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1
Khalil, Ali E. "Time violating amplitudes in the (3He, p) reactions." Canadian Journal of Physics 66, no. 7 (July 1, 1988): 612–17. http://dx.doi.org/10.1139/p88-101.
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The difference between the polarization (P) of protons in the reaction (3He, [Formula: see text]) and the analyzing power (A) in the inverse reaction ([Formula: see text], 3He) has been calculated using a spin-independent isospin-independent, time reversal violating interaction in the form [α(r)[Formula: see text] + Hermitian conjugate]. The interaction strength is adjusted to be 1% of the time conserving optical potentials. A distorted-wave Born approximation (DWBA) calculation assuming a direct reaction mechanism has been performed. The relative values of the time violating amplitudes have no signatures for any measurable time violating effects.
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Wang, X., and J. D. Horisberger. "A conformation of Na(+)-K+ pump is permeable to proton." American Journal of Physiology-Cell Physiology 268, no. 3 (March 1, 1995): C590—C595. http://dx.doi.org/10.1152/ajpcell.1995.268.3.c590.
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The Na(+)-K+ pump is thought to operate through a two-conformation (E1-E2) transport cycle in which the cation binding sites are accessible only from one side at a time. Using Na(+)-loaded Xenopus oocytes in which Na(+)-K+ pumps were overexpressed by injection of cRNA of the Xenopus Na(+)-K+ pump alpha-and beta-sub units, we observed a Na(+)-K+ pump-mediated (ouabain-sensitive) inward current in the absence of other transportable cations, except H+, in the external solution. This inward current was strongly inwardly rectifying, pH dependent, and larger at acid pH. Under conditions favoring a large ouabain-sensitive inward current, we observed a ouabain-sensitive intracellular acidification, and the amplitude of the acidification was significantly related to the ouabain-sensitive current, indicating that this current was carried by protons. The reversal potential of the ouabain-sensitive current was dependent on external pH as expected for a proton-conductive pathway. We conclude that in the absence of external K+ the Na(+)-K+ pump can mediate a large inward electrogenic transport of proton. This is most easily explained by the hypothesis that the E2 conformation of the Na(+)-K+ pump with cation binding sites exposed to the outside is accessible to protons from both sides and thus provides a channellike pathway for protons.
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McDonald, A. B. "Nuclear tests of fundamental interactions." Canadian Journal of Physics 67, no. 8 (August 1, 1989): 785–91. http://dx.doi.org/10.1139/p89-136.
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Measurements of parity violation in nuclei can determine properties of the basic weak nucleon–nucleon interaction, thereby testing electroweak theory and quark models of nucleons. Experiments observing parity violation in the photodisintegration of deuterium, in the scattering of protons from hydrogen, and in the emission of circularly polarized γ rays from 18F are described. A new technique for polarizing 3He is described, and the use of polarized 3He in measurements of parity and time reversal violation is presented. Finally, new directions in γ-ray spectroscopy are illustrated by the Sudbury Neutrino Observatory and new ultrahigh resolution bolometric detectors.
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Heber, B., G. Sarri, G. Wibberenz, C. Paizis, P. Ferrando, A. Raviart, A. Posner, R. Müller-Mellin, and H. Kunow. "The Ulysses fast latitude scans: COSPIN/KET results." Annales Geophysicae 21, no. 6 (June 30, 2003): 1275–88. http://dx.doi.org/10.5194/angeo-21-1275-2003.
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Abstract. Ulysses, launched in October 1990, began its second out-of-ecliptic orbit in December 1997, and its second fast latitude scan in September 2000. In contrast to the first fast latitude scan in 1994/1995, during the second fast latitude scan solar activity was close to maximum. The solar magnetic field reversed its polarity around July 2000. While the first latitude scan mainly gave a snapshot of the spatial distribution of galactic cosmic rays, the second one is dominated by temporal variations. Solar particle increases are observed at all heliographic latitudes, including events that produce >250 MeV protons and 50 MeV electrons. Using observations from the University of Chicago’s instrument on board IMP8 at Earth, we find that most solar particle events are observed at both high and low latitudes, indicating either acceleration of these particles over a broad latitude range or an efficient latitudinal transport. The latter is supported by "quiet time" variations in the MeV electron background, if interpreted as Jovian electrons. No latitudinal gradient was found for >106 MeV galactic cosmic ray protons, during the solar maximum fast latitude scan. The electron to proton ratio remains constant and has practically the same value as in the previous solar maximum. Both results indicate that drift is of minor importance. It was expected that, with the reversal of the solar magnetic field and in the declining phase of the solar cycle, this ratio should increase. This was, however, not observed, probably because the transition to the new magnetic cycle was not completely terminated within the heliosphere, as indicated by the Ulysses magnetic field and solar wind measurements. We argue that the new A<0-solar magnetic modulation epoch will establish itself once both polar coronal holes have developed.Key words. Interplanetary physics (cosmic rays; energetic particles; interplanetary magnetic fields)
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Sánchez, C. M., P. R. Levstein, L. Buljubasich, H. M. Pastawski, and A. K. Chattah. "Quantum dynamics of excitations and decoherence in many-spin systems detected with Loschmidt echoes: its relation to their spreading through the Hilbert space." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 374, no. 2069 (June 13, 2016): 20150155. http://dx.doi.org/10.1098/rsta.2015.0155.
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In this work, we overview time-reversal nuclear magnetic resonance (NMR) experiments in many-spin systems evolving under the dipolar Hamiltonian. The Loschmidt echo (LE) in NMR is the signal of excitations which, after evolving with a forward Hamiltonian, is recovered by means of a backward evolution. The presence of non-diagonal terms in the non-equilibrium density matrix of the many-body state is directly monitored experimentally by encoding the multiple quantum coherences. This enables a spin counting procedure, giving information on the spreading of an excitation through the Hilbert space and the formation of clusters of correlated spins. Two samples representing different spin systems with coupled networks were used in the experiments. Protons in polycrystalline ferrocene correspond to an ‘infinite’ network. By contrast, the liquid crystal N -(4-methoxybenzylidene)-4-butylaniline in the nematic mesophase represents a finite proton system with a hierarchical set of couplings. A close connection was established between the LE decay and the spin counting measurements, confirming the hypothesis that the complexity of the system is driven by the coherent dynamics.
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MURILLO, Isabel, and Lydia M. HENDERSON. "Expression of gp91phox/Nox2 in COS-7 cells: cellular localization of the protein and the detection of outward proton currents." Biochemical Journal 385, no. 3 (January 24, 2005): 649–57. http://dx.doi.org/10.1042/bj20040829.
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We have reported previously that gp91phox, expressed in CHO (Chinese hamster ovary) cells, functions as a voltage-dependent proton channel. However, others have reported that COS-7 cells expressing gp91phox failed to exhibit outward proton currents, and concluded that gp91phox does not function as a proton channel. To investigate this clear difference in findings, we have examined the expression and cellular localization of the fusion protein EGFP-C–91, in which gp91phox is fused to the C-terminus of enhanced green fluorescent protein. EGFP-C–91 was observed in the plasma membrane and intracellular membranes of 30% of the transfected COS-7 cells. In the remaining COS-7 cells, EGFP-C–91 was detected in the intracellular membranes only. In CHO cells EGFP-C–91 was present in both the plasma membrane and the intracellular membranes of all transfected cells. Under the whole-cell configuration, outward currents were recorded from COS-7 cells expressing gp91phox. These increased in magnitude and lost their ‘droop’ over time as the pipette solution equilibrated with the cell cytoplasm (50 min). The threshold activation voltage for the currents was shifted by ∼60 mV for a 1 unit difference in bath pH. Zn2+ inhibited the outward currents observed in COS-7 cells expressing gp91phox. The tail current reversal potential was −64 mV at a pHo (external pH) of 8.0, −40 mV at pHo 7.4 and −8 mV at pHo 7.0, indicating that the current arises from the movement of protons. Outward currents were exhibited by 37.5% of the COS-7 cells expressing gp91phox. Proton currents were recorded following the excision of inside-out patches from cells transfected with gp91phox. The presence of outward proton currents in COS-7 cells expressing gp91phox provides further support for our proposed role for gp91phox as the NADPH oxidase-associated proton channel.
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Belov, A. V., E. A. Eroshenko, B. Heber, V. G. Yanke, A. Raviart, R. Müller-Mellin, and H. Kunow. "Latitudinal and radial variation of >2 GeV/n protons and alpha-particles at solar maximum: ULYSSES COSPIN/KET and neutron monitor network observations." Annales Geophysicae 21, no. 6 (June 30, 2003): 1295–302. http://dx.doi.org/10.5194/angeo-21-1295-2003.
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Abstract. Ulysses, launched in October 1990, began its second out-of-ecliptic orbit in September 1997. In 2000/2001 the spacecraft passed from the south to the north polar regions of the Sun in the inner heliosphere. In contrast to the first rapid pole to pole passage in 1994/1995 close to solar minimum, Ulysses experiences now solar maximum conditions. The Kiel Electron Telescope (KET) measures also protons and alpha-particles in the energy range from 5 MeV/n to >2 GeV/n. To derive radial and latitudinal gradients for >2 GeV/n protons and alpha-particles, data from the Chicago instrument on board IMP-8 and the neutron monitor network have been used to determine the corresponding time profiles at Earth. We obtain a spatial distribution at solar maximum which differs greatly from the solar minimum distribution. A steady-state approximation, which was characterized by a small radial and significant latitudinal gradient at solar minimum, was interchanged with a highly variable one with a large radial and a small – consistent with zero – latitudinal gradient. A significant deviation from a spherically symmetric cosmic ray distribution following the reversal of the solar magnetic field in 2000/2001 has not been observed yet. A small deviation has only been observed at northern polar regions, showing an excess of particles instead of the expected depression. This indicates that the reconfiguration of the heliospheric magnetic field, caused by the reappearance of the northern polar coronal hole, starts dominating the modulation of galactic cosmic rays already at solar maximum.Key words. Interplanetary physics (cosmic rays; energetic particles) – Space plasma physics (charged particle motion and acceleration)
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Burbidge, G. "Explosive Cosmogony and the Quasi-Steady State Cosmology." Symposium - International Astronomical Union 183 (1999): 286–89. http://dx.doi.org/10.1017/s0074180900132954.
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Modern cosmology began with the realization that there were solutions to Einstein's theory of gravity discovered by Friedmann and Lemaitre which when combined with the redshift distance relation of Hubble and others could be interpreted as showing that we live in an expanding universe. By 1930, the scientific establishment and many of the lay public believed this. It was then only elementary logic to argue that if time reversal was applied, the universe must originally have been so compact that we could talk of a beginning. Lemaitre tried to describe this state as the “Primeval Atom.” For a decade or so after the war, Gamow, Alpher and Herman and other leading physicists explored this dense configuration trying to make the chemical elements from protons and neutrons. They soon learned that this was not possible because of the absence of stable masses of five and eight, but they also realized that if such an early stage had occurred the universe would contain an expanding cloud of radiation which would preserve its black body form. Dicke and his colleagues in Princeton rediscovered this idea and decided to try and detect the radiation. Penzias and Wilson found such a radiation field, and COBE has demonstrated that it has a perfect black body form out to radio wavelengths. This history of the discovery together with the fact that the light elements D, He3 and He4 in about the right amounts can be made in a hot big bang has led to the widely held, but simplistic view, that the standard cosmology - the hot big bang - is correct.
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Coady, Michael J., Bernadette Wallendorff, and Jean-Yves Lapointe. "Characterization of the transport activity of SGLT2/MAP17, the renal low-affinity Na+-glucose cotransporter." American Journal of Physiology-Renal Physiology 313, no. 2 (August 1, 2017): F467—F474. http://dx.doi.org/10.1152/ajprenal.00628.2016.
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The cotransporter SGLT2 is responsible for 90% of renal glucose reabsorption, and we recently showed that MAP17 appears to work as a required β-subunit. We report in the present study a detailed functional characterization of human SGLT2 in coexpression with human MAP17 in Xenopus laevis oocytes. Addition of external glucose generates a large inward current in the presence of Na, confirming an electrogenic transport mechanism. At a membrane potential of −50 mV, SGLT2 affinity constants for glucose and Na are 3.4 ± 0.4 and 18 ± 6 mM, respectively. The change in the reversal potential of the cotransport current as a function of external glucose concentration clearly confirms a 1:1 Na-to-glucose transport stoichiometry. SGLT2 is selective for glucose and α-methylglucose but also transports, to a lesser extent, galactose and 3- O-methylglucose. SGLT2 can be inhibited in a competitive manner by phlorizin ( Ki = 31 ± 4 nM) and by dapagliflozin ( Ki = 0.75 ± 0.3 nM). Similarly to SGLT1, SGLT2 can be activated by Na, Li, and protons. Pre-steady-state currents for SGLT2 do exist but are small in amplitude and relatively fast (a time constant of ~2 ms). The leak current defined as the phlorizin-sensitive current in the absence of substrate was extremely small in the case of SGLT2. In summary, in comparison with SGLT1, SGLT2 has a lower affinity for glucose, a transport stoichiometry of 1:1, very small pre-steady-state and leak currents, a 10-fold higher affinity for phlorizin, and an affinity for dapagliflozin in the subnanomolar range.
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Nan, Beiyan, Jigar N. Bandaria, Kathy Y. Guo, Xue Fan, Amirpasha Moghtaderi, Ahmet Yildiz, and David R. Zusman. "The polarity of myxobacterial gliding is regulated by direct interactions between the gliding motors and the Ras homolog MglA." Proceedings of the National Academy of Sciences 112, no. 2 (December 30, 2014): E186—E193. http://dx.doi.org/10.1073/pnas.1421073112.
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Gliding motility in Myxococcus xanthus is powered by flagella stator homologs that move in helical trajectories using proton motive force. The Frz chemosensory pathway regulates the cell polarity axis through MglA, a Ras family GTPase; however, little is known about how MglA establishes the polarity of gliding, because the gliding motors move simultaneously in opposite directions. Here we examined the localization and dynamics of MglA and gliding motors in high spatial and time resolution. We determined that MglA localizes not only at the cell poles, but also along the cell bodies, forming a decreasing concentration gradient toward the lagging cell pole. MglA directly interacts with the motor protein AglR, and the spatial distribution of AglR reversals is positively correlated with the MglA gradient. Thus, the motors moving toward lagging cell poles are less likely to reverse, generating stronger forward propulsion. MglB, the GTPase-activating protein of MglA, regulates motor reversal by maintaining the MglA gradient. Our results suggest a mechanism whereby bacteria use Ras family proteins to modulate cellular polarity.
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Azzu, Vian, Nadeene Parker, and Martin D. Brand. "High membrane potential promotes alkenal-induced mitochondrial uncoupling and influences adenine nucleotide translocase conformation." Biochemical Journal 413, no. 2 (June 26, 2008): 323–32. http://dx.doi.org/10.1042/bj20080321.
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Mitochondria generate reactive oxygen species, whose downstream lipid peroxidation products, such as 4-hydroxynonenal, induce uncoupling of oxidative phosphorylation by increasing proton leak through mitochondrial inner membrane proteins such as the uncoupling proteins and adenine nucleotide translocase. Using mitochondria from rat liver, which lack uncoupling proteins, in the present study we show that energization (specifically, high membrane potential) is required for 4-hydroxynonenal to activate proton conductance mediated by adenine nucleotide translocase. Prolonging the time at high membrane potential promotes greater uncoupling. 4-Hydroxynonenal-induced uncoupling via adenine nucleotide translocase is prevented but not readily reversed by addition of carboxyatractylate, suggesting a permanent change (such as adduct formation) that renders the translocase leaky to protons. In contrast with the irreversibility of proton conductance, carboxyatractylate added after 4-hydroxynonenal still inhibits nucleotide translocation, implying that the proton conductance and nucleotide translocation pathways are different. We propose a model to relate adenine nucleotide translocase conformation to proton conductance in the presence or absence of 4-hydroxynonenal and/or carboxyatractylate.
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Uzikov, Yu N. "Proton-Deuteron Scattering and Test of Time-Reversal Invariance." EPJ Web of Conferences 113 (2016): 04027. http://dx.doi.org/10.1051/epjconf/201611304027.
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Eversheim, D., Yu Valdau, and B. Lorentz. "Test of Time-Reversal Invariance at COSY (TRIC)." International Journal of Modern Physics: Conference Series 40 (January 2016): 1660079. http://dx.doi.org/10.1142/s201019451660079x.
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At the Cooler Synchrotron COSY a novel (P-even, T-odd) null test of time-reversal invariance to an accuracy of 10[Formula: see text] is planned as an internal target transmission experiment. The parity conserving time-reversal violating observable is the total cross-section asymmetry A[Formula: see text]. This quantity is measured using a polarized proton beam with an energy of 135 MeV and an internal tensor polarized deuteron target from the PAX atomic beam source. The reaction rate will be determined by the lifetime of the beam. Consequently, the accuracy of the current measurement of the circulating proton beam is crucial for this experiment. Thus, the cooler synchroton ring serves as an ideal forward spectrometer, as a detector, and an accelerator.
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Beyer, Michael. "Test of time-reversal symmetry in the proton-deuteron system." Nuclear Physics A 560, no. 4 (August 1993): 895–908. http://dx.doi.org/10.1016/0375-9474(93)90137-m.
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Uzikov, Yu N., and A. A. Temerbayev. "Test of Time-Reversal Symmetry in the Proton-Deuteron Scattering." International Journal of Modern Physics: Conference Series 40 (January 2016): 1660080. http://dx.doi.org/10.1142/s2010194516600806.
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The integrated cross section [Formula: see text] for a special type of double polarized proton-deuteron scattering constitutes a null test for time-invariance violating but P-parity conserving effects. Using Glauber theory for the [Formula: see text] elastic scattering and different types of phenomenological T-odd P-even NN-interactions we show that the contribution of the lowest mass meson exchange, i.e. the [Formula: see text]-meson, to the null-test signal [Formula: see text] vanishes. Variation of the cross section [Formula: see text] due to strong hadronic and Coulomb interaction is studied and its energy dependence is calculated in the GeV region.
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Henderson, Lydia M., and Robert W. Meech. "Evidence That the Product of the Human X-Linked Cgd Gene, Gp91-phox, Is a Voltage-Gated H+ Pathway." Journal of General Physiology 114, no. 6 (November 15, 1999): 771–86. http://dx.doi.org/10.1085/jgp.114.6.771.
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Expression of gp91-phox in Chinese hamster ovary (CHO91) cells is correlated with the presence of a voltage-gated H+ conductance. As one component of NADPH oxidase in neutrophils, gp91-phox is responsible for catalyzing the production of superoxide (O2·2). Suspensions of CHO91 cells exhibit arachidonate-activatable H+ fluxes (Henderson, L.M., G. Banting, and J.B. Chappell. 1995. J. Biol. Chem. 270:5909–5916) and we now characterize the electrical properties of the pathway. Voltage-gated currents were recorded from CHO91 cells using the whole-cell configuration of the patch-clamp technique under conditions designed to exclude a contribution from ions other than H+. As in other voltage-gated proton currents (Byerly, L., R. Meech, and W. Moody. 1984. J. Physiol. 351:199–216; DeCoursey, T.E., and V.V. Cherny. 1993. Biophys. J. 65:1590–1598), a lowered external pH (pHo) shifted activation to more positive voltages and caused the tail current reversal potential to shift in the manner predicted by the Nernst equation. The outward currents were also reversibly inhibited by 200 μM zinc. Voltage-gated currents were not present immediately upon perforating the cell membrane, but showed a progressive increase over the first 10–20 min of the recording period. This time course was consistent with a gradual shift in activation to more negative potentials as the pipette solution, pH 6.5, equilibrated with the cell contents (reported by Lucifer yellow included in the patch pipette). Use of the pH-sensitive dye 2′7′ bis-(2-carboxyethyl)-5(and 6) carboxyfluorescein (BCECF) suggested that the final intracellular pH (pHi) was ∼6.9, as though pHi was largely determined by endogenous cellular regulation. Arachidonate (20 μM) increased the amplitude of the currents by shifting activation to more negative voltages and by increasing the maximally available conductance. Changes in external Cl− concentration had no effect on either the time scale or the appearance of the currents. Examination of whole cell currents from cells expressing mutated versions of gp91-phox suggest that: (a) voltage as well as arachidonate sensitivity was retained by cells with only the NH2-terminal 230 amino acids, (b) histidine residues at positions 111, 115, and 119 on a putative membrane-spanning helical region of the protein contribute to H+ permeation, (c) histidine residues at positions 111 and 119 may contribute to voltage gating, (d) the histidine residue at position 115 is functionally important for H+ selectivity. Mechanisms of H+ permeation through gp91-phox include the possible protonation/deprotonation of His-115 as it is exposed alternatively to the interior and exterior faces of the cell membrane (see Starace, D.M., E. Stefani, and F. Bezanilla. 1997. Neuron. 19:1319–1327) and the transfer of protons across an “H-X-X-X-H-X-X-X-H” motif lining a conducting pore.
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Cherkas, Sergey. "Possible time reversal symmetry breaking at proton-deuteron forward elastic scattering." Czechoslovak Journal of Physics 50, S1 (January 2000): 207–10. http://dx.doi.org/10.1007/s10582-000-0027-8.
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Иванов, П. А., М. Ф. Кудояров, А. С. Потапов, and Т. П. Самсонова. "Коррекция характеристик обратного восстановления высоковольтных инжекционных 4H-SiC диодов с помощью протонного облучения." Физика и техника полупроводников 53, no. 6 (2019): 862. http://dx.doi.org/10.21883/ftp.2019.06.47743.9073.
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The effect of proton irradiation on electrical characteristics of high-voltage (3 kV) 4H-SiC junction diodes have been investigated. The diodes were irradiated through 10-µm thick Ni-film. The energy of protons and irradiation dose were 2.8 MeV and 4×1011 cm-2, respectively. After proton irradiation, the diodes exhibited 35-% increasing in on-state resistance, about 3 times decreasing in the reverse recovery charge with the reverse recovery character being "hard".
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Cherkas, S. L. "Possibility of time reversal symmetry violation at proton–deuteron forward elastic scattering." Nuclear Physics A 671, no. 1-4 (May 2000): 461–70. http://dx.doi.org/10.1016/s0375-9474(99)00843-x.
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Ansell, Jack, Bryan Laulicht, Sasha Bakhru, Xiaohui Luo, and Stephen Villano. "Reversal of Anticoagulation By Ciraparantag: Time to Onset and Duration of Effect." Blood 136, Supplement 1 (November 5, 2020): 24. http://dx.doi.org/10.1182/blood-2020-140524.
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Introduction: There is an unmet need for safe and effective anticoagulant reversal agents, with rapid onset of effects, for use in cases such as serious or life-threating bleeding, prior to urgent or emergency surgery, after major trauma, or in cases of anticoagulant overdose. Ciraparantag, an anticoagulant reversal agent with broad activity, binds directly to anticoagulant molecules including direct oral anticoagulants (DOACs), enoxaparin, and unfractionated heparin, without binding to endogenous coagulation factors or other plasma proteins. Two Phase 2 studies evaluated the safety and efficacy of ciraparantag for reversal of anticoagulation induced by apixaban or rivaroxaban in healthy adults. Methods: Two randomized, placebo-controlled, dose-ranging studies were conducted in healthy subjects 50-75 years of age. Subjects received apixaban or rivaroxaban until steady state. Study 1 subjects received apixaban 10 mg orally twice daily for 3.5 days. Study 2 subjects received rivaroxaban 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous (IV) dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120 or 180 mg) or placebo. Efficacy was based on manual whole blood clotting time (WBCT) at multiple timepoints over 24 hours beginning at 15 minutes after dosing. Subjects and technicians performing the WBCT testing were blinded to treatment. WBCT measures were performed in triplicate (simultaneous testing by 3 different evaluators) at 3 separate timepoints to analyze inter-observer variability using an analysis of variance (ANOVA) model with effects for observer and subject. Results: In Study 1 (apixaban), 49 subjects were randomized to receive study drug (36 ciraparantag, 13 placebo) and completed the study as planned. In Study 2 (rivaroxaban), 64 subjects were randomized to receive study drug (48 ciraparantag, 16 placebo) and all but one subject completed the study as planned. Ciraparantag demonstrated a rapid and dose-dependent reversal of apixaban and rivaroxaban anticoagulation as measured by the proportion of subjects whose WBCT decreased to within 10% above baseline at 15 minutes after study drug infusion. A lower dose of ciraparantag was required to achieve reversal of apixaban in a large fraction of subjects compared to the dose required for reversal of rivaroxaban (Figure). Reversal of anticoagulation was sustained in these subjects throughout the 24-hour measurement period. In both studies, there was good agreement among the triplicate manual WBCT measurements; all inter-observer coefficient of variance values were <5%. Ciraparantag was well tolerated; the most frequent adverse events were mild, transient sensations of warmth during or soon after infusion. Conclusions: In healthy subjects at steady-state levels of anticoagulation, ciraparantag single IV doses were well tolerated and produced rapid reversal of anticoagulation in high proportions of subjects within 15 minutes of administration (the first timepoint assessed) at doses ≥60 mg for apixaban and at a dose of 180 mg for rivaroxaban which were maintained throughout the 24-hour measurement period. Figure. Proportion of subjects with WBCT reversed to within 10% above baseline at 15 minutes and 30 minutes after dosing Disclosures Ansell: Amag Pharmaceuticals, Inc.: Consultancy. Bakhru:Pherosphere Technologies, Inc.: Current Employment. Luo:Amag Pharmaceuticals, Inc.: Current Employment. Villano:Amag Pharmaceuticals, Inc.: Consultancy. OffLabel Disclosure: Ciraparantag is an investigational drug being evaluated for the reversal of anticoagulation induced by direct oral anticoagulant (DOAC) therapies.
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Иванов, П. А., А. С. Потапов, М. Ф. Кудояров, and Т. П. Самсонова. "Влияние низкодозного протонного облучения на характеристики инжекционных диодов на основе 4H-SiC." Физика и техника полупроводников 52, no. 10 (2018): 1187. http://dx.doi.org/10.21883/ftp.2018.10.46459.8863.
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AbstractThe effect of low-dose proton irradiation (irradiation dose 10^10–1 . 8 × 10^11 cm^–2) on the capacitance–voltage, forward current–voltage, and reverse-recovery characteristics of 4 H -SiC p – n _ o junction diodes is studied. Irradiation is performed with 1.8-MeV protons through a 10-μm-thick Ni-film (the proton energy and Ni-film thickness were chosen so that the projected proton range in silicon carbide is approximately equal to the p – n _ o junction depth). It is shown that proton irradiation in the above doses (i) does not change the concentration of majority carriers, (ii) leads to a dramatic decrease in the lifetime of nonequilibrium carriers (at a low injection level) (by several tens of times at the highest irradiation dose), and (iii) decreases the reverse-recovery charge at a high injection level (by up to a factor of 3 at the highest irradiation dose).
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Mainwood, G. W., J. M. Renaud, and M. J. Mason. "The pH dependence of the contractile response of fatigued skeletal muscle." Canadian Journal of Physiology and Pharmacology 65, no. 4 (April 1, 1987): 648–58. http://dx.doi.org/10.1139/y87-108.
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Following a period of intense repetitive stimulation (e.g., brief tetanic stimuli every second for 3 min), muscle isometric tension development is reduced by about 80%. This suppression is reversible at a high external pH (8.0) with a half time of 15–20 min, but if the external pH is low (6.4) or the buffer concentration is low, recovery is prevented. Inhibition of recovery is associated with a slowed rate of lactate loss, which may suggest that intracellular lactacidosis is the cause of the inhibition. Alternatively, a low external pH may affect recovery from fatigue quite independently of its effect on lactate efflux. The possibility that surface membrane properties are changed by fatigue in a pH-dependent fashion was examined by measuring the cable properties and action potentials of fatigued fibres at different external pH values. A low external pH during recovery from fatigue was shown to result in a prolonged membrane depolarization of 10–12 mV, an increased transmembrane resistance, and a prolonged action potential. At a high external pH transmembrane resistance is lowered by fatigue, the depolarization lasts only about 10–15 min, and there is a smaller effect on the action potential. While the fatigued fibre membrane does show a changed response that is dependent on external pH, it is not clear that this could be related to the suppression of contraction. Direct measurements of intracellular pH show a fall of about 0.4 to 0.5 pH units in the surface fibres following fatigue. This results from the lactic acid generated during activity. It is now clear that lactate crosses the membrane in association with protons and at least part of this flux is mediated by a specific carrier mechanism. Efflux is limited by the transmembrane pH gradient, which in turn depends on the extracellular buffer concentration in the diffusion limited space around the fibres. Intracellular lactacidosis in resting muscles can be generated by a reversal of the normal flux. Fibres can be loaded with lactate (L) by increasing the extracellular [H+][L−] product with a resultant fall in intracellular pH. Lactate loads similar to those seen in fatigued muscle simulate some but not all of the responses seen in the postfatigue state. The twitch is prolonged with a slow relaxation phase, an increased time to peak tension but with an increase in peak tension. The effects are reversible but usually result in a reduced contractile response following the washout. Tetanic tension is reduced, but the effect is small compared with that seen in fatigue. Relaxation from the tetanus is also slowed by the intracellular lactacidosis in a reversible fashion. It is concluded that intracellular lactacidosis is not the main cause of the suppressed tension found in the type of fatigue studied here but that the acidosis slows relaxation and may also prevent or slow some step in the transition from the fatigued to the normal state.
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VAN OERS, WILLEM T. H. "CONSTRAINTS ON A PARITY-CONSERVING/TIME-REVERSAL-NON-CONSERVING INTERACTION." International Journal of Modern Physics E 08, no. 06 (December 1999): 513–26. http://dx.doi.org/10.1142/s0218301399000355.
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Time-reversal-invariance non-conservation has for the first time been unequivocally demonstrated in a direct measurement at CPLEAR. One then can ask the question: What about tests of time-reversal-invariance in systems other than the kaon system? Tests of time-reversal-invariance can be distinguished as belonging to two classes: the first one deals with parity violating (P-odd)/time-reversal-invariance-odd (T-odd) interactions, while the second one deals with P-even/T-odd interactions (assuming CPT conservation this implies C-conjugation non-conservation). Limits on a P-odd/T-odd interaction follow from measurements of the electric dipole moment of the neutron (with a present upper limit of 6 × 10-26 e.cm [95% C.L.]). It provides a limit on a P-odd/T-odd pion-nucleon coupling constant which is less than 10-4 times the weak interaction strength. Experimental limits on a P-even/T-odd interaction are much less stringent. Following the standard approach of describing the nucleon-nucleon interaction in terms of meson exchanges it can be shown that only charged rho-meson exchange and A 1-meson exchange can lead to a P-even/T-odd interaction. The better constraints stem from measurements of the electric dipole moment of the neutron and from measurements of charge-symmetry breaking in neutron-proton elastic scattering. The latter experiments were executed at TRIUMF (497 and 347 MeV) and at IUCF (183 MeV). Weak decay experiments may provide limits which will possibly be comparable. All other experiments, like gamma decay experiments, detailed balance experiments, polarization–analyzing power difference determinations, and five-fold correlation experiments with polarized incident nucleons and aligned nuclear targets, have been shown to be at least an order of magnitude less sensitive. The question then emerges: is there room for further experimentation?
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Haerter, Friederike, Jeroen Cedric Peter Simons, Urs Foerster, Ingrid Moreno Duarte, Daniel Diaz-Gil, Shweta Ganapati, Katharina Eikermann-Haerter, et al. "Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-depolarizing Neuromuscular-blocking Agents." Anesthesiology 123, no. 6 (December 1, 2015): 1337–49. http://dx.doi.org/10.1097/aln.0000000000000868.
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Abstract Background The authors evaluated the comparative effectiveness of calabadion 2 to reverse non-depolarizing neuromuscular-blocking agents (NMBAs) by binding and inactivation. Methods The dose–response relationship of drugs to reverse vecuronium-, rocuronium-, and cisatracurium-induced neuromuscular block (NMB) was evaluated in vitro (competition binding assays and urine analysis), ex vivo (n = 34; phrenic nerve hemidiaphragm preparation), and in vivo (n = 108; quadriceps femoris muscle of the rat). Cumulative dose–response curves of calabadions, neostigmine, or sugammadex were created ex vivo at a steady-state deep NMB. In living rats, the authors studied the dose–response relationship of the test drugs to reverse deep block under physiologic conditions, and they measured the amount of calabadion 2 excreted in the urine. Results In vitro experiments showed that calabadion 2 binds rocuronium with 89 times the affinity of sugammadex (Ka = 3.4 × 109 M−1 and Ka = 3.8 × 107 M−1). The results of urine analysis (proton nuclear magnetic resonance), competition binding assays, and ex vivo study obtained in the absence of metabolic deactivation are in accordance with an 1:1 binding ratio of sugammadex and calabadion 2 toward rocuronium. In living rats, calabadion 2 dose-dependently and rapidly reversed all NMBAs tested. The molar potency of calabadion 2 to reverse vecuronium and rocuronium was higher compared with that of sugammadex. Calabadion 2 was eliminated renally and did not affect blood pressure or heart rate. Conclusions Calabadion 2 reverses NMB induced by benzylisoquinolines and steroidal NMBAs in rats more effectively, i.e., faster than sugammadex. Calabadion 2 is eliminated in the urine and well tolerated in rats.
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Yu, Yajun, Zhongxing Li, Dong Zhang, Lei Xing, and Hao Peng. "Simulation studies of time reversal‐based protoacoustic reconstruction for range and dose verification in proton therapy." Medical Physics 46, no. 8 (July 5, 2019): 3649–62. http://dx.doi.org/10.1002/mp.13661.
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Lin, Rui, Hang Yu, Di Zhong, Lihang Han, Ying Lu, Shenghao Tang, and Zhixian Hao. "Investigation of real-time changes and recovery of proton exchange membrane fuel cell in voltage reversal." Energy Conversion and Management 236 (May 2021): 114037. http://dx.doi.org/10.1016/j.enconman.2021.114037.
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Rodríguez, E. M., D. Jaque, E. Cantelar, F. Cussó, G. Lifante, A. C. Busacca, A. Cino, and S. R. Sanseverino. "Time resolved confocal luminescence investigations on Reverse Proton Exchange Nd:LiNbO_3 channel waveguides." Optics Express 15, no. 14 (2007): 8805. http://dx.doi.org/10.1364/oe.15.008805.
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Herzog, Eva, Franz Kaspereit, Wilfried Krege, Peter Niebl, Stefan Schulte, and Gerhard Dickneite. "Four-Factor Prothrombin Complex Concentrate (4F-PCC) Is Superior to Three-Factor Prothombin Comlex Concentrates (3F-PCC) for Reversal of Coumarin Anticoagulation." Blood 124, no. 21 (December 6, 2014): 1472. http://dx.doi.org/10.1182/blood.v124.21.1472.1472.
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Abstract Due to its wide range of therapeutic indications approximately 2.5 million adults and children are currently receiving vitamin K antagonist (VKA) therapy in the US (Pengo et al., 2006). Bleeding is the major risk of anticoagulation, with an incidence of major hemorrhage in VKA-treated patients of 1.7-3.4% per year (Schulman et al., 2008). The 4-factor prothrombin complex concentrate (4F-PCC), which contains the human coagulation factors II, VII, IX and X together with the endogenous inhibitor proteins S and C, is indicated for the urgent reversal of acquired coagulation factor deficiency induced by VKA (e.g. warfarin or coumarin) therapy in adult patients with acute major bleeding. In contrast, the 3-factor prothrombin complex concentrates (3F-PCC), which contain factors II, IX, X and only minimal amounts of factor VII, are only indicated for the prevention and control of hemorrhagic episodes in hemophilia B patients. Nevertheless, the use of 3F-PCC for correcting hemostasis following warfarin overdose has been discussed (Imberti et al. 2011, Holland et al. 2009). However, the lack of factor VII in these 3F-PCC products has raised questions about efficacy in comparison to 4F-PCC (Sarode et al. 2012). To date, no studies have directly compared 3F-PCC vs. 4F-PCC regarding their efficacy for reversal of VKA anticoagulation. Therefore, this study was conducted as a head-to-head comparison of 4F-PCC and 3F-PCC for effective reversal of VKA (coumarin) induced anticoagulation using an established rat model of acute bleeding (Dickneite et al. 2007). Rats received an oral dose of 2.5 mg/kg phenprocoumon. At 15.75 hours post dosing, animals were treated with a single intravenous dose of saline, 4F-PCC (Beriplex® P/N, Kcentra®, CSL Behring) or 3F-PCC (Bebulin® VH and Profilnine® SD). Study endpoints included bleeding following tail clip, activated partial thromboplastin time (aPTT), and prothrombin time (PT). In addition, the plasma levels of vitamin K dependent coagulation factors were determined. Acute coumarin anticoagulation of rats induced a rise in median bleeding time by ≥2 fold from an average of 823 to 1800 seconds (max. observation period) compared to untreated animals. In parallel, PT and aPTT were prolonged from 8.9 to 29.9 seconds and 14.5 to 25.5 seconds, respectively. Treatment with 4F-PCC was able to fully and statistically significantly reverse bleeding, achieving average bleeding times of 676 seconds. In parallel, the elevation in PT was reversed to 15.1 seconds. In contrast, the 3F-PCCs were not or only partially able to reduce coumarin induced bleeding with average bleeding times of 1398 and 1708 seconds post treatment. This also correlated with inferior reductions in PT which achieved minimum levels of 23.8 and 29.5 seconds. There was no reduction in aPTT seen for any treatment option. In conclusion, this first direct comparison of 4F-PCC and 3F-PCCs for the reversal of VKA anticoagulation in a rat model of acute bleeding suggests that replenishment of all vitamin K-dependent coagulation factors including factor VII as achieved using a 4F-PCC may result in superior efficacy compared to the use of 3F-PCCs. References Dickneite G: Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation. Thromb Res 119:643–651, 2007 Holland L, Warkentin TE, Refaai M, et al. Suboptimal effect of three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic INR due to warfarin overdose. Transfusion 2009;49:1171–7. Imberti D, Barillari G, Biasioli C, et al. Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus 2011;9:148–55. Pengo V, Pegoraro C, Cucchini U, IIiceto S. The management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis 2006;21:73-7 Sarode R, Matevosyan K, Bhagat R, Rutherford C, Madden C, Beshay JE. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage.J Neurosurg 116:491–497, 2012 Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: american college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;13:257S-98S Disclosures Herzog: CSL Behring GmbH: Employment. Off Label Use: Non-clinical data on the use of 3F-PCC for reversal of VKA . Kaspereit:CSL Behring GmbH: Employment. Krege:CSL Behring GmbH: Employment. Niebl:CSL Behring GmbH: Employment. Schulte:CSL Behring GmbH: Employment. Dickneite:CSL Behring GmbH: Employment.
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Halim, Abdel-Baset, Yan Li, Evan Stein, and Jeanne Mendell. "Low Concentrations of rhFVIIa or FEIBA Significantly and Rapidly Reverse the Anticoagulant Effects of Supratherapeutic Edoxaban." Blood 118, no. 21 (November 18, 2011): 1252. http://dx.doi.org/10.1182/blood.v118.21.1252.1252.
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Abstract Abstract 1252 Introduction: Edoxaban is an oral, direct factor Xa (FXa) inhibitor currently in phase 3 clinical development for stroke prevention in nonvalvular atrial fibrillation (AF) and the treatment and secondary prevention of venous thromboembolism (VTE). Guidance for the emergency management of serious bleeding and strategies for reversing the anticoagulant effects edoxaban are needed. Both recombinant human FVIIa (rhFVIIa; NovoSeven®) and a human plasma fraction containing nonactivated forms of FII, FIX, and FX/proteins C and S and activated FVII (FEIBA; factor eight inhibitor bypassing activity) have been identified as potential reversal agents for edoxaban. The minimum effective doses and the time course required for either rhFVIIa or FEIBA to reverse supratherapeutic concentrations of edoxaban in an anticoagulated patient have yet to be established. This ex vivo study was conducted to assess the effects and establish the time course of various concentrations of rhFVIIa and FEIBA on the reversal of edoxaban's anticoagulant effects. Methods: Edoxaban at supratherapeutic concentrations of 500 and 1000 ng/mL (therapeutic level is ∼250 ng/mL for Cmax of a 60-mg dose) was added to fresh blood drawn from healthy subjects; control samples were diluent alone. After 60 min of incubation, rhFVIIa, FEIBA, or control was added to the samples. rhFVIIa was added to produce final concentrations of 0.8 and 1.8 μg/mL, which correspond to known maximal observed human plasma concentrations at doses of 40 and 90 μg/kg. FEIBA was added to produce concentrations of 0.75 and 1.4 U/mL, which correspond to human plasma concentrations at the therapeutic doses of FEIBA of 50 to 100 U/kg. In order to determine reversal of anticoagulant effects over time, coagulation assays (PT, aPTT, anti-Xa, intrinsic FXa activity, thrombin generation assay [TGA], D-dimer, and FVIIa activity) were measured at times 0, 0.25, 0.50, 1, 2, and 4 h after incubation with rhFVIIa, FEIBA, or control. Results: In edoxaban alone and control samples, PT, aPTT, and anti-Xa results reflected previously established anticoagulant activity. Both 500 and 1000 ng/mL of edoxaban completely inhibited intrinsic FXa and thrombin generation as measured by TGA (peak). Measures of FVIIa activity indicated that the concentrations of rhFVIIa utilized were consistent with previously reported responses. With the exception of thrombin levels, reversal of edoxaban anticoagulant activity by both rhFVIIa and FEIBA was observed for PT, aPTT, and anti-Xa beginning at 0.25 h and was maintained across the experimental period. At 1000 ng/mL edoxaban, the observed decrease at 0.25 h post-reversal of anticoagulant activity was 82% for anti-Xa, 72% for PT, and 58% for aPTT. Compared with baseline, the maximum reversal of intrinsic FXa activity for edoxaban 500 ng/mL was ∼30% and for 1000 ng/mL was 15% across all concentrations of rhFVIIa and FEIBA. The TGA assay indicated both rhFVIIa and FEIBA reversed ∼45% and 20% of the effect of edoxaban at 500 ng/mL and 1000 ng/mL, respectively, 4 h after adding the reversal agents. With the exception of 1 baseline sample, levels of D-dimer did not show significant changes with the addition of edoxaban or with its subsequent reversal by either rhFVIIa or FEIBA. Conclusion: Low therapeutic concentrations of rhFVIIa and FEIBA showed significant and rapid reversal of supratherapeutic concentrations of the anticoagulant activity induced by edoxaban based on PT, aPTT, and anti-Xa activity. Disclosures: Halim: Daiichi Sankyo Pharma Development: Employment. Li:Daiichi Sankyo Pharma Development: Employment. Stein:Daiichi Sankyo: Consultancy, Research Funding; AACC: Consultancy, Honoraria, Research Funding; Abbott: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; FDA: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; ISIS: Consultancy, Honoraria, Research Funding; Merck & Co: Consultancy, Honoraria, Research Funding; National Lipid Association: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Reliant: Consultancy, Honoraria, Research Funding; Regeneron: Consultancy, Honoraria, Research Funding; SanofiAventis: Consultancy, Honoraria, Research Funding; Schering-Plough: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Wyeth: Consultancy, Honoraria, Research Funding. Mendell:Daiichi Sankyo Pharma Development: Employment.
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Villano, Stephen, Sasha Bakhru, Xiaohui Luo, and Daniel Freedman. "Design of a Randomized, Controlled Study to Evaluate Reversal of Anticoagulation of Ciraparantag in Healthy Adults: Whole Blood Clotting Time Assessed By Automated and Manual Methods." Blood 136, Supplement 1 (November 5, 2020): 20–21. http://dx.doi.org/10.1182/blood-2020-142798.
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There is a need for safe and effective reversal agents for patients on chronic anticoagulant therapy in cases such as serious or life-threatening bleeding, urgent or emergency surgery, after major trauma, or in cases of anticoagulant overdose. Ciraparantag, an anticoagulant reversal agent in clinical development, which is believed to bind directly to anticoagulant molecules through non-covalent bonds, with no binding to blood coagulation factors or proteins in the blood. Phase 2 clinical studies have shown that ciraparantag reverses anticoagulation in healthy volunteers treated with edoxaban, enoxaparin, apixaban, or rivaroxaban as assessed by manual whole blood clotting time (WBCT). WBCT is the key pharmacodynamic marker because ciraparantag is cationic and binds to the anionic substances in standard blood collection tubes, and to anionic, colloidal activators used in the traditional coagulation assays such as PT or aPTT. Therefore, such assays are not appropriate markers for measuring ciraparantag's effect. WBCT is a direct measure of the time required for blood clot formation ex vivo and uses blood drawn into reagent-free collection equipment, using only glass as the activating agent. A Phase 2b clinical study is planned to evaluate the efficacy and safety of ciraparantag for reversal of anticoagulation as measured by WBCT using an automated point-of-care (PoC) coagulometer (developed by Perosphere Technologies, Inc.) compared with a manual testing method. This is a randomized, double-blind, placebo-controlled study in healthy adults 18 to 75 years of age who are anticoagulated with apixaban (10 mg PO twice daily) or rivaroxaban (20 mg PO once daily). Subjects who reach steady-state anticoagulation will be stratified into 2 age groups and randomized 2:1 to receive a single IV dose of ciraparantag or placebo, followed by serial WBCT testing and standard safety assessments over 24 hours. The primary efficacy endpoint is based on the extent and timing of reversal of anticoagulation following ciraparantag administration as compared with placebo, based on WBCT measured using the PoC coagulometer. Manual WBCT testing also will be performed at selected timepoints in order to describe the correlation between results obtained with the two methods. The coagulometer is expected to provide greater sensitivity and precision compared to the manual method. Further details of the design of this study will be provided. The results of this study will inform dose selection for the future Phase 3 clinical trial and will provide data on the use of the PoC coagulometer for assessment of ciraparantag for reversal of anticoagulation. Disclosures Villano: Amag Pharmaceuticals, Inc.: Consultancy. Bakhru:Pherosphere Technologies, Inc.: Current Employment. Luo:Amag Pharmaceuticals, Inc.: Current Employment. Freedman:Amag Pharmaceuticals, Inc.: Current Employment. OffLabel Disclosure: Ciraparantag is an investigational drug being evaluated for the reversal of anticoagulation induced by direct oral anticoagulant (DOAC) therapies.
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Graziani, Maura. "Precision Measurement of the monthly cosmic Ray fluxes e−, e+, p, He) with the Alpha Magnetic Spectrometer on the ISS." EPJ Web of Conferences 209 (2019): 01052. http://dx.doi.org/10.1051/epjconf/201920901052.
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The precision measurements of the monthly cosmic ray fluxes with Alpha Magnetic Spectrometer on the International Space Station are presented. Individual electron, positron, proton and helium spectra have been measured for each Bartel’s rotation period (27 days) in the time range from May 2011 to May 2017. This period covers the ascending phase of solar cycle #24 together with the reversal of the Sun’s magnetic field polarity through the minimum. The fluxes reveal a characteristic time dependence below 20 GeV. The data show a strong charge-sign dependent effects corresponding to the the polarity reversal of the solar magnetic field.
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Kumar, Umesh, Ujjawal Sharma, and Garima Rathi. "Reversal of hypermethylation and reactivation of glutathione S-transferase pi 1 gene by curcumin in breast cancer cell line." Tumor Biology 39, no. 2 (February 2017): 101042831769225. http://dx.doi.org/10.1177/1010428317692258.
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One of the mechanisms for epigenetic silencing of tumor suppressor genes is hypermethylation of cytosine residue at CpG islands at their promoter region that contributes to malignant progression of tumor. Therefore, activation of tumor suppressor genes that have been silenced by promoter methylation is considered to be very attractive molecular target for cancer therapy. Epigenetic silencing of glutathione S-transferase pi 1, a tumor suppressor gene, is involved in various types of cancers including breast cancer. Epigenetic silencing of tumor suppressor genes can be reversed by several molecules including natural compounds such as polyphenols that can act as a hypomethylating agent. Curcumin has been found to specifically target various tumor suppressor genes and alter their expression. To check the effect of curcumin on the methylation pattern of glutathione S-transferase pi 1 gene in MCF-7 breast cancer cell line in dose-dependent manner. To check the reversal of methylation pattern of hypermethylated glutathione S-transferase pi 1, MCF-7 breast cancer cell line was treated with different concentrations of curcumin for different time periods. DNA and proteins of treated and untreated cell lines were isolated, and methylation status of the promoter region of glutathione S-transferase pi 1 was analyzed using methylation-specific polymerase chain reaction assay, and expression of this gene was analyzed by immunoblotting using specific antibodies against glutathione S-transferase pi 1. A very low and a nontoxic concentration (10 µM) of curcumin treatment was able to reverse the hypermethylation and led to reactivation of glutathione S-transferase pi 1 protein expression in MCF-7 cells after 72 h of treatment, although the IC50 value of curcumin was found to be at 20 µM. However, curcumin less than 3 µM of curcumin could not alter the promoter methylation pattern of glutathione S-transferase pi 1. Treatment of breast cancer MCF-7 cells with curcumin causes complete reversal of glutathione S-transferase pi 1 promoter hypermethylation and leads to re-expression of glutathione S-transferase pi 1, suggesting it to be an excellent nontoxic hypomethylating agent.
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Lu, Genmin, Francis R. DeGuzman, Sanjay Lakhotia, Stanley J. Hollenbach, David R. Phillips, and Uma Sinha. "Recombinant Antidote for Reversal of Anticoagulation by Factor Xa Inhibitors." Blood 112, no. 11 (November 16, 2008): 983. http://dx.doi.org/10.1182/blood.v112.11.983.983.
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Abstract Individuals anticoagulated with warfarin or heparin are typically treated with specific antidotes such as vitamin K or protamine, respectively, if they bleed or require surgery. In contrast, specific and effective antidotes are not available for the reversal of the anticoagulant effects of the low molecular weight heparins (LMWH) or the new oral anticoagulants targeting factor Xa (fXa) which are predictably only marginally affected by standard treatments using rfVIIa or fresh frozen plasma. The present study was designed to test the hypothesis that plasma-derived or recombinant fXa, modified to lack catalytic and membrane binding activities, could neutralize the anticoagulant activities of small molecule fXa inhibitors and LMWH. Plasma derived antidote (pd-Antidote) was prepared by chemical modification of the active site serine of fXa followed by chymotryptic removal of the Gla domain. Preliminary experiments showed that pd-Antidote dose dependently reversed the activity of rivaroxaban, apixaban or betrixaban, three small molecule fXa inhibitors currently in clinical trials. In a fXa amidolytic assay with 3nM enzyme, half maximal reversal of inhibitory activities (EC50) was attained at the following pd-Antidote concentrations: rivaroxaban =49 nM, apixaban = 122 nM, betrixaban = 41 nM. The pd-Antidote had no effect on the activity of fXa in the absence of inhibitors. Thus, active site inactivated pd-Antidote retained the ability to bind small molecule inhibitors of fXa. The activity of pd-Antidote was not limited to reversal of purified fXa catalytic activity. In a tissue factor-initiated thrombin generation assay in plasma, while pd-Antidote did not interfere with the normal function of prothrombinase complexes, it dose-dependently and completely reversed the inhibition produced by the small molecule fXa inhibitors. Pd-Antidote also demonstrated reversal of the in-vitro anticoagulant activity of the LMWH, enoxaparin. Addition of pd-Antidote (515nM) produced a 37% reduction of the clotting activity of enoxaparin (1.25Units/ml). In an activated partial thromboplastin time assay (aPTT), pd-Antidote also dose-dependently reversed the inhibitory effects of the fXa inhibitors. For example, aPTT prolongation by betrixaban (400nM) was reversed with an estimated EC50=650nM. Baseline aPTT was not altered upon addition of pd-Antidote up to a concentration of 2.5 μM, the highest concentration studied. Recombinant antidote (r-Antidote) was expressed in mammalian cells (Chinese hamster ovary) using a construct for human fXa with the S195A mutation and lacking the Gla-domain. The EC50’s for purified r-Antidote in reversing 7.5 nM fXa inhibitors in the fXa catalytic activity assay were: rivaroxaban =17 nM, apixaban = 45 nM, betrixaban = 15 nM. As expected, there was no inhibition of fXa activity by r-Antidote alone. Purified r-Antidote also reversed anticoagulant activity in plasma clotting assays. Prothrombin time (PT) extensions achieved by supratherapeutic concentrations of rivaroxaban (1 μM) or apixaban (1 μM) were completely normalized upon addition of r-Antidote (1.5 μM). Ex vivo clotting prolongation by an excess of betrixaban (300 nM) was essentially reversed (88% correction) by pre-incubation with r-Antidote (570 nM) prior to addition of aPTT reagents. The concentration of r-Antidote required for corrective activity was related to the inhibitory potency of the oral fXa inhibitors. PT or aPTT baselines did not change upon addition of r-Antidote alone at 1.9 μM, the highest concentration tested. We also examined the ability of both pd-Antidote and r-Antidote to alleviate inhibitory activities produced upon oral dosing of fXa inhibitors in mice. Perturbation of whole blood PT/INR in dosed animals was followed as a marker of anticoagulation. The effect following dosing of a fXa inhibitor could be reversed by a single intravenous injection of antidote. INR measurements in blood samples of treated animals showed a >50% reduction of observed inhibitory activity compared to control animals. Our results suggest that these plasma derived or recombinant proteins have the potential to act as universal antidotes for reversal of anticoagulation of all current fXa inhibitors, both small molecule and antithrombin dependent, in patients with bleeding related medical emergencies or those requiring cessation of anticoagulation prior to surgery.
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Sparrow, Alexander J., Hugh Watkins, Matthew J. Daniels, Charles Redwood, and Paul Robinson. "Mavacamten rescues increased myofilament calcium sensitivity and dysregulation of Ca2+ flux caused by thin filament hypertrophic cardiomyopathy mutations." American Journal of Physiology-Heart and Circulatory Physiology 318, no. 3 (March 1, 2020): H715—H722. http://dx.doi.org/10.1152/ajpheart.00023.2020.
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Thin filament hypertrophic cardiomyopathy (HCM) mutations increase myofilament Ca2+ sensitivity and alter Ca2+ handling and buffering. The myosin inhibitor mavacamten reverses the increased contractility caused by HCM thick filament mutations, and we here test its effect on HCM thin filament mutations where the mode of action is not known. Mavacamten (250 nM) partially reversed the increased Ca2+ sensitivity caused by HCM mutations Cardiac troponin T (cTnT) R92Q, and cardiac troponin I (cTnI) R145G in in vitro ATPase assays. The effect of mavacamten was also analyzed in cardiomyocyte models of cTnT R92Q and cTnI R145G containing cytoplasmic and myofilament specific Ca2+ sensors. While mavacamten rescued the hypercontracted basal sarcomere length, the reduced fractional shortening did not improve with mavacamten. Both mutations caused an increase in peak systolic Ca2+ detected at the myofilament, and this was completely rescued by 250 nM mavacamten. Systolic Ca2+ detected by the cytoplasmic sensor was also reduced by mavacamten treatment, although only R145G increased cytoplasmic Ca2+. There was also a reversal of Ca2+ decay time prolongation caused by both mutations at the myofilament but not in the cytoplasm. We thus show that mavacamten reverses some of the Ca2+-sensitive molecular and cellular changes caused by the HCM mutations, particularly altered Ca2+ flux at the myofilament. The reduction of peak systolic Ca2+ as a consequence of mavacamten treatment represents a novel mechanism by which the compound is able to reduce contractility, working synergistically with its direct effect on the myosin motor. NEW & NOTEWORTHY Mavacamten, a myosin inhibitor, is currently in phase-3 clinical trials as a pharmacotherapy for hypertrophic cardiomyopathy (HCM). Its efficacy in HCM caused by mutations in thin filament proteins is not known. We show in reductionist and cellular models that mavacamten can rescue the effects of thin filament mutations on calcium sensitivity and calcium handling although it only partially rescues the contractile cellular phenotype and, in some cases, exacerbates the effect of the mutation.
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Dai, Xiangyan, Xinkai Cheng, Jianfei Huang, Yanping Gao, Deshou Wang, Zhi Feng, Gang Zhai, et al. "Rbm46, a novel germ cell-specific factor, modulates meiotic progression and spermatogenesis." Biology of Reproduction 104, no. 5 (February 2, 2021): 1139–53. http://dx.doi.org/10.1093/biolre/ioab016.
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Abstract It has been suggested that many novel RNA-binding proteins (RBPs) are required for gametogenesis, but the necessity of few of these proteins has been functionally verified. Here, we identified one RBP, Rbm46, and investigated its expression pattern and role in zebrafish reproduction. We found that rbm46 is maternally provided and specifically expressed in the germ cells of gonadal tissues using in situ hybridization, reverse transcription-PCR, and quantitative real-time polymerase chain reaction (qRT-PCR). Two independent rbm46 mutant zebrafish lines were generated via the transcription activator-like effector nuclease technique. Specific disruption of rbm46 resulted in masculinization and infertility in the mutants. Although the spermatogonia appeared grossly normal in the mutants, spermatogenesis was impaired, and meiosis events were not observed. The introduction of a tp53M214K mutation could not rescue the female-to-male sex-reversal phenotype, indicating that rbm46 acts independently of the p53-dependent apoptotic pathway. RNA sequencing and qRT-PCR subsequently indicated that Rbm46 might be involved in the posttranscriptional regulation of functional genes essential for germ cell development, such as nanos3, dazl, and sycp3, during gametogenesis. Together, our results reveal for the first time the crucial role of rbm46 in regulating germ cell development in vivo through promotion of germ cell progression through meiosis prophase I.
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Daniel, E. E., Gregory Bodie, Marco Mannarino, Geoffrey Boddy, and Woo-Jung Cho. "Changes in membrane cholesterol affect caveolin-1 localization and ICC-pacing in mouse jejunum." American Journal of Physiology-Gastrointestinal and Liver Physiology 287, no. 1 (July 2004): G202—G210. http://dx.doi.org/10.1152/ajpgi.00356.2003.
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Pacing of mouse is dependent on the spontaneous activity of interstitial cells of Cajal in the myenteric plexus (ICC-MP). These ICC, as well as intestinal smooth muscle, contain small membrane invaginations called caveolae. Caveolae are signaling centers formed by insertions of caveolin proteins in the inner aspect of the plasma membrane. Caveolins bind signaling proteins and thereby negatively modulate their signaling. We disrupted caveolae by treating intestinal segments with methyl β-clodextrin (CD) to remove cholesterol or with water- soluble cholesterol (WSC) to load cholesterol. Both of these treatments reduced pacing frequencies, and these effects were reversed by the other agent. These treatments also inhibited paced contractions, but complete reversal was not observed. To evaluate the specificity of the effects of CD and WSC, additional studies were made of their effects on responses to carbamoyl choline and to stimulation of cholinergic nerves. Neither of these treatments affected these sets of responses compared with their respective time controls. Immunochemical and ultrastructural studies showed that caveolin 1 was present in smooth muscle membranes and ICC-MP. CD depleted both caveolin 1 and caveolae, whereas WSC increased the amount of caveolin 1 immunoreactivity and altered its distribution but failed to increase the number of caveolae. The effects of each agent were reversed in major part by the other. We conclude that signaling through caveolae may play a role in pacing by ICC but does not affect responses to acetylcholine from nerves or when added exogenously.
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Matsuda, James J., Mohammed S. Filali, Kenneth A. Volk, Malia M. Collins, Jessica G. Moreland, and Fred S. Lamb. "Overexpression of CLC-3 in HEK293T cells yields novel currents that are pH dependent." American Journal of Physiology-Cell Physiology 294, no. 1 (January 2008): C251—C262. http://dx.doi.org/10.1152/ajpcell.00338.2007.
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ClC-3 is a member of the ClC family of anion channels/transporters. Recently, the closely related proteins ClC-4 and ClC-5 were shown to be Cl−/H+ antiporters ( 39 , 44 ). The function of ClC-3 has been controversial. We studied anion currents in HEK293T cells expressing wild-type or mutant ClC-3. The basic biophysical properties of ClC-3 currents were very similar to those of ClC-4 and ClC-5, and distinct from those of the swelling-activated anion channel. ClC-3 expression induced currents with time-dependent activation that rectified sharply in the outward direction. The reversal potential of the current shifted by −48.3 ± 2.5 mV per 10-fold (decade) change in extracellular Cl− concentration, which did not conform to the behavior of an anion-selective channel based upon the Nernst equation, which predicts a −58.4 mV/decade shift at 22°C. Manipulation of extracellular pH (6.35–8.2) altered reversal potential by 10.2 ± 3.0 mV/decade, suggesting that ClC-3 currents were coupled to proton movement. Mutation of a specific glutamate residue (E224A) changed voltage dependence in a manner similar to that observed in other ClC Cl−/H+ antiporters. Mutant currents exhibited Nernstian changes in reversal potential in response to altered extracellular Cl− concentration that averaged −60 ± 3.4 mV/decade and were pH independent. Thus ClC-3 overexpression induced a pH-sensitive conductance in HEK293T cells that is biophysically similar to ClC-4 and ClC-5.
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Zhu, Hong, Xia Zou, ShiXin Lin, Xin Hu, and Jun Gao. "Effects of naringin on reversing cisplatin resistance and the Wnt/β-catenin pathway in human ovarian cancer SKOV3/CDDP cells." Journal of International Medical Research 48, no. 10 (October 2020): 030006051988786. http://dx.doi.org/10.1177/0300060519887869.
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Objective Ovarian cancer is one of three malignant tumors of the female reproductive system. Our previous studies showed that the traditional Chinese medicine naringin significantly inhibited the proliferation of platinum-resistant ovarian cancer cells in vitro, and that the mechanism may be related to the NF-κB pathway. Methods The MTT assay was used to detect the sensitivity of SKOV3 and SKOV3/CDDP cells to cisplatin, the effect of different naringin concentrations on the proliferation of SKOV3/CDDP cells, and the reversal of cisplatin resistance in naringin-treated SKOV3/CDDP cells. Western blotting was used to detect β-catenin, c-Myc, and cyclin D1 protein levels in the different cell lines. Results MTT results showed that different concentrations of naringin inhibited the proliferation of SKOV3 and SKOV3/CDDP cells, and that the inhibition increased with increasing concentrations and prolonged incubation times. Western blotting revealed that compared with controls (SKOV3/CDDP-0), β-catenin, c-Myc and cyclin D1 proteins levels were significantly decreased in SKOV3/CDDP-C, SKOV3/CDDP-N 20, and SKOV3/CDDP-CN 20 cells, suggesting that naringin inhibited the proliferation of SKOV3/CDDP cells in a concentration and time dependent manner. Conclusions Non-cytotoxic naringin reduced the expression of β-catenin, c-Myc, and cyclin D1 in SKOV3/CDDP cells and partially reversed cisplatin resistance in SKOV3/CDDP CN 20 cells.
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Lim, T. L., J. J. Quenby, M. K. Reuss, E. Keppler, H. Kunow, B. Heber, and R. J. Forsyth. "ULYSSES observations of energetic particle acceleration and the superposed CME and CIR events of November 1992." Annales Geophysicae 14, no. 4 (April 30, 1996): 400–410. http://dx.doi.org/10.1007/s00585-996-0400-4.
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Abstract. During November 1992, a series of forward and reverse shocks passed the ULYSSES spacecraft. Spectral and anisotropy measurements are reported for protons and alpha particles between 0.28 and 6 MeV observed by the Energetic Particle Composition Experiment, data recorded by the Magnetometer Experiment and the high-energy (2.7–300 MeV) proton data from the Kiel Electron Telescope. An analysis of energetic particle, plasma and magnetometer data from ULYSSES has allowed a unique study of the corresponding arrival of fare particles, particles within a corotating interaction region and particles transported with a coronal mass ejection. We present an analysis of these data in terms of possible diffusive shock acceleration but conclude that this is likely to be incompatible with the short transit time of the particles. Shock drift acceleration of particles with energies 0.3 MeV/nucleon or solar acceleration followed by particle trapping behind the shock front are alternative possibilities.
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Crow, Terry, Juan-Juan Xue-Bian, and Vilma Siddiqi. "Protein Synthesis–Dependent and mRNA Synthesis–Independent Intermediate Phase of Memory in Hermissenda." Journal of Neurophysiology 82, no. 1 (July 1, 1999): 495–500. http://dx.doi.org/10.1152/jn.1999.82.1.495.
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The conditioned stimulus pathway in Hermissenda has been used to examine the time-dependent mechanisms of memory consolidation following one-trial conditioning. Here we report an intermediate phase of memory consolidation following one-trial conditioning that requires protein synthesis, but not mRNA synthesis. In conditioned animals, enhanced excitability normally expressed during an intermediate phase of memory was reversed by the protein synthesis inhibitor anisomycin, but not by the mRNA synthesis inhibitor 5,6-dichloro-1-β-d-ribobenzimidazole (DRB). Associated with the intermediate phase of memory is an increase in the phosphorylation of a 24-kDa protein. Anisomycin present during the intermediate phase blocked the increased phosphorylation of the 24-kDa phosphoprotein, but did not block the increased phosphorylation of other proteins associated with conditioning or significantly change their baseline phosphorylation. DRB did not reverse enhanced excitability or decrease protein phosphorylation expressed during the intermediate phase of memory formation, but it did reverse enhanced excitability 3.5 h after conditioning. Phosphorylation of the 24-kDa protein may support enhanced excitability during the intermediate phase, in the transition period between short- and long-term memory.
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Orfila, James E., Himmat Grewal, Robert M. Dietz, Frank Strnad, Takeru Shimizu, Myriam Moreno, Christian Schroeder, et al. "Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke." Journal of Cerebral Blood Flow & Metabolism 39, no. 6 (December 28, 2017): 1005–14. http://dx.doi.org/10.1177/0271678x17750761.
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The current study focuses on the ability to improve cognitive function after stroke with interventions administered at delayed/chronic time points. In light of recent studies demonstrating delayed GABA antagonists improve motor function, we utilized electrophysiology, biochemistry and neurobehavioral methods to investigate the role of α5 GABAA receptors on hippocampal plasticity and functional recovery following ischemic stroke. Male C57Bl/6 mice were exposed to 45 min transient middle cerebral artery occlusion and analysis of synaptic and functional deficits performed 7 or 30 days after recovery. Our findings indicate that hippocampal long-term potentiation (LTP) is impaired 7 days after stroke and remain impaired for at least 30 days. We demonstrate that ex vivo administration of L655,708 reversed ischemia-induced plasticity deficits and importantly, in vivo administration at delayed time-points reversed stroke-induced memory deficits. Western blot analysis of hippocampal tissue reveals proteins responsible for GABA synthesis are upregulated (GAD65/67 and MAOB), increasing GABA in hippocampal interneurons 30 days after stroke. Thus, our data indicate that both synaptic plasticity and memory impairments observed after stroke are caused by excessive tonic GABA activity, making inhibition of specific GABA activity at delayed timepoints a potential therapeutic approach to improve functional recovery and reverse cognitive impairments after stroke.
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Heidrich-Meisner, Verena, Lars Berger, and Robert F. Wimmer-Schweingruber. "Proton-proton collisional age to order solar wind types." Astronomy & Astrophysics 636 (April 2020): A103. http://dx.doi.org/10.1051/0004-6361/201937378.
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Context. The properties of a solar wind stream are determined by its source region and by transport effects. Independently of the solar wind type, the solar wind measured in situ is always affected by both. This means that reliably determining the solar wind type from in situ observations is useful for the analysis of its solar origin and its evolution during the travel time to the spacecraft that observes the solar wind. In addition, the solar wind type also influences the interaction of the solar wind with other plasma such as Earth’s magnetosphere. Aims. We consider the proton-proton collisional age as an ordering parameter for the solar wind at 1 AU and explore its relation to the solar wind classification scheme developed by Xu & Borovsky (2015, J. Geophys. Res.: Space Phys., 120, 70). We use this to show that explicit magnetic field information is not required for this solar wind classification. Furthermore, we illustrate that solar wind classification schemes that rely on threshold values of solar wind parameters should depend on the phase in the solar activity cycle since the respective parameters change with the solar activity cycle. Methods. The categorization of the solar wind following Xu & Borovsky (2015, J. Geophys. Res.: Space Phys., 120, 70) was taken as our reference for determining the solar wind type. Based on the observation that the three basic solar wind types from this categorization cover different regimes in terms of proton-proton collisional age acol, p-p, we propose a simplified solar wind classification scheme that is only based on the proton-proton collisional age. We call the resulting method the PAC solar wind classifier. For this purpose, we derive time-dependent threshold values in the proton-proton collisional age for two variants of the proposed PAC scheme: (1) similarity-PAC is based on the similarity to the full Xu & Borovsky (2015, J. Geophys. Res.: Space Phys., 120, 70) scheme, and (2) distribution-PAC is based directly on the distribution of the proton-proton collisional age. Results. The proposed simplified solar wind categorization scheme based on the proton-proton collisional age represents an equivalent alternative to the full Xu & Borovsky (2015, J. Geophys. Res.: Space Phys., 120, 70) solar wind classification scheme and leads to a classification that is very similar to the full Xu & Borovsky (2015, J. Geophys. Res.: Space Phys., 120, 70) scheme. The proposed PAC solar wind categorization separates coronal hole wind from helmet-streamer plasma as well as helmet-streamer plasma (slow solar wind without a current sheet crossing) from sector-reversal plasma (slow solar wind with a current sheet crossing). Unlike the full Xu & Borovsky (2015, J. Geophys. Res.: Space Phys., 120, 70) scheme, PAC does not require information on the magnetic field as input. Conclusions. The solar wind is well ordered by the proton-proton collisional age. This implies underlying intrinsic relationships between the plasma properties, in particular, proton temperature and magnetic field strength in each plasma regime. We argue that sector-reversal plasma is a combination of particularly slow and dense solar wind and most stream interaction boundaries. Most solar wind parameters (e.g., the magnetic field strength, B, and the oxygen charge state ratio no7+/no6+) change with the solar activity cycle. Thus, all solar wind categorization schemes based on threshold values need to be adapted to the solar activity cycle as well. Because it does not require magnetic field information but only proton plasma measurements, the proposed PAC solar wind classifier can be applied directly to solar wind data from the Solar and Heliospheric Observatoty (SOHO), which is not equipped with a magnetometer.
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Oz, Murat, and Leo P. Renaud. "Angiotensin AT1-Receptors Depolarize Neonatal Spinal Motoneurons and Other Ventral Horn Neurons Via Two Different Conductances." Journal of Neurophysiology 88, no. 5 (November 1, 2002): 2857–63. http://dx.doi.org/10.1152/jn.00978.2001.
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Angiotensin receptors are highly expressed in neonatal spinal cord. To identify their influence on neuronal excitability, we used patch-clamp recordings in spinal cord slices to assess responses of neonatal rat (5–12 days) ventral horn neurons to bath-applied angiotensin II (ANG II; 1 μM). In 14/34 identified motoneurons tested under current clamp, ANG II induced a slowly rising and prolonged membrane depolarization, blockable with Losartan ( n = 5) and (Sar1, Val5, Ala8)-ANG II (Saralasin, n = 4) but not PD123319 (1 μM each; n = 4). Under voltage clamp ( V H −65 mV), 7/22 motoneurons displayed an ANG-II-induced tetrodotoxin-resistant inward current (−128 ± 31 pA) with a similar time course, an associated reduction in membrane conductance and net current reversal at −98.8 ± 3.9 mV. Losartan-sensitive ANG II responses were also evoked in 27/78 tested ventral horn “interneurons.” By contrast with motoneurons, their ANG-II-induced inward current was smaller (−39.9 ± 5.2 pA) and analysis of their I-V plots revealed three patterns. In eight cells, membrane conductance decreased with net inward current reversing at −103.8 ± 4.1 mV. In seven cells, membrane conductance increased with net current reversing at −37.9 ± 3.6 mV. In 12 cells, I-V lines remained parallel with no reversal within the current range tested. Intracellular dialysis with GTP-γ-S significantly prolonged the ANG II effect in seven responsive interneurons and GDP-β-S significantly reduced the ANG II response in four other cells. Peak inward currents were significantly reduced in all 13 responding neurons recorded in slices incubated in pertussis toxin (5 μg/ml) for 12–18 h or in 12 neurons perfused with N-ethylmaleimide. Of 29 interneurons sensitive to pertussis toxin or N-ethylmaleimide treatment, 9 cells displayed a decrease in membrane conductance that reversed at −101.3 ± 3.8 mV. In eight cells, membrane conductance increased and reversed at −38.7 ± 3.4 mV. In 12 cells, the I-V lines remained parallel with no reversal within the current range tested, suggesting that both conductances are modulated by pertussis toxin-sensitive G proteins. These observations reveal a direct, G-protein-mediated depolarizing action of ANG II on neonatal rat ventral horn neurons. They also imply involvement of two distinct conductances that are differentially distributed among different cell types.
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Olkkonen, Vesa M., and Timothy P. Levine. "Oxysterol binding proteins: in more than one place at one time?" Biochemistry and Cell Biology 82, no. 1 (February 1, 2004): 87–98. http://dx.doi.org/10.1139/o03-088.
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Oxysterols are potent signalling lipids that directly bind liver X receptors (LXRs) and a subset of oxysterol binding protein (OSBP) related proteins (ORPs). It is relatively well established that the oxysterol-regulated function of LXRs is to control the expression of genes involved in reverse cholesterol transport, catabolism of cholesterol, and lipogenesis. In contrast, the mechanisms by which oxysterols and ORPs affect cellular lipid metabolism have remained poorly understood. In this review, we summarize the information available on function of the ORPs and compare the two families of proteins binding oxysterol to demonstrate the different responses that similar lipids can elicit within cells. The other focus is on the membrane targeting determinants and the protein interaction partners of ORPs, which provide interesting clues to the mode(s) of ORP action. Specifically, we suggest a model in which a general property of ORPs is to function at membrane contact sites, specialized zones of communication between two different organelles.Key words: endoplasmic reticulum, lipid transport, LXR, membrane contact sites, ORP, OSBP, Osh, sterol metabolism.
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Khalili-Araghi, Fatemeh, Brigitte Ziervogel, James C. Gumbart, and Benoît Roux. "Molecular dynamics simulations of membrane proteins under asymmetric ionic concentrations." Journal of General Physiology 142, no. 4 (September 30, 2013): 465–75. http://dx.doi.org/10.1085/jgp.201311014.
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A computational method is developed to allow molecular dynamics simulations of biomembrane systems under realistic ionic gradients and asymmetric salt concentrations while maintaining the conventional periodic boundary conditions required to minimize finite-size effects in an all-atom explicit solvent representation. The method, which consists of introducing a nonperiodic energy step acting on the ionic species at the edge of the simulation cell, is first tested with illustrative applications to a simple membrane slab model and a phospholipid membrane bilayer. The nonperiodic energy-step method is then used to calculate the reversal potential of the bacterial porin OmpF, a large cation-specific β-barrel channel, by simulating the I-V curve under an asymmetric 10:1 KCl concentration gradient. The calculated reversal potential of 28.6 mV is found to be in excellent agreement with the values of 26–27 mV measured from lipid bilayer experiments, thereby demonstrating that the method allows realistic simulations of nonequilibrium membrane transport with quantitative accuracy. As a final example, the pore domain of Kv1.2, a highly selective voltage-activated K+ channel, is simulated in a lipid bilayer under conditions that recreate, for the first time, the physiological K+ and Na+ concentration gradients and the electrostatic potential difference of living cells.
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Kosińska, A., ChavanUD, and R. Amarowicz. "Separation of low molecular weight rapeseed proteins by RP-HPLC-DAD – a short report." Czech Journal of Food Sciences 24, No. 1 (November 9, 2011): 41–44. http://dx.doi.org/10.17221/3292-cjfs.
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Low molecular weight proteins were extracted and isolated from rapeseed and analysed using the HPLC-DAD method. The separation of proteins and phenolic compounds was done on the reversed phase C<sub>18</sub> column with a gradient of acetonitrile in water. The chromatogram was characterised by two peaks of low molecular weight proteins with the retention times of 19.92 and 23.24 min. Additional three main peaks of phenolic constituents were recorded on the chromatogram. One of them with maximum of UV spectrum at 328 nm was identified as sinapic acid derivatives.
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Chung, Dillon J., Beata Szyszka, Jason C. L. Brown, Norman P. A. Hüner, and James F. Staples. "Changes in the mitochondrial phosphoproteome during mammalian hibernation." Physiological Genomics 45, no. 10 (May 15, 2013): 389–99. http://dx.doi.org/10.1152/physiolgenomics.00171.2012.
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Mammalian hibernation involves periods of substantial suppression of metabolic rate (torpor) allowing energy conservation during winter. In thirteen-lined ground squirrels ( Ictidomys tridecemlineatus ), suppression of liver mitochondrial respiration during entrance into torpor occurs rapidly (within 2 h) before core body temperature falls below 30°C, whereas reversal of this suppression occurs slowly during arousal from torpor. We hypothesized that this pattern of rapid suppression in entrance and slow reversal during arousal was related to changes in the phosphorylation state of mitochondrial enzymes during torpor catalyzed by temperature-dependent kinases and phosphatases. We compared mitochondrial protein phosphorylation among hibernation metabolic states using immunoblot analyses and assessed how phosphorylation related to mitochondrial respiration rates. No proteins showed torpor-specific changes in phosphorylation, nor did phosphorylation state correlate with mitochondrial respiration. However, several proteins showed seasonal (summer vs. winter) differences in phosphorylation of threonine or serine residues. Using matrix-assisted laser desorption/ionization-time of flight/time of flight mass spectrometry, we identified three of these proteins: F1-ATPase α-chain, long chain-specific acyl-CoA dehydrogenase, and ornithine transcarbamylase. Therefore, we conclude that protein phosphorylation is likely a mechanism involved in bringing about seasonal changes in mitochondrial metabolism in hibernating ground squirrels, but it seems unlikely to play any role in acute suppression of mitochondrial metabolism during torpor.
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Gao, Yiwen, Nan Zhang, Chunmei Lv, Na Li, Xueqin Li, and Weiwei Li. "lncRNA SNHG1 Knockdown Alleviates Amyloid-β-Induced Neuronal Injury by Regulating ZNF217 via Sponging miR-361-3p in Alzheimer’s Disease." Journal of Alzheimer's Disease 77, no. 1 (September 1, 2020): 85–98. http://dx.doi.org/10.3233/jad-191303.
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Background: Long noncoding RNAs have been proven to play an important role in the progression of Alzheimer’s disease (AD). However, the function of small nucleolar RNA host gene 1 (SNHG1) in AD progression remains to be studied. Objective: To explore the role of SNHG1 in AD progression and clarify its potential mechanism. Methods: Amyloid β-protein (Aβ) was used to construct an AD cell model in vitro. The expression levels of SNHG1 and miR-361-3p were determined by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit 8 assay and flow cytometry. The levels of apoptosis-related proteins and zinc finger gene 217 (ZNF217) protein were evaluated by western blot analysis. Additionally, the contents of inflammatory cytokines and oxidative stress markers were tested by enzyme-linked immunosorbent assay. Furthermore, dual-luciferase reporter and RNA immunoprecipitation assays were used to verify the interaction between miR-361-3p and SNHG1 or ZNF217. Results: Aβ could induce cell injury, while resveratrol could reverse this effect. SNHG1 expression was positively regulated by Aβ and negatively regulated by resveratrol. SNHG1 knockdown could reverse the promotion effect of Aβ on cell injury. Moreover, SNHG1 sponged miR-361-3p, and miR-361-3p targeted ZNF217. Additionally, miR-361-3p overexpression reversed the promotion effect of SNHG1 overexpression on cell injury, and ZNF217 silencing also reversed the promotion effect of miR-361-3p inhibitor on cell injury. Conclusion: SNHG1 promoted cell injury by regulating the miR-361-3p/ZNF217 axis, which might provide a theoretical basis for molecular therapy of AD.
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Jandera, Pavel, Zdeňka Kučerová, and Jiří Urban. "Retention times and bandwidths in reversed-phase gradient liquid chromatography of peptides and proteins." Journal of Chromatography A 1218, no. 49 (December 2011): 8874–89. http://dx.doi.org/10.1016/j.chroma.2011.06.064.
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Kapadia, S., G. Torre-Amione, T. Yokoyama, and D. L. Mann. "Soluble TNF binding proteins modulate the negative inotropic properties of TNF-alpha in vitro." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 2 (February 1, 1995): H517—H525. http://dx.doi.org/10.1152/ajpheart.1995.268.2.h517.
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Soluble tumor necrosis factor (TNF) binding proteins (TNF-BPs) were characterized with respect to their capacity to modulate the negative inotropic properties of TNF-alpha in isolated contracting cardiac myocytes. Three TNF-BPs were evaluated: two natural monomeric human TNF monomeric binding proteins, TNF-BP1 and TNF-BP2, and sTNFR:Fc, a dimer of two molecules of human TNF-BP2 linked by the Fc portion of the human immunoglobulin G1 molecule. When TNF-alpha (25 pM) was allowed to form TNF-BP-TNF-alpha complexes, the negative inotropic effects of TNF-alpha were completely prevented by “neutralizing concentrations” of TNF-BPs, whereas lesser concentrations of TNF-BPs only partially attenuated the negative inotropic effects of TNF-alpha. The dimeric binding protein sTNFR:Fc was more effective on a molar basis than either of the monomeric binding proteins (TNF-BP1 or TNF-BP2) with respect to blocking the negative inotropic effects of TNF-alpha. When cardiac myocytes that had been treated with TNF-alpha (25 pM) were exposed to neutralizing concentrations of TNF-BP1, TNF-BP2, and sTNFR:Fc, the negative inotropic effects were completely reversed within 30 min. Thus these studies show for the first time that TNF-BPs are sufficient to prevent, as well as reverse, the negative inotropic properties of TNF-alpha in vitro.