insight into the actions of eukaryotic RAD51 orthologs and their regulators, BRCA2 and other tumor suppressors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

    OpenAIRE

    Lee, Erinna F.; Clarke, Oliver B.; Evangelista, Marco; Feng, Zhiping; Speed, Terence P.; Tchoubrieva, Elissaveta B.; Strasser, Andreas; Kalinna, Bernd H.; Colman, Peter M.; Fairlie, W. Douglas

    2011-01-01

    Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2–regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2–like molecules, and Bax/Bak-like proteins that facilitate mitochondrial ou...

  16. Influence of radiation-induced apoptosis on development brain in molecular regulation

    International Nuclear Information System (INIS)

    Gu Guixiong

    2000-01-01

    An outline of current status on the influence of radiation on the development brain was given. Some genes as immediate early gene, Bcl-2 family, p53, heat shock protein and AT gene play an important regulation role in ionizing radiation-induced development brain cells apoptosis. And such biological factor as nerve growth factor, interleukin-1, tumor necrosis factor, basic fibroblast growth factor, transforming growth factor and so on have a vital protection function against ionizing radiation-induced cells apoptosis

  17. Molecular mechanisms regulating flowering time in sweet cherry (Prunus avium L.)

    DEFF Research Database (Denmark)

    Ionescu, Irina Alexandra

    The timing of flowering is a well-researched but at the same time incredibly complex process in angiosperms. Although we are in possession of detailed knowledge on the genetic level of flowering time regulation in the model plant Arabidopsis thaliana, it is often difficult to transfer this knowle......The timing of flowering is a well-researched but at the same time incredibly complex process in angiosperms. Although we are in possession of detailed knowledge on the genetic level of flowering time regulation in the model plant Arabidopsis thaliana, it is often difficult to transfer...... as a result of hydrogen cyanamide treatment: the jasmonate pathway, the hydrogen cyanide pathway and the cytokinin pathway. We further analyzed the levels of cyanogenic glucosides and their derivatives during endodormancy and its release in sweet cherry and almond (Prunus dulcis (Mill.) D. A. Webb). Prunasin...... and its amide coincided with flowering time in both species. Taken together, these results contribute to elucidating parts of the complex network regulating flowering time in perennial plants....

  18. Molecular and biophysical mechanisms regulating hypertrophic differentiation in chondrocytes and mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    D Studer

    2012-07-01

    Full Text Available Chondrocyte hypertrophy is one of the key physiological processes involved in the longitudinal growth of long bones, yet the regulation of hypertrophy is also becoming increasingly relevant for clinical application of mesenchymal stem cells (MSCs and screening for drugs to treat hypertrophic osteoarthritis. The extraordinary cell volume increase during hypertrophy is accompanied by an up-regulation of collagen X, matrix metalloproteinases (MMPs, and vascular endothelial growth factor (VEGF, all which are targets of the runt-related transcription factor 2 (Runx2. Many pathways, including parathyroid hormone-related protein (PTHrP/Indian Hedgehog, Wingless/Int (Wnt/β-catenin, and transforming growth factor beta (TGF-β/Sma and Mad Related Family (Smad pathways, can regulate hypertrophy, but factors as diverse as hypoxia, co-culture, epigenetics and biomaterial composition can also potently affect Runx2 expression. Control of hypertrophic differentiation can be exploited both for cartilage repair, where a stable phenotype is desired, but also in bone regeneration, where hypertrophic cartilage could act as a template for endochondral bone formation. We hope this review will motivate the design of novel engineered microenvironments for skeletal regeneration applications.

  19. Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy.

    Science.gov (United States)

    van de Laar, Lianne; Coffer, Paul J; Woltman, Andrea M

    2012-04-12

    Dendritic cells (DCs) represent a small and heterogeneous fraction of the hematopoietic system, specialized in antigen capture, processing, and presentation. The different DC subsets act as sentinels throughout the body and perform a key role in the induction of immunogenic as well as tolerogenic immune responses. Because of their limited lifespan, continuous replenishment of DC is required. Whereas the importance of GM-CSF in regulating DC homeostasis has long been underestimated, this cytokine is currently considered a critical factor for DC development under both steady-state and inflammatory conditions. Regulation of cellular actions by GM-CSF depends on the activation of intracellular signaling modules, including JAK/STAT, MAPK, PI3K, and canonical NF-κB. By directing the activity of transcription factors and other cellular effector proteins, these pathways influence differentiation, survival and/or proliferation of uncommitted hematopoietic progenitors, and DC subset-specific precursors, thereby contributing to specific aspects of DC subset development. The specific intracellular events resulting from GM-CSF-induced signaling provide a molecular explanation for GM-CSF-dependent subset distribution as well as clues to the specific characteristics and functions of GM-CSF-differentiated DCs compared with DCs generated by fms-related tyrosine kinase 3 ligand. This knowledge can be used to identify therapeutic targets to improve GM-CSF-dependent DC-based strategies to regulate immunity.

  20. Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly.

    Science.gov (United States)

    Yeo, Giselle C; Tarakanova, Anna; Baldock, Clair; Wise, Steven G; Buehler, Markus J; Weiss, Anthony S

    2016-02-01

    The assembly of the tropoelastin monomer into elastin is vital for conferring elasticity on blood vessels, skin, and lungs. Tropoelastin has dual needs for flexibility and structure in self-assembly. We explore the structure-dynamics-function interplay, consider the duality of molecular order and disorder, and identify equally significant functional contributions by local and global structures. To study these organizational stratifications, we perturb a key hinge region by expressing an exon that is universally spliced out in human tropoelastins. We find a herniated nanostructure with a displaced C terminus and explain by molecular modeling that flexible helices are replaced with substantial β sheets. We see atypical higher-order cross-linking and inefficient assembly into discontinuous, thick elastic fibers. We explain this dysfunction by correlating local and global structural effects with changes in the molecule's assembly dynamics. This work has general implications for our understanding of elastomeric proteins, which balance disordered regions with defined structural modules at multiple scales for functional assembly.

  1. Star cluster formation in a turbulent molecular cloud self-regulated by photoionization feedback

    Science.gov (United States)

    Gavagnin, Elena; Bleuler, Andreas; Rosdahl, Joakim; Teyssier, Romain

    2017-12-01

    Most stars in the Galaxy are believed to be formed within star clusters from collapsing molecular clouds. However, the complete process of star formation, from the parent cloud to a gas-free star cluster, is still poorly understood. We perform radiation-hydrodynamical simulations of the collapse of a turbulent molecular cloud using the RAMSES-RT code. Stars are modelled using sink particles, from which we self-consistently follow the propagation of the ionizing radiation. We study how different feedback models affect the gas expulsion from the cloud and how they shape the final properties of the emerging star cluster. We find that the star formation efficiency is lower for stronger feedback models. Feedback also changes the high-mass end of the stellar mass function. Stronger feedback also allows the establishment of a lower density star cluster, which can maintain a virial or sub-virial state. In the absence of feedback, the star formation efficiency is very high, as well as the final stellar density. As a result, high-energy close encounters make the cluster evaporate quickly. Other indicators, such as mass segregation, statistics of multiple systems and escaping stars confirm this picture. Observations of young star clusters are in best agreement with our strong feedback simulation.

  2. Colorless to purple-red switching electrochromic anthraquinone imides with broad visible/near-IR absorptions in the radical anion state: simulation-aided molecular design.

    Science.gov (United States)

    Chen, Fengkun; Zhang, Jie; Jiang, Hong; Wan, Xinhua

    2013-07-01

    The large redshift of near-infrared (NIR) absorptions of nitro-substituted anthraquinone imide (Nitro-AQI) radical anions, relative to other AQI derivatives, is rationalized based on quantum chemical calculations. Calculations reveal that the delocalization effects of electronegative substitution in the radical anion states is dramatically enhanced, thus leading to a significant decrease in the HOMO-LUMO band gap in the radical anion states. Based on this understanding, an AQI derivative with an even stronger electron-withdrawing dicyanovinyl (di-CN) substituent was designed and prepared. The resulting molecule, di-CN-AQI, displays no absorption in the Vis/NIR region in the neutral state, but absorbs intensively in the range of λ=700-1000 (λmax ≈860 nm) and λ=1100-1800 nm (λmax ≈1400 nm) upon one-electron reduction; this is accompanied by a transition from a highly transmissive colorless solution to one that is purple-red. The relationship between calculated radical anionic HOMO-LUMO gaps and the electron-withdrawing capacity of the substituents is also determined by employing Hammett parameter, which could serve as a theoretical tool for further molecular design. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Hydrophobic fluorine mediated switching of the hydrogen bonding site as well as orientation of water molecules in the aqueous mixture of monofluoroethanol: IR, molecular dynamics and quantum chemical studies.

    Science.gov (United States)

    Mondal, Saptarsi; Biswas, Biswajit; Nandy, Tonima; Singh, Prashant Chandra

    2017-09-20

    The local structures between water-water, alcohol-water and alcohol-alcohol have been investigated for aqueous mixtures of ethanol (ETH) and monofluoroethanol (MFE) by the deconvolution of IR bands in the OH stretching region, molecular dynamics simulation and quantum chemical calculations. It has been found that the addition of a small amount of ETH into the aqueous medium increases the strength of the hydrogen bonds between water molecules. In an aqueous mixture of MFE, the substitution of a single fluorine induces a change in the orientation as well as the hydrogen bonding site of water molecules from the oxygen to the fluorine terminal of MFE. The switching of the hydrogen bonding site of water in the aqueous mixture of MFE results in comparatively strong hydrogen bonds between MFE and water molecules as well as less clustering of water molecules, unlike the case of the aqueous mixture of ETH. These findings about the modification of a hydrogen bond network by the hydrophobic fluorine group probably make fluorinated molecules useful for pharmaceutical as well as biological applications.

  4. Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival

    Directory of Open Access Journals (Sweden)

    Sebastian Horn

    2017-04-01

    Full Text Available Formation of the death-inducing signaling complex (DISC initiates extrinsic apoptosis. Caspase-8 and its regulator cFLIP control death signaling by binding to death-receptor-bound FADD. By elucidating the function of the caspase-8 homolog, caspase-10, we discover that caspase-10 negatively regulates caspase-8-mediated cell death. Significantly, we reveal that caspase-10 reduces DISC association and activation of caspase-8. Furthermore, we extend our co-operative/hierarchical binding model of caspase-8/cFLIP and show that caspase-10 does not compete with caspase-8 for binding to FADD. Utilizing caspase-8-knockout cells, we demonstrate that caspase-8 is required upstream of both cFLIP and caspase-10 and that DISC formation critically depends on the scaffold function of caspase-8. We establish that caspase-10 rewires DISC signaling to NF-κB activation/cell survival and demonstrate that the catalytic activity of caspase-10, and caspase-8, is redundant in gene induction. Thus, our data are consistent with a model in which both caspase-10 and cFLIP coordinately regulate CD95L-mediated signaling for death or survival.

  5. Cloning, overexpression, purification, crystallization and preliminary X-ray analysis of CheY3, a response regulator that directly interacts with the flagellar ‘switch complex’ in Vibrio cholerae

    International Nuclear Information System (INIS)

    Khamrui, Susmita; Biswas, Maitree; Sen, Udayaditya; Dasgupta, Jhimli

    2010-01-01

    A chemotaxis response regulator CheY3 from V. cholerae has been cloned, overexpressed, purified and crystallized. The crystals of CheY3 diffracted to 1.86 Å resolution. Vibrio cholerae is the aetiological agent of the severe diarrhoeal disease cholera. This highly motile organism uses the processes of motility and chemotaxis to travel and colonize the intestinal epithelium. Chemotaxis in V. cholerae is far more complex than that in Escherichia coli or Salmonella typhimurium, with multiple paralogues of various chemotaxis genes. In contrast to the single copy of the chemotaxis response-regulator protein CheY in E. coli, V. cholerae contains four CheYs (CheY1–CheY4), of which CheY3 is primarily responsible for interacting with the flagellar motor protein FliM, which is one of the major constituents of the ‘switch complex’ in the flagellar motor. This interaction is the key step that controls flagellar rotation in response to environmental stimuli. CheY3 has been cloned, overexpressed and purified by Ni–NTA affinity chromatography followed by gel filtration. Crystals of CheY3 were grown in space group R3, with a calculated Matthews coefficient of 2.33 Å 3 Da −1 (47% solvent content) assuming the presence of one molecule per asymmetric unit

  6. Computational modelling and analysis of the molecular network regulating sporulation initiation in Bacillus subtilis.

    Science.gov (United States)

    Ihekwaba, Adaoha E C; Mura, Ivan; Barker, Gary C

    2014-10-24

    Bacterial spores are important contaminants in food, and the spore forming bacteria are often implicated in food safety and food quality considerations. Spore formation is a complex developmental process involving the expression of more than 500 genes over the course of 6 to 8 hrs. The process culminates in the formation of resting cells capable of resisting environmental extremes and remaining dormant for long periods of time, germinating when conditions promote further vegetative growth. Experimental observations of sporulation and germination are problematic and time consuming so that reliable models are an invaluable asset in terms of prediction and risk assessment. In this report we develop a model which assists in the interpretation of sporulation dynamics. This paper defines and analyses a mathematical model for the network regulating Bacillus subtilis sporulation initiation, from sensing of sporulation signals down to the activation of the early genes under control of the master regulator Spo0A. Our model summarises and extends other published modelling studies, by allowing the user to execute sporulation initiation in a scenario where Isopropyl β-D-1-thiogalactopyranoside (IPTG) is used as an artificial sporulation initiator as well as in modelling the induction of sporulation in wild-type cells. The analysis of the model results and the comparison with experimental data indicate that the model is good at predicting inducible responses to sporulation signals. However, the model is unable to reproduce experimentally observed accumulation of phosphorelay sporulation proteins in wild type B. subtilis. This model also highlights that the phosphorelay sub-component, which relays the signals detected by the sensor kinases to the master regulator Spo0A, is crucial in determining the response dynamics of the system. We show that there is a complex connectivity between the phosphorelay features and the master regulatory Spo0A. Additional we discovered that the

  7. Asymmetric switching in a homodimeric ABC transporter: a simulation study.

    Directory of Open Access Journals (Sweden)

    Jussi Aittoniemi

    2010-04-01

    Full Text Available ABC transporters are a large family of membrane proteins involved in a variety of cellular processes, including multidrug and tumor resistance and ion channel regulation. Advances in the structural and functional understanding of ABC transporters have revealed that hydrolysis at the two canonical nucleotide-binding sites (NBSs is co-operative and non-simultaneous. A conserved core architecture of bacterial and eukaryotic ABC exporters has been established, as exemplified by the crystal structure of the homodimeric multidrug exporter Sav1866. Currently, it is unclear how sequential ATP hydrolysis arises in a symmetric homodimeric transporter, since it implies at least transient asymmetry at the NBSs. We show by molecular dynamics simulation that the initially symmetric structure of Sav1866 readily undergoes asymmetric transitions at its NBSs in a pre-hydrolytic nucleotide configuration. MgATP-binding residues and a network of charged residues at the dimer interface are shown to form a sequence of putative molecular switches that allow ATP hydrolysis only at one NBS. We extend our findings to eukaryotic ABC exporters which often consist of two non-identical half-transporters, frequently with degeneracy substitutions at one of their two NBSs. Interestingly, many residues involved in asymmetric conformational switching in Sav1866 are substituted in degenerate eukaryotic NBS. This finding strengthens recent suggestions that the interplay of a consensus and a degenerate NBS in eukaroytic ABC proteins pre-determines the sequence of hydrolysis at the two NBSs.

  8. The induction and regulation of radiogenic transformation in vitro: Cellular and molecular mechanisms

    International Nuclear Information System (INIS)

    Borek, C.

    1987-01-01

    Rodent and human cells in culture, transformed in vitro by ionizing radiation, ultraviolet light, or chemicals into malignant cells afford us the opportunity to probe into early and late events in the neoplastic process at a cellular and molecular level. Transformation can be regarded as an abnormal expression of cellular genes. The initiating agents disrupt the integrity of the genetic apparatus altering DNA in ways that result in the activation of cellular transforming genes (oncogenes) during some stage of the neoplastic process. Events associated with initiation and promotion may overlap to some degree, but in order for them to occur, cellular permissive conditions must prevail. Permissive factors include thyroid and steroid hormones, specific states of differentiation, certain stages in the cell cycle, specific genetic impairment, and inadequate antioxidants. Genetically susceptible cells require physiological states conducive to transformation. These may differ with age, tissue, and species and in part may be responsible for the observed lower sensitivity of human cells to transformation

  9. Molecular regulation of MICA expression after HDAC inhibitor treatment of cancer cells

    DEFF Research Database (Denmark)

    Jensen, Helle

    and NKG2D-ligands are upregulated on the surface of abnormal cells. We have previously shown that cancer cells can be stimulated to express the NKG2D-ligands MICA/B after exposure to HDAC-inhibitors (HDAC-i), an occurrence that is not observed in healthy cells. Here we characterize the molecular signal...... pathways that lead to MICA expression after HDAC-inhibitor treatment of cancer cells. Chelating Calcium with Bapta-AM or EGTA potently inhibited HDAC-inhibitor and CMV mediated MICA/B expression. It was further observed that ER Calcium stores were depleted after HDAC-inhibitor treatment. NF-kB activity can...

  10. Polyunsaturated fatty acid regulation of gene transcription: a molecular mechanism to improve the metabolic syndrome.

    Science.gov (United States)

    Clarke, S D

    2001-04-01

    This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the (n-3) family, play pivotal roles as "fuel partitioners" in that they direct fatty acids away from triglyceride storage and toward oxidation, and that they enhance glucose flux to glycogen. In doing this, PUFA may protect against the adverse symptoms of the metabolic syndrome and reduce the risk of heart disease. PUFA exert their beneficial effects by up-regulating the expression of genes encoding proteins involved in fatty acid oxidation while simultaneously down-regulating genes encoding proteins of lipid synthesis. PUFA govern oxidative gene expression by activating the transcription factor peroxisome proliferator-activated receptor alpha. PUFA suppress lipogenic gene expression by reducing the nuclear abundance and DNA-binding affinity of transcription factors responsible for imparting insulin and carbohydrate control to lipogenic and glycolytic genes. In particular, PUFA suppress the nuclear abundance and expression of sterol regulatory element binding protein-1 and reduce the DNA-binding activities of nuclear factor Y, Sp1 and possibly hepatic nuclear factor-4. Collectively, the studies discussed suggest that the fuel "repartitioning" and gene expression actions of PUFA should be considered among criteria used in defining the dietary needs of (n-6) and (n-3) and in establishing the dietary ratio of (n-6) to (n-3) needed for optimum health benefit.

  11. Arabidopsis CPR5 regulates ethylene signaling via molecular association with the ETR1 receptor.

    Science.gov (United States)

    Wang, Feifei; Wang, Lijuan; Qiao, Longfei; Chen, Jiacai; Pappa, Maria Belen; Pei, Haixia; Zhang, Tao; Chang, Caren; Dong, Chun-Hai

    2017-11-01

    The plant hormone ethylene plays various functions in plant growth, development and response to environmental stress. Ethylene is perceived by membrane-bound ethylene receptors, and among the homologous receptors in Arabidopsis, the ETR1 ethylene receptor plays a major role. The present study provides evidence demonstrating that Arabidopsis CPR5 functions as a novel ETR1 receptor-interacting protein in regulating ethylene response and signaling. Yeast split ubiquitin assays and bi-fluorescence complementation studies in plant cells indicated that CPR5 directly interacts with the ETR1 receptor. Genetic analyses indicated that mutant alleles of cpr5 can suppress ethylene insensitivity in both etr1-1 and etr1-2, but not in other dominant ethylene receptor mutants. Overexpression of Arabidopsis CPR5 either in transgenic Arabidopsis plants, or ectopically in tobacco, significantly enhanced ethylene sensitivity. These findings indicate that CPR5 plays a critical role in regulating ethylene signaling. CPR5 is localized to endomembrane structures and the nucleus, and is involved in various regulatory pathways, including pathogenesis, leaf senescence, and spontaneous cell death. This study provides evidence for a novel regulatory function played by CPR5 in the ethylene receptor signaling pathway in Arabidopsis. © 2017 Institute of Botany, Chinese Academy of Sciences.

  12. Nitrogen fixation and molecular oxygen: comparative genomic reconstruction of transcription regulation in Alphaproteobacteria

    Directory of Open Access Journals (Sweden)

    Olga V Tsoy

    2016-08-01

    Full Text Available Biological nitrogen fixation plays a crucial role in the nitrogen cycle. An ability to fix atmospheric nitrogen, reducing it to ammonium, was described for multiple species of Bacteria and Archaea. Being a complex and sensitive process, nitrogen fixation requires a complicated regulatory system, also, on the level of transcription. The transcriptional regulatory network for nitrogen fixation was extensively studied in several representatives of the class Alphaproteobacteria. This regulatory network includes the activator of nitrogen fixation NifA, working in tandem with the alternative sigma-factor RpoN as well as oxygen-responsive regulatory systems, one-component regulators FnrN/FixK and two-component system FixLJ. Here we used a comparative genomics analysis for in silico study of the transcriptional regulatory network in 50 genomes of Alphaproteobacteria. We extended the known regulons and proposed the scenario for the evolution of the nitrogen fixation transcriptional network. The reconstructed network substantially expands the existing knowledge of transcriptional regulation in nitrogen-fixing microorganisms and can be used for genetic experiments, metabolic reconstruction, and evolutionary analysis.

  13. Dormancy and activation of human oocytes from primordial and primary follicles: molecular clues to oocyte regulation

    DEFF Research Database (Denmark)

    Ernst, Emil Hagen; Grøndahl, Marie Louise; Grund, Simon

    2017-01-01

    ® software. Finally, qPCR and immunohistochemistry were employed to explore expression and localization of selected genes and products in human ovarian tissue. MAIN RESULTS AND THE ROLE OF CHANCE: We found 223 and 268 genes down-regulated and up-regulated, respectively, in the oocytes during the human...... SCALE DATA: http://users-birc.au.dk/biopv/published_data/ernst_2017/. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive analysis and no functional studies were performed. The study was based on a limited number of patients and the experimental design could not take into account the natural.......H. and S.F. were supported by an MRC (UK) project grant MR/M012638/1. K.L.H. was supported by grants from Fonden til Lægevidenskabens Fremme, Kong Christian Den Tiendes Fond. K.L.H. and L.S. were supported by the IDEAS grant from Aarhus University Research Foundation (AUFF). There are no conflicts...

  14. Molecular biology of C4 phosphoenolpyruvate carboxylase: Structure, regulation and genetic engineering.

    Science.gov (United States)

    Rajagopalan, A V; Devi, M T; Raghavendra, A S

    1994-02-01

    Three to four families of nuclear genes encode different isoforms of phosphoenolpyruvate (PEP) carboxylase (PEPC): C4-specific, C3 or etiolated, CAM and root forms. C4 leaf PEPC is encoded by a single gene (ppc) in sorghum and maize, but multiple genes in the C4-dicot Flaveria trinervia. Selective expression of ppc in only C4-mesophyll cells is proposed to be due to nuclear factors, DNA methylation and a distinct gene promoter. Deduced amino acid sequences of C4-PEPC pinpoint the phosphorylatable serine near the N-terminus, C4-specific valine and serine residues near the C-terminus, conserved cysteine, lysine and histidine residues and PEP binding/catalytic sites. During the PEPC reaction, PEP and bicarbonate are first converted into carboxyphosphate and the enolate of pyruvate. Carboxyphosphate decomposes within the active site into Pi and CO2, the latter combining with the enolate to form oxalacetate. Besides carboxylation, PEPC catalyzes a HCO3 (-)-dependent hydrolysis of PEP to yield pyruvate and Pi. Post-translational regulation of PEPC occurs by a phosphorylation/dephosphorylation cascade in vivo and by reversible enzyme oligomerization in vitro. The interrelation between phosphorylation and oligomerization of the enzyme is not clear. PEPC-protein kinase (PEPC-PK), the enzyme responsible for phosphorylation of PEPC, has been studied extensively while only limited information is available on the protein phosphatase 2A capable of dephosphorylating PEPC. The C4 ppc was cloned and expressed in Escherichia coli as well as tobacco. The transformed E. coli produced a functional/phosphorylatable C4 PEPC and the transgenic tobacco plants expressed both C3 and C4 isoforms. Site-directed mutagenesis of ppc indicates the importance of His(138), His(579) and Arg(587) in catalysis and/or substrate-binding by the E. coli enzyme, Ser(8) in the regulation of sorghum PEPC. Important areas for further research on C4 PEPC are: mechanism of transduction of light signal during

  15. Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

    Science.gov (United States)

    Majed, Batoule H.

    2012-01-01

    Prostacyclin (PGI2) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A2, cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI2 is produced by endothelial cells and influences many cardiovascular processes. PGI2 acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI2 analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI2/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca2+]i, and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI2 intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI2 counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A2 (TXA2), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI2/TXA2 balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI2/TXA2 ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI2 activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI2 analogs in the management of pregnancy-associated and neonatal

  16. Optical packet switched networks

    DEFF Research Database (Denmark)

    Hansen, Peter Bukhave

    1999-01-01

    Optical packet switched networks are investigated with emphasis on the performance of the packet switch blocks. Initially, the network context of the optical packet switched network is described showing that a packet network will provide transparency, flexibility and bridge the granularity gap...... in interferometric wavelength converters is investigated showing that a 10 Gbit/s 19 4x4 swich blocks can be cascaded at a BER of 10-14. An analytical traffic model enables the calculation of the traffice performance of a WDM packet network. Hereby the importance of WDM and wavelegth conversion in the switch blocks...... is established as a flexible means to reduce the optical buffer, e.g., the number of fibre delay lines for a 16x16 switch block is reduced from 23 to 6 by going from 2 to 8 wavelength channels pr. inlet. Additionally, a component count analysis is carried out to illustrate the trade-offs in the switch block...

  17. Saturated Switching Systems

    CERN Document Server

    Benzaouia, Abdellah

    2012-01-01

    Saturated Switching Systems treats the problem of actuator saturation, inherent in all dynamical systems by using two approaches: positive invariance in which the controller is designed to work within a region of non-saturating linear behaviour; and saturation technique which allows saturation but guarantees asymptotic stability. The results obtained are extended from the linear systems in which they were first developed to switching systems with uncertainties, 2D switching systems, switching systems with Markovian jumping and switching systems of the Takagi-Sugeno type. The text represents a thoroughly referenced distillation of results obtained in this field during the last decade. The selected tool for analysis and design of stabilizing controllers is based on multiple Lyapunov functions and linear matrix inequalities. All the results are illustrated with numerical examples and figures many of them being modelled using MATLAB®. Saturated Switching Systems will be of interest to academic researchers in con...

  18. Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline.

    Science.gov (United States)

    Lupo, Giuseppe; Nisi, Paola S; Esteve, Pilar; Paul, Yu-Lee; Novo, Clara Lopes; Sidders, Ben; Khan, Muhammad A; Biagioni, Stefano; Liu, Hai-Kun; Bovolenta, Paola; Cacci, Emanuele; Rugg-Gunn, Peter J

    2018-06-01

    Adult neurogenesis declines with aging due to the depletion and functional impairment of neural stem/progenitor cells (NSPCs). An improved understanding of the underlying mechanisms that drive age-associated neurogenic deficiency could lead to the development of strategies to alleviate cognitive impairment and facilitate neuroregeneration. An essential step towards this aim is to investigate the molecular changes that occur in NSPC aging on a genomewide scale. In this study, we compare the transcriptional, histone methylation and DNA methylation signatures of NSPCs derived from the subventricular zone (SVZ) of young adult (3 months old) and aged (18 months old) mice. Surprisingly, the transcriptional and epigenomic profiles of SVZ-derived NSPCs are largely unchanged in aged cells. Despite the global similarities, we detect robust age-dependent changes at several hundred genes and regulatory elements, thereby identifying putative regulators of neurogenic decline. Within this list, the homeobox gene Dbx2 is upregulated in vitro and in vivo, and its promoter region has altered histone and DNA methylation levels, in aged NSPCs. Using functional in vitro assays, we show that elevated Dbx2 expression in young adult NSPCs promotes age-related phenotypes, including the reduced proliferation of NSPC cultures and the altered transcript levels of age-associated regulators of NSPC proliferation and differentiation. Depleting Dbx2 in aged NSPCs caused the reverse gene expression changes. Taken together, these results provide new insights into the molecular programmes that are affected during mouse NSPC aging, and uncover a new functional role for Dbx2 in promoting age-related neurogenic decline. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  19. The role of the molecular chaperone heat shock protein A2 (HSPA2 in regulating human sperm-egg recognition

    Directory of Open Access Journals (Sweden)

    Brett Nixon

    2015-01-01

    Full Text Available One of the most common lesions present in the spermatozoa of human infertility patients is an idiopathic failure of sperm-egg recognition. Although this unique cellular interaction can now be readily by-passed by assisted reproductive strategies such as intracytoplasmic sperm injection (ICSI, recent large-scale epidemiological studies have encouraged the cautious use of this technology and highlighted the need for further research into the mechanisms responsible for defective sperm-egg recognition. Previous work in this field has established that the sperm domains responsible for oocyte interaction are formed during spermatogenesis prior to being dynamically modified during epididymal maturation and capacitation in female reproductive tract. While the factors responsible for the regulation of these sequential maturational events are undoubtedly complex, emerging research has identified the molecular chaperone, heat shock protein A2 (HSPA2, as a key regulator of these events in human spermatozoa. HSPA2 is a testis-enriched member of the 70 kDa heat shock protein family that promotes the folding, transport, and assembly of protein complexes and has been positively correlated with in vitro fertilization (IVF success. Furthermore, reduced expression of HSPA2 from the human sperm proteome leads to an impaired capacity for cumulus matrix dispersal, sperm-egg recognition and fertilization following both IVF and ICSI. In this review, we consider the evidence supporting the role of HSPA2 in sperm function and explore the potential mechanisms by which it is depleted in the spermatozoa of infertile patients. Such information offers novel insights into the molecular mechanisms governing sperm function.

  20. Molecular Mimicry Regulates ABA Signaling by SnRK2 Kinases and PP2C Phosphatases

    Science.gov (United States)

    Soon, Fen-Fen; Ng, Ley-Moy; Zhou, X. Edward; West, Graham M.; Kovach, Amanda; Tan, M. H. Eileen; Suino-Powell, Kelly M.; He, Yuanzheng; Xu, Yong; Chalmers, Michael J.; Brunzelle, Joseph S.; Zhang, Huiming; Yang, Huaiyu; Jiang, Hualiang; Li, Jun; Yong, Eu-Leong; Cutler, Sean; Zhu, Jian-Kang; Griffin, Patrick R.; Melcher, Karsten; Xu, H. Eric

    2013-01-01

    Abscisic acid (ABA) is an essential hormone for plants to survive environmental stresses. At the center of the ABA signaling network is a subfamily of type 2C protein phosphatases (PP2Cs), which form exclusive interactions with ABA receptors and subfamily 2 Snfl-related kinase (SnRK2s). Here, we report a SnRK2-PP2C complex structure, which reveals marked similarity in PP2C recognition by SnRK2 and ABA receptors. In the complex, the kinase activation loop docks into the active site of PP2C, while the conserved ABA-sensing tryptophan of PP2C inserts into the kinase catalytic cleft, thus mimicking receptor-PP2C interactions. These structural results provide a simple mechanism that directly couples ABA binding to SnRK2 kinase activation and highlight a new paradigm of kinase-phosphatase regulation through mutual packing of their catalytic sites. PMID:22116026

  1. Molecular Mimicry Regulates ABA Signaling by SnRK2 Kinases and PP2C Phosphatases

    International Nuclear Information System (INIS)

    Soon, Fen-Fen; Ng, Ley-Moy; Zhou, X. Edward; West, Graham M.; Kovach, Amanda; Tan, M.H. Eileen; Suino-Powell, Kelly M.; He, Yuanzheng; Xu, Yong; Chalmers, Michael J.; Brunzelle, Joseph S.; Zhang, Huiming; Yang, Huaiyu; Jiang, Hualiang; Li, Jun; Yong, Eu-Leong; Cutler, Sean; Zhu, Jian-Kang; Griffin, Patrick R.; Melcher, Karsten; Xu, H. Eric

    2012-01-01

    Abscisic acid (ABA) is an essential hormone for plants to survive environmental stresses. At the center of the ABA signaling network is a subfamily of type 2C protein phosphatases (PP2Cs), which form exclusive interactions with ABA receptors and subfamily 2 Snfl-related kinase (SnRK2s). Here, we report a SnRK2-PP2C complex structure, which reveals marked similarity in PP2C recognition by SnRK2 and ABA receptors. In the complex, the kinase activation loop docks into the active site of PP2C, while the conserved ABA-sensing tryptophan of PP2C inserts into the kinase catalytic cleft, thus mimicking receptor-PP2C interactions. These structural results provide a simple mechanism that directly couples ABA binding to SnRK2 kinase activation and highlight a new paradigm of kinase-phosphatase regulation through mutual packing of their catalytic sites.

  2. Molecular kinetics. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics.

    Science.gov (United States)

    Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen; Christensen, Sune M; Abel, Steven M; Iwig, Jeff; Wu, Hung-Jen; Gureasko, Jodi; Rhodes, Christopher; Petit, Rebecca S; Hansen, Scott D; Thill, Peter; Yu, Cheng-Han; Stamou, Dimitrios; Chakraborty, Arup K; Kuriyan, John; Groves, Jay T

    2014-07-04

    Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average. Copyright © 2014, American Association for the Advancement of Science.

  3. Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease

    DEFF Research Database (Denmark)

    Nielsen, Thomas Svava; Jessen, Niels; Jørgensen, Jens Otto Lunde

    2014-01-01

    is tightly regulated by hormonal and nutritional factors. Under conditions of negative energy balance such as fasting and exercise, stimulation of lipolysis results in a profound increase in FFA release from adipose tissue. This response is crucial in order to provide the organism with a sufficient supply......Lipolysis is the process by which triglycerides are hydrolyzed to free fatty acids (FFA) and glycerol. In adipocytes, this is achieved by the sequential action of Adipose Triglyceride Lipase (ATGL), Hormone Sensitive Lipase (HSL) and Monoglyceride Lipase (MGL). The activity in the lipolytic pathway...... of substrate for oxidative metabolism. However, failure to efficiently suppress lipolysis when FFA demands are low can have serious metabolic consequences and is believed to be a key mechanism in the development of type 2 diabetes in obesity. Since the discovery of ATGL in 2004, substantial progress has been...

  4. Molecular Mimicry Regulates ABA Signaling by SnRK2 Kinases and PP2C Phosphatases

    Energy Technology Data Exchange (ETDEWEB)

    Soon, Fen-Fen; Ng, Ley-Moy; Zhou, X. Edward; West, Graham M.; Kovach, Amanda; Tan, M.H. Eileen; Suino-Powell, Kelly M.; He, Yuanzheng; Xu, Yong; Chalmers, Michael J.; Brunzelle, Joseph S.; Zhang, Huiming; Yang, Huaiyu; Jiang, Hualiang; Li, Jun; Yong, Eu-Leong; Cutler, Sean; Zhu, Jian-Kang; Griffin, Patrick R.; Melcher, Karsten; Xu, H. Eric (Van Andel); (Scripps); (NWU); (Purdue); (UCR); (Chinese Aca. Sci.); (NU Singapore)

    2014-10-02

    Abscisic acid (ABA) is an essential hormone for plants to survive environmental stresses. At the center of the ABA signaling network is a subfamily of type 2C protein phosphatases (PP2Cs), which form exclusive interactions with ABA receptors and subfamily 2 Snfl-related kinase (SnRK2s). Here, we report a SnRK2-PP2C complex structure, which reveals marked similarity in PP2C recognition by SnRK2 and ABA receptors. In the complex, the kinase activation loop docks into the active site of PP2C, while the conserved ABA-sensing tryptophan of PP2C inserts into the kinase catalytic cleft, thus mimicking receptor-PP2C interactions. These structural results provide a simple mechanism that directly couples ABA binding to SnRK2 kinase activation and highlight a new paradigm of kinase-phosphatase regulation through mutual packing of their catalytic sites.

  5. Effective switching frequency multiplier inverter

    Science.gov (United States)

    Su, Gui-Jia [Oak Ridge, TN; Peng, Fang Z [Okemos, MI

    2007-08-07

    A switching frequency multiplier inverter for low inductance machines that uses parallel connection of switches and each switch is independently controlled according to a pulse width modulation scheme. The effective switching frequency is multiplied by the number of switches connected in parallel while each individual switch operates within its limit of switching frequency. This technique can also be used for other power converters such as DC/DC, AC/DC converters.

  6. Clinical and pathogenetic interrelation between molecular regulation of apoptosis and cell differentiation in osteoarthritis

    Directory of Open Access Journals (Sweden)

    M A Kabalyk

    2018-02-01

    Full Text Available Aim. To determine clinical and pathogenetic relationship between the levels of apoptosis and growth and differentiation regulation (growth inhibitor 1 induced by oxidative stress, growth/differentiation factor 5 in osteoarthritis. Methods. In a rheumatology office of Vladivostok polyclinic №3 65 patients with knee osteoarthritis Kellgren grade 1-4 aged 66.5±8.0 years were examined. 25 healthy volunteers matched by sex and age without clinical and radiologic manifestations of osteoarthritis were included into control group. To measure concentration of the studied molecules in study patients’ blood, ELISA method was used. Results. Patients with osteoarthritis compared to control group had statistically significantly increased levels of Fas, growth/differentiation factor 5 and ratio of growth/differentiation factor 5/growth inhibitor 1 induced by oxidative stress. Fas levels were significantly lower in late stages 2-4 of osteoarthritis compared to stages 1 and 2. Growth/differentiation factor 5 level was lower in patients with stage 3-4 of osteoarthritis compared to stages 1 and 2. As radiologic signs of osteoarthritis progressed, decrease of the ratio of growth/differentiation factor 5/growth inhibitor 1 induced by oxidative stress, was registered which was significantly lower in stages 2 and 3 compared to stage 1. Conclusion. Extrinsic pathway of apoptosis plays a big role in forming pain syndrome in osteoarthritis, and its maintenance is provided by other mechanisms which include influence of oxidative stress via inhibition of cell cycle mediated by growth inhibitor 1 induced by oxidative stress, reduced involvement of growth/differentiation factor 5 in differentiation processes and regulation of protein synthesis of extracellular cartilaginous tissue matrix.

  7. Identification and molecular regulation of neural stem cells in the olfactory epithelium

    International Nuclear Information System (INIS)

    Beites, Crestina L.; Kawauchi, Shimako; Crocker, Candice E.; Calof, Anne L.

    2005-01-01

    The sensory neurons that subserve olfaction, olfactory receptor neurons (ORNs), are regenerated throughout life, making the neuroepithelium in which they reside [the olfactory epithelium (OE)] an excellent model for studying how intrinsic and extrinsic factors regulate stem cell dynamics and neurogenesis during development and regeneration. Numerous studies indicate that transcription factors and signaling molecules together regulate generation of ORNs from stem and progenitor cells during development, and work on regenerative neurogenesis indicates that these same factors may operate at postnatal ages as well. This review describes our current knowledge of the identity of the OE neural stem cell; the different cell types that are thought to be the progeny (directly or indirectly) of this stem cell; and the factors that influence cell differentiation in the OE neuronal lineage. We review data suggesting that (1) the ORN lineage contains three distinct proliferating cell types-a stem cell and two populations of transit amplifying cells; (2) in established OE, these three cell types are present within the basal cell compartment of the epithelium; and (3) the stem cell that gives rise ultimately to ORNs may also generate two glial cell types of the primary olfactory pathway: sustentacular cells (SUS), which lie within OE proper; and olfactory ensheathing cells (OEC), which envelope the olfactory nerve. In addition, we describe factors that are both made by and found within the microenvironment of OE stem and progenitor cells, and which exert crucial growth regulatory effects on these cells. Thus, as with other regenerating tissues, the basis of regeneration in the OE appears be a population of stem cells, which resides within a microenvironment (niche) consisting of factors crucial for maintenance of its capacity for proliferation and differentiation

  8. FreeSWITCH Cookbook

    CERN Document Server

    Minessale, Anthony

    2012-01-01

    This is a problem-solution approach to take your FreeSWITCH skills to the next level, where everything is explained in a practical way. If you are a system administrator, hobbyist, or someone who uses FreeSWITCH on a regular basis, this book is for you. Whether you are a FreeSWITCH expert or just getting started, this book will take your skills to the next level.

  9. Elements of magnetic switching

    International Nuclear Information System (INIS)

    Aaland, K.

    1983-01-01

    This chapter describes magnetic switching as a method of connecting a capacitor bank (source) to a load; reviews several successful applications of magnetic switching, and discusses switching transformers, limitations and future possibilities. Some of the inflexibility and especially the high cost of magnetic materials may be overcome with the availability of the new splash cooled ribbons (Metglas). Experience has shown that magnetics works despite shock, radiation or noise interferences

  10. Pemodelan Markov Switching Autoregressive

    OpenAIRE

    Ariyani, Fiqria Devi; Warsito, Budi; Yasin, Hasbi

    2014-01-01

    Transition from depreciation to appreciation of exchange rate is one of regime switching that ignored by classic time series model, such as ARIMA, ARCH, or GARCH. Therefore, economic variables are modeled by Markov Switching Autoregressive (MSAR) which consider the regime switching. MLE is not applicable to parameters estimation because regime is an unobservable variable. So that filtering and smoothing process are applied to see the regime probabilities of observation. Using this model, tran...

  11. Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling (Review).

    Science.gov (United States)

    Yan, Fenggen; Mo, Xiumei; Liu, Junfeng; Ye, Siqi; Zeng, Xing; Chen, Dacan

    2017-11-01

    The thymus is critical in establishing and maintaining the appropriate microenvironment for promoting the development and selection of T cells. The function and structure of the thymus gland has been extensively studied, particularly as the thymus serves an important physiological role in the lymphatic system. Numerous studies have investigated the morphological features of thymic involution. Recently, research attention has increasingly been focused on thymic proteins as targets for drug intervention. Omics approaches have yielded novel insights into the thymus and possible drug targets. The present review addresses the signaling and transcriptional functions of the thymus, including the molecular mechanisms underlying the regulatory functions of T cells and their role in the immune system. In addition, the levels of cytokines secreted in the thymus have a significant effect on thymic functions, including thymocyte migration and development, thymic atrophy and thymic recovery. Furthermore, the regulation and molecular mechanisms of stress‑mediated thymic atrophy and involution were investigated, with particular emphasis on thymic function as a potential target for drug development and discovery using proteomics.

  12. microRNA-mediated R gene regulation: molecular scabbards for double-edged swords.

    Science.gov (United States)

    Deng, Yingtian; Liu, Minglei; Li, Xiaofei; Li, Feng

    2018-02-01

    Plant resistance (R) proteins are immune receptors that recognize pathogen effectors and trigger rapid defense responses, namely effector-triggered immunity. R protein-mediated pathogen resistance is usually race specific. During plant-pathogen coevolution, plant genomes accumulated large numbers of R genes. Even though plant R genes provide important natural resources for breeding disease-resistant crops, their presence in the plant genome comes at a cost. Misregulation of R genes leads to developmental defects, such as stunted growth and reduced fertility. In the past decade, many microRNAs (miRNAs) have been identified to target various R genes in plant genomes. miRNAs reduce R gene levels under normal conditions and allow induction of R gene expression under various stresses. For these reasons, we consider R genes to be double-edged "swords" and miRNAs as molecular "scabbards". In the present review, we summarize the contributions and potential problems of these "swords" and discuss the features and production of the "scabbards", as well as the mechanisms used to pull the "sword" from the "scabbard" when needed.

  13. Studies on Antiviral and Immuno-Regulation Activity of Low Molecular Weight Fucoidan from Laminaria japonica

    Science.gov (United States)

    Sun, Taohua; Zhang, Xinhui; Miao, Ying; Zhou, Yang; Shi, Jie; Yan, Meixing; Chen, Anjin

    2018-06-01

    The antiviral activity in vitro and in vivo and the effect of the immune system of two fucoidan fractions with low molecular weight and different sulfate content from Laminaria japonica (LMW fucoidans) were investigated in order to examine the possible mechanism. In vitro, I-type influenza virus, adenovirus and Parainfluenza virus I were used to infect Hep-2, Hela and MDCK cells, respectively. And 50% tissue culture infective dose was calculated to detect the antiviral activity of two LMW fucoidans. The results indicated that compared with the control group, 2 kinds of LMW fucoidans had remarkable antiviral activity in vitro in middle and high doses, while at low doses, the antiviral activity of 2 kinds of LMW fucoidans was not statistically different from that in the blank control group. And there was no statistically difference between two LMW fucoidans in antiviral activity. In vivo, LMW fucoidans could prolong the survival time of virus-infected mice, and could improve the lung index of virus-infected mice significantly, which have statistical differences with the control group significantly ( p 0.05). In this study, it was shown that both of two LMW fucoidans (LF1, LF2) could increase the thymus index, spleen index, phagocytic index, phagocytosis coefficient and half hemolysin value in middle and high doses, which suggested that LMW fucoidans could play an antiviral role by improving the quality of immune organs, improving immune cell phagocytosis and humoral immunity.

  14. Light-Induced Switching of Tunable Single-Molecule Junctions

    KAUST Repository

    Sendler, Torsten

    2015-04-16

    A major goal of molecular electronics is the development and implementation of devices such as single-molecular switches. Here, measurements are presented that show the controlled in situ switching of diarylethene molecules from their nonconductive to conductive state in contact to gold nanoelectrodes via controlled light irradiation. Both the conductance and the quantum yield for switching of these molecules are within a range making the molecules suitable for actual devices. The conductance of the molecular junctions in the opened and closed states is characterized and the molecular level E 0, which dominates the current transport in the closed state, and its level broadening Γ are identified. The obtained results show a clear light-induced ring forming isomerization of the single-molecule junctions. Electron withdrawing side-groups lead to a reduction of conductance, but do not influence the efficiency of the switching mechanism. Quantum chemical calculations of the light-induced switching processes correlate these observations with the fundamentally different low-lying electronic states of the opened and closed forms and their comparably small modification by electron-withdrawing substituents. This full characterization of a molecular switch operated in a molecular junction is an important step toward the development of real molecular electronics devices.

  15. Light-Induced Switching of Tunable Single-Molecule Junctions

    KAUST Repository

    Sendler, Torsten; Luka-Guth, Katharina; Wieser, Matthias; Lokamani; Wolf, Jannic Sebastian; Helm, Manfred; Gemming, Sibylle; Kerbusch, Jochen; Scheer, Elke; Huhn, Thomas; Erbe, Artur

    2015-01-01

    A major goal of molecular electronics is the development and implementation of devices such as single-molecular switches. Here, measurements are presented that show the controlled in situ switching of diarylethene molecules from their nonconductive to conductive state in contact to gold nanoelectrodes via controlled light irradiation. Both the conductance and the quantum yield for switching of these molecules are within a range making the molecules suitable for actual devices. The conductance of the molecular junctions in the opened and closed states is characterized and the molecular level E 0, which dominates the current transport in the closed state, and its level broadening Γ are identified. The obtained results show a clear light-induced ring forming isomerization of the single-molecule junctions. Electron withdrawing side-groups lead to a reduction of conductance, but do not influence the efficiency of the switching mechanism. Quantum chemical calculations of the light-induced switching processes correlate these observations with the fundamentally different low-lying electronic states of the opened and closed forms and their comparably small modification by electron-withdrawing substituents. This full characterization of a molecular switch operated in a molecular junction is an important step toward the development of real molecular electronics devices.

  16. Molecular imaging of the transcription factor NF-κB, a primary regulator of stress response

    International Nuclear Information System (INIS)

    Carlsen, Harald; Alexander, George; Austenaa, Liv M.I.; Ebihara, Kanae; Blomhoff, Rune

    2004-01-01

    A wide range of environmental stress and human disorders involves inappropriate regulation of NF-κB, including cancers and numerous inflammatory conditions. We have developed transgenic mice that express luciferase under the control of NF-κB, enabling real-time non-invasive imaging of NF-κB activity in intact animals. We show that, in the absence of stimulation, strong, intrinsic luminescence is evident in lymph nodes in the neck region, thymus, and Peyer's patches. Treating mice with stressors, such as TNF-α, IL-1α, or lipopolysaccharide (LPS) increases the luminescence in a tissue-specific manner, with the strongest activity observable in the skin, lungs, spleen, Peyer's patches, and the wall of the small intestine. Liver, kidney, heart, muscle, and adipose tissue exhibit less intense activities. Exposure of the skin to a low dose of UV-B radiation increases luminescence in the exposed areas. In ocular experiments, LPS- and TNF-α injected NF-κB-luciferase transgenic mice exhibit a 20-40-fold increase in lens NF-κB activity, similar to other LPS- and TNF-α-responsive organs. Peak NF-κB activity occurs 6 h after injection of TNF-α and 12 h after injection of LPS. Peak activities occur, respectively, 3 and 6 h later than that in other tissues. Mice exposed to 360 J/m 2 of UV-B exhibit a 16-fold increase in NF-κB activity 6 h after exposure, characteristically similar to TNF-α-exposed mice. Thus, in NF-κB-luciferase transgenic mice, NF-κB activity also occurs in lens epithelial tissue and is activated when the intact mouse is exposed to classical stressors. Furthermore, as revealed by real-time non-invasive imaging, induction of chronic inflammation resembling rheumatoid arthritis produces strong NF-κB activity in the affected joints. Finally, we have used the model to demonstrate NF-κB regulation by manipulating the Vitamin A status in mice. NF-κB activity is elevated in mice fed a Vitamin A deficient (VAD) diet, and suppressed by surplus doses of

  17. The translation initiation factor eIF4E regulates the sex-specific expression of the master switch gene Sxl in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Patricia L Graham

    2011-07-01

    Full Text Available In female fruit flies, Sex-lethal (Sxl turns off the X chromosome dosage compensation system by a mechanism involving a combination of alternative splicing and translational repression of the male specific lethal-2 (msl-2 mRNA. A genetic screen identified the translation initiation factor eif4e as a gene that acts together with Sxl to repress expression of the Msl-2 protein. However, eif4e is not required for Sxl mediated repression of msl-2 mRNA translation. Instead, eif4e functions as a co-factor in Sxl-dependent female-specific alternative splicing of msl-2 and also Sxl pre-mRNAs. Like other factors required for Sxl regulation of splicing, eif4e shows maternal-effect female-lethal interactions with Sxl. This female lethality can be enhanced by mutations in other co-factors that promote female-specific splicing and is caused by a failure to properly activate the Sxl-positive autoregulatory feedback loop in early embryos. In this feedback loop Sxl proteins promote their own synthesis by directing the female-specific alternative splicing of Sxl-Pm pre-mRNAs. Analysis of pre-mRNA splicing when eif4e activity is compromised demonstrates that Sxl-dependent female-specific splicing of both Sxl-Pm and msl-2 pre-mRNAs requires eif4e activity. Consistent with a direct involvement in Sxl-dependent alternative splicing, eIF4E is associated with unspliced Sxl-Pm pre-mRNAs and is found in complexes that contain early acting splicing factors--the U1/U2 snRNP protein Sans-fils (Snf, the U1 snRNP protein U1-70k, U2AF38, U2AF50, and the Wilms' Tumor 1 Associated Protein Fl(2d--that have been directly implicated in Sxl splicing regulation.

  18. Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes.

    Science.gov (United States)

    Lee, Erinna F; Clarke, Oliver B; Evangelista, Marco; Feng, Zhiping; Speed, Terence P; Tchoubrieva, Elissaveta B; Strasser, Andreas; Kalinna, Bernd H; Colman, Peter M; Fairlie, W Douglas

    2011-04-26

    Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2-regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2-like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with "BH3 mimetic" drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.

  19. Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

    Science.gov (United States)

    Lee, Erinna F.; Clarke, Oliver B.; Evangelista, Marco; Feng, Zhiping; Speed, Terence P.; Tchoubrieva, Elissaveta B.; Strasser, Andreas; Kalinna, Bernd H.; Colman, Peter M.; Fairlie, W. Douglas

    2011-01-01

    Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2–regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2–like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with “BH3 mimetic” drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment. PMID:21444803

  20. A Molecular Mechanism to Regulate Lysosome Motility for Lysosome Positioning and Tubulation

    Science.gov (United States)

    Li, Xinran; Rydzewski, Nicholas; Hider, Ahmad; Zhang, Xiaoli; Yang, Junsheng; Wang, Wuyang; Gao, Qiong; Cheng, Xiping; Xu, Haoxing

    2016-01-01

    To mediate the degradation of bio-macromolecules, lysosomes must traffic towards cargo-carrying vesicles for subsequent membrane fusion or fission. Mutations of the lysosomal Ca2+ channel TRPML1 cause lysosome storage disease (LSD) characterized by disordered lysosomal membrane trafficking in cells. Here we show that TRPML1 activity is required to promote Ca2+-dependent centripetal movement of lysosomes towards the perinuclear region, where autophagosomes accumulate, upon autophagy induction. ALG-2, an EF-hand-containing protein, serves as a lysosomal Ca2+ sensor that associates physically with the minus-end directed dynactin-dynein motor, while PI(3,5)P2, a lysosome-localized phosphoinositide, acts upstream of TRPML1. Furthermore, the PI(3,5)P2-TRPML1-ALG-2-dynein signaling is necessary for lysosome tubulation and reformation. In contrast, the TRPML1 pathway is not required for the perinuclear accumulation of lysosomes observed in many LSDs, which is instead likely caused by secondary cholesterol accumulation that constitutively activates Rab7-RILP-dependent retrograde transport. Collectively, Ca2+ release from lysosomes provides an on-demand mechanism regulating lysosome motility, positioning, and tubulation. PMID:26950892

  1. Functional O-GlcNAc modifications: Implications in molecular regulation and pathophysiology

    Science.gov (United States)

    Wells, Lance

    2016-01-01

    O-linked β-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational modification of intracellular proteins. The dynamic and inducible cycling of the modification is governed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in response to UDP-GlcNAc levels in the hexosamine biosynthetic pathway (HBP). Due to its reliance on glucose flux and substrate availability, a major focus in the field has been on how O-GlcNAc contributes to metabolic disease. For years this post-translational modification has been known to modify thousands of proteins implicated in various disorders, but direct functional connections have until recently remained elusive. New research is beginning to reveal the specific mechanisms through which O-GlcNAc influences cell dynamics and disease pathology including clear examples of O-GlcNAc modification at a specific site on a given protein altering its biological functions. The following review intends to focus primarily on studies in the last half decade linking O-GlcNAc modification of proteins with chromatin-directed gene regulation, developmental processes, and several metabolically related disorders including Alzheimer’s, heart disease and cancer. These studies illustrate the emerging importance of this post-translational modification in biological processes and multiple pathophysiologies. PMID:24524620

  2. Regulating Toxin-Antitoxin Expression: Controlled Detonation of Intracellular Molecular Timebombs

    Directory of Open Access Journals (Sweden)

    Finbarr Hayes

    2014-01-01

    Full Text Available Genes for toxin-antitoxin (TA complexes are widely disseminated in bacteria, including in pathogenic and antibiotic resistant species. The toxins are liberated from association with the cognate antitoxins by certain physiological triggers to impair vital cellular functions. TAs also are implicated in antibiotic persistence, biofilm formation, and bacteriophage resistance. Among the ever increasing number of TA modules that have been identified, the most numerous are complexes in which both toxin and antitoxin are proteins. Transcriptional autoregulation of the operons encoding these complexes is key to ensuring balanced TA production and to prevent inadvertent toxin release. Control typically is exerted by binding of the antitoxin to regulatory sequences upstream of the operons. The toxin protein commonly works as a transcriptional corepressor that remodels and stabilizes the antitoxin. However, there are notable exceptions to this paradigm. Moreover, it is becoming clear that TA complexes often form one strand in an interconnected web of stress responses suggesting that their transcriptional regulation may prove to be more intricate than currently understood. Furthermore, interference with TA gene transcriptional autoregulation holds considerable promise as a novel antibacterial strategy: artificial release of the toxin factor using designer drugs is a potential approach to induce bacterial suicide from within.

  3. The NAC transcription factor family in maritime pine (Pinus Pinaster): molecular regulation of two genes involved in stress responses.

    Science.gov (United States)

    Pascual, Ma Belén; Cánovas, Francisco M; Ávila, Concepción

    2015-10-24

    NAC transcription factors comprise a large plant-specific gene family involved in the regulation of diverse biological processes. Despite the growing number of studies on NAC transcription factors in various species, little information is available about this family in conifers. The goal of this study was to identify the NAC transcription family in maritime pine (Pinus pinaster), to characterize ATAF-like genes in response to various stresses and to study their molecular regulation. We have isolated two maritime pine NAC genes and using a transient expression assay in N. benthamiana leaves estudied the promoter jasmonate response. In this study, we identified 37 NAC genes from maritime pine and classified them into six main subfamilies. The largest group includes 12 sequences corresponding to stress-related genes. Two of these NAC genes, PpNAC2 and PpNAC3, were isolated and their expression profiles were examined at various developmental stages and in response to various types of stress. The expression of both genes was strongly induced by methyl jasmonate (MeJA), mechanical wounding, and high salinity. The promoter regions of these genes were shown to contain cis-elements involved in the stress response and plant hormonal regulation, including E-boxes, which are commonly found in the promoters of genes that respond to jasmonate, and binding sites for bHLH proteins. Using a transient expression assay in N. benthamiana leaves, we found that the promoter of PpNAC3 was rapidly induced upon MeJA treatment, while this response disappeared in plants in which the transcription factor NbbHLH2 was silenced. Our results suggest that PpNAC2 and PpNAC3 encode stress-responsive NAC transcription factors involved in the jasmonate response in pine. Furthermore, these data also suggest that the jasmonate signaling pathway is conserved between angiosperms and gymnosperms. These findings may be useful for engineering stress tolerance in pine via biotechnological approaches.

  4. Transient-Switch-Signal Suppressor

    Science.gov (United States)

    Bozeman, Richard J., Jr.

    1995-01-01

    Circuit delays transmission of switch-opening or switch-closing signal until after preset suppression time. Used to prevent transmission of undesired momentary switch signal. Basic mode of operation simple. Beginning of switch signal initiates timing sequence. If switch signal persists after preset suppression time, circuit transmits switch signal to external circuitry. If switch signal no longer present after suppression time, switch signal deemed transient, and circuit does not pass signal on to external circuitry, as though no transient switch signal. Suppression time preset at value large enough to allow for damping of underlying pressure wave or other mechanical transient.

  5. Optimal switching using coherent control

    DEFF Research Database (Denmark)

    Kristensen, Philip Trøst; Heuck, Mikkel; Mørk, Jesper

    2013-01-01

    that the switching time, in general, is not limited by the cavity lifetime. Therefore, the total energy required for switching is a more relevant figure of merit than the switching speed, and for a particular two-pulse switching scheme we use calculus of variations to optimize the switching in terms of input energy....

  6. Signal regulatory protein α associated with the progression of oral leukoplakia and oral squamous cell carcinoma regulates phenotype switch of macrophages.

    Science.gov (United States)

    Ye, Xiaojing; Zhang, Jing; Lu, Rui; Zhou, Gang

    2016-12-06

    Signal regulatory protein α (SIRPα) is a cell-surface protein expressed on macrophages that are regarded as an important component of the tumor microenvironment. The expression of SIRPα in oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC), and further explored the role of SIRPα on the phenotype, phagocytosis ability, migration, and invasion of macrophages in OSCC were investigated. The expression of SIRPα in OLK was higher than in OSCC, correlating with the expression of CD68 and CD163 on macrophages. After cultured with the conditioned media of oral cancer cells, the expression of SIRPα on THP-1 cells was decreased gradually. In co-culture system, macrophages were induced into M2 phenotype by oral cancer cells. Blockade of SIRPα inhibited phagocytosis ability and IL-6, TNF-α productions of macrophages. In addition, the proliferation, migration, and IL-10, TGF-β productions of macrophages were upregulated after blockade of SIRPα. Macrophages upregulated the expression of SIRPα and phagocytosis ability, and inhibited the migration and invasion when the activation of NF-κB was inhibited by pyrrolidine dithiocarbamate ammonium (PDTC). Hence, SIRPα might play an important role in the progression of OLK and oral cancer, and could be a pivotal therapeutic target in OSCC by regulating the phenotype of macrophages via targeting NF-κB.

  7. A Biotin Switch-Based Proteomics Approach Identifies 14-3-3ζ as a Target of Sirt1 in the Metabolic Regulation of Caspase-2

    Science.gov (United States)

    Andersen, Joshua L.; Thompson, J. Will; Lindblom, Kelly R.; Johnson, Erika S.; Yang, Chih-Sheng; Lilley, Lauren R.; Freel, Christopher D.; Moseley, M. Arthur; Kornbluth, Sally

    2011-01-01

    While lysine acetylation in the nucleus is well characterized, comparatively little is known about its significance in cytoplasmic signaling. Here we show that inhibition of the Sirt1 deacetylase, which is primarily cytoplasmic in cancer cell lines, sensitizes these cells to caspase-2-dependent death. To identify relevant Sirt1 substrates, we developed a novel proteomics strategy, enabling the identification of a range of putative substrates, including 14-3-3ζ, a known direct regulator of caspase-2. We show here that inhibition of Sirtuin activity accelerates caspase activation and overrides caspase-2 suppression by nutrient abundance. Furthermore, 14-3-3ζ is acetylated prior to caspase activation, and supplementation of Xenopus egg extract with glucose-6-phosphate, which promotes caspase-2/14-3-3ζ binding, enhances 14-3-3ζ-directed Sirtuin activity. Conversely, inhibiting Sirtuin activity promotes 14-3-3ζ dissociation from caspase-2 in both egg extract and human cell lines. These data reveal a role for Sirt1 in modulating apoptotic sensitivity, in response to metabolic changes, by antagonizing 14-3-3ζ acetylation. PMID:21884983

  8. Switched reluctance motor drives

    Indian Academy of Sciences (India)

    Davis RM, Ray WF, Blake RJ 1981 Inverter drive for switched reluctance: circuits and component ratings. Inst. Elec. Eng. Proc. B128: 126-136. Ehsani M. 1991 Position Sensor elimination technique for the switched reluctance motor drive. US Patent No. 5,072,166. Ehsani M, Ramani K R 1993 Direct control strategies based ...

  9. Manually operated coded switch

    International Nuclear Information System (INIS)

    Barnette, J.H.

    1978-01-01

    The disclosure related to a manually operated recodable coded switch in which a code may be inserted, tried and used to actuate a lever controlling an external device. After attempting a code, the switch's code wheels must be returned to their zero positions before another try is made

  10. Switch on, switch off: stiction in nanoelectromechanical switches

    KAUST Repository

    Wagner, Till J W

    2013-06-13

    We present a theoretical investigation of stiction in nanoscale electromechanical contact switches. We develop a mathematical model to describe the deflection of a cantilever beam in response to both electrostatic and van der Waals forces. Particular focus is given to the question of whether adhesive van der Waals forces cause the cantilever to remain in the \\'ON\\' state even when the electrostatic forces are removed. In contrast to previous studies, our theory accounts for deflections with large slopes (i.e. geometrically nonlinear). We solve the resulting equations numerically to study how a cantilever beam adheres to a rigid electrode: transitions between \\'free\\', \\'pinned\\' and \\'clamped\\' states are shown to be discontinuous and to exhibit significant hysteresis. Our findings are compared to previous results from linearized models and the implications for nanoelectromechanical cantilever switch design are discussed. © 2013 IOP Publishing Ltd.

  11. Avalanche photoconductive switching

    Science.gov (United States)

    Pocha, M. D.; Druce, R. L.; Wilson, M. J.; Hofer, W. W.

    This paper describes work being done at Lawrence Livermore National Laboratory on the avalanche mode of operation of laser triggered photoconductive switches. We have been able to generate pulses with amplitudes of 2 kV to 35 kV and rise times of 300 to 500 ps, and with a switching gain (energy of output electrical pulse vs energy of trigger optical pulse) of 10(exp 3) to over 10(exp 5). Switches with two very different physical configurations and with two different illumination wavelengths (1.06 micrometer, 890 nm) exhibit very similar behavior. The avalanche switching behavior, therefore, appears to be related to the material parameters rather than the optical wavelength or switch geometry. Considerable further work needs to be done to fully characterize and understand this mode of operation.

  12. Avalanche photoconductive switching

    Energy Technology Data Exchange (ETDEWEB)

    Pocha, M.D.; Druce, R.L.; Wilson, M.J.; Hofer, W.W.

    1989-01-01

    This paper describes work being done at Lawrence Livermore National Laboratory on the avalanche mode of operation of laser triggered photoconductive switches. We have been able to generate pulses with amplitudes of 2 kV--35 kV and rise times of 300--500 ps, and with a switching gain (energy of output electrical pulse vs energy of trigger optical pulse) of 10{sup 3} to over 10{sup 5}. Switches with two very different physical configurations and with two different illumination wavelengths (1.06 {mu}m, 890 nm) exhibit very similar behavior. The avalanche switching behavior, therefore, appears to be related to the material parameters rather than the optical wavelength or switch geometry. Considerable further work needs to be done to fully characterize and understand this mode of operation. 3 refs., 6 figs.

  13. Behavioral plasticity through the modulation of switch neurons.

    Science.gov (United States)

    Vassiliades, Vassilis; Christodoulou, Chris

    2016-02-01

    A central question in artificial intelligence is how to design agents capable of switching between different behaviors in response to environmental changes. Taking inspiration from neuroscience, we address this problem by utilizing artificial neural networks (NNs) as agent controllers, and mechanisms such as neuromodulation and synaptic gating. The novel aspect of this work is the introduction of a type of artificial neuron we call "switch neuron". A switch neuron regulates the flow of information in NNs by selectively gating all but one of its incoming synaptic connections, effectively allowing only one signal to propagate forward. The allowed connection is determined by the switch neuron's level of modulatory activation which is affected by modulatory signals, such as signals that encode some information about the reward received by the agent. An important aspect of the switch neuron is that it can be used in appropriate "switch modules" in order to modulate other switch neurons. As we show, the introduction of the switch modules enables the creation of sequences of gating events. This is achieved through the design of a modulatory pathway capable of exploring in a principled manner all permutations of the connections arriving on the switch neurons. We test the model by presenting appropriate architectures in nonstationary binary association problems and T-maze tasks. The results show that for all tasks, the switch neuron architectures generate optimal adaptive behaviors, providing evidence that the switch neuron model could be a valuable tool in simulations where behavioral plasticity is required. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Omics analysis of human bone to identify genes and molecular networks regulating skeletal remodeling in health and disease.

    Science.gov (United States)

    Reppe, Sjur; Datta, Harish K; Gautvik, Kaare M

    2017-08-01

    The skeleton is a metabolically active organ throughout life where specific bone cell activity and paracrine/endocrine factors regulate its morphogenesis and remodeling. In recent years, an increasing number of reports have used multi-omics technologies to characterize subsets of bone biological molecular networks. The skeleton is affected by primary and secondary disease, lifestyle and many drugs. Therefore, to obtain relevant and reliable data from well characterized patient and control cohorts are vital. Here we provide a brief overview of omics studies performed on human bone, of which our own studies performed on trans-iliacal bone biopsies from postmenopausal women with osteoporosis (OP) and healthy controls are among the first and largest. Most other studies have been performed on smaller groups of patients, undergoing hip replacement for osteoarthritis (OA) or fracture, and without healthy controls. The major findings emerging from the combined studies are: 1. Unstressed and stressed bone show profoundly different gene expression reflecting differences in bone turnover and remodeling and 2. Omics analyses comparing healthy/OP and control/OA cohorts reveal characteristic changes in transcriptomics, epigenomics (DNA methylation), proteomics and metabolomics. These studies, together with genome-wide association studies, in vitro observations and transgenic animal models have identified a number of genes and gene products that act via Wnt and other signaling systems and are highly associated to bone density and fracture. Future challenge is to understand the functional interactions between bone-related molecular networks and their significance in OP and OA pathogenesis, and also how the genomic architecture is affected in health and disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Molecular evolution of the two-component system BvgAS involved in virulence regulation in Bordetella.

    Directory of Open Access Journals (Sweden)

    Julien Herrou

    Full Text Available The whooping cough agent Bordetella pertussis is closely related to Bordetella bronchiseptica, which is responsible for chronic respiratory infections in various mammals and is occasionally found in humans, and to Bordetella parapertussis, one lineage of which causes mild whooping cough in humans and the other ovine respiratory infections. All three species produce similar sets of virulence factors that are co-regulated by the two-component system BvgAS. We characterized the molecular diversity of BvgAS in Bordetella by sequencing the two genes from a large number of diverse isolates. The response regulator BvgA is virtually invariant, indicating strong functional constraints. In contrast, the multi-domain sensor kinase BvgS has evolved into two different types. The pertussis type is found in B. pertussis and in a lineage of essentially human-associated B. bronchiseptica, while the bronchiseptica type is associated with the majority of B. bronchiseptica and both ovine and human B. parapertussis. BvgS is monomorphic in B. pertussis, suggesting optimal adaptation or a recent population bottleneck. The degree of diversity of the bronchiseptica type BvgS is markedly different between domains, indicating distinct evolutionary pressures. Thus, absolute conservation of the putative solute-binding cavities of the two periplasmic Venus Fly Trap (VFT domains suggests that common signals are perceived in all three species, while the external surfaces of these domains vary more extensively. Co-evolution of the surfaces of the two VFT domains in each type and domain swapping experiments indicate that signal transduction in the periplasmic region may be type-specific. The two distinct evolutionary solutions for BvgS confirm that B. pertussis has emerged from a specific B. bronchiseptica lineage. The invariant regions of BvgS point to essential parts for its molecular mechanism, while the variable regions may indicate adaptations to different lifestyles. The

  16. Microprocessor Controlled Capacitor Bank Switching System for ...

    African Journals Online (AJOL)

    In this work, analysis and development of a microprocessor controlled capacitor bank switching system for deployment in a smart distribution network was carried out. This system was implemented by the use of discreet components such as resistors, capacitors, transistor, diode, automatic voltage regulator, with the ...

  17. Computational Studies of the Active and Inactive Regulatory Domains of Response Regulator PhoP Using Molecular Dynamics Simulations.

    Science.gov (United States)

    Qing, Xiao-Yu; Steenackers, Hans; Venken, Tom; De Maeyer, Marc; Voet, Arnout

    2017-11-01

    The response regulator PhoP is part of the PhoP/PhoQ two-component system, which is responsible for regulating the expression of multiple genes involved in controlling virulence, biofilm formation, and resistance to antimicrobial peptides. Therefore, modulating the transcriptional function of the PhoP protein is a promising strategy for developing new antimicrobial agents. There is evidence suggesting that phosphorylation-mediated dimerization in the regulatory domain of PhoP is essential for its transcriptional function. Disruption or stabilization of protein-protein interactions at the dimerization interface may inhibit or enhance the expression of PhoP-dependent genes. In this study, we performed molecular dynamics simulations on the active and inactive dimers and monomers of the PhoP regulatory domains, followed by pocket-detecting screenings and a quantitative hot-spot analysis in order to assess the druggability of the protein. Consistent with prior hypothesis, the calculation of the binding free energy shows that phosphorylation enhances dimerization of PhoP. Furthermore, we have identified two different putative binding sites at the dimerization active site (the α4-β5-α5 face) with energetic "hot-spot" areas, which could be used to search for modulators of protein-protein interactions. This study delivers insight into the dynamics and druggability of the dimerization interface of the PhoP regulatory domain, and may serve as a basis for the rational identification of new antimicrobial drugs. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Flicking the switch on a molecular gate

    KAUST Repository

    Gascon, Jorge

    2017-01-01

    The use of external stimuli to manipulate the properties of well-defined materials may find applications in on-demand drug delivery, separation of molecules, sensing, smart coatings, or artificial tissues (1). Most of these applications rely on changes in the shape, stiffness, pore size, or other properties of soft materials in response to external pressure, temperature changes, or electric or magnetic fields. However, the lack of long-range order in polymers makes it difficult to control their porosity and, hence, permeability. On page 347 of this issue, Knebel et al. (2) instead manipulate metal-organic framework (MOF) membranes. They show that the membrane pore size can change upon exposure to an external electric field, enabling precise separation of different gas molecules.

  19. Flicking the switch on a molecular gate

    KAUST Repository

    Gascon, Jorge

    2017-10-19

    The use of external stimuli to manipulate the properties of well-defined materials may find applications in on-demand drug delivery, separation of molecules, sensing, smart coatings, or artificial tissues (1). Most of these applications rely on changes in the shape, stiffness, pore size, or other properties of soft materials in response to external pressure, temperature changes, or electric or magnetic fields. However, the lack of long-range order in polymers makes it difficult to control their porosity and, hence, permeability. On page 347 of this issue, Knebel et al. (2) instead manipulate metal-organic framework (MOF) membranes. They show that the membrane pore size can change upon exposure to an external electric field, enabling precise separation of different gas molecules.

  20. Energy losses in switches

    International Nuclear Information System (INIS)

    Martin, T.H.; Seamen, J.F.; Jobe, D.O.

    1993-01-01

    The authors experiments show energy losses between 2 and 10 times that of the resistive time predictions. The experiments used hydrogen, helium, air, nitrogen, SF 6 polyethylene, and water for the switching dielectric. Previously underestimated switch losses have caused over predicting the accelerator outputs. Accurate estimation of these losses is now necessary for new high-efficiency pulsed power devices where the switching losses constitute the major portion of the total energy loss. They found that the switch energy losses scale as (V peak I peak ) 1.1846 . When using this scaling, the energy losses in any of the tested dielectrics are almost the same. This relationship is valid for several orders of magnitude and suggested a theoretical basis for these results. Currents up to .65 MA, with voltages to 3 MV were applied to various gaps during these experiments. The authors data and the developed theory indicates that the switch power loss continues for a much longer time than the resistive time, with peak power loss generally occurring at peak current in a ranging discharge instead of the early current time. All of the experiments were circuit code modeled after developing a new switch loss version based on the theory. The circuit code predicts switch energy loss and peak currents as a function of time. During analysis of the data they noticed slight constant offsets between the theory and data that depended on the dielectric. They modified the plasma conductivity for each tested dielectric to lessen this offset

  1. Orientation of KRb molecules in a switched electrostatic field

    International Nuclear Information System (INIS)

    Huang Yun-Xia; Xu Shu-Wu; Yang Xiao-Hua

    2013-01-01

    We theoretically investigate the orientation of the cold KRb molecules induced in a switched electrostatic field by numerically solving the full time-dependent Schrödinger equation. The results show that the periodic field-free molecular orientation can be realized for the KRb molecules by rapidly switching off the electrostatic field. Meanwhile, by varying the switching times of the electrostatic field, the adiabatic and nonadiabatic interactions of the molecules with the applied field can be realized. Moreover, the influences of the electrostatic field strength and the rotational temperature to the degree of the molecular orientation are studied. The investigations show that increasing the electrostatic field will increase the degree of the molecular orientation, both in the constant-field regime and in the field-free regime, while the increasing of the rotational temperature of the cold molecules will greatly decrease the degree of the molecular orientation. (atomic and molecular physics)

  2. Electromechanical magnetization switching

    Energy Technology Data Exchange (ETDEWEB)

    Chudnovsky, Eugene M. [Department of Physics and Astronomy, Lehman College and Graduate School, The City University of New York, 250 Bedford Park Boulevard West, Bronx, New York 10468-1589 (United States); Jaafar, Reem [Department of Mathematics, Engineering and Computer Science, LaGuardia Community College, The City University of New York, 31-10 Thomson Avenue, Long Island City, New York 11101 (United States)

    2015-03-14

    We show that the magnetization of a torsional oscillator that, in addition to the magnetic moment also possesses an electrical polarization, can be switched by the electric field that ignites mechanical oscillations at the frequency comparable to the frequency of the ferromagnetic resonance. The 180° switching arises from the spin-rotation coupling and is not prohibited by the different symmetry of the magnetic moment and the electric field as in the case of a stationary magnet. Analytical equations describing the system have been derived and investigated numerically. Phase diagrams showing the range of parameters required for the switching have been obtained.

  3. Electromechanical magnetization switching

    International Nuclear Information System (INIS)

    Chudnovsky, Eugene M.; Jaafar, Reem

    2015-01-01

    We show that the magnetization of a torsional oscillator that, in addition to the magnetic moment also possesses an electrical polarization, can be switched by the electric field that ignites mechanical oscillations at the frequency comparable to the frequency of the ferromagnetic resonance. The 180° switching arises from the spin-rotation coupling and is not prohibited by the different symmetry of the magnetic moment and the electric field as in the case of a stationary magnet. Analytical equations describing the system have been derived and investigated numerically. Phase diagrams showing the range of parameters required for the switching have been obtained

  4. JUNOS Enterprise Switching

    CERN Document Server

    Reynolds, Harry

    2009-01-01

    JUNOS Enterprise Switching is the only detailed technical book on Juniper Networks' new Ethernet-switching EX product platform. With this book, you'll learn all about the hardware and ASIC design prowess of the EX platform, as well as the JUNOS Software that powers it. Not only is this extremely practical book a useful, hands-on manual to the EX platform, it also makes an excellent study guide for certification exams in the JNTCP enterprise tracks. The authors have based JUNOS Enterprise Switching on their own Juniper training practices and programs, as well as the configuration, maintenanc

  5. Switch mode power supply

    International Nuclear Information System (INIS)

    Kim, Hui Jun

    1993-06-01

    This book concentrates on switch mode power supply. It has four parts, which are introduction of switch mode power supply with DC-DC converter such as Buck converter boost converter, Buck-boost converter and PWM control circuit, explanation for SMPS with DC-DC converter modeling and power mode control, resonance converter like resonance switch, converter, multi resonance converter and series resonance and parallel resonance converters, basic test of SMPS with PWM control circuit, Buck converter, Boost converter, flyback converter, forward converter and IC for control circuit.

  6. A molecular toolbox for rapid generation of viral vectors to up- or down-regulate in vivo neuronal gene expression

    Directory of Open Access Journals (Sweden)

    Melanie D. White

    2011-07-01

    Full Text Available We introduce a molecular toolbox for manipulation of neuronal gene expression in vivo. The toolbox includes promoters, ion channels, optogenetic tools, fluorescent proteins and intronic artificial microRNAs. The components are easily assembled into adeno-associated virus (AAV or lentivirus vectors using recombination cloning. We demonstrate assembly of toolbox components into lentivirus and AAV vectors and use these vectors for in vivo expression of inwardly rectifying potassium channels (Kir2.1, Kir3.1 and Kir3.2 and an artificial microRNA targeted against the ion channel HCN1 (HCN1 miR. We show that AAV assembled to express HCN1 miR produces efficacious and specific in vivo knockdown of HCN1 channels. Comparison of in vivo viral transduction using HCN1 miR with mice containing a germ line deletion of HCN1 reveals similar physiological phenotypes in cerebellar Purkinje cells. The easy assembly and re-usability of the toolbox components, together with the ability to up- or down-regulate neuronal gene expression in vivo, may be useful for applications in many areas of neuroscience.

  7. Regulation

    International Nuclear Information System (INIS)

    Ballereau, P.

    1999-01-01

    The different regulations relative to nuclear energy since the first of January 1999 are given here. Two points deserve to be noticed: the decree of the third august 1999 authorizing the national Agency for the radioactive waste management to install and exploit on the commune of Bures (Meuse) an underground laboratory destined to study the deep geological formations where could be stored the radioactive waste. The second point is about the uranium residues and the waste notion. The judgment of the administrative tribunal of Limoges ( 9. july 1998) forbidding the exploitation of a storage installation of depleted uranium considered as final waste and qualifying it as an industrial waste storage facility has been annulled bu the Court of Appeal. It stipulated that, according to the law number 75663 of the 15. july 1965, no criteria below can be applied to depleted uranium: production residue (possibility of an ulterior enrichment), abandonment of a personal property or simple intention to do it ( future use aimed in the authorization request made in the Prefecture). This judgment has devoted the primacy of the waste notion on this one of final waste. (N.C.)

  8. Activator Protein-1: redox switch controlling structure and DNA-binding.

    Science.gov (United States)

    Yin, Zhou; Machius, Mischa; Nestler, Eric J; Rudenko, Gabby

    2017-11-02

    The transcription factor, activator protein-1 (AP-1), binds to cognate DNA under redox control; yet, the underlying mechanism has remained enigmatic. A series of crystal structures of the AP-1 FosB/JunD bZIP domains reveal ordered DNA-binding regions in both FosB and JunD even in absence DNA. However, while JunD is competent to bind DNA, the FosB bZIP domain must undergo a large conformational rearrangement that is controlled by a 'redox switch' centered on an inter-molecular disulfide bond. Solution studies confirm that FosB/JunD cannot undergo structural transition and bind DNA when the redox-switch is in the 'OFF' state, and show that the mid-point redox potential of the redox switch affords it sensitivity to cellular redox homeostasis. The molecular and structural studies presented here thus reveal the mechanism underlying redox-regulation of AP-1 Fos/Jun transcription factors and provide structural insight for therapeutic interventions targeting AP-1 proteins. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  9. Intermittent metabolic switching, neuroplasticity and brain health

    Science.gov (United States)

    Mattson, Mark P.; Moehl, Keelin; Ghena, Nathaniel; Schmaedick, Maggie; Cheng, Aiwu

    2018-01-01

    During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease. PMID:29321682

  10. Spiers Memorial Lecture. Molecular mechanics and molecular electronics.

    Science.gov (United States)

    Beckman, Robert; Beverly, Kris; Boukai, Akram; Bunimovich, Yuri; Choi, Jang Wook; DeIonno, Erica; Green, Johnny; Johnston-Halperin, Ezekiel; Luo, Yi; Sheriff, Bonnie; Stoddart, Fraser; Heath, James R

    2006-01-01

    We describe our research into building integrated molecular electronics circuitry for a diverse set of functions, and with a focus on the fundamental scientific issues that surround this project. In particular, we discuss experiments aimed at understanding the function of bistable rotaxane molecular electronic switches by correlating the switching kinetics and ground state thermodynamic properties of those switches in various environments, ranging from the solution phase to a Langmuir monolayer of the switching molecules sandwiched between two electrodes. We discuss various devices, low bit-density memory circuits, and ultra-high density memory circuits that utilize the electrochemical switching characteristics of these molecules in conjunction with novel patterning methods. We also discuss interconnect schemes that are capable of bridging the micrometre to submicrometre length scales of conventional patterning approaches to the near-molecular length scales of the ultra-dense memory circuits. Finally, we discuss some of the challenges associated with fabricated ultra-dense molecular electronic integrated circuits.

  11. 49 CFR 236.330 - Locking dog of switch-and-lock movement.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Locking dog of switch-and-lock movement. 236.330 Section 236.330 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Rules and Instructions § 236.330 Locking dog of switch-and-lock movement. Locking dog of switch-and-lock...

  12. Optical switching systems using nanostructures

    DEFF Research Database (Denmark)

    Stubkjær, Kristian

    2004-01-01

    High capacity multiservice optical networks require compact and efficient switches. The potential benefits of optical switch elements based on nanostructured material are reviewed considering various material systems.......High capacity multiservice optical networks require compact and efficient switches. The potential benefits of optical switch elements based on nanostructured material are reviewed considering various material systems....

  13. Dissection of Molecular Mechanisms Regulating Protein Body Formation in Maize Endosperm - DE-FG03-95-ER20183

    International Nuclear Information System (INIS)

    Larkins, Brian A.

    2003-01-01

    Dissection of Molecular Mechanisms Regulating Protein Body Formation in Maize Endosperm - DE-FG03-95-ER20183 Final Technical Report and Patent Summary Dr. Brian A. Larkins, Department of Plant Sciences, University of Arizona, Tucson, AZ 85721 Endosperm texture is an important quality trait in maize, as it influences the shipping characteristics of the grain, its susceptibility to insects, the yield of grits from dry milling, energy costs during wet milling, and the baking and digestibility properties of the flour. There appears to be a causal relationship between kernel hardness and the formation of zein-containing protein bodies, as mutations affecting protein body number and structure are associated with a soft, starchy kernel. In this project we used a variety of approaches to better understand this relationship and investigate the molecular and biochemical changes associated with starchy endosperm mutants. We characterized the distribution of zein mRNAs on endosperm rough endoplasmic reticulum (RER) membranes and the interactions between zein proteins, as each of these could influence the structure of protein bodies. Based on in situ hybridization, mRNAs encoding the 22-kD alpha- and 27-kD gamma-zeins are randomly distributed on RER; hence, mRNA targeting does not appear to influence the formation of protein bodies. Investigation of the interactions between zein proteins (alpha, beta, gamma, delta) with the yeast two-hybrid system showed that interactions between the 19- and 22-alpha-zeins are relatively weak, although each of them interacted strongly with the 10-kD delta-zein. Strong interactions were detected between the alpha- and delta-zeins and the 16-kD gamma- and 15-kD beta-zeins; however, the 50-kD and 27-kD gamma-zeins did not interact detectably with the alpha- and delta-zein proteins. The NH2- and COOH-terminal domains of the 22-kD alpha-zein were found to interact most strongly with the 15-kD beta- and 16-kD gamma-zeins, suggesting the 16-kD and 15

  14. Delineation of molecular pathways that regulate hepatic PCSK9 and LDL receptor expression during fasting in normolipidemic hamsters

    Science.gov (United States)

    Wu, Minhao; Dong, Bin; Cao, Aiqin; Li, Hai; Liu, Jingwen

    2015-01-01

    Background PCSK9 has emerged as a key regulator of serum LDL-C metabolism by promoting the degradation of hepatic LDL receptor (LDLR). In this study, we investigated the effect of fasting on serum PCSK9, LDL-C, and hepatic LDLR expression in hamsters and further delineated the molecular pathways involved in fasting-induced repression of PCSK9 transcription. Results Fasting had insignificant effects on serum total cholesterol and HDL-C levels, but reduced LDL-C, triglyceride and insulin levels. The decrease in serum LDL-C was accompanied by marked reductions of hepatic PCSK9 mRNA and serum PCSK9 protein levels with concomitant increases of hepatic LDLR protein amounts. Fasting produced a profound impact on SREBP1 expression and its transactivating activity, while having modest effects on mRNA expressions of SREBP2 target genes in hamster liver. Although PPARα mRNA levels in hamster liver were elevated by fasting, ligand-induced activation of PPARα with WY14643 compound in hamster primary hepatocytes did not affect PCSK9 mRNA or protein expressions. Further investigation on HNF1α, a critical transactivator of PCSK9, revealed that fasting did not alter its mRNA expression, however, the protein abundance of HNF1α in nuclear extracts of hamster liver was markedly reduced by prolonged fasting. Conclusion Fasting lowered serum LDL-C in hamsters by increasing hepatic LDLR protein amounts via reductions of serum PCSK9 levels. Importantly, our results suggest that attenuation of SREBP1 transactivating activity owing to decreased insulin levels during fasting is primarily responsible for compromised PCSK9 gene transcription, which was further suppressed after prolonged fasting by a reduction of nuclear HNF1α protein abundance. PMID:22954675

  15. Modular design strategies for protein sensors and switches

    NARCIS (Netherlands)

    Merkx, M.; Ryadnov, M.; Brunsveld, L.; Suga, H.

    2014-01-01

    Protein-based sensors and switches provide attractive tools for the real-time monitoring and control of molecular processes in complex biological environments, with applications ranging from intracellular imaging to the rewiring of signal transduction pathways and molecular diagnostics. A

  16. Study of solar array switching power management technology for space power system

    Science.gov (United States)

    Cassinelli, J. E.

    1982-01-01

    This report documents work performed on the Solar Array Switching Power Management Study. Mission characteristics for three missions were defined to the depth necessary to determine their power management requirements. Solar array switching concepts which could satisfy the mission requirements were identified. The switching concepts were compared with a conventional buck regulator system for cost, weight and volume, reliability, efficiency and thermal control. Solar array switching provided significant advantages in all areas of comparison for the reviewed missions.

  17. Switch I-dependent allosteric signaling in a G-protein chaperone-B12 enzyme complex.

    Science.gov (United States)

    Campanello, Gregory C; Lofgren, Michael; Yokom, Adam L; Southworth, Daniel R; Banerjee, Ruma

    2017-10-27

    G-proteins regulate various processes ranging from DNA replication and protein synthesis to cytoskeletal dynamics and cofactor assimilation and serve as models for uncovering strategies deployed for allosteric signal transduction. MeaB is a multifunctional G-protein chaperone, which gates loading of the active 5'-deoxyadenosylcobalamin cofactor onto methylmalonyl-CoA mutase (MCM) and precludes loading of inactive cofactor forms. MeaB also safeguards MCM, which uses radical chemistry, against inactivation and rescues MCM inactivated during catalytic turnover by using the GTP-binding energy to offload inactive cofactor. The conserved switch I and II signaling motifs used by G-proteins are predicted to mediate allosteric regulation in response to nucleotide binding and hydrolysis in MeaB. Herein, we targeted conserved residues in the MeaB switch I motif to interrogate the function of this loop. Unexpectedly, the switch I mutations had only modest effects on GTP binding and on GTPase activity and did not perturb stability of the MCM-MeaB complex. However, these mutations disrupted multiple MeaB chaperone functions, including cofactor editing, loading, and offloading. Hence, although residues in the switch I motif are not essential for catalysis, they are important for allosteric regulation. Furthermore, single-particle EM analysis revealed, for the first time, the overall architecture of the MCM-MeaB complex, which exhibits a 2:1 stoichiometry. These EM studies also demonstrate that the complex exhibits considerable conformational flexibility. In conclusion, the switch I element does not significantly stabilize the MCM-MeaB complex or influence the affinity of MeaB for GTP but is required for transducing signals between MeaB and MCM. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Molecular Regulation of the Mitochondrial F1Fo-ATPsynthase: Physiological and Pathological Significance of the Inhibitory Factor 1 (IF 1

    Directory of Open Access Journals (Sweden)

    Danilo Faccenda

    2012-01-01

    Full Text Available In mammals, the mitochondrial F1Fo-ATPsynthase sets out the energy homeostasis by producing the bulk of cellular ATP. As for every enzyme, the laws of thermodynamics command it; however, it is privileged to have a dedicated molecular regulator that controls its rotation. This is the so-called ATPase Inhibitory Factor 1 (IF1 that blocks its reversal to avoid the consumption of cellular ATP when the enzyme acts as an ATP hydrolase. Recent evidence has also demonstrated that IF1 may control the alignment of the enzyme along the mitochondrial inner membrane, thus increasing the interest for the molecule. We conceived this review to outline the fundamental knowledge of the F1Fo-ATPsynthase and link it to the molecular mechanisms by which IF1 regulates its way of function, with the ultimate goal to highlight this as an important and possibly unique means to control this indispensable enzyme in both physiological and pathological settings.

  19. Energy reversible switching from amorphous metal based nanoelectromechanical switch

    KAUST Repository

    Mayet, Abdulilah M.; Smith, Casey; Hussain, Muhammad Mustafa

    2013-01-01

    We report observation of energy reversible switching from amorphous metal based nanoelectromechanical (NEM) switch. For ultra-low power electronics, NEM switches can be used as a complementary switching element in many nanoelectronic system applications. Its inherent zero power consumption because of mechanical detachment is an attractive feature. However, its operating voltage needs to be in the realm of 1 volt or lower. Appropriate design and lower Young's modulus can contribute achieving lower operating voltage. Therefore, we have developed amorphous metal with low Young's modulus and in this paper reporting the energy reversible switching from a laterally actuated double electrode NEM switch. © 2013 IEEE.

  20. Energy reversible switching from amorphous metal based nanoelectromechanical switch

    KAUST Repository

    Mayet, Abdulilah M.

    2013-08-01

    We report observation of energy reversible switching from amorphous metal based nanoelectromechanical (NEM) switch. For ultra-low power electronics, NEM switches can be used as a complementary switching element in many nanoelectronic system applications. Its inherent zero power consumption because of mechanical detachment is an attractive feature. However, its operating voltage needs to be in the realm of 1 volt or lower. Appropriate design and lower Young\\'s modulus can contribute achieving lower operating voltage. Therefore, we have developed amorphous metal with low Young\\'s modulus and in this paper reporting the energy reversible switching from a laterally actuated double electrode NEM switch. © 2013 IEEE.

  1. Nondissipative optimum charge regulator

    Science.gov (United States)

    Rosen, R.; Vitebsky, J. N.

    1970-01-01

    Optimum charge regulator provides constant level charge/discharge control of storage batteries. Basic power transfer and control is performed by solar panel coupled to battery through power switching circuit. Optimum controller senses battery current and modifies duty cycle of switching circuit to maximize current available to battery.

  2. Optical computer switching network

    Science.gov (United States)

    Clymer, B.; Collins, S. A., Jr.

    1985-01-01

    The design for an optical switching system for minicomputers that uses an optical spatial light modulator such as a Hughes liquid crystal light valve is presented. The switching system is designed to connect 80 minicomputers coupled to the switching system by optical fibers. The system has two major parts: the connection system that connects the data lines by which the computers communicate via a two-dimensional optical matrix array and the control system that controls which computers are connected. The basic system, the matrix-based connecting system, and some of the optical components to be used are described. Finally, the details of the control system are given and illustrated with a discussion of timing.

  3. Stochastic Switching Dynamics

    DEFF Research Database (Denmark)

    Simonsen, Maria

    This thesis treats stochastic systems with switching dynamics. Models with these characteristics are studied from several perspectives. Initially in a simple framework given in the form of stochastic differential equations and, later, in an extended form which fits into the framework of sliding...... mode control. It is investigated how to understand and interpret solutions to models of switched systems, which are exposed to discontinuous dynamics and uncertainties (primarily) in the form of white noise. The goal is to gain knowledge about the performance of the system by interpreting the solution...

  4. Design of a Comprehensive Biochemistry and Molecular Biology Experiment: Phase Variation Caused by Recombinational Regulation of Bacterial Gene Expression

    Science.gov (United States)

    Sheng, Xiumei; Xu, Shungao; Lu, Renyun; Isaac, Dadzie; Zhang, Xueyi; Zhang, Haifang; Wang, Huifang; Qiao, Zheng; Huang, Xinxiang

    2014-01-01

    Scientific experiments are indispensable parts of Biochemistry and Molecular Biology. In this study, a comprehensive Biochemistry and Molecular Biology experiment about "Salmonella enterica" serovar Typhi Flagellar phase variation has been designed. It consisted of three parts, namely, inducement of bacterial Flagellar phase variation,…

  5. Rotation Impact of Reed Switch

    International Nuclear Information System (INIS)

    Park, Yun Bum; Lee, Jae Seon; Kim, Jong Wook; Han, Eun Sil; Park, Hee June

    2016-01-01

    A CRDM (Control Rod Drive Mechanism) is an electromagnetic device which drives a control rod assembly linearly to regulate the reactivity of a nuclear core. A RPIS (Rod Position Indication System) is used as a position indicator of a control rod assembly for a CRDM of a nuclear reactor, SMART. A highly accurate RPIS for SMART is required because the reactivity of a nuclear core for a small modular reactor is more sensitive than the commercial ones. In this study, the effect of positioning direction of the reeds in a reed switch for the CRDM RPIS has been studied using the electromagnetic FE analysis. It is found that the positioning direction of the reeds slightly but not significantly affects the formation of attraction. Analysis results will be used as the basis on estimated accuracy of full RPIS system.

  6. Rotation Impact of Reed Switch

    Energy Technology Data Exchange (ETDEWEB)

    Park, Yun Bum; Lee, Jae Seon; Kim, Jong Wook [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Han, Eun Sil [Taesung S and E, Seoul (Korea, Republic of); Park, Hee June [Woojin Inc., Hwaseong (Korea, Republic of)

    2016-10-15

    A CRDM (Control Rod Drive Mechanism) is an electromagnetic device which drives a control rod assembly linearly to regulate the reactivity of a nuclear core. A RPIS (Rod Position Indication System) is used as a position indicator of a control rod assembly for a CRDM of a nuclear reactor, SMART. A highly accurate RPIS for SMART is required because the reactivity of a nuclear core for a small modular reactor is more sensitive than the commercial ones. In this study, the effect of positioning direction of the reeds in a reed switch for the CRDM RPIS has been studied using the electromagnetic FE analysis. It is found that the positioning direction of the reeds slightly but not significantly affects the formation of attraction. Analysis results will be used as the basis on estimated accuracy of full RPIS system.

  7. Very high plasma switches. Basic plasma physics and switch technology

    International Nuclear Information System (INIS)

    Doucet, H.J.; Roche, M.; Buzzi, J.M.

    1988-01-01

    A review of some high power switches recently developed for very high power technology is made with a special attention to the aspects of plasma physics involved in the mechanisms, which determine the limits of the possible switching parameters

  8. Ultrafast gas switching experiments

    International Nuclear Information System (INIS)

    Frost, C.A.; Martin, T.H.; Patterson, P.E.; Rinehart, L.F.; Rohwein, G.J.; Roose, L.D.; Aurand, J.F.; Buttram, M.T.

    1993-01-01

    We describe recent experiments which studied the physics of ultrafast gas breakdown under the extreme overvoltages which occur when a high pressure gas switch is pulse charged to hundreds of kV in 1 ns or less. The highly overvolted peaking gaps produce powerful electromagnetic pulses with risetimes Khz at > 100 kV/m E field

  9. An integrated circuit switch

    Science.gov (United States)

    Bonin, E. L.

    1969-01-01

    Multi-chip integrated circuit switch consists of a GaAs photon-emitting diode in close proximity with S1 phototransistor. A high current gain is obtained when the transistor has a high forward common-emitter current gain.

  10. The Octopus switch

    NARCIS (Netherlands)

    Havinga, Paul J.M.

    2000-01-01

    This chapter1 discusses the interconnection architecture of the Mobile Digital Companion. The approach to build a low-power handheld multimedia computer presented here is to have autonomous, reconfigurable modules such as network, video and audio devices, interconnected by a switch rather than by a

  11. Untriggered water switching

    International Nuclear Information System (INIS)

    Van Devender, J.P.; Martin, T.H.

    Recent experiments indicate that synchronous untriggered multichannel switching in water will permit the development of relatively simple, ultra-low impedance, short pulse, relativistic electron beam (REB) accelerators. These experiments resulted in the delivery of a 1.5 MV, 0.75 MA, 15 ns pulse into a two-ohm line with a current risetime of 2 x 10 14 A/sec. The apparatus consisted of a 3 MV Marx generator and a series of three 112 cm wide strip water lines separated by two edge-plane water-gap switches. The Marx generator charged the first line in less than 400 ns. The first switch then formed five or more channels. The second line was charged in 60 ns and broke down with 10 to 25 channels at a mean field of 1.6 MV/cm. The closure time of each spark channel along both switches was measured with a streak camera and showed low jitter. The resulting fast pulse line construction is simpler and should provide considerable costs savings from previous designs. Multiples of these low impedance lines in parallel can be employed to obtain power levels in the 10 14 W range for REB fusion studies. (U.S.)

  12. Optical processes in the performance and recovery of gas-phase switches

    International Nuclear Information System (INIS)

    Gundersen, M.

    1982-01-01

    In this paper several optical processes that may be used to affect gas-phase switch performance and operation are discussed, and approaches using a laser to increase recovery rates of switches are presented. In the latter the laser is used during the recovery phase rather than the conductive or closure phase. This papper suggests that it should be possible to use a low-power laser (e.g., one that is technologically feasible to use as part of a switch) to assist in opening the switch by quenching excited atomic and/or molecular species. The application of laser-induced energy extraction to gas-phase switches is also discussed

  13. Denoising of genetic switches based on Parrondo's paradox

    Science.gov (United States)

    Fotoohinasab, Atiyeh; Fatemizadeh, Emad; Pezeshk, Hamid; Sadeghi, Mehdi

    2018-03-01

    Random decision making in genetic switches can be modeled as tossing a biased coin. In other word, each genetic switch can be considered as a game in which the reactive elements compete with each other to increase their molecular concentrations. The existence of a very small number of reactive element molecules has caused the neglect of effects of noise to be inevitable. Noise can lead to undesirable cell fate in cellular differentiation processes. In this paper, we study the robustness to noise in genetic switches by considering another switch to have a new gene regulatory network (GRN) in which both switches have been affected by the same noise and for this purpose, we will use Parrondo's paradox. We introduce two networks of games based on possible regulatory relations between genes. Our results show that the robustness to noise can increase by combining these noisy switches. We also describe how one of the switches in network II can model lysis/lysogeny decision making of bacteriophage lambda in Escherichia coli and we change its fate by another switch.

  14. Control synthesis of switched systems

    CERN Document Server

    Zhao, Xudong; Niu, Ben; Wu, Tingting

    2017-01-01

    This book offers its readers a detailed overview of the synthesis of switched systems, with a focus on switching stabilization and intelligent control. The problems investigated are not only previously unsolved theoretically but also of practical importance in many applications: voltage conversion, naval piloting and navigation and robotics, for example. The book considers general switched-system models and provides more efficient design methods to bring together theory and application more closely than was possible using classical methods. It also discusses several different classes of switched systems. For general switched linear systems and switched nonlinear systems comprising unstable subsystems, it introduces novel ideas such as invariant subspace theory and the time-scheduled Lyapunov function method of designing switching signals to stabilize the underlying systems. For some typical switched nonlinear systems affected by various complex dynamics, the book proposes novel design approaches based on inte...

  15. Synchronization Between Two Different Switched Chaotic Systems By Switching Control

    Directory of Open Access Journals (Sweden)

    Du Li Ming

    2016-01-01

    Full Text Available This paper is concerned with the synchronization problem of two different switched chaotic systems, considering the general case that the master-slave switched chaotic systems have uncertainties. Two basic problems are considered: one is projective synchronization of switched chaotic systems under arbitrary switching; the other is projective synchronization of switched chaotic systems by design of switching when synchronization cannot achieved by using any subsystems alone. For the two problems, common Lyapunov function method and multiple Lyapunov function method are used respectively, an adaptive control scheme has been presented, some sufficient synchronization conditions are attainted, and the switching signal is designed. Finally, the numerical simulation is provide to show the effectiveness of our method.

  16. Immunoglobulin class-switch recombination deficiencies.

    Science.gov (United States)

    Durandy, Anne; Kracker, Sven

    2012-07-30

    Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches.

  17. Robust mitotic entry is ensured by a latching switch

    Directory of Open Access Journals (Sweden)

    Chloe Tuck

    2013-07-01

    Cell cycle events are driven by Cyclin dependent kinases (CDKs and by their counter-acting phosphatases. Activation of the Cdk1:Cyclin B complex during mitotic entry is controlled by the Wee1/Myt1 inhibitory kinases and by Cdc25 activatory phosphatase, which are themselves regulated by Cdk1:Cyclin B within two positive circuits. Impairing these two feedbacks with chemical inhibitors induces a transient entry into M phase referred to as mitotic collapse. The pathology of mitotic collapse reveals that the positive circuits play a significant role in maintaining the M phase state. To better understand the function of these feedback loops during G2/M transition, we propose a simple model for mitotic entry in mammalian cells including spatial control over Greatwall kinase phosphorylation. After parameter calibration, the model is able to recapture the complex and non-intuitive molecular dynamics reported by Potapova et al. (Potapova et al., 2011. Moreover, it predicts the temporal patterns of other mitotic regulators which have not yet been experimentally tested and suggests a general design principle of cell cycle control: latching switches buffer the cellular stresses which accompany cell cycle processes to ensure that the transitions are smooth and robust.

  18. Robust mitotic entry is ensured by a latching switch.

    Science.gov (United States)

    Tuck, Chloe; Zhang, Tongli; Potapova, Tamara; Malumbres, Marcos; Novák, Béla

    2013-01-01

    Cell cycle events are driven by Cyclin dependent kinases (CDKs) and by their counter-acting phosphatases. Activation of the Cdk1:Cyclin B complex during mitotic entry is controlled by the Wee1/Myt1 inhibitory kinases and by Cdc25 activatory phosphatase, which are themselves regulated by Cdk1:Cyclin B within two positive circuits. Impairing these two feedbacks with chemical inhibitors induces a transient entry into M phase referred to as mitotic collapse. The pathology of mitotic collapse reveals that the positive circuits play a significant role in maintaining the M phase state. To better understand the function of these feedback loops during G2/M transition, we propose a simple model for mitotic entry in mammalian cells including spatial control over Greatwall kinase phosphorylation. After parameter calibration, the model is able to recapture the complex and non-intuitive molecular dynamics reported by Potapova et al. (Potapova et al., 2011). Moreover, it predicts the temporal patterns of other mitotic regulators which have not yet been experimentally tested and suggests a general design principle of cell cycle control: latching switches buffer the cellular stresses which accompany cell cycle processes to ensure that the transitions are smooth and robust.

  19. Physical chemistry: Molecular motion watched

    Science.gov (United States)

    Siwick, Bradley; Collet, Eric

    2013-04-01

    A laser pulse can switch certain crystals from an insulating phase to a highly conducting phase. The ultrafast molecular motions that drive the transition have been directly observed using electron diffraction. See Letter p.343

  20. Iaverage current mode (ACM) control for switching power converters

    OpenAIRE

    2014-01-01

    Providing a fast current sensor direct feedback path to a modulator for controlling switching of a switched power converter in addition to an integrating feedback path which monitors average current for control of a modulator provides fast dynamic response consistent with system stability and average current mode control. Feedback of output voltage for voltage regulation can be combined with current information in the integrating feedback path to limit bandwidth of the voltage feedback signal.

  1. Laser activated superconducting switch

    International Nuclear Information System (INIS)

    Wolf, A.A.

    1976-01-01

    A superconducting switch or bistable device is described consisting of a superconductor in a cryogen maintaining a temperature just below the transition temperature, having a window of the proper optical frequency band for passing a laser beam which may impinge on the superconductor when desired. The frequency of the laser is equal to or greater than the optical absorption frequency of the superconducting material and is consistent with the ratio of the gap energy of the switch material to Planck's constant, to cause depairing of electrons, and thereby normalize the superconductor. Some embodiments comprise first and second superconducting metals. Other embodiments feature the two superconducting metals separated by a thin film insulator through which the superconducting electrons tunnel during superconductivity

  2. Optical fiber switch

    Science.gov (United States)

    Early, James W.; Lester, Charles S.

    2002-01-01

    Optical fiber switches operated by electrical activation of at least one laser light modulator through which laser light is directed into at least one polarizer are used for the sequential transport of laser light from a single laser into a plurality of optical fibers. In one embodiment of the invention, laser light from a single excitation laser is sequentially transported to a plurality of optical fibers which in turn transport the laser light to separate individual remotely located laser fuel ignitors. The invention can be operated electro-optically with no need for any mechanical or moving parts, or, alternatively, can be operated electro-mechanically. The invention can be used to switch either pulsed or continuous wave laser light.

  3. Coulomb Blockade Plasmonic Switch.

    Science.gov (United States)

    Xiang, Dao; Wu, Jian; Gordon, Reuven

    2017-04-12

    Tunnel resistance can be modulated with bias via the Coulomb blockade effect, which gives a highly nonlinear response current. Here we investigate the optical response of a metal-insulator-nanoparticle-insulator-metal structure and show switching of a plasmonic gap from insulator to conductor via Coulomb blockade. By introducing a sufficiently large charging energy in the tunnelling gap, the Coulomb blockade allows for a conductor (tunneling) to insulator (capacitor) transition. The tunnelling electrons can be delocalized over the nanocapacitor again when a high energy penalty is added with bias. We demonstrate that this has a huge impact on the plasmonic resonance of a 0.51 nm tunneling gap with ∼70% change in normalized optical loss. Because this structure has a tiny capacitance, there is potential to harness the effect for high-speed switching.

  4. Cryogenic switched MOSFET characterization

    Science.gov (United States)

    1981-01-01

    Both p channel and n channel enhancement mode MOSFETs can be readily switched on and off at temperatures as low as 2.8 K so that switch sampled readout of a VLWIR Ge:Ga focal plane is electronically possible. Noise levels as low as 100 rms electrons per sample (independent of sample rate) can be achieved using existing p channel MOSFETs, at overall rates up to 30,000 samples/second per multiplexed channel (e.g., 32 detectors at a rate of almost 1,000 frames/second). Run of the mill devices, including very low power dissipation n channel FETs would still permit noise levels of the order of 500 electrons/sample.

  5. Composite Material Switches

    Science.gov (United States)

    Javadi, Hamid (Inventor)

    2002-01-01

    A device to protect electronic circuitry from high voltage transients is constructed from a relatively thin piece of conductive composite sandwiched between two conductors so that conduction is through the thickness of the composite piece. The device is based on the discovery that conduction through conductive composite materials in this configuration switches to a high resistance mode when exposed to voltages above a threshold voltage.

  6. MCT/MOSFET Switch

    Science.gov (United States)

    Rippel, Wally E.

    1990-01-01

    Metal-oxide/semiconductor-controlled thyristor (MCT) and metal-oxide/semiconductor field-effect transistor (MOSFET) connected in switching circuit to obtain better performance. Offers high utilization of silicon, low forward voltage drop during "on" period of operating cycle, fast turnon and turnoff, and large turnoff safe operating area. Includes ability to operate at high temperatures, high static blocking voltage, and ease of drive.

  7. Python Switch Statement

    Directory of Open Access Journals (Sweden)

    2008-06-01

    Full Text Available The Python programming language does not have a built in switch/case control structure as found in many other high level programming languages. It is thought by some that this is a deficiency in the language, and the control structure should be added. This paper demonstrates that not only is the control structure not needed, but that the methods available in Python are more expressive than built in case statements in other high level languages.

  8. Single-Molecule Rotational Switch on a Dangling Bond Dimer Bearing.

    Science.gov (United States)

    Godlewski, Szymon; Kawai, Hiroyo; Kolmer, Marek; Zuzak, Rafał; Echavarren, Antonio M; Joachim, Christian; Szymonski, Marek; Saeys, Mark

    2016-09-27

    One of the key challenges in the construction of atomic-scale circuits and molecular machines is to design molecular rotors and switches by controlling the linear or rotational movement of a molecule while preserving its intrinsic electronic properties. Here, we demonstrate both the continuous rotational switching and the controlled step-by-step single switching of a trinaphthylene molecule adsorbed on a dangling bond dimer created on a hydrogen-passivated Ge(001):H surface. The molecular switch is on-surface assembled when the covalent bonds between the molecule and the dangling bond dimer are controllably broken, and the molecule is attached to the dimer by long-range van der Waals interactions. In this configuration, the molecule retains its intrinsic electronic properties, as confirmed by combined scanning tunneling microscopy/spectroscopy (STM/STS) measurements, density functional theory calculations, and advanced STM image calculations. Continuous switching of the molecule is initiated by vibronic excitations when the electrons are tunneling through the lowest unoccupied molecular orbital state of the molecule. The switching path is a combination of a sliding and rotation motion over the dangling bond dimer pivot. By carefully selecting the STM conditions, control over discrete single switching events is also achieved. Combined with the ability to create dangling bond dimers with atomic precision, the controlled rotational molecular switch is expected to be a crucial building block for more complex surface atomic-scale devices.

  9. Environmental regulation of plant gene expression: an RT-qPCR laboratory project for an upper-level undergraduate biochemistry or molecular biology course.

    Science.gov (United States)

    Eickelberg, Garrett J; Fisher, Alison J

    2013-01-01

    We present a novel laboratory project employing "real-time" RT-qPCR to measure the effect of environment on the expression of the FLOWERING LOCUS C gene, a key regulator of floral timing in Arabidopsis thaliana plants. The project requires four 3-hr laboratory sessions and is aimed at upper-level undergraduate students in biochemistry or molecular biology courses. The project provides students with hands-on experience with RT-qPCR, the current "gold standard" for gene expression analysis, including detailed data analysis using the common 2-ΔΔCT method. Moreover, it provides a convenient starting point for many inquiry-driven projects addressing diverse questions concerning ecological biochemistry, naturally occurring genetic variation, developmental biology, and the regulation of gene expression in nature. Copyright © 2013 Wiley Periodicals, Inc.

  10. All-electric-controlled spin current switching in single-molecule magnet-tunnel junctions

    Science.gov (United States)

    Zhang, Zheng-Zhong; Shen, Rui; Sheng, Li; Wang, Rui-Qiang; Wang, Bai-Gen; Xing, Ding-Yu

    2011-04-01

    A single-molecule magnet (SMM) coupled to two normal metallic electrodes can both switch spin-up and spin-down electronic currents within two different windows of SMM gate voltage. Such spin current switching in the SMM tunnel junction arises from spin-selected single electron resonant tunneling via the lowest unoccupied molecular orbit of the SMM. Since it is not magnetically controlled but all-electrically controlled, the proposed spin current switching effect may have potential applications in future spintronics.

  11. Molecular sensors and molecular logic gates

    International Nuclear Information System (INIS)

    Georgiev, N.; Bojinov, V.

    2013-01-01

    Full text: The rapid grow of nanotechnology field extended the concept of a macroscopic device to the molecular level. Because of this reason the design and synthesis of (supra)-molecular species capable of mimicking the functions of macroscopic devices are currently of great interest. Molecular devices operate via electronic and/or nuclear rearrangements and, like macroscopic devices, need energy to operate and communicate between their elements. The energy needed to make a device work can be supplied as chemical energy, electrical energy, or light. Luminescence is one of the most useful techniques to monitor the operation of molecular-level devices. This fact determinates the synthesis of novel fluorescence compounds as a considerable and inseparable part of nanoscience development. Further miniaturization of semiconductors in electronic field reaches their limit. Therefore the design and construction of molecular systems capable of performing complex logic functions is of great scientific interest now. In semiconductor devices the logic gates work using binary logic, where the signals are encoded as 0 and 1 (low and high current). This process is executable on molecular level by several ways, but the most common are based on the optical properties of the molecule switches encoding the low and high concentrations of the input guest molecules and the output fluorescent intensities with binary 0 and 1 respectively. The first proposal to execute logic operations at the molecular level was made in 1988, but the field developed only five years later when the analogy between molecular switches and logic gates was experimentally demonstrated by de Silva. There are seven basic logic gates: AND, OR, XOR, NOT, NAND, NOR and XNOR and all of them were achieved by molecules, the fluorescence switching as well. key words: fluorescence, molecular sensors, molecular logic gates

  12. A density-dependent switch drives stochastic clustering and polarization of signaling molecules.

    Directory of Open Access Journals (Sweden)

    Alexandra Jilkine

    2011-11-01

    Full Text Available Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered "off" state is desired? And, what limits the spread of clusters when an "on" state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off; above this threshold, highly localized clusters are recurrently generated. Clustering occurs only in the stochastic regime, suggesting that finite sizes of molecular populations cannot be ignored in signal transduction networks. The emergence of a dominant cluster for finite numbers of molecules is partly a phenomenon of random sampling, analogous to the fixation or loss of neutral mutations in finite populations. We refer to our model as the "neutral drift polarity model." Regulating the density of signaling molecules provides a simple mechanism for a positive feedback circuit to robustly switch between clustered and un-clustered states. The intrinsic ability of positive feedback both to create and suppress clustering is a general mechanism that could operate within diverse biological networks to create dynamic spatial organization.

  13. Activator Protein-1: redox switch controlling structure and DNA-binding

    Energy Technology Data Exchange (ETDEWEB)

    Yin, Zhou; Machius, Mischa; Nestler, Eric J.; Rudenko, Gabby (Texas-MED); (Icahn)

    2017-09-07

    The transcription factor, activator protein-1 (AP-1), binds to cognate DNA under redox control; yet, the underlying mechanism has remained enigmatic. A series of crystal structures of the AP-1 FosB/JunD bZIP domains reveal ordered DNA-binding regions in both FosB and JunD even in absence DNA. However, while JunD is competent to bind DNA, the FosB bZIP domain must undergo a large conformational rearrangement that is controlled by a ‘redox switch’ centered on an inter-molecular disulfide bond. Solution studies confirm that FosB/JunD cannot undergo structural transition and bind DNA when the redox-switch is in the ‘OFF’ state, and show that the mid-point redox potential of the redox switch affords it sensitivity to cellular redox homeostasis. The molecular and structural studies presented here thus reveal the mechanism underlying redox-regulation of AP-1 Fos/Jun transcription factors and provide structural insight for therapeutic interventions targeting AP-1 proteins.

  14. A chemical biology approach to interrogate quorum-sensing regulated behaviors at the molecular and cellular level.

    Science.gov (United States)

    Lowery, Colin A; Matamouros, Susana; Niessen, Sherry; Zhu, Jie; Scolnick, Jonathan; Lively, Jenny M; Cravatt, Benjamin F; Miller, Samuel I; Kaufmann, Gunnar F; Janda, Kim D

    2013-07-25

    Small molecule probes have been used extensively to explore biologic systems and elucidate cellular signaling pathways. In this study, we use an inhibitor of bacterial communication to monitor changes in the proteome of Salmonella enterica serovar Typhimurium with the aim of discovering unrecognized processes regulated by AI-2-based quorum-sensing (QS), a mechanism of bacterial intercellular communication that allows for the coordination of gene expression in a cell density-dependent manner. In S. typhimurium, this system regulates the uptake and catabolism of intercellular signals and has been implicated in pathogenesis, including the invasion of host epithelial cells. We demonstrate that our QS antagonist is capable of selectively inhibiting the expression of known QS-regulated proteins in S. typhimurium, thus attesting that QS inhibitors may be used to confirm proposed and elucidate previously unidentified QS pathways without relying on genetic manipulation. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Impact analysis of tap switch out of step for converter transformer

    Science.gov (United States)

    Hong-yue, ZHANG; Zhen-hua, ZHANG; Zhang-xue, XIONG; Gao-wang, YU

    2017-06-01

    AC transformer load regulation is mainly used to adjust the load side voltage level, improve the quality of power supply, the voltage range is relatively narrow. In DC system, converter transformer is the core equipment of AC and DC power converter and inverter. converter transformer tap adjustment can maintain the normal operation of the converter in small angle range control, the absorption of reactive power, economic operation, valve less stress, valve damping circuit loss, AC / DC harmonic component is also smaller. In this way, the tap switch action is more frequent, and a large range of the tap switch adjustment is required. Converter transformer with a more load voltage regulation switch, the voltage regulation range of the switch is generally 20~30%, the adjustment of each file is 1%~2%. Recently it is often found that the tap switch of Converter Transformers is out of step in Converter station. In this paper, it is analyzed in detail the impact of tap switch out of step for differential protection, overexcitation protection and zero sequence over current protection. Analysis results show that: the tap switch out of step has no effect on the differential protection and the overexcitation protection including the tap switch. But the tap switch out of step has effect on zero sequence overcurrent protection of out of step star-angle converter transformer. The zero sequence overcurrent protection will trip when the tap switch out of step is greater than 3 for out of step star-angle converter transformer.

  16. Switched Control Strategies of Aggregated Commercial HVAC Systems for Demand Response in Smart Grids

    Directory of Open Access Journals (Sweden)

    Kai Ma

    2017-07-01

    Full Text Available This work proposes three switched control strategies for aggregated heating, ventilation, and air conditioning (HVAC systems in commercial buildings to track the automatic generation control (AGC signal in smart grid. The existing control strategies include the direct load control strategy and the setpoint regulation strategy. The direct load control strategy cannot track the AGC signal when the state of charge (SOC of the aggregated thermostatically controlled loads (TCLs exceeds their regulation capacity, while the setpoint regulation strategy provides flexible regulation capacity, but causes larger tracking errors. To improve the tracking performance, we took the advantages of the two control modes and developed three switched control strategies. The control strategies switch between the direct load control mode and the setpoint regulation mode according to different switching indices. Specifically, we design a discrete-time controller and optimize the controller parameter for the setpoint regulation strategy using the Fibonacci optimization algorithm, enabling us to propose two switched control strategies across multiple time steps. Furthermore, we extend the switched control strategies by introducing a two-stage regulation in a single time step. Simulation results demonstrate that the proposed switched control strategies can reduce the tracking errors for frequency regulation.

  17. The AMPK enzyme-complex: from the regulation of cellular energy homeostasis to a possible new molecular target in the management of chronic inflammatory disorders.

    Science.gov (United States)

    Antonioli, Luca; Colucci, Rocchina; Pellegrini, Carolina; Giustarini, Giulio; Sacco, Deborah; Tirotta, Erika; Caputi, Valentina; Marsilio, Ilaria; Giron, Maria Cecilia; Németh, Zoltán H; Blandizzi, Corrado; Fornai, Matteo

    2016-01-01

    Adenosine monophosphate-activated protein kinase (AMPK), known as an enzymatic complex that regulates the energetic metabolism, is emerging as a pivotal enzyme and enzymatic pathway involved in the regulation of immune homeostatic networks. It is also involved in the molecular mechanisms underlying the pathophysiology of chronic inflammatory diseases. AMPK is expressed in several immune cell types including macrophages, lymphocytes, neutrophils and dendritic cells, and governs a broad array of cell functions, which include cytokine production, chemotaxis, cytotoxicity, apoptosis and proliferation. Based on its wide variety of immunoregulatory actions, the AMPK system has been targeted to reveal its impact on the course of immune-related diseases, such as atherosclerosis, psoriasis, joint inflammation and inflammatory bowel diseases. The identification of AMPK subunits responsible for specific anti-inflammatory actions and the understanding of the underlying molecular mechanisms will promote the generation of novel AMPK activators, endowed with improved pharmacodynamic and pharmacokinetic profiles. These new tools will aid us to utilize AMPK pathway activation in the management of acute and chronic inflammatory diseases, while minimizing potential adverse reactions related to the effects of AMPK on metabolic energy.

  18. Elucidating the Molecular Basis and Regulation of Chromium(VI) Reduction by Shewanella oneidensis MR-1 and Resistance to Metal Toxicity Using Integrated Biochemical, Genomic and Proteomic Approaches

    Energy Technology Data Exchange (ETDEWEB)

    Dorothea K. Thompson; Robert Hettich

    2007-02-06

    Shewanella oneidensis MR-1 is a model environmental organism that possesses diverse respiratory capacities, including the ability to reduce soluble Cr(VI) to sparingly soluble, less toxic Cr(III). Chromate is a serious anthropogenic pollutant found in subsurface sediment and groundwater environments due to its widespread use in defense and industrial applications. Effective bioremediation of chromate-contaminated sites requires knowledge of the molecular mechanisms and regulation of heavy metal resistance and biotransformation by dissimilatory metal-reducing bacteria. Towards this goal, our ERSP-funded work was focused on the identification and functional analysis of genes/proteins comprising the response pathways for chromate detoxification and/or reduction. Our work utilized temporal transcriptomic profiling and whole-cell proteomic analyses to characterize the dynamic molecular response of MR-1 to an acute chromate shock (up to 90 min) as well as to a 24-h, low-dose exposure. In addition, we have examined the transcriptome of MR-1 cells actively engaged in chromate reduction. These studies implicated the involvement of a functionally undefined DNA-binding response regulator (SO2426) and a putative azoreductase (SO3585) in the chromate stress response of MR-1.

  19. A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation.

    Science.gov (United States)

    Sun, Jiaqi; Bonaguidi, Michael A; Jun, Heechul; Guo, Junjie U; Sun, Gerald J; Will, Brett; Yang, Zhengang; Jang, Mi-Hyeon; Song, Hongjun; Ming, Guo-li; Christian, Kimberly M

    2015-09-04

    A converging body of evidence indicates that levels of adult hippocampal neurogenesis vary along the septo-temporal axis of the dentate gyrus, but the molecular mechanisms underlying this regional heterogeneity are not known. We previously identified a niche mechanism regulating proliferation and neuronal development in the adult mouse dentate gyrus resulting from the activity-regulated expression of secreted frizzled-related protein 3 (sfrp3) by mature neurons, which suppresses activation of radial glia-like neural stem cells (RGLs) through inhibition of Wingless/INT (WNT) protein signaling. Here, we show that activation rates within the quiescent RGL population decrease gradually along the septo-temporal axis in the adult mouse dentate gyrus, as defined by MCM2 expression in RGLs. Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development. Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus. Our study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.

  20. Switching benefits and costs in the Irish health insurance market: an analysis of consumer surveys.

    Science.gov (United States)

    Keegan, Conor; Teljeur, Conor; Turner, Brian; Thomas, Steve

    2018-05-10

    Relatively little analysis has taken place internationally on the consumer-reported benefits and costs to switching insurer in multi-payer health insurance markets. Ideally, consumers should be willing to switch out of consideration for price and quality and switching should be able to take place without incurring significant switching costs. Costs to switching come in many forms and understanding the nature of these costs is necessary if policy interventions to improve market competition are to be successful. This study utilises data from consumer surveys of the Irish health insurance market collected between 2009 and 2013 (N [Formula: see text] 1703) to examine consumer-reported benefits and costs to switching insurer. Probit regression models are specified to examine the relationship between consumer characteristics and reported switching costs, and switching behaviour, respectively. Overall evidence suggests that switchers in the Irish market mainly did so out of consideration for price. Transaction cost was the most common switching cost identified, reported by just under 1 in 7 non-switchers. Psychological switching costs may also be impacting behaviour. Moreover, high-risk individuals were more likely to experience switching costs and this was reflected in actual switching behaviour. A recent information campaign launched by the market regulator may prove beneficial in reducing perceived transaction costs in the market, however, a more focused campaign aimed at high-risk consumers may be necessary to reduce inequalities. Policy-makers should also consider the impact insurer behaviour may have on decision-making.

  1. MiR-155-regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis.

    Science.gov (United States)

    Rothchild, Alissa C; Sissons, James R; Shafiani, Shahin; Plaisier, Christopher; Min, Deborah; Mai, Dat; Gilchrist, Mark; Peschon, Jacques; Larson, Ryan P; Bergthaler, Andreas; Baliga, Nitin S; Urdahl, Kevin B; Aderem, Alan

    2016-10-11

    The regulation of host-pathogen interactions during Mycobacterium tuberculosis (Mtb) infection remains unresolved. MicroRNAs (miRNAs) are important regulators of the immune system, and so we used a systems biology approach to construct an miRNA regulatory network activated in macrophages during Mtb infection. Our network comprises 77 putative miRNAs that are associated with temporal gene expression signatures in macrophages early after Mtb infection. In this study, we demonstrate a dual role for one of these regulators, miR-155. On the one hand, miR-155 maintains the survival of Mtb-infected macrophages, thereby providing a niche favoring bacterial replication; on the other hand, miR-155 promotes the survival and function of Mtb-specific T cells, enabling an effective adaptive immune response. MiR-155-induced cell survival is mediated through the SH2 domain-containing inositol 5-phosphatase 1 (SHIP1)/protein kinase B (Akt) pathway. Thus, dual regulation of the same cell survival pathway in innate and adaptive immune cells leads to vastly different outcomes with respect to bacterial containment.

  2. Bistability in a Metabolic Network Underpins the De Novo Evolution of Colony Switching in Pseudomonas fluorescens

    DEFF Research Database (Denmark)

    Gallie, Jenna; Libby, Eric; Bertels, Frederic

    2015-01-01

    Phenotype switching is commonly observed in nature. This prevalence has allowed the elucidation of a number of underlying molecular mechanisms. However, little is known about how phenotypic switches arise and function in their early evolutionary stages. The first opportunity to provide empirical ...

  3. MENGAPA PERUSAHAAN MELAKUKAN AUDITOR SWITCH?

    Directory of Open Access Journals (Sweden)

    Kadek Sumadi

    2011-01-01

    Full Text Available The existence of a large number of accounting firms allowsprovides companies choices whether to stay with current firm or switchto another accounting firm. Decision of Minister of FinanceNo.423/KMK.06/2002 states that a company must switch auditor afterfive years of consecutive assignment. This is mandatory. The questionrises when a company voluntarily switches its auditor. Why does thishappen?One of the reasons is that management does not satisfy withauditor opinion, except for unqualified opinion. New management teamwould directly or indirectly encourage auditor switch to align accountingand reporting policies. Moreover an expanding company expects positivereaction when it does auditor switch. Profitability is also one reason fora company to switch auditor, for example, when a company earns moreprofit it tends to hire more credible auditor. On the other hand, when thecompany faces a financial distress, it probably would switch auditor aswell.

  4. Low-Crosstalk Composite Optical Crosspoint Switches

    Science.gov (United States)

    Pan, Jing-Jong; Liang, Frank

    1993-01-01

    Composite optical switch includes two elementary optical switches in tandem, plus optical absorbers. Like elementary optical switches, composite optical switches assembled into switch matrix. Performance enhanced by increasing number of elementary switches. Advantage of concept: crosstalk reduced to acceptably low level at moderate cost of doubling number of elementary switches rather than at greater cost of tightening manufacturing tolerances and exerting more-precise control over operating conditions.

  5. Compound semiconductor optical waveguide switch

    Science.gov (United States)

    Spahn, Olga B.; Sullivan, Charles T.; Garcia, Ernest J.

    2003-06-10

    An optical waveguide switch is disclosed which is formed from III-V compound semiconductors and which has a moveable optical waveguide with a cantilevered portion that can be bent laterally by an integral electrostatic actuator to route an optical signal (i.e. light) between the moveable optical waveguide and one of a plurality of fixed optical waveguides. A plurality of optical waveguide switches can be formed on a common substrate and interconnected to form an optical switching network.

  6. Neuromorphic atomic switch networks.

    Directory of Open Access Journals (Sweden)

    Audrius V Avizienis

    Full Text Available Efforts to emulate the formidable information processing capabilities of the brain through neuromorphic engineering have been bolstered by recent progress in the fabrication of nonlinear, nanoscale circuit elements that exhibit synapse-like operational characteristics. However, conventional fabrication techniques are unable to efficiently generate structures with the highly complex interconnectivity found in biological neuronal networks. Here we demonstrate the physical realization of a self-assembled neuromorphic device which implements basic concepts of systems neuroscience through a hardware-based platform comprised of over a billion interconnected atomic-switch inorganic synapses embedded in a complex network of silver nanowires. Observations of network activation and passive harmonic generation demonstrate a collective response to input stimulus in agreement with recent theoretical predictions. Further, emergent behaviors unique to the complex network of atomic switches and akin to brain function are observed, namely spatially distributed memory, recurrent dynamics and the activation of feedforward subnetworks. These devices display the functional characteristics required for implementing unconventional, biologically and neurally inspired computational methodologies in a synthetic experimental system.

  7. Recent developments in switching theory

    CERN Document Server

    Mukhopadhyay, Amar

    2013-01-01

    Electrical Science Series: Recent Developments in Switching Theory covers the progress in the study of the switching theory. The book discusses the simplified proof of Post's theorem on completeness of logic primitives; the role of feedback in combinational switching circuits; and the systematic procedure for the design of Lupanov decoding networks. The text also describes the classical results on counting theorems and their application to the classification of switching functions under different notions of equivalence, including linear and affine equivalences. The development of abstract har

  8. Software Switching for Data Acquisition

    CERN Multimedia

    CERN. Geneva; Malone, David

    2016-01-01

    In this talk we discuss the feasibility of replacing telecom-class routers with a topology of commodity servers acting as software switches in data acquisition. We extend the popular software switch, Open vSwitch, with a dedicated, throughput-oriented buffering mechanism. We compare the performance under heavy many-to-one congestion to typical Ethernet switches and evaluate the scalability when building larger topologies, exploiting the integration with software-defined networking technologies. Please note that David Malone will speak on behalf of Grzegorz Jereczek.

  9. Photochromic systems as models for opto-electrical switches

    Czech Academy of Sciences Publication Activity Database

    Lutsyk, P.; Sworakowski, J.; Janus, K.; Nešpůrek, Stanislav; Kochalska, Anna

    2010-01-01

    Roč. 522, - (2010), s. 511-528 ISSN 1542-1406 R&D Projects: GA AV ČR KAN401770651 Institutional research plan: CEZ:AV0Z40500505 Keywords : charge carrier transport * molecular material * opto-electrical switch Subject RIV: JA - Electronics ; Optoelectronics, Electrical Engineering Impact factor: 0.543, year: 2010

  10. Experimental Studies of the Molecular Pathways Regulated by Exercise and Resveratrol in Heart, Skeletal Muscle and the Vasculature

    Directory of Open Access Journals (Sweden)

    Vernon W. Dolinsky

    2014-09-01

    Full Text Available Regular exercise contributes to healthy aging and the prevention of chronic disease. Recent research has focused on the development of molecules, such as resveratrol, that activate similar metabolic and stress response pathways as exercise training. In this review, we describe the effects of exercise training and resveratrol on some of the organs and tissues that act in concert to transport oxygen throughout the body. In particular, we focus on animal studies that investigate the molecular signaling pathways induced by these interventions. We also compare and contrast the effects of exercise and resveratrol in diseased states.

  11. Ferroelectric Polarization Switching Dynamics and Domain Growth of Triglycine Sulfate and Imidazolium Perchlorate

    KAUST Repository

    Ma, He; Gao, Wenxiu; Wang, Junling; Wu, Tao; Yuan, Guoliang; Liu, Junming; Liu, Zhiguo

    2016-01-01

    The weak bond energy and large anisotropic domain wall energy induce many special characteristics of the domain nucleation, growth, and polarization switch in triglycine sulfate (TGS) and imidazolium perchlorate (IM), two typical molecular

  12. Hybrid switch for resonant power converters

    Science.gov (United States)

    Lai, Jih-Sheng; Yu, Wensong

    2014-09-09

    A hybrid switch comprising two semiconductor switches connected in parallel but having different voltage drop characteristics as a function of current facilitates attainment of zero voltage switching and reduces conduction losses to complement reduction of switching losses achieved through zero voltage switching in power converters such as high-current inverters.

  13. LCT protective dump-switch tests

    International Nuclear Information System (INIS)

    Parsons, W.M.

    1981-01-01

    Each of the six coils in the Large Coil Task (LCT) has a separate power supply, dump resistor, and switching circuit. Each switching circuit contains five switches, two of which are redundant. The three remaining switches perform separate duties in an emergency dump situation. These three switches were tested to determine their ability to meet the LCT conditions

  14. Second-chance signal transduction explains cooperative flagellar switching.

    Science.gov (United States)

    Zot, Henry G; Hasbun, Javier E; Minh, Nguyen Van

    2012-01-01

    The reversal of flagellar motion (switching) results from the interaction between a switch complex of the flagellar rotor and a torque-generating stationary unit, or stator (motor unit). To explain the steeply cooperative ligand-induced switching, present models propose allosteric interactions between subunits of the rotor, but do not address the possibility of a reaction that stimulates a bidirectional motor unit to reverse direction of torque. During flagellar motion, the binding of a ligand-bound switch complex at the dwell site could excite a motor unit. The probability that another switch complex of the rotor, moving according to steady-state rotation, will reach the same dwell site before that motor unit returns to ground state will be determined by the independent decay rate of the excited-state motor unit. Here, we derive an analytical expression for the energy coupling between a switch complex and a motor unit of the stator complex of a flagellum, and demonstrate that this model accounts for the cooperative switching response without the need for allosteric interactions. The analytical result can be reproduced by simulation when (1) the motion of the rotor delivers a subsequent ligand-bound switch to the excited motor unit, thereby providing the excited motor unit with a second chance to remain excited, and (2) the outputs from multiple independent motor units are constrained to a single all-or-none event. In this proposed model, a motor unit and switch complex represent the components of a mathematically defined signal transduction mechanism in which energy coupling is driven by steady-state and is regulated by stochastic ligand binding. Mathematical derivation of the model shows the analytical function to be a general form of the Hill equation (Hill AV (1910) The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 40: iv-vii).

  15. Molecular, Biochemical, and Dietary Regulation Features of α-Amylase in a Carnivorous Crustacean, the Spiny Lobster Panulirus argus

    Science.gov (United States)

    Martos-Sitcha, Juan Antonio; Perdomo-Morales, Rolando; Casuso, Antonio; Montero-Alejo, Vivian; García-Galano, Tsai; Martínez-Rodríguez, Gonzalo; Mancera, Juan Miguel

    2016-01-01

    Alpha-amylases are ubiquitously distributed throughout microbials, plants and animals. It is widely accepted that omnivorous crustaceans have higher α-amylase activity and number of isoforms than carnivorous, but contradictory results have been obtained in some species, and carnivorous crustaceans have been less studied. In addition, the physiological meaning of α-amylase polymorphism in crustaceans is not well understood. In this work we studied α-amylase in a carnivorous lobster at the gene, transcript, and protein levels. It was showed that α-amylase isoenzyme composition (i.e., phenotype) in lobster determines carbohydrate digestion efficiency. Most frequent α-amylase phenotype has the lowest digestion efficiency, suggesting this is a favoured trait. We revealed that gene and intron loss have occurred in lobster α-amylase, thus lobsters express a single 1830 bp cDNA encoding a highly conserved protein with 513 amino acids. This protein gives rise to two isoenzymes in some individuals by glycosylation but not by limited proteolysis. Only the glycosylated isoenzyme could be purified by chromatography, with biochemical features similar to other animal amylases. High carbohydrate content in diet down-regulates α-amylase gene expression in lobster. However, high α-amylase activity occurs in lobster gastric juice irrespective of diet and was proposed to function as an early sensor of the carbohydrate content of diet to regulate further gene expression. We concluded that gene/isoenzyme simplicity, post-translational modifications and low Km, coupled with a tight regulation of gene expression, have arose during evolution of α-amylase in the carnivorous lobster to control excessive carbohydrate digestion in the presence of an active α-amylase. PMID:27391425

  16. Molecular, Biochemical, and Dietary Regulation Features of α-Amylase in a Carnivorous Crustacean, the Spiny Lobster Panulirus argus.

    Directory of Open Access Journals (Sweden)

    Leandro Rodríguez-Viera

    Full Text Available Alpha-amylases are ubiquitously distributed throughout microbials, plants and animals. It is widely accepted that omnivorous crustaceans have higher α-amylase activity and number of isoforms than carnivorous, but contradictory results have been obtained in some species, and carnivorous crustaceans have been less studied. In addition, the physiological meaning of α-amylase polymorphism in crustaceans is not well understood. In this work we studied α-amylase in a carnivorous lobster at the gene, transcript, and protein levels. It was showed that α-amylase isoenzyme composition (i.e., phenotype in lobster determines carbohydrate digestion efficiency. Most frequent α-amylase phenotype has the lowest digestion efficiency, suggesting this is a favoured trait. We revealed that gene and intron loss have occurred in lobster α-amylase, thus lobsters express a single 1830 bp cDNA encoding a highly conserved protein with 513 amino acids. This protein gives rise to two isoenzymes in some individuals by glycosylation but not by limited proteolysis. Only the glycosylated isoenzyme could be purified by chromatography, with biochemical features similar to other animal amylases. High carbohydrate content in diet down-regulates α-amylase gene expression in lobster. However, high α-amylase activity occurs in lobster gastric juice irrespective of diet and was proposed to function as an early sensor of the carbohydrate content of diet to regulate further gene expression. We concluded that gene/isoenzyme simplicity, post-translational modifications and low Km, coupled with a tight regulation of gene expression, have arose during evolution of α-amylase in the carnivorous lobster to control excessive carbohydrate digestion in the presence of an active α-amylase.

  17. Molecular, Biochemical, and Dietary Regulation Features of α-Amylase in a Carnivorous Crustacean, the Spiny Lobster Panulirus argus.

    Science.gov (United States)

    Rodríguez-Viera, Leandro; Perera, Erick; Martos-Sitcha, Juan Antonio; Perdomo-Morales, Rolando; Casuso, Antonio; Montero-Alejo, Vivian; García-Galano, Tsai; Martínez-Rodríguez, Gonzalo; Mancera, Juan Miguel

    2016-01-01

    Alpha-amylases are ubiquitously distributed throughout microbials, plants and animals. It is widely accepted that omnivorous crustaceans have higher α-amylase activity and number of isoforms than carnivorous, but contradictory results have been obtained in some species, and carnivorous crustaceans have been less studied. In addition, the physiological meaning of α-amylase polymorphism in crustaceans is not well understood. In this work we studied α-amylase in a carnivorous lobster at the gene, transcript, and protein levels. It was showed that α-amylase isoenzyme composition (i.e., phenotype) in lobster determines carbohydrate digestion efficiency. Most frequent α-amylase phenotype has the lowest digestion efficiency, suggesting this is a favoured trait. We revealed that gene and intron loss have occurred in lobster α-amylase, thus lobsters express a single 1830 bp cDNA encoding a highly conserved protein with 513 amino acids. This protein gives rise to two isoenzymes in some individuals by glycosylation but not by limited proteolysis. Only the glycosylated isoenzyme could be purified by chromatography, with biochemical features similar to other animal amylases. High carbohydrate content in diet down-regulates α-amylase gene expression in lobster. However, high α-amylase activity occurs in lobster gastric juice irrespective of diet and was proposed to function as an early sensor of the carbohydrate content of diet to regulate further gene expression. We concluded that gene/isoenzyme simplicity, post-translational modifications and low Km, coupled with a tight regulation of gene expression, have arose during evolution of α-amylase in the carnivorous lobster to control excessive carbohydrate digestion in the presence of an active α-amylase.

  18. Functional and molecular characterization of transmembrane intracellular pH regulators in human dental pulp stem cells.

    Science.gov (United States)

    Chen, Gunng-Shinng; Lee, Shiao-Pieng; Huang, Shu-Fu; Chao, Shih-Chi; Chang, Chung-Yi; Wu, Gwo-Jang; Li, Chung-Hsing; Loh, Shih-Hurng

    2018-06-01

    Homeostasis of intracellular pH (pH i ) plays vital roles in many cell functions, such as proliferation, apoptosis, differentiation and metastasis. Thus far, Na + -H + exchanger (NHE), Na + -HCO 3 - co-transporter (NBC), Cl - /HCO 3 - exchanger (AE) and Cl - /OH - exchanger (CHE) have been identified to co-regulate pH i homeostasis. However, functional and biological pH i -regulators in human dental pulp stem cells (hDPSCs) have yet to be identified. Microspectrofluorimetry technique with pH-sensitive fluorescent dye, BCECF, was used to detect pH i changes. NH 4 Cl and Na + -acetate pre-pulse were used to induce intracellular acidosis and alkalosis, respectively. Isoforms of pH i -regulators were detected by Western blot technique. The resting pH i was no significant difference between that in HEPES-buffered (nominal HCO 3 - -free) solution or CO 2 /HCO 3 -buffered system (7.42 and 7.46, respectively). The pH i recovery following the induced-intracellular acidosis was blocked completely by removing [Na + ] o , while only slowed (-63%) by adding HOE694 (a NHE1 specific inhibitor) in HEPES-buffered solution. The pH i recovery was inhibited entirely by removing [Na + ] o , while adding HOE 694 pulse DIDS (an anion-transporter inhibitor) only slowed (-55%) the acid extrusion. Both in HEPES-buffered and CO 2 /HCO 3 -buffered system solution, the pH i recovery after induced-intracellular alkalosis was entirely blocked by removing [Cl - ] o . Western blot analysis showed the isoforms of pH i regulators, including NHE1/2, NBCe1/n1, AE1/2/3/4 and CHE in the hDPSCs. We demonstrate for the first time that resting pH i is significantly higher than 7.2 and meditates functionally by two Na + -dependent acid extruders (NHE and NBC), two Cl - -dependent acid loaders (CHE and AE) and one Na + -independent acid extruder(s) in hDPSCs. These findings provide novel insight for basic and clinical treatment of dentistry. Copyright © 2018 Elsevier Ltd. All rights reserved.

  19. Circuit switched optical networks

    DEFF Research Database (Denmark)

    Kloch, Allan

    2003-01-01

    Some of the most important components required for enabling optical networking are investigated through both experiments and modelling. These all-optical components are the wavelength converter, the regenerator and the space switch. When these devices become "off-the-shelf" products, optical cross......, it is expected that the optical solution will offer an economical benefit for hight bit rate networks. This thesis begins with a discussion of the expected impact on communications systems from the rapidly growing IP traffic, which is expected to become the dominant source for traffic. IP traffic has some...... characteristics, which are best supported by an optical network. The interest for such an optical network is exemplified by the formation of the ACTS OPEN project which aim was to investigate the feasibility of an optical network covering Europe. Part of the work presented in this thesis is carried out within...

  20. Photo-switching element

    Energy Technology Data Exchange (ETDEWEB)

    Masaki, Yuichi

    1987-10-31

    Photo-input MOS transistor (Photo-switching element) cannot give enough ON/OFF ratio but requires an auxiliary condenser for a certain type of application. In addition, PN junction of amorphous silicon is not practical because it gives high leak current resulting in low electromotive force. In this invention, a solar cell was constructed with a lower electrode consisting of a transparent electro-conducting film, a photosensitive part consisting of an amorphous Si layer of p-i-n layer construction, and an upper metal electrode consisting of Cr or Nichrome, and a thin film transistor was placed on the solar cell, and further the upper metal electrode was co-used as a gate electrode of the thin film transistor; this set-up of this invention enabled to attain an efficient photo-electric conversion of the incident light, high electromotive force of the solar cell, and the transistor with high ON/OFF ratio. (3 figs)

  1. Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations.

    Directory of Open Access Journals (Sweden)

    Jo Meagan Garner

    Full Text Available Malignant glioblastoma (GBM is a highly aggressive brain tumor with a dismal prognosis and limited therapeutic options. Genomic profiling of GBM samples has identified four molecular subtypes (Proneural, Neural, Classical and Mesenchymal, which may arise from different glioblastoma stem-like cell (GSC populations. We previously showed that adherent cultures of GSCs grown on laminin-coated plates (Ad-GSCs and spheroid cultures of GSCs (Sp-GSCs had high expression of stem cell markers (CD133, Sox2 and Nestin, but low expression of differentiation markers (βIII-tubulin and glial fibrillary acid protein. In the present study, we characterized GBM tumors produced by subcutaneous and intracranial injection of Ad-GSCs and Sp-GSCs isolated from a patient-derived xenoline. Although they formed tumors with identical histological features, gene expression analysis revealed that xenografts of Sp-GSCs had a Classical molecular subtype similar to that of bulk tumor cells. In contrast xenografts of Ad-GSCs expressed a Mesenchymal gene signature. Adherent GSC-derived xenografts had high STAT3 and ANGPTL4 expression, and enrichment for stem cell markers, transcriptional networks and pro-angiogenic markers characteristic of the Mesenchymal subtype. Examination of clinical samples from GBM patients showed that STAT3 expression was directly correlated with ANGPTL4 expression, and that increased expression of these genes correlated with poor patient survival and performance. A pharmacological STAT3 inhibitor abrogated STAT3 binding to the ANGPTL4 promoter and exhibited anticancer activity in vivo. Therefore, Ad-GSCs and Sp-GSCs produced histologically identical tumors with different gene expression patterns, and a STAT3/ANGPTL4 pathway is identified in glioblastoma that may serve as a target for therapeutic intervention.

  2. Battery switch for downhole tools

    Science.gov (United States)

    Boling, Brian E.

    2010-02-23

    An electrical circuit for a downhole tool may include a battery, a load electrically connected to the battery, and at least one switch electrically connected in series with the battery and to the load. The at least one switch may be configured to close when a tool temperature exceeds a selected temperature.

  3. Improved switch-resistor packaging

    Science.gov (United States)

    Redmerski, R. E.

    1980-01-01

    Packaging approach makes resistors more accessible and easily identified with specific switches. Failures are repaired more quickly because of improved accessibility. Typical board includes one resistor that acts as circuit breaker, and others are positioned so that their values can be easily measured when switch is operated. Approach saves weight by using less wire and saves valuable panel space.

  4. Bone mineralization is regulated by signaling cross talk between molecular factors of local and systemic origin: the role of fibroblast growth factor 23.

    Science.gov (United States)

    Sapir-Koren, Rony; Livshits, Gregory

    2014-01-01

    Body phosphate homeostasis is regulated by a hormonal counter-balanced intestine-bone-kidney axis. The major systemic hormones involved in this axis are parathyroid hormone (PTH), 1,25-dihydroxyvitamin-D, and fibroblast growth factor-23 (FGF23). FGF23, produced almost exclusively by the osteocytes, is a phosphaturic hormone that plays a major role in regulation of the bone remodeling process. Remodeling composite components, bone mineralization and resorption cycles create a continuous influx-efflux loop of the inorganic phosphate (Pi) through the skeleton. This "bone Pi loop," which is formed, is controlled by local and systemic factors according to phosphate homeostasis demands. Although FGF23 systemic actions in the kidney, and for the production of PTH and 1,25-dihydroxyvitamin-D are well established, its direct involvement in bone metabolism is currently poorly understood. This review presents the latest available evidence suggesting two aspects of FGF23 bone local activity: (a) Regulation of FGF23 production by both local and systemic factors. The suggested local factors include extracellular levels of Pi and pyrophosphate (PPi), (the Pi/PPi ratio), and another osteocyte-derived protein, sclerostin. In addition, 1,25-dihydroxyvitamin-D, synthesized locally by bone cells, may contribute to regulation of FGF23 production. The systemic control is achieved via PTH and 1,25-dihydroxyvitamin-D endocrine functions. (b) FGF23 acts as a local agent, directly affecting bone mineralization. We support the assumption that under balanced physiological conditions, sclerostin, by para- autocrine signaling, upregulates FGF23 production by the osteocyte. FGF23, in turn, acts as a mineralization inhibitor, by stimulating the generation of the major mineralization antagonist-PPi. © 2014 International Union of Biochemistry and Molecular Biology.

  5. Schizothorax prenanti corticotropin-releasing hormone (CRH): molecular cloning, tissue expression, and the function of feeding regulation.

    Science.gov (United States)

    Wang, Tao; Zhou, Chaowei; Yuan, Dengyue; Lin, Fangjun; Chen, Hu; Wu, Hongwei; Wei, Rongbin; Xin, Zhiming; Liu, Ju; Gao, Yundi; Li, Zhiqiong

    2014-10-01

    Corticotropin-releasing hormone (CRH) is a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress. For a better understanding of the structure and function of the CRH gene and to study its effect on feeding regulation in cyprinid fish, the cDNA of the CRH gene from the brain of Schizothorax prenanti was cloned and sequenced. The full-length CRH cDNA consisted of 1,046 bp with an open reading frame of 489 bp encoding a protein of 162 amino acids. Real-time quantitative PCR analyses revealed that CRH was widely expressed in central and peripheral tissues. In particular, high expression level of CRH was detected in brain. Furthermore, CRH mRNA expression was examined in different brain regions, especially high in hypothalamus. In addition, there was no significant change in CRH mRNA expression in fed group compared with the fasted group in the S. prenanti hypothalamus during short-term fasting. However, CRH gene expression presented significant decrease in the hypothalamus in fasted group compared with the fed group (P < 0.05) on day 7; thereafter, re-feeding could lead to a significant increase in CRH mRNA expression in fasted group on day 9. The results suggest that the CRH may play a critical role in feeding regulation in S. prenanti.

  6. Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines

    Directory of Open Access Journals (Sweden)

    Govindarajan Kunde R

    2011-05-01

    Full Text Available Abstract Background The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines. Methods Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen and an anti-estrogen (ICI 182,780. Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa. Results Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE, is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry

  7. Switched-mode converters (one quadrant)

    CERN Document Server

    Barrade, P

    2006-01-01

    Switched-mode converters are DC/DC converters that supply DC loads with a regulated output voltage, and protection against overcurrents and short circuits. These converters are generally fed from an AC network via a transformer and a conventional diode rectifier. Switched-mode converters (one quadrant) are non-reversible converters that allow the feeding of a DC load with unipolar voltage and current. The switched-mode converters presented in this contribution are classified into two families. The first is dedicated to the basic topologies of DC/DC converters, generally used for low- to mid-power applications. As such structures enable only hard commutation processes, the main drawback of such topologies is high commutation losses. A typical multichannel evolution is presented that allows an interesting decrease in these losses. Deduced from this direct DC/DC converter, an evolution is also presented that allows the integration of a transformer into the buck and the buck–boost structure. This enables an int...

  8. Superconductivity, energy storage and switching

    International Nuclear Information System (INIS)

    Laquer, H.L.

    1974-01-01

    The phenomenon of superconductivity can contribute to the technology of energy storage and switching in two distinct ways. On one hand the zero resistivity of the superconductor can produce essentially infinite time constants so that an inductive storage system can be charged from very low power sources. On the other hand, the recovery of finite resistivity in a normal-going superconducting switch can take place in extremely short times, so that a system can be made to deliver energy at a very high power level. Topics reviewed include: physics of superconductivity, limits to switching speed of superconductors, physical and engineering properties of superconducting materials and assemblies, switching methods, load impedance considerations, refrigeration economics, limitations imposed by present day and near term technology, performance of existing and planned energy storage systems, and a comparison with some alternative methods of storing and switching energy. (U.S.)

  9. Amorphous metal based nanoelectromechanical switch

    KAUST Repository

    Mayet, Abdulilah M.; Smith, Casey; Hussain, Muhammad Mustafa

    2013-01-01

    Nanoelectromechanical (NEM) switch is an interesting ultra-low power option which can operate in the harsh environment and can be a complementary element in complex digital circuitry. Although significant advancement is happening in this field, report on ultra-low voltage (pull-in) switch which offers high switching speed and area efficiency is yet to be made. One key challenge to achieve such characteristics is to fabricate nano-scale switches with amorphous metal so the shape and dimensional integrity are maintained to achieve the desired performance. Therefore, we report a tungsten alloy based amorphous metal with fabrication process development of laterally actuated dual gated NEM switches with 100 nm width and 200 nm air-gap to result in <5 volts of actuation voltage (Vpull-in). © 2013 IEEE.

  10. Amorphous metal based nanoelectromechanical switch

    KAUST Repository

    Mayet, Abdulilah M.

    2013-04-01

    Nanoelectromechanical (NEM) switch is an interesting ultra-low power option which can operate in the harsh environment and can be a complementary element in complex digital circuitry. Although significant advancement is happening in this field, report on ultra-low voltage (pull-in) switch which offers high switching speed and area efficiency is yet to be made. One key challenge to achieve such characteristics is to fabricate nano-scale switches with amorphous metal so the shape and dimensional integrity are maintained to achieve the desired performance. Therefore, we report a tungsten alloy based amorphous metal with fabrication process development of laterally actuated dual gated NEM switches with 100 nm width and 200 nm air-gap to result in <5 volts of actuation voltage (Vpull-in). © 2013 IEEE.

  11. Molecular cloning of cDNA for rat brain metallothionein-2 and regulation of its gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Saijoh, Kiyofumi; Sumino, Kimiaki [Department of Public Health, Kobe University School of Medicine (Japan); Kuno, Takayoshi; Shuntoh, Hisato; Tanaka, Chikako [Department of Pharmacology, Kobe University of Medicine (Japan)

    1989-01-01

    A rat brain metallothionein-II (MT-II) complementary DNA (cDNA) clone was isolated from a cDNA plasmid library, which was prepared from non-treated rat brain mRNA, by a colony screening procedure using /sup 32/P-labeled synthetic oligonucleotide probes. It is deduced that the clone encodes for a protein of 61 amino acids comprising 20 cysteines, which is highly homologous to MT-IIs in other species. Northern blot analysis demonstrated major mRNA species in the brain, liver and kidneys (approximately 350 b in size), which is induced in response to dexamethasone, zinc, cadmium and mercury but not to methyl mercury. These findings confirm that MT-II genes are expressed and regulated both by steroid and heavy metals in the brain as well as in peripheral organs. (author).

  12. Molecular cloning of cDNA for rat brain metallothionein-2 and regulation of its gene expression

    International Nuclear Information System (INIS)

    Saijoh, Kiyofumi; Sumino, Kimiaki; Kuno, Takayoshi; Shuntoh, Hisato; Tanaka, Chikako

    1989-01-01

    A rat brain metallothionein-II (MT-II) complementary DNA (cDNA) clone was isolated from a cDNA plasmid library, which was prepared from non-treated rat brain mRNA, by a colony screening procedure using 32 P-labeled synthetic oligonucleotide probes. It is deduced that the clone encodes for a protein of 61 amino acids comprising 20 cysteines, which is highly homologous to MT-IIs in other species. Northern blot analysis demonstrated major mRNA species in the brain, liver and kidneys (approximately 350 b in size), which is induced in response to dexamethasone, zinc, cadmium and mercury but not to methyl mercury. These findings confirm that MT-II genes are expressed and regulated both by steroid and heavy metals in the brain as well as in peripheral organs. (author)

  13. Switching Phenomena in a System with No Switches

    Science.gov (United States)

    Preis, Tobias; Stanley, H. Eugene

    2010-02-01

    It is widely believed that switching phenomena require switches, but this is actually not true. For an intriguing variety of switching phenomena in nature, the underlying complex system abruptly changes from one state to another in a highly discontinuous fashion. For example, financial market fluctuations are characterized by many abrupt switchings creating increasing trends ("bubble formation") and decreasing trends ("financial collapse"). Such switching occurs on time scales ranging from macroscopic bubbles persisting for hundreds of days to microscopic bubbles persisting only for a few seconds. We analyze a database containing 13,991,275 German DAX Future transactions recorded with a time resolution of 10 msec. For comparison, a database providing 2,592,531 of all S&P500 daily closing prices is used. We ask whether these ubiquitous switching phenomena have quantifiable features independent of the time horizon studied. We find striking scale-free behavior of the volatility after each switching occurs. We interpret our findings as being consistent with time-dependent collective behavior of financial market participants. We test the possible universality of our result by performing a parallel analysis of fluctuations in transaction volume and time intervals between trades. We show that these financial market switching processes have properties similar to those of phase transitions. We suggest that the well-known catastrophic bubbles that occur on large time scales—such as the most recent financial crisis—are no outliers but single dramatic representatives caused by the switching between upward and downward trends on time scales varying over nine orders of magnitude from very large (≈102 days) down to very small (≈10 ms).

  14. Excess boron responsive regulations of antioxidative mechanism at physio-biochemical and molecular levels in Arabidopsis thaliana.

    Science.gov (United States)

    Kayıhan, Doğa Selin; Kayıhan, Ceyhun; Çiftçi, Yelda Özden

    2016-12-01

    This work was aimed to evaluate the effect of boron (B) toxicity on oxidative damage level, non-enzymatic antioxidant accumulation such as anthocyanin, flavonoid and proline and expression levels of antioxidant enzymes including superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT) and glutathione reductase (GR) and their respective activities as well as expression levels of miR398 and miR408 in Arabidopsis thaliana. Plants were germinated and grown on MS medium containing 1 mM B (1B) and 3 mM B (3B) for 14 d. Toxic B led to a decrease of photosynthetic pigments and an increase in accumulation of total soluble and insoluble sugars in accordance with phenotypically viewed chlorosis of seedlings through increasing level of B concentration. Along with these inhibitions, a corresponding increase in contents of flavonoid, anthocyanin and proline occurred that provoked oxidative stress tolerance. 3B caused a remarkable increase in total SOD activity whereas the activities of APX, GR and CAT remained unchanged as verified by expected increase in H 2 O 2 content. In contrast to GR, the coincidence was found between the expressions of SOD and APX genes and their respective activities. 1B induced mir398 expression, whereas 3B did not cause any significant change in expression of mir408 and mir398. Expression levels of GR genes were coordinately regulated with DHAR2 expression. Moreover, the changes in expression level of MDAR2 was in accordance with changes in APX6 expression and total APX activity, indicating fine-tuned regulation of ascorbate-glutathione cycle which might trigger antioxidative responses against B toxicity in Arabidopsis thaliana. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Elucidating the Molecular Basis and Regulation of Chromium (VI) Reduction by Shewanella oneidensis MR-1 Using Biochemical, Genomic, and Proteomic Approaches

    Energy Technology Data Exchange (ETDEWEB)

    Hettich, Robert L.

    2006-10-30

    Although microbial metal reduction has been investigated intensively from physiological and biochemical perspectives, little is known about the genetic basis and regulatory mechanisms underlying the ability of certain bacteria to transform, detoxify, or immobilize a wide array of heavy metals contaminating DOE-relevant environments. The major goal of this work is to elucidate the molecular components comprising the chromium(VI) response pathway, with an emphasis on components involved in Cr(VI) detoxification and the enzyme complex catalyzing the terminal step in Cr(VI) reduction by Shewanella oneidensis MR-1. We have identified and characterized (in the case of DNA-binding response regulator [SO2426] and a putative azoreductase [SO3585]) the genes and gene products involved in the molecular response of MR-1 to chromium(VI) stress using whole-genome sequence information for MR-1 and recently developed proteomic technology, in particular liquid chromatographymass spectrometry (LC-MS), in conjunction with conventional protein purification and characterization techniques. The proteome datasets were integrated with information from whole-genome expression arrays for S. oneidensis MR-1 (as illustrated in Figure 1). The genes and their encoded products identified in this study are of value in understanding metal reduction and bacterial resistance to metal toxicity and in developing effective metal immobilization strategies.

  16. Water-compatible dummy molecularly imprinted resin prepared in aqueous solution for green miniaturized solid-phase extraction of plant growth regulators.

    Science.gov (United States)

    Wang, Mingyu; Chang, Xiaochen; Wu, Xingyu; Yan, Hongyuan; Qiao, Fengxia

    2016-08-05

    A water-compatible dummy molecularly imprinted resin (MIR) was synthesized in water using melamine, urea, and formaldehyde as hydrophilic monomers of co-polycondensation. A triblock copolymer (PEO-PPO-PEO, P123) was used as porogen to dredge the network structure of MIR, and N-(1-naphthyl) ethylenediamine dihydrochloride, which has similar shape and size to the target analytes, was the dummy template of molecular imprinting. The obtained MIR was used as the adsorbent in a green miniaturized solid-phase extraction (MIR⬜mini-SPE) of plant growth regulators, and there was no organic solvent used in the entire MIR⬜mini-SPE procedure. The calibration linearity of MIR⬜mini-SPE⬜HPLC method was obtained in a range 5⬜250ngmL(↙1) for IAA, IPA, IBA, and NAA with correlation coefficient (r) Ⱕ0.9998. Recoveries at three spike levels are in the range of 87.6⬜100.0% for coconut juice with relative standard deviations Ⱔ8.1%. The MIR⬜mini-SPE method possesses the advantages of environmental friendliness, simple operation, and high efficiency, so it is potential to apply the green pretreatment strategy to extraction of trace analytes in aqueous samples. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. The poplar MYB master switches bind to the SMRE site and activate the secondary wall biosynthetic program during wood formation.

    Directory of Open Access Journals (Sweden)

    Ruiqin Zhong

    Full Text Available Wood is mainly composed of secondary walls, which constitute the most abundant stored carbon produced by vascular plants. Understanding the molecular mechanisms controlling secondary wall deposition during wood formation is not only an important issue in plant biology but also critical for providing molecular tools to custom-design wood composition suited for diverse end uses. Past molecular and genetic studies have revealed a transcriptional network encompassing a group of wood-associated NAC and MYB transcription factors that are involved in the regulation of the secondary wall biosynthetic program during wood formation in poplar trees. Here, we report the functional characterization of poplar orthologs of MYB46 and MYB83 that are known to be master switches of secondary wall biosynthesis in Arabidopsis. In addition to the two previously-described PtrMYB3 and PtrMYB20, two other MYBs, PtrMYB2 and PtrMYB21, were shown to be MYB46/MYB83 orthologs by complementation and overexpression studies in Arabidopsis. The functional roles of these PtrMYBs in regulating secondary wall biosynthesis were further demonstrated in transgenic poplar plants showing an ectopic deposition of secondary walls in PtrMYB overexpressors and a reduction of secondary wall thickening in their dominant repressors. Furthermore, PtrMYB2/3/20/21 together with two other tree MYBs, the Eucalyptus EgMYB2 and the pine PtMYB4, were shown to differentially bind to and activate the eight variants of the 7-bp SMRE consensus sequence, composed of ACC(A/TA(A/C(T/C. Together, our results indicate that the tree MYBs, PtrMYB2/3/20/21, EgMYB2 and PtMYB4, are master transcriptional switches that activate the SMRE sites in the promoters of target genes and thereby regulate secondary wall biosynthesis during wood formation.

  18. Molecular initiating events of the intersex phenotype: Low-dose exposure to 17α-ethinylestradiol rapidly regulates molecular networks associated with gonad differentiation in the adult fathead minnow testis

    International Nuclear Information System (INIS)

    Feswick, April; Loughery, Jennifer R.; Isaacs, Meghan A.; Munkittrick, Kelly R.; Martyniuk, Christopher J.

    2016-01-01

    Highlights: • Male fathead minnow were exposed to 17alpha ethinylestradiol (EE2). • Both 11-ketotestosterone and testosterone production was decreased relative to controls. • A gene network associated with doublesex and mab-3 related transcription factor 1 were suppressed. • Genes involved in granulosa cell development were increased and sensitive to EE2 exposure. • Molecular initiating events that may be related to the intersex condition were identified. - Abstract: Intersex, or the presence of oocytes in the testes, has been documented in fish following exposure to wastewater effluent and estrogenic compounds. However, the molecular networks underlying the intersex condition are not completely known. To address this, we exposed male fathead minnows to a low, environmentally-relevant concentration of 17alpha-ethinylestradiol (EE2) (15 ng/L) and measured the transcriptome response in the testis after 96 h to identify early molecular initiating events that may proceed the intersex condition. The short-term exposure to EE2 did not affect gonadosomatic index and proportion of gametes within the testes. However, the production of 11-ketotestosterone and testosterone from the testis in vitro was decreased relative to controls. Expression profiling using a 8 × 60 K fathead minnow microarray identified 10 transcripts that were differentially expressed in the testes, the most dramatic change being that of coagulation factor XIII A chain (20-fold increase). Transcripts that included guanine nucleotide binding protein (Beta Polypeptide 2), peroxisome proliferator-activated receptor delta, and WNK lysine deficient protein kinase 1a, were down-regulated by EE2. Subnetwork enrichment analysis revealed that EE2 suppressed transcriptional networks associated with steroid metabolism, hormone biosynthesis, and sperm mobility. Most interesting was that gene networks associated with doublesex and mab-3 related transcription factor 1 (dmrt1) were suppressed in the adult

  19. Molecular initiating events of the intersex phenotype: Low-dose exposure to 17α-ethinylestradiol rapidly regulates molecular networks associated with gonad differentiation in the adult fathead minnow testis

    Energy Technology Data Exchange (ETDEWEB)

    Feswick, April; Loughery, Jennifer R.; Isaacs, Meghan A.; Munkittrick, Kelly R.; Martyniuk, Christopher J., E-mail: cmartyni@yahoo.ca

    2016-12-15

    Highlights: • Male fathead minnow were exposed to 17alpha ethinylestradiol (EE2). • Both 11-ketotestosterone and testosterone production was decreased relative to controls. • A gene network associated with doublesex and mab-3 related transcription factor 1 were suppressed. • Genes involved in granulosa cell development were increased and sensitive to EE2 exposure. • Molecular initiating events that may be related to the intersex condition were identified. - Abstract: Intersex, or the presence of oocytes in the testes, has been documented in fish following exposure to wastewater effluent and estrogenic compounds. However, the molecular networks underlying the intersex condition are not completely known. To address this, we exposed male fathead minnows to a low, environmentally-relevant concentration of 17alpha-ethinylestradiol (EE2) (15 ng/L) and measured the transcriptome response in the testis after 96 h to identify early molecular initiating events that may proceed the intersex condition. The short-term exposure to EE2 did not affect gonadosomatic index and proportion of gametes within the testes. However, the production of 11-ketotestosterone and testosterone from the testis in vitro was decreased relative to controls. Expression profiling using a 8 × 60 K fathead minnow microarray identified 10 transcripts that were differentially expressed in the testes, the most dramatic change being that of coagulation factor XIII A chain (20-fold increase). Transcripts that included guanine nucleotide binding protein (Beta Polypeptide 2), peroxisome proliferator-activated receptor delta, and WNK lysine deficient protein kinase 1a, were down-regulated by EE2. Subnetwork enrichment analysis revealed that EE2 suppressed transcriptional networks associated with steroid metabolism, hormone biosynthesis, and sperm mobility. Most interesting was that gene networks associated with doublesex and mab-3 related transcription factor 1 (dmrt1) were suppressed in the adult

  20. Molecular basis for the regulation of hypoxia-inducible factor-1α levels by 2-deoxy-D-ribose.

    Science.gov (United States)

    Ikeda, Ryuji; Tabata, Sho; Tajitsu, Yusuke; Nishizawa, Yukihiko; Minami, Kentaro; Furukawa, Tatsuhiko; Yamamoto, Masatatsu; Shinsato, Yoshinari; Akiyama, Shin-Ichi; Yamada, Katsushi; Takeda, Yasuo

    2013-09-01

    The angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy-D-ribose, a degradation product of thymidine generated by TP enzymatic activity, inhibits the upregulation of hypoxia-inducible factor (HIF) 1α, BNIP3 and caspase-3 induced by hypoxia. In the present study, we investigated the molecular basis for the suppressive effect of 2-deoxy-D-ribose on the upregulation of HIF-1α. 2-Deoxy-D-ribose enhanced the interaction of HIF-1α and the von Hippel-Lindau (VHL) protein under hypoxic conditions. It did not affect the expression of HIF-1α, prolyl hydroxylase (PHD)1/2/3 and VHL mRNA under normoxic or hypoxic conditions, but enhanced the interaction of HIF-1α and PHD2 under hypoxic conditions. 2-Deoxy-D-ribose also increased the amount of hydroxy-HIF-1α in the presence of the proteasome inhibitor MG-132. The expression levels of TP are elevated in many types of malignant solid tumors and, thus, 2-deoxy-D-ribose generated by TP in these tumors may play an important role in tumor progression by preventing hypoxia-induced apoptosis.

  1. The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit.

    Science.gov (United States)

    Bouchard-Cannon, Pascale; Mendoza-Viveros, Lucia; Yuen, Andrew; Kærn, Mads; Cheng, Hai-Ying M

    2013-11-27

    The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  2. The Circadian Molecular Clock Regulates Adult Hippocampal Neurogenesis by Controlling the Timing of Cell-Cycle Entry and Exit

    Directory of Open Access Journals (Sweden)

    Pascale Bouchard-Cannon

    2013-11-01

    Full Text Available The subgranular zone (SGZ of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.

  3. Fast switching of bistable magnetic nanowires through collective spin reversal

    Science.gov (United States)

    Vindigni, Alessandro; Rettori, Angelo; Bogani, Lapo; Caneschi, Andrea; Gatteschi, Dante; Sessoli, Roberta; Novak, Miguel A.

    2005-08-01

    The use of magnetic nanowires as memory units is made possible by the exponential divergence of the characteristic time for magnetization reversal at low temperature, but the slow relaxation makes the manipulation of the frozen magnetic states difficult. We suggest that finite-size segments can show a fast switching if collective reversal of the spins is taken into account. This mechanism gives rise at low temperatures to a scaling law for the dynamic susceptibility that has been experimentally observed for the dilute molecular chain Co(hfac)2NitPhOMe. These results suggest a possible way of engineering nanowires for fast switching of the magnetization.

  4. Evidence of a local negative role for cocaine and amphetamine regulated transcript (CART, inhibins and low molecular weight insulin like growth factor binding proteins in regulation of granulosa cell estradiol production during follicular waves in cattle

    Directory of Open Access Journals (Sweden)

    Ireland James J

    2006-04-01

    Full Text Available Abstract The ability of ovarian follicles to produce large amounts of estradiol is a hallmark of follicle health status. Estradiol producing capacity is lost in ovarian follicles before morphological signs of atresia. A prominent wave like pattern of growth of antral follicles is characteristic of monotocous species such as cattle, horses and humans. While our knowledge of the role of pituitary gonadotropins in support of antral follicle growth and development is well established, the intrinsic factors that suppress estradiol production and may help promote atresia during follicular waves are not well understood. Numerous growth factors and cytokines have been reported to suppress granulosa cell estradiol production in vitro, but the association of expression of many such factors in vivo with follicle health status and their physiological significance are not clear. The purpose of this review is to discuss the in vivo and in vitro evidence supporting a local physiological role for cocaine and amphetamine regulated transcript, inhibins and low molecular weight insulin like growth factor binding proteins in negative regulation of granulosa cell estradiol production, with emphasis on evidence from the bovine model system.

  5. Numerical Simulations of Turbulent Molecular Clouds Regulated by Radiation Feedback Forces. II. Radiation-Gas Interactions and Outflows

    Science.gov (United States)

    Raskutti, Sudhir; Ostriker, Eve C.; Skinner, M. Aaron

    2017-12-01

    Momentum deposition by radiation pressure from young, massive stars may help to destroy molecular clouds and unbind stellar clusters by driving large-scale outflows. We extend our previous numerical radiation hydrodynamic study of turbulent star-forming clouds to analyze the detailed interaction between non-ionizing UV radiation and the cloud material. Our simulations trace the evolution of gas and star particles through self-gravitating collapse, star formation, and cloud destruction via radiation-driven outflows. These models are idealized in that we include only radiation feedback and adopt an isothermal equation of state. Turbulence creates a structure of dense filaments and large holes through which radiation escapes, such that only ˜50% of the radiation is (cumulatively) absorbed by the end of star formation. The surface density distribution of gas by mass as seen by the central cluster is roughly lognormal with {σ }{ln{{Σ }}}=1.3{--}1.7, similar to the externally projected surface density distribution. This allows low surface density regions to be driven outwards to nearly 10 times their initial escape speed {v}{esc}. Although the velocity distribution of outflows is broadened by the lognormal surface density distribution, the overall efficiency of momentum injection to the gas cloud is reduced because much of the radiation escapes. The mean outflow velocity is approximately twice the escape speed from the initial cloud radius. Our results are also informative for understanding galactic-scale wind driving by radiation, in particular, the relationship between velocity and surface density for individual outflow structures and the resulting velocity and mass distributions arising from turbulent sources.

  6. A systems biology, whole-genome association analysis of the molecular regulation of biomass growth and composition in Populus deltoides

    Energy Technology Data Exchange (ETDEWEB)

    Kirst, Matias [Univ. of Florida, Gainesville, FL (United States)

    2014-04-14

    Poplars trees are well suited for biofuel production due to their fast growing habit, favorable wood composition and adaptation to a broad range of environments. The availability of a reference genome sequence, ease of vegetative propagation and availability of transformation methods also make poplar an ideal model for the study of wood formation and biomass growth in woody, perennial plants. The objective of this project was to conduct a genome-wide association genetics study to identify genes that regulate bioenergy traits in Populus deltoides (eastern cottonwood). Populus deltoides is a genetically diverse keystone forest species in North America and an important short rotation woody crop for the bioenergy industry. We searched for associations between eight growth and wood composition traits and common and low-frequency single-nucleotide polymorphisms (SNPs) detected by targeted resequencing of 18,153 genes in a population of 391 unrelated individuals. To increase power to detect associations with low-frequency variants, multiple-marker association tests were used in combination with single-marker association tests. Significant associations were discovered for all phenotypes and are indicative that low-frequency polymorphisms contribute to phenotypic variance of several bioenergy traits. These polymorphism are critical tools for the development of specialized plant feedstocks for bioenergy.

  7. A systems biology, whole-genome association analysis of the molecular regulation of biomass growth and composition in Populus deltoides

    Energy Technology Data Exchange (ETDEWEB)

    Kirst, Matias [Univ. of Florida, Gainesville, FL (United States)

    2015-04-15

    Poplars trees are well suited for biofuel production due to their fast growing habit, favorable wood composition and adaptation to a broad range of environments. The availability of a reference genome sequence, ease of vegetative propagation and availability of transformation methods also make poplar an ideal model for the study of wood formation and biomass growth in woody, perennial plants. The objective of this project was to conduct a genome-wide association genetics study to identify genes that regulate bioenergy traits in Populus deltoides (eastern cottonwood). Populus deltoides is a genetically diverse keystone forest species in North America and an important short rotation woody crop for the bioenergy industry. We searched for associations between eight growth and wood composition traits and common and low-frequency single-nucleotide polymorphisms (SNPs) detected by targeted resequencing of 18,153 genes in a population of 391 unrelated individuals. To increase power to detect associations with low-frequency variants, multiple-marker association tests were used in combination with single-marker association tests. Significant associations were discovered for all phenotypes and are indicative that low-frequency polymorphisms contribute to phenotypic variance of several bioenergy traits. These polymorphism are critical tools for the development of specialized plant feedstocks for bioenergy.

  8. Molecular characterization of melanin-concentrating hormone (MCH) in Schizothorax prenanti: cloning, tissue distribution and role in food intake regulation.

    Science.gov (United States)

    Wang, Tao; Yuan, Dengyue; Zhou, Chaowei; Lin, Fangjun; Wei, Rongbin; Chen, Hu; Wu, Hongwei; Xin, Zhiming; Liu, Ju; Gao, Yundi; Chen, Defang; Yang, Shiyong; Wang, Yan; Pu, Yundan; Li, Zhiqiong

    2016-06-01

    Melanin-concentrating hormone (MCH) is a crucial neuropeptide involved in various biological functions in both mammals and fish. In this study, the full-length MCH cDNA was obtained from Schizothorax prenanti by rapid amplification of cDNA ends polymerase chain reaction. The full-length MCH cDNA contained 589 nucleotides including an open reading frame of 375 nucleotides encoding 256 amino acids. MCH mRNA was highly expressed in the brain by real-time quantitative PCR analysis. Within the brain, expression of MCH mRNA was preponderantly detected in the hypothalamus. In addition, the MCH mRNA expression in the S. prenanti hypothalamus of fed group was significantly decreased compared with the fasted group at 1 and 3 h post-feeding, respectively. Furthermore, the MCH gene expression presented significant increase in the hypothalamus of fasted group compared with the fed group during long-term fasting. After re-feeding, there was a dramatic decrease in MCH mRNA expression in the hypothalamus of S. prenanti. The results indicate that the expression of MCH is affected by feeding status. Taken together, our results suggest that MCH may be involved in food intake regulation in S. prenanti.

  9. Towards an understanding of the molecular regulation of carbon allocation in diatoms: the interaction of energy and carbon allocation.

    Science.gov (United States)

    Wagner, Heiko; Jakob, Torsten; Fanesi, Andrea; Wilhelm, Christian

    2017-09-05

    In microalgae, the photosynthesis-driven CO 2 assimilation delivers cell building blocks that are used in different biosynthetic pathways. Little is known about how the cell regulates the subsequent carbon allocation to, for example, cell growth or for storage. However, knowledge about these regulatory mechanisms is of high biotechnological and ecological importance. In diatoms, the situation becomes even more complex because, as a consequence of their secondary endosymbiotic origin, the compartmentation of the pathways for the primary metabolic routes is different from green algae. Therefore, the mechanisms to manipulate the carbon allocation pattern cannot be adopted from the green lineage. This review describes the general pathways of cellular energy distribution from light absorption towards the final allocation of carbon into macromolecules and summarizes the current knowledge of diatom-specific allocation patterns. We further describe the (limited) knowledge of regulatory mechanisms of carbon partitioning between lipids, carbohydrates and proteins in diatoms. We present solutions to overcome the problems that hinder the identification of regulatory elements of carbon metabolism.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. © 2017 The Author(s).

  10. DETERMINANT OF DOWNWARD AUDITOR SWITCHING

    Directory of Open Access Journals (Sweden)

    Totok Budisantoso

    2017-12-01

    Full Text Available Abstract: Determinant of Downward Auditor Switching. This study examines the factors that influence downward auditor switching in five ASEAN countries. Fixed effect logistic regression was used as analytical method. This study found that opinion shopping occurred in ASEAN, especially in distress companies. Companies with complex businesses will retain the Big Four auditors to reduce complexity and audit costs. Audit and public committees serve as guardians of auditor quality. On the other hand, shareholders failed to maintain audit quality. It indicates that there is entrenchment effect in auditor switching.

  11. Electrically switched ion exchange

    Energy Technology Data Exchange (ETDEWEB)

    Lilga, M.A. [Pacific Northwest National Lab., Richland, WA (United States); Schwartz, D.T.; Genders, D.

    1997-10-01

    A variety of waste types containing radioactive {sup 137}Cs are found throughout the DOE complex. These waste types include water in reactor cooling basins, radioactive high-level waste (HLW) in underground storage tanks, and groundwater. Safety and regulatory requirements and economics require the removal of radiocesium before these wastes can be permanently disposed of. Electrically Switched Ion Exchange (ESIX) is an approach for radioactive cesium separation that combines IX and electrochemistry to provide a selective, reversible, and economic separation method that also produces little or no secondary waste. In the ESIX process, an electroactive IX film is deposited electrochemically onto a high-surface area electrode, and ion uptake and elution are controlled directly by modulating the potential of the film. For cesium, the electroactive films under investigation are ferrocyanides, which are well known to have high selectivities for cesium in concentrated sodium solutions. When a cathode potential is applied to the film, Fe{sup +3} is reduced to the Fe{sup +2} state, and a cation must be intercalated into the film to maintain charge neutrality (i.e., Cs{sup +} is loaded). Conversely, if an anodic potential is applied, a cation must be released from the film (i.e., Cs{sup +} is unloaded). Therefore, to load the film with cesium, the film is simply reduced; to unload cesium, the film is oxidized.

  12. Widening consumer access to medicines: a comparison of prescription to non-prescription medicine switch in Australia and New Zealand.

    Directory of Open Access Journals (Sweden)

    Natalie J Gauld

    Full Text Available Despite similarities in health systems and Trans-Tasman Harmonization of medicines scheduling, New Zealand is more active than Australia in 'switching' (reclassifying medicines from prescription to non-prescription.To identify and compare enablers and barriers to switch in New Zealand and Australia.We conducted and analyzed 27 in-depth personal interviews with key participants in NZ and Australia and international participants previously located in Australia, and analyzed records of meetings considering switches (2000-2013. Analysis of both sets of data entailed a heuristic qualitative approach that embraced the lead researcher's knowledge and experience.The key themes identified were conservatism and political influences in Australia, and an open attitude, proactivity and flexibility in NZ. Pharmacist-only medicine schedules and individuals holding a progressive attitude were proposed to facilitate switch in both countries. A pharmacy retail group drove many switches in NZ ('third-party switch', unlike Australia. Barriers to switch in both countries included small market sizes, funding of prescription medicines and cost of doctor visits, and lack of market exclusivity. In Australia, advertising limitations for pharmacist-only medicines reportedly discouraged industry from submitting switch applications. Perceptions of pharmacy performance could help or hinder switches.Committee and regulator openness to switch, and confidence in pharmacy appear to influence consumer access to medicines. The pharmacist-only medicine schedule in Australasia and the rise of third-party switch and flexibility in switch in NZ could be considered elsewhere to enable switch.

  13. Widening consumer access to medicines: a comparison of prescription to non-prescription medicine switch in Australia and New Zealand.

    Science.gov (United States)

    Gauld, Natalie J; Kelly, Fiona S; Emmerton, Lynne M; Buetow, Stephen A

    2015-01-01

    Despite similarities in health systems and Trans-Tasman Harmonization of medicines scheduling, New Zealand is more active than Australia in 'switching' (reclassifying) medicines from prescription to non-prescription. To identify and compare enablers and barriers to switch in New Zealand and Australia. We conducted and analyzed 27 in-depth personal interviews with key participants in NZ and Australia and international participants previously located in Australia, and analyzed records of meetings considering switches (2000-2013). Analysis of both sets of data entailed a heuristic qualitative approach that embraced the lead researcher's knowledge and experience. The key themes identified were conservatism and political influences in Australia, and an open attitude, proactivity and flexibility in NZ. Pharmacist-only medicine schedules and individuals holding a progressive attitude were proposed to facilitate switch in both countries. A pharmacy retail group drove many switches in NZ ('third-party switch'), unlike Australia. Barriers to switch in both countries included small market sizes, funding of prescription medicines and cost of doctor visits, and lack of market exclusivity. In Australia, advertising limitations for pharmacist-only medicines reportedly discouraged industry from submitting switch applications. Perceptions of pharmacy performance could help or hinder switches. Committee and regulator openness to switch, and confidence in pharmacy appear to influence consumer access to medicines. The pharmacist-only medicine schedule in Australasia and the rise of third-party switch and flexibility in switch in NZ could be considered elsewhere to enable switch.

  14. Transcriptome Analysis of Ullrich Congenital Muscular Dystrophy Fibroblasts Reveals a Disease Extracellular Matrix Signature and Key Molecular Regulators.

    Directory of Open Access Journals (Sweden)

    Sonia Paco

    Full Text Available Collagen VI related myopathies encompass a range of phenotypes with involvement of skeletal muscle, skin and other connective tissues. They represent a severe and relatively common form of congenital disease for which there is no treatment. Collagen VI in skeletal muscle and skin is produced by fibroblasts.In order to gain insight into the consequences of collagen VI mutations and identify key disease pathways we performed global gene expression analysis of dermal fibroblasts from patients with Ullrich Congenital Muscular Dystrophy with and without vitamin C treatment. The expression data were integrated using a range of systems biology tools. Results were validated by real-time PCR, western blotting and functional assays.We found significant changes in the expression levels of almost 600 genes between collagen VI deficient and control fibroblasts. Highly regulated genes included extracellular matrix components and surface receptors, including integrins, indicating a shift in the interaction between the cell and its environment. This was accompanied by a significant increase in fibroblasts adhesion to laminin. The observed changes in gene expression profiling may be under the control of two miRNAs, miR-30c and miR-181a, which we found elevated in tissue and serum from patients and which could represent novel biomarkers for muscular dystrophy. Finally, the response to vitamin C of collagen VI mutated fibroblasts significantly differed from healthy fibroblasts. Vitamin C treatment was able to revert the expression of some key genes to levels found in control cells raising the possibility of a beneficial effect of vitamin C as a modulator of some of the pathological aspects of collagen VI related diseases.

  15. Calcium Regulates Molecular Interactions of Otoferlin with Soluble NSF Attachment Protein Receptor (SNARE) Proteins Required for Hair Cell Exocytosis*

    Science.gov (United States)

    Ramakrishnan, Neeliyath A.; Drescher, Marian J.; Morley, Barbara J.; Kelley, Philip M.; Drescher, Dennis G.

    2014-01-01

    Mutations in otoferlin, a C2 domain-containing ferlin family protein, cause non-syndromic hearing loss in humans (DFNB9 deafness). Furthermore, transmitter secretion of cochlear inner hair cells is compromised in mice lacking otoferlin. In the present study, we show that the C2F domain of otoferlin directly binds calcium (KD = 267 μm) with diminished binding in a pachanga (D1767G) C2F mouse mutation. Calcium was found to differentially regulate binding of otoferlin C2 domains to target SNARE (t-SNARE) proteins and phospholipids. C2D–F domains interact with the syntaxin-1 t-SNARE motif with maximum binding within the range of 20–50 μm Ca2+. At 20 μm Ca2+, the dissociation rate was substantially lower, indicating increased binding (KD = ∼10−9) compared with 0 μm Ca2+ (KD = ∼10−8), suggesting a calcium-mediated stabilization of the C2 domain·t-SNARE complex. C2A and C2B interactions with t-SNAREs were insensitive to calcium. The C2F domain directly binds the t-SNARE SNAP-25 maximally at 100 μm and with reduction at 0 μm Ca2+, a pattern repeated for C2F domain interactions with phosphatidylinositol 4,5-bisphosphate. In contrast, C2F did not bind the vesicle SNARE protein synaptobrevin-1 (VAMP-1). Moreover, an antibody targeting otoferlin immunoprecipitated syntaxin-1 and SNAP-25 but not synaptobrevin-1. As opposed to an increase in binding with increased calcium, interactions between otoferlin C2F domain and intramolecular C2 domains occurred in the absence of calcium, consistent with intra-C2 domain interactions forming a “closed” tertiary structure at low calcium that “opens” as calcium increases. These results suggest a direct role for otoferlin in exocytosis and modulation of calcium-dependent membrane fusion. PMID:24478316

  16. High current vacuum closing switch

    International Nuclear Information System (INIS)

    Dolgachev, G.I.; Maslennikov, D.D.; Romanov, A.S.; Ushakov, A.G.

    2005-01-01

    The paper proposes a powerful pulsed closing vacuum switch for high current commutation consisting of series of the vacuum diodes with near 1 mm gaps having closing time determined by the gaps shortening with the near-electrode plasmas [ru

  17. Wide Bandgap Extrinsic Photoconductive Switches

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, James S. [State Univ. of New York (SUNY), Plattsburgh, NY (United States); Univ. of California, Davis, CA (United States)

    2012-01-20

    Photoconductive semiconductor switches (PCSS) have been investigated since the late 1970s. Some devices have been developed that withstand tens of kilovolts and others that switch hundreds of amperes. However, no single device has been developed that can reliably withstand both high voltage and switch high current. Yet, photoconductive switches still hold the promise of reliable high voltage and high current operation with subnanosecond risetimes. Particularly since good quality, bulk, single crystal, wide bandgap semiconductor materials have recently become available. In this chapter we will review the basic operation of PCSS devices, status of PCSS devices and properties of the wide bandgap semiconductors 4H-SiC, 6H-SiC and 2H-GaN.

  18. Aurora oil switch upgrade program

    International Nuclear Information System (INIS)

    Warren, T.

    1989-03-01

    This report describes the short pulse synchronization requirements, the original Aurora trigger scheme, and the PI/SNLA approach to improving the synchronization. It also describes the oil switching design study undertaken as the first phase of the program. A discussion of oil-switch closure analysis and the conceptual design motivated by this analysis are presented. This paper also describes the oil-switch trigger pulser tests required to validate the concept. This includes the design of the testing facility, a description of the test goals, and a discussion of the results. This paper finally describes oil-switch trigger pulser testing on one of the four Aurora Blumlein modules, which includes the hardware design and operation, the testing goals, hardware installation, and test results. 9 refs., 26 figs

  19. Solid state bistable power switch

    Science.gov (United States)

    Bartko, J.; Shulman, H.

    1970-01-01

    Tin and copper provide high current and switching time capabilities for high-current resettable fuses. They show the best performance for trip current and degree of reliability, and have low coefficients of thermal expansion.

  20. Intrinsic nanofilamentation in resistive switching

    KAUST Repository

    Wu, Xing; Cha, Dong Kyu; Bosman, Michel; Raghavan, Nagarajan; Migas, Dmitri B.; Borisenko, Victor E.; Zhang, Xixiang; Li, Kun; Pey, Kin-Leong

    2013-01-01

    -chip circuitry and non-volatile memory storage. Here, we provide insight into the mechanisms that govern highly reproducible controlled resistive switching via a nanofilament by using an asymmetric metal-insulator-semiconductor structure. In-situ transmission