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Sample records for density regulates switches

  1. Optical switching of polariton density patterns in a semiconductor microcavity

    NASA Astrophysics Data System (ADS)

    Kwong, N. H.; Tsang, C. Y.; Luk, Samuel M. H.; Tse, Y. C.; Chan, Chris K. P.; Lewandowski, P.; Leung, P. T.; Schumacher, Stefan; Binder, R.

    2017-03-01

    Phase-conjugate scattering can trigger modulational instabilities in a fluid of exciton-polaritons created in a pumped semiconductor quantum-well microcavity. These instabilities can settle into density patterns, e.g. hexagons and stripes, which produce corresponding patterns in the emitted light. The density patterns can be switched by relatively weak control optical beams. This paper reviews progress in our theoretical understanding of the physical processes that regulate the competitions among various patterns and drive the optical switching. Simulation results of pattern switching using a microscopic model of polariton dynamics are shown, and the mechanisms underlying competitions and switching are analyzed using reduced models that restrict the polariton motions to a limited number of relevant modes. We also briefly indicate the effects of the spin dependence of the polariton dynamics on the patterns.

  2. Unity power factor switching regulator

    NASA Technical Reports Server (NTRS)

    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.

  3. Hobetron current regulating switch tube

    SciTech Connect

    True, R.B.; Hansen, R.J.; Deb, D.N.; Good, G.R.; Reass, W.A.

    1999-07-01

    This paper describes a novel high power electron tube that can hold off voltages up to hundreds of kilovolts, and switch hundreds of amps of current. They call the divide the Hobertron since it utilizes a hollow electron beam. Unlike magnetron injection gun (MIG) switch tubes, it does not require a magnet. Further, it uses nonintercepting control laments, and a dispenser cathode for long life and reliability. Finally, it features a double walled Faraday cage collector for high power dissipation capability. Current is very tightly controlled against changes in voltage across the switch (it is an almost perfect pentode), thus this tube is ideally suited for direct series switching applications. In the paper, various Hobertron designs, and the computer codes and methods used to create them, will be described.

  4. Voltage-Boosting Driver For Switching Regulator

    NASA Technical Reports Server (NTRS)

    Trump, Ronald C.

    1990-01-01

    Driver circuit assures availability of 10- to 15-V gate-to-source voltage needed to turn on n-channel metal oxide/semiconductor field-effect transistor (MOSFET) acting as switch in switching voltage regulator. Includes voltage-boosting circuit efficiently providing gate voltage 10 to 15 V above supply voltage. Contains no exotic parts and does not require additional power supply. Consists of NAND gate and dual voltage booster operating in conjunction with pulse-width modulator part of regulator.

  5. Quantum coherent switch utilizing commensurate nanoelectrode and charge density periodicities

    DOEpatents

    Harrison; Neil , Singleton; John , Migliori; Albert

    2008-08-05

    A quantum coherent switch having a substrate formed from a density wave (DW) material capable of having a periodic electron density modulation or spin density modulation, a dielectric layer formed onto a surface of the substrate that is orthogonal to an intrinsic wave vector of the DW material; and structure for applying an external spatially periodic electrostatic potential over the dielectric layer.

  6. Fast electronic resistance switching involving hidden charge density wave states

    NASA Astrophysics Data System (ADS)

    Vaskivskyi, I.; Mihailovic, I. A.; Brazovskii, S.; Gospodaric, J.; Mertelj, T.; Svetin, D.; Sutar, P.; Mihailovic, D.

    2016-05-01

    The functionality of computer memory elements is currently based on multi-stability, driven either by locally manipulating the density of electrons in transistors or by switching magnetic or ferroelectric order. Another possibility is switching between metallic and insulating phases by the motion of ions, but their speed is limited by slow nucleation and inhomogeneous percolative growth. Here we demonstrate fast resistance switching in a charge density wave system caused by pulsed current injection. As a charge pulse travels through the material, it converts a commensurately ordered polaronic Mott insulating state in 1T-TaS2 to a metastable electronic state with textured domain walls, accompanied with a conversion of polarons to band states, and concurrent rapid switching from an insulator to a metal. The large resistance change, high switching speed (30 ps) and ultralow energy per bit opens the way to new concepts in non-volatile memory devices manipulating all-electronic states.

  7. Fast electronic resistance switching involving hidden charge density wave states

    PubMed Central

    Vaskivskyi, I.; Mihailovic, I. A.; Brazovskii, S.; Gospodaric, J.; Mertelj, T.; Svetin, D.; Sutar, P.; Mihailovic, D.

    2016-01-01

    The functionality of computer memory elements is currently based on multi-stability, driven either by locally manipulating the density of electrons in transistors or by switching magnetic or ferroelectric order. Another possibility is switching between metallic and insulating phases by the motion of ions, but their speed is limited by slow nucleation and inhomogeneous percolative growth. Here we demonstrate fast resistance switching in a charge density wave system caused by pulsed current injection. As a charge pulse travels through the material, it converts a commensurately ordered polaronic Mott insulating state in 1T–TaS2 to a metastable electronic state with textured domain walls, accompanied with a conversion of polarons to band states, and concurrent rapid switching from an insulator to a metal. The large resistance change, high switching speed (30 ps) and ultralow energy per bit opens the way to new concepts in non-volatile memory devices manipulating all-electronic states. PMID:27181483

  8. The role of G-density in switch region repeats for immunoglobulin class switch recombination.

    PubMed

    Zhang, Zheng Z; Pannunzio, Nicholas R; Hsieh, Chih-Lin; Yu, Kefei; Lieber, Michael R

    2014-12-01

    The boundaries of R-loops are well-documented at immunoglobulin heavy chain loci in mammalian B cells. Within primary B cells or B cell lines, the upstream boundaries of R-loops typically begin early in the repetitive portion of the switch regions. Most R-loops terminate within the switch repetitive zone, but the remainder can extend a few hundred base pairs further, where G-density on the non-template DNA strand gradually drops to the genome average. Whether the G-density determines how far the R-loops extend is an important question. We previously studied the role of G-clusters in initiating R-loop formation, but we did not examine the role of G-density in permitting the elongation of the R-loop, after it had initiated. Here, we vary the G-density of different portions of the switch region in a murine B cell line. We find that both class switch recombination (CSR) and R-loop formation decrease significantly when the overall G-density is reduced from 46% to 29%. Short 50 bp insertions with low G-density within switch regions do not appear to affect either CSR or R-loop elongation, whereas a longer (150 bp) insertion impairs both. These results demonstrate that G-density is an important determinant of the length over which mammalian genomic R-loops extend.

  9. Input filter compensation for switching regulators

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

    A novel input filter compensation scheme for a buck regulator that eliminates the interaction between the input filter output impedance and the regulator control loop is presented. The scheme is implemented using a feedforward loop that senses the input filter state variables and uses this information to modulate the duty cycle signal. The feedforward design process presented is seen to be straightforward and the feedforward easy to implement. Extensive experimental data supported by analytical results show that significant performance improvement is achieved with the use of feedforward in the following performance categories: loop stability, audiosusceptibility, output impedance and transient response. The use of feedforward results in isolating the switching regulator from its power source thus eliminating all interaction between the regulator and equipment upstream. In addition the use of feedforward removes some of the input filter design constraints and makes the input filter design process simpler thus making it possible to optimize the input filter. The concept of feedforward compensation can also be extended to other types of switching regulators.

  10. High current density contacts for photoconductive semiconductor switches

    SciTech Connect

    Baca, A.G.; Hjalmarson, H.P.; Loubriel, G.M.; McLaughlin, D.L.; Zutavern, F.J.

    1993-08-01

    The current densities implied by current filaments in GaAs photoconductive semiconductor switches (PCSS) are in excess of 1 MA/cm{sup 2}. As the lateral switches are tested repeatedly, damage accumulates at the contacts until electrical breakdown occurs across the surface of the insulating region. In order to improve the switch lifetime, the incorporation of n- and p-type ohmic contacts in lateral switches as well as surface geometry modifications have been investigated. By using p-type AuBe ohmic contacts at the anode and n-type AuGe ohmic contacts at the cathode, contact lifetime improvements of 5--10x were observed compared to switches with n-type contacts at both anode and cathode. Failure analysis on samples operated for 1--1,000 shots show that extensive damage still exists for at least one contact on all switches observed and that temperatures approaching 500{degrees}C are can be reached. However, the n-type AuGe cathode is often found to have no damage observable by scanning electron microscopy (SEM). The observed patterns of contact degradation indicate directions for future contact improvements in lateral switches.

  11. Carrier Density Modulation in Ge Heterostructure by Ferroelectric Switching

    SciTech Connect

    Ponath, Patrick; Fredrickson, Kurt; Posadas, Agham B.; Ren, Yuan; Vasudevan, Rama K.; Okatan, Mahmut Baris; Jesse, Stephen; Aoki, Toshihiro; McCartney, Martha; Smith, David J.; Kalinin, Sergei V.; Lai, Keji; Demkov, Alexander A.

    2015-01-14

    The development of nonvolatile logic through direct coupling of spontaneous ferroelectric polarization with semiconductor charge carriers is nontrivial, with many issues, including epitaxial ferroelectric growth, demonstration of ferroelectric switching, and measurable semiconductor modulation. Here we report a true ferroelectric field effect carrier density modulation in an underlying Ge(001) substrate by switching of the ferroelectric polarization in the epitaxial c-axis-oriented BaTiO3 (BTO) grown by molecular beam epitaxy (MBE) on Ge. Using density functional theory, we demonstrate that switching of BTO polarization results in a large electric potential change in Ge. Aberration-corrected electron microscopy confirms the interface sharpness, and BTO tetragonality. Electron-energy-loss spectroscopy (EELS) indicates the absence of any low permittivity interlayer at the interface with Ge. Using piezoelectric force microscopy (PFM), we confirm the presence of fully switchable, stable ferroelectric polarization in BTO that appears to be single domain. Using microwave impedance microscopy (MIM), we clearly demonstrate a ferroelectric field effect.

  12. Carrier Density Modulation in Ge Heterostructure by Ferroelectric Switching

    DOE PAGES

    Ponath, Patrick; Fredrickson, Kurt; Posadas, Agham B.; ...

    2015-01-14

    The development of nonvolatile logic through direct coupling of spontaneous ferroelectric polarization with semiconductor charge carriers is nontrivial, with many issues, including epitaxial ferroelectric growth, demonstration of ferroelectric switching, and measurable semiconductor modulation. Here we report a true ferroelectric field effect carrier density modulation in an underlying Ge(001) substrate by switching of the ferroelectric polarization in the epitaxial c-axis-oriented BaTiO3 (BTO) grown by molecular beam epitaxy (MBE) on Ge. Using density functional theory, we demonstrate that switching of BTO polarization results in a large electric potential change in Ge. Aberration-corrected electron microscopy confirms the interface sharpness, and BTO tetragonality. Electron-energy-lossmore » spectroscopy (EELS) indicates the absence of any low permittivity interlayer at the interface with Ge. Using piezoelectric force microscopy (PFM), we confirm the presence of fully switchable, stable ferroelectric polarization in BTO that appears to be single domain. Using microwave impedance microscopy (MIM), we clearly demonstrate a ferroelectric field effect.« less

  13. State switching in regions of high modal density

    NASA Astrophysics Data System (ADS)

    Lopp, Garrett K.; Kauffman, Jeffrey L.

    2016-04-01

    Performance of piezoelectric-based, semi-active vibration reduction approaches has been studied extensively in the past decade. Originally analyzed with single-degree-of-freedom systems, these approaches have been extended to multi-mode vibration reduction. However, the accompanying analysis typically assumes well-separated modes, which is often not the case for plate structures. Because the semi-active approaches induce a shift in the structural resonance frequency (at least temporarily), targeting a specific mode for vibration reduction can actually lead to additional vibration in an adjacent mode. This paper presents an analysis using a simplified model of a two-degree-of-freedom mass-spring-damper system with lightly-coupled masses to achieve two closely-spaced modes. This investigation is especially applicable to the resonance frequency detuning approach previously proposed to reduce vibrations caused by transient excitation in turbomachinery blades where regions of high modal density exist. More generally, this paper addresses these effects of stiffness state switches in frequency ranges containing regions of high modal density and subject to frequency sweep excitation. Of the approaches analyzed, synchronized switch damping on an inductor offers the greatest vibration reduction performance, whereas resonance frequency detuning and state switching each yield similar performance. Additionally, as the relative distance between resonance peaks decreases, the performance for the vibration reduction methods approaches that of a single-degree-of-freedom system; however, there are distances between these resonant peaks that diminish vibration reduction potential.

  14. A mammalian acetate switch regulates stress erythropoiesis

    PubMed Central

    Xu, Min; Nagati, Jason S.; Xie, Jian; Li, Jiwen; Walters, Holly; Moon, Young-Ah; Gerard, Robert D.; Huang, Chou-Long; Comerford, Sarah A.; Hammer, Robert E.; Horton, Jay D.; Chen, Rui; Garcia, Joseph A.

    2014-01-01

    Endocrine erythropoietin (Epo), which is synthesized in the kidney or liver of adult mammals, controls erythrocyte production and is regulated by the stress-responsive transcription factor Hypoxia Inducible Factor 2 (HIF-2). We previously reported that the lysine acetyltransferase Cbp is required for HIF-2α acetylation and efficient HIF-2 dependent Epo induction during hypoxia. We now show these processes require acetate-dependent acetyl CoA synthetase 2 (Acss2). In Hep3B hepatoma cells and in Epo-generating organs of hypoxic or acutely anemic mice, acetate levels increase and Acss2 is required for HIF-2α acetylation, Cbp/HIF-2α complex formation and recruitment to the Epo enhancer, and efficient Epo induction. In acutely anemic mice, acetate supplementation augments stress erythropoiesis in an Acss2-dependent manner. In acquired and genetic chronic anemia mouse models, acetate supplementation also increases Epo expression and resting hematocrits. Thus, a mammalian stress-responsive acetate switch controls HIF-2 signaling and Epo induction during pathophysiological states marked by tissue hypoxia. PMID:25108527

  15. Toehold Switches: De-Novo-Designed Regulators of Gene Expression

    PubMed Central

    Green, Alexander A.; Silver, Pamela A.; Collins, James J.; Yin, Peng

    2014-01-01

    SUMMARY Efforts to construct synthetic networks in living cells have been hindered by the limited number of regulatory components that provide wide dynamic range and low crosstalk. Here, we report a new class of de-novo-designed prokaryotic riboregulators called toehold switches that activate gene expression in response to cognate RNAs with arbitrary sequences. Toehold switches provide a high level of orthogonality and can be forward-engineered to provide average dynamic range above 400. We show that switches can be integrated into the genome to regulate endogenous genes and use them as sensors that respond to endogenous RNAs. We exploit the orthogonality of toehold switches to regulate 12 genes independently and to construct a genetic circuit that evaluates 4-input AND logic. Toehold switches, with their wide dynamic range, orthogonality, and programmability, represent a versatile and powerful platform for regulation of translation, offering diverse applications in molecular biology, synthetic biology, and biotechnology. PMID:25417166

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

    DOEpatents

    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.

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

    DOEpatents

    Dyer, G.R.

    1983-11-29

    A dc switching regulated power supply for driving an inductive load is provided. The regulator basic circuit is a bridge arrangement of diodes and transistors. 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. A dc power supply is connected to the input of the bridge and the output is connected to the load. A servo controller is provided to control the switching rate of the transistors to maintain a desired current to the load. 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.

  18. Low-frequency switching voltage regulators for terrestrial photovoltaic systems

    NASA Technical Reports Server (NTRS)

    Delombard, R.

    1984-01-01

    The photovoltaic technology project and the stand alone applications project are discussed. Two types of low frequency switching type regulators were investigated. The design, operating characteristics and field application of these regulators is described. The regulators are small in size, low in cost, very low in power dissipation, reliable and allow considerable flexibility in system design.

  19. Input filter compensation for switching regulators

    NASA Technical Reports Server (NTRS)

    Lee, F. C.

    1984-01-01

    Problems caused by input filter interaction and conventional input filter design techniques are discussed. The concept of feedforward control is modeled with an input filter and a buck regulator. Experimental measurement and comparison to the analytical predictions is carried out. Transient response and the use of a feedforward loop to stabilize the regulator system is described. Other possible applications for feedforward control are included.

  20. Switching current density reduction in perpendicular magnetic anisotropy spin transfer torque magnetic tunneling junctions

    SciTech Connect

    You, Chun-Yeol

    2014-01-28

    We investigate the switching current density reduction of perpendicular magnetic anisotropy spin transfer torque magnetic tunneling junctions using micromagnetic simulations. We find that the switching current density can be reduced with elongated lateral shapes of the magnetic tunnel junctions, and additional reduction can be achieved by using a noncollinear polarizer layer. The reduction is closely related to the details of spin configurations during switching processes with the additional in-plane anisotropy.

  1. Astrocytes regulate cortical state switching in vivo

    PubMed Central

    Poskanzer, Kira E.; Yuste, Rafael

    2016-01-01

    The role of astrocytes in neuronal function has received increasing recognition, but disagreement remains about their function at the circuit level. Here we use in vivo two-photon calcium imaging of neocortical astrocytes while monitoring the activity state of the local neuronal circuit electrophysiologically and optically. We find that astrocytic calcium activity precedes spontaneous circuit shifts to the slow-oscillation–dominated state, a neocortical rhythm characterized by synchronized neuronal firing and important for sleep and memory. Further, we show that optogenetic activation of astrocytes switches the local neuronal circuit to this slow-oscillation state. Finally, using two-photon imaging of extracellular glutamate, we find that astrocytic transients in glutamate co-occur with shifts to the synchronized state and that optogenetically activated astrocytes can generate these glutamate transients. We conclude that astrocytes can indeed trigger the low-frequency state of a cortical circuit by altering extracellular glutamate, and therefore play a causal role in the control of cortical synchronizations. PMID:27122314

  2. A phosphotyrosine switch regulates organic cation transporters.

    PubMed

    Sprowl, Jason A; Ong, Su Sien; Gibson, Alice A; Hu, Shuiying; Du, Guoqing; Lin, Wenwei; Li, Lie; Bharill, Shashank; Ness, Rachel A; Stecula, Adrian; Offer, Steven M; Diasio, Robert B; Nies, Anne T; Schwab, Matthias; Cavaletti, Guido; Schlatter, Eberhard; Ciarimboli, Giuliano; Schellens, Jan H M; Isacoff, Ehud Y; Sali, Andrej; Chen, Taosheng; Baker, Sharyn D; Sparreboom, Alex; Pabla, Navjotsingh

    2016-03-16

    Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive 'transporter-phosphoproteome' with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation.

  3. Switching on cilia: transcriptional networks regulating ciliogenesis.

    PubMed

    Choksi, Semil P; Lauter, Gilbert; Swoboda, Peter; Roy, Sudipto

    2014-04-01

    Cilia play many essential roles in fluid transport and cellular locomotion, and as sensory hubs for a variety of signal transduction pathways. Despite having a conserved basic morphology, cilia vary extensively in their shapes and sizes, ultrastructural details, numbers per cell, motility patterns and sensory capabilities. Emerging evidence indicates that this diversity, which is intimately linked to the different functions that cilia perform, is in large part programmed at the transcriptional level. Here, we review our understanding of the transcriptional control of ciliary biogenesis, highlighting the activities of FOXJ1 and the RFX family of transcriptional regulators. In addition, we examine how a number of signaling pathways, and lineage and cell fate determinants can induce and modulate ciliogenic programs to bring about the differentiation of distinct cilia types.

  4. Heparan sulfate regulates ADAM12 through a molecular switch mechanism.

    PubMed

    Sørensen, Hans Peter; Vivès, Romain R; Manetopoulos, Christina; Albrechtsen, Reidar; Lydolph, Magnus C; Jacobsen, Jonas; Couchman, John R; Wewer, Ulla M

    2008-11-14

    The disintegrin and metalloproteases (ADAMs) are emerging as therapeutic targets in human disease, but specific drug design is hampered by potential redundancy. Unlike other metzincins, ADAM prodomains remain bound to the mature enzyme to regulate activity. Here ADAM12, a protease that promotes tumor progression and chondrocyte proliferation in osteoarthritic cartilage, is shown to possess a prodomain/catalytic domain cationic molecular switch, regulated by exogenous heparan sulfate and heparin but also endogenous cell surface proteoglycans and the polyanion, calcium pentosan polysulfate. Sheddase functions of ADAM12 are regulated by the switch, as are proteolytic functions in placental tissue and sera of pregnant women. Moreover, human heparanase, an enzyme also linked to tumorigenesis, can promote ADAM12 sheddase activity at the cell surface through cleavage of the inhibitory heparan sulfate. These data present a novel concept that might allow targeting of ADAM12 and suggest that other ADAMs may have specific regulatory activity embedded in their prodomain and catalytic domain structures.

  5. A density-dependent switch drives stochastic clustering and polarization of signaling molecules.

    PubMed

    Jilkine, Alexandra; Angenent, Sigurd B; Wu, Lani F; Altschuler, Steven J

    2011-11-01

    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.

  6. MTL–Independent Phenotypic Switching in Candida tropicalis and a Dual Role for Wor1 in Regulating Switching and Filamentation

    PubMed Central

    Porman, Allison M.; Wang, Na; Bennett, Richard J.

    2013-01-01

    Phenotypic switching allows for rapid transitions between alternative cell states and is important in pathogenic fungi for colonization and infection of different host niches. In Candida albicans, the white-opaque phenotypic switch plays a central role in regulating the program of sexual mating as well as interactions with the mammalian host. White-opaque switching is controlled by genes encoded at the MTL (mating-type-like) locus that ensures that only a or α cells can switch from the white state to the mating-competent opaque state, while a/α cells are refractory to switching. Here, we show that the related pathogen C. tropicalis undergoes white-opaque switching in all three cell types (a, α, and a/α), and thus switching is independent of MTL control. We also demonstrate that C. tropicalis white cells are themselves mating-competent, albeit at a lower efficiency than opaque cells. Transcriptional profiling of C. tropicalis white and opaque cells reveals significant overlap between switch-regulated genes in MTL homozygous and MTL heterozygous cells, although twice as many genes are white-opaque regulated in a/α cells as in a cells. In C. albicans, the transcription factor Wor1 is the master regulator of the white-opaque switch, and we show that Wor1 also regulates switching in C. tropicalis; deletion of WOR1 locks a, α, and a/α cells in the white state, while WOR1 overexpression induces these cells to adopt the opaque state. Furthermore, we show that WOR1 overexpression promotes both filamentous growth and biofilm formation in C. tropicalis, independent of the white-opaque switch. These results demonstrate an expanded role for C. tropicalis Wor1, including the regulation of processes necessary for infection of the mammalian host. We discuss these findings in light of the ancestral role of Wor1 as a transcriptional regulator of the transition between yeast form and filamentous growth. PMID:23555286

  7. Switching responses: spatial and temporal regulators of axon guidance.

    PubMed

    Kaplan, Andrew; Kent, Christopher B; Charron, Frédéric; Fournier, Alyson E

    2014-04-01

    The ability of the axonal growth cone to switch between attraction and repulsion in response to guidance cues in the extracellular environment during nervous system development is fundamental to the precise wiring of complex neural circuits. Regulation of cell-surface receptors by means of transcriptional control, local translation, trafficking and proteolytic processing are powerful mechanisms to regulate the response of the growth cone. Important work has also revealed how intracellular signalling pathways, including calcium and cyclic nucleotide signalling, can alter the directional response elicited by a particular cue. Here, we describe how these multiple regulatory mechanisms influence growth cone turning behaviour. We focus on recent evidence that suggests a significant role for 14-3-3 adaptor proteins in modifying growth cone turning behaviour and mediating directional polarity switches during development. Characterizing how 14-3-3 s regulate growth cone signalling will provide invaluable insight into nervous system development and may facilitate the identification of novel targets for promoting nerve regeneration following injury.

  8. Stomagen positively regulates stomatal density in Arabidopsis.

    PubMed

    Sugano, Shigeo S; Shimada, Tomoo; Imai, Yu; Okawa, Katsuya; Tamai, Atsushi; Mori, Masashi; Hara-Nishimura, Ikuko

    2010-01-14

    Stomata in the epidermal tissues of leaves are valves through which passes CO(2), and as such they influence the global carbon cycle. The two-dimensional pattern and density of stomata in the leaf epidermis are genetically and environmentally regulated to optimize gas exchange. Two putative intercellular signalling factors, EPF1 and EPF2, function as negative regulators of stomatal development in Arabidopsis, possibly by interacting with the receptor-like protein TMM. One or more positive intercellular signalling factors are assumed to be involved in stomatal development, but their identities are unknown. Here we show that a novel secretory peptide, which we designate as stomagen, is a positive intercellular signalling factor that is conserved among vascular plants. Stomagen is a 45-amino-rich peptide that is generated from a 102-amino-acid precursor protein designated as STOMAGEN. Both an in planta analysis and a semi-in-vitro analysis with recombinant and chemically synthesized stomagen peptides showed that stomagen has stomata-inducing activity in a dose-dependent manner. A genetic analysis showed that TMM is epistatic to STOMAGEN (At4g12970), suggesting that stomatal development is finely regulated by competitive binding of positive and negative regulators to the same receptor. Notably, STOMAGEN is expressed in inner tissues (the mesophyll) of immature leaves but not in the epidermal tissues where stomata develop. This study provides evidence of a mesophyll-derived positive regulator of stomatal density. Our findings provide a conceptual advancement in understanding stomatal development: inner photosynthetic tissues optimize their function by regulating stomatal density in the epidermis for efficient uptake of CO(2).

  9. Systematic Genetic Screen for Transcriptional Regulators of the Candida albicans White-Opaque Switch.

    PubMed

    Lohse, Matthew B; Ene, Iuliana V; Craik, Veronica B; Hernday, Aaron D; Mancera, Eugenio; Morschhäuser, Joachim; Bennett, Richard J; Johnson, Alexander D

    2016-08-01

    The human fungal pathogen Candida albicans can reversibly switch between two cell types named "white" and "opaque," each of which is stable through many cell divisions. These two cell types differ in their ability to mate, their metabolic preferences and their interactions with the mammalian innate immune system. A highly interconnected network of eight transcriptional regulators has been shown to control switching between these two cell types. To identify additional regulators of the switch, we systematically and quantitatively measured white-opaque switching rates of 196 strains, each deleted for a specific transcriptional regulator. We identified 19 new regulators with at least a 10-fold effect on switching rates and an additional 14 new regulators with more subtle effects. To investigate how these regulators affect switching rates, we examined several criteria, including the binding of the eight known regulators of switching to the control region of each new regulatory gene, differential expression of the newly found genes between cell types, and the growth rate of each mutant strain. This study highlights the complexity of the transcriptional network that regulates the white-opaque switch and the extent to which switching is linked to a variety of metabolic processes, including respiration and carbon utilization. In addition to revealing specific insights, the information reported here provides a foundation to understand the highly complex coupling of white-opaque switching to cellular physiology.

  10. Degenerate resistive switching and ultrahigh density storage in resistive memory

    SciTech Connect

    Lohn, Andrew J. Mickel, Patrick R. James, Conrad D.; Marinella, Matthew J.

    2014-09-08

    We show that in tantalum oxide resistive memories, activation power provides a multi-level variable for information storage that can be set and read separately from the resistance. These two state variables (resistance and activation power) can be precisely controlled in two steps: (1) the possible activation power states are selected by partially reducing resistance, then (2) a subsequent partial increase in resistance specifies the resistance state and the final activation power state. We show that these states can be precisely written and read electrically, making this approach potentially amenable for ultra-high density memories. We provide a theoretical explanation for information storage and retrieval from activation power and experimentally demonstrate information storage in a third dimension related to the change in activation power with resistance.

  11. G0/G1 Switch Gene 2 Regulates Cardiac Lipolysis*

    PubMed Central

    Heier, Christoph; Radner, Franz P. W.; Moustafa, Tarek; Schreiber, Renate; Grond, Susanne; Eichmann, Thomas O.; Schweiger, Martina; Schmidt, Albrecht; Cerk, Ines K.; Oberer, Monika; Theussl, H.-Christian; Wojciechowski, Jacek; Penninger, Josef M.; Zimmermann, Robert; Zechner, Rudolf

    2015-01-01

    The anabolism and catabolism of myocardial triacylglycerol (TAG) stores are important processes for normal cardiac function. TAG synthesis detoxifies and stockpiles fatty acids to prevent lipotoxicity, whereas TAG hydrolysis (lipolysis) remobilizes fatty acids from endogenous storage pools as energy substrates, signaling molecules, or precursors for complex lipids. This study focused on the role of G0/G1 switch 2 (G0S2) protein, which was previously shown to inhibit the principal TAG hydrolase adipose triglyceride lipase (ATGL), in the regulation of cardiac lipolysis. Using wild-type and mutant mice, we show the following: (i) G0S2 is expressed in the heart and regulated by the nutritional status with highest expression levels after re-feeding. (ii) Cardiac-specific overexpression of G0S2 inhibits cardiac lipolysis by direct protein-protein interaction with ATGL. This leads to severe cardiac steatosis. The steatotic hearts caused by G0S2 overexpression are less prone to fibrotic remodeling or cardiac dysfunction than hearts with a lipolytic defect due to ATGL deficiency. (iii) Conversely to the phenotype of transgenic mice, G0S2 deficiency results in a de-repression of cardiac lipolysis and decreased cardiac TAG content. We conclude that G0S2 acts as a potent ATGL inhibitor in the heart modulating cardiac substrate utilization by regulating cardiac lipolysis. PMID:26350455

  12. The broadcasting mechanism of master regulator NFκB switches

    NASA Astrophysics Data System (ADS)

    Potoyan, Davit

    The transcription factor NFκB is involved in many cellular responses. Therefore there is a large number of sites in the genome to which NFκB binds thereby activating myriad of genes as a response to various environmental stimuli. Kinetics becomes an important feature to reckon with in eukaryotic regulatory networks with many targets like the NFκB system. In particular models based on the classical picture of genetic switches predict slow down regulation of NFκB which can lead to wasteful over-exression of genes. A way to resolve this difficulty is to evolve faster ways of deactivating NFκB . There is evidence from experiments and our simulations that this is done by an IκB induced process of stripping NFκB off directly from its genetic sites instead of waiting for autonomous dissociation. The broadcasting mechanism proposed in this work solves the time scale problem inherent in the classical picture. Using combination of stochastic and deterministic models we show how such a mechanism results in efficient regulation of NFκB network.

  13. In-situ observation of self-regulated switching behavior in WO{sub 3-x} based resistive switching devices

    SciTech Connect

    Hong, D. S.; Wang, W. X.; Chen, Y. S. Sun, J. R.; Shen, B. G.

    2014-09-15

    The transmittance of tungsten oxides can be adjusted by oxygen vacancy (V{sub o}) concentration due to its electrochromic property. Here, we report an in-situ observation of resistive switching phenomenon in the oxygen-deficient WO{sub 3-x} planar devices. Besides directly identifying the formation/rupture of dark-colored conductive filaments in oxide layer, the stripe-like WO{sub 3-x} device demonstrated self-regulated switching behavior during the endurance testing, resulting in highly consistent switching parameters after a stabilizing process. For very high V{sub o}s mobility was demonstrated in the WO{sub 3-x} film by the pulse experiment, we suggested that the electric-field-induced homogeneous migration of V{sub o}s was the physical origin for such unique switching characteristics.

  14. 47 CFR 69.123 - Density pricing zones for special access and switched transport.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Density pricing zones for special access and...) COMMON CARRIER SERVICES (CONTINUED) ACCESS CHARGES Computation of Charges § 69.123 Density pricing zones... price cap regulation may establish any number of density zones within a study area that is used...

  15. 47 CFR 69.123 - Density pricing zones for special access and switched transport.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 3 2013-10-01 2013-10-01 false Density pricing zones for special access and...) COMMON CARRIER SERVICES (CONTINUED) ACCESS CHARGES Computation of Charges § 69.123 Density pricing zones... price cap regulation may establish any number of density zones within a study area that is used...

  16. 47 CFR 69.123 - Density pricing zones for special access and switched transport.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 3 2012-10-01 2012-10-01 false Density pricing zones for special access and...) COMMON CARRIER SERVICES (CONTINUED) ACCESS CHARGES Computation of Charges § 69.123 Density pricing zones... price cap regulation may establish any number of density zones within a study area that is used...

  17. 47 CFR 69.123 - Density pricing zones for special access and switched transport.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 3 2011-10-01 2011-10-01 false Density pricing zones for special access and...) COMMON CARRIER SERVICES (CONTINUED) ACCESS CHARGES Computation of Charges § 69.123 Density pricing zones... price cap regulation may establish any number of density zones within a study area that is used...

  18. 47 CFR 69.123 - Density pricing zones for special access and switched transport.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 3 2014-10-01 2014-10-01 false Density pricing zones for special access and...) COMMON CARRIER SERVICES (CONTINUED) ACCESS CHARGES Computation of Charges § 69.123 Density pricing zones... price cap regulation may establish any number of density zones within a study area that is used...

  19. Regulation of the switch from early to late bacteriophage lambda DNA replication.

    PubMed

    Baranska, S; Gabig, M; Wegrzyn, A; Konopa, G; Herman-Antosiewicz, A; Hernandez, P; Schvartzman, J B; Helinski, D R; Wegrzyn, G

    2001-03-01

    There are two modes of bacteriophage lambda DNA replication following infection of its host, Escherichia coli. Early after infection, replication occurs according to the theta (theta or circle-to-circle) mode, and is later switched to the sigma (sigma or rolling-circle) mode. It is not known how this switch, occurring at a specific time in the infection cycle, is regulated. Here it is demonstrated that in wild-type cells the replication starting from orilambda proceeds both bidirectionally and unidirectionally, whereas in bacteria devoid of a functional DnaA protein, replication from orilambda is predominantly unidirectional. The regulation of directionality of replication from orilambda is mediated by positive control of lambda p(R) promoter activity by DnaA, since the mode of replication of an artificial lambda replicon bearing the p(tet) promoter instead of p(R) was found to be independent of DnaA function. These findings and results of density-shift experiments suggest that in dnaA mutants infected with lambda, phage DNA replication proceeds predominantly according to the unidirectional theta mechanism and is switched early after infection to the sigma mode. It is proposed that in wild-type E. coli cells infected with lambda, phage DNA replication proceeds according to a bidirectional theta mechanism early after infection due to efficient transcriptional activation of orilambda, stimulated by the host DnaA protein. After a few rounds of this type of replication, the resulting increased copy number of lambda genomic DNA may cause a depletion of free DnaA protein because of its interaction with the multiple DnaA-binding sites in lambda DNA. It is proposed that this may lead to inefficient transcriptional activation of orilambda resulting in unidirectional theta replication followed by sigma type replication.

  20. Collective motion of self-propelled particles with density-dependent switching effect

    NASA Astrophysics Data System (ADS)

    Chen, Qiu-shi; Ma, Yu-qiang

    2016-05-01

    We study the effect of density-dependent angular response on large scale collective motion, that particles are more likely to switch their moving direction within lower local density region. We show that the presence of density-dependent angular response leads to three typical phases: polar liquid, micro-phase separation and disordered gas states. In our model, the transition between micro-phase separation and disordered gas is discontinuous. Giant number fluctuation is observed in polar liquid phase with statistically homogeneous order. In the micro-phase separation parameter space, high order and high density bands dominate the dynamics. We also compare our results with Vicsek model and show that the density-dependent directional switching response can stabilize the band state to very low noise condition. This band stripe could recruit almost all the particles in the system, which greatly enhances the coherence of the system. Our results could be helpful for understanding extremely coherent motion in nature and also would have practical implications for designing novel self-organization pattern.

  1. Regulation of a pulsed random fiber laser in the Q-switched regime

    NASA Astrophysics Data System (ADS)

    Zeng, X. P.; Zhang, W. L.; Ma, R.; Yang, Z. J.; Zeng, X.; Dong, X.; Rao, Y. J.

    2016-11-01

    A random fiber laser with regulated Q-switched pulses has been proposed and realized through a half-open cavity, which is formed between a compound fiber-based optic ring resonator (ORR) and a segment of 500 m dispersion compensation fiber (DCF). The compound fiber-based ORR provides frequency filtered feedback, which together with Brillouin scattering of the DCF forms a Q-switched mechanism. As a result, Q-switched pulses are generated randomly. Nevertheless, each Q-switched event typically consists of several ordered sub-pulses with the same pulse interval thanks to resonant interferences of the compound fiber-based ORR. Compared with former reports, the shape and the interval of pulses in each Q-switch event are regulated greatly.

  2. Regulated and non-regulated emissions from in-use diesel-electric switching locomotives.

    PubMed

    Sawant, Aniket A; Nigam, Abhilash; Miller, J Wayne; Johnson, Kent C; Cocker, David R

    2007-09-01

    Diesel-electric locomotives are vital to the operation of freight railroads in the United States, and emissions from this source category have generated interest in recent years. They are also gaining attention as an important emission source under the larger set of nonroad sources, both from a regulated emissions and health effects standpoint. The present work analyzes regulated (NOx, PM, THC, CO) and non-regulated emissions from three in-use diesel-electric switching locomotives using standardized sampling and analytical techniques. The engines tested in this work were from 1950, 1960, and 1970 and showed a range of NOx and PM emissions. In general, non-regulated gaseous emissions showed a sharp increase as engines shifted from non-idle to idle operating modes. This is interesting from an emissions perspective since activity data shows that these locomotives spend around 60% of their time idling. In terms of polycyclicaromatic hydrocarbon (PAH) contributions, the dominance of naphthalene and its derivatives over the total PAH emissions was apparent, similar to observations for on-road diesel tractors. Among nonnaphthalenic species, itwas observed that lower molecular weight PAHs and n-alkanes dominated their respective compound classes. Regulated emissions from a newer technology engine used in a back-up generator (BUG) application were also compared againstthe present engines; it was determined that use of the newer engine may lower NOx and PM emissions by up to 30%. Another area of interest to regulators is better estimation of the marine engine inventory for port operations. Toward that end, a comparison of emissions from these engines with engine manufacturer data and the newer technology BUG engine was also performed for a marine duty cycle, another application where these engines are used typically with little modifications.

  3. Regulation of high density lipoprotein levels

    SciTech Connect

    Krauss, R.M.

    1982-03-01

    An increasing awareness of the physiologic and pathologic importance of serum high density lipoproteins (HDL) has led to a large number of observations regarding factors which influence their concentrations. HDL consists of a heterogeneous collection of macromolecules with diverse physical properties and chemical constituents. While laboratory techniques have made it possible to measure HDL and their individual components, there are as yet large gaps in our knowledge of the biochemical mechanisms and clinical significance of changes in these laboratory parameters. In this review, current concepts of the structure and metabolism of HDL will be briefly summarized, and the factors influencing their levels in humans will be surveyed. 313 references.

  4. An Atypical Phr Peptide Regulates the Developmental Switch Protein RapH ▿ †

    PubMed Central

    Mirouze, Nicolas; Parashar, Vijay; Baker, Melinda D.; Dubnau, David A.; Neiditch, Matthew B.

    2011-01-01

    Under conditions of nutrient limitation and high population density, the bacterium Bacillus subtilis can initiate a variety of developmental pathways. The signaling systems regulating B. subtilis differentiation are tightly controlled by switch proteins called Raps, named after the founding members of the family, which were shown to be response regulator aspartate phosphatases. A phr gene encoding a secreted pentapeptide that regulates the activity of its associated Rap protein was previously identified downstream of 8 of the chromosomally encoded rap genes. We identify and validate here the sequence of an atypical Phr peptide, PhrH, by in vivo and in vitro analyses. Using a luciferase reporter bioassay combined with in vitro experiments, we found that PhrH is a hexapeptide (TDRNTT), in contrast to the other characterized Phr pentapeptides. We also determined that phrH expression is driven by a promoter lying within rapH. Unlike the previously identified dedicated σH-driven phr promoters, it appears that phrH expression most likely requires σA. Furthermore, we show that PhrH can antagonize both of the known activities of RapH: the dephosphorylation of Spo0F and the sequestration of ComA, thus promoting the development of spores and the competent state. Finally, we propose that PhrH is the prototype of a newly identified class of Phr signaling molecules consisting of six amino acids. This class likely includes PhrI, which regulates RapI and the expression, excision, and transfer of the mobile genetic element ICEBs1. PMID:21908671

  5. Density regulation in Sarsia tubulosa (Hydrozoa)

    NASA Astrophysics Data System (ADS)

    Leonard, J. L.

    1980-03-01

    The majority of wild-caught Sarsia tubulosa M. Sars medusae are less dense than the surrounding water. The bell of S. tubulosa is the buoyant structure; the tentacles and manubrium sink if cut off from the bell. S. tubulosa individuals placed in dilute seawater sink initially but recover positive or neutral buoyancy and normal activity within a couple of hours. In all cases observed animals were able to achieve positive buoyancy in seawater of 20.25 ‰ S and some individuals were able to adjust to lower salinities. In most cases where positive buoyancy was not attained within two hours the animal did not achieve positive buoyancy within twelve hours and died within that period. While the mechanism of regulation is not known, ionic pumping, possibly involving the extrusion of sulphate ion, has been suggested to be responsible for the buoyancy of mesoglea in other jellyfishes.

  6. Switched magnetospheric regulation of pulsar spin-down.

    PubMed

    Lyne, Andrew; Hobbs, George; Kramer, Michael; Stairs, Ingrid; Stappers, Ben

    2010-07-23

    Pulsars are famed for their rotational clocklike stability and their highly repeatable pulse shapes. However, it has long been known that there are unexplained deviations (often termed timing noise) from the rate at which we predict these clocks should run. We show that timing behavior often results from two different spin-down rates. Pulsars switch abruptly between these states, often quasi-periodically, leading to the observed spin-down patterns. We show that for six pulsars the timing noise is correlated with changes in the pulse shape. Many pulsar phenomena, including mode changing, nulling, intermittency, pulse-shape variability, and timing noise, are therefore linked and are caused by changes in the pulsar's magnetosphere. We consider the possibility that high-precision monitoring of pulse profiles could lead to the formation of highly stable pulsar clocks.

  7. Micromagnetic model for studies on Magnetic Tunnel Junction switching dynamics, including local current density

    NASA Astrophysics Data System (ADS)

    Frankowski, Marek; Czapkiewicz, Maciej; Skowroński, Witold; Stobiecki, Tomasz

    2014-02-01

    We present a model introducing the Landau-Lifshitz-Gilbert equation with a Slonczewski's Spin-Transfer-Torque (STT) component in order to take into account spin polarized current influence on the magnetization dynamics, which was developed as an Object Oriented MicroMagnetic Framework extension. We implement the following computations: magnetoresistance of vertical channels is calculated from the local spin arrangement, local current density is used to calculate the in-plane and perpendicular STT components as well as the Oersted field, which is caused by the vertical current flow. The model allows for an analysis of all listed components separately, therefore, the contribution of each physical phenomenon in dynamic behavior of Magnetic Tunnel Junction (MTJ) magnetization is discussed. The simulated switching voltage is compared with the experimental data measured in MTJ nanopillars.

  8. Rab35, acting through ACAP2 switching off Arf6, negatively regulates oligodendrocyte differentiation and myelination

    PubMed Central

    Miyamoto, Yuki; Yamamori, Natsuki; Torii, Tomohiro; Tanoue, Akito; Yamauchi, Junji

    2014-01-01

    Oligodendrocyte precursor cells differentiate to produce myelin sheaths that insulate axons to ensure fast propagation of action potentials. Many aspects of differentiation are regulated by multiple extracellular signals. However, their intracellular signalings remain elusive. We show that Rab35 and its effector, ACAP2, a GTPase-activating protein that switches off Arf6 activity, negatively regulate oligodendrocyte morphological differentiation. Knockdown of Rab35 or ACAP2 with their respective small interfering RNAs promotes differentiation. As differentiation initiates, the activities of Rab35 and ACAP2 are down-regulated. The activity of Arf6, in contrast, is up-regulated. Arf6 knockdown inhibits differentiation, indicating that Rab35 and ACAP2 negatively regulate differentiation by down-regulating Arf6. Importantly, as differentiation proceeds, the activity of cytohesin-2, a guanine nucleotide exchange factor that switches on Arf6 activity, is up-regulated. Pharmacological inhibition of cytohesin-2 inhibits differentiation, suggesting that cytohesin-2 promotes differentiation by activating Arf6. Furthermore, using oligodendrocyte-neuronal cocultures, we find that knockdown of Rab35 or ACAP2 promotes myelination, whereas inhibition of cytohesin-2 or knockdown of Arf6 inhibits myelination. Thus Rab35/ACAP2 and cytohesin-2 antagonistically control oligodendrocyte differentiation and myelination through Arf6 regulation, presenting a unique small GTPase on/off switching mechanism. PMID:24600047

  9. Gap formation processes in a high-density plasma opening switch

    NASA Astrophysics Data System (ADS)

    Grossmann, J. M.; Swanekamp, S. B.; Ottinger, P. F.; Commisso, R. J.; Hinshelwood, D. D.; Weber, B. V.

    1995-01-01

    A gap opening process in plasma opening switches (POS) is examined with the aid of numerical simulations. In these simulations, a high density (ne=1014-5×1015 cm-3) uniform plasma initially bridges a small section of the coaxial transmission line of an inductive energy storage generator. A short section of vacuum transmission line connects the POS to a short circuit load. The results presented here extend previous simulations in the ne=1012-1013 cm-3 density regime. The simulations show that a two-dimensional (2-D) sheath forms in the plasma near a cathode. This sheath is positively charged, and electrostatic sheath potentials that are large compared to the anode-cathode voltage develop. Initially, the 2-D sheath is located at the generator edge of the plasma. As ions are accelerated out of the sheath, it retains its original 2-D structure, but migrates axially toward the load creating a magnetically insulated gap in its wake. When the sheath reaches the load edge of the POS, the POS stops conducting current and the load current increases rapidly. At the end of the conduction phase a gap exists in the POS whose size is determined by the radial dimensions of the 2-D sheath. Simulations at various plasma densities and current levels show that the radial size of the gap scales roughly as B/ne, where B is the magnetic field. The results of this work are discussed in the context of long-conduction-time POS physics, but exhibit the same physical gap formation mechanisms as earlier lower density simulations more relevant to short-conduction-time POS.

  10. Multichannel microwave interferometer with an antenna switching system for electron density measurement in a laboratory plasma experiment

    SciTech Connect

    Kawamori, Eiichirou; Lin, Yu-Hsiang; Mase, Atsushi; Nishida, Yasushi; Cheng, C. Z.

    2014-02-15

    This study presents a simple and powerful technique for multichannel measurements of the density profile in laboratory plasmas by microwave interferometry. This technique uses electromechanical microwave switches to temporally switch the connection between multiple receiver antennas and one phase-detection circuit. Using this method, the phase information detected at different positions is rearranged into a time series that can be acquired from a minimum number of data acquisition channels (e.g., two channels in the case of quadrature detection). Our successfully developed multichannel microwave interferometer that uses the antenna switching method was applied to measure the radial electron density profiles in a magnetized plasma experiment. The advantage of the proposed method is its compactness and scalability to multidimensional measurement systems at low cost.

  11. An adaptive-control switching buck regulator - Implementation, analysis, and design

    NASA Technical Reports Server (NTRS)

    Lee, F. C.; Yu, Y.

    1980-01-01

    Describing-function techniques and averaging methods have been employed to characterize a multiloop switching buck regulator by three functional blocks: power stage, analog signal processor, and pulse modulator. The model is employed to explore possible forms of pole-zero cancellation and the adaptive nature of the control to filter parameter changes. Analysis-based design guidelines are provided including a suggested additional RC-compensation loop to optimize regulator performances such as stability, audiosusceptibility, output impedance, and load transient response.

  12. Control of neural stem cell adhesion and density by an electronic polymer surface switch.

    PubMed

    Saltó, Carmen; Saindon, Emilien; Bolin, Maria; Kanciurzewska, Anna; Fahlman, Mats; Jager, Edwin W H; Tengvall, Pentti; Arenas, Ernest; Berggren, Magnus

    2008-12-16

    Adhesion is an essential parameter for stem cells. It regulates the overall cell density along the carrying surface, which further dictates the differentiation scheme of stem cells toward a more matured and specified population as well as tissue. Electronic control of the seeding density of neural stem cells (c17.2) is here reported. Thin electrode films of poly(3,4-ethylenedioxythiophene) (PEDOT):Tosylate were manufactured along the floor of cell growth dishes. As the oxidation state of the conjugated polymer electrodes was controlled, the seeding density could be varied by a factor of 2. Along the oxidized PEDOT:Tosylate-electrodes, a relatively lower density of, and less tightly bonded, human serum albumin (HSA) was observed as compared to reduced electrodes. We found that this favors adhesion of the specific stem cells studied. Surface analysis experiments, such as photoelectron spectroscopy, and water contact angle measurements, were carried out to investigate the mechanisms responsible for the electronic control of the seeding density of the c17.2 neural stem cells. Further, our findings may provide an opening for electronic control of stem cell differentiation.

  13. Revisting the Density Matrix Expansion with Regulated Chiral Interactions

    NASA Astrophysics Data System (ADS)

    Dyhdalo, Alexander; Furnstahl, Richard; Bogner, Scott; Schunck, Nicolas; Navarro Perez, Rodrigo

    2016-09-01

    The density matrix expansion provides a general way to map microscopic interactions to a local functional. Previous density matrix expansion formulations added unregulated chiral long-range potentials to a Skyrme-type functional, which accounted for the short-range contributions. We implement the expansion with new coordinate space regulators using the regulator cutoff as a tool to adiabatically turn on finite-range pion interactions. We discuss `smoking guns' for correct inclusion of 3-body forces, which are implemented in a normal-ordering prescription, and compare to ab initio calculations.

  14. Receptor Tyrosine Kinases: Molecular Switches Regulating CNS Axon Regeneration

    PubMed Central

    Vigneswara, Vasanthy; Kundi, Sarina; Ahmed, Zubair

    2012-01-01

    The poor or lack of injured adult central nervous system (CNS) axon regeneration results in devastating consequences and poor functional recovery. The interplay between the intrinsic and extrinsic factors contributes to robust inhibition of axon regeneration of injured CNS neurons. The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury. In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands. This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration. PMID:22848811

  15. Cooperative Adaptive Output Regulation for Second-Order Nonlinear Multiagent Systems With Jointly Connected Switching Networks.

    PubMed

    Liu, Wei; Huang, Jie

    2017-01-11

    This paper studies the cooperative global robust output regulation problem for a class of heterogeneous second-order nonlinear uncertain multiagent systems with jointly connected switching networks. The main contributions consist of the following three aspects. First, we generalize the result of the adaptive distributed observer from undirected jointly connected switching networks to directed jointly connected switching networks. Second, by performing a new coordinate and input transformation, we convert our problem into the cooperative global robust stabilization problem of a more complex augmented system via the distributed internal model principle. Third, we solve the stabilization problem by a distributed state feedback control law. Our result is illustrated by the leader-following consensus problem for a group of Van der Pol oscillators.

  16. A conformational switch regulates the ubiquitin ligase HUWE1

    PubMed Central

    Sander, Bodo; Xu, Wenshan; Eilers, Martin; Popov, Nikita; Lorenz, Sonja

    2017-01-01

    The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly. Our studies reveal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conformational equilibrium of HUWE1 toward the inactive state. We propose a model, in which the activity of HUWE1 underlies conformational control in response to physiological cues—a mechanism that may be exploited for cancer therapy. DOI: http://dx.doi.org/10.7554/eLife.21036.001 PMID:28193319

  17. A Multistate Toggle Switch Defines Fungal Cell Fates and Is Regulated by Synergistic Genetic Cues.

    PubMed

    Anderson, Matthew Z; Porman, Allison M; Wang, Na; Mancera, Eugenio; Huang, Denis; Cuomo, Christina A; Bennett, Richard J

    2016-10-01

    Heritable epigenetic changes underlie the ability of cells to differentiate into distinct cell types. Here, we demonstrate that the fungal pathogen Candida tropicalis exhibits multipotency, undergoing stochastic and reversible switching between three cellular states. The three cell states exhibit unique cellular morphologies, growth rates, and global gene expression profiles. Genetic analysis identified six transcription factors that play key roles in regulating cell differentiation. In particular, we show that forced expression of Wor1 or Efg1 transcription factors can be used to manipulate transitions between all three cell states. A model for tristability is proposed in which Wor1 and Efg1 are self-activating but mutually antagonistic transcription factors, thereby forming a symmetrical self-activating toggle switch. We explicitly test this model and show that ectopic expression of WOR1 can induce white-to-hybrid-to-opaque switching, whereas ectopic expression of EFG1 drives switching in the opposite direction, from opaque-to-hybrid-to-white cell states. We also address the stability of induced cell states and demonstrate that stable differentiation events require ectopic gene expression in combination with chromatin-based cues. These studies therefore experimentally test a model of multistate stability and demonstrate that transcriptional circuits act synergistically with chromatin-based changes to drive cell state transitions. We also establish close mechanistic parallels between phenotypic switching in unicellular fungi and cell fate decisions during stem cell reprogramming.

  18. A Multistate Toggle Switch Defines Fungal Cell Fates and Is Regulated by Synergistic Genetic Cues

    PubMed Central

    Anderson, Matthew Z.; Porman, Allison M.; Wang, Na; Mancera, Eugenio; Bennett, Richard J.

    2016-01-01

    Heritable epigenetic changes underlie the ability of cells to differentiate into distinct cell types. Here, we demonstrate that the fungal pathogen Candida tropicalis exhibits multipotency, undergoing stochastic and reversible switching between three cellular states. The three cell states exhibit unique cellular morphologies, growth rates, and global gene expression profiles. Genetic analysis identified six transcription factors that play key roles in regulating cell differentiation. In particular, we show that forced expression of Wor1 or Efg1 transcription factors can be used to manipulate transitions between all three cell states. A model for tristability is proposed in which Wor1 and Efg1 are self-activating but mutually antagonistic transcription factors, thereby forming a symmetrical self-activating toggle switch. We explicitly test this model and show that ectopic expression of WOR1 can induce white-to-hybrid-to-opaque switching, whereas ectopic expression of EFG1 drives switching in the opposite direction, from opaque-to-hybrid-to-white cell states. We also address the stability of induced cell states and demonstrate that stable differentiation events require ectopic gene expression in combination with chromatin-based cues. These studies therefore experimentally test a model of multistate stability and demonstrate that transcriptional circuits act synergistically with chromatin-based changes to drive cell state transitions. We also establish close mechanistic parallels between phenotypic switching in unicellular fungi and cell fate decisions during stem cell reprogramming. PMID:27711197

  19. Drosophila switch gene Sex-lethal can bypass its switch-gene target transformer to regulate aspects of female behavior.

    PubMed

    Evans, Daniel S; Cline, Thomas W

    2013-11-19

    The switch gene Sex-lethal (Sxl) was thought to elicit all aspects of Drosophila female somatic differentiation other than size dimorphism by controlling only the switch gene transformer (tra). Here we show instead that Sxl controls an aspect of female sexual behavior by acting on a target other than or in addition to tra. We inferred the existence of this unknown Sxl target from the observation that a constitutively feminizing tra transgene that restores fertility to tra(-) females failed to restore fertility to Sxl-mutant females that were adult viable but functionally tra(-). The sterility of these mutant females was caused by an ovulation failure. Because tra expression is not sufficient to render these Sxl-mutant females fertile, we refer to this pathway as the tra-insufficient feminization (TIF) branch of the sex-determination regulatory pathway. Using a transgene that conditionally expresses two Sxl feminizing isoforms, we find that the TIF branch is required developmentally for neurons that also sex-specifically express fruitless, a tra gene target controlling sexual behavior. Thus, in a subset of fruitless neurons, targets of the TIF and tra pathways appear to collaborate to control ovulation. In most insects, Sxl has no sex-specific functions, and tra, rather than Sxl, is both the target of the primary sex signal and the gene that maintains the female developmental commitment via positive autoregulation. The TIF pathway may represent an ancestral female-specific function acquired by Sxl in an early evolutionary step toward its becoming the regulator of tra in Drosophila.

  20. Prediction of subharmonic oscillation in switching regulators: from a slope to a ripple standpoint

    NASA Astrophysics Data System (ADS)

    El Aroudi, A.; Al-Numay, M.; Calvente, J.; Giral, R.; Rodriguez, E.; Alarcón, E.

    2016-12-01

    New exact critical conditions for predicting subharmonic instability in switching regulators are approximated by simple design-oriented expressions valid under practical conditions. These simplified expressions contain the ripple and slope information of the feedback control signal. Depending on the converter topology, the controller used and values of parasitic parameters, either the slope or the ripple can be dominant in predicting instability. A discussion on the validity of this interpretation is illustrated through six different examples of switching regulators using the concept of the spectral radius and the relative degree of the system loop. Using this approach, the boundary between the desired stable region and the subharmonic instability can be easily obtained. The theoretical results are validated by means of numerical simulations.

  1. A new current regulator for the APS storage ring correction magnet bipolar switching mode converters.

    SciTech Connect

    Wang, J.; Accelerator Systems Division

    2004-01-01

    The correction magnets in the Advanced Photon Source's storage ring are powered by PWM-controlled bipolar switching-mode converters. These converters are designed to operate at up to {+-}150 A. The original control circuit used a polarity detection circuit with a hysteresis to determine which IGBT was needed to regulate the current with a given polarity. Only the required IGBT was switched with PWM pulses while others were held on or off continuously. The overall IGBT switching losses were minimized by the design. The shortcoming of the design was that the converter's output was unstable near zero current because of the hysteresis. To improve the stability, a new current regulator using a different PWM method has been developed to eliminate the requirement of the polarity detection. With the new design, converters can operate smoothly in the full range of {+-}150 A. The new design also meets tighter specs in terms of the ripple current and dynamic response. This paper describes the design of the new regulator and the test results.

  2. Molecular basis of RNA polymerase promoter specificity switch revealed through studies of Thermus bacteriophage transcription regulator

    PubMed Central

    Severinov, Konstantin; Minakhin, Leonid; Sekine, Shun-ichi; Lopatina, Anna; Yokoyama, Shigeyuki

    2014-01-01

    Transcription initiation is the central point of gene expression regulation. Understanding of molecular mechanism of transcription regulation requires, ultimately, the structural understanding of consequences of transcription factors binding to DNA-dependent RNA polymerase (RNAP), the enzyme of transcription. We recently determined a structure of a complex between transcription factor gp39 encoded by a Thermus bacteriophage and Thermus RNAP holoenzyme. In this addendum to the original publication, we highlight structural insights that explain the ability of gp39 to act as an RNAP specificity switch which inhibits transcription initiation from a major class of bacterial promoters, while allowing transcription from a minor promoter class to continue. PMID:25105059

  3. Distributed formation output regulation of switching heterogeneous multi-agent systems

    NASA Astrophysics Data System (ADS)

    Wang, Xiaoli

    2013-11-01

    In this article, the distributed formation output regulation problem of linear heterogeneous multi-agent systems with uncertainty under switching topology is considered. It is a generalised framework for multi-agent coordination problems, which contains or concerns a variety of important multi-agent problems in a quite unified way. Its background includes active leader following formation for the agents to maintain desired relative distances and orientations to the leader with a predefined trajectory, and multi-agent formation with environmental inputs. With the help of canonical internal model we design a distributed dynamic output feedback to handle the distributed formation output regulation problem.

  4. A receptor-based switch that regulates anthrax toxin pore formation.

    PubMed

    Pilpa, Rosemarie M; Bayrhuber, Monika; Marlett, John M; Riek, Roland; Young, John A T

    2011-12-01

    Cellular receptors can act as molecular switches, regulating the sensitivity of microbial proteins to conformational changes that promote cellular entry. The activities of these receptor-based switches are only partially understood. In this paper, we sought to understand the mechanism that underlies the activity of the ANTXR2 anthrax toxin receptor-based switch that binds to domains 2 and 4 of the protective antigen (PA) toxin subunit. Receptor-binding restricts structural changes within the heptameric PA prepore that are required for pore conversion to an acidic endosomal compartment. The transfer cross-saturation (TCS) NMR approach was used to monitor changes in the heptameric PA-receptor contacts at different steps during prepore-to-pore conversion. These studies demonstrated that receptor contact with PA domain 2 is weakened prior to pore conversion, defining a novel intermediate in this pathway. Importantly, ANTXR2 remained bound to PA domain 4 following pore conversion, suggesting that the bound receptor might influence the structure and/or function of the newly formed pore. These studies provide new insights into the function of a receptor-based molecular switch that controls anthrax toxin entry into cells.

  5. Delays Induce Different Switch in a Stochastic Single Genetic Regulation System with a Positive Autoregulatory Feedback Loop

    NASA Astrophysics Data System (ADS)

    Wang, Can-Jun

    2013-04-01

    The steady properties of a stochastic single genetic regulation system with the different time delays, which appear in the deterministic and fluctuating forces, are investigated based on the small delay time approximation method. Using the approximation probability density approach, the delayed Fokker-Planck equation is obtained. The effects of two different time delays on the stationary probability distribution and the mean value are discussed. It is found that with the time delay τ1 in the deterministic force increasing, the TF-A monomer concentration shifts from "off" state to "on" state. However, with the time delay τ2 in the fluctuating force increasing, the TF-A monomer concentration shifts from "on" state to "off" state. In the switch process, two kinds of time delays play an opposite role. The theoretical predictions are found to be in good agreement with numerical results.

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

    NASA Astrophysics Data System (ADS)

    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

  7. Plasma density evolution in plasma opening switch obtained by a time-resolved sensitive He-Ne interferometer

    NASA Astrophysics Data System (ADS)

    Chen, Lin; Ren, Jing; Guo, Fan; Zhou, LiangJi; Li, Ye; He, An; Jiang, Wei

    2014-03-01

    To understand the formation process of vacuum gap in coaxial microsecond conduction time plasma opening switch (POS), we have made measurements of the line-integrated plasma density during switch operation using a time-resolved sensitive He-Ne interferometer. The conduction current and conduction time in experiments are about 120 kA and 1 μs, respectively. As a result, more than 85% of conduction current has been transferred to an inductive load with rise time of 130 ns. The radial dependence of the density is measured by changing the radial location of the line-of-sight for shots with the same nominal POS parameters. During the conduction phase, the line-integrated plasma density in POS increases at all radial locations over the gun-only case by further ionization of material injected from the guns. The current conduction is observed to cause a radial redistribution of the switch plasma. A vacuum gap forms rapidly in the plasma at 5.5 mm from the center conductor, which is consistent with the location where magnetic pressure is the largest, allowing current to be transferred from the POS to the load.

  8. The Single-phase AC Regulator on Base of Bidirectional IGBT Switches

    NASA Astrophysics Data System (ADS)

    Cimanis, Vladimirs; Hramcovs, Vladimirs; Rankis, Ivars

    2010-01-01

    In the work one of the methods for regulation of sinus shape AC voltage for middle-power loads with activeinductive character is observed. Such a regulator keeping output voltage of sinus shape must be fast-reacting and work in closed-loop system. It's shown, that for providing such features Buck and Boost pulse regulators can be applied. The only difference from DC pulse converters is that electronic switches in the system must be with bidirectional conductivity. For this reason an IGBT transistors can be applied with implemented in structure reverse diodes and if such two transistors are connected in series and with contrary conductivity then at activating both one of them will be in on-state. Realization of AC regulators with such switches is described in the work. Results of computer modeling also are given. Output voltage ripples are investigated on subject of their range and efficiency of filtering equipment on LC base. Such regulators can be applied for instance in electrical transport self supply systems.

  9. The Calcium-Dependent Switch Helix of L-Plastin Regulates Actin Bundling

    PubMed Central

    Ishida, Hiroaki; Jensen, Katharine V.; Woodman, Andrew G.; Hyndman, M. Eric; Vogel, Hans J.

    2017-01-01

    L-plastin is a calcium-regulated actin-bundling protein that is expressed in cells of hematopoietic origin and in most metastatic cancer cells. These cell types are mobile and require the constant remodeling of their actin cytoskeleton, where L-plastin bundles filamentous actin. The calcium-dependent regulation of the actin-bundling activity of L-plastin is not well understood. We have used NMR spectroscopy to determine the solution structure of the EF-hand calcium-sensor headpiece domain. Unexpectedly, this domain does not bind directly to the four CH-domains of L-plastin. A novel switch helix is present immediately after the calcium-binding region and it binds tightly to the EF-hand motifs in the presence of calcium. We demonstrate that this switch helix plays a major role during actin-bundling. Moreover a peptide that competitively inhibits the association between the EF-hand motifs and the switch helix was shown to deregulate the actin-bundling activity of L-plastin. Overall, these findings may help to develop new drugs that target the L-plastin headpiece and interfere in the metastatic activity of cancer cells. PMID:28145401

  10. A three-phase soft-switched high-power-density dc/dc converter for high power applications

    SciTech Connect

    DeDoncker, R.W.A.A. ); Divan, D.M.; Kheraluwala, M.H. )

    1991-01-01

    In this paper three dc/dc converter topologies suitable for high-power-density high-power applications are presented. All three circuits operate in a soft-switched manner, making possible a reduction in device switching losses and an increase in switching frequency. The three-phase dual-bridge converter proposed is seen to have the most favorable characteristics. This converter consists of two three-phase inverter stages operating in a high-frequency six-step mode. In contrast to existing single-phase ac-link dc/dc converters, lower turn-off peak currents in the power devices and lower rms current ratings for both the input and output filter capacitors are obtained. This is in addition to smaller filter element values due to the higher-frequency content of the input and output waveforms. Furthermore, the use of a three phase symmetrical transformer instead of single-phase transformers and a better utilization of the available apparent power of the transformer (as a consequence of the controlled output inverter) significantly increase the power density attainable.

  11. Fluctuations of the electromagnetic local density of states as a probe for structural phase switching

    NASA Astrophysics Data System (ADS)

    de Sousa, N.; Sáenz, J. J.; Scheffold, F.; García-Martín, A.; Froufe-Pérez, L. S.

    2016-10-01

    We study the statistics of the fluorescence decay rates for single quantum emitters embedded in a scattering medium undergoing a phase transition. Under certain circumstances, the structural properties of the scattering medium explore a regime in which the system dynamically switches between two different phases. While in that regime the light-scattering properties of both phases are hardly distinguishable, we demonstrate that the lifetime statistics of single emitters with low diffusivity is clearly dependent on the dynamical state in which the medium evolves. Hence, lifetime statistics provides clear signatures of phase switching in systems where light scattering does not.

  12. Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle.

    PubMed

    Siligardi, Giuliano; Hu, Bin; Panaretou, Barry; Piper, Peter W; Pearl, Laurence H; Prodromou, Chrisostomos

    2004-12-10

    ATP hydrolysis by the Hsp90 molecular chaperone requires a connected set of conformational switches triggered by ATP binding to the N-terminal domain in the Hsp90 dimer. Central to this is a segment of the structure, which closes like a "lid" over bound ATP, promoting N-terminal dimerization and assembly of a competent active site. Hsp90 mutants that influence these conformational switches have strong effects on ATPase activity. ATPase activity is specifically regulated by Hsp90 co-chaperones, which directly influence the conformational switches. Here we have analyzed the effect of Hsp90 mutations on binding (using isothermal titration calorimetry and difference circular dichroism) and ATPase regulation by the co-chaperones Aha1, Sti1 (Hop), and Sba1 (p23). The ability of Sti1 to bind Hsp90 and arrest its ATPase activity was not affected by any of the mutants screened. Sba1 bound in the presence of AMPPNP to wild-type and ATPase hyperactive mutants with similar affinity but only very weakly to hypoactive mutants despite their wild-type ATP affinity. Unexpectedly, in all cases Sba1 bound to Hsp90 with a 1:2 molar stoichiometry. Aha1 binding to mutants was similar to wild-type, but the -fold activation of their ATPase varied substantially between mutants. Analysis of complex formation with co-chaperone mixtures showed Aha1 and p50cdc37 able to bind Hsp90 simultaneously but without direct interaction. Sba1 and p50cdc37 bound independently to Hsp90-AMPPNP but not together. These data indicated that Sba1 and Aha1 regulate Hsp90 by influencing the conformational state of the "ATP lid" and consequent N-terminal dimerization, whereas Sti1 does not.

  13. The WOR 1 5′ untranslated region regulates white‐opaque switching in C andida albicans by reducing translational efficiency

    PubMed Central

    Guan, Zhiyun

    2015-01-01

    Summary The human fungal pathogen C andida albicans undergoes white‐opaque phenotypic switching, which enhances its adaptation to host niches. Switching is controlled by a transcriptional regulatory network of interlocking feedback loops acting on the transcription of WOR 1, the master regulator of white‐opaque switching, but regulation of the network on the translational level is not yet explored. Here, we show that the long 5′ untranslated region of WOR 1 regulates the white‐opaque phenotype. Deletion of the WOR 1 5′ UTR promotes white‐to‐opaque switching and stabilizes the opaque state. The WOR 1 5′ UTR reduces translational efficiency and the association of the transcript with polysomes. Reduced polysome association was observed for additional key regulators of cell fate and morphology with long 5′ UTR as well. Overall, we find a novel regulatory step of white‐opaque switching at the translational level. This translational regulation is implicated for many key regulators of cell fate and morphology in C . albicans. PMID:25831958

  14. DNA Replication Origins in Immunoglobulin Switch Regions Regulate Class Switch Recombination in an R-Loop-Dependent Manner.

    PubMed

    Wiedemann, Eva-Maria; Peycheva, Mihaela; Pavri, Rushad

    2016-12-13

    Class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) locus generates antibody isotypes. CSR depends on double-strand breaks (DSBs) induced by activation-induced cytidine deaminase (AID). Although DSB formation and repair machineries are active in G1 phase, efficient CSR is dependent on cell proliferation and S phase entry; however, the underlying mechanisms are obscure. Here, we show that efficient CSR requires the replicative helicase, the Mcm complex. Mcm proteins are enriched at IgH switch regions during CSR, leading to assembly of facultative replication origins that require Mcm helicase function for productive CSR. Assembly of CSR-associated origins is facilitated by R loops and promotes the physical proximity (synapsis) of recombining switch regions, which is reduced by R loop inhibition or Mcm complex depletion. Thus, R loops contribute to replication origin specification that promotes DSB resolution in CSR. This suggests a mechanism for the dependence of CSR on S phase and cell division.

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

    PubMed

    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.

  16. Studies of High Power Density, Pico-Second Rise-Time Light Activated Semiconductor Switch

    DTIC Science & Technology

    1988-12-31

    34 Proceedings of the IEEE, vol.55, pp.2192-2193, 1967. 3. McKay, K., K. McAfee, "Electron Multiplication in Silicon and Germanium ," Physical Review...Conwell, E., "Properties of Silicon and Germanium : II," Proceedings of the Institute of Radio Engineers. vol.46, pp.1281-1300, 1958. 6. Zucker, 0...light activated semiconductor switches made of silicon junction diode have been demonstrated. A novel optical delay line has been designed in sampling

  17. Information recovery in molecular biology: causal modelling of regulated promoter switching experiments.

    PubMed

    Anderssen, Robert S; Helliwell, Christopher A

    2013-07-01

    The recovery of information from indirect measurements takes different forms depending on the sophistication with which the process being researched can be modelled mathematically. The forms range from (1) the historical and classical inverse problems regularization situation where explicit models which guaranteed existence and uniqueness have been formulated, through (2) situations where model formulation is performed implicitly as a calibration-and-prediction ansatz, to (3) the exploratory (biology) situation where the underlying mechanism is unknown and constraining information about its dynamics is being sought through appropriate experimentation. Each represents a different aspect of the solution of inverse problems. It is the nature of the exploratory form that is discussed in this paper. The focus is the causal modelling of regulated promoter switching experiments performed to understand the dynamics of the genetic control of various biological developmental processes such as vernalization in plants; in particular, regulated promoter switching experiments used to examine the relationship between FLC transcription activity and the associated histone H3 lysine 27 trimethylation at a vernalization-responsive gene in plants. Using a causal representation with Kohlrausch function fading memory, it is shown how such modelling can be used to quantitatively assess the closeness of the linking of one biological process with another, and, in particular, to conclude that the dynamics of FLC transcription and associated H3K27me3 activity are closely linked biologically.

  18. The Structural Basis of Cooperative Regulation at an Alternate Genetic Switch

    SciTech Connect

    Pinkett,H.; Shearwin, K.; Stayrook, S.; Dodd, I.; Burr, T.; Hochschild, A.; Egan, J.; Lewis, M.

    2006-01-01

    Bacteriophage {gamma} is a paradigm for understanding the role of cooperativity in gene regulation. Comparison of the regulatory regions of {gamma} and the unrelated temperate bacteriophage 186 provides insight into alternate ways to assemble functional genetic switches. The structure of the C-terminal domain of the 186 repressor, determined at 2.7 Angstroms resolution, reveals an unusual heptamer of dimers, consistent with presented genetic studies. In addition, the structure of a cooperativity mutant of the full-length 186 repressor, identified by genetic screens, was solved to 1.95 Angstroms resolution. These structures provide a molecular basis for understanding lysogenic regulation in 186. Whereas the overall fold of the 186 and {gamma} repressor monomers is remarkably similar, the way the two repressors cooperatively assemble is quite different and explains in part the differences in their regulatory activity.

  19. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression.

    PubMed

    Gallimore, Andrew R; Aricescu, A Radu; Yuzaki, Michisuke; Calinescu, Radu

    2016-01-01

    The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins-glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)-regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process.

  20. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression

    PubMed Central

    Gallimore, Andrew R.; Aricescu, A. Radu; Yuzaki, Michisuke; Calinescu, Radu

    2016-01-01

    The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins–glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)–regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process. PMID:26807999

  1. Pet-1 Switches Transcriptional Targets Postnatally to Regulate Maturation of Serotonin Neuron Excitability

    PubMed Central

    Wyler, Steven C.; Spencer, W. Clay; Green, Noah H.; Rood, Benjamin D.; Crawford, LaTasha; Craige, Caryne; Gresch, Paul; McMahon, Douglas G.; Beck, Sheryl G.

    2016-01-01

    Newborn neurons enter an extended maturation stage, during which they acquire excitability characteristics crucial for development of presynaptic and postsynaptic connectivity. In contrast to earlier specification programs, little is known about the regulatory mechanisms that control neuronal maturation. The Pet-1 ETS (E26 transformation-specific) factor is continuously expressed in serotonin (5-HT) neurons and initially acts in postmitotic precursors to control acquisition of 5-HT transmitter identity. Using a combination of RNA sequencing, electrophysiology, and conditional targeting approaches, we determined gene expression patterns in maturing flow-sorted 5-HT neurons and the temporal requirements for Pet-1 in shaping these patterns for functional maturation of mouse 5-HT neurons. We report a profound disruption of postmitotic expression trajectories in Pet-1−/− neurons, which prevented postnatal maturation of 5-HT neuron passive and active intrinsic membrane properties, G-protein signaling, and synaptic responses to glutamatergic, lysophosphatidic, and adrenergic agonists. Unexpectedly, conditional targeting revealed a postnatal stage-specific switch in Pet-1 targets from 5-HT synthesis genes to transmitter receptor genes required for afferent modulation of 5-HT neuron excitability. 5-HT1a autoreceptor expression depended transiently on Pet-1, thus revealing an early postnatal sensitive period for control of 5-HT excitability genes. Chromatin immunoprecipitation followed by sequencing revealed that Pet-1 regulates 5-HT neuron maturation through direct gene activation and repression. Moreover, Pet-1 directly regulates the 5-HT neuron maturation factor Engrailed 1, which suggests Pet-1 orchestrates maturation through secondary postmitotic regulatory factors. The early postnatal switch in Pet-1 targets uncovers a distinct neonatal stage-specific function for Pet-1, during which it promotes maturation of 5-HT neuron excitability. SIGNIFICANCE STATEMENT The

  2. Modulated switching current density and spin-orbit torques in MnGa/Ta films with inserting ferromagnetic layers

    PubMed Central

    Meng, Kangkang; Miao, Jun; Xu, Xiaoguang; Wu, Yong; Xiao, Jiaxing; Zhao, Jianhua; Jiang, Yong

    2016-01-01

    We report modulated switching current density and spin-orbit torques (SOT) in MnGa/Ta films with inserting very thin Co2FeAl and Co layers. Ferromagnetic coupling has been found in MnGa/Co2FeAl/Ta, resulting in a decreased effective anisotropy field. On the contrary, in MnGa/Co/Ta, antiferromagnetic coupling plays a dominant role. The switching current density Jc in MnGa/Ta is 8.5 × 107 A/cm2. After inserting 0.8-nm-thick Co2FeAl and Co, theJc becomes 5 × 107 A/cm2 and 9 × 107 A/cm2, respectively. By performing adiabatic harmonic Hall voltage measurements, it is demonstrated that the inserted Co2FeAl layer has mainly enhanced the field-like torques, while in MnGa/Co/Ta the damping-like torques have been enhanced. Finally, the enhanced spin Hall effect (SHE) has also been studied using the spin Hall magnetoresistance measurement. The modulated Jc and SOT are ascribed to the combination of magnetic coupling, Rashba effect and SHE at the interfaces. PMID:27910938

  3. Modulated switching current density and spin-orbit torques in MnGa/Ta films with inserting ferromagnetic layers

    NASA Astrophysics Data System (ADS)

    Meng, Kangkang; Miao, Jun; Xu, Xiaoguang; Wu, Yong; Xiao, Jiaxing; Zhao, Jianhua; Jiang, Yong

    2016-12-01

    We report modulated switching current density and spin-orbit torques (SOT) in MnGa/Ta films with inserting very thin Co2FeAl and Co layers. Ferromagnetic coupling has been found in MnGa/Co2FeAl/Ta, resulting in a decreased effective anisotropy field. On the contrary, in MnGa/Co/Ta, antiferromagnetic coupling plays a dominant role. The switching current density Jc in MnGa/Ta is 8.5 × 107 A/cm2. After inserting 0.8-nm-thick Co2FeAl and Co, theJc becomes 5 × 107 A/cm2 and 9 × 107 A/cm2, respectively. By performing adiabatic harmonic Hall voltage measurements, it is demonstrated that the inserted Co2FeAl layer has mainly enhanced the field-like torques, while in MnGa/Co/Ta the damping-like torques have been enhanced. Finally, the enhanced spin Hall effect (SHE) has also been studied using the spin Hall magnetoresistance measurement. The modulated Jc and SOT are ascribed to the combination of magnetic coupling, Rashba effect and SHE at the interfaces.

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

    SciTech Connect

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

    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.

  5. Nova2 regulates neuronal migration through an RNA switch in disabled-1 signaling

    PubMed Central

    Yano, Masato; Hayakawa-Yano, Yoshika; Mele, Aldo; Darnell, Robert B.

    2010-01-01

    SUMMARY Neuronal migration leads to a highly organized laminar structure in the mammalian brain and its mis-regulation causes lissencephaly, behavioral and cognitive defects. Reelin signaling, mediated in part by a key adaptor, disabled-1 (Dab1), plays a critical but incompletely understood role in this process. We found that the neuron-specific RNA binding protein Nova2 regulates neuronal migration in late-generated cortical and Purkinje neurons. An unbiased HITS-CLIP and exon junction array search for Nova-dependent RNAs at E14.5 focused on components of the reelin pathway revealed only one candidate—an alternatively spliced isoform of Dab1 (Dab1.7bc). In utero electroporation demonstrated that Dab1.7bc was sufficient to induce neuronal migration defects in wild-type mice and exacerbate defects when Dab1 levels were reduced, while Dab1 overexpression mitigates defects in Nova2-null mice. Thus Nova2 regulates an RNA switch controlling the ability of Dab1 to mediate neuronal responsiveness to reelin signaling and neuronal migration, suggesting new links between splicing regulation, brain disease and development. PMID:20620871

  6. A monoallelic-to-biallelic T-cell transcriptional switch regulates GATA3 abundance

    PubMed Central

    Ku, Chia-Jui; Lim, Kim-Chew; Kalantry, Sundeep; Maillard, Ivan; Engel, James Douglas; Hosoya, Tomonori

    2015-01-01

    Protein abundance must be precisely regulated throughout life, and nowhere is the stringency of this requirement more evident than during T-cell development: A twofold increase in the abundance of transcription factor GATA3 results in thymic lymphoma, while reduced GATA3 leads to diminished T-cell production. GATA3 haploinsufficiency also causes human HDR (hypoparathyroidism, deafness, and renal dysplasia) syndrome, often accompanied by immunodeficiency. Here we show that loss of one Gata3 allele leads to diminished expansion (and compromised development) of immature T cells as well as aberrant induction of myeloid transcription factor PU.1. This effect is at least in part mediated transcriptionally: We discovered that Gata3 is monoallelically expressed in a parent of origin-independent manner in hematopoietic stem cells and early T-cell progenitors. Curiously, half of the developing cells switch to biallelic Gata3 transcription abruptly at midthymopoiesis. We show that the monoallelic-to-biallelic transcriptional switch is stably maintained and therefore is not a stochastic phenomenon. This unique mechanism, if adopted by other regulatory genes, may provide new biological insights into the rather prevalent phenomenon of monoallelic expression of autosomal genes as well as into the variably penetrant pathophysiological spectrum of phenotypes observed in many human syndromes that are due to haploinsufficiency of the affected gene. PMID:26385963

  7. Global gene regulation during activation of immunoglobulin class switching in human B cells

    PubMed Central

    Zhang, Youming; Fear, David J.; Willis-Owen, Saffron A. G.; Cookson, William O.; Moffatt, Miriam F.

    2016-01-01

    Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease. To profile the B-cell transcriptional responses underlying the activation of the germinal centre activities leading to the generation of IgE, naïve human B-cells were stimulated with IL-4 and anti-CD40. Gene expression and alternative splicing were profiled over 12 days using the Affymetrix Human Exon 1.0 ST Array. A total of 1,399 genes, forming 13 temporal profiles were differentially expressed. CCL22 and CCL17 were dramatically induced but followed a temporal trajectory distinct from classical mediators of isotype switching. AICDA, NFIL3, IRF4, XBP1 and BATF3 shared a profile with several genes involved in innate immunity, but with no recognised role in CSR. A transcription factor BHLHE40 was identified at the core of this profile. B-cell activation was also accompanied by variation in exon retention affecting >200 genes including CCL17. The data indicate a circadian component and central roles for the Th2 chemokines CCL22 and CCL17 in the activation of CSR. PMID:27897229

  8. Measurement of Gene Regulation in Individual Cells Reveals Rapid Switching Between Promoter States

    PubMed Central

    Sepúlveda, Leonardo A.; Xu, Heng; Zhang, Jing; Wang, Mengyu; Golding, Ido

    2016-01-01

    In vivo mapping of transcription-factor binding to the transcriptional output of the regulated gene is hindered by probabilistic promoter occupancy, the presence of multiple gene copies, and cell-to-cell variability. We demonstrate how to overcome these obstacles in the lysogeny maintenance promoter of bacteriophage lambda, PRM. We simultaneously measured the concentration of the lambda repressor CI and the number of mRNAs from PRM in individual E. coli cells, and used a theoretical model to identify the stochastic activity corresponding to different CI binding configurations. We found that switching between promoter configurations is faster than mRNA lifetime, and that individual gene copies within the same cell act independently. The simultaneous quantification of transcription factor and promoter activity, followed by stochastic theoretical analysis, provides a tool that can be applied to other genetic circuits. PMID:26965629

  9. Low-current-density spin-transfer switching in Gd{sub 22}Fe{sub 78}-MgO magnetic tunnel junction

    SciTech Connect

    Kinjo, Hidekazu Machida, Kenji; Aoshima, Ken-ichi; Kato, Daisuke; Kuga, Kiyoshi; Kikuchi, Hiroshi; Shimidzu, Naoki; Matsui, Koichi

    2014-05-28

    Magnetization switching of a relatively thick (9 nm) Gd-Fe free layer was achieved with a low spin injection current density of 1.0 × 10{sup 6} A/cm{sup 2} using MgO based magnetic tunnel junction devices, fabricated for light modulators. At about 560 × 560 nm{sup 2} in size, the devices exhibited a tunneling magnetoresistance ratio of 7%. This low-current switching is mainly attributed to thermally assisted spin-transfer switching in consequence of its thermal magnetic behavior arising from Joule heating.

  10. Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch.

    PubMed

    Ling, Kun; Doughman, Renee L; Iyer, Vidhya V; Firestone, Ari J; Bairstow, Shawn F; Mosher, Deane F; Schaller, Michael D; Anderson, Richard A

    2003-12-22

    Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a "molecular switch" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.

  11. Effect of oxyfluorinated multi-walled carbon nanotube additives on positive temperature coefficient/negative temperature coefficient behavior in high-density polyethylene polymeric switches

    SciTech Connect

    Bai, Byong Chol; Kang, Seok Chang; Im, Ji Sun; Lee, Se Hyun; Lee, Young-Seak

    2011-09-15

    Graphical abstract: The electrical properties of MWCNT-filled HDPE polymeric switches and their effect on oxyfluorination. Highlights: {yields} Oxyfluorinated MWCNTs were used to reduce the PTC/NTC phenomenon in MWCNT-filled HDPE polymeric switches. {yields} Electron mobility is difficult in MWCNT particles when the number of oxygen functional groups (C-O, C=O) increases by oxyfluorination. {yields} A mechanism of improved electrical properties of oxyfluorinated MWCNT-filled HDPE polymeric switches was suggested. -- Abstract: Multi-walled carbon nanotubes (MWCNTs) were embedded into high-density polyethylene (HDPE) to improve the electrical properties of HDPE polymeric switches. The MWCNT surfaces were modified by oxyfluorination to improve their positive temperature coefficient (PTC) and negative temperature coefficient (NTC) behaviors in HDPE polymeric switches. HDPE polymeric switches exhibit poor electron mobility between MWCNT particles when the number of oxygen functional groups is increased by oxyfluorination. Thus, the PTC intensity of HDPE polymeric switches was increased by the destruction of the electrical conductivity network. The oxyfluorination of MWCNTs also leads to weak NTC behavior in the MWCNT-filled HDPE polymeric switches. This result is attributed to the reduction of the mutual attraction between the MWCNT particles at the melting temperature of HDPE, which results from a decrease in the surface free energy of the C-F bond in MWCNT particles.

  12. Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication.

    PubMed

    Buehler, Jason; Zeltzer, Sebastian; Reitsma, Justin; Petrucelli, Alex; Umashankar, Mahadevaiah; Rak, Mike; Zagallo, Patricia; Schroeder, Joyce; Terhune, Scott; Goodrum, Felicia

    2016-05-01

    Herpesviruses persist indefinitely in their host through complex and poorly defined interactions that mediate latent, chronic or productive states of infection. Human cytomegalovirus (CMV or HCMV), a ubiquitous β-herpesvirus, coordinates the expression of two viral genes, UL135 and UL138, which have opposing roles in regulating viral replication. UL135 promotes reactivation from latency and virus replication, in part, by overcoming replication-suppressive effects of UL138. The mechanism by which UL135 and UL138 oppose one another is not known. We identified viral and host proteins interacting with UL138 protein (pUL138) to begin to define the mechanisms by which pUL135 and pUL138 function. We show that pUL135 and pUL138 regulate the viral cycle by targeting that same receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR). EGFR is a major homeostatic regulator involved in cellular proliferation, differentiation, and survival, making it an ideal target for viral manipulation during infection. pUL135 promotes internalization and turnover of EGFR from the cell surface, whereas pUL138 preserves surface expression and activation of EGFR. We show that activated EGFR is sequestered within the infection-induced, juxtanuclear viral assembly compartment and is unresponsive to stress. Intriguingly, these findings suggest that CMV insulates active EGFR in the cell and that pUL135 and pUL138 function to fine-tune EGFR levels at the cell surface to allow the infected cell to respond to extracellular cues. Consistent with the role of pUL135 in promoting replication, inhibition of EGFR or the downstream phosphoinositide 3-kinase (PI3K) favors reactivation from latency and replication. We propose a model whereby pUL135 and pUL138 together with EGFR comprise a molecular switch that regulates states of latency and replication in HCMV infection by regulating EGFR trafficking to fine tune EGFR signaling.

  13. Lifetime of high-power GaAs photoconductive semiconductor switch triggered by laser of different power density

    NASA Astrophysics Data System (ADS)

    Liu, Yi; Wang, Wei; Shen, Yi; Shi, Jinshui; Zhang, Linwen; Xia, Liansheng

    2015-02-01

    Conduction modes of GaAs photoconductive semiconductor switch (PCSS) and their conditions are expounded. Laser diode and high-power picosecond Nd:YAG lasers are used as triggers for nonlinear mode and quasi-linear mode respectively in high-power conduction experiment. GaAs PCSS`s failure mechanisms and factors influencing lifetime in both modes are analyzed. It is found that the power density of laser at trigger time determines in which mode GaAs PCSS operates. Low-power laser triggers a nonlinear mode conduction in which GaAs PCSS`s lifetime is only 103, while high-power laser triggers a quasi-linear mode conduction in which GaAs PCSS`s lifetime is up to 105. According to the findings, the compact high-power pulsed power system based on mass of GaAs PCSSs demands for miniature high-power laser generators.

  14. Magnetic force microscopy study of the switching field distribution of low density arrays of single domain magnetic nanowires

    NASA Astrophysics Data System (ADS)

    Tabasum, M. R.; Zighem, F.; De La Torre Medina, J.; Encinas, A.; Piraux, L.; Nysten, B.

    2013-05-01

    In the present work, we report on the in situ magnetic force microscopy (MFM) study of the magnetization reversal in two-dimensional arrays of ferromagnetic Ni80Fe20 and Co55Fe45 nanowires (NW) with different diameters (40, 50, 70, and 100 nm) deposited inside low porosity (P < 1%) nanoporous polycarbonate membranes. In such arrays, the nanowires are sufficiently isolated from each other so that long range dipolar interactions can be neglected. The MFM experiments performed for different magnetization states at the same spot of the samples are analysed to determine the switching field distribution (SFD). The magnetization curves obtained from the MFM images are relatively square shaped. The SFD widths are narrower compared to those obtained for high density arrays. The weak broadening of the curves may be ascribed to the NW intrinsic SFD. The influence of diameter and composition of the ferromagnetic NW is also investigated.

  15. Highly-Ordered 3D Vertical Resistive Switching Memory Arrays with Ultralow Power Consumption and Ultrahigh Density.

    PubMed

    Al-Haddad, Ahmed; Wang, Chengliang; Qi, Haoyuan; Grote, Fabian; Wen, Liaoyong; Bernhard, Jörg; Vellacheri, Ranjith; Tarish, Samar; Nabi, Ghulam; Kaiser, Ute; Lei, Yong

    2016-09-07

    Resistive switching random access memories (RRAM) have attracted great scientific and industrial attention for next generation data storage because of their advantages of nonvolatile properties, high density, low power consumption, fast writing/erasing speed, good endurance, and simple and small operation system. Here, by using a template-assisted technique, we demonstrate a three-dimensional highly ordered vertical RRAM device array with density as high as that of the nanopores of the template (10(8)-10(9) cm(-2)), which can also be fabricated in large area. The high crystallinity of the materials, the large contact area and the intimate semiconductor/electrode interface (3 nm interfacial layer) make the ultralow voltage operation (millivolt magnitude) and ultralow power consumption (picowatt) possible. Our procedure for fabrication of the nanodevice arrays in large area can be used for producing many other different materials and such three-dimensional electronic device arrays with the capability to adjust the device densities can be extended to other applications of the next generation nanodevice technology.

  16. IKK regulates the deubiquitinase CYLD at the postsynaptic density

    SciTech Connect

    Thein, Soe; Pham, Anna; Bayer, K. Ulrich; Tao-Cheng, Jung-Hwa; Dosemeci, Ayse

    2014-07-18

    Highlights: • CYLD is phosphorylated by IKK in isolated PSDs in the absence of Ca{sup 2+}. • CYLD is phosphorylated by IKK at the PSDs of intact neurons in basal conditions. • Phosphorylation of CYLD by IKK increases its deubiquitinase activity. • The process is likely to influence protein trafficking at the PSD in basal conditions. - Abstract: K63-linked polyubiquitination of proteins regulates their trafficking into specific cellular pathways such as endocytosis and autophagy. CYLD, a deubiquitinase specific for K63-linked polyubiquitins, is present in high quantities at the postsynaptic density (PSD). It was previously shown that, under excitatory conditions, CaMKII activates CYLD in a Ca{sup 2+}-dependent manner. The observation that CYLD can also be phosphorylated in the absence of Ca{sup 2+} in isolated PSDs led us to further explore the regulation of CYLD under basal conditions. A possible involvement of the autonomous form of CaMKII and IKK, both kinases known to be localized at the PSD, was examined. A CaMKII inhibitor CN21 had no effect on CYLD phosphorylation in the absence of Ca{sup 2+}, but two different IKK inhibitors, IKK16 and tatNEMO, inhibited its phosphorylation. Immuno-electron microscopy on hippocampal cultures, using an antibody for CYLD phosphorylated at S-418, revealed that the phosphorylated form of CYLD is present at the PSD under basal conditions. Phosphorylation of CYLD under basal conditions was inhibited by IKK16. NMDA treatment further promoted phosphorylation of CYLD at the PSD, but IKK16 failed to block the NMDA-induced effect. In vitro experiments using purified proteins demonstrated direct phosphorylation and activation of CYLD by the beta catalytic subunit of IKK. Activation of IKK in isolated PSDs also promoted phosphorylation of CYLD and an increase in endogenous deubiquitinase activity for K63-linked polyubiquitins. Altogether, the results suggest that in the absence of excitatory conditions, constitutive IKK activity

  17. Properties of an intergenic terminator and start site switch that regulate IMD2 transcription in yeast.

    PubMed

    Jenks, M Harley; O'Rourke, Thomas W; Reines, Daniel

    2008-06-01

    The IMD2 gene in Saccharomyces cerevisiae is regulated by intracellular guanine nucleotides. Regulation is exerted through the choice of alternative transcription start sites that results in synthesis of either an unstable short transcript terminating upstream of the start codon or a full-length productive IMD2 mRNA. Start site selection is dictated by the intracellular guanine nucleotide levels. Here we have mapped the polyadenylation sites of the upstream, unstable short transcripts that form a heterogeneous family of RNAs of approximately 200 nucleotides. The switch from the upstream to downstream start sites required the Rpb9 subunit of RNA polymerase II. The enzyme's ability to locate the downstream initiation site decreased exponentially as the start was moved downstream from the TATA box. This suggests that RNA polymerase II's pincer grip is important as it slides on DNA in search of a start site. Exosome degradation of the upstream transcripts was highly dependent upon the distance between the terminator and promoter. Similarly, termination was dependent upon the Sen1 helicase when close to the promoter. These findings extend the emerging concept that distinct modes of termination by RNA polymerase II exist and that the distance of the terminator from the promoter, as well as its sequence, is important for the pathway chosen.

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

    PubMed Central

    Tsuchiya, Yuichi; Nakabayashi, Osamu; Nakano, Hiroyasu

    2015-01-01

    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. PMID:26694384

  19. Integrated mixed signal control IC for 500-kHz switching frequency buck regulator

    NASA Astrophysics Data System (ADS)

    Chen, Keng; Zhang, Hong

    2015-12-01

    The main purpose for this work is to study the challenges of designing a digital buck regulator using pipelined analog to digital converter (ADC). Although pipelined ADC can achieve high sampling speed, it will introduce additional phase lag to the buck circuit. Along with the latency brought by processing time of additional digital circuits, as well as the time delay associated with the switching frequency, the closed loop will be unstable; moreover, raw ADC outputs have low signal-to-noise ratio, which usually need back-end calibration. In order to compensate these phase lag and make control loop unconditional stable, as well as boost up signal-to-noise ratio of the ADC block with cost-efficient design, a finite impulse response filter followed by digital proportional-integral-derivative blocks were designed. All these digital function blocks were optimised with processing speed. In the system simulation, it can be found that this controller achieved output regulation within 10% of nominal 5 V output voltage under 1 A/µs load transient condition; moreover, with the soft-start method, there is no turn-on overshooting. The die size of this controller is controlled within 3 mm2 by using 180 nm CMOS technology.

  20. MxaY regulates the lanthanide-mediated methanol dehydrogenase switch in Methylomicrobium buryatense

    PubMed Central

    Chu, Frances; Beck, David A.C.

    2016-01-01

    Many methylotrophs, microorganisms that consume carbon compounds lacking carbon–carbon bonds, use two different systems to oxidize methanol for energy production and biomass accumulation. The MxaFI methanol dehydrogenase (MDH) contains calcium in its active site, while the XoxF enzyme contains a lanthanide in its active site. The genes encoding the MDH enzymes are differentially regulated by the presence of lanthanides. In this study, we found that the histidine kinase MxaY controls the lanthanide-mediated switch in Methylomicrobium buryatense 5GB1C. MxaY controls the transcription of genes encoding MxaFI and XoxF at least partially by controlling the transcript levels of the orphan response regulator MxaB. We identify a constitutively active version of MxaY, and identify the mutated residue that may be involved in lanthanide sensing. Lastly, we find evidence to suggest that tight control of active MDH production is required for wild-type growth rates. PMID:27651996

  1. Reduced Dislocation Density in GaxIn1-xP Compositionally Graded Buffer Layers through Engineered Glide Plane Switch

    SciTech Connect

    Schulte, Kevin L.; France, Ryan M.; McMahon, William E.; Norman, Andrew G.; Guthrey, Harvey L.; Geisz, John F.

    2016-11-17

    In this work we develop control over dislocation glide dynamics in GaxIn1-xP compositionally graded buffer layers (CGBs) through control of CuPt ordering on the group-III sublattice. The ordered structure is metastable in the bulk, so any glissile dislocation that disrupts the ordered pattern will release stored energy, and experience an increased glide force. Here we show how this connection between atomic ordering and dislocation glide force can be exploited to control the threading dislocation density (TDD) in GaxIn1-xP CGBs. When ordered GaxIn1-xP is graded from the GaAs lattice constant to InP, the order parameter ..eta.. decreases as x decreases, and dislocation glide switches from one set of glide planes to the other. This glide plane switch (GPS) is accompanied by the nucleation of dislocations on the new glide plane, which typically leads to increased TDD. We develop control of the GPS position within a GaxIn1-xP CGB through manipulation of deposition temperature, surfactant concentration, and strain-grading rate. We demonstrate a two-stage GaxIn1-xP CGB from GaAs to InP with sufficiently low TDD for high performance devices, such as the 4-junction inverted metamorphic multi-junction solar cell, achieved through careful control the GPS position. Experimental results are analyzed within the context of a model that considers the force balance on dislocations on the two competing glide planes as a function of the degree of ordering.

  2. Reduced dislocation density in GaxIn1-xP compositionally graded buffer layers through engineered glide plane switch

    NASA Astrophysics Data System (ADS)

    Schulte, K. L.; France, R. M.; McMahon, W. E.; Norman, A. G.; Guthrey, H. L.; Geisz, J. F.

    2017-04-01

    In this work we develop control over dislocation glide dynamics in GaxIn1-xP compositionally graded buffer layers (CGBs) through control of CuPt ordering on the group-III sublattice. The ordered structure is metastable in the bulk, so any glissile dislocation that disrupts the ordered pattern will release stored energy, and experience an increased glide force. Here we show how this connection between atomic ordering and dislocation glide force can be exploited to control the threading dislocation density (TDD) in GaxIn1-xP CGBs. When ordered GaxIn1-xP is graded from the GaAs lattice constant to InP, the order parameter η decreases as x decreases, and dislocation glide switches from one set of glide planes to the other. This glide plane switch (GPS) is accompanied by the nucleation of dislocations on the new glide plane, which typically leads to increased TDD. We develop control of the GPS position within a GaxIn1-xP CGB through manipulation of deposition temperature, surfactant concentration, and strain-grading rate. We demonstrate a two-stage GaxIn1-xP CGB from GaAs to InP with sufficiently low TDD for high performance devices, such as the 4-junction inverted metamorphic multi-junction solar cell, achieved through careful control the GPS position. Experimental results are analyzed within the context of a model that considers the force balance on dislocations on the two competing glide planes as a function of the degree of ordering.

  3. Coupling between Switching Regulation and Torque Generation in Bacterial Flagellar Motor

    NASA Astrophysics Data System (ADS)

    Bai, Fan; Minamino, Tohru; Wu, Zhanghan; Namba, Keiichi; Xing, Jianhua

    2012-04-01

    The bacterial flagellar motor plays a crucial role in both bacterial locomotion and chemotaxis. Recent experiments reveal that the switching dynamics of the motor depend on the rotation speed of the motor, and thus the motor torque, nonmonotonically. Here we present a unified mathematical model which treats motor torque generation based on experimental torque-speed curves and the torque-dependent switching based on the conformational spread model. The model successfully reproduces the observed switching rate as a function of the rotation speed, and provides a generic physical explanation independent of most details. A stator affects the switching dynamics through two mechanisms: accelerating the conformational flipping rate of individual rotor-switching units, which contributes most when the stator works at a high torque and thus a low speed; and influencing a larger number of rotor-switching units within unit time, whose contribution is the greatest when the motor rotates at a high speed. Consequently, the switching rate shows a maximum at intermediate speed, where the above two mechanisms find an optimal output. The load-switching relation may serve as a mechanism for sensing the physical environment, similar to the chemotaxis mechanism for sensing the chemical environment. It may also coordinate the switch dynamics of motors within the same cell.

  4. Confluence switch signaling regulates ECM composition and the plasmin proteolytic cascade in keratinocytes.

    PubMed

    Botta, Adrien; Delteil, Frédéric; Mettouchi, Amel; Vieira, Andhira; Estrach, Soline; Négroni, Luc; Stefani, Caroline; Lemichez, E; Meneguzzi, Guerrino; Gagnoux-Palacios, Laurent

    2012-09-15

    In culture, cell confluence generates signals that commit actively growing keratinocytes to exit the cell cycle and differentiate to form a stratified epithelium. Using a comparative proteomic approach, we studied this 'confluence switch' and identified a new pathway triggered by cell confluence that regulates basement membrane (BM) protein composition by suppressing the uPA-uPAR-plasmin pathway. Indeed, confluence triggers adherens junction maturation and enhances TGF-β and activin A activity, resulting in increased deposition of PAI-1 and perlecan in the BM. Extracellular matrix (ECM)-accumulated PAI-1 suppresses the uPA-uPAR-plasmin pathway and further enhances perlecan deposition by inhibiting its plasmin-dependent proteolysis. We show that perlecan deposition in the ECM strengthens cell adhesion, inhibits keratinocyte motility and promotes additional accumulation of PAI-1 in the ECM at confluence. In agreement, during wound-healing, perlecan concentrates at the wound-margin, where BM matures to stabilize keratinocyte adhesion. Our results demonstrate that confluence-dependent signaling orchestrates not only growth inhibition and differentiation, but also controls ECM proteolysis and BM formation. These data suggest that uncontrolled integration of confluence-dependent signaling, might favor skin disorders, including tumorigenesis, not only by promoting cell hyperproliferation, but also by altering protease activity and deposition of ECM components.

  5. The On-off Switch in Regulated Myosins: Different Triggers but Related Mechanisms

    SciTech Connect

    Himmel, D.; Mui, S; O' Neall-Hennessey, E; Szent-Györgyi, A; Cohen, C

    2009-01-01

    In regulated myosin, motor and enzymatic activities are toggled between the on-state and off-state by a switch located on its lever arm domain, here called the regulatory domain (RD). This region consists of a long {alpha}-helical 'heavy chain' stabilized by a 'regulatory' light chain (RLC) and an 'essential' light chain (ELC). The on-state is activated by phosphorylation of the RLC of vertebrate smooth muscle RD or by direct binding of Ca{sup 2+} to the ELC of molluscan RD. Crystal structures are available only for the molluscan RD. To understand in more detail the pathway between the on-state and the off-state, we have now also determined the crystal structure of a molluscan (scallop) RD in the absence of Ca{sup 2+}. Our results indicate that loss of Ca{sup 2+} abolishes most of the interactions between the light chains and may increase the flexibility of the RD heavy chain. We propose that disruption of critical links with the C-lobe of the RLC is the key event initiating the off-state in both smooth muscle myosins and molluscan myosins.

  6. TGF-β regulates isoform switching of FGF receptors and epithelial–mesenchymal transition

    PubMed Central

    Shirakihara, Takuya; Horiguchi, Kana; Miyazawa, Keiji; Ehata, Shogo; Shibata, Tatsuhiro; Morita, Ikuo; Miyazono, Kohei; Saitoh, Masao

    2011-01-01

    The epithelial–mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair, and cancer progression in adult tissues. Here, we demonstrate that transforming growth factor (TGF)-β induced EMT and that long-term exposure to TGF-β elicited the epithelial–myofibroblastic transition (EMyoT) by inactivating the MEK-Erk pathway. During the EMT process, TGF-β induced isoform switching of fibroblast growth factor (FGF) receptors, causing the cells to become sensitive to FGF-2. Addition of FGF-2 to TGF-β-treated cells perturbed EMyoT by reactivating the MEK-Erk pathway and subsequently enhanced EMT through the formation of MEK-Erk-dependent complexes of the transcription factor δEF1/ZEB1 with the transcriptional corepressor CtBP1. Consequently, normal epithelial cells that have undergone EMT as a result of combined TGF-β and FGF-2 stimulation promoted the invasion of cancer cells. Thus, TGF-β and FGF-2 may cooperate with each other and may regulate EMT of various kinds of cells in cancer microenvironment during cancer progression. PMID:21224849

  7. Coupling between Switching Regulation and Torque Generation in Bacterial Flagellar Motor

    NASA Astrophysics Data System (ADS)

    Xing, Jianhua; Bai, Fan; Minamino, Tohru; Wu, Zhanghan; Namba, Keiichi

    2013-03-01

    The bacterial flagellar motor plays a crucial role in both bacterial locomotion and chemotaxis. Recent experiments reveal that the switching dynamics of the motor depend on the rotation speed of the motor, and thus the motor torque, nonmonotonically. Here we present a unified mathematical model that treats motor torque generation based on experimental torque-speed curves and the torque-dependent switching based on the Ising type conformational spread model. The model successfully reproduces the observed switching rate as a function of the rotation speed, and provides a generic physical explanation independent of most details. A stator affects the switching dynamics through two mechanisms: accelerating the conformational flipping rate of individual rotor-switching units, which contributes most when the stator works at a high torque and thus a low speed; and influencing a larger number of rotor-switching units within unit time, whose contribution is the greatest when the motor rotates at a high speed. Consequently, the switching rate shows a maximum at intermediate speed, where the above two mechanisms find an optimal output. The load-switching relation may serve as a mechanism for sensing the physical environment, similar to the chemotaxis mechanism for sensing the chemical environment.

  8. The fission yeast homologue of CENP-B, Abp1, regulates directionality of mating-type switching.

    PubMed

    Aguilar-Arnal, Lorena; Marsellach, Francesc-Xavier; Azorín, Fernando

    2008-04-09

    In fission yeast, mating-type switching involves replacing genetic information contained at the expressed mat1 locus by that of either the mat2P or mat3M donor loci. Donor selection is nonrandom, as mat1P cells preferentially use mat3M for switching, whereas mat1M cells use mat2P. Switching directionality is determined by the cell-type-specific distribution of the Swi2-Swi5 complex that, in mat1P cells, localises to mat3M and, only in mat1M cells, spreads to mat2P in a heterochromatin-dependent manner. Mechanisms regulating spreading of Swi2-Swi5 across heterochromatin are not fully understood. Here, we show that the fission yeast homologue of CENP-B, Abp1, binds to the silent domain of the mating-type locus and regulates directionality of switching. Deletion of abp1 prevents utilisation of mat2P, as when heterochromatin is disrupted and spreading of Swi2-Swi5 is impaired. Our results show that, indeed, deletion of abp1 abolishes spreading of Swi2-Swi5 to mat2P. However, in abp1Delta cells, heterochromatin organisation at the mating-type locus is preserved, indicating that Abp1 is actually required for efficient spreading of Swi2-Swi5 through heterochromatin. Cbh1 and Cbh2, which are also homologous to CENP-B, have only a minor contribution to the regulation of directionality of switching, which is in contrast with the strong effects observed for Abp1.

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

    NASA Astrophysics Data System (ADS)

    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

  10. Regulating infidelity: RNA-mediated recruitment of AID to DNA during class switch recombination.

    PubMed

    DiMenna, Lauren J; Chaudhuri, Jayanta

    2016-03-01

    The mechanism by which the DNA deaminase activation-induced cytidine deaminase (AID) is specifically recruited to repetitive switch region DNA during class switch recombination is still poorly understood. Work over the past decade has revealed a strong link between transcription and RNA polymerase-associated factors in AID recruitment, yet none of these processes satisfactorily explain how AID specificity is affected. Here, we review a recent finding wherein AID is guided to switch regions not by a protein factor but by an RNA moiety, and especially one associated with a noncoding RNA that has been long thought of as being inert. This work explains the long-standing requirement of splicing of noncoding transcripts during class switching, and has implications in both B cell-mediated immunity as well as the underlying pathological syndromes associated with the recombination reaction.

  11. Regulating infidelity: RNA-mediated recruitment of AID to DNA during class switch recombination

    PubMed Central

    DiMenna, Lauren; Chaudhuri, Jayanta

    2016-01-01

    The mechanism by which the DNA deaminase AID is specifically recruited to repetitive switch region DNA during class switch recombination is still poorly understood. Work over the past decade has revealed a strong link between transcription and RNA polymerase-associated factors in AID recruitment, yet none of these processes satisfactorily explain how AID specificity is effected. Here we review a recent finding wherein AID is guided to switch regions not by a protein factor but by an RNA moiety, and especially one associated with a non-coding RNA that has been long thought of as being inert. This work explains the long-standing requirement of splicing of non-coding transcripts during class switching, and has implications in both B-cell-mediated immunity as well as the underlying pathological syndromes associated with the recombination reaction. PMID:26799454

  12. Nucleosome Switches

    NASA Astrophysics Data System (ADS)

    Schwab, David J.; Bruinsma, Robijn F.; Rudnick, Joseph; Widom, Jonathan

    2008-06-01

    We present a statistical-mechanical model for the positioning of nucleosomes along genomic DNA molecules as a function of the strength of the binding potential and the chemical potential of the nucleosomes. We show that a significant section of the DNA is composed of two-level nucleosome switching regions where the nucleosome distribution undergoes a localized, first-order transition. The location of the nucleosome switches shows a strong correlation with the location of gene-regulation regions.

  13. Nucleosome switches.

    PubMed

    Schwab, David J; Bruinsma, Robijn F; Rudnick, Joseph; Widom, Jonathan

    2008-06-06

    We present a statistical-mechanical model for the positioning of nucleosomes along genomic DNA molecules as a function of the strength of the binding potential and the chemical potential of the nucleosomes. We show that a significant section of the DNA is composed of two-level nucleosome switching regions where the nucleosome distribution undergoes a localized, first-order transition. The location of the nucleosome switches shows a strong correlation with the location of gene-regulation regions.

  14. Nanoparticle Density: A Critical Biophysical Regulator of Endothelial Permeability.

    PubMed

    Tay, Chor Yong; Setyawati, Magdiel Inggrid; Leong, David Tai

    2017-03-17

    The integrity of the vasculature system is intrinsically sensitive to a short list of biophysical cues spanning from nano to micro scales. We have earlier found that certain nanomaterials could induce endothelial leakiness (nanoparticle induced endothelial leakiness, nanoEL). In this study, we report that the density of the nanomaterial, a basic intrinsic material property not implicated in many nanoparticle-mediated biological effects, predominantly dictates the nanoEL effect. We demonstrated that the impinging force exerted by a library of increasing effective densities but consistently sized silica nanoparticles (SiNPs) could directly increase endothelial permeability. The crossover effective particle density that induced nanoEL was determined to be between 1.57 g/cm(3) to 1.72 g/cm(3). It was also found that a cumulative gravitational-mediated force of around 1.8 nN/μm along the boundaries of the vascular endothelial cadherin (VE-cad) adherens junctions appeared to be a critical threshold force required to perturb endothelial cell-cell adhesion. The net result is the "snapping" of the mechanically pretensed VE-cad (Nanosnap), leading to the formation of micron-sized gaps that would dramatically increase endothelial leakiness.

  15. Surface regulated arsenenes as Dirac materials: From density functional calculations

    NASA Astrophysics Data System (ADS)

    Yuan, Junhui; Xie, Qingxing; Yu, Niannian; Wang, Jiafu

    2017-02-01

    Using first principle calculations based on density functional theory (DFT), we have systematically investigated the structure stability and electronic properties of chemically decorated arsenenes, AsX (X = CN, NC, NCO, NCS and NCSe). Phonon dispersion and formation energy analysis reveal that all the five chemically decorated buckled arsenenes are energetically favorable and could be synthesized. Our study shows that wide-bandgap arsenene would turn into Dirac materials when functionalized by -X (X = CN, NC, NCO, NCS and NCSe) groups, rendering new promises in next generation high-performance electronic devices.

  16. Development of a Tightly Controlled Off Switch for Saccharomyces cerevisiae Regulated by Camphor, a Low-Cost Natural Product

    PubMed Central

    Ikushima, Shigehito; Zhao, Yu; Boeke, Jef D.

    2015-01-01

    Here we describe the engineering of a distant homolog of the Tet repressor, CamR, isolated from Pseudomonas putida, that is regulated by camphor, a very inexpensive small molecule (at micromolar concentrations) for use in Saccharomyces cerevisiae. The repressor was engineered by expression from a constitutive yeast promoter, fusion to a viral activator protein cassette, and codon optimization. A suitable promoter responsive to the CamR fusion protein was engineered by embedding a P. putida operator binding sequence within an upstream activating sequence (UAS)-less CYC1 promoter from S. cerevisiae. The switch, named the Camphor-Off switch, activates expression of a reporter gene in camphor-free media and represses it with micromolar concentrations of camphor. PMID:26206350

  17. Prognostic health monitoring in switch-mode power supplies with voltage regulation

    NASA Technical Reports Server (NTRS)

    Hofmeister, James P (Inventor); Judkins, Justin B (Inventor)

    2009-01-01

    The system includes a current injection device in electrical communication with the switch mode power supply. The current injection device is positioned to alter the initial, non-zero load current when activated. A prognostic control is in communication with the current injection device, controlling activation of the current injection device. A frequency detector is positioned to receive an output signal from the switch mode power supply and is able to count cycles in a sinusoidal wave within the output signal. An output device is in communication with the frequency detector. The output device outputs a result of the counted cycles, which are indicative of damage to an a remaining useful life of the switch mode power supply.

  18. Regulation and targeting of recombination in extrachromosomal substrates carrying immunoglobulin switch region sequences.

    PubMed Central

    Leung, H; Maizels, N

    1994-01-01

    We have used extrachromosomal substrates carrying immunoglobulin heavy-chain S mu and S gamma 3 switch region sequences to study activation and targeting of recombination by a transcriptional enhancer element. Substrates are transiently introduced into activated primary murine B cells, in which recombination involving S-region sequences deletes a conditionally lethal marker, and recombination is measured by transformation of Escherichia coli in the second step of the assay. Previously we found that as many as 25% of replicated substrates recombined during 40-h transfection of lipopolysaccharide (LPS)-stimulated primary cells and that efficient recombination was dependent on the presence of S-region sequences as well as a transcriptional activator region in the constructs (H. Leung and N. Maizels, Proc. Natl. Acad. Sci. USA 89:4154-4158, 1992). Here we show that recombination of the switch substrates is threefold more efficient in LPS-cultured primary B cells than in the T-cell line EL4; the activities responsible for switch substrate recombination thus appear to be more abundant or more active in cells which can carry out chromosomal switch recombination. We test the role of the transcriptional activator region and show that the immunoglobulin heavy-chain intron enhancer (E mu) alone stimulates recombination as well as E mu combined with a heavy-chain promoter and that mutations that diminish enhancer-dependent transcription 500-fold diminish recombinational activation less than 2-fold. These observations suggest that the enhancer stimulates recombination by a mechanism that does not depend on transcript production or that is insensitive to the level of transcript production over a very broad range. Furthermore, we find that E mu stimulates recombination when located either upstream or downstream of S mu but that the position of the recombinational activator does affect the targeting of recombination junctions, suggesting that the relatively imprecise targeting of

  19. Arginine methylation regulates antibody responses through modulating cell division and isotype switching in B cells.

    PubMed

    Hata, Kikumi; Mizuguchi, Junichiro

    2013-03-01

    Protein arginine methylation plays crucial roles, including signal transduction, transcriptional control, cell proliferation and/or differentiation. B cells undergo clonal division, isotype switching and differentiate into antibody forming cells following stimulation with Toll-like receptor-ligand, lipopolysaccharide (LPS) and T cell-derived signals, including CD40-ligand (CD40-L) and interleukin 4 (IL-4). Whether protein arginine methylation affects B cell division and/or isotype switching to IgG1 in response to LPS, IL-4, and CD40-L was examined using the arginine methyl transferase inhibitor adenosine-2',3'-dialdehyde (AdOx). Addition of AdOx substantially reduced the number of division cycles of stimulated B cells, whereas cell viability remained intact. Upon stimulation with LPS/IL-4/CD40-L, the proportion of surface IgG1 positive cells in each division cycle was slightly diminished by AdOx. However, the degree of expression of γ1 germ line transcript and activation-induced cytidine deaminase (AID) in response to LPS/IL-4/CD40-L were unaffected by addition of AdOx, suggesting that AdOx influences class switch recombination independent of AID expression through transcriptional control. Taken together, arginine methylation appears to be involved in B cell isotype switching, as well as in clonal expansion of B cells in response to LPS/IL-4/CD40-L.

  20. Chromatin remodelling and antisense-mediated up-regulation of the developmental switch gene eud-1 control predatory feeding plasticity

    PubMed Central

    Serobyan, Vahan; Xiao, Hua; Namdeo, Suryesh; Rödelsperger, Christian; Sieriebriennikov, Bogdan; Witte, Hanh; Röseler, Waltraud; Sommer, Ralf J.

    2016-01-01

    Phenotypic plasticity has been suggested to act through developmental switches, but little is known about associated molecular mechanisms. In the nematode Pristionchus pacificus, the sulfatase eud-1 was identified as part of a developmental switch controlling mouth-form plasticity governing a predatory versus bacteriovorous mouth-form decision. Here we show that mutations in the conserved histone-acetyltransferase Ppa-lsy-12 and the methyl-binding-protein Ppa-mbd-2 mimic the eud-1 phenotype, resulting in the absence of one mouth-form. Mutations in both genes cause histone modification defects and reduced eud-1 expression. Surprisingly, Ppa-lsy-12 mutants also result in the down-regulation of an antisense-eud-1 RNA. eud-1 and antisense-eud-1 are co-expressed and further experiments suggest that antisense-eud-1 acts through eud-1 itself. Indeed, overexpression of the antisense-eud-1 RNA increases the eud-1-sensitive mouth-form and extends eud-1 expression. In contrast, this effect is absent in eud-1 mutants indicating that antisense-eud-1 positively regulates eud-1. Thus, chromatin remodelling and antisense-mediated up-regulation of eud-1 control feeding plasticity in Pristionchus. PMID:27487725

  1. Allosteric communication pathways routed by Ca2+/Mg2+ exchange in GCAP1 selectively switch target regulation modes

    PubMed Central

    Marino, Valerio; Dell’Orco, Daniele

    2016-01-01

    GCAP1 is a neuronal calcium sensor protein that regulates the phototransduction cascade in vertebrates by switching between activator and inhibitor of the target guanylate cyclase (GC) in a Ca2+-dependent manner. We carried out exhaustive molecular dynamics simulations of GCAP1 and determined the intramolecular communication pathways involved in the specific GC activator/inhibitor switch. The switch was found to depend on the Mg2+/Ca2+ loading states of the three EF hands and on the way the information is transferred from each EF hand to specific residues at the GCAP1/GC interface. Post-translational myristoylation is fundamental to mediate long range allosteric interactions including the EF2-EF4 coupling and the communication between EF4 and the GC binding interface. Some hubs in the identified protein network are the target of retinal dystrophy mutations, suggesting that the lack of complete inhibition of GC observed in many cases is likely due to the perturbation of intra/intermolecular communication routes. PMID:27739433

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

    NASA Astrophysics Data System (ADS)

    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.

  3. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells.

    PubMed

    Ise, Wataru; Kohyama, Masako; Schraml, Barbara U; Zhang, Tingting; Schwer, Bjoern; Basu, Uttiya; Alt, Frederick W; Tang, Jun; Oltz, Eugene M; Murphy, Theresa L; Murphy, Kenneth M

    2011-06-01

    The transcription factor BATF controls the differentiation of interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) by regulating expression of the transcription factor RORγt itself and RORγt target genes such as Il17. Here we report the mechanism by which BATF controls in vivo class-switch recombination (CSR). In T cells, BATF directly controlled expression of the transcription factors Bcl-6 and c-Maf, both of which are needed for development of follicular helper T cells (T(FH) cells). Restoring T(FH) cell activity to Batf(-/-) T cells in vivo required coexpression of Bcl-6 and c-Maf. In B cells, BATF directly controlled the expression of both activation-induced cytidine deaminase (AID) and of germline transcripts of the intervening heavy-chain region and constant heavy-chain region (I(H)-C(H)). Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo.

  4. The horizontally-acquired response regulator SsrB drives a Salmonella lifestyle switch by relieving biofilm silencing

    PubMed Central

    Desai, Stuti K; Winardhi, Ricksen S; Periasamy, Saravanan; Dykas, Michal M; Jie, Yan; Kenney, Linda J

    2016-01-01

    A common strategy by which bacterial pathogens reside in humans is by shifting from a virulent lifestyle, (systemic infection), to a dormant carrier state. Two major serovars of Salmonella enterica, Typhi and Typhimurium, have evolved a two-component regulatory system to exist inside Salmonella-containing vacuoles in the macrophage, as well as to persist as asymptomatic biofilms in the gallbladder. Here we present evidence that SsrB, a transcriptional regulator encoded on the SPI-2 pathogenicity-island, determines the switch between these two lifestyles by controlling ancestral and horizontally-acquired genes. In the acidic macrophage vacuole, the kinase SsrA phosphorylates SsrB, and SsrB~P relieves silencing of virulence genes and activates their transcription. In the absence of SsrA, unphosphorylated SsrB directs transcription of factors required for biofilm formation specifically by activating csgD (agfD), the master biofilm regulator by disrupting the silenced, H-NS-bound promoter. Anti-silencing mechanisms thus control the switch between opposing lifestyles. DOI: http://dx.doi.org/10.7554/eLife.10747.001 PMID:26880544

  5. Regulation of spine morphology and spine density by NMDA receptor signaling in vivo

    PubMed Central

    Ultanir, Sila K.; Kim, Ji-Eun; Hall, Benjamin J.; Deerinck, Thomas; Ellisman, Mark; Ghosh, Anirvan

    2007-01-01

    Dendritic spines are the major sites of excitatory synaptic transmission in the CNS, and their size and density influence the functioning of neuronal circuits. Here we report that NMDA receptor signaling plays a critical role in regulating spine size and density in the developing cortex. Genetic deletion of the NR1 subunit of the NMDA receptor in the cortex leads to a decrease in spine density and an increase in spine head size in cortical layer 2/3 pyramidal neurons. This process is accompanied by an increase in the presynaptic axon bouton volume and the postsynaptic density area, as well as an increase in the miniature excitatory postsynaptic current amplitude and frequency. These observations indicate that NMDA receptors regulate synapse structure and function in the developing cortex. PMID:18048342

  6. Regulation of spine morphology and spine density by NMDA receptor signaling in vivo.

    PubMed

    Ultanir, Sila K; Kim, Ji-Eun; Hall, Benjamin J; Deerinck, Thomas; Ellisman, Mark; Ghosh, Anirvan

    2007-12-04

    Dendritic spines are the major sites of excitatory synaptic transmission in the CNS, and their size and density influence the functioning of neuronal circuits. Here we report that NMDA receptor signaling plays a critical role in regulating spine size and density in the developing cortex. Genetic deletion of the NR1 subunit of the NMDA receptor in the cortex leads to a decrease in spine density and an increase in spine head size in cortical layer 2/3 pyramidal neurons. This process is accompanied by an increase in the presynaptic axon bouton volume and the postsynaptic density area, as well as an increase in the miniature excitatory postsynaptic current amplitude and frequency. These observations indicate that NMDA receptors regulate synapse structure and function in the developing cortex.

  7. Keratan Sulfate Regulates the Switch from Motor Neuron to Oligodendrocyte Generation During Development of the Mouse Spinal Cord.

    PubMed

    Hashimoto, Hirokazu; Ishino, Yugo; Jiang, Wen; Yoshimura, Takeshi; Takeda-Uchimura, Yoshiko; Uchimura, Kenji; Kadomatsu, Kenji; Ikenaka, Kazuhiro

    2016-02-01

    Keratan sulfate (KS) is a sulfated glycosaminoglycan and has been shown to bind to sonic hedgehog (Shh), which act as a morphogen to regulate the embryonic spinal cord development. We found highly sulfated KS was present in the floor plate (including lateral floor plate) and the notochord . This expression colocalized with Shh expression. To understand the roles of KS, we analyzed the embryonic spinal cord of GlcNAc6ST-1, KS chain synthesizing enzyme, knock-out (KO) mice. At E12.5, the pMN domain, whose formation is controlled by Shh signaling, became shifted ventrally in GlcNAc6ST-1 KO mice. In addition, the expression patterns of Patched1 and Gli1, two Shh signaling reporter genes, differed between wild type (WT) and GlcNAc6ST-1 KO mice at E12.5. Next, we focused on cell types generated from the pMN domain; namely, motor neurons and subsequently oligodendrocytes. The number of PDGFRα(+) [a marker for oligodendrocyte precursor cells (OPCs)] cells was low in the E12.5 mutant spinal cord, while motor neuron production was increased. Thus the switch from motor neuron generation to OPC generation was delayed in the pMN domain. Furthermore, we investigated the cause for this delayed switch in the pMN domain. The number of Olig2, Nkx2.2 double-positive cells was less in GlcNAc6ST-1 KO mice than in WT mice. In contrast, the number of Olig2, Neurogenin2 (Ngn2) double-positive cells related to the motor neuron specification was significantly greater in the KO mice. These results indicate that KS is important for the late phase Shh signaling and contributes to motor neuron to OPC generation switch.

  8. RNA Polymerase: Chromosome Domain Boundary Maker and Regulator of Supercoil Density

    PubMed Central

    Higgins, N. Patrick

    2014-01-01

    Summary Most bacterial chromosomes and plasmids are covalently closed circular molecules that are maintained in a dynamic supercoiled state. Average supercoil density differs significantly between E. coli and Salmonella. Two related questions are: 1) What protein(s) create supercoil domain boundaries in a bacterial chromosome? 2) How is supercoil density regulated in different bacterial species? RNA polymerase plays pivotal roles in both of these topological phenomena. PMID:25460807

  9. Heterotypic interactions regulate cell shape and density during color pattern formation in zebrafish

    PubMed Central

    Mahalwar, Prateek; Singh, Ajeet Pratap; Fadeev, Andrey; Nüsslein-Volhard, Christiane

    2016-01-01

    ABSTRACT The conspicuous striped coloration of zebrafish is produced by cell-cell interactions among three different types of chromatophores: black melanophores, orange/yellow xanthophores and silvery/blue iridophores. During color pattern formation xanthophores undergo dramatic cell shape transitions and acquire different densities, leading to compact and orange xanthophores at high density in the light stripes, and stellate, faintly pigmented xanthophores at low density in the dark stripes. Here, we investigate the mechanistic basis of these cell behaviors in vivo, and show that local, heterotypic interactions with dense iridophores regulate xanthophore cell shape transition and density. Genetic analysis reveals a cell-autonomous requirement of gap junctions composed of Cx41.8 and Cx39.4 in xanthophores for their iridophore-dependent cell shape transition and increase in density in light-stripe regions. Initial melanophore-xanthophore interactions are independent of these gap junctions; however, subsequently they are also required to induce the acquisition of stellate shapes in xanthophores of the dark stripes. In summary, we conclude that, whereas homotypic interactions regulate xanthophore coverage in the skin, their cell shape transitions and density is regulated by gap junction-mediated, heterotypic interactions with iridophores and melanophores. PMID:27742608

  10. Switching on sex: transcriptional regulation of the testis-determining gene Sry.

    PubMed

    Larney, Christian; Bailey, Timothy L; Koopman, Peter

    2014-06-01

    Mammalian sex determination hinges on the development of ovaries or testes, with testis fate being triggered by the expression of the transcription factor sex-determining region Y (Sry). Reduced or delayed Sry expression impairs testis development, highlighting the importance of its accurate spatiotemporal regulation and implying a potential role for SRY dysregulation in human intersex disorders. Several epigenetic modifiers, transcription factors and kinases are implicated in regulating Sry transcription, but it remains unclear whether or how this farrago of factors acts co-ordinately. Here we review our current understanding of Sry regulation and provide a model that assembles all known regulators into three modules, each converging on a single transcription factor that binds to the Sry promoter. We also discuss potential future avenues for discovering the cis-elements and trans-factors required for Sry regulation.

  11. A developmentally regulated switch from stem cells to dedifferentiation for limb muscle regeneration in newts.

    PubMed

    Tanaka, Hibiki Vincent; Ng, Nathaniel Chuen Yin; Yang Yu, Zhan; Casco-Robles, Martin Miguel; Maruo, Fumiaki; Tsonis, Panagiotis A; Chiba, Chikafumi

    2016-03-30

    The newt, a urodele amphibian, is able to repeatedly regenerate its limbs throughout its lifespan, whereas other amphibians deteriorate or lose their ability to regenerate limbs after metamorphosis. It remains to be determined whether such an exceptional ability of the newt is either attributed to a strategy, which controls regeneration in larvae, or on a novel one invented by the newt after metamorphosis. Here we report that the newt switches the cellular mechanism for limb regeneration from a stem/progenitor-based mechanism (larval mode) to a dedifferentiation-based one (adult mode) as it transits beyond metamorphosis. We demonstrate that larval newts use stem/progenitor cells such as satellite cells for new muscle in a regenerated limb, whereas metamorphosed newts recruit muscle fibre cells in the stump for the same purpose. We conclude that the newt has evolved novel strategies to secure its regenerative ability of the limbs after metamorphosis.

  12. Regulation of osmoadaptation in the moderate halophile Halobacillus halophilus: chloride, glutamate and switching osmolyte strategies

    PubMed Central

    Saum, Stephan H; Müller, Volker

    2008-01-01

    The moderate halophile Halobacillus halophilus is the paradigm for chloride dependent growth in prokaryotes. Recent experiments shed light on the molecular basis of the chloride dependence that is reviewed here. In the presence of moderate salinities Halobacillus halophilus mainly accumulates glutamine and glutamate to adjust turgor. The transcription of glnA2 (encoding a glutamine synthetase) as well as the glutamine synthetase activity were identified as chloride dependent steps. Halobacillus halophilus switches its osmolyte strategy and produces proline as the main compatible solute at high salinities. Furthermore, Halobacillus halophilus also shifts its osmolyte strategy at the transition from the exponential to the stationary phase where proline is exchanged by ectoine. Glutamate was found as a “second messenger” essential for proline production. This observation leads to a new model of sensing salinity by sensing the physico-chemical properties of different anions. PMID:18442383

  13. A developmentally regulated switch from stem cells to dedifferentiation for limb muscle regeneration in newts

    PubMed Central

    Tanaka, Hibiki Vincent; Ng, Nathaniel Chuen Yin; Yang Yu, Zhan; Casco-Robles, Martin Miguel; Maruo, Fumiaki; Tsonis, Panagiotis A.; Chiba, Chikafumi

    2016-01-01

    The newt, a urodele amphibian, is able to repeatedly regenerate its limbs throughout its lifespan, whereas other amphibians deteriorate or lose their ability to regenerate limbs after metamorphosis. It remains to be determined whether such an exceptional ability of the newt is either attributed to a strategy, which controls regeneration in larvae, or on a novel one invented by the newt after metamorphosis. Here we report that the newt switches the cellular mechanism for limb regeneration from a stem/progenitor-based mechanism (larval mode) to a dedifferentiation-based one (adult mode) as it transits beyond metamorphosis. We demonstrate that larval newts use stem/progenitor cells such as satellite cells for new muscle in a regenerated limb, whereas metamorphosed newts recruit muscle fibre cells in the stump for the same purpose. We conclude that the newt has evolved novel strategies to secure its regenerative ability of the limbs after metamorphosis. PMID:27026263

  14. EDITORIAL: Molecular switches at surfaces Molecular switches at surfaces

    NASA Astrophysics Data System (ADS)

    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

  15. PEAK1 Acts as a Molecular Switch to Regulate Context-Dependent TGFβ Responses in Breast Cancer

    PubMed Central

    Agajanian, Megan; Campeau, Anaamika; Hoover, Malachia; Hou, Alexander; Brambilla, Daniel; Kim, Sa La; Klemke, Richard L.; Kelber, Jonathan A.

    2015-01-01

    Transforming Growth Factor β (TGFβ) has dual functions as both a tumor suppressor and a promoter of cancer progression within the tumor microenvironment, but the molecular mechanisms by which TGFβ signaling switches between these outcomes and the contexts in which this switch occurs remain to be fully elucidated. We previously identified PEAK1 as a new non-receptor tyrosine kinase that associates with the cytoskeleton, and facilitates signaling of HER2/Src complexes. We also showed PEAK1 functions downstream of KRas to promote tumor growth, metastasis and therapy resistance using preclinical in vivo models of human tumor progression. In the current study, we analyzed PEAK1 expression in human breast cancer samples and found PEAK1 levels correlate with mesenchymal gene expression, poor cellular differentiation and disease relapse. At the cellular level, we also observed that PEAK1 expression was highest in mesenchymal breast cancer cells, correlated with migration potential and increased in response to TGFβ-induced epithelial-mesenchymal transition (EMT). Thus, we sought to evaluate the role of PEAK1 in the switching of TGFβ from a tumor suppressing to tumor promoting factor. Notably, we discovered that high PEAK1 expression causes TGFβ to lose its anti-proliferative effects, and potentiates TGFβ-induced proliferation, EMT, cell migration and tumor metastasis in a fibronectin-dependent fashion. In the presence of fibronectin, PEAK1 caused a switching of TGFβ signaling from its canonical Smad2/3 pathway to non-canonical Src and MAPK signaling. This report is the first to provide evidence that PEAK1 mediates signaling cross talk between TGFβ receptors and integrin/Src/MAPK pathways and that PEAK1 is an important molecular regulator of TGFβ-induced tumor progression and metastasis in breast cancer. Finally, PEAK1 overexpression/upregulation cooperates with TGFβ to reduce breast cancer sensitivity to Src kinase inhibition. These findings provide a rational

  16. Current rectifying and resistive switching in high density BiFeO3 nanocapacitor arrays on Nb-SrTiO3 substrates.

    PubMed

    Zhao, Lina; Lu, Zengxing; Zhang, Fengyuan; Tian, Guo; Song, Xiao; Li, Zhongwen; Huang, Kangrong; Zhang, Zhang; Qin, Minghui; SujuanWu; Lu, Xubing; Zeng, Min; Gao, Xingsen; Dai, Jiyan; Liu, Jun-Ming

    2015-04-08

    Ultrahigh density well-registered oxide nanocapacitors are very essential for large scale integrated microelectronic devices. We report the fabrication of well-ordered multiferroic BiFeO3 nanocapacitor arrays by a combination of pulsed laser deposition (PLD) method and anodic aluminum oxide (AAO) template method. The capacitor cells consist of BiFeO3/SrRuO3 (BFO/SRO) heterostructural nanodots on conductive Nb-doped SrTiO3 (Nb-STO) substrates with a lateral size of ~60 nm. These capacitors also show reversible polarization domain structures, and well-established piezoresponse hysteresis loops. Moreover, apparent current-rectification and resistive switching behaviors were identified in these nanocapacitor cells using conductive-AFM technique, which are attributed to the polarization modulated p-n junctions. These make it possible to utilize these nanocapacitors in high-density (>100 Gbit/inch(2)) nonvolatile memories and other oxide nanoelectronic devices.

  17. Current rectifying and resistive switching in high density BiFeO3 nanocapacitor arrays on Nb-SrTiO3 substrates

    NASA Astrophysics Data System (ADS)

    Zhao, Lina; Lu, Zengxing; Zhang, Fengyuan; Tian, Guo; Song, Xiao; Li, Zhongwen; Huang, Kangrong; Zhang, Zhang; Qin, Minghui; Sujuanwu; Lu, Xubing; Zeng, Min; Gao, Xingsen; Dai, Jiyan; Liu, Jun-Ming

    2015-04-01

    Ultrahigh density well-registered oxide nanocapacitors are very essential for large scale integrated microelectronic devices. We report the fabrication of well-ordered multiferroic BiFeO3 nanocapacitor arrays by a combination of pulsed laser deposition (PLD) method and anodic aluminum oxide (AAO) template method. The capacitor cells consist of BiFeO3/SrRuO3 (BFO/SRO) heterostructural nanodots on conductive Nb-doped SrTiO3 (Nb-STO) substrates with a lateral size of ~60 nm. These capacitors also show reversible polarization domain structures, and well-established piezoresponse hysteresis loops. Moreover, apparent current-rectification and resistive switching behaviors were identified in these nanocapacitor cells using conductive-AFM technique, which are attributed to the polarization modulated p-n junctions. These make it possible to utilize these nanocapacitors in high-density (>100 Gbit/inch2) nonvolatile memories and other oxide nanoelectronic devices.

  18. Ni interferes in the Cu-regulated transcriptional switch petJ/petE in Synechocystis sp. PCC 6803.

    PubMed

    Giner-Lamia, Joaquín; López-Maury, Luis; Florencio, Francisco J

    2016-10-01

    Plastocyanin (petE) plays an essential role in photosynthesis as an electron carrier between cytochrome b6 f and photosystem I, and in some cyanobacteria it can be replaced by the haem-containing protein, cytochrome c6 (petJ). In Synechocystis sp. PCC 6803, transcription of petE and petJ is activated and repressed, respectively, by Cu. Here, we show that Ni can act similarly to Cu in inducing petE and repressing petJ, thus leading to a partial switch between cytochrome c6 and plastocyanin. Transcription of these genes is only altered by Ni in Cu-depleted medium, and none of the Ni-dependent transcription factors described in Synechocystis, NrsR and InrS seem to be involved in this regulation. Finally, we show that plastocyanin is essential for growth under conditions of excess Ni.

  19. A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells.

    PubMed

    Bu, Pengcheng; Chen, Kai-Yuan; Chen, Joyce Huan; Wang, Lihua; Walters, Jewell; Shin, Yong Jun; Goerger, Julian P; Sun, Jian; Witherspoon, Mavee; Rakhilin, Nikolai; Li, Jiahe; Yang, Herman; Milsom, Jeff; Lee, Sang; Zipfel, Warren; Jin, Moonsoo M; Gümüş, Zeynep H; Lipkin, Steven M; Shen, Xiling

    2013-05-02

    microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.

  20. Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation

    PubMed Central

    Kioka, Hidetaka; Kato, Hisakazu; Fujikawa, Makoto; Tsukamoto, Osamu; Suzuki, Toshiharu; Imamura, Hiromi; Nakano, Atsushi; Higo, Shuichiro; Yamazaki, Satoru; Matsuzaki, Takashi; Takafuji, Kazuaki; Asanuma, Hiroshi; Asakura, Masanori; Minamino, Tetsuo; Shintani, Yasunori; Yoshida, Masasuke; Noji, Hiroyuki; Kitakaze, Masafumi; Komuro, Issei; Asano, Yoshihiro; Takashima, Seiji

    2014-01-01

    The oxidative phosphorylation (OXPHOS) system generates most of the ATP in respiring cells. ATP-depleting conditions, such as hypoxia, trigger responses that promote ATP production. However, how OXPHOS is regulated during hypoxia has yet to be elucidated. In this study, selective measurement of intramitochondrial ATP levels identified the hypoxia-inducible protein G0/G1 switch gene 2 (G0s2) as a positive regulator of OXPHOS. A mitochondria-targeted, FRET-based ATP biosensor enabled us to assess OXPHOS activity in living cells. Mitochondria-targeted, FRET-based ATP biosensor and ATP production assay in a semiintact cell system revealed that G0s2 increases mitochondrial ATP production. The expression of G0s2 was rapidly and transiently induced by hypoxic stimuli, and G0s2 interacts with OXPHOS complex V (FoF1-ATP synthase). Furthermore, physiological enhancement of G0s2 expression prevented cells from ATP depletion and induced a cellular tolerance for hypoxic stress. These results show that G0s2 positively regulates OXPHOS activity by interacting with FoF1-ATP synthase, which causes an increase in ATP production in response to hypoxic stress and protects cells from a critical energy crisis. These findings contribute to the understanding of a unique stress response to energy depletion. Additionally, this study shows the importance of assessing intramitochondrial ATP levels to evaluate OXPHOS activity in living cells. PMID:24344269

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

    PubMed Central

    Lee, Seoghyun; Sohn, Kyung-Cheol; Choi, Dae-Kyoung; Won, Minho; Park, Kyeong Ah; Ju, Sung-Kyu; Kang, Kidong; Bae, Young-Ki; Hur, Gang Min; Ro, Hyunju

    2016-01-01

    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. PMID:27673563

  2. Numerical and experimental study of a high port-density WDM optical packet switch architecture for data centers.

    PubMed

    Di Lucente, S; Luo, J; Centelles, R Pueyo; Rohit, A; Zou, S; Williams, K A; Dorren, H J S; Calabretta, N

    2013-01-14

    Data centers have to sustain the rapid growth of data traffic due to the increasing demand of bandwidth-hungry internet services. The current intra-data center fat tree topology causes communication bottlenecks in the server interaction process, power-hungry O-E-O conversions that limit the minimum latency and the power efficiency of these systems. In this paper we numerically and experimentally investigate an optical packet switch architecture with modular structure and highly distributed control that allow configuration times in the order of nanoseconds. Numerical results indicate that the candidate architecture scaled over 4000 ports, provides an overall throughput over 50 Tb/s and a packet loss rate below 10(-6) while assuring sub-microsecond latency. We present experimental results that demonstrate the feasibility of a 16x16 optical packet switch based on parallel 1x4 integrated optical cross-connect modules. Error-free operations can be achieved with 4 dB penalty while the overall energy consumption is of 66 pJ/b. Based on those results, we discuss feasibility to scale the architecture to a much larger port count.

  3. Density-dependent intraspecific aggression regulates survival in northern Yellowstone wolves (Canis lupus).

    PubMed

    Cubaynes, Sarah; MacNulty, Daniel R; Stahler, Daniel R; Quimby, Kira A; Smith, Douglas W; Coulson, Tim

    2014-11-01

    Understanding the population dynamics of top-predators is essential to assess their impact on ecosystems and to guide their management. Key to this understanding is identifying the mechanisms regulating vital rates. Determining the influence of density on survival is necessary to understand the extent to which human-caused mortality is compensatory or additive. In wolves (Canis lupus), empirical evidence for density-dependent survival is lacking. Dispersal is considered the principal way in which wolves adjust their numbers to prey supply or compensate for human exploitation. However, studies to date have primarily focused on exploited wolf populations, in which density-dependent mechanisms are likely weak due to artificially low wolf densities. Using 13 years of data on 280 collared wolves in Yellowstone National Park, we assessed the effect of wolf density, prey abundance and population structure, as well as winter severity, on age-specific survival in two areas (prey-rich vs. prey-poor) of the national park. We further analysed cause-specific mortality and explored the factors driving intraspecific aggression in the prey-rich northern area of the park. Overall, survival rates decreased during the study. In northern Yellowstone, density dependence regulated adult survival through an increase in intraspecific aggression, independent of prey availability. In the interior of the park, adult survival was less variable and density-independent, despite reduced prey availability. There was no effect of prey population structure in northern Yellowstone, or of winter severity in either area. Survival was similar among yearlings and adults, but lower for adults older than 6 years. Our results indicate that density-dependent intraspecific aggression is a major driver of adult wolf survival in northern Yellowstone, suggesting intrinsic density-dependent mechanisms have the potential to regulate wolf populations at high ungulate densities. When low prey availability or high

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

    SciTech Connect

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

    2014-07-01

    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.

  5. The molecular circuitry regulating the switch between iron deficiency and overload in mice.

    PubMed

    Mok, Henry; Mlodnicka, Agnieszka E; Hentze, Matthias W; Muckenthaler, Martina; Schumacher, Armin

    2006-03-24

    Recent positional cloning of the radiation-induced polycythaemia (Pcm) mutation revealed a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), the sole cellular iron exporter identified to date. Here we report a molecular definition of the regulatory mechanisms governing the dynamic changes in iron balance in Pcm heterozygous mice between 3 and 12 weeks of age. Hepatic and/or duodenal response patterns of iron metabolism genes, such as Trfr, cybrd1, and Slc11a2, explained the transition from early postnatal iron deficiency to iron overload by 12 weeks of age. A significant delay in developmental up-regulation of hepcidin (Hamp), the pivotal hormonal regulator of iron homeostasis, correlated with high levels of Fpn1 expression in hepatic Kupffer cells and duodenal epithelial cells at 7 weeks of age. Conversely, upon up-regulation of Hamp expression at 12 weeks of age, Fpn1 expression decreased, indicative of a Hamp-mediated homeostatic loop. Hamp regulation due to iron did not appear dependent on transcription-level changes of the murine homolog of Hemojuvelin (Rgmc). Aged cohorts of Pcm mice exhibited low levels of Fpn1 expression in the context of an iron-deficient erythropoiesis and profound iron sequestration in reticuloendothelial macrophages, duodenum, and other tissues. Thus, similar to the anemia of chronic disease, these findings demonstrate decreased iron bioavailability due to sustained down-regulation of Fpn1 levels by Hamp. We conclude that regulatory alleles, such as Pcm, with highly dynamic changes in iron balance are ideally suited to interrogate the genetic circuitry regulating iron metabolism.

  6. A switch from low to high Shh activity regulates establishment of limb progenitors and signaling centers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The patterning and growth of the embryonic vertebrate limb is dependent on Sonic hedgehog (Shh), a morphogen that regulates the activity of Gli transcription factors. However, "Shh" expression is not observed during the first 12 hours of limb development. During this phase, the limb bud is prepatter...

  7. Density-dependent regulation of the sex ratio in an annual plant.

    PubMed

    Dorken, Marcel E; Pannell, John R

    2008-06-01

    Sex ratios are subject to strong frequency-dependent selection regulated by the mating system and the relative male versus female investment. In androdioecious plant populations, where males co-occur with hermaphrodites, the sex ratio depends on the rate of self-fertilization by hermaphrodites and on the relative pollen production of males versus hermaphrodites. Here, we report evolutionary changes in the sex ratio from experimental mating arrays of the androdioecious plant Mercurialis annua. We found that the progeny sex ratio depended strongly on density, with fewer males in the progeny of plants grown under low density. This occurred in part because of a plastic adjustment in pollen production by hermaphrodites, which produced more pollen when grown at low density than at high density. Our results provide support for the prediction that environmental conditions govern sex ratios through their effects on the relative fertility of unisexual versus hermaphrodite individuals.

  8. POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA

    PubMed Central

    Kühl, Inge; Miranda, Maria; Posse, Viktor; Milenkovic, Dusanka; Mourier, Arnaud; Siira, Stefan J.; Bonekamp, Nina A.; Neumann, Ulla; Filipovska, Aleksandra; Polosa, Paola Loguercio; Gustafsson, Claes M.; Larsson, Nils-Göran

    2016-01-01

    Mitochondria are vital in providing cellular energy via their oxidative phosphorylation system, which requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes (mtDNA). Transcription of the circular mammalian mtDNA depends on a single mitochondrial RNA polymerase (POLRMT). Although the transcription initiation process is well understood, it is debated whether POLRMT also serves as the primase for the initiation of mtDNA replication. In the nucleus, the RNA polymerases needed for gene expression have no such role. Conditional knockout of Polrmt in the heart results in severe mitochondrial dysfunction causing dilated cardiomyopathy in young mice. We further studied the molecular consequences of different expression levels of POLRMT and found that POLRMT is essential for primer synthesis to initiate mtDNA replication in vivo. Furthermore, transcription initiation for primer formation has priority over gene expression. Surprisingly, mitochondrial transcription factor A (TFAM) exists in an mtDNA-free pool in the Polrmt knockout mice. TFAM levels remain unchanged despite strong mtDNA depletion, and TFAM is thus protected from degradation of the AAA+ Lon protease in the absence of POLRMT. Last, we report that mitochondrial transcription elongation factor may compensate for a partial depletion of POLRMT in heterozygous Polrmt knockout mice, indicating a direct regulatory role of this factor in transcription. In conclusion, we present in vivo evidence that POLRMT has a key regulatory role in the replication of mammalian mtDNA and is part of a transcriptional mechanism that provides a switch between primer formation for mtDNA replication and mitochondrial gene expression. PMID:27532055

  9. Regulation of dynamic polarity switching in bacteria by a Ras-like G-protein and its cognate GAP.

    PubMed

    Leonardy, Simone; Miertzschke, Mandy; Bulyha, Iryna; Sperling, Eva; Wittinghofer, Alfred; Søgaard-Andersen, Lotte

    2010-07-21

    The rod-shaped cells of the bacterium Myxococcus xanthus move uni-directionally and occasionally undergo reversals during which the leading/lagging polarity axis is inverted. Cellular reversals depend on pole-to-pole relocation of motility proteins that localize to the cell poles between reversals. We show that MglA is a Ras-like G-protein and acts as a nucleotide-dependent molecular switch to regulate motility and that MglB represents a novel GTPase-activating protein (GAP) family and is the cognate GAP of MglA. Between reversals, MglA/GTP is restricted to the leading and MglB to the lagging pole defining the leading/lagging polarity axis. For reversals, the Frz chemosensory system induces the relocation of MglA/GTP to the lagging pole causing an inversion of the leading/lagging polarity axis. MglA/GTP stimulates motility by establishing correct polarity of motility proteins between reversals and reversals by inducing their pole-to-pole relocation. Thus, the function of Ras-like G-proteins and their GAPs in regulating cell polarity is found not only in eukaryotes, but also conserved in bacteria.

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

    PubMed

    Schweiger, Martina; Paar, Margret; Eder, Christina; Brandis, Janina; Moser, Elena; Gorkiewicz, Gregor; Grond, Susanne; Radner, Franz P W; Cerk, Ines; Cornaciu, Irina; Oberer, Monika; Kersten, Sander; Zechner, Rudolf; Zimmermann, Robert; Lass, Achim

    2012-11-01

    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), which is regulated by two proteins annotated as comparative gene identification-58 (CGI-58) and G0/G1 switch gene-2 (G0S2). CGI-58 activates and G0S2 inhibits ATGL activity. In contrast to mice, the functional role of G0S2 in human adipocyte lipolysis is poorly characterized. Here we show that overexpression or silencing of G0S2 in human SGBS adipocytes decreases and increases lipolysis, respectively. Human G0S2 is upregulated during adipocyte differentiation and inhibits ATGL activity in a dose-dependent manner. Interestingly, C-terminally truncated ATGL mutants, which fail to localize to lipid droplets, translocate to the lipid droplet upon coexpression with G0S2, suggesting that G0S2 anchors ATGL to lipid droplets independent of ATGL's C-terminal lipid binding domain. Taken together, our results indicate that G0S2 also regulates human lipolysis by affecting enzyme activity and intracellular localization of ATGL. Increased lipolysis is known to contribute to the pathogenesis of insulin resistance, and G0S2 expression has been shown to be reduced in poorly controlled type 2 diabetic patients. Our data indicate that downregulation of G0S2 in adipose tissue could represent one of the underlying causes leading to increased lipolysis in the insulin-resistant state.

  11. New Kinase Regulation Mechanism Found in HipBA: a Bacterial Persistence Switch

    SciTech Connect

    Evdokimov, A.; Voznesensky, I; Fennell, K; Anderson, M; Smith, J; Fisher, D

    2009-01-01

    Bacterial persistence is the ability of individual cells to randomly enter a period of dormancy during which the cells are protected against antibiotics. In Escherichia coli, persistence is regulated by the activity of a protein kinase HipA and its DNA-binding partner HipB, which is a strong inhibitor of both HipA activity and hip operon transcription. The crystal structure of the HipBA complex was solved by application of the SAD technique to a mercury derivative. In this article, the fortuitous and interesting effect of mercury soaks on the native HipBA crystals is discussed as well as the intriguing tryptophan-binding pocket found on the HipA surface. A HipA-regulation model is also proposed that is consistent with the available structural and biochemical data.

  12. Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair.

    PubMed

    Matthews, Allysia J; Zheng, Simin; DiMenna, Lauren J; Chaudhuri, Jayanta

    2014-01-01

    Upon encountering antigens, mature IgM-positive B lymphocytes undergo class-switch recombination (CSR) wherein exons encoding the default Cμ constant coding gene segment of the immunoglobulin (Ig) heavy-chain (Igh) locus are excised and replaced with a new constant gene segment (referred to as "Ch genes", e.g., Cγ, Cɛ, or Cα). The B cell thereby changes from expressing IgM to one producing IgG, IgE, or IgA, with each antibody isotype having a different effector function during an immune reaction. CSR is a DNA deletional-recombination reaction that proceeds through the generation of DNA double-strand breaks (DSBs) in repetitive switch (S) sequences preceding each Ch gene and is completed by end-joining between donor Sμ and acceptor S regions. CSR is a multistep reaction requiring transcription through S regions, the DNA cytidine deaminase AID, and the participation of several general DNA repair pathways including base excision repair, mismatch repair, and classical nonhomologous end-joining. In this review, we discuss our current understanding of how transcription through S regions generates substrates for AID-mediated deamination and how AID participates not only in the initiation of CSR but also in the conversion of deaminated residues into DSBs. Additionally, we review the multiple processes that regulate AID expression and facilitate its recruitment specifically to the Ig loci, and how deregulation of AID specificity leads to oncogenic translocations. Finally, we summarize recent data on the potential role of AID in the maintenance of the pluripotent stem cell state during epigenetic reprogramming.

  13. Regulation of Immunoglobulin Class-Switch Recombination: Choreography of Noncoding Transcription, Targeted DNA Deamination, and Long-Range DNA Repair

    PubMed Central

    Matthews, Allysia J.; Zheng, Simin; DiMenna, Lauren J.; Chaudhuri, Jayanta

    2014-01-01

    Upon encountering antigens, mature IgM-positive B lymphocytes undergo class-switch recombination (CSR) wherein exons encoding the default Cμ constant coding gene segment of the immunoglobulin (Ig) heavy-chain (Igh) locus are excised and replaced with a new constant gene segment (referred to as “Ch genes”, e.g., Cγ, Cε, or Cα). The B cell thereby changes from expressing IgM to one producing IgG, IgE, or IgA, with each antibody isotype having a different effector function during an immune reaction. CSR is a DNA deletional-recombination reaction that proceeds through the generation of DNA double-strand breaks (DSBs) in repetitive switch (S) sequences preceding each Ch gene and is completed by end-joining between donor Sμ and acceptor S regions. CSR is a multistep reaction requiring transcription through S regions, the DNA cytidine deaminase AID, and the participation of several general DNA repair pathways including base excision repair, mismatch repair, and classical nonhomologous end-joining. In this review, we discuss our current understanding of how transcription through S regions generates substrates for AID-mediated deamination and how AID participates not only in the initiation of CSR but also in the conversion of deaminated residues into DSBs. Additionally, we review the multiple processes that regulate AID expression and facilitate its recruitment specifically to the Ig loci, and how deregulation of AID specificity leads to oncogenic translocations. Finally, we summarize recent data on the potential role of AID in the maintenance of the pluripotent stem cell state during epigenetic reprogramming. PMID:24507154

  14. Pseudomonas aeruginosa AmpR: an acute–chronic switch regulator

    PubMed Central

    Balasubramanian, Deepak; Kumari, Hansi; Mathee, Kalai

    2015-01-01

    Pseudomonas aeruginosa is one of the most intractable human pathogens that pose serious clinical challenge due to extensive prevalence of multidrug-resistant clinical isolates. Armed with abundant virulence and antibiotic resistance mechanisms, it is a major etiologic agent in a number of acute and chronic infections. A complex and intricate network of regulators dictates the expression of pathogenicity factors in P. aeruginosa. Some proteins within the network play key roles and control multiple pathways. This review discusses the role of one such protein, AmpR, which was initially recognized for its role in antibiotic resistance by regulating AmpC β-lactamase. Recent genomic, proteomic and phenotypic analyses demonstrate that AmpR regulates expression of hundreds of genes that are involved in diverse pathways such as β-lactam and non-β-lactam resistance, quorum sensing and associated virulence phenotypes, protein phosphorylation, and physiological processes. Finally, ampR mutations in clinical isolates are reviewed to shed light on important residues required for its function in antibiotic resistance. The prevalence and evolutionary implications of AmpR in pathogenic and nonpathogenic proteobacteria are also discussed. A comprehensive understanding of proteins at nodal positions in the P. aeruginosa regulatory network is crucial in understanding, and ultimately targeting, the pathogenic stratagems of this organism. PMID:25066236

  15. Two Master Switch Regulators Trigger A40926 Biosynthesis in Nonomuraea sp. Strain ATCC 39727

    PubMed Central

    Lo Grasso, Letizia; Maffioli, Sonia; Sosio, Margherita; Bibb, Mervyn; Puglia, Anna Maria

    2015-01-01

    ABSTRACT The actinomycete Nonomuraea sp. strain ATCC 39727 produces the glycopeptide A40926, the precursor of dalbavancin. Biosynthesis of A40926 is encoded by the dbv gene cluster, which contains 37 protein-coding sequences that participate in antibiotic biosynthesis, regulation, immunity, and export. In addition to the positive regulatory protein Dbv4, the A40926-biosynthetic gene cluster encodes two additional putative regulators, Dbv3 and Dbv6. Independent mutations in these genes, combined with bioassays and liquid chromatography-mass spectrometry (LC-MS) analyses, demonstrated that Dbv3 and Dbv4 are both required for antibiotic production, while inactivation of dbv6 had no effect. In addition, overexpression of dbv3 led to higher levels of A40926 production. Transcriptional and quantitative reverse transcription (RT)-PCR analyses showed that Dbv4 is essential for the transcription of two operons, dbv14-dbv8 and dbv30-dbv35, while Dbv3 positively controls the expression of four monocistronic transcription units (dbv4, dbv29, dbv36, and dbv37) and of six operons (dbv2-dbv1, dbv14-dbv8, dbv17-dbv15, dbv21-dbv20, dbv24-dbv28, and dbv30-dbv35). We propose a complex and coordinated model of regulation in which Dbv3 directly or indirectly activates transcription of dbv4 and controls biosynthesis of 4-hydroxyphenylglycine and the heptapeptide backbone, A40926 export, and some tailoring reactions (mannosylation and hexose oxidation), while Dbv4 directly regulates biosynthesis of 3,5-dihydroxyphenylglycine and other tailoring reactions, including the four cross-links, halogenation, glycosylation, and acylation. IMPORTANCE This report expands knowledge of the regulatory mechanisms used to control the biosynthesis of the glycopeptide antibiotic A40926 in the actinomycete Nonomuraea sp. strain ATCC 39727. A40926 is the precursor of dalbavancin, approved for treatment of skin infections by Gram-positive bacteria. Therefore, understanding the regulation of its biosynthesis

  16. Extracellular Matrix Density Regulates the Rate of Neovessel Growth and Branching in Sprouting Angiogenesis

    PubMed Central

    Edgar, Lowell T.; Underwood, Clayton J.; Guilkey, James E.; Hoying, James B.; Weiss, Jeffrey A.

    2014-01-01

    Angiogenesis is regulated by the local microenvironment, including the mechanical interactions between neovessel sprouts and the extracellular matrix (ECM). However, the mechanisms controlling the relationship of mechanical and biophysical properties of the ECM to neovessel growth during sprouting angiogenesis are just beginning to be understood. In this research, we characterized the relationship between matrix density and microvascular topology in an in vitro 3D organ culture model of sprouting angiogenesis. We used these results to design and calibrate a computational growth model to demonstrate how changes in individual neovessel behavior produce the changes in vascular topology that were observed experimentally. Vascularized gels with higher collagen densities produced neovasculatures with shorter vessel lengths, less branch points, and reduced network interconnectivity. The computational model was able to predict these experimental results by scaling the rates of neovessel growth and branching according to local matrix density. As a final demonstration of utility of the modeling framework, we used our growth model to predict several scenarios of practical interest that could not be investigated experimentally using the organ culture model. Increasing the density of the ECM significantly reduced angiogenesis and network formation within a 3D organ culture model of angiogenesis. Increasing the density of the matrix increases the stiffness of the ECM, changing how neovessels are able to deform and remodel their surroundings. The computational framework outlined in this study was capable of predicting this observed experimental behavior by adjusting neovessel growth rate and branching probability according to local ECM density, demonstrating that altering the stiffness of the ECM via increasing matrix density affects neovessel behavior, thereby regulated vascular topology during angiogenesis. PMID:24465500

  17. Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis.

    PubMed

    Bhat, Ramray; Belardi, Brian; Mori, Hidetoshi; Kuo, Peiwen; Tam, Andrew; Hines, William C; Le, Quynh-Thu; Bertozzi, Carolyn R; Bissell, Mina J

    2016-08-16

    Branching morphogenesis in the mammary gland is achieved by the migration of epithelial cells through a microenvironment consisting of stromal cells and extracellular matrix (ECM). Here we show that galectin-1 (Gal-1), an endogenous lectin that recognizes glycans bearing N-acetyllactosamine (LacNAc) epitopes, induces branching migration of mammary epithelia in vivo, ex vivo, and in 3D organotypic cultures. Surprisingly, Gal-1's effects on mammary patterning were independent of its glycan-binding ability and instead required localization within the nuclei of mammary epithelia. Nuclear translocation of Gal-1, in turn, was regulated by discrete cell-surface glycans restricted to the front of the mammary end buds. Specifically, α2,6-sialylation of terminal LacNAc residues in the end buds masked Gal-1 ligands, thereby liberating the protein for nuclear translocation. Within mammary epithelia, Gal-1 localized within nuclear Gemini bodies and drove epithelial invasiveness. Conversely, unsialylated LacNAc glycans, enriched in the epithelial ducts, sequestered Gal-1 in the extracellular environment, ultimately attenuating invasive potential. We also found that malignant breast cells possess higher levels of nuclear Gal-1 and α2,6-SA and lower levels of LacNAc than nonmalignant cells in culture and in vivo and that nuclear localization of Gal-1 promotes a transformed phenotype. Our findings suggest that differential glycosylation at the level of tissue microanatomy regulates the nuclear function of Gal-1 in the context of mammary gland morphogenesis and in cancer progression.

  18. Flagellum density regulates Proteus mirabilis swarmer cell motility in viscous environments.

    PubMed

    Tuson, Hannah H; Copeland, Matthew F; Carey, Sonia; Sacotte, Ryan; Weibel, Douglas B

    2013-01-01

    Proteus mirabilis is an opportunistic pathogen that is frequently associated with urinary tract infections. In the lab, P. mirabilis cells become long and multinucleate and increase their number of flagella as they colonize agar surfaces during swarming. Swarming has been implicated in pathogenesis; however, it is unclear how energetically costly changes in P. mirabilis cell morphology translate into an advantage for adapting to environmental changes. We investigated two morphological changes that occur during swarming--increases in cell length and flagellum density--and discovered that an increase in the surface density of flagella enabled cells to translate rapidly through fluids of increasing viscosity; in contrast, cell length had a small effect on motility. We found that swarm cells had a surface density of flagella that was ∼5 times larger than that of vegetative cells and were motile in fluids with a viscosity that inhibits vegetative cell motility. To test the relationship between flagellum density and velocity, we overexpressed FlhD(4)C(2), the master regulator of the flagellar operon, in vegetative cells of P. mirabilis and found that increased flagellum density produced an increase in cell velocity. Our results establish a relationship between P. mirabilis flagellum density and cell motility in viscous environments that may be relevant to its adaptation during the infection of mammalian urinary tracts and movement in contact with indwelling catheters.

  19. IGFBP-5 regulates muscle cell differentiation by binding to IGF-II and switching on the IGF-II auto-regulation loop

    PubMed Central

    Ren, Hongxia; Yin, Ping; Duan, Cunming

    2008-01-01

    IGF-II stimulates both mitogenesis and myogenesis through its binding and activation of the IGF-I receptor (IGF-IR). How this growth factor pathway promotes these two opposite cellular responses is not well understood. We investigate whether local IGF binding protein-5 (IGFBP-5) promotes the myogenic action of IGF-II. IGFBP-5 is induced before the elevation of IGF-II expression during myogenesis. Knockdown of IGFBP-5 impairs myogenesis and suppresses IGF-II gene expression. IGF-II up-regulates its own gene expression via the PI3K-Akt signaling pathway. Adding IGF-II or constitutively activating Akt rescues the IGFBP-5 knockdown-caused defects. However, an IGF analogue that binds to the IGF-IR but not IGFBP has only a limited effect. When added with low concentrations of IGF-II, IGFBP-5 restores IGF-II expression and myogenic differentiation, whereas an IGF binding–deficient IGFBP-5 mutant has no effect. These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop. PMID:18762576

  20. Inter-individual variability and conspecific densities: consequences for population regulation and range expansion.

    PubMed

    Cardador, Laura; Carrete, Martina; Mañosa, Santi

    2012-01-01

    The presence of conspecifics can strongly modulate the quality of a breeding site. Both positive and negative effects of conspecifics can act on the same individuals, with the final balance between its costs and benefits depending on individual characteristics. A particular case of inter-individual variation found in many avian species is chromatic variability. Among birds, plumage coloration can co-vary with morphology, physiology and behavior as well as with age. These relationships suggest that cost-benefit balances of conspecific presence may be different for individuals with different colorations. We investigated whether inter-individual variability affects population regulation and expansion processes by analyzing potential differences in density-dependent productivity and settlement patterns in relation to plumage coloration in a population of a long-lived avian species recently undergoing a notable increase in numbers and distribution range. Our results show strong variation in the effect of density on productivity of breeding pairs depending on plumage coloration of their members. Productivity of dark birds decreased along the breeding density gradient while that of lighter breeders remained unchanged with conspecific density. In a similar way, our results showed an uneven occupation of localities by individuals with different plumage coloration in relation to local densities, with the breeding of lighter harriers more aggregated than that of dark-brown ones. At a population scale, darker birds had higher probability of colonization of the most isolated, empty sites. Explanations for species range expansion and population regulation usually make the inferred assumption that species traits are similar among individuals. However, in most species, there could be individual variation in niche requirements or dispersal propensities among individuals with different traits. Our results contribute to the growing appreciation that the individual traits, but not the

  1. Inter-Individual Variability and Conspecific Densities: Consequences for Population Regulation and Range Expansion

    PubMed Central

    Cardador, Laura; Carrete, Martina; Mañosa, Santi

    2012-01-01

    The presence of conspecifics can strongly modulate the quality of a breeding site. Both positive and negative effects of conspecifics can act on the same individuals, with the final balance between its costs and benefits depending on individual characteristics. A particular case of inter-individual variation found in many avian species is chromatic variability. Among birds, plumage coloration can co-vary with morphology, physiology and behavior as well as with age. These relationships suggest that cost-benefit balances of conspecific presence may be different for individuals with different colorations. We investigated whether inter-individual variability affects population regulation and expansion processes by analyzing potential differences in density-dependent productivity and settlement patterns in relation to plumage coloration in a population of a long-lived avian species recently undergoing a notable increase in numbers and distribution range. Our results show strong variation in the effect of density on productivity of breeding pairs depending on plumage coloration of their members. Productivity of dark birds decreased along the breeding density gradient while that of lighter breeders remained unchanged with conspecific density. In a similar way, our results showed an uneven occupation of localities by individuals with different plumage coloration in relation to local densities, with the breeding of lighter harriers more aggregated than that of dark-brown ones. At a population scale, darker birds had higher probability of colonization of the most isolated, empty sites. Explanations for species range expansion and population regulation usually make the inferred assumption that species traits are similar among individuals. However, in most species, there could be individual variation in niche requirements or dispersal propensities among individuals with different traits. Our results contribute to the growing appreciation that the individual traits, but not the

  2. Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis

    PubMed Central

    Bhat, Ramray; Belardi, Brian; Mori, Hidetoshi; Kuo, Peiwen; Tam, Andrew; Hines, William C.; Le, Quynh-Thu; Bertozzi, Carolyn R.; Bissell, Mina J.

    2016-01-01

    Branching morphogenesis in the mammary gland is achieved by the migration of epithelial cells through a microenvironment consisting of stromal cells and extracellular matrix (ECM). Here we show that galectin-1 (Gal-1), an endogenous lectin that recognizes glycans bearing N-acetyllactosamine (LacNAc) epitopes, induces branching migration of mammary epithelia in vivo, ex vivo, and in 3D organotypic cultures. Surprisingly, Gal-1’s effects on mammary patterning were independent of its glycan-binding ability and instead required localization within the nuclei of mammary epithelia. Nuclear translocation of Gal-1, in turn, was regulated by discrete cell-surface glycans restricted to the front of the mammary end buds. Specifically, α2,6–sialylation of terminal LacNAc residues in the end buds masked Gal-1 ligands, thereby liberating the protein for nuclear translocation. Within mammary epithelia, Gal-1 localized within nuclear Gemini bodies and drove epithelial invasiveness. Conversely, unsialylated LacNAc glycans, enriched in the epithelial ducts, sequestered Gal-1 in the extracellular environment, ultimately attenuating invasive potential. We also found that malignant breast cells possess higher levels of nuclear Gal-1 and α2,6–SA and lower levels of LacNAc than nonmalignant cells in culture and in vivo and that nuclear localization of Gal-1 promotes a transformed phenotype. Our findings suggest that differential glycosylation at the level of tissue microanatomy regulates the nuclear function of Gal-1 in the context of mammary gland morphogenesis and in cancer progression. PMID:27496330

  3. Translation initiation factor 3 regulates switching between different modes of ribosomal subunit joining.

    PubMed

    MacDougall, Daniel D; Gonzalez, Ruben L

    2015-05-08

    Ribosomal subunit joining is a key checkpoint in the bacterial translation initiation pathway during which initiation factors (IFs) regulate association of the 30S initiation complex (IC) with the 50S subunit to control formation of a 70S IC that can enter into the elongation stage of protein synthesis. The GTP-bound form of IF2 accelerates subunit joining, whereas IF3 antagonizes subunit joining and plays a prominent role in maintaining translation initiation fidelity. The molecular mechanisms through which IF2 and IF3 collaborate to regulate the efficiency of 70S IC formation, including how they affect the dynamics of subunit joining, remain poorly defined. Here, we use single-molecule fluorescence resonance energy transfer to monitor the interactions between IF2 and the GTPase-associated center (GAC) of the 50S subunit during real-time subunit joining reactions in the absence and presence of IF3. In the presence of IF3, IF2-mediated subunit joining becomes reversible, and subunit joining events cluster into two distinct classes corresponding to formation of shorter- and longer-lifetime 70S ICs. Inclusion of IF3 within the 30S IC was also found to alter the conformation of IF2 relative to the GAC, suggesting that IF3's regulatory effects may stem in part from allosteric modulation of IF2-GAC interactions. The results are consistent with a model in which IF3 can exert control over the efficiency of subunit joining by modulating the conformation of the 30S IC, which in turn influences the formation of stabilizing intersubunit contacts and thus the reaction's degree of reversibility.

  4. Down-regulation of endogenous KLHL1 decreases voltage-gated calcium current density.

    PubMed

    Perissinotti, Paula P; Ethington, Elizabeth G; Cribbs, Leanne; Koob, Michael D; Martin, Jody; Piedras-Rentería, Erika S

    2014-05-01

    The actin-binding protein Kelch-like 1 (KLHL1) can modulate voltage-gated calcium channels in vitro. KLHL1 interacts with actin and with the pore-forming subunits of Cav2.1 and CaV3.2 calcium channels, resulting in up-regulation of P/Q and T-type current density. Here we tested whether endogenous KLHL1 modulates voltage gated calcium currents in cultured hippocampal neurons by down-regulating the expression of KLHL1 via adenoviral delivery of shRNA targeted against KLHL1 (shKLHL1). Control adenoviruses did not affect any of the neuronal properties measured, yet down-regulation of KLHL1 resulted in HVA current densities ~68% smaller and LVA current densities 44% smaller than uninfected controls, with a concomitant reduction in α(1A) and α(1H) protein levels. Biophysical analysis and western blot experiments suggest Ca(V)3.1 and 3.3 currents are also present in shKLHL1-infected neurons. Synapsin I levels, miniature postsynaptic current frequency, and excitatory and inhibitory synapse number were reduced in KLHL1 knockdown. This study corroborates the physiological role of KLHL1 as a calcium channel modulator and demonstrates a novel, presynaptic role.

  5. A complex thiolate switch regulates the Bacillus subtilis organic peroxide sensor OhrR.

    PubMed

    Lee, Jin-Won; Soonsanga, Sumarin; Helmann, John D

    2007-05-22

    Oxidation of protein thiolates is central to numerous redox-regulated processes. Bacillus subtilis OhrR is an organic peroxide sensor that represses expression of an inducible peroxiredoxin, OhrA. Here, we present evidence that oxidation of the sole cysteine residue in OhrR leads to a sulfenic acid-containing intermediate that retains DNA-binding activity: further reaction to generate either a mixed disulfide (S-thiolation) or a protein sulfenamide (sulfenyl-amide) derivative is essential for derepression. Protein S-thiolation protects OhrR from overoxidation and provides for a facile regeneration of active OhrR by thiol-disulfide exchange reactions. The sulfenamide can also be reduced by thiol-disulfide exchange reactions, although this process is much slower than for mixed disulfides. Recovery of oxidized OhrR from B. subtilis identifies three distinct S-thiolated species, including mixed disulfides with a novel 398-Da thiol, cysteine, and CoASH. Evidence for in vivo formation of the sulfenamide derivative is also presented.

  6. 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells

    PubMed Central

    Schmiedel, Benjamin Joachim; Seumois, Grégory; Samaniego-Castruita, Daniela; Cayford, Justin; Schulten, Veronique; Chavez, Lukas; Ay, Ferhat; Sette, Alessandro; Peters, Bjoern; Vijayanand, Pandurangan

    2016-01-01

    Asthma and autoimmune disease susceptibility has been strongly linked to genetic variants in the 17q21 haploblock that alter the expression of ORMDL3; however, the molecular mechanisms by which these variants perturb gene expression and the cell types in which this effect is most prominent are unclear. We found several 17q21 variants overlapped enhancers present mainly in primary immune cell types. CD4+ T cells showed the greatest increase (threefold) in ORMDL3 expression in individuals carrying the asthma-risk alleles, where ORMDL3 negatively regulated interleukin-2 production. The asthma-risk variants rs4065275 and rs12936231 switched CTCF-binding sites in the 17q21 locus, and 4C-Seq assays showed that several distal cis-regulatory elements upstream of the disrupted ZPBP2 CTCF-binding site interacted with the ORMDL3 promoter region in CD4+ T cells exclusively from subjects carrying asthma-risk alleles. Overall, our results suggested that T cells are one of the most prominent cell types affected by 17q21 variants. PMID:27848966

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

    PubMed

    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.

  8. NF-κB-to-AP-1 Switch: A Mechanism Regulating Transition From Endothelial Barrier Injury to Repair in Endotoxemic Mice

    PubMed Central

    Liu, Gang; Ye, Xiaobing; Miller, Edmund J.; Liu, Shu Fang

    2014-01-01

    Endothelial barrier disruption is a hallmark of multiple organ injury (MOI). However, mechanisms governing the restoration of endothelial barrier function are poorly understood. Here, we uncovered an NF-κB-to-AP-1 switch that regulates the transition from barrier injury to repair following endotoxemic MOI. Endothelial NF-κB mediates barrier repair by inhibiting endothelial cell (EC) apoptosis. Blockade of endothelial NF-κB pathway activated the activator protein (AP)-1 pathway (NF-κB-to-AP-1 switch), which compensated for the anti-apoptotic and barrier-repair functions of NF-κB. The NF-κB-to-AP-1 switch occurred at 24 hours (injury to repair transition phase), but not at 48 hours (repair phase) post-LPS, and required an inflammatory signal within the endothelium. In the absence of an inflammatory signal, the NF-κB-to-AP-1 switch failed, resulting in enhanced EC apoptosis, augmented endothelial permeability, and impeded transition from barrier injury to recovery. The NF-κB-to-AP-1 switch is a protective mechanism to ensure timely transition from endothelial barrier injury to repair, accelerating barrier restoration following MOI. PMID:24986487

  9. AraC protein, regulation of the l-arabinose operon in Escherichia coli, and the light switch mechanism of AraC action.

    PubMed

    Schleif, Robert

    2010-09-01

    This review covers the physiological aspects of regulation of the arabinose operon in Escherichia coli and the physical and regulatory properties of the operon's controlling gene, araC. It also describes the light switch mechanism as an explanation for many of the protein's properties. Although many thousands of homologs of AraC exist and regulate many diverse operons in response to many different inducers or physiological states, homologs that regulate arabinose-catabolizing genes in response to arabinose were identified. The sequence similarities among them are discussed in light of the known structure of the dimerization and DNA-binding domains of AraC.

  10. Structural basis of the mercury(II)-mediated conformational switching of the dual-function transcriptional regulator MerR

    PubMed Central

    Chang, Chih-Chiang; Lin, Li-Ying; Zou, Xiao-Wei; Huang, Chieh-Chen; Chan, Nei-Li

    2015-01-01

    The mer operon confers bacterial resistance to inorganic mercury (Hg2+) and organomercurials by encoding proteins involved in sensing, transport and detoxification of these cytotoxic agents. Expression of the mer operon is under tight control by the dual-function transcriptional regulator MerR. The metal-free, apo MerR binds to the mer operator/promoter region as a repressor to block transcription initiation, but is converted into an activator upon Hg2+-binding. To understand how MerR interacts with Hg2+ and how Hg2+-binding modulates MerR function, we report here the crystal structures of apo and Hg2+-bound MerR from Bacillus megaterium, corresponding respectively to the repressor and activator conformation of MerR. To our knowledge, the apo-MerR structure represents the first visualization of a MerR family member in its intact and inducer-free form. And the Hg2+-MerR structure offers the first view of a triligated Hg2+-thiolate center in a metalloprotein, confirming that MerR binds Hg2+ via trigonal planar coordination geometry. Structural comparison revealed the conformational transition of MerR is coupled to the assembly/disassembly of a buried Hg2+ binding site, thereby providing a structural basis for the Hg2+-mediated functional switching of MerR. The pronounced Hg2+-induced repositioning of the MerR DNA-binding domains suggests a plausible mechanism for the transcriptional regulation of the mer operon. PMID:26150423

  11. Spatial distribution of limited resources and local density regulation in juvenile Atlantic salmon.

    PubMed

    Finstad, Anders G; Einum, Sigurd; Ugedal, Ola; Forseth, Torbjørn

    2009-01-01

    1. Spatial heterogeneity of resources may influence competition among individuals and thus have a fundamental role in shaping population dynamics and carrying capacity. In the present study, we identify shelter opportunities as a limiting resource for juvenile Atlantic salmon (Salmo salar L.). Experimental and field studies are combined in order to demonstrate how the spatial distribution of shelters may influence population dynamics on both within and among population scales. 2. In closed experimental streams, fish performance scaled negatively with decreasing shelter availability and increasing densities. In contrast, the fish in open stream channels dispersed according to shelter availability and performance of fish remaining in the streams did not depend on initial density or shelters. 3. The field study confirmed that spatial variation in densities of 1-year-old juveniles was governed both by initial recruit density and shelter availability. Strength of density-dependent population regulation, measured as carrying capacity, increased with decreasing number of shelters. 4. Nine rivers were surveyed for spatial variation in shelter availability and increased shelter heterogeneity tended to decrease maximum observed population size (measured using catch statistics of adult salmon as a proxy). 5. Our studies highlight the importance of small-scale within-population spatial structure in population dynamics and demonstrate that not only the absolute amount of limiting resources but also their spatial arrangement can be an important factor influencing population carrying capacity.

  12. Stochastic seasonality and nonlinear density-dependent factors regulate population size in an African rodent

    USGS Publications Warehouse

    Leirs, H.; Stenseth, N.C.; Nichols, J.D.; Hines, J.E.; Verhagen, R.; Verheyen, W.

    1997-01-01

    Ecology has long been troubled by the controversy over how populations are regulated. Some ecologists focus on the role of environmental effects, whereas others argue that density-dependent feedback mechanisms are central. The relative importance of both processes is still hotly debated, but clear examples of both processes acting in the same population are rare. Keyfactor analysis (regression of population changes on possible causal factors) and time-series analysis are often used to investigate the presence of density dependence, but such approaches may be biased and provide no information on actual demographic rates. Here we report on both density-dependent and density-independent effects in a murid rodent pest species, the multimammate rat Mastomys natalensis (Smith, 1834), using statistical capture-recapture models. Both effects occur simultaneously, but we also demonstrate that they do not affect all demographic rates in the same way. We have incorporated the obtained estimates of demographic rates in a population dynamics model and show that the observed dynamics are affected by stabilizing nonlinear density-dependent components coupled with strong deterministic and stochastic seasonal components.

  13. Does the house mouse self-regulate its density in maturing sorghum and wheat crops?

    PubMed

    Kaboodvandpour, Shahram; Leung, Luke K-P

    2008-09-01

    1. One of the central questions in population ecology and management is: what regulates population growth? House mouse Mus domesticus L. populations erupt occasionally in grain-growing regions in Australia. This study aimed to determine whether mouse populations are self-regulated in maturing sorghum and wheat crops. This was assessed by examining food supply to mice (i.e. yield) and the relationship between initial mouse density (D(I)) and density at harvest (D(H)). Eight levels of D(I) ranging from 89 to 5555 mice ha(-1) were introduced to sorghum at the hard dough stage and to wheat crops at the milky stage in mouse-proofed pens. D(H) was measured by trapping out mice 49 days after the introduction. 2. There were at least 3.11 tonnes ha(-1) of wheat and 1.85 tonnes ha(-1) of sorghum grain available for mice at harvest. The estimated relationship between D(I) and D(H) was asymptotic exponential, with D(H) initially increasing almost linearly with D(I). When D(I) was above c. 500 mice ha(-1), D(H) increased asymptotically with D(I) and then saturated at c. 3100 mice ha(-1). The asymptotic increases in and saturation of D(H) was due partly to more young mice being born and recruited in pens treated with lower levels of D(I). 3. Our findings indicated that mouse densities in maturing cereal crops were driven by a numerical response of mice to the abundant supply of grain, modified by some unknown self-regulation mechanism that reduced this numerical response of mice at higher mouse densities. The mechanism was possibly spacing behaviours. Although the nature of this self-regulation mechanism is not known our model is, nevertheless, useful for predicting increases and eruptions in mouse population density in sorghum and wheat crops. Understanding the nature of this mechanism may provide insights into population processes that can be exploited in controlling mice in cereal crops.

  14. Hippo signaling regulates Microprocessor and links cell density-dependent miRNA biogenesis to cancer

    PubMed Central

    Mori, Masaki; Triboulet, Robinson; Mohseni, Morvarid; Schlegelmilch, Karin; Shrestha, Kriti; Camargo, Fernando D.; Gregory, Richard I.

    2014-01-01

    SUMMARY Global downregulation of microRNAs (miRNAs) is commonly observed in human cancers and can have a causative role in tumorigenesis. The mechanisms responsible for this phenomenon remain poorly understood. Here we show that YAP, the downstream target of the tumor-suppressive Hippo signaling pathway regulates miRNA biogenesis in a cell density-dependent manner. At low cell density, nuclear YAP binds and sequesters p72 (DDX17), a regulatory component of the miRNA processing machinery. At high cell density, Hippo-mediated cytoplasmic retention of YAP facilitates p72 association with Microprocessor and binding to a specific sequence motif in pri-miRNAs. Inactivation of the Hippo pathway or expression of constitutively active YAP causes widespread miRNA suppression in cells and tumors and a corresponding post-transcriptional induction of MYC expression. Thus, the Hippo pathway links contact-inhibition regulation to miRNA biogenesis and may be responsible for the widespread miRNA repression observed in cancer. PMID:24581491

  15. Study of switching transients in high frequency converters

    NASA Technical Reports Server (NTRS)

    Zinger, Donald S.; Elbuluk, Malik E.; Lee, Tony

    1993-01-01

    As the semiconductor technologies progress rapidly, the power densities and switching frequencies of many power devices are improved. With the existing technology, high frequency power systems become possible. Use of such a system is advantageous in many aspects. A high frequency ac source is used as the direct input to an ac/ac pulse-density-modulation (PDM) converter. This converter is a new concept which employs zero voltage switching techniques. However, the development of this converter is still in its infancy stage. There are problems associated with this converter such as a high on-voltage drop, switching transients, and zero-crossing detecting. Considering these problems, the switching speed and power handling capabilities of the MOS-Controlled Thyristor (MCT) makes the device the most promising candidate for this application. A complete insight of component considerations for building an ac/ac PDM converter for a high frequency power system is addressed. A power device review is first presented. The ac/ac PDM converter requires switches that can conduct bi-directional current and block bi-directional voltage. These bi-directional switches can be constructed using existing power devices. Different bi-directional switches for the converter are investigated. Detailed experimental studies of the characteristics of the MCT under hard switching and zero-voltage switching are also presented. One disadvantage of an ac/ac converter is that turn-on and turn-off of the switches has to be completed instantaneously when the ac source is at zero voltage. Otherwise shoot-through current or voltage spikes can occur which can be hazardous to the devices. In order for the devices to switch softly in the safe operating area even under non-ideal cases, a unique snubber circuit is used in each bi-directional switch. Detailed theory and experimental results for circuits using these snubbers are presented. A current regulated ac/ac PDM converter built using MCT's and IGBT's is

  16. Collagen density regulates xenobiotic and hypoxic response of mammary epithelial cells.

    PubMed

    Curran, Colleen S; Carrillo, Esteban R; Ponik, Suzanne M; Keely, Patricia J

    2015-01-01

    Breast density, where collagen I is the dominant component, is a significant breast cancer risk factor. Cell surface integrins interact with collagen, activate focal adhesion kinase (FAK), and downstream cell signals associated with xenobiotics (AhR, ARNT) and hypoxia (HIF-1α, ARNT). We examined if mammary cells cultured in high density (HD) or low density (LD) collagen gels affected xenobiotic or hypoxic responses. ARNT production was significantly reduced by HD culture and in response to a FAK inhibitor. Consistent with a decrease in ARNT, AhR and HIF-1α reporter activation and VEGF production was lower in HD compared to LD. However, P450 production was enhanced in HD and induced by AhR and HIF-1α agonists, possibly in response to increased NF-κB activaton. Thus, collagen density differentially regulates downstream cell signals of AhR and HIF-1α by modulating the activity of FAK, the release of NF-κB transcriptional factors, and the levels of ARNT.

  17. Collagen density regulates xenobiotic and hypoxic response of mammary epithelial cells

    PubMed Central

    Curran, Colleen S.; Carrillo, Esteban R.; Ponik, Suzanne M.; Keely, Patricia J.

    2014-01-01

    Breast density, where collagen I is the dominant component, is a significant breast cancer risk factor. Cell surface integrins interact with collagen, activate focal adhesion kinase (FAK), and downstream cell signals associated with xenobiotics (AhR, ARNT) and hypoxia (HIF-1α, ARNT). We examined if mammary cells cultured in high density (HD) or low density (LD) collagen gels affected xenobiotic or hypoxic responses. ARNT production was significantly reduced by HD culture and in response to a FAK inhibitor. Consistent with a decrease in ARNT, AhR and HIF-1α reporter activation and VEGF production was lower in HD compared to LD. However, P450 production was enhanced in HD and induced by AhR and HIF-1α agonists, possibly in response to increased NF-kB activaton. Thus, collagen density differentially regulates downstream cell signals of AhR and HIF-1α by modulating the activity of FAK, the release of NF-kB transcriptional factors, and the levels of ARNT. PMID:25481308

  18. The Paralogous Histone Deacetylases Rpd3 and Rpd31 Play Opposing Roles in Regulating the White-Opaque Switch in the Fungal Pathogen Candida albicans

    PubMed Central

    Xie, Jing; Jenull, Sabrina; Tscherner, Michael

    2016-01-01

    ABSTRACT Chromatin modifications affect gene regulation in response to environmental stimuli in numerous biological processes. For example, N-acetyl-glucosamine and CO2 induce a morphogenetic conversion between white (W) and opaque (O) cells in MTL (mating-type locus) homozygous and heterozygous (a/α) strains of the human fungal pathogen Candida albicans. Here, we identify 8 histone-modifying enzymes playing distinct roles in the regulation of W/O switching in MTL homozygous and heterozygous strains. Most strikingly, genetic removal of the paralogous genes RPD3 and RPD31, both of which encode almost identical orthologues of the yeast histone deacetylase (HDAC) Rpd3, reveals opposing roles in W/O switching of MTLa/α strains. We show that Rpd3 and Rpd31 functions depend on MTL genotypes. Strikingly, we demonstrate that Rpd3 and Rpd31, which are almost identical except for a divergent C-terminal extension present in Rpd31, exert their functions in distinct regulatory complexes referred to as CaRpd3L and CaRpd31S complexes. Moreover, we identify the Candida orf19.7185 product Ume1, the orthologue of yeast Ume1, as a shared core subunit of CaRpd3L and CaRpd31S. Mechanistically, we show that the opposing roles of Rpd3 and Rpd31 require their deacetylase activities. Importantly, CaRpd3L interacts with the heterodimeric transcriptional repressor a1/α2, thus controlling expression of WOR1 encoding the master regulator of W/O switching. Thus, our work provides novel insight about regulation mechanisms of W/O switching in MTLa/α strains. This is the first example of two highly conserved HDACs exerting opposing regulatory functions in the same process in a eukaryotic cell. PMID:27935838

  19. RAS/Cyclic AMP and Transcription Factor Msn2 Regulate Mating and Mating-Type Switching in the Yeast Kluyveromyces lactis ▿

    PubMed Central

    Barsoum, E.; Rajaei, N.; Åström, S. U.

    2011-01-01

    In response to harsh environmental conditions, ascomycetes produce stress-resistant spores to promote survival. As sporulation requires a diploid DNA content, species with a haploid lifestyle, such as Kluyveromyces lactis, first induce mating in response to stress. In K. lactis, mating and mating-type switching are induced by the DNA-binding protein Mts1. Mts1 expression is known to be upregulated by nutrient limitation, but the mechanism is unknown. We show that a ras2 mutation results in a hyperswitching phenotype. In contrast, strains lacking the phosphodiesterase Pde2 had lower switching rates compared to that of the wild type (WT). As Ras2 promotes cyclic AMP (cAMP) production and Pde2 degrades cAMP, these data suggest that low cAMP levels induce switching. Because the MTS1 regulatory region contains several Msn2 binding sites and Msn2 is a transcription factor that is activated by low cAMP levels, we investigated if Msn2 regulates MTS1 transcription. Consistently with this idea, an msn2 mutant strain displayed lower switching rates than the WT strain. The transcription of MTS1 is highly induced in the ras2 mutant strain. In contrast, an msn2 ras2 double mutant strain displays WT levels of the MTS1 transcript, showing that Msn2 is a critical inducer of MTS1 transcription. Strains lacking Msn2 and Pde2 also exhibit mating defects that can be complemented by the ectopic expression of Mts1. Finally, we show that MTS1 is subjected to negative autoregulation, presumably adding robustness to the mating and switching responses. We suggest a model in which Ras2/cAMP/Msn2 mediates the stress-induced mating and mating-type switching responses in K. lactis. PMID:21890818

  20. New Orthogonal Transcriptional Switches Derived from Tet Repressor Homologues for Saccharomyces cerevisiae Regulated by 2,4-Diacetylphloroglucinol and Other Ligands.

    PubMed

    Ikushima, Shigehito; Boeke, Jef D

    2017-03-17

    Here we describe the development of tightly regulated expression switches in yeast, by engineering distant homologues of Escherichia coli TetR, including the transcriptional regulator PhlF from Pseudomonas and others. Previous studies demonstrated that the PhlF protein bound its operator sequence (phlO) in the absence of 2,4-diacetylphloroglucinol (DAPG) but dissociated from phlO in the presence of DAPG. Thus, we developed a DAPG-Off system in which expression of a gene preceded by the phlO-embedded promoter was activated by a fusion of PhlF to a multimerized viral activator protein (VP16) domain in a DAPG-free environment but repressed when DAPG was added to growth medium. In addition, we constructed a DAPG-On system with the opposite behavior of the DAPG-Off system; i.e., DAPG triggers the expression of a reporter gene. Exposure of DAPG to yeast cells did not cause any serious deleterious effect on yeast physiology in terms of growth. Efforts to engineer additional Tet repressor homologues were partially successful and a known mammalian switch, the p-cumate switch based on CymR from Pseudomonas, was found to function in yeast. Orthogonality between the TetR (doxycycline), CamR (d-camphor), PhlF (DAPG), and CymR (p-cumate)-based Off switches was demonstrated by evaluating all 4 ligands against suitably engineered yeast strains. This study expands the toolbox of "On" and "Off" switches for yeast biotechnology.

  1. Low Density Lipoprotein Receptor Related Proteins as Regulators of Neural Stem and Progenitor Cell Function

    PubMed Central

    Landowski, Lila M.; Young, Kaylene M.

    2016-01-01

    The central nervous system (CNS) is a highly organised structure. Many signalling systems work in concert to ensure that neural stem cells are appropriately directed to generate progenitor cells, which in turn mature into functional cell types including projection neurons, interneurons, astrocytes, and oligodendrocytes. Herein we explore the role of the low density lipoprotein (LDL) receptor family, in particular family members LRP1 and LRP2, in regulating the behaviour of neural stem and progenitor cells during development and adulthood. The ability of LRP1 and LRP2 to bind a diverse and extensive range of ligands, regulate ligand endocytosis, recruit nonreceptor tyrosine kinases for direct signal transduction and signal in conjunction with other receptors, enables them to modulate many crucial neural cell functions. PMID:26949399

  2. Evolution of CONSTANS Regulation and Function after Gene Duplication Produced a Photoperiodic Flowering Switch in the Brassicaceae.

    PubMed

    Simon, Samson; Rühl, Mark; de Montaigu, Amaury; Wötzel, Stefan; Coupland, George

    2015-09-01

    Environmental control of flowering allows plant reproduction to occur under optimal conditions and facilitates adaptation to different locations. At high latitude, flowering of many plants is controlled by seasonal changes in day length. The photoperiodic flowering pathway confers this response in the Brassicaceae, which colonized temperate latitudes after divergence from the Cleomaceae, their subtropical sister family. The CONSTANS (CO) transcription factor of Arabidopsis thaliana, a member of the Brassicaceae, is central to the photoperiodic flowering response and shows characteristic patterns of transcription required for day-length sensing. CO is believed to be widely conserved among flowering plants; however, we show that it arose after gene duplication at the root of the Brassicaceae followed by divergence of transcriptional regulation and protein function. CO has two close homologs, CONSTANS-LIKE1 (COL1) and COL2, which are related to CO by tandem duplication and whole-genome duplication, respectively. The single CO homolog present in the Cleomaceae shows transcriptional and functional features similar to those of COL1 and COL2, suggesting that these were ancestral. We detect cis-regulatory and codon changes characteristic of CO and use transgenic assays to demonstrate their significance in the day-length-dependent activation of the CO target gene FLOWERING LOCUS T. Thus, the function of CO as a potent photoperiodic flowering switch evolved in the Brassicaceae after gene duplication. The origin of CO may have contributed to the range expansion of the Brassicaceae and suggests that in other families CO genes involved in photoperiodic flowering arose by convergent evolution.

  3. Energy Density, Energy Intake, and Body Weight Regulation in Adults12345

    PubMed Central

    Karl, J. Philip; Roberts, Susan B.

    2014-01-01

    The role of dietary energy density (ED) in the regulation of energy intake (EI) is controversial. Methodologically, there is also debate about whether beverages should be included in dietary ED calculations. To address these issues, studies examining the effects of ED on EI or body weight in nonelderly adults were reviewed. Different approaches to calculating dietary ED do not appear to alter the direction of reported relations between ED and body weight. Evidence that lowering dietary ED reduces EI in short-term studies is convincing, but there are currently insufficient data to determine long-term effectiveness for weight loss. The review also identified key barriers to progress in understanding the role of ED in energy regulation, in particular the absence of a standard definition of ED, and the lack of data from multiple long-term clinical trials examining the effectiveness of low-ED diet recommendations for preventing both primary weight gain and weight regain in nonobese individuals. Long-term clinical trials designed to examine the impact of dietary ED on energy regulation, and including multiple ED calculation methods within the same study, are still needed to determine the importance of ED in the regulation of EI and body weight. PMID:25398750

  4. Regulated deficit irrigation and density of Erythroneura spp. (Hemiptera: Cicadellidae) on grape.

    PubMed

    Costello, Michael J

    2008-08-01

    This study looked at regulated deficit irrigation (RDI) on leafhoppers in the genus Erythroneura (Erythroneura elegantula Osborn, or western grape leafhopper, and Erythroneura variabilis Beamer) (Hemiptera: Cicadellidae), which are serious pests of cultivated grape (Vitis vinifera L.) in California. RDI is an irrigation strategy that reduces irrigation during a critical point in the phenology of a cultivated perennial crop, to improve vegetative balance and crop quality. Erythroneura spp. are known to respond negatively to vine water stress, and the second generation ofleafhoppers begins during a potential RDI initiation period, between berry set and veraison (beginning of fruit maturation). In experiments at commercial wine grape vineyards, I imposed deficits of between 25 and 50% of crop full evapotranspiration (ET(c)) between berry set and veraison, with control treatments based on the growers' standard irrigations (typically between 0.8 and 1.0 ET(c)), and then we counted leafhopper nymphs weekly, and leafhopper eggs after the second generation. Results show a consistent reduction of second generation nymphal density with this type of RDI, with average density approximately 50% lower under deficit treatments in all three studies. Deficit irrigation reduced second generation egg density by 54% at one site and by 29.9% at another. These results confirm previous studies regarding the sensitivity of Erythroneura spp. to grapevine water stress, and, in addition, they show that a season-wide irrigation deficit is not necessary for reduction in leafhopper density. Results suggest that lower oviposition at least partly explains the lower nymphal density in the deficit treatments.

  5. Tubulin cofactor B regulates microtubule densities during microglia transition to the reactive states

    SciTech Connect

    Fanarraga, M.L.

    2009-02-01

    Microglia are highly dynamic cells of the CNS that continuously survey the welfare of the neural parenchyma and play key roles modulating neurogenesis and neuronal cell death. In response to injury or pathogen invasion parenchymal microglia transforms into a more active cell that proliferates, migrates and behaves as a macrophage. The acquisition of these extra skills implicates enormous modifications of the microtubule and actin cytoskeletons. Here we show that tubulin cofactor B (TBCB), which has been found to contribute to various aspects of microtubule dynamics in vivo, is also implicated in microglial cytoskeletal changes. We find that TBCB is upregulated in post-lesion reactive parenchymal microglia/macrophages, in interferon treated BV-2 microglial cells, and in neonate amoeboid microglia where the microtubule densities are remarkably low. Our data demonstrate that upon TBCB downregulation both, after microglia differentiation to the ramified phenotype in vivo and in vitro, or after TBCB gene silencing, microtubule densities are restored in these cells. Taken together these observations support the view that TBCB functions as a microtubule density regulator in microglia during activation, and provide an insight into the understanding of the complex mechanisms controlling microtubule reorganization during microglial transition between the amoeboid, ramified, and reactive phenotypes.

  6. 49 CFR 218.103 - Hand-operated switches, including crossover switches.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Hand-operated switches, including crossover switches. 218.103 Section 218.103 Transportation Other Regulations Relating to Transportation (Continued... Equipment, Switches, and Fixed Derails § 218.103 Hand-operated switches, including crossover switches....

  7. 49 CFR 218.103 - Hand-operated switches, including crossover switches.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Hand-operated switches, including crossover switches. 218.103 Section 218.103 Transportation Other Regulations Relating to Transportation (Continued... Equipment, Switches, and Fixed Derails § 218.103 Hand-operated switches, including crossover switches....

  8. Identification of low density lipoprotein as a regulator of Fc receptor-mediated phagocytosis.

    PubMed Central

    Bigler, R D; Khoo, M; Lund-Katz, S; Scerbo, L; Esfahani, M

    1990-01-01

    Optimal expression of the high-affinity Fc receptor for IgG (FcRI) by the human monocyte cell line U-937 requires the presence of low density lipoprotein (LDL), and neither cholesterol nor high density lipoprotein can provide the component necessary for optimal FcRI expression. Here we show that FcR-mediated phagocytosis also requires LDL. U-937 cells were cultured in medium containing interferon gamma and either fetal calf serum (FCS) or delipidated FCS (DLFCS). The phagocytosis of IgG-coated erythrocytes was measured by a colorimetric assay. U-937 cells cultured in DLFCS medium had less than 16% of the phagocytic activity of cells cultured in normal FCS medium. Phagocytosis of IgG-coated erythrocytes could be inhibited 85% by the addition of murine IgG2a myeloma protein (5 micrograms/ml). U-937 cells cultured in DLFCS medium supplemented with pure cholesterol in ethanol (10 micrograms/ml) had only 30% of the phagocytic activity of cells grown in FCS medium. Addition of very low density lipoprotein (0.2 mg of protein per ml) to DLFCS medium also failed to increase phagocytosis. However, the addition of LDL (0.2 mg of protein per ml) to DLFCS medium restored 90% of the phagocytic activity. Since neither pure cholesterol nor very low density lipoprotein restored normal phagocytic function to U-937 cells despite a normalization of cellular cholesterol content, the restoration of phagocytosis observed with LDL replacement cannot be explained by mere delivery of cholesterol by LDL. Thus, LDL is required for the expression of FcRI and FcR-mediated phagocytosis by U-937 cells and may be an important regulator of phagocytic activity of monocytes and macrophages in vivo. PMID:2367519

  9. Regulation of budding yeast mating-type switching donor preference by the FHA domain of Fkh1.

    PubMed

    Li, Jin; Coïc, Eric; Lee, Kihoon; Lee, Cheng-Sheng; Kim, Jung-Ae; Wu, Qiuqin; Haber, James E

    2012-01-01

    During Saccharomyces cerevisiae mating-type switching, an HO endonuclease-induced double-strand break (DSB) at MAT is repaired by recombining with one of two donors, HMLα or HMRa, located at opposite ends of chromosome III. MATa cells preferentially recombine with HMLα; this decision depends on the Recombination Enhancer (RE), located about 17 kb to the right of HML. In MATα cells, HML is rarely used and RE is bound by the MATα2-Mcm1 corepressor, which prevents the binding of other proteins to RE. In contrast, in MATa cells, RE is bound by multiple copies of Fkh1 and a single copy of Swi4/Swi6. We report here that, when RE is replaced with four LexA operators in MATa cells, 95% of cells use HMR for repair, but expression of a LexA-Fkh1 fusion protein strongly increases HML usage. A LexA-Fkh1 truncation, containing only Fkh1's phosphothreonine-binding FHA domain, restores HML usage to 90%. A LexA-FHA-R80A mutant lacking phosphothreonine binding fails to increase HML usage. The LexA-FHA fusion protein associates with chromatin in a 10-kb interval surrounding the HO cleavage site at MAT, but only after DSB induction. This association occurs even in a donorless strain lacking HML. We propose that the FHA domain of Fkh1 regulates donor preference by physically interacting with phosphorylated threonine residues created on proteins bound near the DSB, thus positioning HML close to the DSB at MAT. Donor preference is independent of Mec1/ATR and Tel1/ATM checkpoint protein kinases but partially depends on casein kinase II. RE stimulates the strand invasion step of interchromosomal recombination even for non-MAT sequences. We also find that when RE binds to the region near the DSB at MATa then Mec1 and Tel1 checkpoint kinases are not only able to phosphorylate histone H2A (γ-H2AX) around the DSB but can also promote γ-H2AX spreading around the RE region.

  10. Neurolastin, a dynamin family GTPase, regulates excitatory synapses and spine density

    PubMed Central

    Madan Lomash, Richa; Gu, Xinglong; Youle, Richard J.; Lu, Wei; Roche, Katherine W.

    2015-01-01

    SUMMARY Membrane trafficking and spinogenesis contribute significantly to changes in synaptic strength during development and in various paradigms of synaptic plasticity. GTPases of the dynamin family are key players regulating membrane trafficking. Here, we identify a brain-specific dynamin family GTPase, neurolastin (RNF112/Znf179), with closest homology to atlastin. We demonstrate that neurolastin has functional GTPase and RING domains, making it a unique protein identified with this multi-enzymatic domain organization. We also show that neurolastin is a peripheral membrane protein, which localizes to endosomes and affects endosomal membrane dynamics via its RING domain. In addition, neurolastin knockout mice have fewer dendritic spines, and rescue of the wildtype phenotype requires both the GTPase and RING domains. Furthermore, we find fewer functional synapses and reduced paired pulse facilitation in neurolastin knockout mice. Thus, we identify neurolastin as a dynamin family GTPase that affects endosome size and spine density. PMID:26212327

  11. Regulation of platelet heterogeneity: effects of thrombocytopenia on platelet volume and density.

    PubMed

    Corash, L; Mok, Y; Levin, J; Baker, G

    1990-03-01

    We have examined the effects of variable degrees of acute thrombocytopenia on platelet levels, mean platelet volume (MPV), and buoyant density after induction of thrombocytopenia by platelet antiserum (PAS) in mice with or without spleens. Mice were studied serially 10-16, 36, 48, 60-64, 84, 108, 144, 180, 228, 276, 348-360, 372, and 516 h after PAS treatment. MPV and platelet count (PC) x 10(6)/microliters for normal intact mice (n = 136) were 4.7 +/- 0.3 fl (SD) and 1.69 +/- 0.52 (SD), respectively. Twelve hours after PAS-induced severe thrombocytopenia (PC less than 0.05 x 10(6)/microliters), MPV increased significantly (p less than 0.01) to 6.4 fl, was maximal at 36 h (8.2 fl), remained elevated until 144 h following PAS treatment, and then returned to normal. Platelet density decreased significantly (p less than 0.05) 64 h after PAS treatment and returned to normal at 144 h. Hematocrits of repeatedly bled intact control mice decreased from 45% to 30%, accompanied by thrombocytosis (maximal PC 2.24 x 10(6)/microliters) without significant changes in either MPV or platelet density. Moderate thrombocytopenia (PC 0.1-0.2 x 10(6)/microliters) in intact mice produced significantly (p less than 0.05) increased MPV, at 5.7 fl 12 h after PAS treatment, with a peak MPV of 7.6 fl (p less than 0.001) at 36 h; MPV returned to normal at 84 h. Platelet density decreased (p less than 0.001) 12 h after PAS treatment and returned to baseline at 228 h. Control splenectomized mice (n = 185) had an MPV of 5.0 fl +/- 0.7 fl and a PC of 2.14 +/- 0.6 x 10(6)/microliters. Comparably severe and moderate thrombocytopenia in splenectomized mice produced alterations in platelet count, MPV, and density similar to those in intact mice, although maximal MPV and the degree of rebound thrombocytosis after severe thrombocytopenia were more marked in splenectomized mice. In response to reduction of the platelet mass in both intact and splenectomized mice, MPV increased in proportion to the

  12. Palmitoylation regulates glutamate receptor distributions in postsynaptic densities through control of PSD95 conformation and orientation

    PubMed Central

    Jeyifous, Okunola; Lin, Eric I.; Chen, Xiaobing; Antinone, Sarah E.; Mastro, Ryan; Drisdel, Renaldo; Reese, Thomas S.; Green, William N.

    2016-01-01

    Postsynaptic density protein 95 (PSD95) and synapse-associated protein 97 (SAP97) are homologous scaffold proteins with different N-terminal domains, possessing either a palmitoylation site (PSD95) or an L27 domain (SAP97). Here, we measured PSD95 and SAP97 conformation in vitro and in postsynaptic densities (PSDs) using FRET and EM, and examined how conformation regulated interactions with AMPA-type and NMDA-type glutamate receptors (AMPARs/NMDARs). Palmitoylation of PSD95 changed its conformation from a compact to an extended configuration. PSD95 associated with AMPARs (via transmembrane AMPAR regulatory protein subunits) or NMDARs [via glutamate ionotropic receptor NMDA-type subunit 2B (GluN2B) subunits] only in its palmitoylated and extended conformation. In contrast, in its extended conformation, SAP97 associates with NMDARs, but not with AMPARs. Within PSDs, PSD95 and SAP97 were largely in the extended conformation, but had different orientations. PSD95 oriented perpendicular to the PSD membrane, with its palmitoylated, N-terminal domain at the membrane. SAP97 oriented parallel to the PSD membrane, likely as a dimer through interactions of its N-terminal L27 domain. Changing PSD95 palmitoylation in PSDs altered PSD95 and AMPAR levels but did not affect NMDAR levels. These results indicate that in PSDs, PSD95 palmitoylation, conformation, and its interactions are dynamic when associated with AMPARs and more stable when associated with NMDARs. Altogether, our results are consistent with differential regulation of PSD95 palmitoylation in PSDs resulting from the clustering of palmitoylating and depalmitoylating enzymes into AMPAR nanodomains segregated away from NMDAR nanodomains. PMID:27956638

  13. Langerhans Cells Regulate Cutaneous Innervation Density and Mechanical Sensitivity in Mouse Footpad

    PubMed Central

    Doss, Argenia L. N.; Smith, Peter G.

    2014-01-01

    Langerhans cells are epidermal dendritic cells responsible for antigen presentation during an immune response. Langerhans cells associate intimately with epidermal sensory axons. While there is evidence that Langerhans cells may produce neurotrophic factors, a role in regulating cutaneous innervation has not been established. We used genetically engineered mice in which the diphtheria toxin (DT) receptor is targeted to Langerhans cells (Lang-DTR mice) to assess sensory axon-dendritic cell interactions. Diphtheria toxin administration to wild type mice did not affect epidermal structure, Langerhans cell content, or innervation density. A DT administration regimen supramaximal for completely ablating epidermal Langerhans cells in Lang-DTR mice reduced PGP 9.5–immunoreactive total innervation and calcitonin gene related peptide–immunoreactive peptidergic nociceptor innervation. Quantitative real-time polymerase chain reaction showed that epidermal gene expression of brain derived neurotrophic factor was unchanged, but nerve growth factor and glial cell line-derived neurotrophic factor mRNAs were reduced. Behavioral testing showed that, while thermal sensitivity was unaffected, mice depleted of Langerhans cells displayed mechanical hypersensitivity. These findings provide evidence that Langerhans cells play an important role in determining cutaneous sensory innervation density and mechanical sensitivity. This may involve alterations in neurotrophin production by Langerhans or other epidermal cells, which in turn may affect mechanical sensitivity directly or as a result of neuropathic changes. PMID:24970748

  14. Tissue specific regulation of peripheral-type benzodiazepine receptor density after chemical sympathectomy

    SciTech Connect

    Basile, A.S.; Skolnick, P.

    1988-01-01

    The characteristics of (/sup 3/H)Ro 5-4864 binding to peripheral benzodiazepine receptors (PBR) in the central nervous system and peripheral tissues were examined after chemical sympathectomy with 6-hydroxydopamine (6-OHDA). One week after the intracisternal administration of 6-OHDA, the number of (/sup 3/H)Ro 5-4864 binding sites (Bmax) in the hypothalamus and striatum increased 41 and 50% respectively, concurrent with significant reductions in catecholamine content. An increase (34%) in the Bmax of (/sup 3/H)Ro 5-4864 to cardiac ventricle was observed one week after parenteral 6-OHDA administration. In contrast, the B/sub max/ of (/sup 3/H)Ro 5-4684 to pineal gland decreased 48% after 6-OHDA induced reduction in norepinephrine content. The Bmax values for (/sup 3/H)Ro 5-4864 binding to other tissues (including lung, kidney, spleen, cerebral cortex, cerebellum, hippocampus and olfactory bulbs) were unaffected by 6-OHDA administration. The density of pineal, but not cardiac PBR was also reduced after reserpine treatment, an effect reversed by isoproterenol administration. These findings demonstrate that alterations in sympathetic input may regulate the density of PBR in both the central nervous system and periphery in a tissue specific fashion. 33 references, 4 tables.

  15. Redundant roles of photoreceptors and cytokinins in regulating photosynthetic acclimation to canopy density

    PubMed Central

    Boonman, A.; Prinsen, E.; Voesenek, L. A. C. J.; Pons, T. L.

    2009-01-01

    The regulation of photosynthetic acclimation to canopy density was investigated in tobacco canopies and in tobacco and Arabidopsis plants with part of their foliage experimentally shaded. Both species acclimated to canopy light gradients and partial shading by allocating photosynthetic capacity to leaves in high light and adjusting chloroplast organization to the local light conditions. An investigation was carried out to determine whether signalling mediated by photoreceptors, sugars, cytokinin, and nitrate is involved in and necessary for proper photosynthetic acclimation. No evidence was found for a role for sugars, or for nitrate. The distribution of cytokinins in tobacco stands of contrasting density could be explained in part by irradiance-dependent delivery of cytokinins through the transpiration stream. Functional studies using a comprehensive selection of Arabidopsis mutants and transgenics showed that normal wild-type responses to partial shading were retained when signalling mediated by photoreceptors or cytokinins was disrupted. This indicates that these pathways probably operate in a redundant manner. However, the reduction of the chlorophyll a/b ratio in response to local shade was completely absent in the Arabidopsis Ws-2 accession mutated in PHYTOCHROME D and in the triple phyAphyCphyD mutant. Moreover, cytokinin receptor mutants also showed a reduced response, suggesting a previously unrecognized function of phyD and cytokinins. PMID:19240103

  16. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination.

    PubMed

    Bothmer, Anne; Robbiani, Davide F; Feldhahn, Niklas; Gazumyan, Anna; Nussenzweig, Andre; Nussenzweig, Michel C

    2010-04-12

    Class switch recombination (CSR) diversifies antibodies by joining highly repetitive DNA elements, which are separated by 60-200 kbp. CSR is initiated by activation-induced cytidine deaminase, an enzyme that produces multiple DNA double-strand breaks (DSBs) in switch regions. Switch regions are joined by a mechanism that requires an intact DNA damage response and classical or alternative nonhomologous end joining (A-NHEJ). Among the DNA damage response factors, 53BP1 has the most profound effect on CSR. We explore the role of 53BP1 in intrachromosomal DNA repair using I-SceI to introduce paired DSBs in the IgH locus. We find that the absence of 53BP1 results in an ataxia telangiectasia mutated-dependent increase in DNA end resection and that resected DNA is preferentially repaired by microhomology-mediated A-NHEJ. We propose that 53BP1 favors long-range CSR in part by protecting DNA ends against resection, which prevents A-NHEJ-dependent short-range rejoining of intra-switch region DSBs.

  17. High-Density Cell Systems Incorporating Polymer Microspheres as Microenvironmental Regulators in Engineered Cartilage Tissues

    PubMed Central

    Solorio, Loran D.; Vieregge, Eran L.; Dhami, Chirag D.

    2013-01-01

    To address the significant clinical need for tissue-engineered therapies for the repair and regeneration of articular cartilage, many systems have recently been developed using bioactive polymer microspheres as regulators of the chondrogenic microenvironment within high-density cell cultures. In this review, we highlight various densely cellular systems utilizing polymer microspheres as three-dimensional (3D) structural elements within developing engineered cartilage tissue, carriers for cell expansion and delivery, vehicles for spatiotemporally controlled growth factor delivery, and directors of cell behavior via regulation of cell–biomaterial interactions. The diverse systems described herein represent a shift from the more traditional tissue engineering approach of combining cells and growth factors within a biomaterial scaffold, to the design of modular systems that rely on the assembly of cells and bioactive polymer microspheres as building blocks to guide the creation of articular cartilage. Cell-based assembly of 3D microsphere-incorporated structures represents a promising avenue for the future of tissue engineering. PMID:23126333

  18. High-density cell systems incorporating polymer microspheres as microenvironmental regulators in engineered cartilage tissues.

    PubMed

    Solorio, Loran D; Vieregge, Eran L; Dhami, Chirag D; Alsberg, Eben

    2013-06-01

    To address the significant clinical need for tissue-engineered therapies for the repair and regeneration of articular cartilage, many systems have recently been developed using bioactive polymer microspheres as regulators of the chondrogenic microenvironment within high-density cell cultures. In this review, we highlight various densely cellular systems utilizing polymer microspheres as three-dimensional (3D) structural elements within developing engineered cartilage tissue, carriers for cell expansion and delivery, vehicles for spatiotemporally controlled growth factor delivery, and directors of cell behavior via regulation of cell-biomaterial interactions. The diverse systems described herein represent a shift from the more traditional tissue engineering approach of combining cells and growth factors within a biomaterial scaffold, to the design of modular systems that rely on the assembly of cells and bioactive polymer microspheres as building blocks to guide the creation of articular cartilage. Cell-based assembly of 3D microsphere-incorporated structures represents a promising avenue for the future of tissue engineering.

  19. Binding of the Fkh1 Forkhead Associated Domain to a Phosphopeptide within the Mph1 DNA Helicase Regulates Mating-Type Switching in Budding Yeast

    PubMed Central

    Su, Zhangli; Cherney, Rachel; Choi, Koyi; Denu, John; Zhao, Xiaolan; Fox, Catherine A.

    2016-01-01

    The Saccharomyces cerevisiae Fkh1 protein has roles in cell-cycle regulated transcription as well as a transcription-independent role in recombination donor preference during mating-type switching. The conserved FHA domain of Fkh1 regulates donor preference by juxtaposing two distant regions on chromosome III to promote their recombination. A model posits that this Fkh1-mediated long-range chromosomal juxtaposition requires an interaction between the FHA domain and a partner protein(s), but to date no relevant partner has been described. In this study, we used structural modeling, 2-hybrid assays, and mutational analyses to show that the predicted phosphothreonine-binding FHA domain of Fkh1 interacted with multiple partner proteins. The Fkh1 FHA domain was important for its role in cell-cycle regulation, but no single interaction partner could account for this role. In contrast, Fkh1’s interaction with the Mph1 DNA repair helicase regulated donor preference during mating-type switching. Using 2-hybrid assays, co-immunoprecipitation, and fluorescence anisotropy, we mapped a discrete peptide within the regulatory Mph1 C-terminus required for this interaction and identified two threonines that were particularly important. In vitro binding experiments indicated that at least one of these threonines had to be phosphorylated for efficient Fkh1 binding. Substitution of these two threonines with alanines (mph1-2TA) specifically abolished the Fkh1-Mph1 interaction in vivo and altered donor preference during mating-type switching to the same degree as mph1Δ. Notably, the mph1-2TA allele maintained other functions of Mph1 in genome stability. Deletion of a second Fkh1-interacting protein encoded by YMR144W also resulted in a change in Fkh1-FHA-dependent donor preference. We have named this gene FDO1 for Forkhead one interacting protein involved in donor preference. We conclude that a phosphothreonine-mediated protein-protein interface between Fkh1-FHA and Mph1 contributes

  20. The Timing of the Excitatory-to-Inhibitory GABA Switch Is Regulated by the Oxytocin Receptor via KCC2

    PubMed Central

    Leonzino, Marianna; Busnelli, Marta; Antonucci, Flavia; Verderio, Claudia; Mazzanti, Michele; Chini, Bice

    2016-01-01

    Summary Oxytocin and its receptor (Oxtr) play a crucial role in the postnatal transition of neuronal GABA neurotransmission from excitatory to inhibitory, a developmental process known as the GABA switch. Using hippocampal neurons from Oxtr-null mice, we show that (1) Oxtr is necessary for the correct timing of the GABA switch by upregulating activity of the chloride cotransporter KCC2, (2) Oxtr, in a very early and narrow time window, directly modulates the functional activity of KCC2 by promoting its phosphorylation and insertion/stabilization at the neuronal surface, and (3) in the absence of Oxtr, electrophysiological alterations are recorded in mature neurons, a finding consistent with a reduced level of KCC2 and increased susceptibility to seizures observed in adult Oxtr-null mice. These data identify KCC2 as a key target of oxytocin in postnatal events that may be linked to pathogenesis of neurodevelopmental disorders. PMID:27052180

  1. The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle.

    PubMed

    Pecorella, Shelly R H; Potter, Jennifer V F; Cherry, Anne D; Peacher, Dionne F; Welty-Wolf, Karen E; Moon, Richard E; Piantadosi, Claude A; Suliman, Hagir B

    2015-10-15

    The heme oxygenase-1 (HO-1)/carbon monoxide (CO) system induces mitochondrial biogenesis, but its biological impact in human skeletal muscle is uncertain. The enzyme system generates CO, which stimulates mitochondrial proliferation in normal muscle. Here we examined whether CO breathing can be used to produce a coordinated metabolic and vascular response in human skeletal muscle. In 19 healthy subjects, we performed vastus lateralis muscle biopsies and tested one-legged maximal O2 uptake (V̇o2max) before and after breathing air or CO (200 ppm) for 1 h daily for 5 days. In response to CO, there was robust HO-1 induction along with increased mRNA levels for nuclear-encoded mitochondrial transcription factor A (Tfam), cytochrome c, cytochrome oxidase subunit IV (COX IV), and mitochondrial-encoded COX I and NADH dehydrogenase subunit 1 (NDI). CO breathing did not increase V̇o2max (1.96 ± 0.51 pre-CO, 1.87 ± 0.50 post-CO l/min; P = not significant) but did increase muscle citrate synthase, mitochondrial density (139.0 ± 34.9 pre-CO, 219.0 ± 36.2 post-CO; no. of mitochondrial profiles/field), myoglobin content and glucose transporter (GLUT4) protein level and led to GLUT4 localization to the myocyte membrane, all consistent with expansion of the tissue O2 transport system. These responses were attended by increased cluster of differentiation 31 (CD31)-positive muscle capillaries (1.78 ± 0.16 pre-CO, 2.37 ± 0.59 post-CO; capillaries/muscle fiber), implying the enrichment of microvascular O2 reserve. The findings support that induction of the HO-1/CO system by CO not only improves muscle mitochondrial density, but regulates myoglobin content, GLUT4 localization, and capillarity in accordance with current concepts of skeletal muscle plasticity.

  2. The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle

    PubMed Central

    Pecorella, Shelly R. H.; Potter, Jennifer V. F.; Cherry, Anne D.; Peacher, Dionne F.; Welty-Wolf, Karen E.; Moon, Richard E.; Suliman, Hagir B.

    2015-01-01

    The heme oxygenase-1 (HO-1)/carbon monoxide (CO) system induces mitochondrial biogenesis, but its biological impact in human skeletal muscle is uncertain. The enzyme system generates CO, which stimulates mitochondrial proliferation in normal muscle. Here we examined whether CO breathing can be used to produce a coordinated metabolic and vascular response in human skeletal muscle. In 19 healthy subjects, we performed vastus lateralis muscle biopsies and tested one-legged maximal O2 uptake (V̇o2max) before and after breathing air or CO (200 ppm) for 1 h daily for 5 days. In response to CO, there was robust HO-1 induction along with increased mRNA levels for nuclear-encoded mitochondrial transcription factor A (Tfam), cytochrome c, cytochrome oxidase subunit IV (COX IV), and mitochondrial-encoded COX I and NADH dehydrogenase subunit 1 (NDI). CO breathing did not increase V̇o2max (1.96 ± 0.51 pre-CO, 1.87 ± 0.50 post-CO l/min; P = not significant) but did increase muscle citrate synthase, mitochondrial density (139.0 ± 34.9 pre-CO, 219.0 ± 36.2 post-CO; no. of mitochondrial profiles/field), myoglobin content and glucose transporter (GLUT4) protein level and led to GLUT4 localization to the myocyte membrane, all consistent with expansion of the tissue O2 transport system. These responses were attended by increased cluster of differentiation 31 (CD31)-positive muscle capillaries (1.78 ± 0.16 pre-CO, 2.37 ± 0.59 post-CO; capillaries/muscle fiber), implying the enrichment of microvascular O2 reserve. The findings support that induction of the HO-1/CO system by CO not only improves muscle mitochondrial density, but regulates myoglobin content, GLUT4 localization, and capillarity in accordance with current concepts of skeletal muscle plasticity. PMID:26186946

  3. Genetic regulation of bone mass: from bone density to bone strength.

    PubMed

    Langman, Craig B

    2005-03-01

    Osteoporosis is a common disease characterized in adults by diminished bone density. Bone is an organ that evolves and grows throughout life, and establishing optimal bone density in childhood and adolescence serves to buffer bone loss later in life. Bone density, a measurable entity, is the clinical substitute for bone strength, or the ability to defend against fracture. Chronic diseases may adversely affect optimal peak bone density. Bone density is under genetic control, as revealed by three lines of investigations. These include (1) the finding of quantitative trait loci for bone density, (2) the finding that specific mutations in genes that are important in the development of osteoblast or osteoclast lineages alter bone density, and (3) the linkeage of known polymorphisms for genes involved in mineral homeostasis to bone density and/or fracture. Future therapeutics for improving peak bone density or delaying bone loss later in life may take advantage of the genetic nature of bone density development.

  4. OxyR2 Functions as a Three-state Redox Switch to Tightly Regulate Production of Prx2, a Peroxiredoxin of Vibrio vulnificus.

    PubMed

    Bang, Ye-Ji; Lee, Zee-Won; Kim, Dukyun; Jo, Inseong; Ha, Nam-Chul; Choi, Sang Ho

    2016-07-29

    The bacterial transcriptional regulator OxyR is known to function as a two-state redox switch. OxyR senses cellular levels of H2O2 via a "sensing cysteine" that switches from the reduced to a disulfide state upon H2O2 exposure, inducing the expression of antioxidant genes. The reduced and disulfide states of OxyR, respectively, bind to extended and compact regions of DNA, where the reduced state blocks and the oxidized state allows transcription and further induces target gene expression by interacting with RNA polymerase. Vibrio vulnificus OxyR2 senses H2O2 with high sensitivity and induces the gene encoding the antioxidant Prx2. In this study, we used mass spectrometry to identify a third redox state of OxyR2, in which the sensing cysteine was overoxidized to S-sulfonated cysteine (Cys-SO3H) by high H2O2 in vitro and in vivo, where the modification deterred the transcription of prx2 The DNA binding preferences of OxyR25CA-C206D, which mimics overoxidized OxyR2, suggested that overoxidized OxyR2 binds to the extended DNA site, masking the -35 region of the prx2 promoter. These combined results demonstrate that OxyR2 functions as a three-state redox switch to tightly regulate the expression of prx2, preventing futile production of Prx2 in cells exposed to high levels of H2O2 sufficient to inactivate Prx2. We further provide evidence that another OxyR homolog, OxyR1, displays similar three-state behavior, inviting further exploration of this phenomenon as a potentially general regulatory mechanism.

  5. Switch wear leveling

    DOEpatents

    Wu, Hunter; Sealy, Kylee; Gilchrist, Aaron

    2015-09-01

    An apparatus for switch wear leveling includes a switching module that controls switching for two or more pairs of switches in a switching power converter. The switching module controls switches based on a duty cycle control technique and closes and opens each switch in a switching sequence. The pairs of switches connect to a positive and negative terminal of a DC voltage source. For a first switching sequence a first switch of a pair of switches has a higher switching power loss than a second switch of the pair of switches. The apparatus includes a switch rotation module that changes the switching sequence of the two or more pairs of switches from the first switching sequence to a second switching sequence. The second switch of a pair of switches has a higher switching power loss than the first switch of the pair of switches during the second switching sequence.

  6. Exciter switch

    NASA Technical Reports Server (NTRS)

    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.

  7. Theophylline controllable RNAi-based genetic switches regulate expression of lncRNA TINCR and malignant phenotypes in bladder cancer cells

    PubMed Central

    Chen, Zhicong; Liu, Yuchen; He, Anbang; Li, Jianfa; Chen, Mingwei; Zhan, Yonghao; Lin, Junhao; Zhuang, Chengle; Liu, Li; Zhao, Guoping; Huang, Weiren; Cai, Zhiming

    2016-01-01

    TINCR is a well-known lncRNA which acts as a master regulator in somatic differentiation development. However, it is still unclear whether TINCR is also involved in caner occurrence and progression. In this study, we observed that TINCR was up-regulated in bladder cancer tissues and cells and contributed to oncogenesis and cancer progression. Silencing TINCR expression inhibited cell proliferation and promoted apoptosis in vitro, indicating that TINCR may be the potential therapeutic target for treating bladder urothelial carcinoma. Thus we used the synthetic biology approach to create theophylline controllable RNAi-based genetic switches which silenced TINCR in a dosage-dependent manner. Both RNAi-OFF and ON switches can be used to quantitatively control the expression of TINCR in bladder cancer to suppress the progression of bladder cancer. These findings suggest that lncRNA-TINCR could promote bladder cancer development and progression and artificial control of its expression through inducible RNAi may represent a new kind of therapeutic strategy for treating human bladder cancer. PMID:27586866

  8. Neuronal Actin Dynamics, Spine Density and Neuronal Dendritic Complexity Are Regulated by CAP2.

    PubMed

    Kumar, Atul; Paeger, Lars; Kosmas, Kosmas; Kloppenburg, Peter; Noegel, Angelika A; Peche, Vivek S

    2016-01-01

    Actin remodeling is crucial for dendritic spine development, morphology and density. CAP2 is a regulator of actin dynamics through sequestering G-actin and severing F-actin. In a mouse model, ablation of CAP2 leads to cardiovascular defects and delayed wound healing. This report investigates the role of CAP2 in the brain using Cap2(gt/gt) mice. Dendritic complexity, the number and morphology of dendritic spines were altered in Cap2(gt/gt) with increased number of excitatory synapses. This was accompanied by increased F-actin content and F-actin accumulation in cultured Cap2(gt/gt) neurons. Moreover, reduced surface GluA1 was observed in mutant neurons under basal condition and after induction of chemical LTP. Additionally, we show an interaction between CAP2 and n-cofilin, presumably mediated through the C-terminal domain of CAP2 and dependent on cofilin Ser3 phosphorylation. In vivo, the consequences of this interaction were altered phosphorylated cofilin levels and formation of cofilin aggregates in the neurons. Thus, our studies identify a novel role of CAP2 in neuronal development and neuronal actin dynamics.

  9. Neuronal Actin Dynamics, Spine Density and Neuronal Dendritic Complexity Are Regulated by CAP2

    PubMed Central

    Kumar, Atul; Paeger, Lars; Kosmas, Kosmas; Kloppenburg, Peter; Noegel, Angelika A.; Peche, Vivek S.

    2016-01-01

    Actin remodeling is crucial for dendritic spine development, morphology and density. CAP2 is a regulator of actin dynamics through sequestering G-actin and severing F-actin. In a mouse model, ablation of CAP2 leads to cardiovascular defects and delayed wound healing. This report investigates the role of CAP2 in the brain using Cap2gt/gt mice. Dendritic complexity, the number and morphology of dendritic spines were altered in Cap2gt/gt with increased number of excitatory synapses. This was accompanied by increased F-actin content and F-actin accumulation in cultured Cap2gt/gt neurons. Moreover, reduced surface GluA1 was observed in mutant neurons under basal condition and after induction of chemical LTP. Additionally, we show an interaction between CAP2 and n-cofilin, presumably mediated through the C-terminal domain of CAP2 and dependent on cofilin Ser3 phosphorylation. In vivo, the consequences of this interaction were altered phosphorylated cofilin levels and formation of cofilin aggregates in the neurons. Thus, our studies identify a novel role of CAP2 in neuronal development and neuronal actin dynamics. PMID:27507934

  10. Negative Density Dependence Regulates Two Tree Species at Later Life Stage in a Temperate Forest

    PubMed Central

    Piao, Tiefeng; Chun, Jung Hwa; Yang, Hee Moon; Cheon, Kwangil

    2014-01-01

    Numerous studies have demonstrated that tree survival is influenced by negative density dependence (NDD) and differences among species in shade tolerance could enhance coexistence via resource partitioning, but it is still unclear how NDD affects tree species with different shade-tolerance guilds at later life stages. In this study, we analyzed the spatial patterns for trees with dbh (diameter at breast height) ≥2 cm using the pair-correlation g(r) function to test for NDD in a temperate forest in South Korea after removing the effects of habitat heterogeneity. The analyses were implemented for the most abundant shade-tolerant (Chamaecyparis obtusa) and shade-intolerant (Quercus serrata) species. We found NDD existed for both species at later life stages. We also found Quercus serrata experienced greater NDD compared with Chamaecyparis obtusa. This study indicates that NDD regulates the two abundant tree species at later life stages and it is important to consider variation in species' shade tolerance in NDD study. PMID:25058660

  11. Negative density dependence regulates two tree species at later life stage in a temperate forest.

    PubMed

    Piao, Tiefeng; Chun, Jung Hwa; Yang, Hee Moon; Cheon, Kwangil

    2014-01-01

    Numerous studies have demonstrated that tree survival is influenced by negative density dependence (NDD) and differences among species in shade tolerance could enhance coexistence via resource partitioning, but it is still unclear how NDD affects tree species with different shade-tolerance guilds at later life stages. In this study, we analyzed the spatial patterns for trees with dbh (diameter at breast height) ≥2 cm using the pair-correlation g(r) function to test for NDD in a temperate forest in South Korea after removing the effects of habitat heterogeneity. The analyses were implemented for the most abundant shade-tolerant (Chamaecyparis obtusa) and shade-intolerant (Quercus serrata) species. We found NDD existed for both species at later life stages. We also found Quercus serrata experienced greater NDD compared with Chamaecyparis obtusa. This study indicates that NDD regulates the two abundant tree species at later life stages and it is important to consider variation in species' shade tolerance in NDD study.

  12. Improvement of a Monopartite Ecdysone Receptor Gene Switch and Demonstration of its Utility in Regulation of Transgene Expression in Plants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chemical inducible gene regulation systems provide essential tools for the precise regulation of transgene expression in plants and animals. We have recent developed a two-hybrid ecdysone receptor (EcR) gene regulation system that works in conjunction with the retinoid X receptor of Locusta migrato...

  13. Integration scheme of nanoscale resistive switching memory using bottom-up processes at room temperature for high-density memory applications.

    PubMed

    Han, Un-Bin; Lee, Jang-Sik

    2016-07-01

    A facile and versatile scheme is demonstrated to fabricate nanoscale resistive switching memory devices that exhibit reliable bipolar switching behavior. A solution process is used to synthesize the copper oxide layer into 250-nm via-holes that had been patterned in Si wafers. Direct bottom-up filling of copper oxide can facilitate fabrication of nanoscale memory devices without using vacuum deposition and etching processes. In addition, all materials and processes are CMOS compatible, and especially, the devices can be fabricated at room temperature. Nanoscale memory devices synthesized on wafers having 250-nm via-holes showed reproducible resistive switching programmable memory characteristics with reasonable endurance and data retention properties. This integration strategy provides a solution to overcome the scaling limit of current memory device fabrication methods.

  14. Integration scheme of nanoscale resistive switching memory using bottom-up processes at room temperature for high-density memory applications

    NASA Astrophysics Data System (ADS)

    Han, Un-Bin; Lee, Jang-Sik

    2016-07-01

    A facile and versatile scheme is demonstrated to fabricate nanoscale resistive switching memory devices that exhibit reliable bipolar switching behavior. A solution process is used to synthesize the copper oxide layer into 250-nm via-holes that had been patterned in Si wafers. Direct bottom-up filling of copper oxide can facilitate fabrication of nanoscale memory devices without using vacuum deposition and etching processes. In addition, all materials and processes are CMOS compatible, and especially, the devices can be fabricated at room temperature. Nanoscale memory devices synthesized on wafers having 250-nm via-holes showed reproducible resistive switching programmable memory characteristics with reasonable endurance and data retention properties. This integration strategy provides a solution to overcome the scaling limit of current memory device fabrication methods.

  15. Integration scheme of nanoscale resistive switching memory using bottom-up processes at room temperature for high-density memory applications

    PubMed Central

    Han, Un-Bin; Lee, Jang-Sik

    2016-01-01

    A facile and versatile scheme is demonstrated to fabricate nanoscale resistive switching memory devices that exhibit reliable bipolar switching behavior. A solution process is used to synthesize the copper oxide layer into 250-nm via-holes that had been patterned in Si wafers. Direct bottom-up filling of copper oxide can facilitate fabrication of nanoscale memory devices without using vacuum deposition and etching processes. In addition, all materials and processes are CMOS compatible, and especially, the devices can be fabricated at room temperature. Nanoscale memory devices synthesized on wafers having 250-nm via-holes showed reproducible resistive switching programmable memory characteristics with reasonable endurance and data retention properties. This integration strategy provides a solution to overcome the scaling limit of current memory device fabrication methods. PMID:27364856

  16. Differential regulation of a MYB transcription factor is correlated with transgenerational epigenetic inheritance of trichome density in Mimulus guttatus

    PubMed Central

    Scoville, Alison G.; Barnett, Laryssa L.; Bodbyl-Roels, Sarah; Kelly, John K.; Hileman, Lena C.

    2011-01-01

    Summary Epigenetic inheritance, transgenerational transmission of traits not proximally determined by DNA sequence, has been linked to transmission of chromatin modifications and gene regulation, which are known to be sensitive to environmental factors. Mimulus guttatus increases trichome (plant hair) density in response to simulated herbivore damage. Increased density is expressed in progeny even if progeny do not experience damage. To better understand epigenetic inheritance of trichome production, we tested the hypothesis that candidate gene expression states are inherited in response to parental damage.Using M. guttatus recombinant inbred lines, offspring of leaf-damaged and control plants were raised without damage. Relative expression of candidate trichome development genes was measured in offspring. Line and parental damage effects on trichome density were measured. Associations between gene expression, trichome density, and response to parental damage were determined.We identified M. guttatus MYB MIXTA-like 8 as a possible negative regulator of trichome development. We found that parental leaf damage induces down-regulation of MYB MIXTA-like 8 in progeny, which is associated with epigenetically inherited increased trichome density.Our results link epigenetic transmission of an ecologically important trait with differential gene expression states – providing insight into a mechanism underlying environmentally induced ‘soft inheritance’. PMID:21352232

  17. Spatial Phosphoprotein Profiling Reveals a Compartmentalized Extracellular Signal-regulated Kinase Switch Governing Neurite Growth and Retraction

    SciTech Connect

    Wang, Yingchun; Yang, Feng; Fu, Yi; Huang, Xiahe; Wang, Wei; Jiang, Xining; Gritsenko, Marina A.; Zhao, Rui; Monroe, Matthew E.; Pertz, Olivier C.; Purvine, Samuel O.; Orton, Daniel J.; Jacobs, Jon M.; Camp, David G.; Smith, Richard D.; Klemke, Richard L.

    2011-05-20

    Abstract - Brain development and spinal cord regeneration require neurite sprouting and growth cone navigation in response to extension and collapsing factors present in the extracellular environment. These external guidance cues control neurite growth cone extension and retraction processes through intracellular protein phosphorylation of numerous cytoskeletal, adhesion, and polarity complex signaling proteins. However, the complex kinase/substrate signaling networks that mediate neuritogenesis have not been investigated. Here, we compare the neurite phosphoproteome under growth and retraction conditions using neurite purification methodology combined with mass spectrometry. More than 4000 non-redundant phosphorylation sites from 1883 proteins have been annotated and mapped to signaling pathways that control kinase/phosphatase networks, cytoskeleton remodeling, and axon/dendrite specification. Comprehensive informatics and functional studies revealed a compartmentalized ERK activation/deactivation cytoskeletal switch that governs neurite growth and retraction, respectively. Our findings provide the first system-wide analysis of the phosphoprotein signaling networks that enable neurite growth and retraction and reveal an important molecular switch that governs neuritogenesis.

  18. New ex vivo reporter assay system reveals that σ factors of an unculturable pathogen control gene regulation involved in the host switching between insects and plants.

    PubMed

    Ishii, Yoshiko; Kakizawa, Shigeyuki; Oshima, Kenro

    2013-08-01

    Analysis of the environmental regulation of bacterial gene expression is important for understanding the nature, pathogenicity, and infection route of many pathogens. "Candidatus Phytoplasma asteris", onion yellows strain M (OY-M), is a phytopathogenic bacterium that is able to adapt to quite different host environments, including plants and insects, with a relatively small ~850 kb genome. The OY-M genome encodes two sigma (σ) factors, RpoD and FliA, that are homologous to Escherichia coli σ(70) and σ(28) , respectively. Previous studies show that gene expression of OY-M dramatically changes upon the response to insect and plant hosts. However, very little is known about the relationship between the two σ factors and gene regulatory systems in OY-M, because phytoplasma cannot currently be cultured in vitro. Here, we developed an Escherichia coli-based ex vivo reporter assay (EcERA) system to evaluate the transcriptional induction of phytoplasmal genes by the OY-M-derived σ factors. EcERA revealed that highly expressed genes in insect and plant hosts were regulated by RpoD and FliA, respectively. We also demonstrated that rpoD expression was significantly higher in insect than in plant hosts and fliA expression was similar between the hosts. These data indicate that phytoplasma-derived RpoD and FliA play key roles in the transcriptional switching mechanism during host switching between insects and plants. Our study will be invaluable to understand phytoplasmal transmission, virulence expression in plants, and the effect of infection on insect fitness. In addition, the novel EcERA system could be broadly applied to reveal transcriptional regulation mechanisms in other unculturable bacteria.

  19. Plasmodium falciparum exhibits markers of regulated cell death at high population density in vitro.

    PubMed

    Engelbrecht, Dewaldt; Coetzer, Thérèsa Louise

    2016-12-01

    The asexual erythrocytic cycle of the protozoan parasite Plasmodium falciparum is responsible for the pathogenesis of malaria and causes the overwhelming majority of malaria deaths. Rapidly increasing parasitaemia during this 48hour cycle threatens the survival of the human host and the parasite prior to transmission of the slow-maturing sexual stages to the mosquito host. The parasite may utilise regulated cell death (RCD) to control the burden of infection on the host and thus aid its own survival and transmission. The occurrence of RCD in P. falciparum remains a controversial topic. We provide strong evidence for the occurrence of an apoptosis-like phenotype of RCD in P. falciparum under conditions of high parasite density. P. falciparum was maintained in vitro and stressed by allowing growth to an unrestricted peak parasitaemia. Cell death markers, including morphological changes, DNA fragmentation, mitochondrial polarisation and phosphatidylserine externalisation were used to characterise parasite death at the time of peak parasitaemia and 24h later. At peak parasitaemia, mitochondrial depolarisation was observed, together with phosphatidylserine externalisation in both parasitised- and neighbouring non-infected erythrocytes. DNA fragmentation coincided with a decline in parasitaemia. Fewer merozoites were observed in mature schizonts at peak parasitaemia. Growth recovery to near-peak parasitaemia was noted within two intraerythrocytic cycles. The combination and chronological order of the biochemical markers of cell death suggest the occurrence of an apoptosis-like phenotype. The identification of a RCD pathway in P. falciparum may provide novel drug targets, particularly if the pathway differs from the host machinery.

  20. The lens equator: a platform for molecular machinery that regulates the switch from cell proliferation to differentiation in the vertebrate lens.

    PubMed

    Mochizuki, Toshiaki; Masai, Ichiro

    2014-06-01

    The vertebrate lens is a transparent, spheroidal tissue, located in the anterior region of the eye that focuses visual images on the retina. During development, surface ectoderm associated with the neural retina invaginates to form the lens vesicle. Cells in the posterior half of the lens vesicle differentiate into primary lens fiber cells, which form the lens fiber core, while cells in the anterior half maintain a proliferative state as a monolayer lens epithelium. After formation of the primary fiber core, lens epithelial cells start to differentiate into lens fiber cells at the interface between the lens epithelium and the primary lens fiber core, which is called the equator. Differentiating lens fiber cells elongate and cover the old lens fiber core, resulting in growth of the lens during development. Thus, lens fiber differentiation is spatially regulated and the equator functions as a platform that regulates the switch from cell proliferation to cell differentiation. Since the 1970s, the mechanism underlying lens fiber cell differentiation has been intensively studied, and several regulatory factors that regulate lens fiber cell differentiation have been identified. In this review, we focus on the lens equator, where these regulatory factors crosstalk and cooperate to regulate lens fiber differentiation. Normally, lens epithelial cells must pass through the equator to start lens fiber differentiation. However, there are reports that when the lens epithelium structure is collapsed, lens fiber cell differentiation occurs without passing the equator. We also discuss a possible mechanism that represses lens fiber cell differentiation in lens epithelium.

  1. Coaxial Switch

    DTIC Science & Technology

    2014-04-23

    08-2015 Publication Coaxial Switch David J. Bamford et al Naval Undersea Warfare Center Division, Newport 1176 Howell Street, Bldg 102T, Code 00L...Distribution A A coaxial switch having a housing and a shaft extending through and rotatably mounted to the housing. The shaft extends from opposite...conductor members are electrically connected together. When the coaxial switch is engaged, the conductor members are inserted into the connector body

  2. Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses

    PubMed Central

    Ruane, Darren; Chorny, Alejo; Lee, Haekyung; Faith, Jeremiah; Pandey, Gaurav; Shan, Meimei; Simchoni, Noa; Rahman, Adeeb; Garg, Aakash; Weinstein, Erica G.; Oropallo, Michael; Gaylord, Michelle; Ungaro, Ryan; Cunningham-Rundles, Charlotte; Alexandropoulos, Konstantina; Mucida, Daniel; Merad, Miriam; Cerutti, Andrea

    2016-01-01

    Protective immunoglobulin A (IgA) responses to oral antigens are usually orchestrated by gut dendritic cells (DCs). Here, we show that lung CD103+ and CD24+CD11b+ DCs induced IgA class-switch recombination (CSR) by activating B cells through T cell–dependent or –independent pathways. Compared with lung DCs (LDC), lung CD64+ macrophages had decreased expression of B cell activation genes and induced significantly less IgA production. Microbial stimuli, acting through Toll-like receptors, induced transforming growth factor-β (TGF-β) production by LDCs and exerted a profound influence on LDC-mediated IgA CSR. After intranasal immunization with inactive cholera toxin (CT), LDCs stimulated retinoic acid–dependent up-regulation of α4β7 and CCR9 gut-homing receptors on local IgA-expressing B cells. Migration of these B cells to the gut resulted in IgA-mediated protection against an oral challenge with active CT. However, in germ-free mice, the levels of LDC-induced, CT–specific IgA in the gut are significantly reduced. Herein, we demonstrate an unexpected role of the microbiota in modulating the protective efficacy of intranasal vaccination through their effect on the IgA class-switching function of LDCs. PMID:26712806

  3. Artificial Neural Identification and LMI Transformation for Model Reduction-Based Control of the Buck Switch-Mode Regulator

    NASA Astrophysics Data System (ADS)

    Al-Rabadi, Anas N.

    2009-10-01

    This research introduces a new method of intelligent control for the control of the Buck converter using newly developed small signal model of the pulse width modulation (PWM) switch. The new method uses supervised neural network to estimate certain parameters of the transformed system matrix [Ã]. Then, a numerical algorithm used in robust control called linear matrix inequality (LMI) optimization technique is used to determine the permutation matrix [P] so that a complete system transformation {[B˜], [C˜], [Ẽ]} is possible. The transformed model is then reduced using the method of singular perturbation, and state feedback control is applied to enhance system performance. The experimental results show that the new control methodology simplifies the model in the Buck converter and thus uses a simpler controller that produces the desired system response for performance enhancement.

  4. Optical switches and switching methods

    DOEpatents

    Doty, Michael

    2008-03-04

    A device and method for collecting subject responses, particularly during magnetic imaging experiments and testing using a method such as functional MRI. The device comprises a non-metallic input device which is coupled via fiber optic cables to a computer or other data collection device. One or more optical switches transmit the subject's responses. The input device keeps the subject's fingers comfortably aligned with the switches by partially immobilizing the forearm, wrist, and/or hand of the subject. Also a robust nonmetallic switch, particularly for use with the input device and methods for optical switching.

  5. Continuous Allosteric Regulation of a Viral Packaging Motor by a Sensor that Detects the Density and Conformation of Packaged DNA

    PubMed Central

    Berndsen, Zachary T.; Keller, Nicholas; Smith, Douglas E.

    2015-01-01

    We report evidence for an unconventional type of allosteric regulation of a biomotor. We show that the genome-packaging motor of phage ϕ29 is regulated by a sensor that detects the density and conformation of the DNA packaged inside the viral capsid, and slows the motor by a mechanism distinct from the effect of a direct load force on the motor. Specifically, we show that motor-ATP interactions are regulated by a signal that is propagated allosterically from inside the viral shell to the motor mounted on the outside. This signal continuously regulates the motor speed and pausing in response to changes in either density or conformation of the packaged DNA, and slows the motor before the buildup of large forces resisting DNA confinement. Analysis of motor slipping reveals that the force resisting packaging remains low (<1 pN) until ∼70% and then rises sharply to ∼23 pN at high filling, which is a several-fold lower value than was previously estimated under the assumption that force alone slows the motor. These findings are consistent with recent studies of the stepping kinetics of the motor. The allosteric regulatory mechanism we report allows double-stranded DNA viruses to achieve rapid, high-density packing of their genomes by limiting the buildup of nonequilibrium load forces on the motor. PMID:25606680

  6. New Insights into the Phage Genetic Switch: Effects of Bacteriophage Lambda Operator Mutations on DNA Looping and Regulation of PR, PL, and PRM.

    PubMed

    Lewis, Dale E A; Gussin, Gary N; Adhya, Sankar

    2016-11-06

    One of the best understood systems in genetic regulatory biology is the so-called "genetic switch" that determines the choice the phage-encoded CI repressor binds cooperatively to tripartite operators, OL and OR, in a defined pattern, thus blocking the transcription at two lytic promoters, PL and PR, and auto-regulating the promoter, PRM, which directs CI synthesis by the prophage. Fine-tuning of the maintenance of lysogeny is facilitated by interactions between CI dimers bound to OR and OL through the formation of a loop by the intervening DNA segment. By using a purified in vitro transcription system, we have genetically dissected the roles of individual operator sites in the formation of the DNA loop and thus have gained several new and unexpected insights into the system. First, although both OR and OL are tripartite, the presence of only a single active CI binding site in one of the two operators is sufficient for DNA loop formation. Second, in PL, unlike in PR, the promoter distal operator site, OL3, is sufficient to directly repress PL. Third, DNA looping mediated by the formation of CI octamers arising through the interaction of pairs of dimers bound to adjacent operator sites in OR and OL does not require OR and OL to be aligned "in register", that is, CI bound to "out-of-register" sub-operators, for example, OL1~Ol2 and OR2~OR3, can also mediate loop formation. Finally, based on an examination of the mechanism of activation of PRM when only OR1 or OR2 are wild type, we hypothesize that RNA polymerase bound at PR interferes with DNA loop formation. Thus, the formation of DNA loops involves potential interactions between proteins bound at numerous cis-acting sites, which therefore very subtly contribute to the regulation of the "switch".

  7. CLASP1, astrin and Kif2b form a molecular switch that regulates kinetochore-microtubule dynamics to promote mitotic progression and fidelity

    PubMed Central

    Manning, Amity L; Bakhoum, Samuel F; Maffini, Stefano; Correia-Melo, Clara; Maiato, Helder; Compton, Duane A

    2010-01-01

    Accurate chromosome segregation during mitosis requires precise coordination of various processes, such as chromosome alignment, maturation of proper kinetochore–microtubule (kMT) attachments, correction of erroneous attachments, and silencing of the spindle assembly checkpoint (SAC). How these fundamental aspects of mitosis are coordinately and temporally regulated is poorly understood. In this study, we show that the temporal regulation of kMT attachments by CLASP1, astrin and Kif2b is central to mitotic progression and chromosome segregation fidelity. In early mitosis, a Kif2b–CLASP1 complex is recruited to kinetochores to promote chromosome movement, kMT turnover, correction of attachment errors, and maintenance of SAC signalling. However, during metaphase, this complex is replaced by an astrin–CLASP1 complex, which promotes kMT stability, chromosome alignment, and silencing of the SAC. We show that these two complexes are differentially recruited to kinetochores and are mutually exclusive. We also show that other kinetochore proteins, such as Kif18a, affect kMT attachments and chromosome movement through these proteins. Thus, CLASP1–astrin–Kif2b complex act as a central switch at kinetochores that defines mitotic progression and promotes fidelity by temporally regulating kMT attachments. PMID:20852589

  8. Interferon Regulatory Factor-1 signaling regulates the switch between autophagy and apoptosis to determine breast cancer cell fate

    PubMed Central

    Schwartz-Roberts, Jessica L.; Cook, Katherine L.; Chen, Chun; Shajahan-Haq, Ayesha N.; Axelrod, Margaret; Wärri, Anni; Riggins, Rebecca B.; Jin, Lu; Haddad, Bassem R.; Kallakury, Bhaskar V.; Baumann, William T.; Clarke, Robert

    2015-01-01

    Interferon regulatory factor-1 (IRF1) is a tumor suppressor that regulates cell fate in several cell types. Here we report an inverse correlation in expression of nuclear IRF1 and the autophagy regulator ATG7 in human breast cancer cells that directly impacts their cell fate. In mice harboring mutant Atg7, nuclear IRF1 was increased in mammary tumors, spleen, and kidney. Mechanistic investigations identified ATG7 and the cell death modulator Beclin-1 (BECN1) as negative regulators of IRF1. Silencing ATG7 or BECN1 caused estrogen receptor-α (ERα) to exit the nucleus at the time when IRF1 nuclear localization occurred. Conversely, silencing IRF1 promoted autophagy by increasing BECN1 and blunting IGF-1 receptor and mTOR survival signaling. Loss of IRF1 promoted resistance to anti-estrogens, whereas combined silencing of ATG7 and IRF1 restored sensitivity to these agents. Using a mathematical model to prompt signaling hypotheses, we developed evidence that ATG7 silencing could resensitize IRF1-attenuated cells to apoptosis through mechanisms that involve other estrogen-regulated genes. Overall, our work shows how inhibiting the autophagy proteins ATG7 and BECN1 can regulate IRF1 dependent and independent signaling pathways in ways that engender a new therapeutic strategy to attack breast cancer. PMID:25576084

  9. Immunoglobulin class switching appears to be regulated by B cell antigen receptor-specific T cell action

    PubMed Central

    Lange, Hans; Hecht, Oliver; Zemlin, Michael; Trad, Ahmad; Tanasa, Radu I.; Schroeder, Harry W.; Lemke, Hilmar

    2013-01-01

    Summary Antigen affinity is commonly viewed as the driving force behind the selection for dominant clonotypes that can occur during the T cell-dependent processes of class switch recombination (CSR) and immune maturation. To test this view, we analyzed the variable gene repertoires of natural monoclonal antibodies to the hapten 2-phenyloxazolone (phOx) as well as those generated after phOx protein carrier-induced thymus-dependent or Ficoll-induced thymus independent antigen stimulation. In contrast to expectations, the extent of IgM heterogeneity proved similar and many IgM from these three populations exhibited similar or even greater affinities than the classic Ox1 clonotype that dominates only after CSR among primary and memory IgG. The population of clones that were selected during CSR exhibited a reduced VH/VL repertoire that was enriched for variable domains with shorter and more uniform CDR-H3 lengths and almost completely stripped of variable domains encoded by the large VH1 family. Thus, contrary to the current paradigm, T-cell dependent clonal selection during CSR appeared to select for VH family and CDR-H3 loop content even when the affinity provided by alternative clones exhibited similar to increased affinity for antigen. PMID:22531925

  10. Social density processes regulate the functioning and performance of foraging human teams

    PubMed Central

    King, Andrew J.; Myatt, Julia P.; Fürtbauer, Ines; Oesch, Nathan; Dunbar, Robin I. M.; Sumner, Seirian; Usherwood, James R.; Hailes, Stephen; Brown, M. Rowan

    2015-01-01

    Social density processes impact the activity and order of collective behaviours in a variety of biological systems. Much effort has been devoted to understanding how density of people affects collective human motion in the context of pedestrian flows. However, there is a distinct lack of empirical data investigating the effects of social density on human behaviour in cooperative contexts. Here, we examine the functioning and performance of human teams in a central-place foraging arena using high-resolution GPS data. We show that team functioning (level of coordination) is greatest at intermediate social densities, but contrary to our expectations, increased coordination at intermediate densities did not translate into improved collective foraging performance, and foraging accuracy was equivalent across our density treatments. We suggest that this is likely a consequence of foragers relying upon visual channels (local information) to achieve coordination but relying upon auditory channels (global information) to maximise foraging returns. These findings provide new insights for the development of more sophisticated models of human collective behaviour that consider different networks for communication (e.g. visual and vocal) that have the potential to operate simultaneously in cooperative contexts. PMID:26675584

  11. ION SWITCH

    DOEpatents

    Cook, B.

    1959-02-10

    An ion switch capable of transferring large magnitudes of power is described. An ion switch constructed in accordance with the invention includes a pair of spaced control electrodes disposed in a highly evacuated region for connection in a conventional circuit to control the passing of power therethrough. A controllable ionic conduction path is provided directiy between the control electrodes by a source unit to close the ion switch. Conventional power supply means are provided to trigger the source unit and control the magnitude, durations and pulse repetition rate of the aforementioned ionic conduction path.

  12. The impact of climate change on the bottom up regulation of density dependence in large herbivore populations

    NASA Astrophysics Data System (ADS)

    Ahrestani, F.; Smith, W. A.; Hebblewhite, M.; Running, S. W.; Post, E.

    2013-12-01

    Population dynamics are regulated by either density dependent or, independent (environmental) factors, and climate change may influence populations through either pathway. One key factor in the population dynamics of large herbivores is the dynamics of vegetation nutrient content, which although being an environmental factor, has the potential to impact the degree of density dependence that regulates population dynamics. To understand this bottom up regulatory mechanism and how climate interacts with vegetation, we will estimate the influence of vegetation dynamics on annual abundance estimates of multiple vertebrate populations using time-series analysis. We will test the hypothesis that the strength of density dependence is expected to vary inversely with changes in vegetation availability, i.e., in areas with higher forage abundance and quality, density dependence is expected to be stronger. Extended to climate change, this hypothesis predicts that climate impacts will be stronger in areas of low vegetation availability, such as the arctic and alpine regions. We will analyze a combined dataset of 55 globally distributed Cervus (elk/red deer) and Rangifer (caribou/reindeer) populations that inhabit areas >100km2. These population time-series we will be analyzed using Markov Chain Monte Carlo Bayesian state-space models, and to represent annual vegetation dynamics we will use Global Inventory Monitoring and Modeling System (GIMMS) normalized difference vegetation index (NDVI) data (i.e., third generation GIMMS NDVI from AVHRR sensors).

  13. Density-enhanced Phosphatase 1 Regulates Phosphorylation of Tight Junction Proteins and Enhances Barrier Function of Epithelial Cells*

    PubMed Central

    Sallee, Jennifer L.; Burridge, Keith

    2009-01-01

    Cell-cell adhesion is a dynamic process that can activate multiple signaling pathways. These signaling pathways can be regulated through reversible tyrosine phosphorylation events. The level of tyrosine phosphorylation of junctional proteins reflects the balance between protein-tyrosine kinase and protein-tyrosine phosphatase activity. The receptor-tyrosine phosphatase DEP-1 (CD148/PTP-η) has been implicated in cell growth and differentiation as well as in regulating phosphorylation of junctional proteins. However, the role of DEP-1 in regulating tight junction phosphorylation and the integrity of cell-cell junctions is still under investigation. In this study, we used a catalytically dead substrate-trapping mutant of DEP-1 to identify potential substrates at cell-cell junctions. We have shown that in epithelial cells the trapping mutant of DEP-1 interacts with the tight junction proteins occludin and ZO-1 in a tyrosine phosphorylation-dependent manner. In contrast, PTP-PEST, Shp2, and PTPμ did not interact with these proteins, suggesting that the interaction of DEP-1 with occludin and ZO-1 is specific. In addition, occludin and ZO-1 were dephosphorylated by DEP-1 but not these other phosphatases in vitro. Overexpression of DEP-1 increased barrier function as measured by transepithelial electrical resistance and also reduced paracellular flux of fluorescein isothiocyanate-dextran following a calcium switch. Reduced DEP-1 expression by small interfering RNA had a small but significant increase in junction permeability. These data suggest that DEP-1 can modify the phosphorylation state of tight junction proteins and play a role in regulating permeability. PMID:19332538

  14. Network topology-based detection of differential gene regulation and regulatory switches in cell metabolism and signaling

    PubMed Central

    2014-01-01

    Background Common approaches to pathway analysis treat pathways merely as lists of genes disregarding their topological structures, that is, ignoring the genes' interactions on which a pathway's cellular function depends. In contrast, PathWave has been developed for the analysis of high-throughput gene expression data that explicitly takes the topology of networks into account to identify both global dysregulation of and localized (switch-like) regulatory shifts within metabolic and signaling pathways. For this purpose, it applies adjusted wavelet transforms on optimized 2D grid representations of curated pathway maps. Results Here, we present the new version of PathWave with several substantial improvements including a new method for optimally mapping pathway networks unto compact 2D lattice grids, a more flexible and user-friendly interface, and pre-arranged 2D grid representations. These pathway representations are assembled for several species now comprising H. sapiens, M. musculus, D. melanogaster, D. rerio, C. elegans, and E. coli. We show that PathWave is more sensitive than common approaches and apply it to RNA-seq expression data, identifying crucial metabolic pathways in lung adenocarcinoma, as well as microarray expression data, identifying pathways involved in longevity of Drosophila. Conclusions PathWave is a generic method for pathway analysis complementing established tools like GSEA, and the update comprises efficient new features. In contrast to the tested commonly applied approaches which do not take network topology into account, PathWave enables identifying pathways that are either known be involved in or very likely associated with such diverse conditions as human lung cancer or aging of D. melanogaster. The PathWave R package is freely available at http://www.ichip.de/software/pathwave.html. PMID:24886210

  15. Engineering covalent loops in proteins can serve as an on/off switch to regulate threaded topologies.

    PubMed

    Haglund, Ellinor

    2015-09-09

    Knots in proteins are under active investigation motivating refinements of current techniques and the development of tools to better understand the knotted topology. A strong focus is to identify new knots and expand upon the current understanding of their complex topology. Previous work has shown that the knotted topology, even in the simplest case of knots, encompasses a variety of unique challenges in folding and tying a chain. To bypass many of the in vitro experimental complications involved in working with knots, it is useful to apply methodologies to a more simplified system. The pierced lasso bundles (PLB), we discovered where a single disulphide bridge holds the threaded topology together, presents a simpler system to study knots in vitro. Having a disulphide bridge as an on/off switch between the threaded/unthreaded topology is advantageous because a covalent loop allows manipulation of the knot without directly altering affecting secondary and tertiary structure. Because disulphide bridges are commonly used in protein engineering, a pierced lasso (PL) topology can be easily introduced into a protein of interest to form a knotted topology within a given secondary structure. It is also important to take into account that if formed, disulphides can inadvertently introduce an unwanted PL. This was found upon determination of the crystal structure (PDB code 2YHG) of the recently de novo designed nucleoside hydrolase. Our detailed investigations of the PL presented here will allow researchers to look at the introduction of disulphide bridges in a larger context with respect to potential geometrical consequences on the structure and functional properties of proteins.

  16. Engineering covalent loops in proteins can serve as an on/off switch to regulate threaded topologies

    NASA Astrophysics Data System (ADS)

    Haglund, Ellinor

    2015-09-01

    Knots in proteins are under active investigation motivating refinements of current techniques and the development of tools to better understand the knotted topology. A strong focus is to identify new knots and expand upon the current understanding of their complex topology. Previous work has shown that the knotted topology, even in the simplest case of knots, encompasses a variety of unique challenges in folding and tying a chain. To bypass many of the in vitro experimental complications involved in working with knots, it is useful to apply methodologies to a more simplified system. The pierced lasso bundles (PLB), we discovered where a single disulphide bridge holds the threaded topology together, presents a simpler system to study knots in vitro. Having a disulphide bridge as an on/off switch between the threaded/unthreaded topology is advantageous because a covalent loop allows manipulation of the knot without directly altering affecting secondary and tertiary structure. Because disulphide bridges are commonly used in protein engineering, a pierced lasso (PL) topology can be easily introduced into a protein of interest to form a knotted topology within a given secondary structure. It is also important to take into account that if formed, disulphides can inadvertently introduce an unwanted PL. This was found upon determination of the crystal structure (PDB code 2YHG) of the recently de novo designed nucleoside hydrolase. Our detailed investigations of the PL presented here will allow researchers to look at the introduction of disulphide bridges in a larger context with respect to potential geometrical consequences on the structure and functional properties of proteins.

  17. Src subfamily kinases regulate nuclear export and degradation of transcription factor Nrf2 to switch off Nrf2-mediated antioxidant activation of cytoprotective gene expression.

    PubMed

    Niture, Suryakant K; Jain, Abhinav K; Shelton, Phillip M; Jaiswal, Anil K

    2011-08-19

    Nrf2 (NF-E2-related factor 2) is a nuclear transcription factor that in response to chemical and radiation stress regulates coordinated induction of a battery of cytoprotective gene expressions leading to cellular protection. In this study, we investigated the role of Src kinases in the regulation of Nrf2 and downstream signaling. siRNA-mediated inhibition of Fyn, Src, Yes, and Fgr, but not Lyn, in mouse hepatoma Hepa-1 cells, led to nuclear accumulation of Nrf2 and up-regulation of Nrf2 downstream gene expression. Mouse embryonic fibroblasts with combined deficiency of Fyn/Src/Yes/Fgr supported results from siRNA. In addition, steady-state overexpression of Fyn, Src, and Yes phosphorylated Nrf2Tyr568 that triggered nuclear export and degradation of Nrf2 and down-regulation of Nrf2 downstream gene expression. Exposure of cells to antioxidant, oxidant, or UV radiation increased nuclear import of Fyn, Src, and Yes kinases, which phosphorylated Nrf2Tyr568 resulting in nuclear export and degradation of Nrf2. Further analysis revealed that stress-activated GSK3β acted upstream to the Src kinases and phosphorylated the Src kinases, leading to their nuclear localization and Nrf2 phosphorylation. The overexpression of Src kinases in Hepa-1 cells led to decreased Nrf2, increased apoptosis, and decreased cell survival. Mouse embryonic fibroblasts deficient in Src kinases showed nuclear accumulation of Nrf2, induction of Nrf2 and downstream gene expression, reduced apoptosis, and increased cell survival. The studies together demonstrate that Src kinases play a critical role in nuclear export and degradation of Nrf2, thereby providing a negative feedback mechanism to switch off Nrf2 activation and restore normal cellular homeostasis.

  18. Cell-Autonomous Regulation of Dendritic Spine Density by PirB.

    PubMed

    Vidal, George S; Djurisic, Maja; Brown, Kiana; Sapp, Richard W; Shatz, Carla J

    2016-01-01

    Synapse density on cortical pyramidal neurons is modulated by experience. This process is highest during developmental critical periods, when mechanisms of synaptic plasticity are fully engaged. In mouse visual cortex, the critical period for ocular dominance (OD) plasticity coincides with the developmental pruning of synapses. At this time, mice lacking paired Ig-like receptor B (PirB) have excess numbers of dendritic spines on L5 neurons; these spines persist and are thought to underlie the juvenile-like OD plasticity observed in adulthood. Here we examine whether PirB is required specifically in excitatory neurons to exert its effect on dendritic spine and synapse density during the critical period. In mice with a conditional allele of PirB (PirB(fl/fl)), PirB was deleted only from L2/3 cortical pyramidal neurons in vivo by timed in utero electroporation of Cre recombinase. Sparse mosaic expression of Cre produced neurons lacking PirB in a sea of wild-type neurons and glia. These neurons had significantly elevated dendritic spine density, as well as increased frequency of miniature EPSCs, suggesting that they receive a greater number of synaptic inputs relative to Cre(-) neighbors. The effect of cell-specific PirB deletion on dendritic spine density was not accompanied by changes in dendritic branching complexity or axonal bouton density. Together, results imply a neuron-specific, cell-autonomous action of PirB on synaptic density in L2/3 pyramidal cells of visual cortex. Moreover, they are consistent with the idea that PirB functions normally to corepress spine density and synaptic plasticity, thereby maintaining headroom for cells to encode ongoing experience-dependent structural change throughout life.

  19. Cell-Autonomous Regulation of Dendritic Spine Density by PirB

    PubMed Central

    2016-01-01

    Synapse density on cortical pyramidal neurons is modulated by experience. This process is highest during developmental critical periods, when mechanisms of synaptic plasticity are fully engaged. In mouse visual cortex, the critical period for ocular dominance (OD) plasticity coincides with the developmental pruning of synapses. At this time, mice lacking paired Ig-like receptor B (PirB) have excess numbers of dendritic spines on L5 neurons; these spines persist and are thought to underlie the juvenile-like OD plasticity observed in adulthood. Here we examine whether PirB is required specifically in excitatory neurons to exert its effect on dendritic spine and synapse density during the critical period. In mice with a conditional allele of PirB (PirBfl/fl), PirB was deleted only from L2/3 cortical pyramidal neurons in vivo by timed in utero electroporation of Cre recombinase. Sparse mosaic expression of Cre produced neurons lacking PirB in a sea of wild-type neurons and glia. These neurons had significantly elevated dendritic spine density, as well as increased frequency of miniature EPSCs, suggesting that they receive a greater number of synaptic inputs relative to Cre– neighbors. The effect of cell-specific PirB deletion on dendritic spine density was not accompanied by changes in dendritic branching complexity or axonal bouton density. Together, results imply a neuron-specific, cell-autonomous action of PirB on synaptic density in L2/3 pyramidal cells of visual cortex. Moreover, they are consistent with the idea that PirB functions normally to corepress spine density and synaptic plasticity, thereby maintaining headroom for cells to encode ongoing experience-dependent structural change throughout life. PMID:27752542

  20. HOLLOTRON switch for megawatt lightweight space inverters

    NASA Technical Reports Server (NTRS)

    Poeschel, R. L.; Goebel, D. M.; Schumacher, R. W.

    1991-01-01

    The feasibility of satisfying the switching requirements for a megawatt ultralight inverter system using HOLLOTRON switch technology was determined. The existing experimental switch hardware was modified to investigate a coaxial HOLLOTRON switch configuration and the results were compared with those obtained for a modified linear HOLLOTRON configuration. It was concluded that scaling the HOLLOTRON switch to the current and voltage specifications required for a megawatt converter system is indeed feasible using a modified linear configuration. The experimental HOLLOTRON switch operated at parameters comparable to the scaled coaxial HOLLOTRON. However, the linear HOLLOTRON data verified the capability for meeting all the design objectives simultaneously including current density (greater than 2 A/sq cm), voltage (5 kV), switching frequency (20 kHz), switching time (300 ns), and forward voltage drop (less than or equal to 20 V). Scaling relations were determined and a preliminary design was completed for an engineering model linear HOLLOTRON switch to meet the megawatt converter system specifications.

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

    PubMed

    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".

  2. The ankyrin repeats and DHHC S-acyl transferase domain of AKR1 act independently to regulate switching from vegetative to mating states in yeast.

    PubMed

    Hemsley, Piers A; Grierson, Claire S

    2011-01-01

    Signal transduction from G-protein coupled receptors to MAPK cascades through heterotrimeric G-proteins has been described for many eukaryotic systems. One of the best-characterised examples is the yeast pheromone response pathway, which is negatively regulated by AKR1. AKR1-like proteins are present in all eukaryotes and contain a DHHC domain and six ankyrin repeats. Whilst the DHHC domain dependant S-acyl transferase (palmitoyl transferase) function of AKR1 is well documented it is not known whether the ankyrin repeats are also required for this activity. Here we show that the ankyrin repeats of AKR1 are required for full suppression of the yeast pheromone response pathway, by sequestration of the Gβγ dimer, and act independently of AKR1 S-acylation function. Importantly, the functions provided by the AKR1 ankyrin repeats and DHHC domain are not required on the same molecule to fully restore WT phenotypes and function. We also show that AKR1 molecules are S-acylated at locations other than the DHHC cysteine, increasing the abundance of AKR1 in the cell. Our results have important consequences for studies of AKR1 function, including recent attempts to characterise S-acylation enzymology and kinetics. Proteins similar to AKR1 are found in all eukaryotes and our results have broad implications for future work on these proteins and the control of switching between Gβγ regulated pathways.

  3. Acceleration switch

    DOEpatents

    Abbin, Jr., Joseph P.; Devaney, Howard F.; Hake, Lewis W.

    1982-08-17

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  4. Acceleration switch

    DOEpatents

    Abbin, J.P. Jr.; Devaney, H.F.; Hake, L.W.

    1979-08-29

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  5. The master switch gene Sex-lethal promotes female development by negatively regulating the N signaling pathway

    PubMed Central

    Penn, Jill K M; Schedl, Paul

    2011-01-01

    Summary Notch (N) signaling is used for cell fate determination in many different developmental contexts. Here we show that the master control gene for sex determination in Drosophila melanogaster, Sex-lethal (Sxl), negatively regulates the N signaling pathway in females. In genetic assays, reducing Sxl activity suppresses the phenotypic effects of N mutations while increasing Sxl activity enhances the effects. Sxl appears to negatively regulate the pathway by reducing N protein accumulation and higher levels of N are found in Sxl−clones than in adjacent wild type cells. The inhibition of N expression does not depend on the known downstream targets of Sxl; however we find that Sxl protein can bind to N mRNAs. Finally our results indicate that downregulation of the N pathway by Sxl contributes to sex specific differences in morphology and suggest that it may also play an important role in follicle cell specification during oogenesis. PMID:17276344

  6. 49 CFR 236.820 - Switch, interlocked.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Switch, interlocked. 236.820 Section 236.820 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, interlocked. A switch within the interlocking limits the control of which is interlocked...

  7. 49 CFR 236.821 - Switch, sectionalizing.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Switch, sectionalizing. 236.821 Section 236.821 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, sectionalizing. A switch for disconnecting a section of a power line from the source of energy....

  8. 49 CFR 236.821 - Switch, sectionalizing.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Switch, sectionalizing. 236.821 Section 236.821 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, sectionalizing. A switch for disconnecting a section of a power line from the source of energy....

  9. 49 CFR 236.822 - Switch, spring.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Switch, spring. 236.822 Section 236.822 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, spring. A switch equipped with a spring device which forces the points to their original...

  10. 49 CFR 236.822 - Switch, spring.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Switch, spring. 236.822 Section 236.822 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, spring. A switch equipped with a spring device which forces the points to their original...

  11. 49 CFR 236.820 - Switch, interlocked.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Switch, interlocked. 236.820 Section 236.820 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, interlocked. A switch within the interlocking limits the control of which is interlocked...

  12. 49 CFR 236.821 - Switch, sectionalizing.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Switch, sectionalizing. 236.821 Section 236.821 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, sectionalizing. A switch for disconnecting a section of a power line from the source of energy....

  13. 49 CFR 236.822 - Switch, spring.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Switch, spring. 236.822 Section 236.822 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, spring. A switch equipped with a spring device which forces the points to their original...

  14. 49 CFR 236.820 - Switch, interlocked.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Switch, interlocked. 236.820 Section 236.820 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, interlocked. A switch within the interlocking limits the control of which is interlocked...

  15. 49 CFR 236.821 - Switch, sectionalizing.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Switch, sectionalizing. 236.821 Section 236.821 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, sectionalizing. A switch for disconnecting a section of a power line from the source of energy....

  16. 49 CFR 236.820 - Switch, interlocked.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Switch, interlocked. 236.820 Section 236.820 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, interlocked. A switch within the interlocking limits the control of which is interlocked...

  17. 49 CFR 236.822 - Switch, spring.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Switch, spring. 236.822 Section 236.822 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, spring. A switch equipped with a spring device which forces the points to their original...

  18. 49 CFR 236.822 - Switch, spring.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Switch, spring. 236.822 Section 236.822 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, spring. A switch equipped with a spring device which forces the points to their original...

  19. 49 CFR 236.821 - Switch, sectionalizing.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Switch, sectionalizing. 236.821 Section 236.821 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, sectionalizing. A switch for disconnecting a section of a power line from the source of energy....

  20. 49 CFR 236.820 - Switch, interlocked.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Switch, interlocked. 236.820 Section 236.820 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, interlocked. A switch within the interlocking limits the control of which is interlocked...

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

    PubMed

    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.

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

    PubMed Central

    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

  3. The Metabolic Core and Catalytic Switches Are Fundamental Elements in the Self-Regulation of the Systemic Metabolic Structure of Cells

    PubMed Central

    De la Fuente, Ildefonso M.; Cortes, Jesus M.; Perez-Pinilla, Martin B.; Ruiz-Rodriguez, Vicente; Veguillas, Juan

    2011-01-01

    Background Experimental observations and numerical studies with dissipative metabolic networks have shown that cellular enzymatic activity self-organizes spontaneously leading to the emergence of a metabolic core formed by a set of enzymatic reactions which are always active under all environmental conditions, while the rest of catalytic processes are only intermittently active. The reactions of the metabolic core are essential for biomass formation and to assure optimal metabolic performance. The on-off catalytic reactions and the metabolic core are essential elements of a Systemic Metabolic Structure which seems to be a key feature common to all cellular organisms. Methodology/Principal Findings In order to investigate the functional importance of the metabolic core we have studied different catalytic patterns of a dissipative metabolic network under different external conditions. The emerging biochemical data have been analysed using information-based dynamic tools, such as Pearson's correlation and Transfer Entropy (which measures effective functionality). Our results show that a functional structure of effective connectivity emerges which is dynamical and characterized by significant variations of bio-molecular information flows. Conclusions/Significance We have quantified essential aspects of the metabolic core functionality. The always active enzymatic reactions form a hub –with a high degree of effective connectivity- exhibiting a wide range of functional information values being able to act either as a source or as a sink of bio-molecular causal interactions. Likewise, we have found that the metabolic core is an essential part of an emergent functional structure characterized by catalytic modules and metabolic switches which allow critical transitions in enzymatic activity. Both, the metabolic core and the catalytic switches in which also intermittently-active enzymes are involved seem to be fundamental elements in the self-regulation of the Systemic

  4. Positive density-dependent reproduction regulated by local kinship and size in an understorey tropical tree

    PubMed Central

    Castilla, Antonio R.; Pope, Nathaniel; Jha, Shalene

    2016-01-01

    Background and Aims Global pollinator declines and continued habitat fragmentation highlight the critical need to understand reproduction and gene flow across plant populations. Plant size, conspecific density and local kinship (i.e. neighbourhood genetic relatedness) have been proposed as important mechanisms influencing the reproductive success of flowering plants, but have rarely been simultaneously investigated. Methods We conducted this study on a continuous population of the understorey tree Miconia affinis in the Forest Dynamics Plot on Barro Colorado Island in central Panama. We used spatial, reproductive and population genetic data to investigate the effects of tree size, conspecific neighbourhood density and local kinship on maternal and paternal reproductive success. We used a Bayesian framework to simultaneously model the effects of our explanatory variables on the mean and variance of maternal viable seed set and siring success. Key Results Our results reveal that large trees had lower proportions of viable seeds in their fruits but sired more seeds. We documented differential effects of neighbourhood density and local kinship on both maternal and paternal reproductive components. Trees in more dense neighbourhoods produced on average more viable seeds, although this positive density effect was influenced by variance-inflation with increasing local kinship. Neighbourhood density did not have significant effects on siring success. Conclusions This study is one of the first to reveal an interaction among tree size, conspecific density and local kinship as critical factors differentially influencing maternal and paternal reproductive success. We show that both maternal and paternal reproductive success should be evaluated to determine the population-level and individual traits most essential for plant reproduction. In addition to conserving large trees, we suggest the inclusion of small trees and the conservation of dense patches with low kinship as

  5. Smooth muscle myosin regulation by serum and cell density in cultured rat lung connective tissue cells.

    PubMed

    Babij, P; Zhao, J; White, S; Woodcock-Mitchell, J; Mitchell, J; Absher, M; Baldor, L; Periasamy, M; Low, R B

    1993-08-01

    RNA and protein analyses were used to detect expression of SM1 and SM2 smooth muscle myosin heavy chain (MHC) in cultured adult rat lung connective tissue cells (RL-90). Smooth muscle MHC mRNA expression in confluent cells grown in 10% serum was approximately 50% of the level in adult stomach. Similar results were obtained in cells cultured at low density (25% confluency) in 1% serum. However, in low-density cultures transferred to 10% serum for 24 h, the level of MHC mRNA decreased to approximately 20% of that in adult stomach. Smooth muscle alpha-actin showed a pattern of expression similar to that for smooth muscle MHC. Expression of nonmuscle MHC-A mRNA was higher in all culture conditions compared to stomach. MHC-A mRNA expression was less in low-density cultures in low serum and increased when low-density cultures were transferred to 10% serum for 24 h. MHC-B mRNA expression was less in low- vs. high-density cultures. In contrast to MHC-A, however, MHC-B mRNA expression in low-density cultures was higher in low serum. Immunofluorescence and immunoblotting with SM1-specific antibody demonstrated the presence of the SM1 protein isoform as well as reactivity to a protein band migrating slightly faster than SM2. These results demonstrate that cultured rat lung connective tissue cells express smooth muscle MHC and that expression is modulated by culture conditions.

  6. Innovative switching technology

    NASA Astrophysics Data System (ADS)

    Rosen, A.; Stabile, P. J.; Gombar, A. M.; Janton, W. M.; Gilbert, D. B.; Herczfeld, P. R.; Bahasadri, A.

    1991-03-01

    We have developed an all-semiconductor high-power optical switch. Potential uses include both military applications, such as ultra-wide-band impulse radar and high-frequency antenna couplers, and commercial use, such as high-power switching for utility companies. Under this three-year program, we have demonstrated various switching applications from dc to GHz frequencies. The generic switches comprise a 2-D semiconductor laser diode array and Si or GaAs devices. In the Si area (linear switches - no gain) and dc-biased network, a single two-sided PIN device, activated by two 1 kW laser arrays, has yielded a holding voltage of 1.3 kV and conducted 192 A. Similar devices have later yielded a holding voltage of 3.3 kV, demonstrating the capability of switching more than 500 kW with a single two-sided PIN device. The same generic technology was also demonstrated in high-power high-frequency antenna coupler applications as well as in mm-wave (60 GHz) attenuators and phase shifters. PIN devices tested in a RF circuit between 2-30 MHz yielded an isolation value of between 28 and 49 dB in the off-state, and insertion losses as low as 0.1 dB when illuminated with 280 W (peak) optical power at 808 nm. In the area of GaAs, PIN, and bulk devices under this project, we were able to deliver devices for experiments in both opening and closing switches. We have demonstrated a compact, all-semiconductor switch system that has switched up to 8.5 MW into a 38 (omega) load. The system uses a 2-D laser diode array with a peak power of 850 W to rigger a 1.5 cm long GaAs photoconductor into a high-gain combination mode known as 'lock on'. The highest power switch was pulse-charged to 55 kV and delivered 470 A to a 38 (omega) load in 160 ns long pulse. In the area of 2-D laser arrays, a peak power density of 7 kW/cm(exp 2) was achieved.

  7. A let-7-to-miR-125 MicroRNA Switch Regulates Neuronal Integrity and Lifespan in Drosophila

    PubMed Central

    Chawla, Geetanjali; Deosthale, Padmini; Childress, Sue; Wu, Yen-chi; Sokol, Nicholas S.

    2016-01-01

    Messenger RNAs (mRNAs) often contain binding sites for multiple, different microRNAs (miRNAs). However, the biological significance of this feature is unclear, since such co-targeting miRNAs could function coordinately, independently, or redundantly with one another. Here, we show that two co-transcribed Drosophila miRNAs, let-7 and miR-125, non-redundantly regulate a common target, the transcription factor Chronologically Inappropriate Morphogenesis (Chinmo). We first characterize novel adult phenotypes associated with loss of both let-7 and miR-125, which are derived from a common, polycistronic transcript that also encodes a third miRNA, miR-100. Consistent with the coordinate upregulation of all three miRNAs in aging flies, these phenotypes include brain degeneration and shortened lifespan. However, transgenic rescue analysis reveal separable roles for these miRNAs: adult miR-125 but not let-7 mutant phenotypes are associated with ectopic Chinmo expression in adult brains and are suppressed by chinmo reduction. In contrast, let-7 is predominantly responsible for regulating chinmo during nervous system formation. These results indicate that let-7 and miR-125 function during two distinct stages, development and adulthood, rather than acting at the same time. These different activities are facilitated by an increased rate of processing of let-7 during development and a lower rate of decay of the accumulated miR-125 in the adult nervous system. Thus, this work not only establishes a key role for the highly conserved miR-125 in aging. It also demonstrates that two co-transcribed miRNAs function independently during distinct stages to regulate a common target, raising the possibility that such biphasic control may be a general feature of clustered miRNAs. PMID:27508495

  8. Regulation of Kv2.1 K+ conductance by cell surface channel density

    PubMed Central

    Fox, Philip D.; Loftus, Rob J.; Tamkun, Michael M.

    2013-01-01

    The Kv2.1 voltage-gated K+ channel is found both freely diffusing over the plasma membrane and concentrated in micron-sized clusters localized to the soma, proximal dendrites and axon initial segment of hippocampal neurons. In transfected HEK cells, Kv2.1 channels within cluster microdomains are non-conducting. Using TIRF microscopy the number of GFP-tagged Kv2.1 channels on the HEK cell surface was compared to K+ channel conductance measured by whole-cell voltage-clamp of the same cell. This approach indicated that as channel density increases non-clustered channels cease conducting. At the highest density observed, only 4% of all channels were conducting. Mutant Kv2.1 channels that fail to cluster also possessed the non-conducting state with 17% conducting K+ at higher surface densities. The non-conducting state was specific to Kv2.1 as Kv1.4 was always conducting regardless of the cell-surface expression level. Anti-Kv2.1 immuno-fluorescence intensity, standardized to Kv2.1 surface density in transfected HEK cells, was used to determine the expression levels of endogenous Kv2.1 in cultured rat hippocampal neurons. Endogenous Kv2.1 levels were compared to the number of conducting channels determined by whole-cell voltage clamp. Only 13 and 27% of the endogenous Kv2.1 was conducting in neurons cultured for 14 and 20 days, respectively. Together these data indicate that the non-conducting state depends primarily on surface density as opposed to cluster location and that this non-conducting state also exists for native Kv2.1 found in cultured hippocampal neurons. This excess of Kv2.1 protein relative to K+ conductance further supports a non-conducting role for Kv2.1 in excitable tissues. PMID:23325261

  9. The relation between invertebrate drift and two primary controls, discharge and benthic densities, in a large regulated river

    USGS Publications Warehouse

    Kennedy, Theodore A.; Yackulic, Charles B.; Cross, Wyatt F.; Grams, Paul E.; Yard, Michael D.; Copp, Adam J.

    2014-01-01

    1. Invertebrate drift is a fundamental process in streams and rivers. Studies from laboratory experiments and small streams have identified numerous extrinsic (e.g. discharge, light intensity, water quality) and intrinsic factors (invertebrate life stage, benthic density, behaviour) that govern invertebrate drift concentrations (# m−3), but the factors that govern invertebrate drift in larger rivers remain poorly understood. For example, while large increases or decreases in discharge can lead to large increases in invertebrate drift, the role of smaller, incremental changes in discharge is poorly described. In addition, while we might expect invertebrate drift concentrations to be proportional to benthic densities (# m−2), the benthic–drift relation has not been rigorously evaluated. 2. Here, we develop a framework for modelling invertebrate drift that is derived from sediment transport studies. We use this framework to guide the analysis of high-resolution data sets of benthic density and drift concentration for four important invertebrate taxa from the Colorado River downstream of Glen Canyon Dam (mean daily discharge 325 m3 s−1) that were collected over 18 months and include multiple observations within days. Ramping of regulated flows on this river segment provides an experimental treatment that is repeated daily and allowed us to describe the functional relations between invertebrate drift and two primary controls, discharge and benthic densities. 3. Twofold daily variation in discharge resulted in a >10-fold increase in drift concentrations of benthic invertebrates associated with pools and detritus (i.e. Gammarus lacustris and Potamopyrgus antipodarum). In contrast, drift concentrations of sessile blackfly larvae (Simuliium arcticum), which are associated with high-velocity cobble microhabitats, decreased by over 80% as discharge doubled. Drift concentrations of Chironomidae increased proportional to discharge. 4. Drift of all four taxa was

  10. Regulation of Macrophage Motility by the Water Channel Aquaporin-1: Crucial Role of M0/M2 Phenotype Switch

    PubMed Central

    Tyteca, Donatienne; Nishino, Tomoya; Debaix, Huguette; Van Der Smissen, Patrick; N'Kuli, Francisca; Hoffmann, Delia; Cnops, Yvette; Rabolli, Virginie; van Loo, Geert; Beyaert, Rudi; Huaux, François; Devuyst, Olivier; Courtoy, Pierre J.

    2015-01-01

    The water channel aquaporin-1 (AQP1) promotes migration of many cell types. Although AQP1 is expressed in macrophages, its potential role in macrophage motility, particularly in relation with phenotype polarization, remains unknown. We here addressed these issues in peritoneal macrophages isolated from AQP1-deficient mice, either undifferentiated (M0) or stimulated with LPS to orientate towards pro-inflammatory phenotype (classical macrophage activation; M1). In non-stimulated macrophages, ablation of AQP1 (like inhibition by HgCl2) increased by 2–3 fold spontaneous migration in a Src/PI3K/Rac-dependent manner. This correlated with cell elongation and formation of lamellipodia/ruffles, resulting in membrane lipid and F4/80 recruitment to the leading edge. This indicated that AQP1 normally suppresses migration of resting macrophages, as opposed to other cell types. Resting Aqp1-/- macrophages exhibited CD206 redistribution into ruffles and increased arginase activity like IL4/IL13 (alternative macrophage activation; M2), indicating a M0-M2 shift. In contrast, upon M1 orientation by LPS in vitro or peritoneal inflammation in vivo, migration of Aqp1-/- macrophages was reduced. Taken together, these data indicate that AQP1 oppositely regulates macrophage migration, depending on stimulation or not by LPS, and that macrophage phenotypic and migratory changes may be regulated independently of external cues. PMID:25719758

  11. Proteolytic and non-proteolytic regulation of collective cell invasion: tuning by ECM density and organization.

    PubMed

    Kumar, Sandeep; Kapoor, Aastha; Desai, Sejal; Inamdar, Mandar M; Sen, Shamik

    2016-02-02

    Cancer cells manoeuvre through extracellular matrices (ECMs) using different invasion modes, including single cell and collective cell invasion. These modes rely on MMP-driven ECM proteolysis to make space for cells to move. How cancer-associated alterations in ECM influence the mode of invasion remains unclear. Further, the sensitivity of the two invasion modes to MMP dynamics remains unexplored. In this paper, we address these open questions using a multiscale hybrid computational model combining ECM density-dependent MMP secretion, MMP diffusion, ECM degradation by MMP and active cell motility. Our results demonstrate that in randomly aligned matrices, collective cell invasion is more efficient than single cell invasion. Although increase in MMP secretion rate enhances invasiveness independent of cell-cell adhesion, sustenance of collective invasion in dense matrices requires high MMP secretion rates. However, matrix alignment can sustain both single cell and collective cell invasion even without ECM proteolysis. Similar to our in-silico observations, increase in ECM density and MMP inhibition reduced migration of MCF-7 cells embedded in sandwich gels. Together, our results indicate that apart from cell intrinsic factors (i.e., high cell-cell adhesion and MMP secretion rates), ECM density and organization represent two important extrinsic parameters that govern collective cell invasion and invasion plasticity.

  12. Selective regulation of current densities underlies spontaneous changes in the activity of cultured neurons.

    PubMed

    Turrigiano, G; LeMasson, G; Marder, E

    1995-05-01

    We study the electrical activity patterns and the expression of conductances in adult stomatogastric ganglion (STG) neurons as a function of time in primary cell culture. When first plated in culture, these neurons had few active properties. After 1 d in culture they produced small action potentials that rapidly inactivated during maintained depolarization. After 2 d in culture they fired large action potentials tonically when depolarized, and their properties resembled very closely the properties of STG neurons pharmacologically isolated in the ganglion. After 3-4 d in culture, however, their electrical properties changed and they fired in bursts when depolarized. We characterized the currents expressed by these neurons in culture. They included two TTX-sensitive sodium currents, a calcium current, a delayed-rectifier-like current, a calcium-dependent potassium current, and two A-type currents. The changes in firing properties with time in culture were accompanied by an increase in inward and decrease in outward current densities. A single-compartment conductance-based model of an STG neuron was constructed by fitting the currents measured in the biological neurons. When the current densities in the model neuron were matched to those measured for the biological neurons in each activity state, the model neuron closely reproduced each state, indicating that the changes in current densities are sufficient to account for the changes in intrinsic properties. These data indicate that STG neurons isolated in culture change their intrinsic electrical properties by selectively adjusting the magnitudes of their ionic conductances.

  13. Characteristics of switching plasma in an inverse-pinch switch

    NASA Technical Reports Server (NTRS)

    Lee, Ja H.; Choi, Sang H.; Venable, Demetrius D.; Han, Kwang S.; Nam, Sang H.

    1993-01-01

    Characteristics of the plasma that switches on tens of giga volt-ampere in an inverse-pinch plasma switch (INPIStron) have been made. Through optical and spectroscopic diagnostics of the current carrying plasma, the current density, the motion of current paths, dominant ionic species have been determined in order to access their effects on circuit parameters and material erosion. Also the optimum operational condition of the plasma-puff triggering method required for azimuthally uniform conduction in the INPIStron has been determined.

  14. miR-600 Acts as a Bimodal Switch that Regulates Breast Cancer Stem Cell Fate through WNT Signaling.

    PubMed

    El Helou, Rita; Pinna, Guillaume; Cabaud, Olivier; Wicinski, Julien; Bhajun, Ricky; Guyon, Laurent; Rioualen, Claire; Finetti, Pascal; Gros, Abigaelle; Mari, Bernard; Barbry, Pascal; Bertucci, Francois; Bidaut, Ghislain; Harel-Bellan, Annick; Birnbaum, Daniel; Charafe-Jauffret, Emmanuelle; Ginestier, Christophe

    2017-02-28

    Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define this state are unclear. We have performed two microRNA (miRNA) gain- and loss-of-function screens to identify miRNAs that regulate the choice between bCSC self-renewal and differentiation. We find that micro-RNA (miR)-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal, leading to decreased in vivo tumorigenicity. miR-600 targets stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. In the absence of miR-600, WNT signaling is active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT and promotes bCSC differentiation. In a series of 120 breast tumors, we found that a low level of miR-600 is correlated with active WNT signaling and a poor prognosis. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decisions and influences tumor progression.

  15. High-Density and Very-Low-Density Lipoprotein Have Opposing Roles in Regulating Tumor-Initiating Cells and Sensitivity to Radiation in Inflammatory Breast Cancer

    SciTech Connect

    Wolfe, Adam R.; Atkinson, Rachel L.; Reddy, Jay P.; Debeb, Bisrat G.; Larson, Richard; Li, Li; Masuda, Hiroko; Brewer, Takae; Atkinson, Bradley J.; Brewster, Abeena; Ueno, Naoto T.; Woodward, Wendy A.

    2015-04-01

    Purpose: We previously demonstrated that cholesterol-lowering agents regulate radiation sensitivity of inflammatory breast cancer (IBC) cell lines in vitro and are associated with less radiation resistance among IBC patients who undergo postmastectomy radiation. We hypothesized that decreasing IBC cellular cholesterol induced by treatment with lipoproteins would increase radiation sensitivity. Here, we examined the impact of specific transporters of cholesterol (ie lipoproteins) on the responses of IBC cells to self-renewal and to radiation in vitro and on clinical outcomes in IBC patients. Methods and Materials: Two patient-derived IBC cell lines, SUM 149 and KPL4, were incubated with low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), or high-density lipoproteins (HDL) for 24 hours prior to irradiation (0-6 Gy) and mammosphere formation assay. Cholesterol panels were examined in a cohort of patients with primary IBC diagnosed between 1995 and 2011 at MD Anderson Cancer Center. Lipoprotein levels were then correlated to patient outcome, using the log rank statistical model, and examined in multivariate analysis using Cox regression. Results: VLDL increased and HDL decreased mammosphere formation compared to untreated SUM 149 and KPL4 cells. Survival curves showed enhancement of survival in both of the IBC cell lines when pretreated with VLDL and, conversely, radiation sensitization in all cell lines when pretreated with HDL. In IBC patients, higher VLDL values (>30 mg/dL) predicted a lower 5-year overall survival rate than normal values (hazard ratio [HR] = 1.9 [95% confidence interval [CI]: 1.05-3.45], P=.035). Lower-than-normal patient HDL values (<60 mg/dL) predicted a lower 5-year overall survival rate than values higher than 60 mg/dL (HR = 3.21 [95% CI: 1.25-8.27], P=.015). Conclusions: This study discovered a relationship among the plasma levels of lipoproteins, overall patient response, and radiation resistance in IBC patients

  16. Cell density-regulated recovery of starved biofilm populations of ammonia-oxidizing bacteria.

    PubMed Central

    Batchelor, S E; Cooper, M; Chhabra, S R; Glover, L A; Stewart, G S; Williams, P; Prosser, J I

    1997-01-01

    The speed of recovery of cell suspensions and biofilm populations of the ammonia oxidizer Nitrosomonas europaea, following starvation was determined. Stationary-phase cells, washed and resuspended in ammoniumfree inorganic medium, were starved for periods of up to 42 days, after which the medium was supplemented with ammonium and subsequent growth was monitored by measuring nitrite concentration changes. Cultures exhibited a lag phase prior to exponential nitrite production, which increased from 8.72 h (no starvation) to 153 h after starvation for 42 days. Biofilm populations of N. europaea colonizing sand or soil particles in continuous-flow, fixed column reactors were starved by continuous supply of ammonium-free medium. Following resupply of ammonium, starved biofilms exhibited no lag phase prior to nitrite production, even after starvation for 43.2 days, although there was evidence of cell loss during starvation. Biofilm formation will therefore provide a significant ecological advantage for ammonia oxidizers in natural environments in which the substrate supply is intermittent. Cell density-dependent phenomena in a number of gram-negative bacteria are mediated by N-acyl homoserine lactones (AHL), including N-(3-oxohexanoyl)-L-homoserine lactone (OHHL). Addition of both ammonium and OHHL to cell suspensions starved for 28 days decreased the lag phase in a concentration-dependent manner from 53.4 h to a minimum of 10.8 h. AHL production by N. europaea was detected by using a luxR-luxAB AHL reporter system. The results suggest that rapid recovery of high-density biofilm populations may be due to production and accumulation of OHHL to levels not possible in relatively low-density cell suspensions. PMID:9172348

  17. The small noncoding RNAs (sncRNAs) of murine gammaherpesvirus 68 (MHV-68) are involved in regulating the latent-to-lytic switch in vivo

    PubMed Central

    Steer, Beatrix; Strehle, Martin; Sattler, Christine; Bund, Dagmar; Flach, Britta; Stoeger, Tobias; Haas, Jürgen G.; Adler, Heiko

    2016-01-01

    The human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), which are associated with a variety of diseases including tumors, produce various small noncoding RNAs (sncRNAs) such as microRNAs (miRNAs). Like all herpesviruses, they show two stages in their life cycle: lytic replication and latency. During latency, hardly any viral proteins are expressed to avoid recognition by the immune system. Thus, sncRNAs might be exploited since they are less likely to be recognized. Specifically, it has been proposed that sncRNAs might contribute to the maintenance of latency. This has already been shown in vitro, but the respective evidence in vivo is very limited. A natural model system to explore this question in vivo is infection of mice with murine gammaherpesvirus 68 (MHV-68). We used this model to analyze a MHV-68 mutant lacking the expression of all miRNAs. In the absence of the miRNAs, we observed a higher viral genomic load during late latency in the spleens of mice. We propose that this is due to a disturbed regulation of the latent-to-lytic switch, altering the balance between latent and lytic infection. Hence, we provide for the first time evidence that gammaherpesvirus sncRNAs contribute to the maintenance of latency in vivo. PMID:27561205

  18. Vibrio cholerae anaerobic induction of virulence gene expression is controlled by thiol-based switches of virulence regulator AphB

    PubMed Central

    Liu, Zhi; Yang, Menghua; Peterfreund, Gregory L.; Tsou, Amy M.; Selamoglu, Nur; Daldal, Fevzi; Zhong, Zengtao; Kan, Biao; Zhu, Jun

    2011-01-01

    Bacterial pathogens have evolved sophisticated signal transduction systems to coordinately control the expression of virulence determinants. For example, the human pathogen Vibrio cholerae is able to respond to host environmental signals by activating transcriptional regulatory cascades. The host signals that stimulate V. cholerae virulence gene expression, however, are still poorly understood. Previous proteomic studies indicated that the ambient oxygen concentration plays a role in V. cholerae virulence gene expression. In this study, we found that under oxygen-limiting conditions, an environment similar to the intestines, V. cholerae virulence genes are highly expressed. We show that anaerobiosis enhances dimerization and activity of AphB, a transcriptional activator that is required for the expression of the key virulence regulator TcpP, which leads to the activation of virulence factor production. We further show that one of the three cysteine residues in AphB, C235, is critical for oxygen responsiveness, as the AphBC235S mutant can activate virulence genes under aerobic conditions in vivo and can bind to tcpP promoters in the absence of reducing agents in vitro. Mass spectrometry analysis suggests that under aerobic conditions, AphB is modified at the C235 residue. This modification is reversible between oxygen-rich aquatic environments and oxygen-limited human hosts, suggesting that V. cholerae may use a thiol-based switch mechanism to sense intestinal signals and activate virulence. PMID:21187377

  19. Optical switch

    DOEpatents

    Reedy, Robert P.

    1987-01-01

    An optical switching device (10) is provided whereby light from a first glass fiber (16) or a second glass fiber (14) may be selectively transmitted into a third glass fiber (18). Each glass fiber is provided with a focusing and collimating lens system (26, 28, 30). In one mode of operation, light from the first glass fiber (16) is reflected by a planar mirror (36) into the third glass fiber (18). In another mode of operation, light from the second glass fiber (14) passes directly into the third glass fiber (18). The planar mirror (36) is attached to a rotatable table (32) which is rotated to provide the optical switching.

  20. Vimentin regulates differentiation switch via modulation of keratin 14 levels and their expression together correlates with poor prognosis in oral cancer patients.

    PubMed

    Dmello, Crismita; Sawant, Sharada; Alam, Hunain; Gangadaran, Prakash; Mogre, Saie; Tiwari, Richa; D'Souza, Zinia; Narkar, Manish; Thorat, Rahul; Patil, Komal; Chaukar, Devendra; Kane, Shubhada; Vaidya, Milind

    2017-01-01

    Vimentin is an intermediate filament protein, predominantly expressed in cells of mesenchymal origin, although its aberrant expression is seen in many carcinomas during epithelial mesenchymal transition. In cancer, vimentin expression is associated with the transition from a more differentiated epithelial phenotype to a dedifferentiated state. In view of the perceived role of keratins (Ks) as regulators of differentiation in epithelia, it was important to understand whether vimentin modulates differentiation through the reprogramming of keratins, in transformed cells. To address this, vimentin was stably downregulated in oral cancer derived cells. Further, global keratin profiling was performed after high salt keratin extraction. K5/K14 pair was found to be significantly downregulated, both at protein and mRNA levels upon vimentin downregulation. The previous study from our laboratory has shown a role of the K5/K14 pair in proliferation and differentiation of squamous epithelial cells. Vimentin depleted cells showed an increase in the differentiation state, marked by an increase in the levels of differentiation specific markers K1, involucrin, filaggrin and loricrin while its proliferation status remained unchanged. Rescue experiments with the K5/K14 pair overexpressed in vimentin knockdown background resulted in decreased differentiation state. ΔNp63 emerged as one of the indirect targets of vimentin, through which it modulates the expression levels of K5/K14. Further, immunohistochemistry showed a significant correlation between high vimentin-K14 expression and recurrence/poor survival in oral cancer patients. Thus, in conclusion, vimentin regulates the differentiation switch via modulation of K5/K14 expression. Moreover, vimentin-K14 together may prove to be the novel markers for the prognostication of human oral cancer.

  1. Vimentin regulates differentiation switch via modulation of keratin 14 levels and their expression together correlates with poor prognosis in oral cancer patients

    PubMed Central

    Dmello, Crismita; Sawant, Sharada; Alam, Hunain; Gangadaran, Prakash; Mogre, Saie; Tiwari, Richa; D’Souza, Zinia; Narkar, Manish; Thorat, Rahul; Patil, Komal; Chaukar, Devendra; Kane, Shubhada; Vaidya, Milind

    2017-01-01

    Vimentin is an intermediate filament protein, predominantly expressed in cells of mesenchymal origin, although its aberrant expression is seen in many carcinomas during epithelial mesenchymal transition. In cancer, vimentin expression is associated with the transition from a more differentiated epithelial phenotype to a dedifferentiated state. In view of the perceived role of keratins (Ks) as regulators of differentiation in epithelia, it was important to understand whether vimentin modulates differentiation through the reprogramming of keratins, in transformed cells. To address this, vimentin was stably downregulated in oral cancer derived cells. Further, global keratin profiling was performed after high salt keratin extraction. K5/K14 pair was found to be significantly downregulated, both at protein and mRNA levels upon vimentin downregulation. The previous study from our laboratory has shown a role of the K5/K14 pair in proliferation and differentiation of squamous epithelial cells. Vimentin depleted cells showed an increase in the differentiation state, marked by an increase in the levels of differentiation specific markers K1, involucrin, filaggrin and loricrin while its proliferation status remained unchanged. Rescue experiments with the K5/K14 pair overexpressed in vimentin knockdown background resulted in decreased differentiation state. ΔNp63 emerged as one of the indirect targets of vimentin, through which it modulates the expression levels of K5/K14. Further, immunohistochemistry showed a significant correlation between high vimentin-K14 expression and recurrence/poor survival in oral cancer patients. Thus, in conclusion, vimentin regulates the differentiation switch via modulation of K5/K14 expression. Moreover, vimentin-K14 together may prove to be the novel markers for the prognostication of human oral cancer. PMID:28225793

  2. Regulation of length and density of Arabidopsis root hairs by ammonium and nitrate.

    PubMed

    Vatter, Thomas; Neuhäuser, Benjamin; Stetter, Markus; Ludewig, Uwe

    2015-09-01

    Root hairs expand the effective root surface to increase the uptake of nutrients and water from the soil. Here the local effects of the two major nitrogen sources, ammonium and nitrate, on root hairs were investigated using split plates. In three contrasting accessions of A. thaliana, namely Col-0, Tsu-0 and Sha, root hairs were differentially affected by the nitrogen forms and their concentration. Root hairs in Sha were short in the absence of nitrate. In Col-0, hair length was moderately decreased with increasing nitrate or ammonium. In all accessions, the root hair density was insensitive to 1,000-fold changes in the ammonium concentrations, when supplied locally as the exclusive nitrogen form. In contrast, the root hair density generally increased with nitrate as the exclusive local nitrogen source. The nitrate sensitivity was reduced at mM concentrations in a loss-of-function mutant of the nitrate transporter and sensor gene NRT1;1 (NPF6.3). Little differences with respect to ammonium were found in a mutant lacking four high affinity AMT-type ammonium transporters, but interestingly, the response to high nitrate was reduced and may indicate a general defect in nitrogen signaling in that mutant. Genetic diversity and the presence of the nitrogen transceptor NRT1;1 explain heterogeneity in the responses of root hairs to different nitrogen forms in Arabidopsis accessions.

  3. Regulation of Predation by Prey Density: the Protozoan-Rhizobium Relationship

    PubMed Central

    Danso, S. K. A.; Alexander, M.

    1975-01-01

    Tetramitus rostratus and strains of Hartmanella, Naegleria, and Vahlkampfia consumed large numbers of Rhizobium meliloti cells in a salt solution, but protozoan multiplication and the bacterial decline stopped when the prey density fell to about 106 to 107 cells/ml. At higher prey densities, the maximum numbers of Hartmanella sp. and Naegleria sp. were proportional to the quantity of R. meliloti initially provided to the amoebas. When supplemental rhizobia were supplied to Hartmanella sp. or Naegleria sp. after their active feeding had terminated, presumably because the remaining 106 or 107 bacteria/ml could not be captured, replication of the protozoa was initiated. The rate of elimination of rhizobia present in large populations was proportional to the initial abundance of Naegleria sp., but the final numbers of amoebas and surviving R. meliloti cells were independent of initial numbers of predators. The surviving bacteria were not intrinsically resistant to attack because 98% of the survivors, when concentrated, were consumed. It is suggested that large populations of bacteria in nature may be reduced in size by predatory protozoa, but many of the prey cells will not be eliminated. PMID:1168441

  4. Kinetic modeling of rhamnolipid production by Pseudomonas aeruginosa PAO1 including cell density-dependent regulation.

    PubMed

    Henkel, Marius; Schmidberger, Anke; Vogelbacher, Markus; Kühnert, Christian; Beuker, Janina; Bernard, Thomas; Schwartz, Thomas; Syldatk, Christoph; Hausmann, Rudolf

    2014-08-01

    The production of rhamnolipid biosurfactants by Pseudomonas aeruginosa is under complex control of a quorum sensing-dependent regulatory network. Due to a lack of understanding of the kinetics applicable to the process and relevant interrelations of variables, current processes for rhamnolipid production are based on heuristic approaches. To systematically establish a knowledge-based process for rhamnolipid production, a deeper understanding of the time-course and coupling of process variables is required. By combining reaction kinetics, stoichiometry, and experimental data, a process model for rhamnolipid production with P. aeruginosa PAO1 on sunflower oil was developed as a system of coupled ordinary differential equations (ODEs). In addition, cell density-based quorum sensing dynamics were included in the model. The model comprises a total of 36 parameters, 14 of which are yield coefficients and 7 of which are substrate affinity and inhibition constants. Of all 36 parameters, 30 were derived from dedicated experimental results, literature, and databases and 6 of them were used as fitting parameters. The model is able to describe data on biomass growth, substrates, and products obtained from a reference batch process and other validation scenarios. The model presented describes the time-course and interrelation of biomass, relevant substrates, and products on a process level while including a kinetic representation of cell density-dependent regulatory mechanisms.

  5. 49 CFR 236.817 - Switch, electro-pneumatic.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Switch, electro-pneumatic. 236.817 Section 236.817 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, electro-pneumatic. A switch operated by an electro-pneumatic switch-and-lock movement....

  6. 49 CFR 236.817 - Switch, electro-pneumatic.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Switch, electro-pneumatic. 236.817 Section 236.817 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, electro-pneumatic. A switch operated by an electro-pneumatic switch-and-lock movement....

  7. 49 CFR 236.817 - Switch, electro-pneumatic.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Switch, electro-pneumatic. 236.817 Section 236.817 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, electro-pneumatic. A switch operated by an electro-pneumatic switch-and-lock movement....

  8. 49 CFR 236.817 - Switch, electro-pneumatic.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Switch, electro-pneumatic. 236.817 Section 236.817 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, electro-pneumatic. A switch operated by an electro-pneumatic switch-and-lock movement....

  9. 49 CFR 236.817 - Switch, electro-pneumatic.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Switch, electro-pneumatic. 236.817 Section 236.817 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, electro-pneumatic. A switch operated by an electro-pneumatic switch-and-lock movement....

  10. Conditions for Stabilizability of Linear Switched Systems

    NASA Astrophysics Data System (ADS)

    Minh, Vu Trieu

    2011-06-01

    This paper investigates some conditions that can provide stabilizability for linear switched systems with polytopic uncertainties via their closed loop linear quadratic state feedback regulator. The closed loop switched systems can stabilize unstable open loop systems or stable open loop systems but in which there is no solution for a common Lyapunov matrix. For continuous time switched linear systems, we show that if there exists solution in an associated Riccati equation for the closed loop systems sharing one common Lyapunov matrix, the switched linear systems are stable. For the discrete time switched systems, we derive a Linear Matrix Inequality (LMI) to calculate a common Lyapunov matrix and solution for the stable closed loop feedback systems. These closed loop linear quadratic state feedback regulators guarantee the global asymptotical stability for any switched linear systems with any switching signal sequence.

  11. Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake

    PubMed Central

    Yang, Muhua; Liu, Weidong; Pellicane, Christina; Sahyoun, Christine; Joseph, Biny K.; Gallo-Ebert, Christina; Donigan, Melissa; Pandya, Devanshi; Giordano, Caroline; Bata, Adam; Nickels, Joseph T.

    2014-01-01

    Dysregulation of cholesterol homeostasis is associated with various metabolic diseases, including atherosclerosis and type 2 diabetes. The sterol response element binding protein (SREBP)-2 transcription factor induces the expression of genes involved in de novo cholesterol biosynthesis and low density lipoprotein (LDL) uptake, thus it plays a crucial role in maintaining cholesterol homeostasis. Here, we found that overexpressing microRNA (miR)-185 in HepG2 cells repressed SREBP-2 expression and protein level. miR-185-directed inhibition caused decreased SREBP-2-dependent gene expression, LDL uptake, and HMG-CoA reductase activity. In addition, we found that miR-185 expression was tightly regulated by SREBP-1c, through its binding to a single sterol response element in the miR-185 promoter. Moreover, we found that miR-185 expression levels were elevated in mice fed a high-fat diet, and this increase correlated with an increase in total cholesterol level and a decrease in SREBP-2 expression and protein. Finally, we found that individuals with high cholesterol had a 5-fold increase in serum miR-185 expression compared with control individuals. Thus, miR-185 controls cholesterol homeostasis through regulating SREBP-2 expression and activity. In turn, SREBP-1c regulates miR-185 expression through a complex cholesterol-responsive feedback loop. Thus, a novel axis regulating cholesterol homeostasis exists that exploits miR-185-dependent regulation of SREBP-2 and requires SREBP-1c for function. PMID:24296663

  12. Peroxisome proliferator-activated receptor-γ regulates the expression and function of very-low-density lipoprotein receptor

    PubMed Central

    Tao, Huan; Aakula, Srikanth; Abumrad, Naji N.

    2010-01-01

    Very-low-density lipoprotein receptor (VLDLR) is a member of the low-density receptor family, highly expressed in adipose tissue, heart, and skeletal muscle. It binds apolipoprotein E-triglyceride-rich lipoproteins and plays a significant role in triglyceride metabolism. PPARγ is a primary regulator of lipid metabolism in adipocytes and controls the expression of an array of genes involved in lipid trafficking in adipocytes. However, it is not known whether VLDLR is also under the control of PPARγ. In this study, we investigated the role of PPARγ in the regulation of VLDLR expression and function in vivo and in vitro. During the differentiation of 3T3-L1 preadipocytes, the levels of VLDLR protein and mRNA increased in parallel with the induction of PPARγ expression and reached maximum in mature adipocytes. Treatment of differentiated adipocytes with PPARγ agonist pioglitazone upregulated VLDLR expression in dose- and time-dependent manners. In contrast, specific inhibition of PPARγ significantly downregulated the protein level of VLDLR. Induction of VLDLR is also demonstrated in vivo in adipose tissue of wild-type (WT) mice treated with pioglitazone. In addition, pioglitazone increased plasma triglyceride-rich lipoprotein clearance and increased epididymal fat mass in WT mice but failed to induce similar effects in vldlr−/− mice. These results were further corroborated by the finding that pioglitazone treatment enhanced adipogenesis and lipid deposition in preadipocytes of WT mice, while its effect in VLDLR-null preadipocytes was significantly blunted. These findings provide direct evidence that VLDLR expression is regulated by PPARγ and contributes in lipid uptake and adipogenesis. PMID:19861583

  13. Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma

    PubMed Central

    Wan, Guoqiang; Gómez-Casati, Maria E; Gigliello, Angelica R; Liberman, M Charles; Corfas, Gabriel

    2014-01-01

    Neurotrophin-3 (Ntf3) and brain derived neurotrophic factor (Bdnf) are critical for sensory neuron survival and establishment of neuronal projections to sensory epithelia in the embryonic inner ear, but their postnatal functions remain poorly understood. Using cell-specific inducible gene recombination in mice we found that, in the postnatal inner ear, Bbnf and Ntf3 are required for the formation and maintenance of hair cell ribbon synapses in the vestibular and cochlear epithelia, respectively. We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins. Using a new hair cell CreERT line with mosaic expression, we also found that Ntf3's effect on cochlear synaptogenesis is highly localized. Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. These results indicate that glial-derived neurotrophins play critical roles in inner ear synapse density and synaptic regeneration after injury. DOI: http://dx.doi.org/10.7554/eLife.03564.001 PMID:25329343

  14. Bulk cell density and Wnt/TGFbeta signalling regulate mesendodermal patterning of human pluripotent stem cells

    PubMed Central

    Kempf, Henning; Olmer, Ruth; Haase, Alexandra; Franke, Annika; Bolesani, Emiliano; Schwanke, Kristin; Robles-Diaz, Diana; Coffee, Michelle; Göhring, Gudrun; Dräger, Gerald; Pötz, Oliver; Joos, Thomas; Martinez-Hackert, Erik; Haverich, Axel; Buettner, Falk F. R.; Martin, Ulrich; Zweigerdt, Robert

    2016-01-01

    In vitro differentiation of human pluripotent stem cells (hPSCs) recapitulates early aspects of human embryogenesis, but the underlying processes are poorly understood and controlled. Here we show that modulating the bulk cell density (BCD: cell number per culture volume) deterministically alters anteroposterior patterning of primitive streak (PS)-like priming. The BCD in conjunction with the chemical WNT pathway activator CHIR99021 results in distinct paracrine microenvironments codifying hPSCs towards definitive endoderm, precardiac or presomitic mesoderm within the first 24 h of differentiation, respectively. Global gene expression and secretome analysis reveals that TGFß superfamily members, antagonist of Nodal signalling LEFTY1 and CER1, are paracrine determinants restricting PS progression. These data result in a tangible model disclosing how hPSC-released factors deflect CHIR99021-induced lineage commitment over time. By demonstrating a decisive, functional role of the BCD, we show its utility as a method to control lineage-specific differentiation. Furthermore, these findings have profound consequences for inter-experimental comparability, reproducibility, bioprocess optimization and scale-up. PMID:27934856

  15. Fmrp Interacts with Adar and Regulates RNA Editing, Synaptic Density and Locomotor Activity in Zebrafish

    PubMed Central

    Porath, Hagit T.; Barak, Michal; Pinto, Yishay; Wachtel, Chaim; Zilberberg, Alona; Lerer-Goldshtein, Tali; Efroni, Sol; Levanon, Erez Y.; Appelbaum, Lior

    2015-01-01

    Fragile X syndrome (FXS) is the most frequent inherited form of mental retardation. The cause for this X-linked disorder is the silencing of the fragile X mental retardation 1 (fmr1) gene and the absence of the fragile X mental retardation protein (Fmrp). The RNA-binding protein Fmrp represses protein translation, particularly in synapses. In Drosophila, Fmrp interacts with the adenosine deaminase acting on RNA (Adar) enzymes. Adar enzymes convert adenosine to inosine (A-to-I) and modify the sequence of RNA transcripts. Utilizing the fmr1 zebrafish mutant (fmr1-/-), we studied Fmrp-dependent neuronal circuit formation, behavior, and Adar-mediated RNA editing. By combining behavior analyses and live imaging of single axons and synapses, we showed hyperlocomotor activity, as well as increased axonal branching and synaptic density, in fmr1-/- larvae. We identified thousands of clustered RNA editing sites in the zebrafish transcriptome and showed that Fmrp biochemically interacts with the Adar2a protein. The expression levels of the adar genes and Adar2 protein increased in fmr1-/- zebrafish. Microfluidic-based multiplex PCR coupled with deep sequencing showed a mild increase in A-to-I RNA editing levels in evolutionarily conserved neuronal and synaptic Adar-targets in fmr1-/- larvae. These findings suggest that loss of Fmrp results in increased Adar-mediated RNA editing activity on target-specific RNAs, which, in turn, might alter neuronal circuit formation and behavior in FXS. PMID:26637167

  16. Steroid hormone 20-hydroxyecdysone regulation of the very-high-density lipoprotein (VHDL) receptor phosphorylation for VHDL uptake.

    PubMed

    Dong, Du-Juan; Liu, Wen; Cai, Mei-Juan; Wang, Jin-Xing; Zhao, Xiao-Fan

    2013-04-01

    During the metamorphic stage of holometabolous insects, the biosynthetic precursors needed for the synthesis of a large number of adult proteins are acquired from the selective absorption of storage proteins. The very-high-density lipoprotein (VHDL), a non-hexameric storage protein, is consumed by the fat body from the hemolymph through VHDL receptor (VHDL-R)-mediated endocytosis. However, the mechanism of the uptake of VHDL by a VHDL-R remains unclear. In this study, a VHDL-R from Helicoverpa armigera was found to be involved in 20E-regulated VHDL uptake through the regulation of steroid hormone 20-hydroxyecdysone (20E). The transcripts of VHDL-R were detected mainly in the fat body and integument during the wandering stage. The transcription of VHDL-R was upregulated by 20E through the ecdysteroid receptor (EcRB1) and Ultraspiracle (USP1). In addition, 20E stimulates the phosphorylation of VHDL-R through protein kinase C for ligand binding. VHDL-R knockdown in larvae results the inhibition of development to adulthood. These data imply that 20E regulates VHDL-R on both transcriptional and posttranslational levels for VHDL absorption.

  17. Resource variability, aggregation and direct density dependence in an open context: the local regulation of an African elephant population.

    PubMed

    Chamaillé-Jammes, Simon; Fritz, Hervé; Valeix, Marion; Murindagomo, Felix; Clobert, Jean

    2008-01-01

    1. An emerging perspective in the study of density dependence is the importance of the spatial and temporal heterogeneity of resources. Although this is well understood in temperate ungulates, few studies have been conducted in tropical environments where both food and water are limiting resources. 2. We studied the regulation of one of the world's largest elephant populations in Hwange National Park, Zimbabwe. The study period started in 1986 when the population was released from culling. Using census data we investigated changes in elephant abundance with respect to rainfall and density across the entire park and across waterholes. 3. The population more than doubled since culling stopped. The population increased continuously during the first 6 years, and then fluctuated widely at about 30,000 individuals. Immigration processes must have been involved in the increase of the population size. 4. Population growth rates were negatively related to previous population density by a convex relationship, and negatively related to the ratio of previous population density on annual rainfall by a linear relationship. However, only this latter model (i.e. assuming a fluctuating carrying capacity related to annual rainfall) produced realistic dynamics. Overall, population decreased during dry years when the elephant density was high. 5. During dry years there were fewer waterholes retaining water during the dry season and consequently elephant numbers at waterholes increased, while their aggregation level across waterholes decreased. On the long-run elephant numbers increased only at the less crowded waterholes. 6. We suggest that the interaction between population size and the available foraging range determined by the number of active waterholes during the dry season controls the park population. 7. Our results emphasize the need to understand how key-resource areas cause resource-based aggregation, which ultimately influences the strength of density dependence. More

  18. Kiowa Creek Switching Station

    SciTech Connect

    Not Available

    1990-03-01

    The Western Area Power Administration (Western) proposes to construct, operate, and maintain a new Kiowa Creek Switching Station near Orchard in Morgan County, Colorado. Kiowa Creek Switching Station would consist of a fenced area of approximately 300 by 300 feet and contain various electrical equipment typical for a switching station. As part of this new construction, approximately one mile of an existing 115-kilovolt (kV) transmission line will be removed and replaced with a double circuit overhead line. The project will also include a short (one-third mile) realignment of an existing line to permit connection with the new switching station. In accordance with the Council on Environmental Quality (CEQ) regulations for implementing the procedural provisions of the National Environmental Policy Act of 1969 (NEPA), 40 CFR Parts 1500--1508, the Department of Energy (DOE) has determined that an environmental impact statement (EIS) is not required for the proposed project. This determination is based on the information contained in this environmental assessment (EA) prepared by Western. The EA identifies and evaluates the environmental and socioeconomic effects of the proposed action, and concludes that the advance impacts on the human environment resulting from the proposed project would not be significant. 8 refs., 3 figs., 1 tab.

  19. The hydrometeorological implications of zoning laws: Can land use regulations of urban density and sprawl improve a city's resilience?

    NASA Astrophysics Data System (ADS)

    Bou-Zeid, E.; Ryu, Y. H.; Smith, J. A.; Newburn, D. A.

    2015-12-01

    The intensification of heat waves and of the hydrological cycle due to global climate change pose particularly high risks to urban residents. Cities are already hotter than their surroundings due to the urban heat island effect and are known to result in local intensification of rainfall and flooding due to their coupled impacts on the surface and the lower atmosphere. These interacting local and global changes can adversely affect the health and well being of urban residents, and city administrators are increasing efforts to mitigate and adapt to the potential disruptions though various infrastructure and preparedness programs. However, as cities worldwide continue to expand, a key decision is how to manage that urban sprawl and regulate its spatial features to aid in the mitigation and adaptation effort. This study assesses whether alternative zoning regulations that modify the density and extent of a metropolitan region, but have a minimal impact on total population and demographic growth, have an appreciable impact on its response to extreme weather events, and as such, whether they can be used to increase urban resilience. We consider Baltimore (the city and its surrounding suburbs), which in 1967 adopted one of the first urban growth boundaries (UGBs) in the United States, as our test case. Departing from the urban extent circa 1900, we create alternative land use patterns that, compared to the actual current land use baseline, would have resulted from drastically different policy scenarios and approaches to zoning that the city would have undertaken. We consider various alternatives where the city is smaller and denser, due to stricter regulation, versus larger and less dense than the actual baseline, while maintaining the same total population. Our findings indicate that lower densities have significant benefits: compared to the current landscape and to denser patterns, they reduce both extreme temperatures during heat waves and spatio-temporal rainfall

  20. Oxidized low-density lipoprotein inhibits THP-1-derived macrophage autophagy via TET2 down-regulation.

    PubMed

    Li, Guohua; Peng, Juan; Liu, Yanhui; Li, Xiaohong; Yang, Qin; Li, Yongqing; Tang, Zhihan; Wang, Zuo; Jiang, Zhisheng; Wei, Dangheng

    2015-02-01

    Oxidized low-density lipoprotein (ox-LDL) is an independent risk factor of atherosclerosis. However, the mechanism underlying its pro-atherosclerosis roles has not yet been well explored. DNA demethylation modification, via DNA methyltransferases or ten-eleven-translocation (TET) family, is a crisis epigenetic regulation for various biological and pathological processes. This study aimed to investigate the effects of ox-LDL on macrophage autophagy and its potential epigenetic mechanism. Results showed that after treatment with 0, 10, 20, 40 or 80 mg/L ox-LDL for 24 h, the autophagy markers Beclin 1 and LC3 expression were obviously decreased at protein levels (P < 0.05). The mRNA and protein expression of TET2 was evidently decreased (P < 0.05). After pre-treatment with TET2 siRNA, the mRNA and protein levels of Beclin 1 and LC3 decreased compared with the 80 mg/L treatment group (P < 0.01). The mRNA and protein levels of Beclin 1 and LC3-II were up-regulated (P < 0.05) in the 5-aza-2'-deoxycytidine (a DNA methyltransferase inhibitor) of pretreatment group. Consistent with the Western blot results, cell immunofluorescence showed that the protein concentration of LC3-II decreased in the TET2 siRNA group and increased in the 5-aza-2'-deoxycytidine group. Taken together, these results showed that DNA demethylation modifications regulate ox-LDL-treated THP-1 macrophages autophagy and TET2 might be a novel regulator.

  1. Switch for serial or parallel communication networks

    DOEpatents

    Crosette, Dario B.

    1994-01-01

    A communication switch apparatus and a method for use in a geographically extensive serial, parallel or hybrid communication network linking a multi-processor or parallel processing system has a very low software processing overhead in order to accommodate random burst of high density data. Associated with each processor is a communication switch. A data source and a data destination, a sensor suite or robot for example, may also be associated with a switch. The configuration of the switches in the network are coordinated through a master processor node and depends on the operational phase of the multi-processor network: data acquisition, data processing, and data exchange. The master processor node passes information on the state to be assumed by each switch to the processor node associated with the switch. The processor node then operates a series of multi-state switches internal to each communication switch. The communication switch does not parse and interpret communication protocol and message routing information. During a data acquisition phase, the communication switch couples sensors producing data to the processor node associated with the switch, to a downlink destination on the communications network, or to both. It also may couple an uplink data source to its processor node. During the data exchange phase, the switch couples its processor node or an uplink data source to a downlink destination (which may include a processor node or a robot), or couples an uplink source to its processor node and its processor node to a downlink destination.

  2. Switch for serial or parallel communication networks

    DOEpatents

    Crosette, D.B.

    1994-07-19

    A communication switch apparatus and a method for use in a geographically extensive serial, parallel or hybrid communication network linking a multi-processor or parallel processing system has a very low software processing overhead in order to accommodate random burst of high density data. Associated with each processor is a communication switch. A data source and a data destination, a sensor suite or robot for example, may also be associated with a switch. The configuration of the switches in the network are coordinated through a master processor node and depends on the operational phase of the multi-processor network: data acquisition, data processing, and data exchange. The master processor node passes information on the state to be assumed by each switch to the processor node associated with the switch. The processor node then operates a series of multi-state switches internal to each communication switch. The communication switch does not parse and interpret communication protocol and message routing information. During a data acquisition phase, the communication switch couples sensors producing data to the processor node associated with the switch, to a downlink destination on the communications network, or to both. It also may couple an uplink data source to its processor node. During the data exchange phase, the switch couples its processor node or an uplink data source to a downlink destination (which may include a processor node or a robot), or couples an uplink source to its processor node and its processor node to a downlink destination. 9 figs.

  3. Polarization switching in ferroelectric cathodes

    SciTech Connect

    Rosenman, G.; Shur, D.; Garb, K.; Cohen, R.; Krasik, Y.E.

    1997-07-01

    A new mechanism of polarization switching and electron emission in ferroelectric cathodes is proposed. Surface flashover plasma of a ferroelectric origin was observed on a polar ferroelectric surface [D. Shur, G. Rosenman, and Ya. E. Krasik, Appl. Phys. Lett. {bold 70}, 574 (1997)]. Simultaneous measurements of switched charge and plasma density show that expanding surface plasma represents a dynamic switching electrode. Direct measurements of ion/electron emission currents and surface analysis implemented by different analytic tools indicate that electrons and ions from the surface plasma contribute to spontaneous polarization screening. The high energy of charged particles emitted from the surface plasma is ascribed to a high surface potential during polarization switching. {copyright} {ital 1997 American Institute of Physics.}

  4. The role of Dkk1 in bone mass regulation: correlating serum Dkk1 expression with bone mineral density.

    PubMed

    Butler, Joseph S; Murray, David W; Hurson, Conor J; O'Brien, Julie; Doran, Peter P; O'Byrne, John M

    2011-03-01

    The Wnt/β-catenin pathway is a major signaling cascade in bone biology, playing a key role in regulating bone development and remodeling, with aberrations in signaling resulting in disturbances in bone mass. The objectives of our study were to correlate serum Dkk1 expression with bone mineral density (BMD) and assess the potential role of Dkk1 as a serological marker of bone mass. Serum was collected from a cohort of patients (n = 36), 18 patients with a reduced BMD and 18 control patients. Serum Dkk1 expression as quantified by ELISA was correlated with lumbar and femoral t- and z-scores. Serum Dkk1 concentration in the osteoporosis group was significantly higher than control group (941 ± 116 vs. 558 ± 47 pg/ml, p < 0.01). Serum Dkk1 expression was highly correlated with bone mass variables with inverse associations found between serum Dkk1 expression and lumbar t-score (r = -0.34, p = 0.00433), lumbar z-score (r = -0.22, p = 0.1907), femur t-score (r = -0.42, p = 0.0101), and femur z-score (r = -0.43, p = 0.0089). Our data further emphasizes the pivotal role played by Wnt/β-catenin signaling in bone mass regulation. Dkk1, a powerful antagonist of canonical Wnt signaling, may have a role to play as a serological marker for disorders of bone mass, warranting further evaluation.

  5. Neuronal activity and brain-derived neurotrophic factor regulate the density of inhibitory synapses in organotypic slice cultures of postnatal hippocampus.

    PubMed

    Marty, S; Wehrlé, R; Sotelo, C

    2000-11-01

    Hippocampal interneurons inhibit pyramidal neurons through the release of the neurotransmitter GABA. Given the importance of this inhibition for the proper functioning of the hippocampus, the development of inhibitory synapses must be tightly regulated. In this study, the possibility that neuronal activity and neurotrophins regulate the density of GABAergic inhibitory synapses was investigated in organotypic slice cultures taken from postnatal day 7 rats. In hippocampal slices cultured for 13 d in the presence of the GABA(A) receptor antagonist bicuculline, the density of glutamic acid decarboxylase (GAD) 65-immunoreactive terminals was increased in the CA1 area when compared with control slices. Treatment with the glutamate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione decreased the density of GAD65-immunoreactive terminals in the stratum oriens of CA1. These treatments had parallel effects on the density of GABA-immunoreactive processes. Electron microscopic analysis after postembedding immunogold labeling with antibodies against GABA indicated that bicuculline treatment increased the density of inhibitory but not excitatory synapses. Application of exogenous BDNF partly mimicked the stimulatory effect of bicuculline on GAD65-immunoreactive terminals. Finally, antibodies against BDNF, but not antibodies against nerve growth factor, decrease the density of GAD65-immunoreactive terminals in bicuculline-treated slices. Thus, neuronal activity regulates the density of inhibitory synapses made by postnatal hippocampal interneurons, and BDNF could mediate part of this regulation. This regulation of the density of inhibitory synapses could represent a feedback mechanism aimed at maintaining an appropriate level of activity in the developing hippocampal networks.

  6. Pore size regulates operating stomatal conductance, while stomatal densities drive the partitioning of conductance between leaf sides

    PubMed Central

    Fanourakis, Dimitrios; Giday, Habtamu; Milla, Rubén; Pieruschka, Roland; Kjaer, Katrine H.; Bolger, Marie; Vasilevski, Aleksandar; Nunes-Nesi, Adriano; Fiorani, Fabio; Ottosen, Carl-Otto

    2015-01-01

    Background and Aims Leaf gas exchange is influenced by stomatal size, density, distribution between the leaf adaxial and abaxial sides, as well as by pore dimensions. This study aims to quantify which of these traits mainly underlie genetic differences in operating stomatal conductance (gs) and addresses possible links between anatomical traits and regulation of pore width. Methods Stomatal responsiveness to desiccation, gs-related anatomical traits of each leaf side and estimated gs (based on these traits) were determined for 54 introgression lines (ILs) generated by introgressing segments of Solanum pennelli into the S. lycopersicum ‘M82’. A quantitative trait locus (QTL) analysis for stomatal traits was also performed. Key Results A wide genetic variation in stomatal responsiveness to desiccation was observed, a large part of which was explained by stomatal length. Operating gs ranged over a factor of five between ILs. The pore area per stomatal area varied 8-fold among ILs (2–16 %), and was the main determinant of differences in operating gs between ILs. Operating gs was primarily positioned on the abaxial surface (60–83 %), due to higher abaxial stomatal density and, secondarily, to larger abaxial pore area. An analysis revealed 64 QTLs for stomatal traits in the ILs, most of which were in the direction of S. pennellii. Conclusions The data indicate that operating and maximum gs of non-stressed leaves maintained under stable conditions deviate considerably (by 45–91 %), because stomatal size inadequately reflects operating pore area (R2 = 0·46). Furthermore, it was found that variation between ILs in both stomatal sensitivity to desiccation and operating gs is associated with features of individual stoma. In contrast, genotypic variation in gs partitioning depends on the distribution of stomata between the leaf adaxial and abaxial epidermis. PMID:25538116

  7. Magnetic switching

    SciTech Connect

    Birx, D.; Cook, E.; Hawkins, S.; Poor, S.; Reginato, L.; Schmidt, J.; Smith, M.

    1983-06-01

    The paper discusses the development program in magnetic switching which was aimed at solving the rep-rate and reliability limitations of the ATA spark gaps. The end result has been a prototype physically very similar to the present Advanced Test Accelerator (ATA) pulse power unit but vastly superior in performance. This prototype, which is easily adaptable to the existing systems, has achieved a burst rep-rate of 20 kHz and an output voltage of 500 kV. A one-on-one substitution of the existing pulse power module would result in a 100 MeV accelerator. Furthermore, the high efficiency of the magnetic pulse compression stages has allowed CW operation of the prototype at one kilohertz opening up other applications for the pulse power. Performance and design details will be described.

  8. Protective effect of rosuvastatin treatment by regulating oxidized low-density lipoprotein expression in a rat model of liver fibrosis.

    PubMed

    Yu, Shuiping; Zhou, Xueling; Hou, Bingzong; Tang, Bo; Li, Jian; Zhang, Baimeng

    2016-09-01

    The present study aimed to evaluate the protective effect of rosuvastatin treatment on the mechanism of oxidized low-density lipoprotein (Ox-LDL) in rats with liver fibrosis. In total, 72 male Sprague-Dawley rats were divided into 3 groups: 24 in the control group (A), 24 in the obstructive jaundice models group (B) and 24 in the rosuvastatin group (C). Each group was further divided into four subgroups for assessment at different time-points. The obstructive jaundice models were established and rosuvastatin was administered by gavage. Liver fibrosis indicators, Ox-LDL, malonaldehyde (MDA) and superoxide dismutase (SOD), were measured and liver pathological changes were observed at weeks 1, 2, 3 and 4 after model induction. In groups B and C, the rat models were successfully established, and there were significant changes in the expression of Ox-LDL and the three liver fibrosis indicators when compared to group A (P<0.01). However, the expression of Ox-LDL and the three liver fibrosis indicators in group C were decreased compared with group B (P<0.05), while SOD increased (P<0.05) and MDA decreased (P<0.05). The three liver fibrosis indicators were different in comparison to group B (P<0.05). Thus, there appeared to be an association between the expression of Ox-LDL and liver fibrosis. Treatment with rosuvastatin could regulate the expression of Ox-LDL and improve liver fibrosis in rat models with obstructive jaundice.

  9. Gpr177, a novel locus for bone mineral density and osteoporosis, regulates osteogenesis and chondrogenesis in skeletal development.

    PubMed

    Maruyama, Takamitsu; Jiang, Ming; Hsu, Wei

    2013-05-01

    Human genetic analysis has recently identified Gpr177 as a susceptibility locus for bone mineral density and osteoporosis. Determining the unknown function of this gene is therefore extremely important to furthering our knowledge base of skeletal development and disease. The protein encoded by Gpr177 exhibits an ability to modulate the trafficking of Wnt, similar to the Drosophila Wls/Evi/Srt. Because it plays a critical role in Wnt regulation, Gpr177 might be required for several key steps of skeletogenesis. To overcome the early lethality associated with the inactivation of Gpr177 in mice, conditional gene deletion is used to assess its functionality. Here we report the generation of four different mouse models with Gpr177 deficiency in various skeletogenic cell types. The loss of Gpr177 severely impairs development of the craniofacial and body skeletons, demonstrating its requirement for intramembranous and endochondral ossifications, respectively. Defects in the expansion of skeletal precursors and their differentiation into osteoblasts and chondrocytes suggest that Wnt production and signaling mediated by Gpr177 cannot be substituted. Because the Gpr177 ablation impairs Wnt secretion, we therefore identify the sources of Wnt proteins essential for osteogenesis and chondrogenesis. The intercross of Wnt signaling between distinct cell types is carefully orchestrated and necessary for skeletogenesis. Our findings lead to a proposed mechanism by which Gpr177 controls skeletal development through modulation of autocrine and paracrine Wnt signals in a lineage-specific fashion.

  10. Plasma Switch Development.

    DTIC Science & Technology

    1984-06-08

    switch :9 (1) the low-pressure gas switch 17 (2) the surface flashover switch ,18 (3) the thyrtron,’ŕ (4) the high pressure...spark gap, (5) the magnetic switch .’ 9 20 and (6) the ECS. The ongoing research for both the low pressure gas and surface flashover closing- switches has... investigations into optimizing gas mixtures for opening switch applications 1 ’"’"’’’a𔃻 ; and a preliminary study of the discharge stabili-

  11. Stochastic switching in biology: from genotype to phenotype

    NASA Astrophysics Data System (ADS)

    Bressloff, Paul C.

    2017-03-01

    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

  12. Hump-Shaped Density-Dependent Regulation of Mosquito Oviposition Site-Selection by Conspecific Immature Stages: Theory, Field Test with Aedes albopictus, and a Meta-Analysis

    PubMed Central

    Wasserberg, Gideon; Bailes, Nicholas; Davis, Christopher; Yeoman, Kim

    2014-01-01

    Oviposition site selection by gravid females is an important determinant of the distribution, abundance, and dynamics of dipteran hematophagous insects. The presence of conspecific immature stages in a potential oviposition site could, on the one hand, indicate the suitability of that site but on the other hand could indicate the potential for intraspecific competition. In this paper, we present a graphic model suggesting that the trade-off between these two opposing forces could result in a hump-shaped density-dependent relationship between oviposition rate and conspecific immature stage density (hereafter, the “Hump-shaped regulation model”) with positive effects of aggregation prevailing at low densities and negative effect of intraspecific competition prevailing at higher densities. We field-tested the predictions of this model at both the egg- and the larval levels with Aedes albopictus and evaluated if and how these relationships are affected by resource enrichment. We found support for the hump-shaped regulation model at both the larval and the egg levels. Using oviposition cups containing varying numbers of conspecific larvae, we showed that the oviposition activity of Ae. albopictus first increases and then decreases with larvae number. Medium enrichment resulted in higher hatching rate, and demonstrated linear relations for the no-enrichment treatment where larvae density range was low and hump-shaped relationship for the enriched medium that had a wider larvae density range. Using pairs of oviposition cups, we showed that at low egg densities mosquitoes laid more eggs on substrates containing pre-existing eggs. However, at higher egg densities, mosquitoes laid more eggs on a virgin substrate. Based on our results and on a meta-analysis, we suggest that due to study design or methodological shortcomings the hump-shaped regulation model is often left undetected and that it is likely to be more common than currently thought. PMID:24681526

  13. Switch Transcripts in Immunoglobulin Class Switching

    NASA Astrophysics Data System (ADS)

    Lorenz, Matthias; Jung, Steffen; Radbruch, Andreas

    1995-03-01

    B cells can exchange gene segments for the constant region of the immunoglobulin heavy chain, altering the class and effector function of the antibodies that they produce. Class switching is directed to distinct classes by cytokines, which induce transcription of the targeted DNA sequences. These transcripts are processed, resulting in spliced "switch" transcripts. Switch recombination can be directed to immunoglobulin G1 (IgG1) by the heterologous human metallothionein II_A promoter in mutant mice. Induction of the structurally conserved, spliced switch transcripts is sufficient to target switch recombination to IgG1, whereas transcription alone is not.

  14. 49 CFR 236.386 - Restoring feature on power switches.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Restoring feature on power switches. 236.386 Section 236.386 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Inspection and Tests § 236.386 Restoring feature on power switches. Restoring feature on power switches...

  15. 49 CFR 236.60 - Switch shunting circuit; use restricted.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Switch shunting circuit; use restricted. 236.60 Section 236.60 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Instructions: All Systems Track Circuits § 236.60 Switch shunting circuit; use restricted. Switch...

  16. 49 CFR 236.818 - Switch, facing point.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Switch, facing point. 236.818 Section 236.818 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, facing point. A switch, the points of which face traffic approaching in the direction for...

  17. 49 CFR 236.725 - Circuit, switch shunting.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Circuit, switch shunting. 236.725 Section 236.725 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Circuit, switch shunting. A shunting circuit which is closed through contacts of a switch...

  18. 49 CFR 236.818 - Switch, facing point.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Switch, facing point. 236.818 Section 236.818 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, facing point. A switch, the points of which face traffic approaching in the direction for...

  19. 49 CFR 236.823 - Switch, trailing point.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Switch, trailing point. 236.823 Section 236.823 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, trailing point. A switch, the points of which face away from traffic approaching in the...

  20. 49 CFR 236.60 - Switch shunting circuit; use restricted.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Switch shunting circuit; use restricted. 236.60 Section 236.60 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Instructions: All Systems Track Circuits § 236.60 Switch shunting circuit; use restricted. Switch...

  1. 49 CFR 236.60 - Switch shunting circuit; use restricted.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Switch shunting circuit; use restricted. 236.60 Section 236.60 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Instructions: All Systems Track Circuits § 236.60 Switch shunting circuit; use restricted. Switch...

  2. 49 CFR 236.818 - Switch, facing point.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Switch, facing point. 236.818 Section 236.818 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, facing point. A switch, the points of which face traffic approaching in the direction for...

  3. 49 CFR 236.725 - Circuit, switch shunting.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Circuit, switch shunting. 236.725 Section 236.725 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Circuit, switch shunting. A shunting circuit which is closed through contacts of a switch...

  4. 49 CFR 236.386 - Restoring feature on power switches.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Restoring feature on power switches. 236.386 Section 236.386 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Inspection and Tests § 236.386 Restoring feature on power switches. Restoring feature on power switches...

  5. 49 CFR 236.823 - Switch, trailing point.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Switch, trailing point. 236.823 Section 236.823 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, trailing point. A switch, the points of which face away from traffic approaching in the...

  6. 49 CFR 236.386 - Restoring feature on power switches.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Restoring feature on power switches. 236.386 Section 236.386 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Inspection and Tests § 236.386 Restoring feature on power switches. Restoring feature on power switches...

  7. 49 CFR 236.823 - Switch, trailing point.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Switch, trailing point. 236.823 Section 236.823 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, trailing point. A switch, the points of which face away from traffic approaching in the...

  8. 49 CFR 236.725 - Circuit, switch shunting.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Circuit, switch shunting. 236.725 Section 236.725 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Circuit, switch shunting. A shunting circuit which is closed through contacts of a switch...

  9. 49 CFR 236.819 - Switch, hand operated.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Switch, hand operated. 236.819 Section 236.819 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, hand operated. A non-interlocked switch which can only be operated manually....

  10. 49 CFR 229.87 - Hand-operated switches.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Hand-operated switches. 229.87 Section 229.87 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION....87 Hand-operated switches. All hand-operated switches carrying currents with a potential of more...

  11. 49 CFR 229.87 - Hand-operated switches.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Hand-operated switches. 229.87 Section 229.87 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION....87 Hand-operated switches. All hand-operated switches carrying currents with a potential of more...

  12. 49 CFR 236.819 - Switch, hand operated.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Switch, hand operated. 236.819 Section 236.819 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, hand operated. A non-interlocked switch which can only be operated manually....

  13. 49 CFR 236.819 - Switch, hand operated.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Switch, hand operated. 236.819 Section 236.819 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, hand operated. A non-interlocked switch which can only be operated manually....

  14. 49 CFR 229.87 - Hand-operated switches.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Hand-operated switches. 229.87 Section 229.87 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION....87 Hand-operated switches. All hand-operated switches carrying currents with a potential of more...

  15. 49 CFR 236.60 - Switch shunting circuit; use restricted.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Switch shunting circuit; use restricted. 236.60 Section 236.60 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Instructions: All Systems Track Circuits § 236.60 Switch shunting circuit; use restricted. Switch...

  16. 49 CFR 236.386 - Restoring feature on power switches.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Restoring feature on power switches. 236.386 Section 236.386 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Inspection and Tests § 236.386 Restoring feature on power switches. Restoring feature on power switches...

  17. 49 CFR 236.823 - Switch, trailing point.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Switch, trailing point. 236.823 Section 236.823 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, trailing point. A switch, the points of which face away from traffic approaching in the...

  18. 49 CFR 236.818 - Switch, facing point.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Switch, facing point. 236.818 Section 236.818 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, facing point. A switch, the points of which face traffic approaching in the direction for...

  19. 49 CFR 236.725 - Circuit, switch shunting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Circuit, switch shunting. 236.725 Section 236.725 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Circuit, switch shunting. A shunting circuit which is closed through contacts of a switch...

  20. 49 CFR 236.818 - Switch, facing point.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Switch, facing point. 236.818 Section 236.818 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, facing point. A switch, the points of which face traffic approaching in the direction for...

  1. 49 CFR 236.725 - Circuit, switch shunting.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Circuit, switch shunting. 236.725 Section 236.725 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Circuit, switch shunting. A shunting circuit which is closed through contacts of a switch...

  2. 49 CFR 236.819 - Switch, hand operated.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Switch, hand operated. 236.819 Section 236.819 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, hand operated. A non-interlocked switch which can only be operated manually....

  3. 49 CFR 236.819 - Switch, hand operated.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Switch, hand operated. 236.819 Section 236.819 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, hand operated. A non-interlocked switch which can only be operated manually....

  4. 49 CFR 236.823 - Switch, trailing point.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Switch, trailing point. 236.823 Section 236.823 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Switch, trailing point. A switch, the points of which face away from traffic approaching in the...

  5. 49 CFR 236.60 - Switch shunting circuit; use restricted.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Switch shunting circuit; use restricted. 236.60 Section 236.60 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Instructions: All Systems Track Circuits § 236.60 Switch shunting circuit; use restricted. Switch...

  6. 49 CFR 236.386 - Restoring feature on power switches.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Restoring feature on power switches. 236.386 Section 236.386 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD... Inspection and Tests § 236.386 Restoring feature on power switches. Restoring feature on power switches...

  7. cDNA cloning of the bovine low density lipoprotein receptor: feedback regulation of a receptor mRNA.

    PubMed Central

    Russell, D W; Yamamoto, T; Schneider, W J; Slaughter, C J; Brown, M S; Goldstein, J L

    1983-01-01

    The low density lipoprotein (LDL) receptor belongs to a class of migrant cell surface proteins that mediate endocytosis of macromolecular ligands. No cDNAs for this class of proteins have been isolated to date. In the current paper, we report the isolation of a cDNA clone for the LDL receptor from a bovine adrenal cDNA library. The library was constructed by the Okayama-Berg method from poly(A)+ RNA that had been enriched in receptor mRNA by immunopurification of polysomes. Mixtures of synthetic oligonucleotides encoding the amino acid sequence of two neighboring regions of a single cyanogen bromide fragment were used as hybridization probes to identify a recombinant plasmid containing the LDL receptor cDNA. This plasmid, designated pLDLR-1, contains a 2.8-kilobase (kb) insert that includes a sequence which corresponds to the known amino acid sequence of a 36-residue cyanogen bromide fragment of the receptor. pLDLR-1 hybridized to a mRNA of approximately equal to 5.5 kb in the bovine adrenal gland. This mRNA, like the receptor protein, was 9-fold more abundant in bovine adrenal than in bovine liver. pLDLR-1 cross-hybridized to a mRNA of approximately equal to 5.5 kb in cultured human epidermoid carcinoma A-431 cells. This mRNA was markedly reduced in amount when sterols were added to the culture medium, an observation that explains the previously observed feedback regulation of LDL receptor protein. Southern blot analysis of bovine genomic DNA with 32P-labeled pLDLR-1 revealed a simple pattern of hybridization, consistent with a single-copy gene containing introns. Images PMID:6143315

  8. Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels.

    PubMed

    Mayer, Gaétan; Poirier, Steve; Seidah, Nabil G

    2008-11-14

    The proprotein convertase subtilisin/kexin-type 9 (PCSK9), which promotes degradation of the hepatic low density lipoprotein receptor (LDLR), is now recognized as a major player in plasma cholesterol metabolism. Several gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, and thus, inhibition of PCSK9-induced degradation of the LDLR may be used to treat this deadly disease. Herein, we discovered an endogenous PCSK9 binding partner by Far Western blotting, co-immunoprecipitation, and pull-down assays. Following two-dimensional gel electrophoresis and mass spectrometry analysis, we demonstrated that PCSK9 binds to a approximately 33-kDa protein identified as annexin A2 (AnxA2) but not to the closely related annexin A1. Furthermore, our functional LDLR assays and small hairpin RNA studies show that AnxA2 and the AnxA2.p11 complex could prevent PCSK9-directed LDLR degradation in HuH7, HepG2, and Chinese hamster ovary cells. Immunocytochemistry revealed that PCSK9 and AnxA2 co-localize at the cell surface, indicating a possible competition with the LDLR. Structure-function analyses demonstrated that the C-terminal cysteine-histidine-rich domain of PCSK9 interacts specifically with the N-terminal repeat R1 of AnxA2. Mutational analysis of this 70-amino acid-long repeat indicated that the RRTKK81 sequence of AnxA2 is implicated in this binding because its mutation to AATAA81 prevents its interaction with PCSK9. To our knowledge, this work constitutes the first to show that PCSK9 activity on LDLR can be regulated by an endogenous inhibitor. The identification of the minimal inhibitory sequence of AnxA2 should pave the way toward the development of PCSK9 inhibitory lead molecules for the treatment of hypercholesterolemia.

  9. Increased dendritic spine density and tau expression are associated with individual differences in steroidal regulation of male sexual behavior.

    PubMed

    Bharadwaj, Pranay; McInnis, Christine; Madden, Amanda M K; Bonthuis, Paul J; Zup, Susan; Rissman, Emilie F; Park, Jin Ho

    2013-01-01

    Male sexual behavior (MSB) is modulated by gonadal steroids, yet this relationship is highly variable across species and between individuals. A significant percentage (~30%) of B6D2F1 hybrid male mice demonstrate MSB after long-term orchidectomy (herein after referred to as "maters"), providing an opportunity to examine the mechanisms that underlie individual differences in steroidal regulation of MSB. Use of gene expression arrays comparing maters and non-maters has provided a first pass look at the genetic underpinnings of steroid-independent MSB. Surprisingly, of the ~500 genes in the medial preoptic area (MPOA) that differed between maters and non-maters, no steroid hormone or receptor genes were differentially expressed between the two groups. Interestingly, best known for their association with Alzheimer's disease, amyloid precursor protein (APP) and the microtubule-associated protein tau (MAPT) were elevated in maters. Increased levels of their protein products (APP and tau) in their non-pathological states have been implicated in cell survival, neuroprotection, and supporting synaptic integrity. Here we tested transgenic mice that overexpress tau and found facilitated mounting and intromission behavior after long-term orchidectomy relative to littermate controls. In addition, levels of synaptophysin and spinophilin, proteins generally enriched in synapses and dendritic spines respectively, were elevated in the MPOA of maters. Dendritic morphology was also assessed in Golgi-impregnated brains of orchidectomized B6D2F1 males, and hybrid maters exhibited greater dendritic spine density in MPOA neurons. In sum, we show for the first time that retention of MSB in the absence of steroids is correlated with morphological differences in neurons.

  10. Fragile X mental retardation protein regulates the levels of scaffold proteins and glutamate receptors in postsynaptic densities.

    PubMed

    Schütt, Janin; Falley, Katrin; Richter, Dietmar; Kreienkamp, Hans-Jürgen; Kindler, Stefan

    2009-09-18

    Functional absence of fragile X mental retardation protein (FMRP) causes the fragile X syndrome, a hereditary form of mental retardation characterized by a change in dendritic spine morphology. The RNA-binding protein FMRP has been implicated in regulating postsynaptic protein synthesis. Here we have analyzed whether the abundance of scaffold proteins and neurotransmitter receptor subunits in postsynaptic densities (PSDs) is altered in the neocortex and hippocampus of FMRP-deficient mice. Whereas the levels of several PSD components are unchanged, concentrations of Shank1 and SAPAP scaffold proteins and various glutamate receptor subunits are altered in both adult and juvenile knock-out mice. With the exception of slightly increased hippocampal SAPAP2 mRNA levels in adult animals, altered postsynaptic protein concentrations do not correlate with similar changes in total and synaptic levels of corresponding mRNAs. Thus, loss of FMRP in neurons appears to mainly affect the translation and not the abundance of particular brain transcripts. Semi-quantitative analysis of RNA levels in FMRP immunoprecipitates showed that in the mouse brain mRNAs encoding PSD components, such as Shank1, SAPAP1-3, PSD-95, and the glutamate receptor subunits NR1 and NR2B, are associated with FMRP. Luciferase reporter assays performed in primary cortical neurons from knock-out and wild-type mice indicate that FMRP silences translation of Shank1 mRNAs via their 3'-untranslated region. Activation of metabotropic glutamate receptors relieves translational suppression. As Shank1 controls dendritic spine morphology, our data suggest that dysregulation of Shank1 synthesis may significantly contribute to the abnormal spine development and function observed in brains of fragile X syndrome patients.

  11. Surface flashover threshold and switched fields of photoconductive semiconductor switches

    SciTech Connect

    Loubriel, G.M.; O'Malley, M.W.; Zutavern, F.J.; McKenzie, B.B.; Conley, W.R.

    1988-01-01

    We have shown that Si Photoconductive Semiconductor Switches (PCSS) can be used to switch high voltages (up to 123 kV), high fields (up to 82 kV/cm) and high currents (2.8 kA). The ability of the samples to withstand this type of high voltage, high current switching depends on the way in which the current penetrates the semiconductor. The appropriate use of water or contacts greatly improves the switching capability. We have also shown that the wafers can support large currents (4.0 kA for GaAs and 2.8 kA for Si) and large linear current densities (3.2 kA/cm for GaAs and 1.4 kA/cm for Si). For GaAs this linear current density corresponds to about 1 Ma/cm/sup 2/ given a penetration depth of about 10/sup /minus/3/ cm. 4 refs., 4 figs., 2 tabs.

  12. Latching relay switch assembly

    SciTech Connect

    Duimstra, Frederick A.

    1991-01-01

    A latching relay switch assembly which includes a coil section and a switch or contact section. The coil section includes at least one permanent magnet and at least one electromagnet. The respective sections are, generally, arranged in separate locations or cavities in the assembly. The switch is latched by a permanent magnet assembly and selectively switched by an overriding electromagnetic assembly.

  13. Radiation hard vacuum switch

    DOEpatents

    Boettcher, Gordon E.

    1990-03-06

    A vacuum switch with an isolated trigger probe which is not directly connected to the switching electrodes. The vacuum switch within the plasmatron is triggered by plasma expansion initiated by the trigger probe which travels through an opening to reach the vacuum switch elements. The plasma arc created is directed by the opening to the space between the anode and cathode of the vacuum switch to cause conduction.

  14. Radiation hard vacuum switch

    DOEpatents

    Boettcher, Gordon E.

    1990-01-01

    A vacuum switch with an isolated trigger probe which is not directly connected to the switching electrodes. The vacuum switch within the plasmatron is triggered by plasma expansion initiated by the trigger probe which travels through an opening to reach the vacuum switch elements. The plasma arc created is directed by the opening to the space between the anode and cathode of the vacuum switch to cause conduction.

  15. High-Speed, high-power, switching transistor

    NASA Technical Reports Server (NTRS)

    Carnahan, D.; Ohu, C. K.; Hower, P. L.

    1979-01-01

    Silicon transistor rate for 200 angstroms at 400 to 600 volts combines switching speed of transistors with ruggedness, power capacity of thyristor. Transistor introduces unique combination of increased power-handling capability, unusally low saturation and switching losses, and submicrosecond switching speeds. Potential applications include high power switching regulators, linear amplifiers, chopper controls for high frequency electrical vehicle drives, VLF transmitters, RF induction heaters, kitchen cooking ranges, and electronic scalpels for medical surgery.

  16. A novel, dynamic pattern-based analysis of NF-κB binding during the priming phase of liver regeneration reveals switch-like functional regulation of target genes

    PubMed Central

    Cook, Daniel J.; Patra, Biswanath; Kuttippurathu, Lakshmi; Hoek, Jan B.; Vadigepalli, Rajanikanth

    2015-01-01

    Following partial hepatectomy, a coordinated series of molecular events occurs to regulate hepatocyte entry into the cell cycle to recover lost mass. In rats during the first 6 h following resection, hepatocytes are primed by a tightly controlled cytokine response to prepare hepatocytes to begin replication. Although it appears to be a critical element driving regeneration, the cytokine response to resection has not yet been fully characterized. Specifically, the role of one of the key response elements to cytokine signaling (NF-κB) remains incompletely characterized. In this study, we present a novel, genome-wide, pattern-based analysis characterizing NF-κB binding during the priming phase of liver regeneration. We interrogated the dynamic regulation of priming by NF-κB through categorizing NF-κB binding in different temporal profiles: immediate sustained response, early transient response, and delayed response to partial hepatectomy. We then identified functional regulation of NF-κB binding by relating the temporal response profile to differential gene expression. We found that NF-κB bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy. NF-κB also transiently regulates genes responsible for lipid biosynthesis and transport as well as induction of apoptosis following hepatectomy. By the end of the priming phase, NF-κB regulation of genes involved in inflammatory response, negative regulation of cell death, and extracellular structure organization became prominent. These results suggest that NF-κB regulates target genes through binding and unbinding in immediate, transient, and delayed patterns. Such dynamic switch-like patterns of NF-κB binding may govern different functional transitions that drive the onset of regeneration. PMID:26217230

  17. Adult trees cause density-dependent mortality in conspecific seedlings by regulating the frequency of pathogenic soil fungi.

    PubMed

    Liang, Minxia; Liu, Xubing; Gilbert, Gregory S; Zheng, Yi; Luo, Shan; Huang, Fengmin; Yu, Shixiao

    2016-12-01

    Negative density-dependent seedling mortality has been widely detected in tropical, subtropical and temperate forests, with soil pathogens as a major driver. Here we investigated how host density affects the composition of soil pathogen communities and consequently influences the strength of plant-soil feedbacks. In field censuses of six 1-ha permanent plots, we found that survival was much lower for newly germinated seedlings that were surrounded by more conspecific adults. The relative abundance of pathogenic fungi in soil increased with increasing conspecific tree density for five of nine tree species; more soil pathogens accumulated around roots where adult tree density was higher, and this greater pathogen frequency was associated with lower seedling survival. Our findings show how tree density influences populations of soil pathogens, which creates plant-soil feedbacks that contribute to community-level and population-level compensatory trends in seedling survival.

  18. Temporal switching jitter in photoconductive switches

    SciTech Connect

    GAUDET,JOHN A.; SKIPPER,MICHAEL C.; ABDALLA,MICHAEL D.; AHERN,SEAN M.; MAR,ALAN; LOUBRIEL,GUILLERMO M.; ZUTAVERN,FRED J.; O'MALLEY,MARTIN W.; HELGESON,WESLEY D.; ROMERO,SAMUEL P.

    2000-04-13

    This paper reports on a recent comparison made between the Air Force Research Laboratory (AFRL) gallium arsenide, optically-triggered switch test configuration and the Sandia National Laboratories (SNL) gallium arsenide, optically-triggered switch test configuration. The purpose of these measurements was to compare the temporal switch jitter times. It is found that the optical trigger laser characteristics are dominant in determining the PCSS jitter.

  19. Composite Thermal Switch

    NASA Technical Reports Server (NTRS)

    McDonald, Robert; Brawn, Shelly; Harrison, Katherine; O'Toole, Shannon; Moeller, Michael

    2011-01-01

    Lithium primary and lithium ion secondary batteries provide high specific energy and energy density. The use of these batteries also helps to reduce launch weight. Both primary and secondary cells can be packaged as high-rate cells, which can present a threat to crew and equipment in the event of external or internal short circuits. Overheating of the cell interior from high current flows induced by short circuits can result in exothermic reactions in lithium primary cells and fully charged lithium ion secondary cells. Venting of the cell case, ejection of cell components, and fire have been reported in both types of cells, resulting from abuse, cell imperfections, or faulty electronic control design. A switch has been developed that consists of a thin layer of composite material made from nanoscale particles of nickel and Teflon that conducts electrons at room temperature and switches to an insulator at an elevated temperature, thus interrupting current flow to prevent thermal runaway caused by internal short circuits. The material is placed within the cell, as a thin layer incorporated within the anode and/or the cathode, to control excess currents from metal-to-metal or metal-to-carbon shorts that might result from cell crush or a manufacturing defect. The safety of high-rate cells is thus improved, preventing serious injury to personnel and sensitive equipment located near the battery. The use of recently available nanoscale particles of nickel and Teflon permits an improved, homogeneous material with the potential to be fine-tuned to a unique switch temperature, sufficiently below the onset of a catastrophic chemical reaction. The smaller particles also permit the formation of a thinner control film layer (<50 m), which can be incorporated into commercial high-rate lithium primary and secondary cells. The innovation permits incorporation in current lithium and lithium-ion cell designs with a minimal impact on cell weight and volume. The composite thermal

  20. Latching micro optical switch

    DOEpatents

    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.

  1. Switched-capacitor isolated LED driver

    SciTech Connect

    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.

  2. Shape memory thermal conduction switch

    NASA Technical Reports Server (NTRS)

    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.

  3. 49 CFR 236.202 - Signal governing movements over hand-operated switch.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... switch. 236.202 Section 236.202 Transportation Other Regulations Relating to Transportation (Continued...-operated switch. Signal governing movements over hand-operated switch in the facing direction shall display... over the switch in the normal and in the reverse position, the signal shall display its...

  4. 49 CFR 236.202 - Signal governing movements over hand-operated switch.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... switch. 236.202 Section 236.202 Transportation Other Regulations Relating to Transportation (Continued...-operated switch. Signal governing movements over hand-operated switch in the facing direction shall display... over the switch in the normal and in the reverse position, the signal shall display its...

  5. The effect of oxygen vacancy on switching mechanism of ZnO resistive switching memory

    NASA Astrophysics Data System (ADS)

    Hu, Cong; Wang, Qi; Bai, Shuai; Xu, Min; He, Deyan; Lyu, Deyuan; Qi, Jing

    2017-02-01

    Oxygen vacancy (Vo) is believed to control the switching mechanism of metal oxide resistive switching memory. However, an accurate and quantitative theory to prove this point of view remains absent. In this letter, we propose a model combining the Poole-Frenkel effect, space charge limited current, and the modification of Vo density to simulate the current-voltage curves. The calculated results show reasonable agreements with the experimental data, which indicates that resistive switching between high resistance state and low resistance state in the devices of Al/ZnO/p+-Si is led by the density change of Vo. Furthermore, the essence of this leading effect of Vo density is explained by electrons capture and emission via oxygen vacancies. This research demonstrates the significance of Vo in theory and gives an insight into the switching mechanism.

  6. A sub-1-volt nanoelectromechanical switching device.

    PubMed

    Lee, Jeong Oen; Song, Yong-Ha; Kim, Min-Wu; Kang, Min-Ho; Oh, Jae-Sub; Yang, Hyun-Ho; Yoon, Jun-Bo

    2013-01-01

    Nanoelectromechanical (NEM) switches have received widespread attention as promising candidates in the drive to surmount the physical limitations currently faced by complementary metal oxide semiconductor technology. The NEM switch has demonstrated superior characteristics including quasi-zero leakage behaviour, excellent density capability and operation in harsh environments. However, an unacceptably high operating voltage (4-20 V) has posed a major obstacle in the practical use of the NEM switch in low-power integrated circuits. To utilize the NEM switch widely as a core device component in ultralow power applications, the operation voltage needs to be reduced to 1 V or below. However, sub-1 V actuation has not yet been demonstrated because of fabrication difficulties and irreversible switching failure caused by surface adhesion. Here, we report the sub-1 V operation of a NEM switch through the introduction of a novel pipe clip device structure and an effective air gap fabrication technique. This achievement is primarily attributed to the incorporation of a 4-nm-thick air gap, which is the smallest reported so far for a NEM switch generated using a 'top-down' approach. Our structure and process can potentially be utilized in various nanogap-related applications, including NEM switch-based ultralow-power integrated circuits, NEM resonators, nanogap electrodes for scientific research and sensors.

  7. Coordinate up-regulation of low-density lipoprotein receptor and cyclo-oxygenase-2 gene expression in human colorectal cells and in colorectal adenocarcinoma biopsies

    NASA Technical Reports Server (NTRS)

    Lum, D. F.; McQuaid, K. R.; Gilbertson, V. L.; Hughes-Fulford, M.

    1999-01-01

    Many colorectal cancers have high levels of cyclo-oxygenase 2 (COX-2), an enzyme that metabolizes the essential fatty acids into prostaglandins. Since the low-density lipoprotein receptor (LDLr) is involved in the uptake of essential fatty acids, we studied the effect of LDL on growth and gene regulation in colorectal cancer cells. DiFi cells grown in lipoprotein-deficient sera (LPDS) grew more slowly than cells with LDL. LDLr antibody caused significant inhibition of tumor cell growth but did not affect controls. In addition, LDL uptake did not change in the presence of excess LDL, suggesting that ldlr mRNA lacks normal feedback regulation in some colorectal cancers. Analysis of the ldlr mRNA showed that excess LDL in the medium did not cause down-regulation of the message even after 24 hr. The second portion of the study examined the mRNA expression of ldlr and its co-regulation with cox-2 in normal and tumor specimens from patients with colorectal adenocarcinomas. The ratio of tumor:paired normal mucosa of mRNA expression of ldlr and of cox-2 was measured in specimens taken during colonoscopy. ldlr and cox-2 transcripts were apparent in 11 of 11 carcinomas. There was significant coordinate up-regulation both of ldlr and of cox-2 in 6 of 11 (55%) tumors compared with normal colonic mucosa. There was no up-regulation of cox-2 without concomitant up-regulation of ldlr. These data suggest that the LDLr is abnormally regulated in some colorectal tumors and may play a role in the up-regulation of cox-2. Copyright 1999 Wiley-Liss, Inc.

  8. Remote switch actuator

    DOEpatents

    Haas, Edwin Gerard; Beauman, Ronald; Palo, Jr., Stefan

    2013-01-29

    The invention provides a device and method for actuating electrical switches remotely. The device is removably attached to the switch and is actuated through the transfer of a user's force. The user is able to remain physically removed from the switch site obviating need for protective equipment. The device and method allow rapid, safe actuation of high-voltage or high-current carrying electrical switches or circuit breakers.

  9. Heat switches for ADRs

    NASA Astrophysics Data System (ADS)

    DiPirro, M. J.; Shirron, P. J.

    2014-07-01

    Heat switches are key elements in the cyclic operation of Adiabatic Demagnetization Refrigerators (ADRs). Several of the types of heat switches that have been used for ADRs are described in this paper. Key elements in selection and design of these switches include not only ON/OFF switching ratio, but also method of actuation, size, weight, and structural soundness. Some of the trade-off are detailed in this paper.

  10. Heat Switches for ADRs

    NASA Technical Reports Server (NTRS)

    DiPirro, M. J.; Shirron, P. J.

    2014-01-01

    Heat switches are key elements in the cyclic operation of Adiabatic Demagnetization Refrigerators (ADRs). Several of the types of heat switches that have been used for ADRs are described in this paper. Key elements in selection and design of these switches include not only ON/OFF switching ratio, but also method of actuation, size, weight, and structural soundness. Some of the trade-off are detailed in this paper.

  11. Effect of 7,8-dihydroneopterin mediated CD36 down regulation and oxidant scavenging on oxidised low-density lipoprotein induced cell death in human macrophages.

    PubMed

    Shchepetkina, Anastasia A; Hock, Barry D; Miller, Allison; Kennedy, Martin A; Gieseg, Steven P

    2017-03-26

    The role of CD36 in oxidised low-density lipoprotein (oxLDL) mediated cell death was examined by down regulating the receptor level with the macrophage generated antioxidant 7,8-dihydroneopterin. Down regulation of CD36 protein levels in human monocyte derived macrophages by 7,8-dihydroneopterin corresponded to a decrease in CD36-mRNA. The oxidation products of 7,8-dihydroneopterin, dihydroxanthopterin and neopterin did not significantly down regulate CD36. The CD36 down regulation resulted in a decrease in oxLDL uptake measured as 7-ketocholesterol accumulation. Though less oxLDL was taken up by the macrophages as a result of the 7,8-dihydroneopterin induced down regulation in CD36 levels, the cytotoxicity of the oxLDL was not decreased. Addition of 7,8-dihydroneopterin to oxLDL treated macrophages decreased the concentration of intracellular oxidants. In the presence of oxLDL, 7,8-dihydroneopterin was oxidised to neopterin showing that the 7,8-dihydroneopterin was scavenging intracellular oxidants generated in response to the oxLDL. The results show CD36 down regulation does not protect human macrophages form oxLDL cytotoxicity but 7,8-dihydroneopterin intracellular oxidant scavenging is protective.

  12. A long life plasma switch for space applications

    NASA Technical Reports Server (NTRS)

    Choi, Sang H.; Lee, Ja H.

    1987-01-01

    The use of a novel plasma switch based on the inverse-pinch mechanism can reduce local current density over spacecraft power system electrodes, thereby minimizing damage to the insulator. The current density involved is 2 orders of magnitude smaller than that of the z-pinched current in a spark-gap switch; local heating is therefore about 4 orders of magnitude less than that to the electrodes of the spark-gap switch. Over 2000 tests of the plasma switch have been conducted for a forward current of more than 1 MA and up to 20 kV holdoff voltage.

  13. Thiol-Based Redox Switches

    PubMed Central

    Groitl, Bastian; Jakob, Ursula

    2014-01-01

    Regulation of protein function through thiol-based redox switches plays an important role in the response and adaptation to local and global changes in the cellular levels of reactive oxygen species (ROS). Redox regulation is used by first responder proteins, such as ROS-specific transcriptional regulators, chaperones or metabolic enzymes to protect cells against mounting levels of oxidants, repair the damage and restore redox homeostasis. Redox regulation of phosphatases and kinases is used to control the activity of select eukaryotic signaling pathways, making reactive oxygen species important second messengers that regulate growth, development and differentiation. In this review we will compare different types of reversible protein thiol modifications, elaborate on their structural and functional consequences and discuss their role in oxidative stress response and ROS adaptation. PMID:24657586

  14. Derivation of linearized transfer functions for switching-mode regulations. Phase A: Current step-up and voltage step-up converters

    NASA Technical Reports Server (NTRS)

    Wong, R. C.; Owen, H. A., Jr.; Wilson, T. G.

    1981-01-01

    Small-signal models are derived for the power stage of the voltage step-up (boost) and the current step-up (buck) converters. The modeling covers operation in both the continuous-mmf mode and the discontinuous-mmf mode. The power stage in the regulated current step-up converter on board the Dynamics Explorer Satellite is used as an example to illustrate the procedures in obtaining the small-signal functions characterizing a regulated converter.

  15. Apollo Ring Optical Switch

    SciTech Connect

    Maestas, J.H.

    1987-03-01

    An optical switch was designed, built, and installed at Sandia National Laboratories in Albuquerque, New Mexico, to facilitate the integration of two Apollo computer networks into a single network. This report presents an overview of the optical switch as well as its layout, switch testing procedure and test data, and installation.

  16. Triggered plasma opening switch

    DOEpatents

    Mendel, Clifford W.

    1988-01-01

    A triggerable opening switch for a very high voltage and current pulse includes a transmission line extending from a source to a load and having an intermediate switch section including a plasma for conducting electrons between transmission line conductors and a magnetic field for breaking the plasma conduction path and magnetically insulating the electrons when it is desired to open the switch.

  17. Figuring on energy: fuel-switch mirage

    SciTech Connect

    Schaffer, P.

    1984-06-25

    DOE's Petroleum Supply Annual: 1983 does not support the idea that the 1981-83 drop in natural gas consumption was due to industrial users switching to oil. A consumption breakdown shows a pattern of reduced oil use during the same period. The American Gas Association estimates that gas utilities lost 0.325 quads in 1982 because of dual-fuel switching, but gas consumption continued to decline even after the fuel-switching trend reversed. The author traces the problem to state rate regulators whose policies subsidize residential users at the expense of industry rather than to interfuel competition.

  18. An Element of Determinism in a Stochastic Flagellar Motor Switch

    PubMed Central

    Xie, Li; Altindal, Tuba; Wu, Xiao-Lun

    2015-01-01

    Marine bacterium Vibrio alginolyticus uses a single polar flagellum to navigate in an aqueous environment. Similar to Escherichia coli cells, the polar flagellar motor has two states; when the motor is counter-clockwise, the cell swims forward and when the motor is clockwise, the cell swims backward. V. alginolyticus also incorporates a direction randomization step at the start of the forward swimming interval by flicking its flagellum. To gain an understanding on how the polar flagellar motor switch is regulated, distributions of the forward Δf and backward Δb intervals are investigated herein. We found that the steady-state probability density functions, P(Δf) and P(Δb), of freely swimming bacteria are strongly peaked at a finite time, suggesting that the motor switch is not Poissonian. The short-time inhibition is sufficiently strong and long lasting, i.e., several hundred milliseconds for both intervals, which is readily observed and characterized. Treating motor reversal dynamics as a first-passage problem, which results from conformation fluctuations of the motor switch, we calculated P(Δf) and P(Δb) and found good agreement with the measurements. PMID:26554590

  19. Expression of the Coxsackievirus and Adenovirus Receptor in Cultured Human Umbilical Vein Endothelial Cells: Regulation in Response to Cell Density

    PubMed Central

    Carson, Steven D.; Hobbs, Justin T.; Tracy, Steven M.; Chapman, Nora M.

    1999-01-01

    Primary cultures of human umbilical vein endothelial cells (HUVEC) express the human coxsackievirus and adenovirus receptor (HCAR). Whereas HCAR expression in HeLa cells was constant with respect to cell density, HCAR expression in HUVEC increased with culture confluence. HCAR expression in HUVEC was not quantitatively altered by infection with coxsackievirus B. PMID:10400813

  20. Fish assemblage, density, and growth in lateral habitats within natural and regulated sections of Washington's Elwha River prior to dam removal

    USGS Publications Warehouse

    Connolly, P.J.; Brenkman, S.J.

    2008-01-01

    We characterized seasonal fish assemblage, relative density, and growth in river margins above and between two Elwha River dams scheduled for removal. Fish assemblage and relative density differed in the lateral habitats of the middle-regulated and upper-unregulated sections of the Elwha River. Rainbow trout was the numerically dominant salmonid in both sections, with bull trout present in low numbers. Sculpin were common in the middle section, but not detected in the upper section. In 2004, mean length and biomass of age-0 rainbow trout were significantly smaller in the middle section than in the upper section by the end of the growing season (September). In 2005, an earlier emergence of rainbow trout in the middle section (July) compared to the upper section (August) corresponded with warmer water temperatures in the middle section. Despite lower growth, the margins of mainstem units in the middle section supported higher mean areal densities and biomass of age-0 rainbow trout than the up-per section. These results suggest that growth performance of age-0 rainbow trout was lower in the middle section than in the upper section, which could have been a density-dependent response, or a result of poor food production in the sediment-starved regulated section, or both. Based on our findings, we believe that seasonal sampling of river margins within reference reaches is a cost effective and repeatable method for detection of biologically important short- and long-term changes in emergence timing, density, and growth of rainbow trout before and after dam removals in the Elwha River.

  1. The novel poly(A) polymerase Star-PAP is a signal-regulated switch at the 3'-end of mRNAs.

    PubMed

    Li, Weimin; Laishram, Rakesh S; Anderson, Richard A

    2013-01-01

    The mRNA 3'-untranslated region (3'-UTR) modulates message stability, transport, intracellular location and translation. We have discovered a novel nuclear poly(A) polymerase termed Star-PAP (nuclear speckle targeted PIPKIα regulated-poly(A) polymerase) that couples with the transcriptional machinery and is regulated by the phosphoinositide lipid messenger phosphatidylinositol-4,5-bisphosphate (PI4,5P(2)), the central lipid in phosphoinositide signaling. PI4,5P(2) is generated primarily by type I phosphatidylinositol phosphate kinases (PIPKI). Phosphoinositides are present in the nucleus including at nuclear speckles compartments separate from known membrane structures. PIPKs regulate cellular functions by interacting with PI4,5P(2) effectors where PIPKs generate PI4,5P(2) that then modulates the activity of the associated effectors. Nuclear PIPKIα interacts with and regulates Star-PAP, and PI4,5P(2) specifically activates Star-PAP in a gene- and signaling-dependent manner. Importantly, other select signaling molecules integrated into the Star-PAP complex seem to regulate Star-PAP activities and processivities toward RNA substrates, and unique sequence elements around the Star-PAP binding sites within the 3'-UTR of target genes contribute to Star-PAP specificity for processing. Therefore, Star-PAP and its regulatory molecules form a signaling nexus at the 3'-end of target mRNAs to control the expression of select group of genes including the ones involved in stress responses.

  2. REMOTE CONTROLLED SWITCHING DEVICE

    DOEpatents

    Hobbs, J.C.

    1959-02-01

    An electrical switching device which can be remotely controlled and in which one or more switches may be accurately operated at predetermined times or with predetermined intervening time intervals is described. The switching device consists essentially of a deck, a post projecting from the deck at right angles thereto, cam means mounted for rotation around said posts and a switch connected to said deck and actuated by said cam means. Means is provided for rotating the cam means at a constant speed and the switching apparatus is enclosed in a sealed container with external adjusting means and electrical connection elements.

  3. On the Switching Control

    NASA Astrophysics Data System (ADS)

    Balas, Valentina E.; Balas, Marius M.

    2009-04-01

    The paper is discussing the measures able to reject the instability that may unexpectedly appear in particular conditions, in switching controllers applications. The switching controllers' effect is explained by the combined effects of the unsuitable choice of the switching moments (in the first or third quadrants of the phase trajectory of the switching error) and of the temporal aliasing that can distort the digital control systems when the sampling rate is close to the frequency of the oscillations that are produced by the commutation. The correct switching moments are located into the second and fourth quadrants of the phase trajectory of the switching error, but an active preparation of the commutation may be simply achieved by using a tracking controller, that is driving the output of open loop controller to follow the output of the close loop controller, permanently minimizing the switching error. Simulations issued from a dc driver speed controller and from an aircraft are provided.

  4. A novel class of antihyperlipidemic agents with low density lipoprotein receptor up-regulation via the adaptor protein autosomal recessive hypercholesterolemia.

    PubMed

    Asano, Shigehiro; Ban, Hitoshi; Tsuboya, Norie; Uno, Shinsaku; Kino, Kouichi; Ioriya, Katsuhisa; Kitano, Masafumi; Ueno, Yoshihide

    2010-04-22

    We have previously reported compound 2 as a inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) and up-regulator of the low density lipoprotein receptor (LDL-R) expression. In this study we focused on compound 2, a unique LDL-R up-regulator, and describe the discovery of a novel class of up-regulators of LDL-R. Replacement the methylene urea linker in compound 2 with an acylsulfonamide linker kept a potent LDL-R up-regulatory activity, and subsequent optimization work gave compound 39 as a highly potent LDL-R up-regulator (39; EC(25) = 0.047 microM). Compound 39 showed no ACAT inhibitory activity even at 1 microM. The sodium salts of compound 39 reduced plasma total and LDL cholesterol levels in a dose-dependent manner in an experimental animal model of hyperlipidemia. Moreover, we revealed in this study using RNA interference that autosomal recessive hypercholesterolemia (ARH), an adaptor protein of LDL-R, is essential for compound 39 up-regulation of LDL-R expression.

  5. Protein Phosphatase 2A (PP2A) Regulates Low Density Lipoprotein Uptake through Regulating Sterol Response Element-binding Protein-2 (SREBP-2) DNA Binding*

    PubMed Central

    Rice, Lyndi M.; Donigan, Melissa; Yang, Muhua; Liu, Weidong; Pandya, Devanshi; Joseph, Biny K.; Sodi, Valerie; Gearhart, Tricia L.; Yip, Jenny; Bouchard, Michael; Nickels, Joseph T.

    2014-01-01

    LDL-cholesterol (LDL-C) uptake by Ldlr is regulated at the transcriptional level by the cleavage-dependent activation of membrane-associated sterol response element-binding protein (SREBP-2). Activated SREBP-2 translocates to the nucleus, where it binds to an LDLR promoter sterol response element (SRE), increasing LDLR gene expression and LDL-C uptake. SREBP-2 cleavage and translocation steps are well established. Several SREBP-2 phosphorylation sites have been mapped and functionally characterized. The phosphatases dephosphorylating these sites remain elusive. The phosphatase(s) regulating SREBP-2 represents a novel pharmacological target for treating hypercholesterolemia. Here we show that protein phosphatase 2A (PP2A) promotes SREBP-2 LDLR promoter binding in response to cholesterol depletion. No binding to an LDLR SRE was observed in the presence of the HMG-CoA reductase inhibitor, lovastatin, when PP2A activity was inhibited by okadaic acid or depleted by siRNA methods. SREBP-2 cleavage and nuclear translocation were not affected by loss of PP2A. PP2A activity was required for SREBP-2 DNA binding. In response to cholesterol depletion, PP2A directly interacted with SREBP-2 and altered its phosphorylation state, causing an increase in SREBP-2 binding to an LDLR SRE site. Increased binding resulted in induced LDLR gene expression and increased LDL uptake. We conclude that PP2A activity regulates cholesterol homeostasis and LDL-C uptake. PMID:24770487

  6. Household Density and Academic Standing among Community College Students: The Effects of Time Orientation and Spatial Self-Regulation

    ERIC Educational Resources Information Center

    Campagna, Grace

    2012-01-01

    The purpose of the study was to develop a multifactorial model tracing paths from housing affordances to academic outcomes in higher education. The study sought to connect two areas of psychological research: on one side, the adverse effects of environmental stressors and inadequate self-regulation upon life course prospects and, on the other, the…

  7. MicroRNA miR396 Regulates the Switch between Stem Cells and Transit-Amplifying Cells in Arabidopsis Roots.

    PubMed

    Rodriguez, Ramiro E; Ercoli, María Florencia; Debernardi, Juan Manuel; Breakfield, Natalie W; Mecchia, Martin A; Sabatini, Martin; Cools, Toon; De Veylder, Lieven; Benfey, Philip N; Palatnik, Javier F

    2015-12-01

    To ensure an adequate organ mass, the daughters of stem cells progress through a transit-amplifying phase displaying rapid cell division cycles before differentiating. Here, we show that Arabidopsis thaliana microRNA miR396 regulates the transition of root stem cells into transit-amplifying cells by interacting with GROWTH-REGULATING FACTORs (GRFs). The GRFs are expressed in transit-amplifying cells but are excluded from the stem cells through inhibition by miR396. Inactivation of the GRFs increases the meristem size and induces periclinal formative divisions in transit-amplifying cells. The GRFs repress PLETHORA (PLT) genes, regulating their spatial expression gradient. Conversely, PLT activates MIR396 in the stem cells to repress the GRFs. We identified a pathway regulated by GRF transcription factors that represses stem cell-promoting genes in actively proliferating cells, which is essential for the progression of the cell cycle and the orientation of the cell division plane. If unchecked, the expression of the GRFs in the stem cell niche suppresses formative cell divisions and distorts the organization of the quiescent center. We propose that the interactions identified here between miR396 and GRF and PLT transcription factors are necessary to establish the boundary between the stem cell niche and the transit-amplifying region.

  8. Carbon isotope controlled molecular switches

    NASA Astrophysics Data System (ADS)

    Foster, Brian K.

    Single molecules represent one fundamental limit to the downscaling of electronics. As a prototype element for carbon-based nanoscale science and technology, the detailed behavior of carbon monoxide (CO) on the copper surface Cu(111) has been investigated. These investigations span from individual carbon isotope resolution, to single molecules, to compact clusters assembled by molecular manipulation via a homemade scanning tunneling microscope (STM). Sub-nanoscale devices, composed of only a few molecules, which exploit both lone CO properties and molecule-molecule interaction, have been designed and assembled. The devices function as bi-stable switches and can serve as classical bits with densities > 50 Tbits/cm2. Operated in the nuclear mass sensitive regime, each switch can also function as a molecular "centrifuge" capable of identifying the isotope of a single carbon atom in real-time. A model, based on electron-vibron couping and inelastic tunneling, has been developed and explains the dynamic behavior of the switch. The interaction between pairs of switches was also explored and it was found that their behavior ranges from completely independent to strongly coupled. Larger nanostructures, which were composed of many sub-switches organized to leverage the fully coupled interaction, link two spatially separated "bits" on the surface. Such a linked system can set or read a state non-locally, which is equivalent to bidirectional information transfer. The linked system has also exhibited logic functionality. These experiments demonstrate scalable molecular cells for information storage, and for information processing through cellular automata logic schemes.

  9. Complement Factor H Binds to Human Serum Apolipoprotein E and Mediates Complement Regulation on High Density Lipoprotein Particles.

    PubMed

    Haapasalo, Karita; van Kessel, Kok; Nissilä, Eija; Metso, Jari; Johansson, Tiira; Miettinen, Sini; Varjosalo, Markku; Kirveskari, Juha; Kuusela, Pentti; Chroni, Angelika; Jauhiainen, Matti; van Strijp, Jos; Jokiranta, T Sakari

    2015-11-27

    The alternative pathway of complement is an important part of the innate immunity response against foreign particles invading the human body. To avoid damage to host cells, it needs to be efficiently down-regulated by plasma factor H (FH) as exemplified by various diseases caused by mutations in its domains 19-20 (FH19-20) and 5-7 (FH5-7). These regions are also the main interaction sites for microbial pathogens that bind host FH to evade complement attack. We previously showed that inhibition of FH binding by a recombinant FH5-7 construct impairs survival of FH binding pathogens in human blood. In this study we found that upon exposure to full blood, the addition of FH5-7 reduces survival of, surprisingly, also those microbes that are not able to bind FH. This effect was mediated by inhibition of complement regulation and subsequently enhanced neutrophil phagocytosis by FH5-7. We found that although FH5-7 does not reduce complement regulation in the actual fluid phase of plasma, it reduces regulation on HDL particles in plasma. Using affinity chromatography and mass spectrometry we revealed that FH interacts with serum apolipoprotein E (apoE) via FH5-7 domains. Furthermore, binding of FH5-7 to HDL was dependent on the concentration of apoE on the HDL particles. These findings explain why the addition of FH5-7 to plasma leads to excessive complement activation and phagocytosis of microbes in full anticoagulated blood. In conclusion, our data show how FH interacts with apoE molecules via domains 5-7 and regulates alternative pathway activation on plasma HDL particles.

  10. Differential Phosphorylation Provides a Switch to Control How α-Arrestin Rod1 Down-regulates Mating Pheromone Response in Saccharomyces cerevisiae

    PubMed Central

    Alvaro, Christopher G.; Aindow, Ann; Thorner, Jeremy

    2016-01-01

    G-protein-coupled receptors (GPCRs) are integral membrane proteins that initiate stimulus-dependent activation of cognate heterotrimeric G-proteins, triggering ensuing downstream cellular responses. Tight regulation of GPCR-evoked pathways is required because prolonged stimulation can be detrimental to an organism. Ste2, a GPCR in Saccharomyces cerevisiae that mediates response of MATa haploids to the peptide mating pheromone α-factor, is down-regulated by both constitutive and agonist-induced endocytosis. Efficient agonist-stimulated internalization of Ste2 requires its association with an adaptor protein, the α-arrestin Rod1/Art4, which recruits the HECT-domain ubiquitin ligase Rsp5, allowing for ubiquitinylation of the C-terminal tail of the receptor and its engagement by the clathrin-dependent endocytic machinery. We previously showed that dephosphorylation of Rod1 by calcineurin (phosphoprotein phosphatase 2B) is required for optimal Rod1 function in Ste2 down-regulation. We show here that negative regulation of Rod1 by phosphorylation is mediated by two distinct stress-activated protein kinases, Snf1/AMPK and Ypk1/SGK1, and demonstrate both in vitro and in vivo that this phospho-regulation impedes the ability of Rod1 to promote mating pathway desensitization. These studies also revealed that, in the absence of its phosphorylation, Rod1 can promote adaptation independently of Rsp5-mediated receptor ubiquitinylation, consistent with recent evidence that α-arrestins can contribute to cargo recognition by both clathrin-dependent and clathrin-independent mechanisms. However, in cells lacking a component (formin Bni1) required for clathrin-independent entry, Rod1 derivatives that are largely unphosphorylated and unable to associate with Rsp5 still promote efficient adaptation, indicating a third mechanism by which this α-arrestin promotes desensitization of the pheromone-response pathway. PMID:26920760

  11. Differential Phosphorylation Provides a Switch to Control How α-Arrestin Rod1 Down-regulates Mating Pheromone Response in Saccharomyces cerevisiae.

    PubMed

    Alvaro, Christopher G; Aindow, Ann; Thorner, Jeremy

    2016-05-01

    G-protein-coupled receptors (GPCRs) are integral membrane proteins that initiate stimulus-dependent activation of cognate heterotrimeric G-proteins, triggering ensuing downstream cellular responses. Tight regulation of GPCR-evoked pathways is required because prolonged stimulation can be detrimental to an organism. Ste2, a GPCR in Saccharomyces cerevisiae that mediates response of MATa haploids to the peptide mating pheromone α-factor, is down-regulated by both constitutive and agonist-induced endocytosis. Efficient agonist-stimulated internalization of Ste2 requires its association with an adaptor protein, the α-arrestin Rod1/Art4, which recruits the HECT-domain ubiquitin ligase Rsp5, allowing for ubiquitinylation of the C-terminal tail of the receptor and its engagement by the clathrin-dependent endocytic machinery. We previously showed that dephosphorylation of Rod1 by calcineurin (phosphoprotein phosphatase 2B) is required for optimal Rod1 function in Ste2 down-regulation. We show here that negative regulation of Rod1 by phosphorylation is mediated by two distinct stress-activated protein kinases, Snf1/AMPK and Ypk1/SGK1, and demonstrate both in vitro and in vivo that this phospho-regulation impedes the ability of Rod1 to promote mating pathway desensitization. These studies also revealed that, in the absence of its phosphorylation, Rod1 can promote adaptation independently of Rsp5-mediated receptor ubiquitinylation, consistent with recent evidence that α-arrestins can contribute to cargo recognition by both clathrin-dependent and clathrin-independent mechanisms. However, in cells lacking a component (formin Bni1) required for clathrin-independent entry, Rod1 derivatives that are largely unphosphorylated and unable to associate with Rsp5 still promote efficient adaptation, indicating a third mechanism by which this α-arrestin promotes desensitization of the pheromone-response pathway.

  12. Nodulation Gene Regulation and Quorum Sensing Control Density-Dependent Suppression and Restriction of Nodulation in the Bradyrhizobium japonicum-Soybean Symbiosis▿

    PubMed Central

    Jitacksorn, Siriluck; Sadowsky, Michael J.

    2008-01-01

    The nodulation of Glycine max cv. Lambert and the nodulation-restricting plant introduction (PI) genotype PI 417566 by wild-type Bradyrhizobium japonicum USDA110 is regulated in a population-density-dependent manner. Nodulation on both plant genotypes was suppressed (inhibited) when plants received a high-density inoculum (109 cells/ml) of strain USDA110 grown in complex medium, and more nodules were produced on plants receiving a low-cell-density inoculum (105 cells/ml). Since cell-free supernatants from strain USDA110 grown to high cell density in complex medium decreased the expression of an nodY-lacZ fusion, this phenomenon was attributed to bradyoxetin-induced repression of nod gene expression. Inoculation of either the permissive soybean genotype (cv. Lambert) or PI 417566 with 109 cells/ml of the nodD2, nolA, nodW, and nwsB mutants of USDA110 enhanced nodulation (up to 24%) relative to that seen with inoculations done with 105 cells/ml of the mutants or the wild-type strain, indicating that these genes are involved in population-density-dependent nodulation of soybeans. In contrast, the number of nodules produced by an nodD1 mutant on either soybean genotype was less than those seen with the wild-type strain inoculated at a low inoculum density. The nodD2 mutant outcompeted B. japonicum strain USDA123 for nodulation of G. max cv. Lambert at a high or low inoculum density, and the results of root-tip-marking and time-to-nodulate studies indicated that the nolA and nodD2 mutants nodulated this soybean genotype faster than wild-type USDA110. Taken together, the results from these studies indicate that the nodD2 mutant of B. japonicum may be useful to enhance soybean nodulation at high inoculum densities and that NodD2 is a key repressor influencing host-controlled restriction of nodulation, density-dependent suppression of nodulation, perception of bradyoxetin, and competitiveness in the soybean-B. japonicum symbiosis. PMID:18441104

  13. Optical Plasmonic Switch based on Graphene

    NASA Astrophysics Data System (ADS)

    Moon, Kyungsun; Park, Suk-Young

    2015-03-01

    We have studied an electro-optical plasmonic waveguide, which controls the transmission of incident light by switching the coupling of the surface plasmon polariton (SPP) localized on graphene. It has been previously shown that the propagation length of the SPP localized on the copper surface can be effectively reduced by a factor of two or three by applying external bias potential. In our study, we have demonstrated that the propagation length of the SPP localized on graphene can be dramatically reduced by a factor of ten or so and the wavelength of SPP can be reduced by several hundredths of that of the incident light as well. We have also investigated the effect of scattering times of graphene and active Si layer on switching line shape. Switching occurs upon varying the carrier density of Si layer by ?n/nc ~1% in the vicinity of switching region. For a fixed bias voltage applied just below the critical value, signal laser beam shone into the metal nano-particles may increase the carrier density as such, which will induce switching. This may help develop an all-optical nano-scale plasmonic switch. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2012R1A1A2006927).

  14. Multi-line triggering and interdigitated electrode structure for photoconductive semiconductor switches

    DOEpatents

    Mar, Alan; Zutavern, Fred J.; Loubriel, Guillermo

    2007-02-06

    An improved photoconductive semiconductor switch comprises multiple-line optical triggering of multiple, high-current parallel filaments between the switch electrodes. The switch can also have a multi-gap, interdigitated electrode for the generation of additional parallel filaments. Multi-line triggering can increase the switch lifetime at high currents by increasing the number of current filaments and reducing the current density at the contact electrodes in a controlled manner. Furthermore, the improved switch can mitigate the degradation of switching conditions with increased number of firings of the switch.

  15. Resistance switching memory in perovskite oxides

    SciTech Connect

    Yan, Z.B. Liu, J.-M.

    2015-07-15

    The resistance switching behavior has recently attracted great attentions for its application as resistive random access memories (RRAMs) due to a variety of advantages such as simple structure, high-density, high-speed and low-power. As a leading storage media, the transition metal perovskite oxide owns the strong correlation of electrons and the stable crystal structure, which brings out multifunctionality such as ferroelectric, multiferroic, superconductor, and colossal magnetoresistance/electroresistance effect, etc. The existence of rich electronic phases, metal–insulator transition and the nonstoichiometric oxygen in perovskite oxide provides good platforms to insight into the resistive switching mechanisms. In this review, we first introduce the general characteristics of the resistance switching effects, the operation methods and the storage media. Then, the experimental evidences of conductive filaments, the transport and switching mechanisms, and the memory performances and enhancing methods of perovskite oxide based filamentary RRAM cells have been summarized and discussed. Subsequently, the switching mechanisms and the performances of the uniform RRAM cells associating with the carrier trapping/detrapping and the ferroelectric polarization switching have been discussed. Finally, the advices and outlook for further investigating the resistance switching and enhancing the memory performances are given.

  16. Optoelectronic techniques for broadband switching

    NASA Astrophysics Data System (ADS)

    Su, S. F.; Jou, L.; Lenart, J.

    1988-01-01

    Optoelectronic switching employs a hybrid optical/electronic principle to perform the switching function and is applicable for either analog broadband or high-bit rate digital switching. The major advantages of optoelectronic switching include high isolation, low crosstalk, small physical size, light weight, and low power consumption. These advantages make optoelectronic switching an excellent candidate for on-board satellite switching. This paper describes a number of optoelectronic switching architectures. System components required for implementing these switching architectures are discussed. Performance of these architectures are evaluated by calculating their crosstalk, isolation, insertion loss, matrix size, drive power, throughput, and switching speed. Technologies needed for monolithic optoelectronic switching are also identified.

  17. Vorinostat positively regulates synaptic plasticity genes expression and spine density in HIV infected neurons: role of nicotine in progression of HIV-associated neurocognitive disorder

    PubMed Central

    2014-01-01

    Background HIV-associated neurocognitive disorder (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occurs in approximately 50% of HIV infected individuals. In the United States, the prevalence of cigarette smoking ranges from 35-70% in HIV-infected individuals compared to 20% in general population. Cognitive impairment in heavy cigarette smokers has been well reported. However, the synergistic effects of nicotine and HIV infection and the underlying mechanisms in the development of HAND are unknown. Results In this study, we explored the role of nicotine in the progression of HAND using SK-N-MC, a neuronal cell line. SK-N-MC cells were infected with HIV-1 in the presence or absence of nicotine for 7 days. We observed significant increase in HIV infectivity in SK-N-MC treated with nicotine compared to untreated HIV-infected neuronal cells. HIV and nicotine synergize to significantly dysregulate the expression of synaptic plasticity genes and spine density; with a concomitant increase of HDAC2 levels in SK-N-MC cells. In addition, inhibition of HDAC2 up-regulation with the use of vorinostat resulted in HIV latency breakdown and recovery of synaptic plasticity genes expression and spine density in nicotine/HIV alone and in co-treated SK-N-MC cells. Furthermore, increased eIF2 alpha phosphorylation, which negatively regulates eukaryotic translational process, was observed in HIV alone and in co-treatment with nicotine compared to untreated control and nicotine alone treated SK-N-MC cells. Conclusions These results suggest that nicotine and HIV synergize to negatively regulate the synaptic plasticity gene expression and spine density and this may contribute to the increased risk of HAND in HIV infected smokers. Apart from disrupting latency, vorinostat may be a useful therapeutic to inhibit the negative regulatory effects on synaptic plasticity in HIV infected nicotine abusers. PMID:24886748

  18. Downregulation of postsynaptic density-95-interacting regulator of spine morphogenesis reduces glutamate-induced excitotoxicity by differentially regulating glutamate receptors in rat cortical neurons.

    PubMed

    Luo, Peng; Yang, Yuefan; Liu, Wei; Rao, Wei; Bian, Huan; Li, Xin; Chen, Tao; Liu, Mengdong; Zhao, Yongbo; Dai, Shuhui; Yan, Xu; Fei, Zhou

    2013-12-01

    Glutamate-induced excitotoxicity is involved in many neurological diseases. Preso, a novel postsynaptic scaffold protein, mediates excitatory synaptic transmission and various synaptic functions. In this study, we investigated the role of Preso in the regulation of glutamate-induced excitotoxicity in rat cortical neurons. Knockdown of Preso with small interfering RNA improved neuronal viability and attenuated the elevation of lactate dehydrogenase (LDH) release after glutamate treatment. Downregulation of Preso also inhibited an increase in the BAX/Bcl-2 ratio and cleavage of caspase-9 and caspase-3. Although the expression and distribution of metabotropic glutamate receptor (mGluR) 1/5, NR1, NR2A and NR2B were not changed by knockdown of Preso, downregulation of Preso protected neurons from glutamate-induced excitotoxicity by inhibiting mGluR and N-methyl-D-aspartate receptor function. However, downregulation of Preso neither affected the expression of GluR1 and GluR2 nor influenced the function of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor after glutamate treatment. Furthermore, intracellular Ca(2+) was an important downstream effector of Preso in the regulation of excitotoxicity. These results suggest that expression of Preso promotes the induction of excitotoxicity by facilitating different glutamate receptor signaling pathways. Therefore, Preso might be a potential pharmacological target for preventing and treating neurological diseases.

  19. A novel intra-U1 snRNP cross-regulation mechanism: alternative splicing switch links U1C and U1-70K expression.

    PubMed

    Rösel-Hillgärtner, Tanja Dorothe; Hung, Lee-Hsueh; Khrameeva, Ekaterina; Le Querrec, Patrick; Gelfand, Mikhail S; Bindereif, Albrecht

    2013-01-01

    The U1 small nuclear ribonucleoprotein (snRNP)-specific U1C protein participates in 5' splice site recognition and regulation of pre-mRNA splicing. Based on an RNA-Seq analysis in HeLa cells after U1C knockdown, we found a conserved, intra-U1 snRNP cross-regulation that links U1C and U1-70K expression through alternative splicing and U1 snRNP assembly. To investigate the underlying regulatory mechanism, we combined mutational minigene analysis, in vivo splice-site blocking by antisense morpholinos, and in vitro binding experiments. Alternative splicing of U1-70K pre-mRNA creates the normal (exons 7-8) and a non-productive mRNA isoform, whose balance is determined by U1C protein levels. The non-productive isoform is generated through a U1C-dependent alternative 3' splice site, which requires an adjacent cluster of regulatory 5' splice sites and binding of intact U1 snRNPs. As a result of nonsense-mediated decay (NMD) of the non-productive isoform, U1-70K mRNA and protein levels are down-regulated, and U1C incorporation into the U1 snRNP is impaired. U1-70K/U1C-deficient particles are assembled, shifting the alternative splicing balance back towards productive U1-70K splicing, and restoring assembly of intact U1 snRNPs. Taken together, we established a novel feedback regulation that controls U1-70K/U1C homeostasis and ensures correct U1 snRNP assembly and function.

  20. PdEPF1 regulates water-use efficiency and drought tolerance by modulating stomatal density in poplar.

    PubMed

    Wang, Congpeng; Liu, Sha; Dong, Yan; Zhao, Ying; Geng, Anke; Xia, Xinli; Yin, Weilun

    2016-03-01

    Water deficiency is a critical environmental condition that is seriously reducing global plant production. Improved water-use efficiency (WUE) and drought tolerance are effective strategies to address this problem. In this study, PdEPF1, a member of the EPIDERMAL PATTERNING FACTOR (EPF) family, was isolated from the fast-growing poplar clone NE-19 [Populus nigra × (Populus deltoides × Populus nigra)]. Significantly, higher PdEPF1 levels were detected after induction by dehydration and abscisic acid. To explore the biological functions of PdEPF1, transgenic triploid white poplars (Populus tomentosa 'YiXianCiZhu B385') overexpressing PdEPF1 were constructed. PdEPF1 overexpression resulted in increased water deficit tolerance and greater WUE. We confirmed that the transgenic lines with greater instantaneous WUE had approximately 30% lower transpiration but equivalent CO2 assimilation. Lower transpiration was associated with a 28% reduction in abaxial stomatal density. PdEPF1 overexpression not only strongly enhanced WUE, but also greatly improved drought tolerance, as measured by the leaf relative water content and water potential, under limited water conditions. In addition, the growth of these oxPdEPF1 plants was less adversely affected by reduced water availability than plants with a higher stomatal density, indicating that plants with a low stomatal density may be well suited to grow in water-scarce environments. Taken together, our data suggest that PdEPF1 improves WUE and confers drought tolerance in poplar; thus, it could be used to breed drought-tolerant plants with increased production under conditions of water deficiency.

  1. Switching antibiotics production on and off in actinomycetes by an IclR family transcriptional regulator from Streptomyces peucetius ATCC 27952.

    PubMed

    Chaudhary, Amit Kumar; Singh, Bijay; Maharjan, Sushila; Jha, Amit Kumar; Kim, Byung-Gee; Sohng, Jae Kyung

    2014-08-01

    Doxorubicin, produced by Streptomyces peucetius ATCC 27952, is tightly regulated by dnrO, dnrN, and dnrI regulators. Genome mining of S. peucetius revealed the presence of the IclR (doxR) type family of transcription regulator mediating the signal-dependent expression of operons at the nonribosomal peptide synthetase gene cluster. Overexpression of doxR in native strain strongly repressed the drug production. Furthermore, it also had a negative effect on the regulatory system of doxorubicin, wherein the transcript of dnrI was reduced to the maximum level in comparision with the other two. Interestingly, the overexpression of the same gene also had strong inhibitory effects on the production of actinorhodin (blue pigment) and undecylprodigiosin (red pigment) in Streptomyces coelicolor M145, herboxidiene production in Streptomyces chromofuscus ATCC 49982, and spinosyn production in Saccharopolyspora spinosa NRRL 18395, respectively. Moreover, DoxR exhibited pleiotropic effects on the production of blue and red pigments in S. coelicolor when grown in different agar media, wherein the production of blue pigment was inhibited in R2YE medium and the red pigment was inhibited in YEME medium. However, the production of both blue and red pigments from S. coelicolor harboring doxR was halted in ISP2 medium, whereas S. coelicolor produced both pigmented antibiotics in the same plate. These consequences demonstrate that the on and off production of these antibiotics was not due to salt stress or media compositions, but was selectively controlled in actinomycetes.

  2. Optimal sterile insect release for area-wide integrated pest management in a density regulated pest population.

    PubMed

    Gordillo, Luis F

    2014-06-01

    To determine optimal sterile insect release policies in area-wide integrated pest management is a challenge that users of this pest control method inevitably confront. In this note we provide approximations to best policies of release through the use of simulated annealing. The discrete time model for the population dynamics includes the effects of sterile insect release and density dependence in the pest population. Spatial movement is introduced through integrodifference equations, which allow the use of the stochastic search in cases where movement is described through arbitrary dispersal kernels. As a byproduct of the computations, an assessment of appropriate control zone sizes is possible.

  3. Mitogen-Activated Protein Kinase Phosphatase-1 Is a Key Regulator of Hypoxia-Induced Vascular Endothelial Growth Factor Expression and Vessel Density in Lung

    PubMed Central

    Shields, Kristin M.; Panzhinskiy, Evgeniy; Burns, Nana; Zawada, W. Michael; Das, Mita

    2011-01-01

    Although mitogen-activated protein kinase phosphatase-1 (MKP-1) is a key deactivator of MAP kinases, known effectors of lung vessel formation, whether it plays a role in the expression of proangiogenic vascular endothelial growth factor (VEGF) in hypoxic lung is unknown. We therefore hypothesized that MKP-1 is a crucial modulator of hypoxia-stimulated vessel development by regulating lung VEGF levels. Wild-type MKP-1+/+, heterozygous MKP-1+/−, and deficient MKP-1−/− mice were exposed to sea level (SL), Denver altitude (DA) (1609 m [5280 feet]), and severe high altitude (HYP) (∼5182 m [∼17,000 feet]) for 6 weeks. Hypoxia enhanced phosphorylation of p38 MAP kinase, a substrate of MKP-1, as well as α smooth muscle actin (αSMA) expression in vessels, respiratory epithelium, and interstitium of phosphatase-deficient lung. αSMA-positive vessel (<50 μm outside diameter) densities were markedly reduced, whereas vessel wall thickness was increased in hypoxic MKP-1−/− lung. Mouse embryonic fibroblasts (MEFs) of all three genotypes were isolated to pinpoint the mechanism involved in hypoxia-induced vascular abnormalities of MKP-1−/− lung. Sustained phosphorylation of p38 MAP kinase was observed in MKP-1-null MEFs in response to hypoxia exposure. Although hypoxia up-regulated VEGF levels in MKP-1+/+ MEFs eightfold, only a 70% increase in VEGF expression was observed in MKP-1-deficient cells. Therefore, our data strongly suggest that MKP-1 might be the key regulator of vascular densities through the regulation of VEGF levels in hypoxic lung. PMID:21224048

  4. Effective switching frequency multiplier inverter

    DOEpatents

    Su, Gui-Jia; Peng, Fang Z.

    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.

  5. Thermally actuated thermionic switch

    DOEpatents

    Barrus, Donald M.; Shires, Charles D.

    1988-01-01

    A thermally actuated thermionic switch which responds to an increase of temperature by changing from a high impedance to a low impedance at a predictable temperature set point. The switch has a bistable operation mode switching only on temperature increases. The thermionic material may be a metal which is liquid at the desired operation temperature and held in matrix in a graphite block reservoir, and which changes state (ionizes, for example) so as to be electrically conductive at a desired temperature.

  6. Thermally actuated thermionic switch

    DOEpatents

    Barrus, D.M.; Shires, C.D.

    1982-09-30

    A thermally actuated thermionic switch which responds to an increase of temperature by changing from a high impedance to a low impedance at a predictable temperature set point. The switch has a bistable operation mode switching only on temperature increases. The thermionic material may be a metal which is liquid at the desired operation temperature and held in matrix in a graphite block reservoir, and which changes state (ionizes, for example) so as to be electrically conductive at a desired temperature.

  7. AC magnetohydrodynamic microfluidic switch

    SciTech Connect

    Lemoff, A V; Lee, A P

    2000-03-02

    A microfluidic switch has been demonstrated using an AC Magnetohydrodynamic (MHD) pumping mechanism in which the Lorentz force is used to pump an electrolytic solution. By integrating two AC MHD pumps into different arms of a Y-shaped fluidic circuit, flow can be switched between the two arms. This type of switch can be used to produce complex fluidic routing, which may have multiple applications in {micro}TAS.

  8. Avalanche Photoconductive Switching

    DTIC Science & Technology

    1989-06-01

    held off across the switch. In our case this corresponds to 70 kV/cm and is limited by surface flashover . The pulse length is determined by the...off across the gap of the switch, which in turn appears to be limited by surface flashover . There appears to be a threshold electric field of 20-60...and understand this mode of operation. Introduction Laser activated photoconductive switching in semiconductors is a promising technology for high

  9. High Power Switch Development.

    DTIC Science & Technology

    1979-11-29

    fundamental properties of electron beam triggered LJ switches and determine their capabilities and limitations. 2. Investigate breakdown phenomena at high...discharge is goal have been achieved by laser triggered broad in cross-section. switching 1 (ITS), and by e-beam triggered Voltage, current, and jitter...and J. R. Settis; "The Laser Triggering of High Voltage Switches ". J. , .’-- o, .. Phys. D.: Appl. Phys., Vol. 11, 1577,(1978). c..-- , 2. E. A

  10. Solid state switch

    DOEpatents

    Merritt, Bernard T.; Dreifuerst, Gary R.

    1994-01-01

    A solid state switch, with reverse conducting thyristors, is designed to operate at 20 kV hold-off voltage, 1500 A peak, 1.0 .mu.s pulsewidth, and 4500 pps, to replace thyratrons. The solid state switch is more reliable, more economical, and more easily repaired. The switch includes a stack of circuit card assemblies, a magnetic assist and a trigger chassis. Each circuit card assembly contains a reverse conducting thyristor, a resistor capacitor network, and triggering circuitry.

  11. Intrinsic noise in systems with switching environments

    NASA Astrophysics Data System (ADS)

    Hufton, Peter G.; Lin, Yen Ting; Galla, Tobias; McKane, Alan J.

    2016-05-01

    We study individual-based dynamics in finite populations, subject to randomly switching environmental conditions. These are inspired by models in which genes transition between on and off states, regulating underlying protein dynamics. Similarly, switches between environmental states are relevant in bacterial populations and in models of epidemic spread. Existing piecewise-deterministic Markov process approaches focus on the deterministic limit of the population dynamics while retaining the randomness of the switching. Here we go beyond this approximation and explicitly include effects of intrinsic stochasticity at the level of the linear-noise approximation. Specifically, we derive the stationary distributions of a number of model systems, in good agreement with simulations. This improves existing approaches which are limited to the regimes of fast and slow switching.

  12. Reusable fast opening switch

    DOEpatents

    Van Devender, J.P.; Emin, D.

    1983-12-21

    A reusable fast opening switch for transferring energy, in the form of a high power pulse, from an electromagnetic storage device such as an inductor into a load. The switch is efficient, compact, fast and reusable. The switch comprises a ferromagnetic semiconductor which undergoes a fast transition between conductive and metallic states at a critical temperature and which undergoes the transition without a phase change in its crystal structure. A semiconductor such as europium rich europhous oxide, which undergoes a conductor to insulator transition when it is joule heated from its conductor state, can be used to form the switch.

  13. Reusable fast opening switch

    DOEpatents

    Van Devender, John P.; Emin, David

    1986-01-01

    A reusable fast opening switch for transferring energy, in the form of a high power pulse, from an electromagnetic storage device such as an inductor into a load. The switch is efficient, compact, fast and reusable. The switch comprises a ferromagnetic semiconductor which undergoes a fast transition between conductive and insulating states at a critical temperature and which undergoes the transition without a phase change in its crystal structure. A semiconductor such as europium rich europhous oxide, which undergoes a conductor to insulator transition when it is joule heated from its conductor state, can be used to form the switch.

  14. Alarm toe switch

    DOEpatents

    Ganyard, Floyd P.

    1982-01-01

    An alarm toe switch inserted within a shoe for energizing an alarm circuit n a covert manner includes an insole mounting pad into which a miniature reed switch is fixedly molded. An elongated slot perpendicular to the reed switch is formed in the bottom surface of the mounting pad. A permanent cylindrical magnet positioned in the forward portion of the slot with a diameter greater than the pad thickness causes a bump above the pad. A foam rubber block is also positioned in the slot rearwardly of the magnet and holds the magnet in normal inoperative relation. A non-magnetic support plate covers the slot and holds the magnet and foam rubber in the slot. The plate minimizes bending and frictional forces to improve movement of the magnet for reliable switch activation. The bump occupies the knuckle space beneath the big toe. When the big toe is scrunched rearwardly the magnet is moved within the slot relative to the reed switch, thus magnetically activating the switch. When toe pressure is released the foam rubber block forces the magnet back into normal inoperative position to deactivate the reed switch. The reed switch is hermetically sealed with the magnet acting through the wall so the switch assembly S is capable of reliable operation even in wet and corrosive environments.

  15. Platform switching and bone platform switching.

    PubMed

    Carinci, Francesco; Brunelli, Giorgio; Danza, Matteo

    2009-01-01

    Bone platform switching involves an inward bone ring in the coronal part of the implant that is in continuity with the alveolar bone crest. Bone platform switching is obtained by using a dental fixture with a reverse conical neck. A retrospective study was performed to evaluate the effectiveness of conventional vs reverse conical neck implants. In the period between May 2004 and November 2007, 86 patients (55 females and 31 males; median age, 53 years) were operated and 234 implants were inserted: 40 and 194 were conventional vs reverse conical neck implants, respectively. Kaplan-Meier algorithm and Cox regression were used to detect those variables associated with the clinical outcome. No differences in survival and success rates were detected between conventional vs reverse conical neck implants alone or in combination with any of the studied variables. Although bone platform switching leads to several advantages, no statistical difference in alveolar crest resorption is detected in comparison with reverse conical neck implants. We suppose that the proximity of the implant abutment junction to the alveolar crestal bone gives no protection against the microflora contained in the micrograph. Additional studies on larger series and a combination of platform switching and bone platform switching could lead to improved clinical outcomes.

  16. Therapeutic approaches to the regulation of metabolism of high-density lipoprotein. Novel HDL-directed pharmacological intervention and exercise.

    PubMed

    Zhang, Bo; Kawachi, Emi; Miura, Shin-Ichiro; Uehara, Yoshinari; Matsunaga, Akira; Kuroki, Masahide; Saku, Keijiro

    2013-01-01

    High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles transport cholesterol in plasma and play an important role in cellular cholesterol homeostasis, which influences cell function. The risk of coronary artery disease (CAD) associated with high levels of LDL-cholesterol (LDL-C) can be reduced by treatment with statins, which reduce LDL-C levels by inhibiting cellular cholesterol synthesis. However, patients who are treated with high doses of statins, especially secondary CAD prevention, regardless of their resulting LDL-C levels, are still at high risk of CAD. Therefore, there has been growing interest in HDL-directed therapies. Inhibitors of cholesteryl ester transfer protein (CETP) substantially increase HDL-C levels (by 31-138%). However, it is still unclear whether or not CETP inhibitors can reduce the risk of CAD associated with low HDL-C levels, while reconstituted HDL or apolipoprotein A-I mimetic peptides increase the functionality of HDL. Low levels of HDL-C are often complicated with metabolic disorders, including hypertriglyceridemia, metabolic syndrome, and type 2 diabetes mellitus, and lifestyle changes are effective for correcting these conditions. Physical activity and exercise training increase HDL-C levels, especially HDL2-C levels, by multiple mechanisms. Therefore, although using HDL-directed therapies that increase HDL-C levels and/or improve the function of HDL is a reasonable approach for reducing the residual risk of CAD as a complement to LDL-C-lowering therapy, lifestyle modifications including exercise to improve metabolic disorders should be considered as the first option.

  17. Multiple classes of transcription factors regulate the expression of VASCULAR-RELATED NAC-DOMAIN7, a master switch of xylem vessel differentiation.

    PubMed

    Endo, Hitoshi; Yamaguchi, Masatoshi; Tamura, Taizo; Nakano, Yoshimi; Nishikubo, Nobuyuki; Yoneda, Arata; Kato, Ko; Kubo, Minoru; Kajita, Shinya; Katayama, Yoshihiro; Ohtani, Misato; Demura, Taku

    2015-02-01

    The secondary cell walls of xylem cells, including vessel elements, provide mechanical strength and contribute to the conduction of water and minerals. VASCULAR-RELATED NAC-DOMAIN7 (VND7) is a NAC-domain transcription factor that regulates the expression of genes required for xylem vessel element formation. Transient expression assays using 68 transcription factors that are expressed during xylem vessel differentiation showed that 14 transcription factors, including VND1-VND7, are putative positive regulators of VND7 expression. Electrophoretic mobility shift assays revealed that all seven VND proteins bound to the VND7 promoter region at its SMBE/TERE motif, indicating that VND7 is a direct target of all of the VND transcription factors. Overexpression of VND1-VND5, GATA12 and ANAC075, newly identified transcription factors that function upstream of VND7, resulted in ectopic xylem vessel element formation. These data suggest that VND7 transcription is a regulatory target of multiple classes of transcription factors.

  18. Activation of Yes-Associated Protein in Low-Grade Meningiomas Is Regulated by Merlin, Cell Density, and Extracellular Matrix Stiffness.

    PubMed

    Tanahashi, Kuniaki; Natsume, Atsushi; Ohka, Fumiharu; Motomura, Kazuya; Alim, Adiljan; Tanaka, Ichidai; Senga, Takeshi; Harada, Ichiro; Fukuyama, Ryuichi; Sumiyoshi, Naoyuki; Sekido, Yoshitaka; Wakabayashi, Toshihiko

    2015-07-01

    The NF2 gene product Merlin is a protein containing ezrin, radixin, and moesin domains; it is a member of the 4.1 protein superfamily associated with the membrane cytoskeleton and also interacts with cell surface molecules. The mammalian Hippo cascade, a downstream signaling cascade of merlin, inactivates the Yes-associated protein (YAP). Yes-associated protein is activated by loss of the NF2 gene and functions as an oncogene in meningioma cells; however, the factors controlling YAP expression, phosphorylation, and subcellular localization in meningiomas have not been fully elucidated. Here, we demonstrate that merlin expression is heterogeneous in 1 NF2 gene-negative and 3 NF2 gene-positive World Health Organization grade I meningiomas. In the NF2 gene-positive meningiomas, regions with low levels of merlin (tumor rims) had greater numbers of cells with nuclear YAP versus regions with high merlin levels (tumor cores). Merlin expression and YAP phosphorylation were also affected by cell density in the IOMM-Lee and HKBMM human meningioma cell lines; nuclear localization of YAP was regulated by cell density and extracellular matrix (ECM) stiffness in IOMM-Lee cells. These results suggest that cell density and ECM stiffness may contribute to the heterogeneous loss of merlin and increased nuclear YAP expression in human meningiomas.

  19. Light-induced systemic regulation of photosynthesis in primary and trifoliate leaves of Phaseolus vulgaris: effects of photosynthetic photon flux density (PPFD) versus spectrum.

    PubMed

    Murakami, K; Matsuda, R; Fujiwara, K

    2014-01-01

    The objectives of this work using Phaseolus vulgaris were to examine whether the light spectrum incident on mature primary leaves (PLs) is related to leaf-to-leaf systemic regulation of developing trifoliate leaves (TLs) in photosynthetic characteristics, and to investigate the relative importance of spectrum and photosynthetic photon flux density (PPFD) in light-induced systemic regulation. Systemic regulation was induced by altering PPFD and the spectrum of light incident on PLs using a shading treatment and lighting treatments including either white, blue, green or red light-emitting diodes (LEDs). Photosynthetic characteristics were evaluated by measuring the light-limited and light-saturated net photosynthetic rates and the amounts of nitrogen (N), chlorophyll (Chl) and ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco; EC 4.1.1.39). Shading treatment on PLs decreased the amounts of N, Chl and Rubisco of TLs and tended to decrease the photosynthetic rates. However, we observed no systemic effects induced by the light spectrum on PLs in this study, except that a higher amount of Rubisco of TLs was observed when the PLs were irradiated with blue LEDs. Our results imply that photoreceptors in mature leaves have little influence on photosynthetic rates and amounts of N and Chl of developing leaves through systemic regulation, although the possibility of the action of blue light irradiation on the amount of Rubisco cannot be ruled out. Based on these results, we concluded that the light spectrum incident on mature leaves has little systemic effect on developing leaves in terms of photosynthetic characteristics and that the light-induced systemic regulation was largely accounted for by PPFD.

  20. Asymmetrical Switch Costs in Children

    ERIC Educational Resources Information Center

    Ellefson, Michelle R.; Shapiron, Laura R.; Chater, Nick

    2006-01-01

    Switching between tasks produces decreases in performance as compared to repeating the same task. Asymmetrical switch costs occur when switching between two tasks of unequal difficulty. This asymmetry occurs because the cost is greater when switching to the less difficult task than when switching to the more difficult task. Various theories about…

  1. BMI1 Polycomb Group Protein Acts as a Master Switch for Growth and Death of Tumor Cells: Regulates TCF4-Transcriptional Factor-Induced BCL2 Signaling

    PubMed Central

    Siddique, Hifzur Rahman; Parray, Aijaz; Tarapore, Rohinton S.; Wang, Lei; Mukhtar, Hasan; Karnes, R. Jeffery; Deng, Yibin; Konety, Badrinath R.; Saleem, Mohammad

    2013-01-01

    For advanced prostate cancer (CaP), the progression of tumors to the state of chemoresistance and paucity of knowledge about the mechanism of chemoresistance are major stumbling blocks in the management of this disease. Here, we provide compelling evidence that BMI1 polycomb group protein and a stem cell factor plays a crucial role in determining the fate of tumors vis-à-vis chemotherapy. We show that progressive increase in the levels of BMI1 occurs during the progression of CaP disease in humans. We show that BMI1-rich tumor cells are non-responsive to chemotherapy whereas BMI1-silenced tumor cells are responsive to therapy. By employing microarray, ChIP, immunoblot and Luciferase reporter assays, we identified a unique mechanism through which BMI1 rescues tumor cells from chemotherapy. We found that BMI1 regulates (i) activity of TCF4 transcriptional factor and (ii) binding of TCF4 to the promoter region of anti-apoptotic BCL2 gene. Notably, an increased TCF4 occupancy on BCL2 gene was observed in prostatic tissues exhibiting high BMI1 levels. Using tumor cells other than CaP, we also showed that regulation of TCF4-mediated BCL2 by BMI1 is universal. It is noteworthy that forced expression of BMI1 was observed to drive normal cells to hyperproliferative mode. We show that targeting BMI1 improves the outcome of docetaxel therapy in animal models bearing chemoresistant prostatic tumors. We suggest that BMI1 could be exploited as a potential molecular target for therapeutics to treat chemoresistant tumors. PMID:23671559

  2. BMI1 polycomb group protein acts as a master switch for growth and death of tumor cells: regulates TCF4-transcriptional factor-induced BCL2 signaling.

    PubMed

    Siddique, Hifzur Rahman; Parray, Aijaz; Tarapore, Rohinton S; Wang, Lei; Mukhtar, Hasan; Karnes, R Jeffery; Deng, Yibin; Konety, Badrinath R; Saleem, Mohammad

    2013-01-01

    For advanced prostate cancer (CaP), the progression of tumors to the state of chemoresistance and paucity of knowledge about the mechanism of chemoresistance are major stumbling blocks in the management of this disease. Here, we provide compelling evidence that BMI1 polycomb group protein and a stem cell factor plays a crucial role in determining the fate of tumors vis-à-vis chemotherapy. We show that progressive increase in the levels of BMI1 occurs during the progression of CaP disease in humans. We show that BMI1-rich tumor cells are non-responsive to chemotherapy whereas BMI1-silenced tumor cells are responsive to therapy. By employing microarray, ChIP, immunoblot and Luciferase reporter assays, we identified a unique mechanism through which BMI1 rescues tumor cells from chemotherapy. We found that BMI1 regulates (i) activity of TCF4 transcriptional factor and (ii) binding of TCF4 to the promoter region of anti-apoptotic BCL2 gene. Notably, an increased TCF4 occupancy on BCL2 gene was observed in prostatic tissues exhibiting high BMI1 levels. Using tumor cells other than CaP, we also showed that regulation of TCF4-mediated BCL2 by BMI1 is universal. It is noteworthy that forced expression of BMI1 was observed to drive normal cells to hyperproliferative mode. We show that targeting BMI1 improves the outcome of docetaxel therapy in animal models bearing chemoresistant prostatic tumors. We suggest that BMI1 could be exploited as a potential molecular target for therapeutics to treat chemoresistant tumors.

  3. MicroRNA-9 promotes the switch from early-born to late-born motor neuron populations by regulating Onecut transcription factor expression.

    PubMed

    Luxenhofer, Georg; Helmbrecht, Michaela S; Langhoff, Jana; Giusti, Sebastian A; Refojo, Damian; Huber, Andrea B

    2014-02-15

    Motor neurons in the vertebrate spinal cord are stereotypically organized along the rostro-caudal axis in discrete columns that specifically innervate peripheral muscle domains. Originating from the same progenitor domain, the generation of spinal motor neurons is orchestrated by a spatially and temporally tightly regulated set of secreted molecules and transcription factors such as retinoic acid and the Lim homeodomain transcription factors Isl1 and Lhx1. However, the molecular interactions between these factors remained unclear. In this study we examined the role of the microRNA 9 (miR-9) in the specification of spinal motor neurons and identified Onecut1 (OC1) as one of its targets. miR-9 and OC1 are expressed in mutually exclusive patterns in the developing chick spinal cord, with high OC1 levels in early-born motor neurons and high miR-9 levels in late-born motor neurons. miR-9 efficiently represses OC1 expression in vitro and in vivo. Overexpression of miR-9 leads to an increase in late-born neurons, while miR-9 loss-of-function induces additional OC1(+) motor neurons that display a transcriptional profile typical of early-born neurons. These results demonstrate that regulation of OC1 by miR-9 is a crucial step in the specification of spinal motor neurons and support a model in which miR-9 expression in late-born LMCl neurons downregulates Isl1 expression through inhibition of OC1. In conclusion, our study contributes essential factors to the molecular network specifying spinal motor neurons and emphasizes the importance of microRNAs as key players in the generation of neuronal diversity.

  4. The ATP-binding cassette transporter-2 (ABCA2) regulates cholesterol homeostasis and low-density lipoprotein receptor metabolism in N2a neuroblastoma cells.

    PubMed

    Davis, Warren

    2011-12-01

    The ATP-binding cassette transporter-2 (ABCA2) has been identified as a possible regulator of lipid metabolism. ABCA2 is most highly expressed in the brain but its effects on cholesterol homeostasis in neuronal-type cells have not been characterized. It is important to study the role of ABCA2 in regulating cholesterol homeostasis in neuronal-type cells because ABCA2 has been identified as a possible genetic risk factor for Alzheimer's disease. In this study, the effects of ABCA2 expression on cholesterol homeostasis were examined in mouse N2a neuroblastoma cells. ABCA2 reduced total, free- and esterified cholesterol levels as well as membrane cholesterol but did not perturb cholesterol distribution in organelle or lipid raft compartments. ABCA2 did not modulate de novo cholesterol biosynthesis from acetate. Cholesterol trafficking to the plasma membrane was not affected by ABCA2 but efflux to the physiological acceptor ApoE3 and mobilization of plasma membrane cholesterol to the endoplasmic reticulum for esterification were reduced by ABCA2. ABCA2 reduced esterification of serum and low-density lipoprotein-derived cholesterol but not 25-hydroxycholesterol. ABCA2 decreased low-density lipoprotein receptor (LDLR) mRNA and protein levels and increased its turnover rate. The surface expression of LDLR as well as the uptake of fluroresecent DiI-LDL was also reduced by ABCA2. Reduction of endogenous ABCA2 expression by RNAi treatment of N2a cells and rat primary cortical neurons produced the opposite effects of over-expression of ABCA2, increasing LDLR protein levels. This report identifies ABCA2 as a key regulator of cholesterol homeostasis and LDLR metabolism in neuronal cells.

  5. Attention modulation regulates both motor and non-motor performance: a high-density EEG study in Parkinson's disease.

    PubMed

    Perfetti, B; Moisello, C; Lanzafame, S; Varanese, S; Landsness, E C; Onofrj, M; Di Rocco, A; Tononi, G; Ghilardi, M F

    2010-09-01

    We have previously shown that, in early stages of Parkinson's disease (PD), patients with higher reaction times are also more impaired in visual sequence learning, suggesting that movement preparation shares resources with the learning of visuospatial sequences. Here, we ascertained whether, in patients with PD, the pattern of the neural correlates of attentional processes of movement planning predict sequence learning and working memory abilities. High density Electroencephalography (EEG, 256 electrodes) was recorded in 19 patients with PD performing reaching movements in a choice reaction time paradigm. Patients were also tested with Digit Span and performed a visuomotor sequence learning task that has an important declarative learning component. We found that attenuation of alpha/beta oscillatory activity before the stimulus presentation in frontoparietal regions significantly correlated with reaction time in the choice reaction time task, similarly to what we had previously found in normal subjects. In addition, such activity significantly predicted the declarative indices of sequence learning and the scores in the Digit Span task. These findings suggest that some motor and non motor PD signs might have common neural bases, and thus, might have a similar response to the same behavioral therapy. In addition, these results might help in designing and testing the efficacy of novel rehabilitative approaches to improve specific aspects of motor performance in PD and other neurological disorders.

  6. Behavioral plasticity through the modulation of switch neurons.

    PubMed

    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.

  7. Ovonic type switching in tin selenide thin films

    NASA Technical Reports Server (NTRS)

    Baxter, C. R.; Mclennan, W. D.

    1975-01-01

    Amorphous tin selenide thin films which possess Ovonic type switching properties are fabricated using vacuum deposition techniques. The devices are fabricated in a planar configuration and consist of amorphous tin selenide deposited over silver contacts. Results obtained indicate that Ovonic type memory switching does occur in these films with the energy density required for switching from a high impedance to a low impedance state being dependent on the spacing between the electrodes of the device. There is also a strong implication that the switching is a function of the magnitude of the applied voltage pulse.

  8. Protein Kinase C-α–Mediated Regulation of Low-Density Lipoprotein Receptor–Related Protein and Urokinase Increases Astrocytoma Invasion

    PubMed Central

    Amos, Samson; Mut, Melike; diPierro, Charles G.; Carpenter, Joan E.; Xiao, Aizhen; Kohutek, Zachary A.; Redpath, Gerard T.; Zhao, Yunge; Wang, Jiahu; Shaffrey, Mark E.; Hussaini, Isa M.

    2008-01-01

    Aggressive and infiltrative invasion is one of the hallmarks of glioblastoma. Low-density lipoprotein receptor–related protein (LRP) is expressed by glioblastoma, but the role of this receptor in astrocytic tumor invasion remains poorly understood. We show that activation of protein kinase C-α (PKC-α) phosphorylated and down-regulated LRP expression. Pretreatment of tumor cells with PKC inhibitors, phosphoinositide 3-kinase (PI3K) inhibitor, PKC-α small interfering RNA (siRNA), and short hairpin RNA abrogated phorbol 12-myristate 13-acetate–induced down-regulation of LRP and inhibited astrocytic tumor invasion in vitro. In xenograft glioblastoma mouse model and in vitro transmembrane invasion assay, LRP-deficient cells, which secreted high levels of urokinase-type plasminogen activator (uPA), invaded extensively the surrounding normal brain tissue, whereas the LRP-overexpressing and uPA-deficient cells did not invade into the surrounding normal brain. siRNA, targeted against uPA in LRP-deficient clones, attenuated their invasive potential. Taken together, our results strongly suggest the involvement of PKC-α/PI3K signaling pathways in the regulation of LRP-mediated astrocytoma invasion. Thus, a strategy of combining small molecule inhibitors of PKC-α and PI3K could provide a new treatment paradigm for glioblastomas. PMID:17974965

  9. Quantum cryptography without switching.

    PubMed

    Weedbrook, Christian; Lance, Andrew M; Bowen, Warwick P; Symul, Thomas; Ralph, Timothy C; Lam, Ping Koy

    2004-10-22

    We propose a new coherent state quantum key distribution protocol that eliminates the need to randomly switch between measurement bases. This protocol provides significantly higher secret key rates with increased bandwidths than previous schemes that only make single quadrature measurements. It also offers the further advantage of simplicity compared to all previous protocols which, to date, have relied on switching.

  10. Manually operated coded switch

    DOEpatents

    Barnette, Jon H.

    1978-01-01

    The disclosure relates 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.

  11. Reflective HTS switch

    DOEpatents

    Martens, J.S.; Hietala, V.M.; Hohenwarter, G.K.G.

    1994-09-27

    A HTS (High Temperature Superconductor) switch includes a HTS conductor for providing a superconducting path for an electrical signal and an serpentine wire actuator for controllably heating a portion of the conductor sufficiently to cause that portion to have normal, and not superconducting, resistivity. Mass of the portion is reduced to decrease switching time. 6 figs.

  12. Reflective HTS switch

    SciTech Connect

    Martens, Jon S.; Hietala, Vincent M.; Hohenwarter, Gert K. G.

    1994-01-01

    A HTS switch includes a HTS conductor for providing a superconducting path for an electrical signal and an serpentine wire actuator for controllably heating a portion of the conductor sufficiently to cause that portion to have normal, and not superconducting, resistivity. Mass of the portion is reduced to decrease switching time.

  13. Erected mirror optical switch

    DOEpatents

    Allen, James J.

    2005-06-07

    A microelectromechanical (MEM) optical switching apparatus is disclosed that is based on an erectable mirror which is formed on a rotatable stage using surface micromachining. An electrostatic actuator is also formed on the substrate to rotate the stage and mirror with a high angular precision. The mirror can be erected manually after fabrication of the device and used to redirect an incident light beam at an arbitrary angel and to maintain this state in the absence of any applied electrical power. A 1.times.N optical switch can be formed using a single rotatable mirror. In some embodiments of the present invention, a plurality of rotatable mirrors can be configured so that the stages and mirrors rotate in unison when driven by a single micromotor thereby forming a 2.times.2 optical switch which can be used to switch a pair of incident light beams, or as a building block to form a higher-order optical switch.

  14. 49 CFR 236.732 - Controller, circuit; switch.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... § 236.732 Controller, circuit; switch. A device for opening and closing electric circuits, operated by a... 49 Transportation 4 2013-10-01 2013-10-01 false Controller, circuit; switch. 236.732 Section 236.732 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL...

  15. 49 CFR 236.732 - Controller, circuit; switch.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... § 236.732 Controller, circuit; switch. A device for opening and closing electric circuits, operated by a... 49 Transportation 4 2012-10-01 2012-10-01 false Controller, circuit; switch. 236.732 Section 236.732 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL...

  16. 49 CFR 236.732 - Controller, circuit; switch.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... § 236.732 Controller, circuit; switch. A device for opening and closing electric circuits, operated by a... 49 Transportation 4 2014-10-01 2014-10-01 false Controller, circuit; switch. 236.732 Section 236.732 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL...

  17. The ON:OFF switch, σ1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: Implications in neurological disorders

    PubMed Central

    Rodríguez-Muñoz, María; Cortés-Montero, Elsa; Pozo-Rodrigálvarez, Andrea; Sánchez-Blázquez, Pilar; Garzón-Niño, Javier

    2015-01-01

    In the brain, the histidine triad nucleotide-binding protein 1 (HINT1) and sigma 1 receptors (σ1Rs) coordinate the activity of certain G-protein coupled receptors (GPCRs) with that of glutamate N-methyl-D-aspartate receptors (NMDARs). To determine the role of HINT1-σ1R in the plasticity of GPCR-NMDAR interactions, substances acting at MOR, cannabinoid CB1 receptor, NMDAR and σ1R were injected into mice, and their effects were evaluated through in vivo, ex vivo, and in vitro assays. It was observed that HINT1 protein binds to GPCRs and NMDAR NR1 subunits in a calcium-independent manner, whereas σ1R binding to these proteins increases in the presence of calcium. In this scenario, σ1R agonists keep HINT1 at the GPCR and stimulate GPCR-NMDAR interaction, whereas σ1R antagonists transfer HINT1 to NR1 subunits and disengage both receptors. This regulation is lost in σ1R−/− mice, where HINT1 proteins mostly associate with NMDARs, and GPCRs are physically and functionally disconnected from NMDARs. In HINT1−/− mice, ischemia produces low NMDAR-mediated brain damage, suggesting that several different GPCRs enhance glutamate excitotoxicity via HINT1-σ1R. Thus, several GPCRs associate with NMDARs by a dynamic process under the physiological control of HINT1 proteins and σ1Rs. The NMDAR-HINT1-σ1R complex deserves attention because it offers new therapeutic opportunities. PMID:26461475

  18. Flow management and fish density regulate salmonid recruitment and adult size in tailwaters across western North America.

    PubMed

    Dibble, Kimberly L; Yackulic, Charles B; Kennedy, Theodore A; Budy, Phaedra

    2015-12-01

    Rainbow and brown trout have been intentionally introduced into tailwaters downriver of dams globally and provide billions of dollars in economic benefits. At the same time, recruitment and maximum length of trout populations in tailwaters often fluctuate erratically, which negatively affects the value of fisheries. Large recruitment events may increase dispersal downriver where other fish species may be a priority (e.g., endangered species). There is an urgent need to understand the drivers of trout population dynamics in tailwaters, in particular the role of flow management. Here, we evaluate how flow, fish density, and other physical factors of the river influence recruitment and mean adult length in tailwaters across western North America, using data from 29 dams spanning 1-19 years. Rainbow trout recruitment was negatively correlated with high annual, summer, and spring flow and dam latitude, and positively correlated with high winter flow, subadult brown trout catch, and reservoir storage capacity. Brown trout recruitment was negatively correlated with high water velocity and daily fluctuations in flow (i.e., hydropeaking) and positively correlated with adult rainbow trout catch. Among these many drivers, rainbow trout recruitment was primarily correlated with high winter flow combined with low spring flow, whereas brown trout recruitment was most related to high water velocity. The mean lengths of adult rainbow and brown trout were influenced by similar flow and catch metrics. Length in both species was positively correlated with high annual flow but declined in tailwaters with high daily fluctuations in flow, high catch rates of conspecifics, and when large cohorts recruited to adult size. Whereas brown trout did not respond to the proportion of water allocated between seasons, rainbow trout length increased in rivers that released more water during winter than in spring. Rainbow trout length was primarily related to high catch rates of conspecifics

  19. Power Actuation and Switching Module Test Results

    NASA Technical Reports Server (NTRS)

    Carr, Greg; Deligiannis, Frank; Franco, Lauro; Jones, Loren; Lam, Barbara; Nelson, Ron; Pantaleon, Jose; Ruiz, Ian; Treichler, John; Wester, Gene

    2006-01-01

    The X2000 Power System Electronics (PSE) is a Jet Propulsion Laboratory (JPL) task to develop a new generation of power system building blocks for use on future deep-space missions. The effort includes the development of electronic components and modules that can be used as building blocks in the design of generic spacecraft power systems. All X2000 avionics components and modules are designed for use in centralized or distributed spacecraft architectures. The Power Actuation and Switching Module (PASM) has been developed under the X2000 program. This component enables a modular and scalable design approach for power switching applications, which can result in a wide variety of power switching architectures using this simple building block. The PASM is designed to provide most of the necessary power switching functions of spacecraft for various Deep Space missions including future missions to Mars, comets, Jupiter and its moons. It is fabricated using an ASIC process that is tolerant of high radiation. The development included two application specific integrated circuits (ASICs) and support circuitry all packaged using High Density Interconnect (HDI) technology. It can be operated in series or parallel with other PASMs. It can be used as a high-side or low-side switch and it can drive thruster valves, pyrotechnic devices such as NASA standard initiators, bus shunt resistors, and regular spacecraft component loads. Each PASM contains two independent switches with internal current limiting and over-current trip-off functions to protect the power subsystem from load faults. During turnon and turnoff each switch can limit the rate of current change (di/dt) to a value determined by the user. Three-way majority-voted On/Off commandability and full switch status telemetry (both analog and digital) are built into the module. This paper is a follow up to the one presented at he IECEC 2004 conference that will include the lessons learned and test results from the development.

  20. Characteristics of current filamentation in high gain photoconductive semiconductor switching

    SciTech Connect

    Zutavern, F J; Loubriel, G M; O'Malley, M W; Helgeson, W D; McLaughlin, D L; Denison, G J

    1992-01-01

    Characteristics of current filamentation are reported for high gain photoconductive semiconductor switches (PCSS). Infrared photoluminescence is used to monitor carrier recombination radiation during fast initiation of high gain switching in large (1.5 cm gap) lateral GaAs PCSS. Spatial modulation of the optical trigger, a 200--300 ps pulse width laser, is examined. Effects on the location and number of current filaments, rise time, and delay to high gain switching, minimum trigger energy, and degradation of switch contacts are presented. Implications of these measurements for the theoretical understanding and practical development of these switches are discussed. Efforts to increase current density and reduce switch size and optical trigger energy requirements are described. Results from contact development and device lifetime testing are presented and the impact of these results on practical device applications is discussed.

  1. Electric-field-assisted switching in magnetic tunnel junctions.

    PubMed

    Wang, Wei-Gang; Li, Mingen; Hageman, Stephen; Chien, C L

    2011-11-13

    The advent of spin transfer torque effect accommodates site-specific switching of magnetic nanostructures by current alone without magnetic field. However, the critical current density required for usual spin torque switching remains stubbornly high around 10(6)-10(7) A cm(-2). It would be fundamentally transformative if an electric field through a voltage could assist or accomplish the switching of ferromagnets. Here we report electric-field-assisted reversible switching in CoFeB/MgO/CoFeB magnetic tunnel junctions with interfacial perpendicular magnetic anisotropy, where the coercivity, the magnetic configuration and the tunnelling magnetoresistance can be manipulated by voltage pulses associated with much smaller current densities. These results represent a crucial step towards ultralow energy switching in magnetic tunnel junctions, and open a new avenue for exploring other voltage-controlled spintronic devices.

  2. Submicrosecond Power-Switching Test Circuit

    NASA Technical Reports Server (NTRS)

    Folk, Eric N.

    2006-01-01

    A circuit that changes an electrical load in a switching time shorter than 0.3 microsecond has been devised. This circuit can be used in testing the regulation characteristics of power-supply circuits . especially switching power-converter circuits that are supposed to be able to provide acceptably high degrees of regulation in response to rapid load transients. The combination of this power-switching circuit and a known passive constant load could be an attractive alternative to a typical commercially available load-bank circuit that can be made to operate in nominal constant-voltage, constant-current, and constant-resistance modes. The switching provided by a typical commercial load-bank circuit in the constant-resistance mode is not fast enough for testing of regulation in response to load transients. Moreover, some test engineers do not trust the test results obtained when using commercial load-bank circuits because the dynamic responses of those circuits are, variously, partly unknown and/or excessively complex. In contrast, the combination of this circuit and a passive constant load offers both rapid switching and known (or at least better known) load dynamics. The power-switching circuit (see figure) includes a signal-input section, a wide-hysteresis Schmitt trigger that prevents false triggering in the event of switch-contact bounce, a dual-bipolar-transistor power stage that drives the gate of a metal oxide semiconductor field-effect transistor (MOSFET), and the MOSFET, which is the output device that performs the switching of the load. The MOSFET in the specific version of the circuit shown in the figure is rated to stand off a potential of 100 V in the "off" state and to pass a current of 20 A in the "on" state. The switching time of this circuit (the characteristic time of rise or fall of the potential at the drain of the MOSFET) is .300 ns. The circuit can accept any of three control inputs . which one depending on the test that one seeks to perform: a

  3. Construction of an Effective Landscape for Multistate Genetic Switches

    NASA Astrophysics Data System (ADS)

    Lu, Mingyang; Onuchic, José; Ben-Jacob, Eshel

    2014-08-01

    Multistate genetic switches play a crucial role during embryonic development and tumorigenesis. An archetypical example is the three-way switch regulating epithelial-hybrid-mesenchymal transitions. We devise a special WKB-based approach to investigate white Gaussian and shot noise effects on three-way switches, and construct an effective landscape in good quantitative agreement with stochastic simulations. This approach allows efficient analytical or numerical calculation of the landscape contours, the optimal path, and the state relative stability for general multicomponent multistate switches.

  4. Colored Noise Induced Bistable Switch in the Genetic Toggle Switch Systems.

    PubMed

    Wang, Pei; Lü, Jinhu; Yu, Xinghuo

    2015-01-01

    Noise can induce various dynamical behaviors in nonlinear systems. White noise perturbed systems have been extensively investigated during the last decades. In gene networks, experimentally observed extrinsic noise is colored. As an attempt, we investigate the genetic toggle switch systems perturbed by colored extrinsic noise and with kinetic parameters. Compared with white noise perturbed systems, we show there also exists optimal colored noise strength to induce the best stochastic switch behaviors in the single toggle switch, and the best synchronized switching in the networked systems, which demonstrate that noise-induced optimal switch behaviors are widely in existence. Moreover, under a wide range of system parameter regions, we find there exist wider ranges of white and colored noises strengths to induce good switch and synchronization behaviors, respectively; therefore, white noise is beneficial for switch and colored noise is beneficial for population synchronization. Our observations are very robust to extrinsic stimulus strength, cell density, and diffusion rate. Finally, based on the Waddington's epigenetic landscape and the Wiener-Khintchine theorem, physical mechanisms underlying the observations are interpreted. Our investigations can provide guidelines for experimental design, and have potential clinical implications in gene therapy and synthetic biology.

  5. Sequences of human immunoglobulin switch regions: implications for recombination and transcription.

    PubMed Central

    Mills, F C; Brooker, J S; Camerini-Otero, R D

    1990-01-01

    We have sequenced the entire human S mu and S gamma 4 immunoglobulin heavy chain class switch regions, and have also completed the sequence of human S epsilon. S mu is composed predominantly of GAGCT and GGGCT pentameric repeats, with these units also being found in S epsilon at a much lower density. S mu-S gamma 4 matches are infrequent, but S gamma 4 contains a cluster of repeated sequences similar to units in mouse gamma switch sites and unrelated to the S mu repeats, suggesting that S mu-S gamma homology is not important in mu-gamma switching. We examined our epsilon and gamma 4 sequences for features that could regulate production of 'sterile' transcripts preceding switch recombination. There is an Evolutionarily Conserved Sequence (ECS) upstream from the human and mouse S epsilon regions that overlaps and extends 5' to the start sites for human and mouse epsilon sterile transcripts. Similarly, an ECS upstream from S gamma 4 is homologous to a mouse sequence that overlaps and extends 5' to the start sites for mouse gamma 2b sterile transcripts. The epsilon and gamma 4 conserved segments contain potential Interferon Stimulable Response Elements (ISRE's) that are identical between human epsilon and gamma 4. PMID:2124350

  6. Phosducin-like protein regulates G-protein betagamma folding by interaction with tailless complex polypeptide-1alpha: dephosphorylation or splicing of PhLP turns the switch toward regulation of Gbetagamma folding.

    PubMed

    Humrich, Jan; Bermel, Christina; Bünemann, Moritz; Härmark, Linda; Frost, Robert; Quitterer, Ursula; Lohse, Martin J

    2005-05-20

    Phosducin-like protein (PhLP) exists in two splice variants PhLP(LONG) (PhLP(L)) and PhLP(SHORT) (PhLP(S)). Whereas PhLP(L) directly inhibits Gbetagamma-stimulated signaling, the G betagamma-inhibitory mechanism of PhLP(S) is not understood. We report here that inhibition of Gbetagamma signaling in intact HEK cells by PhLP(S) was independent of direct Gbetagamma binding; however, PhLP(S) caused down-regulation of Gbeta and Ggamma proteins. The down-regulation was partially suppressed by lactacystine, indicating the involvement of proteasomal degradation. N-terminal fusion of Gbeta or Ggamma with a dye-labeling protein resulted in their stabilization against down-regulation by PhLP(S) but did not lead to a functional rescue. Moreover, in the presence of PhLP(S), stabilized Ggamma subunits did not coprecipitate with stabilized Gbeta subunits, suggesting that PhLP(S) might interfere with Gbetagamma folding. PhLP(S) and several truncated mutants of PhLP(S) interacted with the subunit tailless complex polypeptide-1alpha (TCP-1alpha) of the CCT chaperonin complex, which is involved in protein folding. Knock-down of TCP-1alpha in HEK cells by small interfering RNA also led to down-regulation of Gbetagamma. We therefore conclude that the strong inhibitory action of PhLP(S) on Gbetagamma signaling is the result of a previously unrecognized mechanism of Gbetagamma-regulation, inhibition of Gbetagamma-folding by interference with TCP-1alpha.

  7. Optical Circuit Switched Protocol

    NASA Technical Reports Server (NTRS)

    Monacos, Steve P. (Inventor)

    2000-01-01

    The present invention is a system and method embodied in an optical circuit switched protocol for the transmission of data through a network. The optical circuit switched protocol is an all-optical circuit switched network and includes novel optical switching nodes for transmitting optical data packets within a network. Each optical switching node comprises a detector for receiving the header, header detection logic for translating the header into routing information and eliminating the header, and a controller for receiving the routing information and configuring an all optical path within the node. The all optical path located within the node is solely an optical path without having electronic storage of the data and without having optical delay of the data. Since electronic storage of the header is not necessary and the initial header is eliminated by the first detector of the first switching node. multiple identical headers are sent throughout the network so that subsequent switching nodes can receive and read the header for setting up an optical data path.

  8. Optical packet switching

    NASA Astrophysics Data System (ADS)

    Shekel, Eyal; Ruschin, Shlomo; Majer, Daniel; Levy, Jeff; Matmon, Guy; Koenigsberg, Lisa; Vecht, Jacob; Geron, Amir; Harlavan, Rotem; Shfaram, Harel; Arbel, Arnon; McDermott, Tom; Brewer, Tony

    2005-02-01

    We report here a scalable, multichassis, 6.3 terabit core router, which utilizes our proprietary optical switch. The router is commercially available and deployed in several customer sites. Our solution combines optical switching with electronic routing. An internal optical packet switching network interconnects the router"s electronic line cards, where routing and buffering functions take place electronically. The system architecture and performance will be described. The optical switch is based on Optical Phased Array (OPA) technology. It is a 64 x 64, fully non-blocking, optical crossbar switch, capable of switching in a fraction of a nanosecond. The basic principles of operation will be explained. Loss and crosstalk results will be presented, as well as the results of BER measurements of a 160 Gbps transmission through one channel. Basic principles of operation and measured results will be presented for the burst-mode-receivers, arbitration algorithm and synchronization. Finally, we will present some of our current research work on a next-generation optical switch. The technological issues we have solved in our internal optical packet network can have broad applicability to any global optical packet network.

  9. Ovonic switching in tin selenide thin films. Ph.D. Thesis

    NASA Technical Reports Server (NTRS)

    Baxter, C. R.

    1974-01-01

    Amorphous tin selenide thin films which possess Ovonic switching properties were fabricated using vacuum deposition techniques. Results obtained indicate that memory type Ovonic switching does occur in these films the energy density required for switching from a high impedance to a low impedance state is dependent on the spacing between the electrodes of the device. The switching is also function of the magnitude of the applied voltage pulse. A completely automated computer controlled testing procedure was developed which allows precise control over the shape of the applied voltage switching pulse. A survey of previous experimental and theoretical work in the area of Ovonic switching is also presented.

  10. Formation of mos RNA granules in the zebrafish oocyte that differ from cyclin B1 RNA granules in distribution, density and regulation.

    PubMed

    Horie, Mayu; Kotani, Tomoya

    2016-12-01

    Many translationally repressed mRNAs are deposited in the oocyte cytoplasm for progression of the meiotic cell cycle and early development. mos and cyclin B1 mRNAs encode proteins promoting oocyte meiosis, and translational control of these mRNAs is important for normal progression of meiotic cell division. We previously demonstrated that cyclin B1 mRNA forms RNA granules in the zebrafish and mouse oocyte cytoplasm and that the formation of RNA granules is crucial for regulating the timing of translational activation of the mRNA. However, whether the granule formation is specific to cyclin B1 mRNA remains unknown. In this study, we found that zebrafish mos mRNA forms granules distinct from those of cyclin B1 mRNA. Fluorescent in situ hybridization analysis showed that cyclin B1 RNA granules were assembled in dense clusters, while mos RNA granules were distributed diffusely in the animal polar cytoplasm. Sucrose density gradient ultracentrifugation analysis showed that the density of mos RNA granules was partly lower than that of cyclin B1 mRNA. Similar to cyclin B1 RNA granules, mos RNA granules were disassembled after initiation of oocyte maturation at the timing at which the poly(A) tail was elongated. However, while almost all of the granules of cyclin B1 were disassembled simultaneously, a fraction of mos RNA granules firstly disappeared and then a large part of them was disassembled. In addition, while cyclin B1 RNA granules were disassembled in a manner dependent on actin filament depolymerization, certain fractions of mos RNA granules were disassembled independently of actin filaments. These results suggest that cytoplasmic regulation of translationally repressed mRNAs by formation of different RNA granules is a key mechanism for translational control of distinct mRNAs in the oocyte.

  11. Photoconductive switch package

    DOEpatents

    Ca[rasp, George J

    2013-10-22

    A photoconductive switch is formed of a substrate that has a central portion of SiC or other photoconductive material and an outer portion of cvd-diamond or other suitable material surrounding the central portion. Conducting electrodes are formed on opposed sides of the substrate, with the electrodes extending beyond the central portion and the edges of the electrodes lying over the outer portion. Thus any high electric fields produced at the edges of the electrodes lie outside of and do not affect the central portion, which is the active switching element. Light is transmitted through the outer portion to the central portion to actuate the switch.

  12. SPARK GAP SWITCH

    DOEpatents

    Neal, R.B.

    1957-12-17

    An improved triggered spark gap switch is described, capable of precisely controllable firing time while switching very large amounts of power. The invention in general comprises three electrodes adjustably spaced and adapted to have a large potential impressed between the outer electrodes. The central electrode includes two separate elements electrically connected togetaer and spaced apart to define a pair of spark gaps between the end electrodes. Means are provided to cause the gas flow in the switch to pass towards the central electrode, through a passage in each separate element, and out an exit disposed between the two separate central electrode elements in order to withdraw ions from the spark gap.

  13. Photoconductive switch package

    DOEpatents

    Caporaso, George J.

    2015-10-27

    A photoconductive switch is formed of a substrate that has a central portion of SiC or other photoconductive material and an outer portion of cvd-diamond or other suitable material surrounding the central portion. Conducting electrodes are formed on opposed sides of the substrate, with the electrodes extending beyond the central portion and the edges of the electrodes lying over the outer portion. Thus any high electric fields produced at the edges of the electrodes lie outside of and do not affect the central portion, which is the active switching element. Light is transmitted through the outer portion to the central portion to actuate the switch.

  14. Electromechanical magnetization switching

    SciTech Connect

    Chudnovsky, Eugene M.; Jaafar, Reem

    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.

  15. Solid state switch

    DOEpatents

    Merritt, B.T.; Dreifuerst, G.R.

    1994-07-19

    A solid state switch, with reverse conducting thyristors, is designed to operate at 20 kV hold-off voltage, 1,500 A peak, 1.0 [mu]s pulsewidth, and 4,500 pps, to replace thyratrons. The solid state switch is more reliable, more economical, and more easily repaired. The switch includes a stack of circuit card assemblies, a magnetic assist and a trigger chassis. Each circuit card assembly contains a reverse conducting thyristor, a resistor capacitor network, and triggering circuitry. 6 figs.

  16. Essential oil of Pinus koraiensis leaves exerts antihyperlipidemic effects via up-regulation of low-density lipoprotein receptor and inhibition of acyl-coenzyme A: cholesterol acyltransferase.

    PubMed

    Kim, Ji-Hyun; Lee, Hyo-Jung; Jeong, Soo-Jin; Lee, Min-Ho; Kim, Sung-Hoon

    2012-09-01

    Hyperlipidemia is an important factor to induce metabolic syndrome such as obesity, diabetes and cardiovascular diseases. Recently, some antihyperlipidemic agents from herbal medicines have been in the spotlight in the medical science field. Thus, the present study evaluated the antihyperlipidemic activities of the essential oil from the leaves of Pinus koraiensis SIEB (EOPK) that has been used as a folk remedy for heart disease. The reverse transcription polymerase chain reaction (RT-PCR) revealed that EOPK up-regulated low density lipoprotein receptor (LDLR) at the mRNA level as well as negatively suppressed the expression of sterol regulatory element-binding protein (SREBP)-1c, SREBP-2, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), fatty acid synthase (FAS) and glycerol-3-phosphate acyltransferase (GPAT) involved in lipid metabolism in HepG2 cells. Also, western blotting showed that EOPK activated LDLR and attenuated the expression of FAS at the protein level in the cells. Consistently, EOPK significantly inhibited the level of human acylcoenzyme A: cholesterol acyltransferase (hACAT)1 and 2 and reduced the low-density lipoprotein (LDL) oxidation activity. Furthermore, chromatography-mass spectrometry (GC-MS) analysis showed that EOPK, an essential oil mixture, contained camphene (21.11%), d-limonene (21.01%), α-pinene (16.74%) and borneol (11.52%). Overall, the findings suggest that EOPK can be a potent pharmaceutical agent for the prevention and treatment of hyperlipidemia.

  17. Low density lipoprotein receptor-binding activity in human tissues: Quantitative importance of hepatic receptors and evidence for regulation of their expression in vivo

    SciTech Connect

    Rudling, M.J. Karolinska Institutet, Stockholm ); Reihner, E.; Einarsson, K.; Ewerth, S.; Angelin, B. )

    1990-05-01

    The heparin-sensitive binding of {sup 125}I-labeled low-density lipoprotein (LDL) to homogenates from 18 different normal human tissues and some solid tumors was determined. The binding to adrenal and liver homogenates fulfilled criteria established for the binding of LDL to its receptor--namely, (i) saturability, (ii) sensitivity to proteolytic destruction, (iii) inhibition by EDTA, and (iv) heat sensitivity. When the binding of {sup 125}I-labeled LDL was assayed at a constant concentration, the adrenal gland and the ovary had the highest binding of normal tissues. The highest binding per g of tissue overall was obtained in homogenates of a gastric carcinoma and a parotid adenoma. When the weights of the parenchymatous organs were considered, the major amount of LDL receptors was contained in the liver. To study the possible regulation of hepatic LDL-receptor expression, 11 patients were pretreated with cholestyramine. Increased binding activity was obtained in homogenates from liver biopsies from the cholestyramine-treated patients as compared with 12 untreated controls. It is concluded that the liver is the most important organ for LDL catabolism in humans and that the receptor activity in this organ can be regulated upon pharmacologic intervention. Further studies are needed to confirm the possibility that certain solid tumors can exhibit high numbers of LDL receptors.

  18. Oxidized low-density lipoprotein promotes osteoblast differentiation in primary cultures of vascular smooth muscle cells by up-regulating Osterix expression in an Msx2-dependent manner.

    PubMed

    Taylor, Jesse; Butcher, Martin; Zeadin, Melec; Politano, Amanda; Shaughnessy, Stephen G

    2011-02-01

    We have previously shown that oxidized low-density lipoproteins (oxLDLs) act synergistically with β-glycerophosphate to induce the osteogenic differentiation of primary bovine aortic smooth muscle cells (BASMCs). In the present study, we attempt to resolve the mechanism responsible for this effect by examining the expression of several osteoblast-specific transcription factors. Thus, by culturing BASMCs in the absence or presence of β-glycerophosphate and/or oxLDL, we demonstrate that β-glycerophosphate induces both Runx2 and Osterix (Osx) expression. In contrast, oxLDL has no effect on Runx2 expression but rather it enhances β-glycerophosphate-induced osteoblast differentiation by further up-regulating Osx expression. In an attempt to elucidate the mechanism responsible for this latter effect, we examined the ability of oxLDL to affect Msh homeobox 2 (Msx2) expression. Similar to its effect on Osx expression, oxLDL was found to synergistically enhance β-glycerophosphate-induced Msx2 expression in an extracellular signal-regulated kinase 1 and 2 (Erk 1 and 2)-dependent manner. Furthermore, oxLDL's ability to enhance both β-glycerophosphate-induced Osx expression and alkaline phosphatase activity was prevented when the BASMCs were first transfected with Msx2-specific siRNA. Taken together, these findings suggest a plausible mechanism by which oxLDL may promote osteoblast differentiation and vascular calcification in vivo.

  19. Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized low-density lipoprotein (LDL) and oxidized LDL immune complexes: role in phagocytosis and cytokine release.

    PubMed

    Truman, Jean-Philip; Al Gadban, Mohammed M; Smith, Kent J; Jenkins, Russell W; Mayroo, Nalini; Virella, Gabriel; Lopes-Virella, Maria F; Bielawska, Alicja; Hannun, Yusuf A; Hammad, Samar M

    2012-05-01

    Oxidized low-density lipoprotein (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to the formation of lipid-laden macrophages (foam cells). Fcγ receptors mediate uptake of oxLDL-IC, whereas scavenger receptors internalize oxLDL. We have previously reported that oxLDL-IC, but not free oxLDL, activate macrophages and prolong their survival. Sphingomyelin is a major constituent of cell membranes and lipoprotein particles and acid sphingomyelinase (ASMase) hydrolyses sphingomyelin to generate the bioactive lipid ceramide. ASMase exists in two forms: lysosomal (L-ASMase) and secretory (S-ASMase). In this study we examined whether oxLDL and oxLDL-IC regulate ASMase differently, and whether ASMase mediates monocyte/macrophage activation and cytokine release. The oxLDL-IC, but not oxLDL, induced early and consistent release of catalytically active S-ASMase. The oxLDL-IC also consistently stimulated L-ASMase activity, whereas oxLDL induced a rapid transient increase in L-ASMase activity before it steadily declined below baseline. Prolonged exposure to oxLDL increased L-ASMase activity; however, activity remained significantly lower than that induced by oxLDL-IC. Further studies were aimed at defining the function of the activated ASMase. In response to oxLDL-IC, heat-shock protein 70B' (HSP70B') was up-regulated and localized with redistributed ASMase in the endosomal compartment outside the lysosome. Treatment with oxLDL-IC induced the formation and release of HSP70-containing and IL-1β-containing exosomes via an ASMase-dependent mechanism. Taken together, the results suggest that oxLDL and oxLDL-IC differentially regulate ASMase activity, and the pro-inflammatory responses to oxLDL-IC are mediated by prolonged activation of ASMase. These findings may contribute to increased understanding of mechanisms mediating macrophage involvement in atherosclerosis.

  20. Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells.

    PubMed

    Chen, Hung-Chen; Chen, Pei-Yi; Wu, Ming-Jiuan; Tai, Mi-Hsueh; Yen, Jui-Hung

    2016-01-01

    Tanshinone IIA, one of the most pharmacologically bioactive phytochemicals isolated from Salvia miltiorrhiza Bunge, possesses several biological activities such as anti-inflammation, anti-cancer, neuroprotection and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effect of tanshinone IIA in hepatic cells. We demonstrated that tanshinone IIA significantly increased the amount of low-density lipoprotein receptor (LDLR) and LDL uptake activity in HepG2 cells at the post-transcriptional regulation. We further demonstrated that tanshinone IIA inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and mature protein, which may lead to an increase the cell-surface LDLR in hepatic cells. We further identified a regulatory DNA element involved in the tanshinone IIA-mediated PCSK9 down-regulation, which is located between the -411 and -336 positions of the PCSK9 promoter. Moreover, we found that tanshinone IIA markedly increased the nuclear forkhead box O3a (FoxO3a) level, enhanced FoxO3a/PCSK9 promoter complexes formation and decreased the PCSK9 promoter binding capacity of hepatocyte nuclear factor 1α (HNF-1α), resulting in suppression of PCSK9 gene expression. Finally, we found that the statin-induced PCSK9 overexpression was attenuated and the LDLR activity was elevated in a synergic manner by combination of tanshinone IIA treatment in HepG2 cells. Overall, our results reveal that the tanshinone IIA modulates LDLR level and activity via down-regulation of PCSK9 expression in hepatic cells. Our current findings provide a molecular basis of tanshinone IIA to develop PCSK9 inhibitors for cholesterol management.

  1. Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells

    PubMed Central

    Wu, Ming-Jiuan; Tai, Mi-Hsueh; Yen, Jui-Hung

    2016-01-01

    Tanshinone IIA, one of the most pharmacologically bioactive phytochemicals isolated from Salvia miltiorrhiza Bunge, possesses several biological activities such as anti-inflammation, anti-cancer, neuroprotection and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effect of tanshinone IIA in hepatic cells. We demonstrated that tanshinone IIA significantly increased the amount of low-density lipoprotein receptor (LDLR) and LDL uptake activity in HepG2 cells at the post-transcriptional regulation. We further demonstrated that tanshinone IIA inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and mature protein, which may lead to an increase the cell-surface LDLR in hepatic cells. We further identified a regulatory DNA element involved in the tanshinone IIA-mediated PCSK9 down-regulation, which is located between the -411 and -336 positions of the PCSK9 promoter. Moreover, we found that tanshinone IIA markedly increased the nuclear forkhead box O3a (FoxO3a) level, enhanced FoxO3a/PCSK9 promoter complexes formation and decreased the PCSK9 promoter binding capacity of hepatocyte nuclear factor 1α (HNF-1α), resulting in suppression of PCSK9 gene expression. Finally, we found that the statin-induced PCSK9 overexpression was attenuated and the LDLR activity was elevated in a synergic manner by combination of tanshinone IIA treatment in HepG2 cells. Overall, our results reveal that the tanshinone IIA modulates LDLR level and activity via down-regulation of PCSK9 expression in hepatic cells. Our current findings provide a molecular basis of tanshinone IIA to develop PCSK9 inhibitors for cholesterol management. PMID:27617748

  2. An optical switch

    DOEpatents

    Christophorou, L.G.; Hunter, S.R.

    1987-04-30

    The invention is a gas mixture for a diffuse discharge switch having an electron attaching gas wherein electron attachment is brought about by indirect excitation of molecules to long live states by exposure to laser light. 3 figs.

  3. Switching and stopping antidepressants

    PubMed Central

    Keks, Nicholas; Hope, Judy; Keogh, Simone

    2016-01-01

    SUMMARY Switching from one antidepressant to another is frequently indicated due to an inadequate treatment response or unacceptable adverse effects. All antidepressant switches must be carried out cautiously and under close observation. Conservative switching strategies involve gradually tapering the first antidepressant followed by an adequate washout period before the new antidepressant is started. This can take a long time and include periods of no treatment with the risk of potentially life-threatening exacerbations of illness. Clinical expertise is needed for more rapid or cross-taper switching as drug toxicity, including serotonin syndrome, may result from inappropriate co-administration of antidepressants. Some antidepressants must not be combined. Antidepressants can cause withdrawal syndromes if discontinued abruptly after prolonged use. Relapse and exacerbation of depression can also occur. Gradual dose reduction over days to weeks reduces the risk and severity of complications. PMID:27346915

  4. 49 CFR 236.528 - Restrictive condition resulting from open hand-operated switch; requirement.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...-operated switch; requirement. 236.528 Section 236.528 Transportation Other Regulations Relating to... Instructions; Roadway § 236.528 Restrictive condition resulting from open hand-operated switch; requirement. When a facing point hand-operated switch is open one-fourth inch or more, a trailing point...

  5. 49 CFR 236.528 - Restrictive condition resulting from open hand-operated switch; requirement.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...-operated switch; requirement. 236.528 Section 236.528 Transportation Other Regulations Relating to... Instructions; Roadway § 236.528 Restrictive condition resulting from open hand-operated switch; requirement. When a facing point hand-operated switch is open one-fourth inch or more, a trailing point...

  6. 49 CFR 218.105 - Additional operational requirements for hand-operated main track switches.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...-operated main track switches. 218.105 Section 218.105 Transportation Other Regulations Relating to... PRACTICES Handling Equipment, Switches, and Fixed Derails § 218.105 Additional operational requirements for hand-operated main track switches. (a) Each railroad shall adopt and comply with an operating...

  7. 49 CFR 218.105 - Additional operational requirements for hand-operated main track switches.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...-operated main track switches. 218.105 Section 218.105 Transportation Other Regulations Relating to... PRACTICES Handling Equipment, Switches, and Fixed Derails § 218.105 Additional operational requirements for hand-operated main track switches. (a) Each railroad shall adopt and comply with an operating...

  8. 49 CFR 218.107 - Additional operational requirements for hand-operated crossover switches.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...-operated crossover switches. 218.107 Section 218.107 Transportation Other Regulations Relating to... PRACTICES Handling Equipment, Switches, and Fixed Derails § 218.107 Additional operational requirements for hand-operated crossover switches. (a) Each railroad shall adopt and comply with an operating rule...

  9. 49 CFR 218.107 - Additional operational requirements for hand-operated crossover switches.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...-operated crossover switches. 218.107 Section 218.107 Transportation Other Regulations Relating to... PRACTICES Handling Equipment, Switches, and Fixed Derails § 218.107 Additional operational requirements for hand-operated crossover switches. (a) Each railroad shall adopt and comply with an operating rule...

  10. 77 FR 33998 - Make Inoperative Exemptions; Retrofit On-Off Switches for Air Bags

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-08

    ...; Retrofit On-Off Switches for Air Bags AGENCY: National Highway Traffic Safety Administration (NHTSA... regulation that permits motor vehicle dealers and repair businesses to install retrofit on-off switches for air bags in vehicles owned by or used by persons whose request for a switch has been approved by...

  11. 77 FR 52619 - Make Inoperative Exemptions; Retrofit On-Off Switches for Air Bags

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-30

    ...; Retrofit On-Off Switches for Air Bags AGENCY: National Highway Traffic Safety Administration (NHTSA... vehicle dealers and repair businesses to install retrofit on-off switches for air bags in vehicles owned by or used by persons whose request for a switch has been approved by the agency. This regulation...

  12. High Power Switching Transistor

    NASA Technical Reports Server (NTRS)

    Hower, P. L.; Kao, Y. C.; Carnahan, D. C.

    1983-01-01

    Improved switching transistors handle 400-A peak currents and up to 1,200 V. Using large diameter silicon wafers with twice effective area as D60T, form basis for D7 family of power switching transistors. Package includes npn wafer, emitter preform, and base-contact insert. Applications are: 25to 50-kilowatt high-frequency dc/dc inverters, VSCF converters, and motor controllers for electrical vehicles.

  13. Cygnus Water Switch Jitter

    SciTech Connect

    Charles V. Mitton, George D. Corrow, Mark D. Hansen, David J. Henderson, et al.

    2008-03-01

    The Cygnus Dual Beam Radiographic Facility consists of two identical radiographic sources - Cygnus 1 and Cygnus 2. Each source has the following x-ray output: 1-mm diameter spot size, 4 rad at 1 m, 50-ns Full Width Half Max. The diode pulse has the following electrical specifications: 2.25 MV, 60 kA, 60 ns. This Radiographic Facility is located in an underground tunnel test area at the Nevada Test Site (NTS). The sources were developed to produce high-resolution images on subcritical tests which are performed at NTS. Subcritical tests are single-shot, high-value events. For this application, it is desirable to maintain a high level of reproducibility in source output. The major components of the Cygnus machines are: Marx generator, water-filled pulse–forming line (PFL), water-filled coaxial transmission line, three-cell inductive voltage adder, and rod-pinch diode. A primary source of fluctuation in Cygnus shot-to-shot performance is jitter in breakdown of the main PFL switch, which is a “self-break” switch. The PFL switch breakdown time determines the peak PFL charging voltage, which ultimately affects the diode pulse. Therefore, PFL switch jitter contributes to shot-to-shot variation in source endpoint energy and dose. In this paper we will present PFL switch jitter analysis for both Cygnus machines and give the correlation with diode performance. For this analysis the PFL switch on each machine was maintained at a single gap setting which has been used for the majority of shots at NTS. In addition to this analysis, PFL switch performance for different switch gap settings taken recently will be examined. Lastly, implications of source jitter for radiographic diagnosis of subcritical shots will be discussed.

  14. Finding a stabilising switching law for switching nonlinear models

    NASA Astrophysics Data System (ADS)

    Lendek, Zs.; Raica, P.; Lauber, J.; Guerra, T. M.

    2016-09-01

    This paper considers the stabilisation of switching nonlinear models by switching between the subsystems. We assume that arbitrary switching between two subsystems is possible once a subsystem has been active for a predefined number of samples. We use a Takagi-Sugeno representation of the models and a switching Lyapunov function is employed to develop sufficient stability conditions. If the conditions are satisfied, we construct a switching law that stabilises the system. The application of the conditions is illustrated in several examples.

  15. Fast and reversible thermoresponsive polymer switching materials for safer batteries

    NASA Astrophysics Data System (ADS)

    Chen, Zheng; Hsu, Po-Chun; Lopez, Jeffrey; Li, Yuzhang; To, John W. F.; Liu, Nan; Wang, Chao; Andrews, Sean C.; Liu, Jia; Cui, Yi; Bao, Zhenan

    2016-01-01

    Safety issues have been a long-standing obstacle impeding large-scale adoption of next-generation high-energy-density batteries. Materials solutions to battery safety management are limited by slow response and small operating voltage windows. Here we report a fast and reversible thermoresponsive polymer switching material that can be incorporated inside batteries to prevent thermal runaway. This material consists of electrochemically stable graphene-coated spiky nickel nanoparticles mixed in a polymer matrix with a high thermal expansion coefficient. The as-fabricated polymer composite films show high electrical conductivity of up to 50 S cm-1 at room temperature. Importantly, the conductivity decreases within one second by seven to eight orders of magnitude on reaching the transition temperature and spontaneously recovers at room temperature. Batteries with this self-regulating material built in the electrode can rapidly shut down under abnormal conditions such as overheating and shorting, and are able to resume their normal function without performance compromise or detrimental thermal runaway. Our approach offers 103-104 times higher sensitivity to temperature changes than previous switching devices.

  16. Low inductance gas switching.

    SciTech Connect

    Chavez, Ray; Harjes, Henry Charles III; Wallace, Zachariah; Elizondo, Juan E.

    2007-10-01

    The laser trigger switch (LTS) is a key component in ZR-type pulsed power systems. In ZR, the pulse rise time through the LTS is > 200 ns and additional stages of pulse compression are required to achieve the desired <100 ns rise time. The inductance of the LTS ({approx}500nH) in large part determines the energy transfer time through the switch and there is much to be gained in improving system performance and reducing system costs by reducing this inductance. The current path through the cascade section of the ZR LTS is at a diameter of {approx} 6-inches which is certainly not optimal from an inductance point of view. The LTS connects components of much greater diameter (typically 4-5 feet). In this LDRD the viability of switch concepts in which the diameter of cascade section is greatly increased have been investigated. The key technical question to be answered was, will the desired multi-channel behavior be maintained in a cascade section of larger diameter. This LDRD proceeded in 2 distinct phases. The original plan for the LDRD was to develop a promising switch concept and then design, build, and test a moderate scale switch which would demonstrate the key features of the concept. In phase I, a switch concept which meet all electrical design criteria and had a calculated inductance of 150 nH was developed. A 1.5 MV test switch was designed and fabrication was initiated. The LDRD was then redirected due to budgetary concerns. The fabrication of the switch was halted and the focus of the LDRD was shifted to small scale experiments designed to answer the key technical question concerning multi-channel behavior. In phase II, the Multi-channel switch test bed (MCST) was designed and constructed. The purpose of MCST was to provide a versatile, fast turn around facility for the study the multi-channel electrical breakdown behavior of a ZR type cascade switch gap in a parameter space near that of a ZR LTS. Parameter scans on source impedance, gap tilt, gap spacing and

  17. A radiation hard vacuum switch

    DOEpatents

    Boettcher, G.E.

    1988-07-19

    A vacuum switch with an isolated trigger probe which is not directly connected to the switching electrodes. The vacuum switch within the plasmatron is triggered by plasma expansion initiated by the trigger probe which travels through an opening to reach the vacuum switch elements. The plasma arc created is directed by the opening to the space between the anode and cathode of the vacuum switch to cause conduction. 3 figs.

  18. The Cell Cycle Switch Computes Approximate Majority

    NASA Astrophysics Data System (ADS)

    Cardelli, Luca; Csikász-Nagy, Attila

    2012-09-01

    Both computational and biological systems have to make decisions about switching from one state to another. The `Approximate Majority' computational algorithm provides the asymptotically fastest way to reach a common decision by all members of a population between two possible outcomes, where the decision approximately matches the initial relative majority. The network that regulates the mitotic entry of the cell-cycle in eukaryotes also makes a decision before it induces early mitotic processes. Here we show that the switch from inactive to active forms of the mitosis promoting Cyclin Dependent Kinases is driven by a system that is related to both the structure and the dynamics of the Approximate Majority computation. We investigate the behavior of these two switches by deterministic, stochastic and probabilistic methods and show that the steady states and temporal dynamics of the two systems are similar and they are exchangeable as components of oscillatory networks.

  19. Study of solar array switching power management technology for space power system

    NASA Technical Reports Server (NTRS)

    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 were identified that could safisfy the mission requirements. These switching concepts were compared with a conventional buck regulator system on the basis of cost, weight and volume, reliability, efficiency and thermal control. For the missions reviewed, solar array switching provided significant advantages in all areas of comparison.

  20. Study of solar array switching power management technology for space power system

    NASA Technical Reports Server (NTRS)

    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.

  1. Triggered vacuum flashover switch for high-power applications

    SciTech Connect

    Kellogg, J.C.; Boller, J.R.; Commisso, R.J.; Jenkins, D.J. ); Ford, R.D. ); Lupton, W.H. ); Shipman, J.D. Jr. )

    1991-11-01

    A command triggered, high-power, surface-flashover closing switch that operates in vacuum has been developed for use on a prototype inductive-storage pulsed power generator, Pawn. This vacuum flashover switch isolates the high-pressure-gas tamped wire fuse from a second opening switch. The switch consists of an insulating ring sandwiched between electrodes. Plasma and ultraviolet light from eight small spark discharges driven by a 5 keV pulse initiate a flashover across the switch insulator. The entire triggering unit resides inside one of Pawn's metallic conductors. The switch can be triggered after holding off voltage for {congruent}15 {mu}s. Normally, switch closure occurs at 22--45 kV. Time to closure at a voltage of {congruent}30 kV is {congruent}320 ns, with a typical jitter of {plus minus}50 ns. Peak current is typically {congruent}1 MA. Current density in the switch is approximately 25 kA/cm{sup 2}. The average risetime of the fuse output current pulse can be varied by a factor of 2 by triggering the switch at different closing voltages.

  2. Nanoarchitectonic atomic switch networks for unconventional computing

    NASA Astrophysics Data System (ADS)

    Demis, Eleanor C.; Aguilera, Renato; Scharnhorst, Kelsey; Aono, Masakazu; Stieg, Adam Z.; Gimzewski, James K.

    2016-11-01

    Developments in computing hardware are constrained by the operating principles of complementary metal oxide semiconductor (CMOS) technology, fabrication limits of nanometer scaled features, and difficulties in effective utilization of high density interconnects. This set of obstacles has promulgated a search for alternative, energy efficient approaches to computing inspired by natural systems including the mammalian brain. Atomic switch network (ASN) devices are a unique platform specifically developed to overcome these current barriers to realize adaptive neuromorphic technology. ASNs are composed of a massively interconnected network of atomic switches with a density of ∼109 units/cm2 and are structurally reminiscent of the neocortex of the brain. ASNs possess both the intrinsic capabilities of individual memristive switches, such as memory capacity and multi-state switching, and the characteristics of large-scale complex systems, such as power-law dynamics and non-linear transformations of input signals. Here we describe the successful nanoarchitectonic fabrication of next-generation ASN devices using combined top-down and bottom-up processing and experimentally demonstrate their utility as reservoir computing hardware. Leveraging their intrinsic dynamics and transformative input/output (I/O) behavior enabled waveform regression of periodic signals in the absence of embedded algorithms, further supporting the potential utility of ASN technology as a platform for unconventional approaches to computing.

  3. Fibroblast growth factor 10 gene regulation in the second heart field by Tbx1, Nkx2-5, and Islet1 reveals a genetic switch for down-regulation in the myocardium.

    PubMed

    Watanabe, Yusuke; Zaffran, Stéphane; Kuroiwa, Atsushi; Higuchi, Hiroaki; Ogura, Toshihiko; Harvey, Richard P; Kelly, Robert G; Buckingham, Margaret

    2012-11-06

    During cardiogenesis, Fibroblast Growth Factor (Fgf10) is expressed in the anterior second heart field. Together with Fibroblast growth factor 8 (Fgf8), Fgf10 promotes the proliferation of these cardiac progenitor cells that form the arterial pole of the heart. We have identified a 1.7-kb region in the first intron of Fgf10 that is necessary and sufficient to direct transgene expression in this cardiac context. The 1.7-kb sequence is directly controlled by T-box transcription factor 1 (Tbx1) in anterior second heart field cells that contribute to the outflow tract. It also responds to both NK2 transcription factor related, locus 5 (Nkx2-5) and ISL1 transcription factor, LIM/homeodomain (Islet1), acting through overlapping sites. Mutation of these sites reduces transgene expression in the anterior second heart field where the Fgf10 regulatory element is activated by Islet1 via direct binding in vivo. Analysis of the response to Nkx2-5 loss- and Isl1 gain-of-function genetic backgrounds indicates that the observed up-regulation of its activity in Nkx2-5 mutant hearts, reflecting that of Fgf10, is due to the absence of Nkx2-5 repression and to up-regulation of Isl1, normally repressed in the myocardium by Nkx2-5. ChIP experiments show strong binding of Nkx2-5 in differentiated myocardium. Molecular and genetic analysis of the Fgf10 cardiac element therefore reveals how key cardiac transcription factors orchestrate gene expression in the anterior second heart field and how genes, such as Fgf10, normally expressed in the progenitor cell population, are repressed when these cells enter the heart and differentiate into myocardium. Our findings provide a paradigm for transcriptional mechanisms that underlie the changes in regulatory networks during the transition from progenitor state to that of the differentiated tissue.

  4. Fibroblast growth factor 10 gene regulation in the second heart field by Tbx1, Nkx2-5, and Islet1 reveals a genetic switch for down-regulation in the myocardium

    PubMed Central

    Watanabe, Yusuke; Zaffran, Stéphane; Kuroiwa, Atsushi; Higuchi, Hiroaki; Ogura, Toshihiko; Harvey, Richard P.; Kelly, Robert G.; Buckingham, Margaret

    2012-01-01

    During cardiogenesis, Fibroblast Growth Factor (Fgf10) is expressed in the anterior second heart field. Together with Fibroblast growth factor 8 (Fgf8), Fgf10 promotes the proliferation of these cardiac progenitor cells that form the arterial pole of the heart. We have identified a 1.7-kb region in the first intron of Fgf10 that is necessary and sufficient to direct transgene expression in this cardiac context. The 1.7-kb sequence is directly controlled by T-box transcription factor 1 (Tbx1) in anterior second heart field cells that contribute to the outflow tract. It also responds to both NK2 transcription factor related, locus 5 (Nkx2-5) and ISL1 transcription factor, LIM/homeodomain (Islet1), acting through overlapping sites. Mutation of these sites reduces transgene expression in the anterior second heart field where the Fgf10 regulatory element is activated by Islet1 via direct binding in vivo. Analysis of the response to Nkx2-5 loss- and Isl1 gain-of-function genetic backgrounds indicates that the observed up-regulation of its activity in Nkx2-5 mutant hearts, reflecting that of Fgf10, is due to the absence of Nkx2-5 repression and to up-regulation of Isl1, normally repressed in the myocardium by Nkx2-5. ChIP experiments show strong binding of Nkx2-5 in differentiated myocardium. Molecular and genetic analysis of the Fgf10 cardiac element therefore reveals how key cardiac transcription factors orchestrate gene expression in the anterior second heart field and how genes, such as Fgf10, normally expressed in the progenitor cell population, are repressed when these cells enter the heart and differentiate into myocardium. Our findings provide a paradigm for transcriptional mechanisms that underlie the changes in regulatory networks during the transition from progenitor state to that of the differentiated tissue. PMID:23093675

  5. RF Reference Switch for Spaceflight Radiometer Calibration

    NASA Technical Reports Server (NTRS)

    Knuble, Joseph

    2013-01-01

    The goal of this technology is to provide improved calibration and measurement sensitivity to the Soil Moisture Active Passive Mission (SMAP) radiometer. While RF switches have been used in the past to calibrate microwave radiometers, the switch used on SMAP employs several techniques uniquely tailored to the instrument requirements and passive remote-sensing in general to improve radiometer performance. Measurement error and sensitivity are improved by employing techniques to reduce thermal gradients within the device, reduce insertion loss during antenna observations, increase insertion loss temporal stability, and increase rejection of radar and RFI (radio-frequency interference) signals during calibration. The two legs of the single-pole double-throw reference switch employ three PIN diodes per leg in a parallel-shunt configuration to minimize insertion loss and increase stability while exceeding rejection requirements at 1,413 MHz. The high-speed packaged diodes are selected to minimize junction capacitance and resistance while ensuring the parallel devices have very similar I-V curves. Switch rejection is improved by adding high-impedance quarter-wave tapers before and after the diodes, along with replacing the ground via of one diode per leg with an open circuit stub. Errors due to thermal gradients in the switch are reduced by embedding the 50-ohm reference load within the switch, along with using a 0.25-in. (approximately equal to 0.6-cm) aluminum prebacked substrate. Previous spaceflight microwave radiometers did not embed the reference load and thermocouple directly within the calibration switch. In doing so, the SMAP switch reduces error caused by thermal gradients between the load and switch. Thermal issues are further reduced by moving the custom, highspeed regulated driver circuit to a physically separate PWB (printed wiring board). Regarding RF performance, previous spaceflight reference switches have not employed high-impedance tapers to improve

  6. Nondissipative optimum charge regulator

    NASA Technical Reports Server (NTRS)

    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.

  7. Multiple switch actuator

    DOEpatents

    Beyer, Edward T.

    1976-01-06

    The present invention relates to switches and switch actuating devices to be operated for purposes of arming a bomb or other missile as it is dropped or released from an aircraft. The particular bomb or missile in which this invention is applied is one in which there is a plurality of circuits which are to be armed by the closing of switches upon dropping or releasing of the bomb. The operation of the switches to closed position is normally accomplished by means of a pull-out wire; that is, a wire which is withdrawn from the bomb or missile at the time of release of the bomb, one end of the wire being attached to the aircraft. The conditions to be met are that the arming switches must be positively and surely maintained in open position until the bomb is released and the arming action is effected. The action of the pull-out wire in achieving the arming action must be sure and positive with minimum danger of malfunctioning, jamming or binding.

  8. Switching power pulse system

    DOEpatents

    Aaland, K.

    1983-08-09

    A switching system for delivering pulses of power from a source to a load using a storage capacitor charged through a rectifier, and maintained charged to a reference voltage level by a transistor switch and voltage comparator. A thyristor is triggered to discharge the storage capacitor through a saturable reactor and fractional turn saturable transformer having a secondary to primary turn ratio N of n:l/n = n[sup 2]. The saturable reactor functions as a soaker'' while the thyristor reaches saturation, and then switches to a low impedance state. The saturable transformer functions as a switching transformer with high impedance while a load coupling capacitor charges, and then switches to a low impedance state to dump the charge of the storage capacitor into the load through the coupling capacitor. The transformer is comprised of a multilayer core having two secondary windings tightly wound and connected in parallel to add their output voltage and reduce output inductance, and a number of single turn windings connected in parallel at nodes for the primary winding, each single turn winding linking a different one of the layers of the multilayer core. The load may be comprised of a resistive beampipe for a linear particle accelerator and capacitance of a pulse forming network. To hold off discharge of the capacitance until it is fully charged, a saturable core is provided around the resistive beampipe to isolate the beampipe from the capacitance until it is fully charged. 5 figs.

  9. Atomic Scale Plasmonic Switch.

    PubMed

    Emboras, Alexandros; Niegemann, Jens; Ma, Ping; Haffner, Christian; Pedersen, Andreas; Luisier, Mathieu; Hafner, Christian; Schimmel, Thomas; Leuthold, Juerg

    2016-01-13

    The atom sets an ultimate scaling limit to Moore's law in the electronics industry. While electronics research already explores atomic scales devices, photonics research still deals with devices at the micrometer scale. Here we demonstrate that photonic scaling, similar to electronics, is only limited by the atom. More precisely, we introduce an electrically controlled plasmonic switch operating at the atomic scale. The switch allows for fast and reproducible switching by means of the relocation of an individual or, at most, a few atoms in a plasmonic cavity. Depending on the location of the atom either of two distinct plasmonic cavity resonance states are supported. Experimental results show reversible digital optical switching with an extinction ratio of 9.2 dB and operation at room temperature up to MHz with femtojoule (fJ) power consumption for a single switch operation. This demonstration of an integrated quantum device allowing to control photons at the atomic level opens intriguing perspectives for a fully integrated and highly scalable chip platform, a platform where optics, electronics, and memory may be controlled at the single-atom level.

  10. Thermionic gas switch

    DOEpatents

    Hatch, G.L.; Brummond, W.A.; Barrus, D.M.

    1984-04-05

    The present invention is directed to an improved temperature responsive thermionic gas switch utilizing a hollow cathode and a folded emitter surface area. The folded emitter surface area of the thermionic switch substantially increases the on/off ratio by changing the conduction surface area involved in the two modes thereof. The improved switch of this invention provides an on/off ratio of 450:1 compared to the 10:1 ratio of the prior known thermionic switch, while providing for adjusting the on current. In the improved switch of this invention the conduction area is made small in the off mode, while in the on mode the conduction area is made large. This is achieved by utilizing a folded hollow cathode configuration and utilizing a folded emitter surface area, and by making the dimensions of the folds small enough so that a space charge will develop in the convolutions of the folds and suppress unignited current, thus limiting the current carrying surface in the off mode.

  11. Restraint stress up-regulates lectin-like oxidized low-density lipoprotein receptor-1 in aorta of apolipoprotein E-deficient mice.

    PubMed

    Andersson, Irene J; Sankaralingam, Sowndramalingam; Davidge, Sandra T

    2010-09-01

    Psychological stress is a risk factor for cardiovascular disease including atherosclerosis, but the mechanisms are unknown. The vascular lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in vascular pathology and early atherogenesis. We hypothesized that LOX-1 is up-regulated by psychological stress via the formation of oxygen-derived free radicals, and that treatment with EUK-8 (a superoxide dismutase and catalase mimetic) prevents production of oxygen-derived free radicals and leads to reduced expression of LOX-1 in the vascular wall. As a model for psychological stress, we exposed male apolipoprotein E-deficient mice to repeated restraint stress by placement in a conical tube for 2 h per day for 14 consecutive days. Stressed and control mice were treated with EUK-8 (n = 4-5) or vehicle (n = 4-5). Reactive oxygen species and peroxynitrite levels, as detected by oxidative fluorescence microscopy, were increased in the aortic root of mice exposed to stress compared to those of controls by 212 +/- 22% (mean +/- SEM; p < 0.001) and 110 +/- 6% (p < 0.001), respectively. LOX-1, as detected by immunohistochemistry, was increased by 443 +/- 63% in stressed mice compared to control mice (p < 0.001). EUK-8 reduced reactive oxygen species, peroxynitrite, and LOX-1 levels in stressed mice compared to vehicle-treated stressed mice. To conclude, LOX-1 induced by reactive oxygen species and/or peroxynitrite could be one mechanism by which stress promotes cardiovascular disease.

  12. A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density

    PubMed Central

    Walkup, Ward G; Mastro, Tara L; Schenker, Leslie T; Vielmetter, Jost; Hu, Rebecca; Iancu, Ariella; Reghunathan, Meera; Bannon, Barry Dylan; Kennedy, Mary B

    2016-01-01

    SynGAP is a Ras/Rap GTPase-activating protein (GAP) that is a major constituent of postsynaptic densities (PSDs) from mammalian forebrain. Its α1 isoform binds to all three PDZ (PSD-95, Discs-large, ZO-1) domains of PSD-95, the principal PSD scaffold, and can occupy as many as 15% of these PDZ domains. We present evidence that synGAP-α1 regulates the composition of the PSD by restricting binding to the PDZ domains of PSD-95. We show that phosphorylation by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Polo-like kinase-2 (PLK2) decreases its affinity for the PDZ domains by several fold, which would free PDZ domains for occupancy by other proteins. Finally, we show that three critical postsynaptic signaling proteins that bind to the PDZ domains of PSD-95 are present in higher concentration in PSDs isolated from mice with a heterozygous deletion of synGAP. DOI: http://dx.doi.org/10.7554/eLife.16813.001 PMID:27623146

  13. High-Density Lipoprotein (HDL) Counter-Regulates Serum Amyloid A (SAA)-Induced sPLA2-IIE and sPLA2-V Expression in Macrophages

    PubMed Central

    Wang, Angelina; Wong, Sarabeth; Bao, Guoqiang; Li, Jianhua; Yang, Huan; Tracey, Kevin J.; D’Angelo, John

    2016-01-01

    Human serum amyloid A (SAA) has been demonstrated as a chemoattractant and proinflammatory mediator of lethal systemic inflammatory diseases. In the circulation, it can be sequestered by a high-density lipoprotein, HDL, which carries cholesterol, triglycerides, phospholipids and apolipoproteins (Apo-AI). The capture of SAA by HDL results in the displacement of Apo-AI, and the consequent inhibition of SAA’s chemoattractant activities. It was previously unknown whether HDL similarly inhibits SAA-induced sPLA2 expression, as well as the resultant HMGB1 release, nitric oxide (NO) production and autophagy activation. Here we provided compelling evidence that human SAA effectively upregulated the expression and secretion of both sPLA2-IIE and sPLA2-V in murine macrophages, which were attenuated by HDL in a dose-dependent fashion. Similarly, HDL dose-dependently suppressed SAA-induced HMGB1 release, NO production, and autophagy activation. In both RAW 264.7 cells and primary macrophages, HDL inhibited SAA-induced secretion of several cytokines (e.g., IL-6) and chemokines (e.g., MCP-1 and RANTES) that were likely dependent on functional TLR4 signaling. Collectively, these findings suggest that HDL counter-regulates SAA-induced upregulation and secretion of sPLA2-IIE/V in addition to other TLR4-dependent cytokines and chemokines in macrophage cultures. PMID:27898742

  14. Optical computer switching network

    NASA Technical Reports Server (NTRS)

    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.

  15. FAST ACTING CURRENT SWITCH

    DOEpatents

    Batzer, T.H.; Cummings, D.B.; Ryan, J.F.

    1962-05-22

    A high-current, fast-acting switch is designed for utilization as a crowbar switch in a high-current circuit such as used to generate the magnetic confinement field of a plasma-confining and heat device, e.g., Pyrotron. The device particularly comprises a cylindrical housing containing two stationary, cylindrical contacts between which a movable contact is bridged to close the switch. The movable contact is actuated by a differential-pressure, airdriven piston assembly also within the housing. To absorb the acceleration (and the shock imparted to the device by the rapidly driven, movable contact), an adjustable air buffer assembly is provided, integrally connected to the movable contact and piston assembly. Various safety locks and circuit-synchronizing means are also provided to permit proper cooperation of the invention and the high-current circuit in which it is installed. (AEC)

  16. SWITCH user's manual

    NASA Technical Reports Server (NTRS)

    1987-01-01

    The planning program, SWITCH, and its surrounding changed-goal-replanning program, Runaround, are described. The evolution of SWITCH and Runaround from an earlier planner, DEVISER, is recounted. SWITCH's plan representation, and its process of building a plan by backward chaining with strict chronological backtracking, are described. A guide for writing knowledge base files is provided, as are narrative guides for installing the program, running it, and interacting with it while it is running. Some utility functions are documented. For the sake of completeness, a narrative guide to the experimental discrepancy-replanning feature is provided. Appendices contain knowledge base files for a blocksworld domain, and a DRIBBLE file illustrating the output from, and user interaction with, the program in that domain.

  17. Switching power supply

    DOEpatents

    Mihalka, A.M.

    1984-06-05

    The invention is a repratable capacitor charging, switching power supply. A ferrite transformer steps up a dc input. The transformer primary is in a full bridge configuration utilizing power MOSFETs as the bridge switches. The transformer secondary is fed into a high voltage, full wave rectifier whose output is connected directly to the energy storage capacitor. The transformer is designed to provide adequate leakage inductance to limit capacitor current. The MOSFETs are switched to the variable frequency from 20 to 50 kHz to charge a capacitor from 0.6 kV. The peak current in a transformer primary and secondary is controlled by increasing the pulse width as the capacitor charges. A digital ripple counter counts pulses and after a preselected desired number is reached an up-counter is clocked.

  18. Microfabricated triggered vacuum switch

    DOEpatents

    Roesler, Alexander W.; Schare, Joshua M.; Bunch, Kyle

    2010-05-11

    A microfabricated vacuum switch is disclosed which includes a substrate upon which an anode, cathode and trigger electrode are located. A cover is sealed over the substrate under vacuum to complete the vacuum switch. In some embodiments of the present invention, a metal cover can be used in place of the trigger electrode on the substrate. Materials used for the vacuum switch are compatible with high vacuum, relatively high temperature processing. These materials include molybdenum, niobium, copper, tungsten, aluminum and alloys thereof for the anode and cathode. Carbon in the form of graphitic carbon, a diamond-like material, or carbon nanotubes can be used in the trigger electrode. Channels can be optionally formed in the substrate to mitigate against surface breakdown.

  19. Design and Test of Passively Operated Heat Switches for 0.2 to 15 K

    NASA Technical Reports Server (NTRS)

    DiPirro, M. J.; Shirron, P. J.; Canavan, E. R.; Francis, J. J.; Tuttle, J. G.

    2003-01-01

    Heat switches have many uses in cryogenics, from regulating heat flow between refrigeration stages to thermally isolating components once they have cooled to low temperature. Among the techniques one can use for thermal switching, the gas-gap technique has the advantages of wide operating temperature range, high switching ratio, and no moving parts. The traditional gas-gap switch uses copper conductors separated by a small gap and an external getter. The switch is activated by heating and cooling the getter by moving gas into and out of the gap, turning the switch on and off. We have designed, built and tested heat switches that use an internal getter to passively turn off at temperatures between 0.2 and 15 K. The getter is thermally anchored to one side of the switch, and when that side of the switch cools through a transition region, gas adsorbs onto the getter and the switch turns off. The challenges are to make the transition region very narrow and tailorable to a wide range of applications, and to achieve high gas conductance when the switch is on. We have made switches using He-3, He-4, hydrogen, and neon gas, and have used charcoal and various metal substrates as getters. Switching ratios range from 1000 to over 10,000. Design and performance of these switches will be discussed in detail.

  20. Switching behaviors of graphene-boron nitride nanotube heterojunctions

    SciTech Connect

    Parashar, Vyom; Durand, Corentin P.; Hao, Boyi; Amorim, Rodrigo G.; Pandey, Ravindra; Tiwari, Bishnu; Zhang, Dongyan; Liu, Yang; Li, An -Ping; Yap, Yoke Khin

    2015-07-20

    High electron mobility of graphene has enabled their application in high-frequency analogue devices but their gapless nature has hindered their use in digital switches. In contrast, the structural analogous, h-BN sheets and BN nanotubes (BNNTs) are wide band gap insulators. Here we show that the growth of electrically insulating BNNTs on graphene can enable the use of graphene as effective digital switches. These graphene-BNNT heterojunctions were characterized at room temperature by four-probe scanning tunneling microscopy (4-probe STM) under real-time monitoring of scanning electron microscopy (SEM). A switching ratio as high as 105 at a turn-on voltage as low as 0.5 V were recorded. Simulation by density functional theory (DFT) suggests that mismatch of the density of states (DOS) is responsible for these novel switching behaviors.