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Sample records for endocochlear potential depends

  1. Supporting sensory transduction: cochlear fluid homeostasis and the endocochlear potential

    PubMed Central

    Wangemann, Philine

    2006-01-01

    The exquisite sensitivity of the cochlea, which mediates the transduction of sound waves into nerve impulses, depends on the endocochlear potential and requires a highly specialized environment that enables and sustains sensory function. Disturbance of cochlear homeostasis is the cause of many forms of hearing loss including the most frequently occurring syndromic and non-syndromic forms of hereditary hearing loss, Pendred syndrome and Cx26-related deafness. The occurrence of these and other monogenetic disorders illustrates that cochlear fluid homeostasis and the generation of the endocochlear potential are poorly secured by functional redundancy. This review summarizes the most prominent aspects of cochlear fluid homeostasis. It covers cochlear fluid composition, the generation of the endocochlear potential, K+ secretion and cycling and its regulation, the role of gap junctions, mechanisms of acid–base homeostasis, and Ca2+ transport. PMID:16857713

  2. Some organic acids attenuate the effects of furosemide on the endocochlear potential.

    PubMed

    Rybak, L P; Whitworth, C

    1987-01-01

    A series of organic acid transport inhibitors significantly reduced the endocochlear potential (EP) decline produced by furosemide in the chinchilla. Probenecid, sodium salicylate and penicillin G were much more effective than novobiocin, meclofenamate or diatrizoate. Inhibitors of organic base transport, choline and N-methyl nicotinamide, had no effect on the furosemide-induced drop of the EP. These findings suggest that at least part of furosemide ototoxicity may be mediated by organic acid transport. PMID:2951360

  3. Relationship of neural and otoacoustic emission thresholds during endocochlear potential development in the gerbil

    NASA Astrophysics Data System (ADS)

    Mills, David M.

    2004-08-01

    Distortion product otoacoustic emissions and auditory brainstem responses (ABRs) were measured in neonatal gerbils at three ages: at 15-16 days after birth (dab), near the onset of hearing when the endocochlear potential (EP) is known to be still immature; at 22 dab, when the EP first reaches mature levels; and at 30 dab. Comparing individual 15-16 dab animals to the 22 dab group, ABR threshold changes were typically larger than those for cubic distortion tone (CDT, 2f1-f2) emission thresholds which were, in turn, larger than those for the simple difference tone (DT, f2-f1). In contrast, from 22 to 30 dab there were no important changes in CDT or DT emission thresholds. Observed threshold-change relationships were very similar to those found in differential diagnosis investigations, where the EP was experimentally decreased using a chronic furosemide application. Therefore, most of the change in cochlear function over the two week period studied could be attributed to the maturation of EP during the first week. Model calculations further show that relative changes in CDT and DT emission thresholds are compatible with a movement of the operating point of the cochlear amplifier toward its symmetrical ``central'' point as the EP reaches mature levels.

  4. Pannexin1 channels dominate ATP release in the cochlea ensuring endocochlear potential and auditory receptor potential generation and hearing

    PubMed Central

    Chen, Jin; Zhu, Yan; Liang, Chun; Chen, Jing; Zhao, Hong-Bo

    2015-01-01

    Pannexin1 (Panx1) is a gap junction gene in vertebrates whose proteins mainly function as non-junctional channels on the cell surface. Panx1 channels can release ATP under physiological conditions and play critical roles in many physiological and pathological processes. Here, we report that Panx1 deficiency can reduce ATP release and endocochlear potential (EP) generation in the cochlea inducing hearing loss. Panx1 extensively expresses in the cochlea, including the cochlear lateral wall. We found that deletion of Panx1 in the cochlear lateral wall almost abolished ATP release under physiological conditions. Positive EP is a driving force for current through hair cells to produce auditory receptor potential. EP generation requires ATP. In the Panx1 deficient mice, EP and auditory receptor potential as measured by cochlear microphonics (CM) were significantly reduced. However, no apparent hair cell loss was detected. Moreover, defect of connexin hemichannels by deletion of connexin26 (Cx26) and Cx30, which are predominant connexin isoforms in the cochlea, did not reduce ATP release under physiological conditions. These data demonstrate that Panx1 channels dominate ATP release in the cochlea ensuring EP and auditory receptor potential generation and hearing. Panx1 deficiency can reduce ATP release and EP generation causing hearing loss. PMID:26035172

  5. S1PR2 variants associated with auditory function in humans and endocochlear potential decline in mouse.

    PubMed

    Ingham, Neil J; Carlisle, Francesca; Pearson, Selina; Lewis, Morag A; Buniello, Annalisa; Chen, Jing; Isaacson, Rivka L; Pass, Johanna; White, Jacqueline K; Dawson, Sally J; Steel, Karen P

    2016-01-01

    Progressive hearing loss is very common in the population but we still know little about the underlying pathology. A new spontaneous mouse mutation (stonedeaf, stdf ) leading to recessive, early-onset progressive hearing loss was detected and exome sequencing revealed a Thr289Arg substitution in Sphingosine-1-Phosphate Receptor-2 (S1pr2). Mutants aged 2 weeks had normal hearing sensitivity, but at 4 weeks most showed variable degrees of hearing impairment, which became severe or profound in all mutants by 14 weeks. Endocochlear potential (EP) was normal at 2 weeks old but was reduced by 4 and 8 weeks old in mutants, and the stria vascularis, which generates the EP, showed degenerative changes. Three independent mouse knockout alleles of S1pr2 have been described previously, but this is the first time that a reduced EP has been reported. Genomic markers close to the human S1PR2 gene were significantly associated with auditory thresholds in the 1958 British Birth Cohort (n = 6099), suggesting involvement of S1P signalling in human hearing loss. The finding of early onset loss of EP gives new mechanistic insight into the disease process and suggests that therapies for humans with hearing loss due to S1P signalling defects need to target strial function. PMID:27383011

  6. S1PR2 variants associated with auditory function in humans and endocochlear potential decline in mouse

    PubMed Central

    Ingham, Neil J.; Carlisle, Francesca; Pearson, Selina; Lewis, Morag A.; Buniello, Annalisa; Chen, Jing; Isaacson, Rivka L.; Pass, Johanna; White, Jacqueline K.; Dawson, Sally J.; Steel, Karen P.

    2016-01-01

    Progressive hearing loss is very common in the population but we still know little about the underlying pathology. A new spontaneous mouse mutation (stonedeaf, stdf ) leading to recessive, early-onset progressive hearing loss was detected and exome sequencing revealed a Thr289Arg substitution in Sphingosine-1-Phosphate Receptor-2 (S1pr2). Mutants aged 2 weeks had normal hearing sensitivity, but at 4 weeks most showed variable degrees of hearing impairment, which became severe or profound in all mutants by 14 weeks. Endocochlear potential (EP) was normal at 2 weeks old but was reduced by 4 and 8 weeks old in mutants, and the stria vascularis, which generates the EP, showed degenerative changes. Three independent mouse knockout alleles of S1pr2 have been described previously, but this is the first time that a reduced EP has been reported. Genomic markers close to the human S1PR2 gene were significantly associated with auditory thresholds in the 1958 British Birth Cohort (n = 6099), suggesting involvement of S1P signalling in human hearing loss. The finding of early onset loss of EP gives new mechanistic insight into the disease process and suggests that therapies for humans with hearing loss due to S1P signalling defects need to target strial function. PMID:27383011

  7. QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice.

    PubMed

    Ohlemiller, Kevin K; Kiener, Anna L; Gagnon, Patricia M

    2016-06-01

    We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10 mV (Ohlemiller et al. Hear Res 220: 10-26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1 year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht's strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45-58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40-50 mV in BALBs. In about 25 % of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noise-related EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1-CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1-3 h after broadband noise (4-45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced

  8. Activity-dependent regulation of prestin expression in mouse outer hair cells

    PubMed Central

    Song, Yohan; Xia, Anping; Lee, Hee Yoon; Wang, Rosalie; Ricci, Anthony J.

    2015-01-01

    Prestin is a membrane protein necessary for outer hair cell (OHC) electromotility and normal hearing. Its regulatory mechanisms are unknown. Several mouse models of hearing loss demonstrate increased prestin, inspiring us to investigate how hearing loss might feedback onto OHCs. To test whether centrally mediated feedback regulates prestin, we developed a novel model of inner hair cell loss. Injection of diphtheria toxin (DT) into adult CBA mice produced significant loss of inner hair cells without affecting OHCs. Thus, DT-injected mice were deaf because they had no afferent auditory input despite OHCs continuing to receive normal auditory mechanical stimulation and having normal function. Patch-clamp experiments demonstrated no change in OHC prestin, indicating that loss of information transfer centrally did not alter prestin expression. To test whether local mechanical feedback regulates prestin, we used TectaC1509G mice, where the tectorial membrane is malformed and only some OHCs are stimulated. OHCs connected to the tectorial membrane had normal prestin levels, whereas OHCs not connected to the tectorial membrane had elevated prestin levels, supporting an activity-dependent model. To test whether the endocochlear potential was necessary for prestin regulation, we studied TectaC1509G mice at different developmental ages. OHCs not connected to the tectorial membrane had lower than normal prestin levels before the onset of the endocochlear potential and higher than normal prestin levels after the onset of the endocochlear potential. Taken together, these data indicate that OHC prestin levels are regulated through local feedback that requires mechanoelectrical transduction currents. This adaptation may serve to compensate for variations in the local mechanical environment. PMID:25810486

  9. Local density dependent potential for compressible mesoparticles

    NASA Astrophysics Data System (ADS)

    Faure, Gérôme; Maillet, Jean-Bernard; Stoltz, Gabriel

    2014-03-01

    This work proposes a coarse grained description of molecular systems based on mesoparticles representing several molecules, where interactions between mesoparticles are modelled by an interparticle potential of molecular type. Since strong non-equilibrium situations over a wide range of pressure and density are targeted, the internal compressibility of the mesoparticles has to be considered. This is done by introducing a dependence of the potential on the local environment of the mesoparticles. To define local densities, we resort to a three-dimensional Voronoi tessellation instead of standard local, spherical averages. As an example, a local density dependent potential is fitted to reproduce the Hugoniot curve of a model of nitromethane over a large range of pressures and densities.

  10. The potential dependence of porous silicon electroluminescence

    SciTech Connect

    Riley, D.J.; Peter, L.M.; Wielgosz, R.I.

    1996-10-01

    The observation of visible luminescence from porous silicon has resulted in strong interest in this material. It has been demonstrated that the electrochemical reduction of persulfate ions at a porous silicon electrode/electrolyte interface may lead to intense luminescence (electroluminescence). Further, it has been found that the intensity and wavelength of the electroluminescence is potential dependent, this phenomenon is termed {open_quotes}potential tuning{close_quotes}. This paper is concerned with the elucidation of the mechanism of electroluminescence potential tuning. It will be shown that the process is related to the particle size distribution and the dynamics of electron transfer between the bulk silicon substrate, the surface silicon nanocrystals and the electrolyte. Further, the results of combined in-situ FTIR and electroluminescence studies will be reported. The influence of surface chemistry on the electroluminescence will be discussed with reference to the proposed {open_quotes}tuning{close_quotes} mechanism.

  11. Alternative time-dependent optimized effective potential

    NASA Astrophysics Data System (ADS)

    Nazarov, Vladimir

    2013-03-01

    The OEP is known as a single-particle potential minimizing the expectation value of a many-body Hamiltonian on the set of eigen-functions of a single-particle Hamiltonian. The time-dependent (TD) OEP can be constructed with the TD quantum stationary-action principle. Very useful conceptually in DFT and TDDFT, both OEPs are not practicable due to the complexity of their implementations. Here we report a TDOEP by minimizing the difference of LHS and RHS of the TD Schrödinger equation. If the orbitals are varied, then the TD Hartree-Fock equations are reproduced. Similarly, we now find the OEP. New OMP does not involve the inversion of the density-response function χs, which greatly facilitates implementations. Accordingly, the exchange-correlation kernel fxc involves of χs- 1 only, not its quadratic counterpart. To show the power of this method, we work out the fxch (q , ω) of the homogeneous electron gas to be used with the nearly-free electrons theory, where fxch is the main input. Partial support from National Science Council, Taiwan, Grant No. 100-2112-M-001-025-MY3 is acknowledged.

  12. Temperature dependence of soil water potential

    SciTech Connect

    Mohamed, A.M.O.; Yong, R.N. ); Cheung, S.C.H. )

    1992-12-01

    To understand the process of coupled heat and water transport, the relationship between temperature and soil water potential must be known. Two clays, Avonlea bentonite and Lake Agassiz clay, are being considered as the clay-based sealing materials for the Canadian nuclear fuel waste disposal vault. Avonlea bentonite is distinguished from Lake Agassiz clay by its high sealing potential in water. A series of experiments was performed in which the two clays were mixed with equal amounts of sand and were compacted to a dry density of 1.67 Mg/m[sup 3] under various moisture contents and temperatures. A psychrometer was placed within the compacted clay-sand to measure the soil water potential based on the electromotive force measured by the psychrometer. The results indicate that the soil water potential at a particular temperature is higher for both clay-sand mixtures than predicted by the change in the surface tension of water; this effect is much more prominent in the Avonlea bentonite and at low moisture contents. The paper presents empirical equations relating the soil water potential with the moisture content and temperature of the two clay-sand mixtures. 24 refs., 8 figs., 2 tabs.

  13. Dentin Biomodification Potential Depends on Polyphenol Source

    PubMed Central

    Aguiar, T.R.; Vidal, C.M.P.; Phansalkar, R.S.; Todorova, I.; Napolitano, J.G.; McAlpine, J.B.; Chen, S.N.; Pauli, G.F.; Bedran-Russo, A.K.

    2014-01-01

    Although proanthocyanidins (PACs) modify dentin, the effectiveness of different PAC sources and the correlation with their specific chemical composition are still unknown. This study describes the chemical profiling of natural PAC-rich extracts from 7 plants using ultra high pressure/performance liquid chromatography (UHPLC) to determine the overall composition of these extracts and, in parallel, comprehensively evaluate their effect on dentin properties. The total polyphenol content of the extracts was determined (as gallic acid equivalents) using Folin-Ciocalteau assays. Dentin biomodification was assessed by the modulus of elasticity, mass change, and resistance to enzymatic biodegradation. Extracts with a high polyphenol and PAC content from Vitis vinifera, Theobroma cacao, Camellia sinensis, and Pinus massoniana induced a significant increase in modulus of elasticity and mass. The UHPLC analysis showed the presence of multiple types of polyphenols, ranging from simple phenolic acids to oligomeric PACs and highly condensed tannins. Protective effect against enzymatic degradation was observed for all experimental groups; however, statistically significant differences were observed between plant extracts. The findings provide clear evidence that the dentin bioactivities of PACs are source dependent, resulting from a combination of concentration and specific chemical constitution of the complex PAC mixtures. PMID:24574140

  14. Dentin biomodification potential depends on polyphenol source.

    PubMed

    Aguiar, T R; Vidal, C M P; Phansalkar, R S; Todorova, I; Napolitano, J G; McAlpine, J B; Chen, S N; Pauli, G F; Bedran-Russo, A K

    2014-04-01

    Although proanthocyanidins (PACs) modify dentin, the effectiveness of different PAC sources and the correlation with their specific chemical composition are still unknown. This study describes the chemical profiling of natural PAC-rich extracts from 7 plants using ultra high pressure/performance liquid chromatography (UHPLC) to determine the overall composition of these extracts and, in parallel, comprehensively evaluate their effect on dentin properties. The total polyphenol content of the extracts was determined (as gallic acid equivalents) using Folin-Ciocalteau assays. Dentin biomodification was assessed by the modulus of elasticity, mass change, and resistance to enzymatic biodegradation. Extracts with a high polyphenol and PAC content from Vitis vinifera, Theobroma cacao, Camellia sinensis, and Pinus massoniana induced a significant increase in modulus of elasticity and mass. The UHPLC analysis showed the presence of multiple types of polyphenols, ranging from simple phenolic acids to oligomeric PACs and highly condensed tannins. Protective effect against enzymatic degradation was observed for all experimental groups; however, statistically significant differences were observed between plant extracts. The findings provide clear evidence that the dentin bioactivities of PACs are source dependent, resulting from a combination of concentration and specific chemical constitution of the complex PAC mixtures. PMID:24574140

  15. Potential Dependence of Electrochemical Barriers from ab Initio Calculations.

    PubMed

    Chan, Karen; Nørskov, Jens K

    2016-05-01

    We present a simple and computationally efficient method to determine the potential dependence of the activation energies for proton-electron transfer from a single ab initio barrier calculation. We show that the potential dependence of the activation energy is given by the partial charge transferred at the transition state. The method is evaluated against the potential dependence determined explicitly through multiple calculations at varying potential. We show that the transfer coefficient is given by the charge transferred from the initial to transition state, which has significant implications for electrochemical kinetics. PMID:27088442

  16. Time-dependent potential-functional embedding theory

    SciTech Connect

    Huang, Chen; Libisch, Florian; Carter, Emily A.

    2014-03-28

    We introduce a time-dependent potential-functional embedding theory (TD-PFET), in which atoms are grouped into subsystems. In TD-PFET, subsystems can be propagated by different suitable time-dependent quantum mechanical methods and their interactions can be treated in a seamless, first-principles manner. TD-PFET is formulated based on the time-dependent quantum mechanics variational principle. The action of the total quantum system is written as a functional of the time-dependent embedding potential, i.e., a potential-functional formulation. By exploiting the Runge-Gross theorem, we prove the uniqueness of the time-dependent embedding potential under the constraint that all subsystems share a common embedding potential. We derive the integral equation that such an embedding potential needs to satisfy. As proof-of-principle, we demonstrate TD-PFET for a Na{sub 4} cluster, in which each Na atom is treated as one subsystem and propagated by time-dependent Kohn-Sham density functional theory (TDDFT) using the adiabatic local density approximation (ALDA). Our results agree well with a direct TDDFT calculation on the whole Na{sub 4} cluster using ALDA. We envision that TD-PFET will ultimately be useful for studying ultrafast quantum dynamics in condensed matter, where key regions are solved by highly accurate time-dependent quantum mechanics methods, and unimportant regions are solved by faster, less accurate methods.

  17. Polymer dynamics in time-dependent periodic potentials

    NASA Astrophysics Data System (ADS)

    Kauttonen, Janne; Merikoski, Juha; Pulkkinen, Otto

    2008-06-01

    The dynamics of a discrete polymer in time-dependent external potentials is studied with the master equation approach. We consider both stochastic and deterministic switching mechanisms for the potential states and give the essential equations for computing the stationary-state properties of molecules with internal structure in time-dependent periodic potentials on a lattice. As an example, we consider standard and modified Rubinstein-Duke polymers and calculate their mean drift and effective diffusion coefficient in the two-state nonsymmetric flashing potential and symmetric traveling potential. Rich nonlinear behavior of these observables is found. By varying the polymer length, we find current inversions caused by the rebound effect that is only present for molecules with internal structure. These results depend strongly on the polymer type. We also notice increased transport coherence for longer polymers.

  18. Scattering with absorptive interaction: Energy-dependent potentials

    NASA Astrophysics Data System (ADS)

    Cassing, W.; Stingl, M.; Weiguny, A.

    1983-05-01

    The energy dependence and analytic structure of the effective interaction for elastic scattering of composite particles are investigated using Feshbach's projection technique. A generalized Levinson theorem is established for complex, nonlocal, and energy-dependent interactions. The analytical results are illustrated by means of Argand diagrams for a solvable model and the effect of energy averaging is discussed. NUCLEAR REACTIONS Scattering theory, S matrix for absorptive, energy-dependent potentials, Levinson theorem.

  19. Time-dependent induced potentials in convoy electron emission

    NASA Astrophysics Data System (ADS)

    Acuña, G. P.; Miraglia, J. E.

    2006-11-01

    We study the time-dependent induced potentials at the convoy electron position due to the self-interaction with a metal surface and to the shock wave created by the positive hole (vacancy) left. The time evolution of these potentials are calculated using the linear response theory. Results obtained are fitted with simple functions. We find that those two potentials nearly cancel each other in the first ten atomic units of time.

  20. Separable representation of energy-dependent optical potentials

    NASA Astrophysics Data System (ADS)

    Hlophe, L.; Elster, Ch.

    2016-03-01

    Background: One important ingredient for many applications of nuclear physics to astrophysics, nuclear energy, and stockpile stewardship are cross sections for reactions of neutrons with rare isotopes. Since direct measurements are often not feasible, indirect methods, e.g., (d ,p ) reactions, should be used. Those (d ,p ) reactions may be viewed as three-body reactions and described with Faddeev techniques. Purpose: Faddeev equations in momentum space have a long tradition of utilizing separable interactions in order to arrive at sets of coupled integral equations in one variable. Optical potentials representing the effective interactions in the neutron (proton) nucleus subsystem are usually non-Hermitian as well as energy dependent. Potential matrix elements as well as transition matrix elements calculated with them must fulfill the reciprocity theorem. The purpose of this paper is to introduce a separable, energy-dependent representation of complex, energy-dependent optical potentials that fulfill reciprocity exactly. Methods: Momentum space Lippmann-Schwinger integral equations are solved with standard techniques to obtain the form factors for the separable representation. Results: Starting from a separable, energy-independent representation of global optical potentials based on a generalization of the Ernst-Shakin-Thaler (EST) scheme, a further generalization is needed to take into account the energy dependence. Applications to n +48Ca ,n +208Pb , and p +208Pb are investigated for energies from 0 to 50 MeV with special emphasis on fulfilling reciprocity. Conclusions: We find that the energy-dependent separable representation of complex, energy-dependent phenomenological optical potentials fulfills reciprocity exactly. In addition, taking into account the explicit energy dependence slightly improves the description of the S matrix elements.

  1. Saturation dependence of the streaming potential during drainage and imbibition

    NASA Astrophysics Data System (ADS)

    Vinogradov, J.; Leinov, E.; Jackson, M.

    2012-12-01

    The rock pore space in many subsurface settings is saturated with water and one or more immiscible fluid phases; examples include NAPLs in contaminated aquifers, supercritical CO2 during sequestration in deep saline aquifers, the vadose zone, and hydrocarbon reservoirs. To interpret spontaneous potential measurements for groundwater flow and hydraulic properties in these settings requires an understanding of the saturation dependence of the streaming potential. Vinogradov and Jackson [2011] recently reported measurements of the streaming potential during drainage and, for the first time, imbibition in sandstone plugs saturated with water and either undecane or nitrogen. However, they reported effective values of the streaming potential coupling coefficient (C) at partial saturation (Sw), because Sw in the plugs was not uniform during drainage or imbibition. The aim of this study is to determine the true value of C as a function of Sw. We use a three-step approach in which hydraulic and electrical parameters are determined using numerical simulation and either Nelder-Mead simplex unconstrained optimisation or Active-set constrained optimisation algorithm. In the first step, we determine the saturation dependence of the relative permeability and capillary pressure, assuming these are simple exponential functions of Sw (Corey-type) and using an objective function which is a weighted average of the measured (i) pressure drop across the plug, (ii) liquid rate flowing out of the plug, and (iii) fraction of water flowing out of the plug. In the second, we determine the saturation dependence of the electrical conductivity, using the measured conductivity of the plug as the objective function. In the final step, we determine the saturation dependence of the streaming potential, using the measured streaming potential across the plug as the objective function. We obtain a good match between simulated and measured values of C, and find that it (i) exhibits hysteresis, (ii) can

  2. Phase transition of strongly interacting matter with a chemical potential dependent Polyakov loop potential

    NASA Astrophysics Data System (ADS)

    Shao, Guo-yun; Tang, Zhan-duo; Di Toro, Massimo; Colonna, Maria; Gao, Xue-yan; Gao, Ning

    2016-07-01

    We construct a hadron-quark two-phase model based on the Walecka-quantum hadrodynamics and the improved Polyakov-Nambu-Jona-Lasinio (PNJL) model with an explicit chemical potential dependence of Polyakov loop potential (μ PNJL model). With respect to the original PNJL model, the confined-deconfined phase transition is largely affected at low temperature and large chemical potential. Using the two-phase model, we investigate the equilibrium transition between hadronic and quark matter at finite chemical potentials and temperatures. The numerical results show that the transition boundaries from nuclear to quark matter move towards smaller chemical potential (lower density) when the μ -dependent Polyakov loop potential is taken. In particular, for charge asymmetric matter, we compute the local asymmetry of u , d quarks in the hadron-quark coexisting phase, and analyze the isospin-relevant observables possibly measurable in heavy-ion collision (HIC) experiments. In general new HIC data on the location and properties of the mixed phase would bring relevant information on the expected chemical potential dependence of the Polyakov loop contribution.

  3. Perturbation theory for isotropic velocity-dependent potentials: scattering case

    NASA Astrophysics Data System (ADS)

    Jaghoub, Mahmoud

    2010-02-01

    The time-independent Schr"odinger equation with an isotropic velocity-depen-dent potential is considered. Treating the velocity-dependent interaction as a small perturbation we develop analytical formulae for the changes in the scattering phase shifts and wave functions. It is shown that only the zeroth order solution and the perturbing potential are needed to determine the phase shift and wave function corrections. No prior knowledge of the unperturbed scattering states continuum is required. In order to test the validity of our approach we applied it to an exactly solvable model for nucleon-nucleon scattering. The results of the perturbation formalism compare quite well with the those of the exactly solvable model. The developed formalism can be applied in problems concerning pion-nucleon, nucleon-nucleon and electron-atom scattering. It may also be useful in studying the scattering of electrons in semiconductor heterostructures. )

  4. Potential pitfalls of strain rate imaging: angle dependency

    NASA Technical Reports Server (NTRS)

    Castro, P. L.; Greenberg, N. L.; Drinko, J.; Garcia, M. J.; Thomas, J. D.

    2000-01-01

    Strain Rate Imaging (SRI) is a new echocardiographic technique that allows for the real-time determination of myocardial SR, which may be used for the early and accurate detection of coronary artery disease. We sought to study whether SR is affected by scan line alignment in a computer simulation and an in vivo experiment. Through the computer simulation and the in vivo experiment we generated and validated safe scanning sectors within the ultrasound scan sector and showed that while SRI will be an extremely valuable tool in detecting coronary artery disease there are potential pitfalls for the unwary clinician. Only after accounting for these affects due to angle dependency, can clinicians utilize SRI's potential as a valuable tool in detecting coronary artery disease.

  5. Temperature-dependent potential in cluster-decay process

    NASA Astrophysics Data System (ADS)

    Gharaei, R.; Zanganeh, V.

    2016-08-01

    Role of the thermal effects of the parent nucleus in the Coulomb barrier and the half-life of 28 cluster-decays is systematically analyzed within the framework of the proximity formalism, namely proximity potential 2010. The WKB approximation is used to determine the penetration probability of the emitted cluster. It is shown that the height and width of the Coulomb barrier in the temperature-dependent proximity potential are less than its temperature-independent version. Moreover, this investigation reveals that the calculated values of half-life for selected cluster-decays are in better agreement with the experimental data when the mentioned effects are imposed on the proximity approach. A discussion is also presented about the predictions of the present thermal approach for cluster-decay half-lives of the super-heavy-elements.

  6. A novel orientation-dependent potential model for prolate mesogens.

    PubMed

    Martínez-Haya, B; Cuetos, A; Lago, S; Rull, L F

    2005-01-01

    An intermolecular potential is introduced for the study of molecular mesogenic fluids. The model combines distinct features of the well-known Gay-Berne and Kihara potentials by incorporating dispersive interactions dependent on the relative pair orientation to a spherocylinder molecular core. Results of a Monte Carlo simulation study focused on the liquid crystal phases exhibited by the model fluid are presented. For the chosen potential parameters, molecular aspect ratio L*=5 and temperatures T*=2, 3, and 5, isotropic, nematic, smectic-A, and hexatic phases are found. The location of the phase boundaries as well as the equation of state of the fluid and further thermodynamical and structural parameters are discussed and contrasted to the Kihara fluid. In comparison to this latter fluid, the model induces the formation of ordered liquid crystalline phases at lower packing fractions and it favors, in particular, the appearance of layered hexatic ordering as a consequence of the greater attractive interaction assigned to the parallel side-to-side molecular pair configurations. The results contribute to the evaluation of the role of specific interaction energies in the mesogenic behavior of prolate molecular liquids in dense environments. PMID:15638631

  7. A novel orientation-dependent potential model for prolate mesogens

    NASA Astrophysics Data System (ADS)

    Martínez-Haya, B.; Cuetos, A.; Lago, S.; Rull, L. F.

    2005-01-01

    An intermolecular potential is introduced for the study of molecular mesogenic fluids. The model combines distinct features of the well-known Gay-Berne and Kihara potentials by incorporating dispersive interactions dependent on the relative pair orientation to a spherocylinder molecular core. Results of a Monte Carlo simulation study focused on the liquid crystal phases exhibited by the model fluid are presented. For the chosen potential parameters, molecular aspect ratio L*=5 and temperatures T*=2, 3, and 5, isotropic, nematic, smectic-A, and hexatic phases are found. The location of the phase boundaries as well as the equation of state of the fluid and further thermodynamical and structural parameters are discussed and contrasted to the Kihara fluid. In comparison to this latter fluid, the model induces the formation of ordered liquid crystalline phases at lower packing fractions and it favors, in particular, the appearance of layered hexatic ordering as a consequence of the greater attractive interaction assigned to the parallel side-to-side molecular pair configurations. The results contribute to the evaluation of the role of specific interaction energies in the mesogenic behavior of prolate molecular liquids in dense environments.

  8. Mapping potential groundwater-dependent ecosystems for sustainable management.

    PubMed

    Gou, Si; Gonzales, Susana; Miller, Gretchen R

    2015-01-01

    Ecosystems which rely on either the surface expression or subsurface presence of groundwater are known as groundwater-dependent ecosystems (GDEs). A comprehensive inventory of GDE locations at an appropriate management scale is a necessary first-step for sustainable management of supporting aquifers; however, this information is unavailable for most areas of concern. To address this gap, this study created a two-step algorithm which analyzed existing geospatial and remote sensing data to identify potential GDEs at both state/province and aquifer/basin scales. At the state/province scale, a geospatial information system (GIS) database was constructed for Texas, including climate, topography, hydrology, and ecology data. From these data, a GDE index was calculated, which combined vegetative and hydrological indicators. The results indicated that central Texas, particularly the Edwards Aquifer region, had highest potential to host GDEs. Next, an aquifer/basin scale remote sensing-based algorithm was created to provide more detailed maps of GDEs in the Edwards Aquifer region. This algorithm used Landsat ETM+ and MODIS images to track the changes of NDVI for each vegetation pixel. The NDVI dynamics were used to identify the vegetation with high potential to use groundwater--such plants remain high NDVI during extended dry periods and also exhibit low seasonal and inter-annual NDVI changes between dry and wet seasons/years. The results indicated that 8% of natural vegetation was very likely using groundwater. Of the potential GDEs identified, 75% were located on shallow soil averaging 45 cm in depth. The dominant GDE species were live oak, ashe juniper, and mesquite. PMID:24571583

  9. Menthol's potential effects on nicotine dependence: a tobacco industry perspective

    PubMed Central

    2011-01-01

    Objective To examine what the tobacco industry knows about the potential effects menthol may have on nicotine dependence. Methods A snowball strategy was used to systematically search the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu/) between 22 February and 29 April, 2010. Of the approximately 11 million documents available in the Legacy Tobacco Documents Library, the iterative searches returned tens of thousands of results. We qualitatively analysed a final collection of 309 documents relevant the effects of menthol on nicotine dependence. Results The tobacco industry knows that menthol overrides the harsh taste of tobacco and alleviates nicotine's irritating effects, synergistically interacts with nicotine, stimulates the trigeminal nerve to elicit a ‘liking’ response for a tobacco product, and makes low tar, low nicotine tobacco products more acceptable to smokers than non-mentholated low delivery products. Conclusion Menthol is not only used in cigarettes as a flavour additive; tobacco companies know that menthol also has sensory effects and interacts with nicotine to produce tobacco products that are easier to smoke, thereby making it easier to expose smokers, especially those who are new and uninitiated, to the addictive power of nicotine. PMID:21504929

  10. Endocannabinoid dynamics gate spike-timing dependent depression and potentiation

    PubMed Central

    Cui, Yihui; Prokin, Ilya; Xu, Hao; Delord, Bruno; Genet, Stephane; Venance, Laurent; Berry, Hugues

    2016-01-01

    Synaptic plasticity is a cardinal cellular mechanism for learning and memory. The endocannabinoid (eCB) system has emerged as a pivotal pathway for synaptic plasticity because of its widely characterized ability to depress synaptic transmission on short- and long-term scales. Recent reports indicate that eCBs also mediate potentiation of the synapse. However, it is not known how eCB signaling may support bidirectionality. Here, we combined electrophysiology experiments with mathematical modeling to question the mechanisms of eCB bidirectionality in spike-timing dependent plasticity (STDP) at corticostriatal synapses. We demonstrate that STDP outcome is controlled by eCB levels and dynamics: prolonged and moderate levels of eCB lead to eCB-mediated long-term depression (eCB-tLTD) while short and large eCB transients produce eCB-mediated long-term potentiation (eCB-tLTP). Moreover, we show that eCB-tLTD requires active calcineurin whereas eCB-tLTP necessitates the activity of presynaptic PKA. Therefore, just like glutamate or GABA, eCB form a bidirectional system to encode learning and memory. DOI: http://dx.doi.org/10.7554/eLife.13185.001 PMID:26920222

  11. String cosmology with a time-dependent antisymmetric tensor potential

    SciTech Connect

    Copeland, E.J.; Lahiri, A.; Wands, D. )

    1995-02-15

    We present a class of exact solutions for homogeneous, anisotropic cosmologies in four dimensions derived from the low-energy string effective action including a homogeneous dilaton [phi] and antisymmetric tensor potential [ital B][sub [mu][nu

  12. Do galactic potential wells depend on their environment?

    NASA Technical Reports Server (NTRS)

    Mo, H. J.; Lahav, O.

    1993-01-01

    Using galaxies in complete samples as tracers of the galaxy density field and about 1000 galaxies with measured circular velocities as targets, we examine the cross-correlation functions between the targets and tracers as a function of galaxy circular velocities. The correlation strength does not vary with the circular velocities except for elliptical galaxies with the highest velocity dispersions, where the effect may well be due to morphological segregations in clusters of galaxies. This is contrasted with the strong dependence of the correlation functions of dark halos on their circular velocities in some models of galaxy formation.

  13. Visualizing the orientational dependence of an intermolecular potential

    PubMed Central

    Sweetman, Adam; Rashid, Mohammad A.; Jarvis, Samuel P.; Dunn, Janette L.; Rahe, Philipp; Moriarty, Philip

    2016-01-01

    Scanning probe microscopy can now be used to map the properties of single molecules with intramolecular precision by functionalization of the apex of the scanning probe tip with a single atom or molecule. Here we report on the mapping of the three-dimensional potential between fullerene (C60) molecules in different relative orientations, with sub-Angstrom resolution, using dynamic force microscopy (DFM). We introduce a visualization method which is capable of directly imaging the variation in equilibrium binding energy of different molecular orientations. We model the interaction using both a simple approach based around analytical Lennard–Jones potentials, and with dispersion-force-corrected density functional theory (DFT), and show that the positional variation in the binding energy between the molecules is dominated by the onset of repulsive interactions. Our modelling suggests that variations in the dispersion interaction are masked by repulsive interactions even at displacements significantly larger than the equilibrium intermolecular separation. PMID:26879386

  14. Visualizing the orientational dependence of an intermolecular potential

    NASA Astrophysics Data System (ADS)

    Sweetman, Adam; Rashid, Mohammad A.; Jarvis, Samuel P.; Dunn, Janette L.; Rahe, Philipp; Moriarty, Philip

    2016-02-01

    Scanning probe microscopy can now be used to map the properties of single molecules with intramolecular precision by functionalization of the apex of the scanning probe tip with a single atom or molecule. Here we report on the mapping of the three-dimensional potential between fullerene (C60) molecules in different relative orientations, with sub-Angstrom resolution, using dynamic force microscopy (DFM). We introduce a visualization method which is capable of directly imaging the variation in equilibrium binding energy of different molecular orientations. We model the interaction using both a simple approach based around analytical Lennard-Jones potentials, and with dispersion-force-corrected density functional theory (DFT), and show that the positional variation in the binding energy between the molecules is dominated by the onset of repulsive interactions. Our modelling suggests that variations in the dispersion interaction are masked by repulsive interactions even at displacements significantly larger than the equilibrium intermolecular separation.

  15. Potential-dependent dynamic fracture of nanoporous gold.

    PubMed

    Sun, Shaofeng; Chen, Xiying; Badwe, Nilesh; Sieradzki, Karl

    2015-09-01

    When metallic alloys are exposed to a corrosive environment, porous nanoscale morphologies spontaneously form that can adversely affect the mechanical integrity of engineered structures. This form of stress-corrosion cracking is responsible for the well-known 'season cracking' of brass and stainless steel components in nuclear power generating stations. One explanation for this is that a high-speed crack is nucleated within the porous layer, which subsequently injects into non-porous parent-phase material. We study the static and dynamic fracture properties of free-standing monolithic nanoporous gold as a function electrochemical potential using high-speed photography and digital image correlation. The experiments reveal that at electrochemical potentials typical of porosity formation these structures are capable of supporting dislocation-mediated plastic fracture at crack velocities of 200 m s(-1). Our results identify the important role of high-speed fracture in stress-corrosion cracking and are directly applicable to the behaviour of monolithic dealloyed materials at present being considered for a variety of applications. PMID:26099111

  16. Potential-dependent dynamic fracture of nanoporous gold

    NASA Astrophysics Data System (ADS)

    Sun, Shaofeng; Chen, Xiying; Badwe, Nilesh; Sieradzki, Karl

    2015-09-01

    When metallic alloys are exposed to a corrosive environment, porous nanoscale morphologies spontaneously form that can adversely affect the mechanical integrity of engineered structures. This form of stress-corrosion cracking is responsible for the well-known `season cracking’ of brass and stainless steel components in nuclear power generating stations. One explanation for this is that a high-speed crack is nucleated within the porous layer, which subsequently injects into non-porous parent-phase material. We study the static and dynamic fracture properties of free-standing monolithic nanoporous gold as a function electrochemical potential using high-speed photography and digital image correlation. The experiments reveal that at electrochemical potentials typical of porosity formation these structures are capable of supporting dislocation-mediated plastic fracture at crack velocities of 200 m s-1. Our results identify the important role of high-speed fracture in stress-corrosion cracking and are directly applicable to the behaviour of monolithic dealloyed materials at present being considered for a variety of applications.

  17. Electron density dependence of impedance probe plasma potential measurements

    NASA Astrophysics Data System (ADS)

    Walker, D. N.; Blackwell, D. D.; Amatucci, W. E.

    2015-08-01

    In earlier works, we used spheres of various sizes as impedance probes in demonstrating a method of determining plasma potential, φp, when the probe radius is much larger than the Debye length, λD. The basis of the method in those works [Walker et al., Phys. Plasmas 13, 032108 (2006); ibid. 15, 123506 (2008); ibid. 17, 113503 (2010)] relies on applying a small amplitude signal of fixed frequency to a probe in a plasma and, through network analyzer-based measurements, determining the complex reflection coefficient, Γ, for varying probe bias, Vb. The frequency range of the applied signal is restricted to avoid sheath resonant effects and ion contributions such that ωpi ≪ ω ≪ ωpe, where ωpi is the ion plasma frequency and ωpe is the electron plasma frequency. For a given frequency and applied bias, both Re(Zac) and Im(Zac) are available from Γ. When Re(Zac) is plotted versus Vb, a minimum predicted by theory occurs at φp [Walker et al., Phys. Plasmas 17, 113503 (2010)]. In addition, Im(Zac) appears at, or very near, a maximum at φp. As ne decreases and the sheath expands, the minimum becomes harder to discern. The purpose of this work is to demonstrate that when using network analyzer-based measurements, Γ itself and Im(Zac) and their derivatives are useful as accompanying indicators to Re(Zac) in these difficult cases. We note the difficulties encountered by the most commonly used plasma diagnostic, the Langmuir probe. Spherical probe data is mainly used in this work, although we present limited data for a cylinder and a disk. To demonstrate the effect of lowered density as a function of probe geometry, we compare the cylinder and disk using only the indicator Re(Zac).

  18. Androgen dependence in hamsters: overdose, tolerance, and potential opioidergic mechanisms.

    PubMed

    Peters, K D; Wood, R I

    2005-01-01

    Anabolic steroids are drugs of abuse. However, the potential for steroid reward and addiction remains largely unexplored. This study used i.c.v. testosterone self-administration and controlled infusions of testosterone or vehicle in hamsters to explore central mechanisms of androgen overdose. Forty-two hamsters used nose-pokes to self-administer 1 microg/microl testosterone i.c.v. 4 h/day in an operant chamber. During 1-56 days of androgen self-administration, 10 (24%) hamsters died. Deaths correlated with peak daily intake of testosterone. Of the hamsters that self-administered a peak intake of <20 microg/day, there was 100% survival (10/10). Survival decreased to 86% (19/22) when daily testosterone intake peaked at 20-60 microg/day. Only 30% (three of 10) survived when daily testosterone intake exceeded 60 microg/day. Deaths are not due to volume or vehicle because i.c.v. infusions of 80 mul vehicle had no effect. Testosterone overdose resembles opiate intoxication. When male hamsters received infusions of 40 microg testosterone, locomotion (25.1+/-18.8 grid-crossings/10 min), respiration (72.7+/-5.4 breaths/min) and body temperature (33.5+/-0.4 degrees C) were significantly reduced, compared with males receiving vehicle infusions (186.1+/-8.1 crossings/10 min, 117.6+/-1.0 breaths/min, 35.9+/-0.1 degrees C, P<0.05). However, males developed tolerance to continued daily testosterone infusion. After 15 days, locomotion (170.2+/-6.3 crossings), respiration (118.4+/-1.3 breaths/min), and body temperature (35.3+/-0.3 degrees C) in testosterone-infused males were equivalent to that in vehicle controls (P>0.05). The depressive effects of testosterone infusion are blocked by the opioid antagonist, naltrexone. With naltrexone pre-treatment (10 mg/kg s.c.), locomotion (183.7+/-1.8 crossings/10 min), respiration (116.9+/-0.3 breaths/min), and body temperature (36.1+/-0.4 degrees C) during testosterone infusion were equivalent to vehicle controls. Likewise, naltrexone

  19. Electron density dependence of impedance probe plasma potential measurements

    SciTech Connect

    Walker, D. N.; Blackwell, D. D.; Amatucci, W. E.

    2015-08-15

    In earlier works, we used spheres of various sizes as impedance probes in demonstrating a method of determining plasma potential, φ{sub p}, when the probe radius is much larger than the Debye length, λ{sub D}. The basis of the method in those works [Walker et al., Phys. Plasmas 13, 032108 (2006); ibid. 15, 123506 (2008); ibid. 17, 113503 (2010)] relies on applying a small amplitude signal of fixed frequency to a probe in a plasma and, through network analyzer-based measurements, determining the complex reflection coefficient, Γ, for varying probe bias, V{sub b}. The frequency range of the applied signal is restricted to avoid sheath resonant effects and ion contributions such that ω{sub pi} ≪ ω ≪ ω{sub pe}, where ω{sub pi} is the ion plasma frequency and ω{sub pe} is the electron plasma frequency. For a given frequency and applied bias, both Re(Z{sub ac}) and Im(Z{sub ac}) are available from Γ. When Re(Z{sub ac}) is plotted versus V{sub b}, a minimum predicted by theory occurs at φ{sub p} [Walker et al., Phys. Plasmas 17, 113503 (2010)]. In addition, Im(Z{sub ac}) appears at, or very near, a maximum at φ{sub p}. As n{sub e} decreases and the sheath expands, the minimum becomes harder to discern. The purpose of this work is to demonstrate that when using network analyzer-based measurements, Γ itself and Im(Z{sub ac}) and their derivatives are useful as accompanying indicators to Re(Z{sub ac}) in these difficult cases. We note the difficulties encountered by the most commonly used plasma diagnostic, the Langmuir probe. Spherical probe data is mainly used in this work, although we present limited data for a cylinder and a disk. To demonstrate the effect of lowered density as a function of probe geometry, we compare the cylinder and disk using only the indicator Re(Z{sub ac})

  20. Cyclin-dependent kinase inhibitor AT7519 as a potential drug for MYCN-dependent neuroblastoma

    PubMed Central

    Dolman, M. Emmy M.; Poon, Evon; Ebus, Marli E.; den Hartog, Ilona J.M.; van Noesel, Carel J.M.; Jamin, Yann; Hallsworth, Albert; Robinson, Simon P.; Petrie, Kevin; Sparidans, Rolf W.; Kok, Robbert J.; Versteeg, Rogier; Caron, Huib N.; Chesler, Louis; Molenaar, Jan J.

    2015-01-01

    Purpose MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous pre-clinical studies we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo pre-clinical evaluation of the CDK inhibitor AT7519. Experimental Design Pre-clinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma. Results AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoural AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumour regression (average tumour size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumour exposure to the drug. Conclusions This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. PMID:26202950

  1. Density-potential mapping in time-dependent density-functional theory

    SciTech Connect

    Maitra, N. T.; Todorov, T. N.; Woodward, C.; Burke, K.

    2010-04-15

    The key questions of uniqueness and existence in time-dependent density-functional theory are usually formulated only for potentials and densities that are analytic in time. Simple examples, standard in quantum mechanics, lead, however, to nonanalyticities. We reformulate these questions in terms of a nonlinear Schroedinger equation with a potential that depends nonlocally on the wave function.

  2. Using Tensor Momentum Dependent Deuteron Potential to Extract the Asymptotic D/S Ratio

    SciTech Connect

    Emad El-Deen, A. Sultan; Mustafa, Mustafa M.; Zahran, Elbadry S.

    2010-09-30

    A new value for the deuteron asymptotic D/S ratio {eta} = 0.02640{+-}0.00024 is extracted from an empirical linear {eta}-Q relation found for a class of deuteron momentum dependent potentials with tensor momentum dependent part. These potentials fit a recently published phase shift analysis and the binding energy of the deuteron.

  3. Long-distance Lienard-Wiechert potentials and qq-bar spin dependence

    SciTech Connect

    Childers, R.W.

    1987-12-15

    The long-range spin dependence of the qq interaction is considered in a model in which the confining potential is required to be the static limit of retarded scalar and vector potentials analogous to the Lienard-Wiechert potentials of classical electrodynamics. A generalization of Darwin's method is used to obtain the corresponding Hamiltonian. The long-distance spin-dependent interaction is found to be determined completely by only two potentials: namely, the static scalar and vector potentials. This is to be compared with the four potentials required in Eichten and Feinberg's general formulation. Two different solutions are allowed by Gromes's theorem. In one, the scalar potential can be linear; in the other, it must be logarithmic.

  4. Velocity-dependent optical potential for neutron elastic scattering from 1 p -shell nuclei

    NASA Astrophysics Data System (ADS)

    Ghabar, I. N.; Jaghoub, M. I.

    2015-06-01

    Background: The conventional optical model is quite successful in describing the nucleon elastic scattering data from medium and heavy nuclei. However, its success in describing the light 1 p -shell nuclei is somewhat limited. The velocity-dependent optical potential resulted in a significant improvement in describing the elastic angular distributions for light nuclei in the low energy region. Purpose: To extend the formalism of the velocity-dependent potential to higher energies, and to assess its importance in describing neutron elastic scattering data from light 1 p -shell nuclei at high energies. Method: We fit the angular distribution data for neutron elastic scattering from 12C and 16O using (i) the velocity-dependent optical potential and (ii) the conventional optical potential. The results of the two models are then compared. At low energies, we compare our angular distribution fits with the fits of other works that exist in the literature. Furthermore, the total integrated cross sections in addition to the analyzing power are calculated using the velocity-dependent optical potential and compared to the experimental data. Results: The velocity-dependent potential resulted in significant improvements in describing the angular distributions particularly in the large-angle scattering region and for certain energy ranges. This model is important where the experimental data show structural effects from nuclear surface deformations, which are important in light nuclei. Furthermore, the calculated total elastic cross sections and analyzing power are in good agreement with the experimental data. Conclusions: The velocity-dependent potential gives rise to surface-peaked real terms in the optical model. Such terms account, at least partly, for the structural effects seen in the angular distribution data. The energy range over which the surface terms are needed is found to depend on the target nucleus. Other works that have introduced real surface terms in the optical

  5. Isospectral Trigonometric Pöschl-Teller Potentials with Position Dependent Mass Generated by Supersymmetry

    NASA Astrophysics Data System (ADS)

    Santiago-Cruz, C.

    2016-03-01

    In this work a position dependent mass Hamiltonian with the same spectrum of the trigonometric Pöschl-Teller one was constructed by means of the underlying potential algebra. The corresponding wave functions are determined by using the factorization method. A new family of isospectral potentials are constructed by applying a Darboux transformation. An example is presented in order to illustrate the formalism.

  6. Davydov-Chaban Hamiltonian in presence of time-dependent potential

    NASA Astrophysics Data System (ADS)

    Sobhani, Hadi; Hassanabadi, Hassan

    2016-09-01

    In this article, we have investigated collective effects of atomic nuclei in presence of a time-dependent potential in Davydov-Chaban Hamiltonian. Since such potential has an explicit time-dependency, in order to obtain the wave function of considered system, we should face with time-dependent Schrödinger equation. Obtaining the wave function could be possible using Lewis-Riesenfeld dynamical invariant method. Appropriate dynamical invariant has been constructed after determining the wave functions and values, the wave function will obtain.

  7. Transparent Dirac potentials in one dimension: The time-dependent case

    NASA Astrophysics Data System (ADS)

    Dunne, Gerald V.; Thies, Michael

    2013-12-01

    We generalize the original derivation of transparent, static Schrödinger potentials by Kay and Moses, to obtain a large class of time-dependent transparent Dirac potentials in one spatial dimension. They contain previously found transparent potentials as special cases and play a key role in the semiclassical solution of the (1+1)-dimensional, fermionic quantum field theories of Gross-Neveu and Nambu-Jona-Lasinio types.

  8. Isotopic dependence of fusion enhancement of various heavy ion systems using energy dependent Woods-Saxon potential

    NASA Astrophysics Data System (ADS)

    Gautam, Manjeet Singh

    2015-01-01

    In the present work, the fusion of symmetric and asymmetric projectile-target combinations are deeply analyzed within the framework of energy dependent Woods-Saxon potential model (EDWSP model) in conjunction with one dimensional Wong formula and the coupled channel code CCFULL. The neutron transfer channels and the inelastic surface excitations of collision partners are dominating mode of couplings and the coupling of relative motion of colliding nuclei to such relevant internal degrees of freedom produces a significant fusion enhancement at sub-barrier energies. It is quite interesting that the effects of dominant intrinsic degrees of freedom such as multi-phonon vibrational states, neutron transfer channels and proton transfer channels can be simulated by introducing the energy dependence in the nucleus-nucleus potential (EDWSP model). In the EDWSP model calculations, a wide range of diffuseness parameter ranging from a = 0.85 fm to a = 0.97 fm, which is much larger than a value (a = 0.65 fm) extracted from the elastic scattering data, is needed to reproduce sub-barrier fusion data. However, such diffuseness anomaly, which might be an artifact of some dynamical effects, has been resolved by trajectory fluctuation dissipation (TFD) model wherein the resulting nucleus-nucleus potential possesses normal diffuseness parameter.

  9. Coulomb potentials and Taylor expansions in time-dependent density-functional theory

    NASA Astrophysics Data System (ADS)

    Fournais, Søren; Lampart, Jonas; Lewin, Mathieu; Sørensen, Thomas Østergaard

    2016-06-01

    We investigate when Taylor expansions can be used to prove the Runge-Gross theorem, which is at the foundation of time-dependent density-functional theory (TDDFT). We start with a general analysis of the conditions for the Runge-Gross argument, especially the time differentiability of the density. The latter should be questioned in the presence of singular (e.g., Coulomb) potentials. Then we show that a singular potential in a one-body operator considerably decreases the class of time-dependent external potentials to which the original argument can be applied. A two-body singularity has an even stronger impact and an external potential is essentially incompatible with it. For the Coulomb interaction and all reasonable initial many-body states, the Taylor expansion only exists to a finite order, except for constant external potentials. Therefore, high-order Taylor expansions are not the right tool to study atoms and molecules in TDDFT.

  10. Retainability of canonical distributions for a Brownian particle controlled by a time-dependent harmonic potential

    NASA Astrophysics Data System (ADS)

    Li, Geng; Tu, ZhanChun

    2016-04-01

    The retainability of canonical distributions for a Brownian particle controlled by a time-dependent harmonic potential is investigated in the overdamped and underdamped situations, respectively. Because of different time scales, the overdamped and underdamped Langevin equations (as well as the corresponding Fokker-Planck equations) lead to distinctive restrictions on protocols maintaining canonical distributions. Two special cases are analyzed in details: First, a Brownian particle is controlled by a time-dependent harmonic potential and embedded in medium with constant temperature; Second, a Brownian particle is controlled by a timedependent harmonic potential and embedded in a medium whose temperature is tuned together with the potential stiffness to keep a constant effective temperature of the Brownian particle. We find that the canonical distributions are usually retainable for both the overdamped and underdamped situations in the former case. However, the canonical distributions are retainable merely for the overdamped situation in the latter case. We also investigate general time-dependent potentials beyond the harmonic form and find that the retainability of canonical distributions depends sensitively on the specific form of potentials.

  11. Angular-dependent interatomic potential for the aluminum-hydrogen system

    NASA Astrophysics Data System (ADS)

    Apostol, F.; Mishin, Y.

    2010-10-01

    We report on the development of an angular-dependent interatomic potential for hydrogen and the aluminum-hydrogen system. The potential reproduces properties of diatomic hydrogen gas, accurate solution energies of hydrogen atoms in crystalline Al, the energetic preference of the tetrahedral interstitial site occupation over octahedral, the hydrogen diffusion barrier in Al, and a number of other properties. Some of the results predicted by the potential have been tested by molecular dynamics simulations. It is suggested that the new potential can be used in atomistic simulations of the effect of dissolved hydrogen on deformation and fracture of Al, a problem which is relevant to hydrogen-induced degradation of Al alloys.

  12. Bohr Hamiltonian with a deformation-dependent mass term for the Davidson potential

    SciTech Connect

    Bonatsos, Dennis; Georgoudis, P. E.; Lenis, D.; Minkov, N.; Quesne, C.

    2011-04-15

    Analytical expressions for spectra and wave functions are derived for a Bohr Hamiltonian, describing the collective motion of deformed nuclei, in which the mass is allowed to depend on the nuclear deformation. Solutions are obtained for separable potentials consisting of a Davidson potential in the {beta} variable, in the cases of {gamma}-unstable nuclei, axially symmetric prolate deformed nuclei, and triaxial nuclei, implementing the usual approximations in each case. The solution, called the deformation-dependent mass (DDM) Davidson model, is achieved by using techniques of supersymmetric quantum mechanics (SUSYQM), involving a deformed shape invariance condition. Spectra and B(E2) transition rates are compared to experimental data. The dependence of the mass on the deformation, dictated by SUSYQM for the potential used, reduces the rate of increase of the moment of inertia with deformation, removing a main drawback of the model.

  13. Some Exact Results for the Schroedinger Wave Equation with a Time Dependent Potential

    NASA Technical Reports Server (NTRS)

    Campbell, Joel

    2009-01-01

    The time dependent Schroedinger equation with a time dependent delta function potential is solved exactly for many special cases. In all other cases the problem can be reduced to an integral equation of the Volterra type. It is shown that by knowing the wave function at the origin, one may derive the wave function everywhere. Thus, the problem is reduced from a PDE in two variables to an integral equation in one. These results are used to compare adiabatic versus sudden changes in the potential. It is shown that adiabatic changes in the p otential lead to conservation of the normalization of the probability density.

  14. The fermionic projector in a time-dependent external potential: Mass oscillation property and Hadamard states

    NASA Astrophysics Data System (ADS)

    Finster, Felix; Murro, Simone; Röken, Christian

    2016-07-01

    We give a non-perturbative construction of the fermionic projector in Minkowski space coupled to a time-dependent external potential which is smooth and decays faster than quadratically for large times. The weak and strong mass oscillation properties are proven. We show that the integral kernel of the fermionic projector is of the Hadamard form, provided that the time integral of the spatial sup-norm of the potential satisfies a suitable bound. This gives rise to an algebraic quantum field theory of Dirac fields in an external potential with a distinguished pure quasi-free Hadamard state.

  15. Molecular dynamics simulation of alkali borate glass using coordination dependent potential

    SciTech Connect

    Park, B.; Cormack, A.N.

    1997-12-31

    The structure of sodium borate glass was investigated by molecular dynamics simulation using coordination dependent potential model. The simulated alkali borate glass consists of basic units, BO{sub 3} triangle, BO{sub 4} tetrahedra and structural groups such as boroxol ring and triborate units. The coordination of boron is converted from 3 to 4 by adding alkali oxide.

  16. On the Chaplygin system on the sphere with velocity dependent potential

    NASA Astrophysics Data System (ADS)

    Tsiganov, A. V.

    2015-06-01

    We discuss how to get variables of separation, separated relations and the Lax matrix for the Chaplygin system on the sphere with velocity dependent potential starting with the Lax matrix for other integrable system separable in elliptic coordinates on the sphere.

  17. Importance of the energy-dependent geometry in the 16O+ 16O optical model potential

    NASA Astrophysics Data System (ADS)

    Pantis, G.; Ioannidis, K.; Poirier, P.

    1985-08-01

    Optical model potentials with various forms of energy-dependent geometry have been considered for the description of 16O+ 16O elastic scattering. It is shown that the variation with energy of the imaginary radius leads to a reasonable fit of the cross-section data, throughout the energy range.

  18. Numerical density-to-potential inversions in time-dependent density functional theory.

    PubMed

    Jensen, Daniel S; Wasserman, Adam

    2016-08-01

    We treat the density-to-potential inverse problem of time-dependent density functional theory as an optimization problem with a partial differential equation constraint. The unknown potential is recovered from a target density by applying a multilevel optimization method controlled by error estimates. We employ a classical optimization routine using gradients efficiently computed by the discrete adjoint method. The inverted potential has both a real and imaginary part to reduce reflections at the boundaries and other numerical artifacts. We demonstrate this method on model one-dimensional systems. The method can be straightforwardly extended to a variety of numerical solvers of the time-dependent Kohn-Sham equations and to systems in higher dimensions. PMID:26984427

  19. Time course of Ca and Ca-dependent K currents during molluscan nerve cell action potentials.

    PubMed

    Gola, M; Hussy, N; Crest, M; Ducreux, C

    1986-10-20

    The time courses of Ca and Ca-dependent K currents during Ca-dependent action potentials were obtained by recording the membrane currents produced in response to spike-like voltage clamp pulses before and after selective blockade of channels. The Ca current had a biphasic waveform with a first surge and a late, large entry. The Ca-dependent K(Ca) current onset was relatively fast with a peak occurring at half spike repolarization. The fast activation of the K(Ca) current was consecutive to the first Ca entry. It is concluded that K(Ca) currents constitute a powerful spike repolarization mechanism in addition to the voltage-dependent K currents. PMID:2430243

  20. Electrophysiological properties of rat spinal dorsal horn neurones in vitro: calcium-dependent action potentials.

    PubMed Central

    Murase, K; Randić, M

    1983-01-01

    1. The electrophysiological properties of dorsal horn neurones have been investigated in the immature rat in vitro spinal cord slice preparation. 2. Intracellular recordings from dorsal horn neurones show that direct or orthodromic stimulation generates action potentials followed by a brief after-hyperpolarization. Synaptic potentials were elicited by the activation of primary afferent fibres in the dorsal root. 3. Input resistance for dorsal horn neurones ranged from 48 to 267 M omega, and the membrane time constant was in the range of 4-19 ms. 4. In response to strong depolarizing currents dorsal horn neurones perfused with TTX and TEA frequently exhibit a slow regenerative depolarizing potential followed by a slow after-hyperpolarization. The depolarizing potential probably results from an influx of Ca. It is blocked by low concentration Ca, Co or Mn, and enhanced by high levels of extracellular Ca. 5. There is, in addition, a low-threshold Ca-dependent response which is activated at membrane potentials more negative than -65 mV and has a maximum rate of rise at the polarization level of about -80 mV. 6. The addition of Ba or TEA to the perfusing medium provided support for the Ca-dependence of the low- and high-threshold responses, and the lack of fast inactivation of the high-threshold Ca potential. Images Plate 1 PMID:6306228

  1. Kinetic and interaction components of the exact time-dependent correlation potential

    SciTech Connect

    Luo, Kai; Fuks, Johanna I.; Sandoval, Ernesto D.; Maitra, Neepa T.; Elliott, Peter

    2014-05-14

    The exact exchange-correlation (xc) potential of time-dependent density functional theory has been shown to have striking features. For example, step and peak features are generically found when the system is far from its ground-state, and these depend nonlocally on the density in space and time. We analyze the xc potential by decomposing it into kinetic and interaction components and comparing each with their exact-adiabatic counterparts, for a range of dynamical situations in model one-dimensional two-electron systems. We find that often, but not always, the kinetic contribution is largely responsible for these features that are missed by the adiabatic approximation. The adiabatic approximation often makes a smaller error for the interaction component, which we write in two parts, one being the Coulomb potential due to the time-dependent xc hole. Non-adiabatic features of the kinetic component were also larger than those of the interaction component in cases that we studied when there is negligible step structure. In ground-state situations, step and peak structures arise in cases of static correlation, when more than one determinant is essential to describe the interacting state. We investigate the time-dependent natural orbital occupation numbers and find the corresponding relation between these and the dynamical step is more complex than for the ground-state case.

  2. The general operator form for the total-momentum-dependent nucleon-nucleon potential

    NASA Astrophysics Data System (ADS)

    Topolnicki, Kacper; Golak, Jacek; Skibiński, Roman; Witała, Henryk

    2016-07-01

    In this paper we describe a procedure to obtain the general operator form of two-nucleon (2N) potentials and apply it to the case of the 2N potential that has an additional dependence on the total momentum of the system. This violates Galilean invariance but terms including the total momentum appear in some relativistic approaches. In operator form, the potential is expressed as a linear combination of a fixed number of known spin-momentum operators and scalar functions of momenta. Since the scalar functions effectively define the potentials, using the operator form significantly reduces the number of parameters that are needed in numerical implementations. The proposed operator form explicitly obeys the usual symmetries of rotational invariance, particle exchange, time reflection and parity.

  3. Bursting regimes in a reaction-diffusion system with action potential-dependent equilibrium.

    PubMed

    Meier, Stephen R; Lancaster, Jarrett L; Starobin, Joseph M

    2015-01-01

    The equilibrium Nernst potential plays a critical role in neural cell dynamics. A common approximation used in studying electrical dynamics of excitable cells is that the ionic concentrations inside and outside the cell membranes act as charge reservoirs and remain effectively constant during excitation events. Research into brain electrical activity suggests that relaxing this assumption may provide a better understanding of normal and pathophysiological functioning of the brain. In this paper we explore time-dependent ionic concentrations by allowing the ion-specific Nernst potentials to vary with developing transmembrane potential. As a specific implementation, we incorporate the potential-dependent Nernst shift into a one-dimensional Morris-Lecar reaction-diffusion model. Our main findings result from a region in parameter space where self-sustaining oscillations occur without external forcing. Studying the system close to the bifurcation boundary, we explore the vulnerability of the system with respect to external stimulations which disrupt these oscillations and send the system to a stable equilibrium. We also present results for an extended, one-dimensional cable of excitable tissue tuned to this parameter regime and stimulated, giving rise to complex spatiotemporal pattern formation. Potential applications to the emergence of neuronal bursting in similar two-variable systems and to pathophysiological seizure-like activity are discussed. PMID:25823018

  4. Bursting Regimes in a Reaction-Diffusion System with Action Potential-Dependent Equilibrium

    PubMed Central

    Meier, Stephen R.; Lancaster, Jarrett L.; Starobin, Joseph M.

    2015-01-01

    The equilibrium Nernst potential plays a critical role in neural cell dynamics. A common approximation used in studying electrical dynamics of excitable cells is that the ionic concentrations inside and outside the cell membranes act as charge reservoirs and remain effectively constant during excitation events. Research into brain electrical activity suggests that relaxing this assumption may provide a better understanding of normal and pathophysiological functioning of the brain. In this paper we explore time-dependent ionic concentrations by allowing the ion-specific Nernst potentials to vary with developing transmembrane potential. As a specific implementation, we incorporate the potential-dependent Nernst shift into a one-dimensional Morris-Lecar reaction-diffusion model. Our main findings result from a region in parameter space where self-sustaining oscillations occur without external forcing. Studying the system close to the bifurcation boundary, we explore the vulnerability of the system with respect to external stimulations which disrupt these oscillations and send the system to a stable equilibrium. We also present results for an extended, one-dimensional cable of excitable tissue tuned to this parameter regime and stimulated, giving rise to complex spatiotemporal pattern formation. Potential applications to the emergence of neuronal bursting in similar two-variable systems and to pathophysiological seizure-like activity are discussed. PMID:25823018

  5. Experimentally induced postinhibitory rebound in rat nucleus ambiguus is dependent on hyperpolarization parameters and membrane potential.

    PubMed

    Dean, J B; Czyzyk-Krzeska, M; Millhorn, D E

    1989-06-01

    Postinhibitory rebound (PIR), a transient depolarization subsequent to release from experimental hyperpolarization, was identified and characterized in 81% of the cells studied in the nucleus ambiguus in slices from medulla of rat. Hyperpolarizing current pulses were administered via the recording microelectrode in the bridge-balanced mode to test for PIR. The voltage trajectory was characterized by a depolarizing sag during the pulse, rebound depolarization (PIR) after the pulse and increased input resistance during rebound. The amplitude and time course of PIR were dependent on prepulse membrane potential, pulse amplitude and pulse duration. These results suggest a potential role of PIR in respiratory rhythmogenesis. PMID:2771207

  6. Numerical time-dependent solutions of the Schrödinger equation with piecewise continuous potentials

    NASA Astrophysics Data System (ADS)

    van Dijk, Wytse

    2016-06-01

    We consider accurate numerical solutions of the one-dimensional time-dependent Schrödinger equation when the potential is piecewise continuous. Spatial step sizes are defined for each of the regions between the discontinuities and a matching condition at the boundaries of the regions is employed. The Numerov method for spatial integration is particularly appropriate to this approach. By employing Padé approximants for the time-evolution operator, we obtain solutions with significantly improved precision without increased CPU time. This approach is also appropriate for adaptive changes in spatial step size even when there is no discontinuity of the potential.

  7. Task-dependent signal variations in EEG error-related potentials for brain-computer interfaces

    NASA Astrophysics Data System (ADS)

    Iturrate, I.; Montesano, L.; Minguez, J.

    2013-04-01

    Objective. A major difficulty of brain-computer interface (BCI) technology is dealing with the noise of EEG and its signal variations. Previous works studied time-dependent non-stationarities for BCIs in which the user’s mental task was independent of the device operation (e.g., the mental task was motor imagery and the operational task was a speller). However, there are some BCIs, such as those based on error-related potentials, where the mental and operational tasks are dependent (e.g., the mental task is to assess the device action and the operational task is the device action itself). The dependence between the mental task and the device operation could introduce a new source of signal variations when the operational task changes, which has not been studied yet. The aim of this study is to analyse task-dependent signal variations and their effect on EEG error-related potentials.Approach. The work analyses the EEG variations on the three design steps of BCIs: an electrophysiology study to characterize the existence of these variations, a feature distribution analysis and a single-trial classification analysis to measure the impact on the final BCI performance.Results and significance. The results demonstrate that a change in the operational task produces variations in the potentials, even when EEG activity exclusively originated in brain areas related to error processing is considered. Consequently, the extracted features from the signals vary, and a classifier trained with one operational task presents a significant loss of performance for other tasks, requiring calibration or adaptation for each new task. In addition, a new calibration for each of the studied tasks rapidly outperforms adaptive techniques designed in the literature to mitigate the EEG time-dependent non-stationarities.

  8. Membrane potential-dependent integration of synaptic inputs in entorhinal stellate neurons.

    PubMed

    Economo, Michael N; Martínez, Joan José; White, John A

    2014-12-01

    Stellate cells (SCs) of the medial entorhinal cortex exhibit robust spontaneous membrane-potential oscillations (MPOs) in the theta (4-12 Hz) frequency band as well as theta-frequency resonance in their membrane impedance spectra. Past experimental and modeling work suggests that these features may contribute to the phase-locking of SCs to the entorhinal theta rhythm and may be important for forming the hexagonally tiled grid cell place fields exhibited by these neurons in vivo. Among the major biophysical mechanisms contributing to MPOs is a population of persistent (non-inactivating or slowly inactivating) sodium channels. The resulting persistent sodium conductance (GNaP ) gives rise to an apparent increase in input resistance as the cell approaches threshold. In this study, we used dynamic clamp to test the hypothesis that this increased input resistance gives rise to voltage-dependent, and thus MPO phase-dependent, changes in the amplitude of excitatory and inhibitory post-synaptic potential (PSP) amplitudes. We find that PSP amplitude depends on membrane potential, exhibiting a 5-10% increase in amplitude per mV depolarization. The effect is larger than-and sums quasi-linearly with-the effect of the synaptic driving force, V - Esyn . Given that input-driven MPOs 10 mV in amplitude are commonly observed in MEC stellate cells in vivo, this voltage- and phase-dependent synaptic gain is large enough to modulate PSP amplitude by over 50% during theta-frequency MPOs. Phase-dependent synaptic gain may therefore impact the phase locking and phase precession of grid cells in vivo to ongoing network oscillations. © 2014 Wiley Periodicals, Inc. PMID:25044927

  9. Quantum diffusion of a relativistic particle in a time-dependent random potential.

    PubMed

    Sepehrinia, Reza

    2015-04-01

    We present a rigorous study of quantum diffusion of a relativistic particle subjected to a time-dependent random potential with δ correlation in time. We find that in the asymptotic time limit the particle wave packet spreads ballistically in contrast with the nonrelativistic case, which in the same situation exhibits superballistic diffusion. The relativistic suppression of wave packet diffusion is discussed in connection with statistical conservation laws that follow from relativistic dynamics. PMID:25974441

  10. Learning of Precise Spike Times with Homeostatic Membrane Potential Dependent Synaptic Plasticity

    PubMed Central

    Albers, Christian; Westkott, Maren; Pawelzik, Klaus

    2016-01-01

    Precise spatio-temporal patterns of neuronal action potentials underly e.g. sensory representations and control of muscle activities. However, it is not known how the synaptic efficacies in the neuronal networks of the brain adapt such that they can reliably generate spikes at specific points in time. Existing activity-dependent plasticity rules like Spike-Timing-Dependent Plasticity are agnostic to the goal of learning spike times. On the other hand, the existing formal and supervised learning algorithms perform a temporally precise comparison of projected activity with the target, but there is no known biologically plausible implementation of this comparison. Here, we propose a simple and local unsupervised synaptic plasticity mechanism that is derived from the requirement of a balanced membrane potential. Since the relevant signal for synaptic change is the postsynaptic voltage rather than spike times, we call the plasticity rule Membrane Potential Dependent Plasticity (MPDP). Combining our plasticity mechanism with spike after-hyperpolarization causes a sensitivity of synaptic change to pre- and postsynaptic spike times which can reproduce Hebbian spike timing dependent plasticity for inhibitory synapses as was found in experiments. In addition, the sensitivity of MPDP to the time course of the voltage when generating a spike allows MPDP to distinguish between weak (spurious) and strong (teacher) spikes, which therefore provides a neuronal basis for the comparison of actual and target activity. For spatio-temporal input spike patterns our conceptually simple plasticity rule achieves a surprisingly high storage capacity for spike associations. The sensitivity of the MPDP to the subthreshold membrane potential during training allows robust memory retrieval after learning even in the presence of activity corrupted by noise. We propose that MPDP represents a biophysically plausible mechanism to learn temporal target activity patterns. PMID:26900845

  11. Endocrine disrupting chemicals as potential risk factor for estrogen-dependent cancers.

    PubMed

    Rutkowska, Aleksandra Z; Szybiak, Aleksandra; Serkies, Krystyna; Rachoń, Dominik

    2016-08-01

    Civilization, industrialization, and urbanization create an environment where humans are continuously exposed to endocrine disrupting chemicals (EDCs). Some of breast cancers and endometrial cancer, which are the most common female malignant neoplasms, are estrogen-dependent tumors. Prolonged exposure to estrogens or substances with estrogenic properties may be a risk factor for their development. This paper aimed to discuss the potential adverse effect of EDCs on human health, including the role of EDCs in hormone-dependent carcinogenesis. A review of literature regarding the sources of environmental exposure to EDCs and molecular mechanisms of their action was performed. We analyzed the possible mechanisms of how these substances alter the function of the endocrine system, resulting in adverse health effects. Hundreds of substances with endocrine disrupting potential have been identified in our environment. There is accumulating evidence linking exposure to EDCs with the development of mammary and endometrial cancer. By interacting with steroid receptors, EDCs can impact the cellular processes potentially leading to carcinogenesis. There are also data showing the effect of EDCs on immune dysfunction. During lifespan, people are usually exposed to a mixture of various EDCs, which complicates the assessment of individual substances or compounds implicated in cancer development. As the prevalence of hormone-dependent tumors among women continues to increase, their successful prevention is of human benefit. Institutions representing medicine, science, industry, and governments should develop joint strategies to decrease exposure to EDC, and thus to reduce the risk of hormonedependent tumors in women. PMID:27509913

  12. Galactic orbital motions of star clusters: static versus semicosmological time-dependent Galactic potentials

    NASA Astrophysics Data System (ADS)

    Haghi, Hosein; Zonoozi, Akram Hasani; Taghavi, Saeed

    2015-07-01

    In order to understand the orbital history of Galactic halo objects, such as globular clusters, authors usually assume a static potential for our Galaxy with parameters that appear at the present day. According to the standard paradigm of galaxy formation, galaxies grow through a continuous accretion of fresh gas and a hierarchical merging with smaller galaxies from high redshift to the present day. This implies that the mass and size of disc, bulge, and halo change with time. We investigate the effect of assuming a live Galactic potential on the orbital history of halo objects and its consequences on their internal evolution. We numerically integrate backwards the equations of motion of different test objects located in different Galactocentric distances in both static and time-dependent Galactic potentials in order to see if it is possible to discriminate between them. We show that in a live potential, the birth of the objects, 13 Gyr ago, would have occurred at significantly larger Galactocentric distances, compared to the objects orbiting in a static potential. Based on the direct N-body calculations of star clusters carried out with collisional N-body code, NBODY6, we also discuss the consequences of the time-dependence of a Galactic potential on the early- and long-term evolution of star clusters in a simple way, by comparing the evolution of two star clusters embedded in galactic models, which represent the galaxy at present and 12 Gyr ago, respectively. We show that assuming a static potential over a Hubble time for our Galaxy as it is often done, leads to an enhancement of mass-loss, an overestimation of the dissolution rates of globular clusters, an underestimation of the final size of star clusters, and a shallower stellar mass function.

  13. Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth.

    PubMed

    Dhayade, Sandeep; Kaesler, Susanne; Sinnberg, Tobias; Dobrowinski, Hyazinth; Peters, Stefanie; Naumann, Ulrike; Liu, He; Hunger, Robert E; Thunemann, Martin; Biedermann, Tilo; Schittek, Birgit; Simon, Hans-Uwe; Feil, Susanne; Feil, Robert

    2016-03-22

    Sildenafil, an inhibitor of the cGMP-degrading phosphodiesterase 5 that is used to treat erectile dysfunction, has been linked to an increased risk of melanoma. Here, we have examined the potential connection between cGMP-dependent signaling cascades and melanoma growth. Using a combination of biochemical assays and real-time monitoring of melanoma cells, we report a cGMP-dependent growth-promoting pathway in murine and human melanoma cells. We document that C-type natriuretic peptide (CNP), a ligand of the membrane-bound guanylate cyclase B, enhances the activity of cGMP-dependent protein kinase I (cGKI) in melanoma cells by increasing the intracellular levels of cGMP. Activation of this cGMP pathway promotes melanoma cell growth and migration in a p44/42 MAPK-dependent manner. Sildenafil treatment further increases intracellular cGMP concentrations, potentiating activation of this pathway. Collectively, our data identify this cGMP-cGKI pathway as the link between sildenafil usage and increased melanoma risk. PMID:26971999

  14. Strain Loading Mode Dependent Bandgap Deformation Potential in ZnO Micro/Nanowires.

    PubMed

    Fu, Xuewen; Liao, Zhi-Min; Liu, Ren; Lin, Fang; Xu, Jun; Zhu, Rui; Zhong, Wei; Liu, Yingkai; Guo, Wanlin; Yu, Dapeng

    2015-12-22

    The electronic-mechanical coupling in semiconductor nanostructures under different strain loading modes can modulate their photoelectric properties in different manners. Here, we report the systematic investigation on the strain mode dependent bandgap deformation potential of ZnO micro/nanowires under both uniaxial tensile and bending strains at room temperature. Uniaxial stretching-photoluminescence results show that the deformation potential of the smaller ZnO nanowire (with diameter d = 260 nm) is -30.6 meV/%, and is close to the bulk value, whereas it deviates the bulk value and becomes to be -10.6 meV/% when the wire diameter is increased to d = 2 μm. This unconventional size dependence stems from surface effect induced inhomogeneous strain in the surface layer and the core of the ZnO micro/nanowires under uniaxial tension. For bending load mode, the in situ high-resolution transmission electron microscope analysis reveals that the local strain distributes linearly in the bending cross section. Further cathodoluminescence measurements on a bending ZnO microwire (d = 1.8 μm) demonstrate that the deformation potential is -27 meV/%, whose absolute value is much larger than that of the ZnO microwire under uniaxial tension. Further analysis reveals that the distinct deformation potentials originate from the different deforming modes in ZnO micro/nanowires under bending or uniaxial tensile strains. Our results should facilitate the design of flexible optoelectronic nanodevices. PMID:26517647

  15. Charge balance and ionospheric potential dynamics in time dependent global electric circuit model

    NASA Astrophysics Data System (ADS)

    Jansky, J.; Pasko, V. P.

    2014-12-01

    We have developed a time-dependent model of global electric circuit (GEC)in spherical coordinates. The model solves time-dependent charge continuity equation coupledwith Poisson's equation. An implicit time stepping is used to avoid strict dielectricrelaxation time step condition, and boundary conditions for Poisson's equationare implemented to allow accurate description of time evolution of the ionospheric potential.The concept of impulse response of GEC is introduced that allows effective representationof complex time dynamics of various physical quantities in the circuit usingmodel results obtained for instantaneous deposition of a point charge.The more complex problems, like continuous charging of thunderstorms and different typesof lightning dischargesare then reconstructed using convolution and linearity principles.It is shown that for a thundercloud charging phase, typicallyrepresented by a current dipole, the ionospheric potential can be determined from the differenceof time integrals of two ionospheric potential impulse responsescorresponding to charge locations at the opposite ends of the current dipole.During a cloud to ground lightning discharge,the ionospheric potential changes instantaneously by a value proportionalto the charge moment change produced by lightning and then relaxes to zero.We will also discuss processes involving transient conductivity perturbations in GEC associated withextraterrestrial gamma ray bursts and sprites.

  16. The dependence of membrane potential on extracellular chloride concentration in mammalian skeletal muscle fibres.

    PubMed Central

    Dulhunty, A F

    1978-01-01

    1. The steady-state intracellular membrane potential of fibres in thin bundles dissected from mouse extensor digitorum longus or soleus muscles or rat sternomastoid muscles was measured with 3 M-KCl glass micro-electrodes. The steady-state membrane potential was found to depend on the extracellular concentrations of Na, K and Cl ions. 2. The resting membrane potential (3.5 mM-[K]o, 160 mM-[Cl]o) was -74 +/- 1 mV (mean +/- S.E.) and a reduction in [Cl]o to 3.5 mM caused a reversible steady-state hyperpolarization to -94 +/- 1 mV (mean +/- S.E.). 3. The steady-state membrane potentials recorded in fibres exposed to different [K]o and zero [Cl]o were consistent with potentials predicted by the Goldman, Hodgkin & Katz (GHK) equation for Na and K. The results of similar experiments done with Cl as the major external anion could not be fitted by the same equation. 4. The GHK equation for Na, K and Cl did fit data obtained from fibres in solutions containing different [K]o with Cl as the major external anion if the intracellular Cl concentration was allowed to be out of equilibrium with the steady-state membrane potential. 5. It is suggested that an active influx of Cl ions controls the intracellular Cl concentrations in these fibres and hence maintains the Cl equilibrium potential at a depolarized value with respect to the resting membrane potential. 6. The steady-state membrane potential of rat diaphragm fibres was independent of [Cl]o and it seems likely that the intracellular Cl concentration of these fibres is not controlled by active Cl transport. PMID:650497

  17. Kink ratchet induced by a time-dependent symmetric field potential

    NASA Astrophysics Data System (ADS)

    Sánchez-Rey, Bernardo; Casado-Pascual, Jesús; Quintero, Niurka R.

    2016-07-01

    The ratchet effect of a sine-Gordon kink is investigated in the absence of any external force while the symmetry of the field potential at every time instant is maintained. The directed motion appears by a time shift of the sine-Gordon potential through a time-dependent additional phase. A symmetry analysis provides the necessary conditions for the existence of net motion. It is also shown analytically, by using a collective coordinate theory, that the novel physical mechanism responsible for the appearance of the ratchet effect is the coupled dynamics of the kink width with the background field. Biharmonic and dichotomic periodic variations of the additional phase of the sine-Gordon potential are considered. The predictions established by the symmetry analysis and the collective coordinate theory are verified by means of numerical simulations. Inversion and maximization of the resulting current as a function of the system parameters are investigated.

  18. Kink ratchet induced by a time-dependent symmetric field potential.

    PubMed

    Sánchez-Rey, Bernardo; Casado-Pascual, Jesús; Quintero, Niurka R

    2016-07-01

    The ratchet effect of a sine-Gordon kink is investigated in the absence of any external force while the symmetry of the field potential at every time instant is maintained. The directed motion appears by a time shift of the sine-Gordon potential through a time-dependent additional phase. A symmetry analysis provides the necessary conditions for the existence of net motion. It is also shown analytically, by using a collective coordinate theory, that the novel physical mechanism responsible for the appearance of the ratchet effect is the coupled dynamics of the kink width with the background field. Biharmonic and dichotomic periodic variations of the additional phase of the sine-Gordon potential are considered. The predictions established by the symmetry analysis and the collective coordinate theory are verified by means of numerical simulations. Inversion and maximization of the resulting current as a function of the system parameters are investigated. PMID:27575137

  19. Potential of Renewable Energy to Reduce the Dependence of the State of Hawaii on Oil

    SciTech Connect

    Arent, D.; Barnett, J.; Mosey, G.; Wise, A.

    2009-01-01

    Deriving nearly 90% of its primary energy resources from oil, the State of Hawaii is more dependent on oil than any other U.S. state. The price of electricity in Hawaii is also more than twice the U.S. average. The Energy Policy Act of 2005 directed assessment of the economic implications of Hawaii's oil dependence and the feasibility of using renewable energy to help meet the state's electrical generation and transportation fuel use. This paper is based on the assessments and report prepared in response to that directive.Current total installed electrical capacity for the State of Hawaii is 2,414 MWe, 83% of which is fuel-oil generated, but already including about 170 MWe of renewable capacity. The assessments identified about 2,133 MWe (plus another estimated 2,000 MWe of rooftop PV systems) of potential new renewable energy capacity. Most notable, in addition to the rooftop solar potential, is 750 MWe and 140 MWe of geothermal potential on Hawaii and Maui, respectively, 840 MWe of potential wind capacity, primarily on Lanai and Molokai, and one potential 285 MWe capacity specific solar project (PV or solar thermal) identified on Kauai. Important social, political, and electrical-grid infrastructure challenges would need to be overcome to realize this potential. Among multiple crop and acreage scenarios, biofuels assessment found 360,000 acres in Hawaii zoned for agriculture and appropriate for sugarcane, enough to produce 429 million gallons of ethanol-enough to meet about 64% of current 2005 Hawaiian gasoline use. Tropical oil seed crops-potentially grown on the same land-might meet a substantial portion of current diesel use, but there has been little experience growing such crops in Hawaii. The U.S. Department of Energy and the State of Hawaii initiated in January 2008 a program that seeks to reduce Hawaii's oil dependence and provide 70% of the state's primary energy from clean energy sources by 2030. The Hawaii Clean Energy Initiative (HCEI) activities will

  20. Khat (Catha edulis Forsk.) Dependence Potential and Pattern of Use in Saudi Arabia

    PubMed Central

    Abdelwahab, Siddig Ibrahim; Alsanosy, Rashad Mohammed; Rahim, Bahaa-eldin E. A.; Mohan, Syam; Taha, Sara; Mohamed Elhassan, Manal; El-Setouhy, Maged

    2015-01-01

    Background. Catha edulis Forsk. (Khat) is used for its psychoactive effects among people in Africa and the Arabian Peninsula, although its utilization is illegal in some countries such as Saudi Arabia. This study examined the pattern of Khat use and assessed the applicability of the Drug Abuse Screening Test-10 (DAST-10) to measure Khat dependence. Methods. A pretested questionnaire was used to gather data from 603 respondents. Variables included demographic characteristics, pattern of use, reasons for Khat chewing, and DAST-10. Stepwise-logistic regression was used to explore predictors of Khat dependence. Results. The majority of the respondents were married, had a secondary school level of education, were employed, were younger than 35 years old, and were living in rural areas. Many chewers gave more than one reason for using Khat. It was mainly used to increase mental capacity, physical strength, and social entertainment, as well as enhance cheerfulness and orgasms. Statistical modeling of Khat dependence suggested that the most significant predictors were residence (OR = 1.67, P < 0.02), frequency of Khat chewing (OR = 4.8, P < 0.01), age of starting Khat chewing (OR = 1.15, P < 0.01), and time of Khat effect (OR = 1.15, P < 0.04). Conclusion. Our study provides important information on the pattern of Khat use and its potential to cause dependence. PMID:26380288

  1. Screened environment-dependent reactive empirical bond-order potential for atomistic simulations of carbon materials

    NASA Astrophysics Data System (ADS)

    Perriot, Romain; Gu, Xiang; Lin, You; Zhakhovsky, Vasily V.; Oleynik, Ivan I.

    2013-08-01

    A screened environment-dependent reactive empirical bond-order (SED-REBO) potential has been developed for large-scale molecular dynamics (MD) simulations of carbon materials. Based on the second-generation REBO potential developed by Brenner and co-workers [J. Phys.: Condens. MatterJCOMEL0953-898410.1088/0953-8984/14/4/312 14, 783 (2002)], the SED-REBO potential overcomes the deficiencies of the REBO potential, which arise from a short range of interatomic interactions and their abrupt switching off at the cutoff distance, by increasing the range of interatomic interactions and eliminating the explicit switching function while introducing a simple yet efficient screening function. The increased cutoff distance allows the inclusion of interactions critically important for the physically correct description of bond breaking and bond remaking. An analytic form of the attractive and repulsive pairwise terms was devised to automatically become zero at distances above the cutoff, thus, eliminating the need for the switching function. The screening function effectively screens off the second- and further-nearest-neighbor interactions for calculation of energy and forces in a smooth and continuous way for both compression and expansion. The pairwise attractive and repulsive terms were refitted within a wide range of interatomic distances to properly describe large compressions and expansions of diamond and graphene as well as their behavior near equilibrium. Good performances of the SED-REBO potential to describe bond-breaking processes at extreme tensile stresses are demonstrated in large-scale MD simulations of the nanoindentation of graphene membranes. A computationally efficient version of the SED-REBO potential is introduced for large-scale MD simulations of shock-wave compression in carbon materials. The SED-REBO potential is implemented as a module in the Large-Scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) and is freely available.

  2. Specific anion effects on the pressure dependence of the protein-protein interaction potential.

    PubMed

    Möller, Johannes; Grobelny, Sebastian; Schulze, Julian; Steffen, Andre; Bieder, Steffen; Paulus, Michael; Tolan, Metin; Winter, Roland

    2014-04-28

    We present a study on ion specific effects on the intermolecular interaction potential V(r) of dense protein solutions under high hydrostatic pressure conditions. Small-angle X-ray scattering in combination with a liquid-state theoretical approach was used to determine the effect of structure breaking/making salt anions (Cl(-), SO4(2-), PO4(3-)) on the intermolecular interaction of lysozyme molecules. It was found that besides the Debye-Hückel charge screening effect, reducing the repulsiveness of the interaction potential V(r) at low salt concentrations, a specific ion effect is observed at high salt concentrations for the multivalent kosmotropic anions, which modulates also the pressure dependence of the protein-protein interaction potential. Whereas sulfate and phosphate strongly influence the pressure dependence of V(r), chloride anions do not. The strong structure-making effect of the multivalent anions, dominating for the triply charged PO4(3-), renders the solution structure less bulk-water-like at high salt concentrations, which leads to an altered behavior of the pressure dependence of V(r). Hence, the particular structural properties of the salt solutions are able to influence the spatial organization and the intermolecular interactions of the proteins, in particular upon compression. These results are of interest for exploring the combined effects of ionic strength, temperature and pressure on the phase behavior of protein solutions, but may also be of relevance for understanding pressure effects on the hydration behavior of biological matter under extreme environmental conditions. PMID:24626853

  3. The Role of Steroid Receptor Coactivators in Hormone Dependent Cancers and Their Potential as Therapeutic Targets.

    PubMed

    Wang, Lei; Lonard, David M; O'Malley, Bert W

    2016-08-01

    Steroid receptor coactivator (SRC) family members (SRC-1, SRC-2, SRC-3) interact with nuclear receptors (NRs) and many transcription factors to enhance target gene transcription. Deregulation of SRCs is widely implicated in NR mediated diseases, especially hormone dependent cancers. By integrating steroid hormone signaling and growth factor pathways, SRC proteins exert multiple modes of oncogenic regulation in cancers and represent emerging targets for cancer therapeutics. Recent work has identified SRC-targeting agents that show promise in blocking tumor growth in vitro and in vivo, and have the potential to function as powerful and broadly encompassing treatments for different cancers. PMID:27125199

  4. Strong field ionization rates simulated with time-dependent configuration interaction and an absorbing potential

    SciTech Connect

    Krause, Pascal; Sonk, Jason A.; Schlegel, H. Bernhard

    2014-05-07

    Ionization rates of molecules have been modeled with time-dependent configuration interaction simulations using atom centered basis sets and a complex absorbing potential. The simulations agree with accurate grid-based calculations for the ionization of hydrogen atom as a function of field strength and for charge resonance enhanced ionization of H{sub 2}{sup +} as the bond is elongated. Unlike grid-based methods, the present approach can be applied to simulate electron dynamics and ionization in multi-electron polyatomic molecules. Calculations on HCl{sup +} and HCO{sup +} demonstrate that these systems also show charge resonance enhanced ionization as the bonds are stretched.

  5. Size dependence of vacancy migration energy in ionic nano particles: A potential energy landscape perspective

    NASA Astrophysics Data System (ADS)

    Niiyama, Tomoaki; Okushima, Teruaki; Ikeda, Kensuke S.; Shimizu, Yasushi

    2016-06-01

    Size dependence of vacancy migration energy in ionic nano particles is investigated by analysis of potential energy surfaces in potassium chloride clusters. Numerical methods are used to find almost all local minima and transition states for vacancy migration in clusters of different sizes, and reveal characteristic features of energy surface structure. It is shown that migration energy is significantly lower near a cluster surface than near a cluster core, and the mean first-passage time for migration of a vacancy decreases with cluster size. These results are consistent with observations of high diffusion rates in small clusters.

  6. Angular dependent potential for α-boron and large-scale molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Pokatashkin, P.; Kuksin, A.; Yanilkin, A.

    2015-06-01

    Both quantum mechanical and molecular-dynamics (MD) simulations of α-boron are done at this work. Angular dependent interatomic potential (ADP) for boron is obtained using force-matching technique. Fitting data are based on ab initio results within  -20..100 GPa pressure range and temperatures up to 2000 K. Characteristics of α-boron, obtained using ADP potential such as bond lengths at equilibrium condition, bulk modulus, pressure-volume relations, Gruneisen coefficient, thermal expansion coefficient are in good agreement with both ab initio data, obtained in this work and known experimental data. As an example of application, the propagation of shock waves through a single crystal of α-boron is also explored by large-scale MD simulations.

  7. Temperature dependent effective potential method for accurate free energy calculations of solids

    NASA Astrophysics Data System (ADS)

    Hellman, Olle; Steneteg, Peter; Abrikosov, I. A.; Simak, S. I.

    2013-03-01

    We have developed a thorough and accurate method of determining anharmonic free energies, the temperature dependent effective potential technique (TDEP). It is based on ab initio molecular dynamics followed by a mapping onto a model Hamiltonian that describes the lattice dynamics. The formalism and the numerical aspects of the technique are described in detail. A number of practical examples are given, and results are presented, which confirm the usefulness of TDEP within ab initio and classical molecular dynamics frameworks. In particular, we examine from first principles the behavior of force constants upon the dynamical stabilization of the body centered phase of Zr, and show that they become more localized. We also calculate the phase diagram for 4He modeled with the Aziz potential and obtain results which are in favorable agreement both with respect to experiment and established techniques.

  8. Influence of Site Dependent Effects on the Assessment of the Radiative _COOLING Potential

    NASA Astrophysics Data System (ADS)

    García, Pérez M.; Luis, De

    2002-01-01

    The assessment the radiative cooling potential requires the knowledge of some site dependent boundary conditions affecting to the performance of the respective technological systems. These boundary conditions are mainly related to the existence of certain climatological solicitations that will determine the feasibility or not for each application. This paper presents a contribution to a more accurate assessment of the radiative cooling potential based on the analysis of the influence in the estimation of effective sky temperature and effective sky temperature depression of local or transient effects associated to the existence of a non standard vertical atmospheric structure. These eventual deviations are usually not considered in the conventional estimation models, based exclusively on surface information, and the suitability of the proposed approach is established by comparison with measured data.

  9. Solutions to position-dependent mass quantum mechanics for a new class of hyperbolic potentials

    SciTech Connect

    Christiansen, H. R.; Grupo de Física Teórica, State University of Ceara , Av. Paranjana 1700, 60740-903 Fortaleza-CE ; Cunha, M. S.

    2013-12-15

    We analytically solve the position-dependent mass (PDM) 1D Schrödinger equation for a new class of hyperbolic potentials V{sub q}{sup p}(x)=−V{sub 0}(sinh{sup p}x/cosh{sup q}x), p=−2,0,⋯q [see C. A. Downing, J. Math. Phys. 54, 072101 (2013)] among several hyperbolic single- and double-wells. For a solitonic mass distribution, m(x)=m{sub 0} sech{sup 2}(x), we obtain exact analytic solutions to the resulting differential equations. For several members of the class, the quantum mechanical problems map into confluent Heun differential equations. The PDM Poschl-Teller potential is considered and exactly solved as a particular case.

  10. Charge balance and ionospheric potential dynamics in time-dependent global electric circuit model

    NASA Astrophysics Data System (ADS)

    Jánský, Jaroslav; Pasko, Victor P.

    2014-12-01

    We have developed a time-dependent model of global electric circuit (GEC) in spherical coordinates. The model solves time-dependent charge continuity equation coupled with Poisson's equation. An implicit time stepping is used to avoid a strict dielectric relaxation time step condition, and boundary conditions for Poisson's equation are implemented to allow accurate description of time evolution of the ionospheric potential. The concept of impulse response of GEC is introduced that allows effective representation of complex time dynamics of various physical quantities in the circuit using model results obtained for instantaneous deposition of a point charge. The more complex problems are then reconstructed using convolution and linearity principles. For a point charge instantaneously deposited at a typical thundercloud altitude the impulse response of the charge density shows induction of the same value and polarity charge at the ionospheric boundary, while charge of the same value but opposite sign is moving down logarithmically with time and neutralizes the source point charge on time scale corresponding to the dielectric relaxation time at altitude of the source point charge. The ionospheric potential is modified immediately with input of the source point charge based on free space solution of Poisson's equation. Then the ionospheric potential relaxes. It is shown that during formation of two main charge centers of the thundercloud, typically represented by a current dipole, the ionospheric potential can be determined from the difference of time integrals of two ionospheric potential impulse responses corresponding to charge locations at the opposite ends of the current dipole. For latitude- and longitude-independent conductivity model, the total charge on the Earth is exactly zero at all times. During cloud-to-ground lightning discharge, the ionospheric potential changes instantaneously by a value proportional to the charge moment change produced by lightning

  11. Size-dependent error of the density functional theory ionization potential in vacuum and solution

    SciTech Connect

    Sosa Vazquez, Xochitl A.; Isborn, Christine M.

    2015-12-28

    Density functional theory is often the method of choice for modeling the energetics of large molecules and including explicit solvation effects. It is preferable to use a method that treats systems of different sizes and with different amounts of explicit solvent on equal footing. However, recent work suggests that approximate density functional theory has a size-dependent error in the computation of the ionization potential. We here investigate the lack of size-intensivity of the ionization potential computed with approximate density functionals in vacuum and solution. We show that local and semi-local approximations to exchange do not yield a constant ionization potential for an increasing number of identical isolated molecules in vacuum. Instead, as the number of molecules increases, the total energy required to ionize the system decreases. Rather surprisingly, we find that this is still the case in solution, whether using a polarizable continuum model or with explicit solvent that breaks the degeneracy of each solute, and we find that explicit solvent in the calculation can exacerbate the size-dependent delocalization error. We demonstrate that increasing the amount of exact exchange changes the character of the polarization of the solvent molecules; for small amounts of exact exchange the solvent molecules contribute a fraction of their electron density to the ionized electron, but for larger amounts of exact exchange they properly polarize in response to the cationic solute. In vacuum and explicit solvent, the ionization potential can be made size-intensive by optimally tuning a long-range corrected hybrid functional.

  12. Size-dependent error of the density functional theory ionization potential in vacuum and solution

    SciTech Connect

    Sosa Vazquez, Xochitl A.; Isborn, Christine M.

    2015-12-22

    Density functional theory is often the method of choice for modeling the energetics of large molecules and including explicit solvation effects. It is preferable to use a method that treats systems of different sizes and with different amounts of explicit solvent on equal footing. However, recent work suggests that approximate density functional theory has a size-dependent error in the computation of the ionization potential. We here investigate the lack of size-intensivity of the ionization potential computed with approximate density functionals in vacuum and solution. We show that local and semi-local approximations to exchange do not yield a constant ionization potential for an increasing number of identical isolated molecules in vacuum. Instead, as the number of molecules increases, the total energy required to ionize the system decreases. Rather surprisingly, we find that this is still the case in solution, whether using a polarizable continuum model or with explicit solvent that breaks the degeneracy of each solute, and we find that explicit solvent in the calculation can exacerbate the size-dependent delocalization error. We demonstrate that increasing the amount of exact exchange changes the character of the polarization of the solvent molecules; for small amounts of exact exchange the solvent molecules contribute a fraction of their electron density to the ionized electron, but for larger amounts of exact exchange they properly polarize in response to the cationic solute. As a result, in vacuum and explicit solvent, the ionization potential can be made size-intensive by optimally tuning a long-range corrected hybrid functional.

  13. The Role of Homer1c in Metabotropic Glutamate Receptor-dependent Long-Term Potentiation

    PubMed Central

    O’Riordan, Kenneth; Gerstein, Hilary; Hullinger, Rikki; Burger, Corinna

    2016-01-01

    Group I metabotropic glutamate receptors (mGluR1/5) play a role in synaptic plasticity and they demonstrate direct interactions with the neuronal Homer1c protein. We have previously shown that Homer1c can restore the plasticity deficits in Homer1 knockout mice (H1-KO). Here, we investigated the role of Homer1c in mGluR-dependent synaptic plasticity in wild-type mice, H1-KO, and H1-KO mice overexpressing Homer1c (KO+H1c). We used a form of plasticity induced by activation of mGluR1/5 that transforms short-term potentiaion (STP) induced by a subthreshold theta burst stimulation into long-term potentiation (LTP). We have shown that although acute hippocampal slices from wild-type animals can induce LTP using this stimulation protocol, H1-KO only show STP. Gene delivery of Homer1c into the hippocampus of H1-KO mice rescued LTP to wild-type levels. This form of synaptic plasticity was dependent on mGluR5 but not mGluR1 activation both in wild-type mice and in KO+H1c. mGluR1/5-dependent LTP was blocked with inhibitors of the MEK-ERK and PI3K-mTOR pathways in KO+H1c mice. Moreover, blocking Homer1c–mGluR5 interactions prevented the maintenance of LTP in acute hippocampal slices from KO+H1c. These data indicate that Homer1c–mGluR5 interactions are necessary for mGluR-dependent LTP, and that mGluR1/5-dependent LTP involves PI3K and ERK activation. PMID:24167026

  14. Microwave bistatic reflectivity dependence on the moisture content and matric potential of bare soil

    NASA Technical Reports Server (NTRS)

    Waite, W. P.; Sadeghi, A. M.; Scott, H. D.

    1984-01-01

    Results are presented of an experimental program to determine the functional dependence of the microwave reflectivity of nonvegetated soil surfaces upon volumetric soil moisture and matric potential. A combination evaporation-drainage field experiment was conducted on a bare Captina slit loam with reflectivity, soil moisture content, and matric potential monitored for extended time periods. Results show that for a restricted pressure range (approximately -0.05 to -0.75 bar) there is excellent linear correlation between the log of bistatic reflectivity and both volumetric moisture content and matric potential. Layering effects due to steep moisture content (and matric potential) gradients in the profile are demonstrated to have two distinct and significant effects on the reflectivity response. At near saturation of rough surfaces a very thin dry surface layer appears to modify the effective roughness. This leads to a saturation of reflectivity at high moisture contents. As the surface proceeds to dry further, deeper layers produce coherent interference patterns in the reflectivity response, particularly at the higher frequencies.

  15. Classical nuclear dynamics on a single time-dependent potential in electronic non-adiabatic processes

    NASA Astrophysics Data System (ADS)

    Agostini, Federica; Abedi, Ali; Suzuki, Yasumitsu; Min, Seung Kyu; Maitra, Neepa T.; Gross, E. K. U.

    2015-03-01

    The Born-Oppenheimer (BO) approximation allows to visualize the coupled electron-nuclear dynamics in molecular systems as a set of nuclei moving on a single potential energy surface representing the effect of the electrons in a given eigenstate. Many interesting phenomena, however, such as vision or charge separation in organic photovoltaic materials, take place in conditions beyond its range of validity. Nevertheless, the basic construct of the adiabatic treatment, the BO potential energy surfaces, is employed to describe non-adiabatic processes and the full problem is represented in terms of adiabatic states and transitions among them in regions of strong non-adiabatic coupling. But the concept of single potential energy is lost. The alternative point of view arising in the framework of the exact factorization of the electron-nuclear wave function will be presented. A single, time-dependent, potential energy provides the force driving the nuclear motion and is adopted as starting point for the development of quantum-classical approximations to the full quantum mechanical problem.

  16. Effect of coupled channels on the energy dependence of phenomenological optical potential parameters

    NASA Astrophysics Data System (ADS)

    Al-Rayashi, W. S.; Jaghoub, M. I.

    2016-06-01

    The phenomenological optical potential parameters are known to vary with incident energy due to sources of nonlocalities in the nucleon-nucleus elastic scattering process. Here we investigate the effect of one source, which is coupling the ground-state elastic channel to collective inelastic excitations on the energy dependence of the optical potential parameters. For incident energies in the range 10-70 MeV, we considered elastic and inelastic nucleon scattering from light, medium, and heavy nuclei ranging from 6Li to 208Pb. The potential parameters were first determined by fitting the elastic angular distributions only. Then we included coupling to collective excitation channels and determined the potential parameters that reproduced the elastic and inelastic angular distribution data simultaneously. Our results show that coupling to inelastic excitations reduces the energy variations of the potential parameters compared to that of the elastic scattering case. In particular, the our best fit values for the real part of the spin-orbit term are highly stable as a function of energy. The values of the surface imaginary term are not only more stable but are also reduced compared to the elastic case. The reduction is a direct consequence of the channel coupling accounting explicitly for part of the flux removed from the elastic channel. In the fitting process we also searched for the best fit values of the deformation parameters. Our values compare well with the corresponding ones obtained in previous works. Finally, we used our best fit values for the potential and deformation parameters to theoretically predict the total elastic, total cross section, and polarization data. The predicted values are in very good agreement with the experimental data.

  17. Effect of potential on temperature-dependent SERS spectra of neuromedin B on Cu electrode.

    PubMed

    Ignatjev, Ilja; Proniewicz, Edyta; Proniewicz, Leonard M; Niaura, Gediminas

    2013-01-21

    Adsorption of decapeptide neuromedin B (NMB) on copper electrode has been investigated by in situ surface-enhanced Raman scattering (SERS) spectroelectrochemistry in the temperature interval from 12 to 72 °C at -0.600 and -1.000 V potentials. It was found that intensities of peptide bands decrease at temperatures above 30 °C with higher decrease slope at -1.000 V. Frequency of F12 mode (1004 cm(-1)) of non-surface-interactive phenylalanine residue was found to be insensitive to temperature variation at both studied electrode potentials, while frequency-temperature curves for surface-interactive groups (Amide-III, methylene) were found to be controlled by the potential. In particular, opposite frequency-temperature trends were detected for Amide-III (Am-III) mode indicating decrease in H-bonding interaction strength of amide C[double bond, length as m-dash]O and N-H groups above 38 °C for -0.600 V, and increase in H-bonding interaction strength between 12 and 72 °C for -1.000 V. Anomalous Am-III temperature-dependence of the frequency at -1.000 V was explained by temperature-induced transformation of a disordered secondary structure to a helix-like conformation. The potential-difference spectrum revealed interaction of methylene groups with Cu surface at sufficiently negative potential values because of the appearance of a soft C-H stretching band near 2825 cm(-1) and a broad band near 2904 cm(-1) assigned to vibration of a distal C-H bond of the surface-confined methylene group. Consequently, a rapid decrease in frequency of CH(2)-stretching band with temperature was observed at -1.000 V, while no essential frequency changes were detected for this mode at -0.600 V. The results show that electrode potential controls the temperature-dependence of the frequency for vibrations associated with surface-interactive molecular groups. PMID:23202809

  18. Temperature- and potential-dependent structure of the mercury-electrolyte interface

    NASA Astrophysics Data System (ADS)

    Runge, Benjamin; Festersen, Sven; Koops, Christian T.; Elsen, Annika; Deutsch, Moshe; Ocko, Benjamin M.; Seeck, Oliver H.; Murphy, Bridget M.; Magnussen, Olaf M.

    2016-04-01

    The atomic-scale structure of the mercury-electrolyte (0.01 M NaF) interface was studied as a function of temperature and potential by x-ray reflectivity and x-ray diffuse scattering measurements. The capillary wave contribution is determined and removed from the data, giving access to the intrinsic surface-normal electron density profile at the interface, especially to the surface layering in the Hg phase. A temperature dependent roughness anomaly known from the Hg-air interface is found to persist also at the Hg-electrolyte interface. Additionally, a temperature dependence of the layering period was discovered. The increase in the layer spacing with increasing temperature is approximately four times lager than the increase expected from thermal expansion. Finally, the interface is found to broaden towards the electrolyte side as the potential becomes more negative, in agreement with the Schmickler-Henderson theory. Our results favor a model for the interface structure, which is different to the model formerly used in comparable studies.

  19. Sub-barrier fusion excitation function data and energy dependent Woods-Saxon potential

    NASA Astrophysics Data System (ADS)

    Gautam, Manjeet Singh

    2016-07-01

    This paper analyzed the role of intrinsic degrees of freedom of colliding nuclei in the enhancement of sub-barrier fusion cross-section data of various heavy ion fusion reactions. The influences of inelastic surface vibrations of colliding pairs are found to be dominant and their couplings result in the significantly larger fusion enhancement over the predictions of the one dimensional barrier penetration model at sub-barrier energies. The theoretical calculations are performed by using energy dependent Woods-Saxon potential model (EDWSP model) in conjunction with the one dimensional Wong formula. The effects of dominant intrinsic channels are entertained within framework of the coupled channel calculations obtained by using the code CCFULL. It is quite interesting to note that the energy dependence in Woods-Saxon potential simulates the effects of inelastic surface vibrational states of reactants wherein significantly larger value of diffuseness parameter ranging from a = 0.85 fm to a = 0.95 fm is required to address the observed fusion excitation function data of the various heavy ion fusion reactions.

  20. The flavonoid baicalein promotes NMDA receptor-dependent long-term potentiation and enhances memory

    PubMed Central

    Wang, Wei; Wang, Fang; Yang, Yuan-Jian; Hu, Zhuang-Li; Long, Li-Hong; Fu, Hui; Xie, Na; Chen, Jian-Guo

    2011-01-01

    BACKGROUND AND PURPOSE There is growing interest in the physiological functions of flavonoids, especially in their effects on cognitive function and on neurodegenerative diseases. The aim of the current investigation was to evaluate the role of the flavonoid baicalein in long-term potentiation (LTP) in the hippocampal CA1 region and cognitive behavioural performance. EXPERIMENTAL APPROACH Effects of baicalein on LTP in rat hippocampal slices were investigated by electrophysiological methods. Phosphorylation of Akt (at Ser473), the extracellular signal-regulated kinase (ERK1/2) and the transcription factor cAMP response element-binding protein (CREB) (at Ser133) were analysed by Western blot. Fear conditioning was used to determine whether baicalein could improve learning and memory in rats. KEY RESULTS Baicalein enhanced the N-methyl-d-aspartate glutamate receptor-dependent LTP in a bell-shaped concentration-dependent manner. Addition of the lipoxygenase metabolites 12(S)-HETE and 12(S)-HPETE did not reverse these effects of baicalein. Baicalein treatment enhanced phosphorylation of Akt during induction of LTP with the same bell-shaped dose–response curve. LTP potentiation induced by baicalein was blocked by inhibitors of phosphoinositide 3-kinase. CREB phosphorylation was also increased in the CA1 region of baicalein-treated slices. Baicalein-treated rats performed significantly better than controls in a hippocampus-dependent contextual fear conditioning task. Furthermore, baicalein treatment selectively increased the phosphorylation of Akt and CREB in the CA1 region of hippocampus, but not in the prefrontal cortex, after fear conditioning training. CONCLUSIONS AND IMPLICATIONS Our results demonstrate that the flavonoid baicalein can facilitate memory, and therefore it might be useful in the treatment of patients with memory disorders. PMID:21133890

  1. Osmotic Dependence of the Transmembrane Potential Difference of Broadbean Mesocarp Cells 1

    PubMed Central

    Li, Ze-Sheng; Delrot, Serge

    1987-01-01

    Pod walls of broadbean (Vicia faba L. cv Aguadulce) were harvested at the import (S1), at the transition (S2) or at the export (S3) phase for assimilate transport. Measurements of the transmembrane potential difference (PD) of mesocarp cells were made under various osmotic conditions. Internal osmotic potentials and cell turgor were calculated from osmolality measurements of cell saps recovered by freeze-thawing, after correction for the contribution of the free-space solution. Changes in the mannitol concentration of the medium altered the PD within a few minutes, and new stable values of PD were reached within 20 minutes after the osmotic change. With mannitol as the osmoticum, the most negative PD was measured at an external osmotic potential of -0.70 megapascals (MPa) for S1 and S2, while the most negative was at -0.40 MPa for S3. Ethylene glycol, a permeant osmoticum, had little effect on PD, showing that the PD was sensitive to turgor, not to solute potential per se. For S1 and S2, the PD was less negative for turgor potentials lower than 0.1 MPa or greater than 0.3 MPa. S3 samples exhibited a different turgor dependence, with a sharp optimum of the negativity of the PD at 0.3 MPa. The data are consistent with the proposal that the proton pump acts as a transducer of the osmotic conditions. They show that the osmotic sensitivity of the PD of mesocarp cells of broadbean changes with the stage of development of the pod. PMID:16665540

  2. Size-dependent error of the density functional theory ionization potential in vacuum and solution

    DOE PAGESBeta

    Sosa Vazquez, Xochitl A.; Isborn, Christine M.

    2015-12-22

    Density functional theory is often the method of choice for modeling the energetics of large molecules and including explicit solvation effects. It is preferable to use a method that treats systems of different sizes and with different amounts of explicit solvent on equal footing. However, recent work suggests that approximate density functional theory has a size-dependent error in the computation of the ionization potential. We here investigate the lack of size-intensivity of the ionization potential computed with approximate density functionals in vacuum and solution. We show that local and semi-local approximations to exchange do not yield a constant ionization potentialmore » for an increasing number of identical isolated molecules in vacuum. Instead, as the number of molecules increases, the total energy required to ionize the system decreases. Rather surprisingly, we find that this is still the case in solution, whether using a polarizable continuum model or with explicit solvent that breaks the degeneracy of each solute, and we find that explicit solvent in the calculation can exacerbate the size-dependent delocalization error. We demonstrate that increasing the amount of exact exchange changes the character of the polarization of the solvent molecules; for small amounts of exact exchange the solvent molecules contribute a fraction of their electron density to the ionized electron, but for larger amounts of exact exchange they properly polarize in response to the cationic solute. As a result, in vacuum and explicit solvent, the ionization potential can be made size-intensive by optimally tuning a long-range corrected hybrid functional.« less

  3. Intronic regions of plant genes potentially encode RDR (RNA-dependent RNA polymerase)-dependent small RNAs

    PubMed Central

    Qin, Jingping; Ma, Xiaoxia; Yi, Zili; Tang, Zhonghai; Meng, Yijun

    2015-01-01

    Recent research has linked the non-coding intronic regions of plant genes to the production of small RNAs (sRNAs). Certain introns, called ‘mirtrons’ and ‘sirtrons’, could serve as the single-stranded RNA precursors for the generation of microRNA and small interfering RNA, respectively. However, whether the intronic regions could serve as the template for double-stranded RNA synthesis and then for sRNA biogenesis through an RDR (RNA-dependent RNA polymerase)-dependent pathway remains unclear. In this study, a genome-wide search was made for the RDR-dependent sRNA loci within the intronic regions of the Arabidopsis genes. Hundreds of intronic regions encoding three or more RDR-dependent sRNAs were found to be covered by dsRNA-seq (double-stranded RNA sequencing) reads, indicating that the intron-derived sRNAs were indeed generated from long double-stranded RNA precursors. More interestingly, phase-distributed sRNAs were discovered on some of the dsRNA-seq read-covered intronic regions, and those sRNAs were largely 24 nt in length. Based on these results, the opinion is put forward that the intronic regions might serve as the genomic origins for the RDR-dependent sRNAs. This opinion might add a novel layer to the current biogenesis model of the intron-derived sRNAs. PMID:25609829

  4. Adipogenic potential in human mesenchymal stem cells strictly depends on adult or foetal tissue harvest.

    PubMed

    Ragni, Enrico; Viganò, Mariele; Parazzi, Valentina; Montemurro, Tiziana; Montelatici, Elisa; Lavazza, Cristiana; Budelli, Silvia; Vecchini, Alba; Rebulla, Paolo; Giordano, Rosaria; Lazzari, Lorenza

    2013-11-01

    Cell-based therapies promise important developments for regenerative medicine purposes. Adipose tissue and the adipogenic process has become central to an increasing number of translational efforts in addition to plastic and reconstructive surgical applications. In recent experimental clinical trials, human mesenchymal stem cells (MSC) have been proven to be well tolerated because of their low immunoreactivity. MSC are multipotent cells found among mature cells in different tissues and organs with the potentiality to differentiate in many cell types, including osteocytes, chondrocytes and adipocytes, thus being a suitable cell source for tissue engineering strategies. We compared the adipogenic potential of MSC originated from two adult sources as fat pads and bone marrow, and from four foetal sources as umbilical cord blood, Wharton's jelly, amniotic fluid and preterm umbilical cord perivascular cells. Surprisingly, adult MSC displayed higher differentiation capacities confirmed by gene expression analysis on a selected panel of adipogenesis-related genes. Further, an in-depth molecular analysis highlighted the early and vigorous activation of the PPARγ transcription factor-cascade in adipose-derived MSC that resulted to be both delayed and reduced in foetal MSC accounting for their lack of adipogenic potential. Thus, MSC show a different degree of phenotypic plasticity depending on the source tissue, that should be taken into consideration for the selection of the most appropriate MSC type for specific tissue regeneration purposes. PMID:23942228

  5. Forecasting Corrosion of Steel in Concrete Introducing Chloride Threshold Dependence on Steel Potential

    NASA Astrophysics Data System (ADS)

    Sanchez, Andrea Nathalie

    Corrosion initiates in reinforced concrete structures exposed to marine environments when the chloride ion concentration at the surface of an embedded steel reinforcing bar exceeds the chloride corrosion threshold (CT) value. The value of CT is generally assumed to have a conservative fixed value ranging from 0.2% to - 0.5 % of chloride ions by weight of cement. However, extensive experimental investigations confirmed that C T is not a fixed value and that the value of CT depends on many variables. Among those, the potential of passive steel embedded in concrete is a key influential factor on the value of CT and has received little attention in the literature. The phenomenon of a potential-dependent threshold (PDT) permits accounting for corrosion macrocell coupling between active and passive steel assembly components in corrosion forecast models, avoiding overly conservative long-term damage projections and leading to more efficient design. The objectives of this investigation was to 1) expand by a systematic experimental assessment the knowledge and data base on how dependent the chloride threshold is on the potential of the steel embedded in concrete and 2) introduce the chloride threshold dependence on steel potential as an integral part of corrosion-related service life prediction of reinforced concrete structures. Experimental assessments on PDT were found in the literature but for a limited set of conditions. Therefore, experiments were conducted with mortar and concrete specimens and exposed to conditions more representative of the field than those previously available. The experimental results confirmed the presence of the PDT effect and provided supporting information to use a value of -550 mV per decade of Cl- for the cathodic prevention slope betaCT, a critical quantitative input for implementation in a practical model. A refinement of a previous corrosion initiation-propagation model that incorporated PDT in a partially submerged reinforced concrete

  6. Condition dependence, quantitative genetics, and the potential signal content of iridescent ultraviolet butterfly coloration.

    PubMed

    Kemp, Darrell J; Rutowski, Ronald L

    2007-01-01

    Structural colors result from an interaction between light and the fine-scale physical structure of a surface, and are often extremely bright, chromatic, and iridescent. Given that these visual features depend upon the aggregate abundance and architectural precision of photonic structures, structurally colored sexual ornaments seem well placed to indicate a range of mate quality characteristics. We tested this hypothesis by investigating the signaling potential of structural coloration in the sexually dimorphic butterfly Colias eurytheme. Males of this species display iridescent ultraviolet (UV) markings (arising from multilayer thin films) that overlay a broad area of yellowish-orange pigmentation on their dorsal wing surface. Only the structural UV has demonstrated function as a sexual signal; hence we predicted that it should contain more reliable phenotypic and/or genetic quality information, which would be indicated by phenotypic and/or genetically mediated condition dependence. In two split-family breeding experiments we manipulated condition by exposing full siblings to different stressors at two different juvenile life-history stages: (1) reduced larval host-plant quality and (2) transient heat/cold shocks during metamorphosis. Both stressors had profound effects on key developmental and life-history traits. Each stressor also significantly affected male dorsal coloration; thus, the expression of both structural and pigmentary coloration is phenotypically condition dependent. As predicted, the strongest condition dependence was evident in the brightness and angular visibility (i.e., iridescence) of the UV. Characteristics of both the iridescent UV and pigmentary orange also exhibited moderate-high and significant heritability (H(2) approximately h(2) approximately 0.4-0.9). However, genetic and residual variances did not increase under stress; thus, the observed condition dependence was not genetically mediated as predicted if wing color trait signals "good

  7. Optimized Effective Potential for Quantum Electrodynamical Time-Dependent Density Functional Theory.

    PubMed

    Pellegrini, Camilla; Flick, Johannes; Tokatly, Ilya V; Appel, Heiko; Rubio, Angel

    2015-08-28

    We propose an orbital exchange-correlation functional for applying time-dependent density functional theory to many-electron systems coupled to cavity photons. The time nonlocal equation for the electron-photon optimized effective potential (OEP) is derived. In the static limit our OEP energy functional reduces to the Lamb shift of the ground state energy. We test the new approximation in the Rabi model. It is shown that the OEP (i) reproduces quantitatively the exact ground-state energy from the weak to the deep strong coupling regime and (ii) accurately captures the dynamics entering the ultrastrong coupling regime. The present formalism opens the path to a first-principles description of correlated electron-photon systems, bridging the gap between electronic structure methods and quantum optics for real material applications. PMID:26371646

  8. Mechanism of voltage production and frequency dependence of the ultrasonic vibration potential

    NASA Astrophysics Data System (ADS)

    Nguyen, Cuong K.; Wang, Shougang; Diebold, Gerald

    2009-05-01

    Imaging with the ultrasonic vibration potential is based on voltage generation by a colloidal or ionic suspension in response to the passage of ultrasound. The polarization within a body arising from the oscillatory displacement in the ultrasonic field produces a current in a pair of external electrodes that is measured as a function of time or frequency. Existing theory gives the current in the electrodes as arising from both a time varying polarization and ionic conduction. Here, experiments are reported that show the production of the polarization current is the dominant mechanism for current generation in soft tissue. Experiments are also reported giving the frequency dependence of the ultrasonic vibration current in canine blood and in several dilutions of aqueous silica suspensions.

  9. Potential use of pharmacological cyclin-dependent kinase inhibitors as anti-HIV therapeutics.

    PubMed

    Pumfery, Anne; de la Fuente, Cynthia; Berro, Reem; Nekhai, Sergei; Kashanchi, Fatah; Chao, Sheng-Hao

    2006-01-01

    Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and RNA polymerase II transcription. Several pharmacological CDK inhibitors (PCIs) are currently in clinical trials as potential cancer therapeutics since CDK hyperactivation is detected in the majority of neoplasias. Within the last few years, the anti-viral effects of PCIs have also been observed against various viruses, including human immunodeficiency virus (HIV), herpes simplex virus, and murine leukemia virus. Through the inhibition of CDK2 and 9, the cellular co-factors for HIV-1 Tat transactivation, HIV-1 replication is blocked by two specific PCIs, CYC202 and flavopiridol, respectively. In this article, we will review the inhibitory mechanisms of flavopiridol and CYC202 and discuss their possible usage in AIDS treatment. PMID:16787240

  10. Cyclin-dependent kinases inhibitors as potential anticancer, antineurodegenerative, antiviral and antiparasitic agents.

    PubMed

    Meijer, Laurent

    2000-04-01

    Cyclin-dependent kinases (CDKs) play a key role in the cell division cycle, in neuronal functions, in transcription and in apoptosis. Intensive screening with these kinases as targets has lead to the identification of highly selective and potent small - molecule inhibitors. Co-crystallization with CDK2 shows that these flat heterocyclic hydrophobic compounds bind through two or three hydrogen bonds with the side chains of two amino acids located in the ATP-binding pocket of the kinase. These inhibitors are anti-proliferative; they arrest cells in G1 and in G2/M phase. Furthermore they facilitate or even trigger apoptosis in proliferating cells while they protect neuronal cells and thymocytes from apoptosis. The potential use of these inhibitors is being extensively evaluated for cancer chemotherapy and also in other therapeutic areas: neurology (Alzheimer's disease), cardiovascular (restenosis, angiogenesis), nephrology (glomerulonephritis), parasitology (Plasmodium, Trypanosoma, Toxoplasma, etc.) and virology (cytomegalovirus, HIV, herpes virus). Copyright 2000 Harcourt Publishers Ltd. PMID:11498372

  11. Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy

    PubMed Central

    Clausse, V; Goloudina, A R; Uyanik, B; Kochetkova, E Y; Richaud, S; Fedorova, O A; Hammann, A; Bardou, M; Barlev, N A; Garrido, C; Demidov, O N

    2016-01-01

    Inactivation of p53 found in more than half of human cancers is often associated with increased tumor resistance to anti-cancer therapy. We have previously shown that overexpression of the phosphatase Wip1 in p53-negative tumors sensitizes them to chemotherapeutic agents, while protecting normal tissues from the side effects of anti-cancer treatment. In this study, we decided to search for kinases that prevent Wip1-mediated sensitization of cancer cells, thereby interfering with efficacy of genotoxic anti-cancer drugs. To this end, we performed a flow cytometry-based screening in order to identify kinases that regulated the levels of γH2AX, which were used as readout. Another criterion of the screen was increased sensitivity of p53-negative tumor cells to cisplatin (CDDP) in a Wip1-dependent manner. We have found that a treatment with a low dose (75 nM) of MK-1775, a recently described specific chemical inhibitor of Wee1, decreases CDDP-induced H2AX phosphorylation in p53-negative cells and enhances the Wip1-sensitization of p53-negative tumors. We were able to reduce CDDP effective concentration by 40% with a combination of Wip1 overexpression and Wee1 kinase inhibition. We have observed that Wee1 inhibition potentiates Wip1-dependent tumor sensitization effect by reducing levels of Hipk2 kinase, a negative regulator of Wip1 pathway. In addition, during CDDP treatment, the combination of Wee1 inhibition and Wip1 overexpression has a mild but significant protective effect in normal cells and tissues. Our results indicate that inhibition of the negative regulators of Wip1 pathway, Wee1 and Hipk2, in p53-negative tumors could potentiate efficiency of chemotherapeutic agents without concomitant increase of cytotoxicity in normal tissues. The development and clinical use of Wee1 and Hipk1 kinase chemical inhibitors might be a promising strategy to improve anti-cancer therapy. PMID:27077811

  12. Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy.

    PubMed

    Clausse, V; Goloudina, A R; Uyanik, B; Kochetkova, E Y; Richaud, S; Fedorova, O A; Hammann, A; Bardou, M; Barlev, N A; Garrido, C; Demidov, O N

    2016-01-01

    Inactivation of p53 found in more than half of human cancers is often associated with increased tumor resistance to anti-cancer therapy. We have previously shown that overexpression of the phosphatase Wip1 in p53-negative tumors sensitizes them to chemotherapeutic agents, while protecting normal tissues from the side effects of anti-cancer treatment. In this study, we decided to search for kinases that prevent Wip1-mediated sensitization of cancer cells, thereby interfering with efficacy of genotoxic anti-cancer drugs. To this end, we performed a flow cytometry-based screening in order to identify kinases that regulated the levels of γH2AX, which were used as readout. Another criterion of the screen was increased sensitivity of p53-negative tumor cells to cisplatin (CDDP) in a Wip1-dependent manner. We have found that a treatment with a low dose (75 nM) of MK-1775, a recently described specific chemical inhibitor of Wee1, decreases CDDP-induced H2AX phosphorylation in p53-negative cells and enhances the Wip1-sensitization of p53-negative tumors. We were able to reduce CDDP effective concentration by 40% with a combination of Wip1 overexpression and Wee1 kinase inhibition. We have observed that Wee1 inhibition potentiates Wip1-dependent tumor sensitization effect by reducing levels of Hipk2 kinase, a negative regulator of Wip1 pathway. In addition, during CDDP treatment, the combination of Wee1 inhibition and Wip1 overexpression has a mild but significant protective effect in normal cells and tissues. Our results indicate that inhibition of the negative regulators of Wip1 pathway, Wee1 and Hipk2, in p53-negative tumors could potentiate efficiency of chemotherapeutic agents without concomitant increase of cytotoxicity in normal tissues. The development and clinical use of Wee1 and Hipk1 kinase chemical inhibitors might be a promising strategy to improve anti-cancer therapy. PMID:27077811

  13. Manipulating graphene's lattice to create pseudovector potentials, discover anomalous friction, and measure strain dependent thermal conductivity

    NASA Astrophysics Data System (ADS)

    Kitt, Alexander Luke

    Graphene is a single atomic sheet of graphite that exhibits a diverse range of unique properties. The electrons in intrinsic graphene behave like relativistic Dirac fermions; graphene has a record high Young's modulus but extremely low bending rigidity; and suspended graphene exhibits very high thermal conductivity. These properties are made more intriguing because with a thickness of only a single atomic layer, graphene is both especially affected by its environment and readily manipulated. In this dissertation the interaction between graphene and its environment as well as the exciting new physics realized by manipulating graphene's lattice are investigated. Lattice manipulations in the form of strain cause alterations in graphene's electrical dispersion mathematically analogous to the vector potential associated with a magnetic field. We complete the standard description of the strain-induced vector potential by explicitly including the lattice deformations and find new, leading order terms. Additionally, a strain engineered device with large, localized, plasmonically enhanced pseudomagnetic fields is proposed to couple light to pseudomagnetic fields. Accurate strain engineering requires a complete understanding of the interactions between a two dimensional material and its environment, particularly the adhesion and friction between graphene and its supporting substrate. We measure the load dependent sliding friction between mono-, bi-, and trilayer graphene and the commonly used silicon dioxide substrate by analyzing Raman spectra of circular, graphene sealed microchambers under variable external pressure. We find that the sliding friction for trilayer graphene behaves normally, scaling with the applied load, whereas the friction for monolayer and bilayer graphene is anomalous, scaling with the inverse of the strain in the graphene. Both strain and graphene's environment are expected to affect the quadratically dispersed out of plane acoustic phonon. Although

  14. A Single Brief Burst Induces GluR1-Dependent Associative Short-Term Potentiation: A Potential Mechanism for Short-Term Memory

    ERIC Educational Resources Information Center

    Erickson, Martha A.; Maramara, Lauren A.; Lisman, John

    2010-01-01

    Recent work showed that short-term memory (STM) is selectively reduced in GluR1 knockout mice. This raises the possibility that a form of synaptic modification dependent on GluR1 might underlie STM. Studies of synaptic plasticity have shown that stimuli too weak to induce long-term potentiation induce short-term potentiation (STP), a phenomenon…

  15. Size dependent transitions induced by an electron collecting electrode near the plasma potential

    NASA Astrophysics Data System (ADS)

    Barnat, Edward; Laity, George; Hopkins, Matt; Baalrud, Scott

    2014-10-01

    As the size of a positively biased electrode increases, the nature of the interface formed between the electrode and the host plasma undergoes a transition from an electron-rich structure (electron sheath) to an intermediate structure containing both ion and electron rich regions (double layer) and ultimately forms an electron-depleted structure (ion sheath). In this study, measurements are performed to further test how the key scaling relationship relating the area of the electrode to that of the area of the vessel containing the plasma discharge impacts this transition. This was accomplished using a segmented disk electrode in which individual segments were individually biased to change the effective surface area of the anode. Measurements on bulk plasma parameters such as the collected current density, plasma potential, electron density, electron temperature and optical emission are made as both the size and the bias placed on the electrode are varied. Size dependent transitions in the voltage dependence of the plasma parameters are identified in both argon and helium discharges and are compared to the interface transitions predicted by global current balance. This work was supported by the Office of Fusion Energy Science at the U.S. Department of Energy under Contract DE-AC04-94SL85000.

  16. The tunneling solutions of the time-dependent Schroedinger equation for a square-potential barrier

    SciTech Connect

    Elci, A.; Hjalmarson, H. P.

    2009-10-15

    The exact tunneling solutions of the time-dependent Schroedinger equation with a square-potential barrier are derived using the continuous symmetry group G{sub S} for the partial differential equation. The infinitesimal generators and the elements for G{sub S} are represented and derived in the jet space. There exist six classes of wave functions. The representative (canonical) wave functions for the classes are labeled by the eigenvalue sets, whose elements arise partially from the reducibility of a Lie subgroup G{sub LS} of G{sub S} and partially from the separation of variables. Each eigenvalue set provides two or more time scales for the wave function. The ratio of two time scales can act as the duration of an intrinsic clock for the particle motion. The exact solutions of the time-dependent Schroedinger equation presented here can produce tunneling currents that are orders of magnitude larger than those produced by the energy eigenfunctions. The exact solutions show that tunneling current can be quantized under appropriate boundary conditions and tunneling probability can be affected by a transverse acceleration.

  17. Isospin dependence of {sup 6}He+p optical potential and the symmetry energy

    SciTech Connect

    Khoa, Dao T.; Hoang Sy Than

    2005-04-01

    A consistent folding analysis of the elastic p({sup 6}He,{sup 6}He)p scattering and charge exchange p({sup 6}He,{sup 6}Li{sup *})n reaction data measured at E{sub lab}=41.6A MeV has been performed within the coupled channels formalism. We have used the isovector coupling to link the isospin dependence of {sup 6}He+p optical potential to the cross section of p({sup 6}He,{sup 6}Li{sup *})n reaction exciting the 0{sup +} isobaric analog state (IAS) at 3.563 MeV in {sup 6}Li. Based on these results and the Hartree-Fock calculation of asymmetric nuclear matter using the same isospin-dependent effective nucleon-nucleon interaction, we were able to confirm that the most realistic value of the symmetry energy E{sub sym} is around 31 MeV. Our analysis has also shown that the measured charge exchange p({sup 6}He,{sup 6}Li{sup *})n data are quite sensitive to the halo tail of the {sup 6}He density used in the folding calculation and the IAS of {sup 6}Li is likely to have a halo structure similar to that established for the ground state of {sup 6}He.

  18. Potential benefits of quetiapine in the treatment of substance dependence disorders

    PubMed Central

    Sattar, S. Pirzada; Bhatia, Subhash C.; Petty, Frederick

    2004-01-01

    Objective Some antipsychotic medications prescribed for the treatment of psychoses, mood disorders or post-traumatic stress disorder in patients with coexisting substance dependence disorders (SDD) have reduced substance dependence. We studied the potential benefits of quetiapine in the treatment of SDD. Methods We conducted a retrospective chart review of data for 9 patients who were admitted to a 28-day residential rehabilitation program designed for individuals with SDD during a 3-month period from January 2003 through March 2003 and treated with quetiapine for nonpsychotic anxiety. These patients also met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for alcohol, cocaine and/or methamphetamine dependence and substance-induced anxiety disorder. The patients were assessed using the Hamilton-D Rating Scale for Depression (Ham-D), a 10-point Likert scale to measure alcohol or drug cravings, and random Breathalyzer and urine drug screens. Results Quetiapine was generally well tolerated. Only 1 of the 9 patients stopped taking the medication because of increased anxiety. Other patients reported improvement in sleep and anxiety. The mean decrease in Ham-D score at discharge for the responders was 18.5 (p < 0.005). The biggest decreases on the Ham-D occurred on the subscales of insomnia, agitation, somatic anxiety, psychologic anxiety, hypochondriasis and obsessional symptoms. The mean decrease in the Likert 10-point craving scale was 5.9 for the responders (p < 0.005). These patients' periodic Breathalyzer and urine test results suggested that they remained abstinent from alcohol and other drug use. Conclusion Quetiapine was beneficial in the treatment of SDD in patients with nonpsychotic anxiety. PMID:15644986

  19. Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential

    PubMed Central

    Zimmer, Brenna M.; Howell, Michelle E.; Wei, Qin; Ma, Linlin; Romsdahl, Trevor; Loughman, Eileen G.; Markham, Jonathan E.; Seravalli, Javier; Barycki, Joseph J.; Simpson, Melanie A.

    2016-01-01

    Prostate epithelial cells control the potency and availability of androgen hormones in part by inactivation and elimination. UDP-glucose dehydrogenase (UGDH) catalyzes the NAD+-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. UGDH expression is androgen stimulated, which increases the production of UDP-glucuronate, and fuels UGT-catalyzed glucuronidation. In this study, we compared the glucuronidation potential and its impact on androgen-mediated gene expression in an isogenic LNCaP model for androgen dependent versus castration resistant prostate cancer. Despite significantly lower androgen-glucuronide output, LNCaP 81 castration resistant tumor cells expressed higher levels of UGDH, UGT2B15, and UGT2B17. However, the magnitude of androgen-activated UGDH and PSA expression, as well as the AR-dependent repression of UGT2B15 and UGT2B17, was blunted several-fold in these cells. Consistent with these results, the ligand-activated binding of AR to the PSA promoter and subsequent transcriptional activation were also significantly reduced in castration resistant cells. Analysis of the UDP-sugar pools and flux through pathways downstream of UDP-glucuronate production revealed that these glucuronidation precursor metabolites were channeled through proteoglycan and glycosaminoglycan biosynthetic pathways, leading to increased surface expression of Notch 1. Knockdown of UGDH diminished Notch1 and increased glucuronide output. Overall, these results support a model in which the aberrant partitioning of UDP-glucuronate and other UDP-sugars into alternative pathways during androgen deprivation contributes to the loss of prostate tumor cell androgen sensitivity by promoting altered cell surface proteoglycan expression. PMID:27307252

  20. Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential.

    PubMed

    Zimmer, Brenna M; Howell, Michelle E; Wei, Qin; Ma, Linlin; Romsdahl, Trevor; Loughman, Eileen G; Markham, Jonathan E; Seravalli, Javier; Barycki, Joseph J; Simpson, Melanie A

    2016-08-01

    Prostate epithelial cells control the potency and availability of androgen hormones in part by inactivation and elimination. UDP-glucose dehydrogenase (UGDH) catalyzes the NAD(+)-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. UGDH expression is androgen stimulated, which increases the production of UDP-glucuronate and fuels UGT-catalyzed glucuronidation. In this study, we compared the glucuronidation potential and its impact on androgen-mediated gene expression in an isogenic LNCaP model for androgen-dependent versus castration-resistant prostate cancer. Despite significantly lower androgen-glucuronide output, LNCaP 81 castration-resistant tumor cells expressed higher levels of UGDH, UGT2B15, and UGT2B17. However, the magnitude of androgen-activated UGDH and prostate-specific antigen (PSA) expression, as well as the androgen receptor (AR)-dependent repression of UGT2B15 and UGT2B17, was blunted several-fold in these cells. Consistent with these results, the ligand-activated binding of AR to the PSA promoter and subsequent transcriptional activation were also significantly reduced in castration-resistant cells. Analysis of the UDP-sugar pools and flux through pathways downstream of UDP-glucuronate production revealed that these glucuronidation precursor metabolites were channeled through proteoglycan and glycosaminoglycan biosynthetic pathways, leading to increased surface expression of Notch1. Knockdown of UGDH diminished Notch1 and increased glucuronide output. Overall, these results support a model in which the aberrant partitioning of UDP-glucuronate and other UDP-sugars into alternative pathways during androgen deprivation contributes to the loss of prostate tumor cell androgen sensitivity by promoting altered cell surface proteoglycan expression. PMID:27307252

  1. LUNAR DUST GRAIN CHARGING BY ELECTRON IMPACT: DEPENDENCE OF THE SURFACE POTENTIAL ON THE GRAIN SIZE

    SciTech Connect

    Nemecek, Z.; Pavlu, J.; Safrankova, J.; Beranek, M.; Richterova, I.; Vaverka, J.; Mann, I.

    2011-09-01

    The secondary electron emission is believed to play an important role for the dust charging at and close to the lunar surface. However, our knowledge of emission properties of the dust results from model calculations and rather rare laboratory investigations. The present paper reports laboratory measurements of the surface potential on Lunar Highlands Type regolith simulants with sizes between 0.3 and 3 {mu}m in an electron beam with energy below 700 eV. This investigation is focused on a low-energy part, i.e., {<=}100 eV. We found that the equilibrium surface potential of this simulant does not depend on the grain size in our ranges of grain dimensions and the beam energies, however, it is a function of the primary electron beam energy. The measurements are confirmed by the results of the simulation model of the secondary emission from the spherical samples. Finally, we compare our results with those obtained in laboratory experiments as well as those inferred from in situ observations.

  2. Dependence of electric potentials at trench surfaces on ion angular distribution in plasma etching processes

    NASA Astrophysics Data System (ADS)

    Palov, A. P.; Mankelevich, Yu A.; Rakhimova, T. V.; Baklanov, M. R.

    2016-03-01

    Ion-stimulated etching of dielectrics in radio frequency plasma results in positive charging of a trench bottom because of the significant difference in the angular distribution functions of ions and electrons. They are anisotropic for ions and quasi-isotropic for electrons. The charging leads to a decrease in the energy of the ions bombarding the trench bottom and to undesirable sputtering of the walls near the trench bottom because of the curving of the ion trajectories. This process is normally investigated by Monte Carlo methods in the absence of experimental data. In this paper the analytical dependence of the ion flux bombarding the trench bottom on a trench aspect ratio and ion angular distribution function is obtained. Numerical calculations of the electric potential on the trench bottom for a set of trench aspect ratios and angles of the ion angular distribution function were performed based on a Monte Carlo method to demonstrate the ion flux and electric potential correlated well with each other. The proposed formula for an ion flux is suggested to be helpful for analyzing charging the trenches with different aspect ratios in plasma with an arbitrary angular ion distribution function.

  3. Redox probing study of the potential dependence of charge transport through Li2O2

    DOE PAGESBeta

    Knudsen, Kristian B.; Luntz, Alan C.; Jensen, Søren H.; Vegge, Tejs; Hjelm, Johan

    2015-11-20

    In the field of energy storage devices the pursuit for cheap, high energy density, reliable secondary batteries is at the top of the agenda. The Li–O2 battery is one of the possible technologies that, in theory, should be able to close the gap, which exists between the present state-of-the-art Li-ion technologies and the demand placed on batteries by technologies such as electrical vehicles. Here we present a redox probing study of the charge transfer across the main deposition product lithium peroxide, Li2O2, in the Li–O2 battery using outer-sphere redox shuttles. The change in heterogeneous electron transfer exchange rate as amore » function of the potential and the Li2O2 layer thickness (~depth-of-discharge) was determined using electrochemical impedance spectroscopy. In addition, the attenuation of the electron transfer exchange rate with film thickness is dependent on the probing potential, providing evidence that hole transport is the dominant process for charge transfer through Li2O2 and showing that the origin of the sudden death observed upon discharge is due to charge transport limitations.« less

  4. Ca2+/calmodulin-dependent transcriptional pathways: potential mediators of skeletal muscle growth and development.

    PubMed

    Al-Shanti, Nasser; Stewart, Claire E

    2009-11-01

    The loss of muscle mass with age and disuse has a significant impact on the physiological and social well-being of the aged; this is an increasingly important problem as the population becomes skewed towards older age. Exercise has psychological benefits but it also impacts on muscle protein synthesis and degradation, increasing muscle tissue volume in both young and older individuals. Skeletal muscle hypertrophy involves an increase in muscle mass and cross-sectional area and associated increased myofibrillar protein content. Attempts to understand the molecular mechanisms that underlie muscle growth, development and maintenance, have focused on characterising the molecular pathways that initiate, maintain and regenerate skeletal muscle. Such understanding may aid in improving targeted interventional therapies for age-related muscle loss and muscle wasting associated with diseases. Two major routes through which skeletal muscle development and growth are regulated are insulin-like growth factor I (IGF-I) and Ca(2+)/calmodulin-dependent transcriptional pathways. Many reviews have focused on understanding the signalling pathways of IGF-I and its receptor, which govern skeletal muscle hypertrophy. However, alternative molecular signalling pathways such as the Ca(2+)/calmodulin-dependent transcriptional pathways should also be considered as potential mediators of muscle growth. These latter pathways have received relatively little attention and the purpose herein is to highlight the progress being made in the understanding of these pathways and associated molecules: calmodulin, calmodulin kinases (CaMKs), calcineurin and nuclear factor of activated T-cell (NFAT), which are involved in skeletal muscle regulation. We describe: (1) how conformational changes in the Ca(2+) sensor calmodulin result in the exposure of binding pockets for the target proteins (CaMKs and calcineurin). (2) How Calmodulin consequently activates either the Ca(2+)/calmodulin-dependent kinases

  5. Plasma screening effects on the energies of hydrogen atom under the influence of velocity-dependent potential

    SciTech Connect

    Bahar, M. K.

    2014-07-15

    In order to examine the plasma screening and velocity-dependent potential effects on the hydrogen atom, the Schrödinger equation including a more general exponential cosine screened Coulomb and velocity-dependent potential is solved numerically in the framework asymptotic iteration method. The more general exponential cosine screened Coulomb potential is used to model Debye and quantum plasma for the specific values of the parameters in its structure. However, in order to examine effects of velocity-dependent potential on energy values of hydrogen atom in Debye and quantum plasma, the isotropic form factor of velocity-dependent potential is given as harmonic oscillator type, ρ(r)=ρ{sub o}r{sup 2}. Then, the energies of s and p states are calculated numerically without any approximation. In order to investigate thoroughly plasma screening effects and contribution of velocity-dependent potential on energy values of hydrogen atom, the corresponding calculations are carried out by using different values of parameters of more general exponential cosine screened Coulomb potential and isotropic dependence, results of which are discussed.

  6. Analysis of the potential-dependent changes in optical retardation in the squid giant axon.

    PubMed

    Cohen, L B; Hille, B; Keynes, R D; Landowne, D; Rojas, E

    1971-10-01

    1. An analysis has been made of the change in optical retradation of the membrane elicited by the application of voltage-clamp pulses in squid giant axons.2. The retardation response consists of three separate voltage-dependent components. For freshly mounted axons, defined as being in state 1, hyperpolarizing pulses give a rapid increase in the light intensity measured with crossed polarizers which has been termed the fast phase. This is followed by a rather slow return towards the base line termed the rebound. On treatment of the axon with certain agents that include tetrodotoxin, high calcium and terbium, the rebound disappears and the fast phase slows down, increases in size, and has a new slow component added to it. This transition from state 1 to a second state, 2, appears to be irreversible.3. In state 1, the time constant of the fast phase is 20-40 musec at 13 degrees C; it has a very large negative temperature coefficient (Q(10) = Ca.(1/8)). The size of the retardation change is independent of temperature and varies as the square of the applied voltage, but the voltage-retardation curve is symmetrical about a point well beyond zero membrane potential, at an internal potential of around + 70 mV. In state 2, the time constant is about five times larger, and varies much less markedly with temperature; the apex of the voltage-retardation curve is shifted to + 200 mV.4. The rebound has a time constant of the order of 20 msec at 13 degrees C. A 10 degrees rise in temperature more than halves the time constant and roughly doubles the amplitude of the rebound. The voltage dependence of the rebound differed from that of the fast phase.5. The slow component of state 2 has a time constant of about 2 msec which does not change noticeably between 10 and 25 degrees C. The size of this component seems to be linearly dependent on the applied voltage, rather than obeying a square law.6. A tenfold increase in external calcium concentration had no discernible effect on the

  7. Sleep-Dependent Gene Expression in the Hippocampus and Prefrontal Cortex Following Long-Term Potentiation

    PubMed Central

    Romcy-Pereira, Rodrigo N.; Erraji-Benchekroun, Loubna; Smyrniotopoulos, Peggy; Ogawa, Sonoko; Mello, Claudio V.; Sibille, Etienne; Pavlides, Constantine

    2009-01-01

    The activity-dependent transcription factor zif268 is re-activated in sleep following hippocampal long-term potentiation (LTP). However, the activation of secondary genes, possibly involved in modifying local synaptic strengths and ultimately stabilizing memory traces during sleep, has not yet been studied. Here, we investigated changes in hippocampal and cortical gene expression at a time point subsequent to the previously reported initial zif268 re-activation during sleep. Rats underwent unilateral hippocampal LTP and were assigned to SLEEP or AWAKE groups. Eighty minutes after a long rapid-eye-movement sleep (REMS) episode (or an equivalent amount of time for awake group) animals had their hippocampi dissected and processed for gene microarray hybridization. Prefrontal and parietal cortices were also collected for qRT-PCR analysis. The microarray analysis identified 28 up-regulated genes in the hippocampus: 11 genes were enhanced in the LTPed hemisphere of sleep animals; 13 genes were enhanced after sleep, regardless of hemisphere; and 4 genes were enhanced in LTPed hemisphere, regardless of behavioral state. qRT-PCR analysis confirmed the upregulation of aif-1 and sc-65 during sleep. Moreover, we observed a down-regulation of the purinergic receptor, P2Y4R in the LTP hemisphere of awake animals and a trend for the protein kinase, CaMKI to be up-regulated in the LTP hemisphere of sleep animals. In the prefrontal cortex, we showed a significant LTP-dependent down-regulation of gluR1 and spinophilin specifically during sleep. Zif268 was downregulated in sleep regardless of the hemisphere. No changes in gene expression were observed in the parietal cortex. Our findings indicate that a set of synaptic plasticity-related genes have their expression modulated during sleep following LTP, which can reflect biochemical events associated with reshaping of synaptic connections in sleep following learning. PMID:19389414

  8. Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel

    PubMed Central

    Badheka, Doreen; Borbiro, Istvan

    2015-01-01

    Phosphoinositides are emerging as general regulators of the functionally diverse transient receptor potential (TRP) ion channel family. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) has been reported to positively regulate many TRP channels, but in several cases phosphoinositide regulation is controversial. TRP melastatin 3 (TRPM3) is a heat-activated ion channel that is also stimulated by chemical agonists, such as pregnenolone sulfate. Here, we used a wide array of approaches to determine the effects of phosphoinositides on TRPM3. We found that channel activity in excised inside-out patches decreased over time (rundown), an attribute of PI(4,5)P2-dependent ion channels. Channel activity could be restored by application of either synthetic dioctanoyl (diC8) or natural arachidonyl stearyl (AASt) PI(4,5)P2. The PI(4,5)P2 precursor phosphatidylinositol 4-phosphate (PI(4)P) was less effective at restoring channel activity. TRPM3 currents were also restored by MgATP, an effect which was inhibited by two different phosphatidylinositol 4-kinase inhibitors, or by pretreatment with a phosphatidylinositol-specific phospholipase C (PI-PLC) enzyme, indicating that MgATP acted by generating phosphoinositides. In intact cells, reduction of PI(4,5)P2 levels by chemically inducible phosphoinositide phosphatases or a voltage-sensitive 5′-phosphatase inhibited channel activity. Activation of PLC via muscarinic receptors also inhibited TRPM3 channel activity. Overall, our data indicate that TRPM3 is a phosphoinositide-dependent ion channel and that decreasing PI(4,5)P2 abundance limits its activity. As all other members of the TRPM family have also been shown to require PI(4,5)P2 for activity, our data establish PI(4,5)P2 as a general positive cofactor of this ion channel subfamily. PMID:26123195

  9. Dimerization of the thyrotropin-releasing hormone receptor potentiates hormone-dependent receptor phosphorylation.

    PubMed

    Song, Gyun Jee; Jones, Brian W; Hinkle, Patricia M

    2007-11-13

    The G protein-coupled thyrotropin (TSH)-releasing hormone (TRH) receptor forms homodimers. Regulated receptor dimerization increases TRH-induced receptor endocytosis. These studies test whether dimerization increases receptor phosphorylation, which could potentiate internalization. Phosphorylation at residues 355-365, which is critical for internalization, was measured with a highly selective phospho-site-specific antibody. Two strategies were used to drive receptor dimerization. Dimerization of a TRH receptor-FK506-binding protein (FKBP) fusion protein was stimulated by a dimeric FKBP ligand. The chemical dimerizer caused a large increase in TRH-dependent phosphorylation within 1 min, whereas a monomeric FKBP ligand had no effect. The dimerizer did not alter phoshorylation of receptors lacking the FKBP domain. Dimerization of receptors containing an N-terminal HA epitope also was induced with anti-HA antibody. Anti-HA IgG strongly increased TRH-induced phosphorylation, whereas monomeric Fab fragments had no effect. Anti-HA antibody did not alter phosphorylation in receptors lacking an HA tag. Furthermore, two phosphorylation-defective TRH receptors functionally complemented one another and permitted phosphorylation. Receptors with a D71A mutation in the second transmembrane domain do not signal, whereas receptors with four Ala mutations in the 355-365 region signal normally but lack phosphorylation sites. When D71A- and 4Ala-TRH receptors were expressed alone, neither underwent TRH-dependent phosphorylation. When they were expressed together, D71A receptor was phosphorylated by G protein-coupled receptor kinases in response to TRH. These results suggest that the TRH receptor is phosphorylated preferentially when it is in dimers or when preexisting receptor dimers are driven into microaggregates. Increased receptor phosphorylation may amplify desensitization. PMID:17989235

  10. Draft Genome Sequence of a Potential Nitrate-Dependent Fe(II)-Oxidizing Bacterium, Aquabacterium parvum B6

    PubMed Central

    Zhang, Xiaoxin

    2016-01-01

    Aquabacterium parvum B6 is a potential nitrate-dependent Fe(II)-oxidizing bacterium. The genes related to its denitrifying mechanism and iron metabolisms were unknown. We present the draft genome of Aquabacterium parvum B6, which could provide further insight into the nitrate-dependent Fe(II)-oxidizing mechanism of strain B6. PMID:26823591

  11. Draft Genome Sequence of a Potential Nitrate-Dependent Fe(II)-Oxidizing Bacterium, Aquabacterium parvum B6.

    PubMed

    Zhang, Xiaoxin; Ma, Fang; Szewzyk, Ulrich

    2016-01-01

    Aquabacterium parvum B6 is a potential nitrate-dependent Fe(II)-oxidizing bacterium. The genes related to its denitrifying mechanism and iron metabolisms were unknown. We present the draft genome of Aquabacterium parvum B6, which could provide further insight into the nitrate-dependent Fe(II)-oxidizing mechanism of strain B6. PMID:26823591

  12. Novel B(12)-dependent acyl-CoA mutases and their biotechnological potential.

    PubMed

    Cracan, Valentin; Banerjee, Ruma

    2012-08-01

    The recent spate of discoveries of novel acyl-CoA mutases has engendered a growing appreciation for the diversity of 5'-deoxyadenosylcobalamin-dependent rearrangement reactions. The prototype of the reaction catalyzed by these enzymes is the 1,2 interchange of a hydrogen atom with a thioester group leading to a change in the degree of carbon skeleton branching. These enzymes are predicted to share common architectural elements: a Rossman fold and a triose phosphate isomerase (TIM)-barrel domain for binding cofactor and substrate, respectively. Within this family, methylmalonyl-CoA mutase (MCM) is the best studied and is the only member found in organisms ranging from bacteria to man. MCM interconverts (2R)-methylmalonyl-CoA and succinyl-CoA. The more recently discovered family members include isobutyryl-CoA mutase (ICM), which interconverts isobutyryl-CoA and n-butyryl-CoA; ethylmalonyl-CoA mutase, which interconverts (2R)-ethylmalonyl-CoA and (2S)-methylsuccinyl-CoA; and 2-hydroxyisobutyryl-CoA mutase, which interconverts 2-hydroxyisobutyryl-CoA and (3S)-hydroxybutyryl-CoA. A variant in which the two subunits of ICM are fused to a G-protein chaperone, IcmF, has been described recently. In addition to its ICM activity, IcmF also catalyzes the interconversion of isovaleryl-CoA and pivalyl-CoA. This review focuses on the involvement of acyl-CoA mutases in central carbon and secondary bacterial metabolism and on their biotechnological potential for applications ranging from bioremediation to stereospecific synthesis of C2-C5 carboxylic acids and alcohols, and for production of potential commodity and specialty chemicals. PMID:22803641

  13. Intermittent Hypoxia-Induced Carotid Body Chemosensory Potentiation and Hypertension Are Critically Dependent on Peroxynitrite Formation

    PubMed Central

    Moya, Esteban A.; Arias, Paulina; Varela, Carlos; Oyarce, María P.; Del Rio, Rodrigo; Iturriaga, Rodrigo

    2016-01-01

    Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO−), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO− scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7 days. Ebselen (10 mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u.), reduced CB chemosensory response to 5% O2 (266.5 ± 13.4 versus 168.6 ± 16.8 Hz), and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO− formation. PMID:26798430

  14. Quasiequilibrium directed hopping in a time-dependent two-well periodic potential

    NASA Astrophysics Data System (ADS)

    Rozenbaum, V. M.; Shapochkina, I. V.

    2011-11-01

    We consider the directed motion of a Brownian particle in a two-well periodic potential with time-varying barriers and wells described by arbitrary periodic functions of time, v(t) and u(t), alternating with the period τ. In the framework of the low-temperature kinetic approach, we obtain explicit formulas for the probabilities of finding the particle in potential wells, average velocity of directed motion, input energy Pin and useful work Pout against additionally introduced stationary load force f. These formulas are considerably simplified by the assumption of the quasiequilibrium regime of motion corresponding to small values of u(t) and f. It is shown that depending on the same or opposite parity of the functions v(t) and u(t) with respect to time reversal, the motion direction of a Brownian particle is retained or reversed under the reversal of the direction of movement along the (v-u) loop in the phase space of the functions v(t) and u(t), and the nondiagonal kinetic coefficients are mutually symmetric or antisymmetric. In the adiabatic limit τ→∞, the average velocity is proportional to τ-1 in two cases: (i) the above loop has a nonzero area, (ii) the functions v(t) and u(t) are proportional to each other (zero loop area) and include intervals of fast changes with small durations τ0 on the period τ of their variations. In both of these cases, the efficiency of energy conversion, η=Pout/Pin, tends to unity at large variations of the barriers v(t). In the second case, the deviation of η from unity can be split into two contributions: The former decreases exponentially with increasing amplitude v0 of v(t), while the latter is a small nonadiabatic correction proportional to v0-3/2. It is the nonadiabatic correction that limits high efficiencies at large variations of barriers.

  15. Calcium/calmodulin-dependent protein kinase IV: A multifunctional enzyme and potential therapeutic target.

    PubMed

    Naz, Huma; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2016-05-01

    The calcium/calmodulin-dependent protein kinase IV (CAMKIV) belongs to the serine/threonine protein kinase family, and is primarily involved in transcriptional regulation in lymphocytes, neurons and male germ cells. CAMKIV operates the signaling cascade and regulates activity of several transcription activators by phosphorylation, which in turn plays pivotal roles in immune response, inflammation and memory consolidation. In this review, we tried to focus on different aspects of CAMKIV to understand the significance of this protein in the biological system. This enzyme is associated with varieties of disorders such as cerebral hypoxia, azoospermia, endometrial and ovarian cancer, systemic lupus, etc., and hence it is considered as a potential therapeutic target. Structure of CAMKIV is comprised of five distinct domains in which kinase domain is responsible for enzyme activity. CAMKIV is involved in varieties of cellular functions such as regulation of gene expression, T-cell maturation, regulation of survival phase of dendritic cells, bone growth and metabolism, memory consolidation, sperm motility, regulation of microtubule dynamics, cell-cycle progression and apoptosis. In this review, we performed an extensive analysis on structure, function and regulation of CAMKIV and associated diseases. PMID:26773169

  16. Prevalence of and potential influencing factors for alcohol dependence in Europe.

    PubMed

    Rehm, Jürgen; Anderson, Peter; Barry, Joe; Dimitrov, Plamen; Elekes, Zsuzsanna; Feijão, Fernanda; Frick, Ulrich; Gual, Antoni; Gmel, Gerrit; Kraus, Ludwig; Marmet, Simon; Raninen, Jonas; Rehm, Maximilien X; Scafato, Emanuele; Shield, Kevin D; Trapencieris, Marcis; Gmel, Gerhard

    2015-01-01

    Alcohol use disorders (AUDs), and alcohol dependence (AD) in particular, are prevalent and associated with a large burden of disability and mortality. The aim of this study was to estimate prevalence of AD in the European Union (EU), Iceland, Norway, and Switzerland for the year 2010, and to investigate potential influencing factors. The 1-year prevalence of AD in the EU was estimated at 3.4% among people 18-64 years of age in Europe (women 1.7%, men 5.2%), resulting in close to 11 million affected people. Taking into account all people of all ages, AD, abuse and harmful use resulted in an estimate of 23 million affected people. Prevalence of AD varied widely between European countries, and was significantly impacted by drinking cultures and social norms. Correlations with level of drinking and other drinking variables and with major known outcomes of heavy drinking, such as liver cirrhosis or injury, were moderate. These results suggest a need to rethink the definition of AUDs. PMID:25342593

  17. [Bisphenol A and hormone-dependent cancers: potential risk and mechanism].

    PubMed

    Rochefort, Henri

    2013-05-01

    Being concerned by the increasing incidence of breast, prostate and testicular cancers, we overviewed the literature on the potential carcinogenic effect of endocrine disruptors (ED). It is extremely difficult to obtain the epidemiological proof of a carcinogenic effect of one ED in human for multi-factorial diseases and the high number of confusing factors. However, many experimental studies in rodents on bis-phenol A (BPA) and its assay in human blood and urine, strongly suggest that BPA might increase the risk of hormone dependant cancers. Contrary to the mitogenic effect of estradiol, directly mediated in mammary cells by the classical nuclear estrogen receptor α, the mechanisms of the deleterious effect of BPA at low doses and in utero remain unknown since the molecular and cellular target(s) have not been defined. Based on all deleterious effects of BPA, France has banned the use of BPA in all food packaging. This should force the food industry to collaborate with members of public research to rapidly find safer substitutes to BPA. PMID:23732105

  18. Two electrical potential-dependent steps are required for transport by the Escherichia coli Tat machinery.

    PubMed

    Bageshwar, Umesh K; Musser, Siegfried M

    2007-10-01

    The twin-arginine translocation (Tat) pathway in Escherichia coli transports fully folded and assembled proteins across the energy-transducing periplasmic membrane. In chloroplasts, Tat transport requires energy input only from the proton motive force. To elucidate the mechanism and energetics of bacterial Tat protein transport, we developed an efficient in vitro transport assay using TatABC-enriched inverted membrane vesicles and the physiological precursor pre-SufI. We report transport efficiencies of 60-80% for nanomolar pre-SufI concentrations. Dissipation of the pH gradient does not reduce pre-SufI transport efficiency. Instead, pre-SufI transport requires at least two electrical potential (Deltapsi)-dependent steps that differ in both the duration and minimum magnitude of the required Deltapsi. The data are consistent with a model in which a substantial Deltapsi of short duration is required for an early transport step, and in which a small Deltapsi of long duration is necessary to drive a later transport step. PMID:17908913

  19. Mapping the chemical potential dependence of current-induced spin polarization in a topological insulator

    NASA Astrophysics Data System (ADS)

    Lee, Joon Sue; Richardella, Anthony; Hickey, Danielle Reifsnyder; Mkhoyan, K. Andre; Samarth, Nitin

    2015-10-01

    We report electrical measurements of the current-induced spin polarization of the surface current in topological insulator devices where contributions from bulk and surface conduction can be disentangled by electrical gating. The devices use a ferromagnetic tunnel junction (permalloy/Al 2O3 ) as a spin detector on a back-gated (Bi,Sb ) 2Te3 channel. We observe hysteretic voltage signals as the magnetization of the detector ferromagnet is switched parallel or antiparallel to the spin polarization of the surface current. The amplitude of the detected voltage change is linearly proportional to the applied dc bias current in the (Bi,Sb ) 2Te3 channel. As the chemical potential is tuned from the bulk bands into the surface state band, we observe an enhancement of the spin-dependent voltages up to 300% within the range of the electrostatic gating. Using a simple model, we extract the spin polarization near charge neutrality (i.e., the Dirac point).

  20. An interpretation of potential scale dependence of the effectivematrix diffusion coefficient

    SciTech Connect

    Liu, H.H.; Zhang, Y.Q.; Zhou, Q.; Molz, F.J.

    2005-11-30

    Matrix diffusion is an important process for solutetransport in fractured rock, and the matrix diffusion coefficient is akey parameter for describing this process. Previous studies indicatedthat the effective matrix diffusion coefficient values, obtained from alarge number of field tracer tests, are enhanced in comparison with localvalues and may increase with test scale. In this study, we have performednumerical experiments to investigate potential mechanisms behind possiblescale-dependent behavior. The focus of the experiments is on solutetransport in flow paths having geometries consistent with percolationtheories and characterized by local flow loops formed mainly bysmall-scale fractures. The water velocity distribution through a flowpath was determined using discrete fracture network flow simulations, andsolute transport was calculated using a previously derivedimpulse-response function and a particle-tracking scheme. Values foreffective (or up-scaled) transport parameters were obtained by matchingbreakthrough curves from numerical experiments with an analyticalsolution for solute transport along a single fracture. Results indicatethat a combination of local flow loops and the associated matrixdiffusion process, together with scaling properties in flow pathgeometry, seems to be the dominant mechanism causing the observed scaledependence of theeffective matrix diffusion coefficient (at a range ofscales).

  1. Elastic constants of defected and amorphous silicon with the environment-dependent interatomic potential

    SciTech Connect

    Allred, Clark L.; Yuan Xianglong; Hobbs, Linn W.; Bazant, Martin Z.

    2004-10-01

    The elastic constants of a wide range of models of defected crystalline and amorphous silicon are calculated, using the environment-dependent interatomic potential (EDIP). The defected crystalline simulation cells contain randomly generated defect distributions. An extensive characterization of point defects is performed, including structure, energy and influence on elastic constants. Three important conclusions are drawn. (1) Defects have independent effects on the elastic constants of silicon up to (at least) a defect concentration of 0.3%. (2) The linear effect of Frenkel pairs on the <110> Young's modulus of silicon is -1653 GPa per defect fraction. (3) 17 different point defect types cause a very similar decrease in the <110> Young's modulus: -(0.28{+-}0.05)% when calculated in isolation using a 1728-atom cell. These principles will be very useful for predicting the effect of radiation damage on the elastic modulus of silicon in the typical case in which point-defect concentrations can be estimated, but the exact distribution and species of defects is unknown. We also study amorphous samples generated in quenching the liquid with EDIP, including an ideal structure of perfect fourfold coordination, samples with threefold and fivefold coordinated defects, one with a nanovoid, and one with an amorphous inclusion in a crystalline matrix. In the last case, a useful finding is that the change in the Young's modulus is simply related to the volume fraction of amorphous material, as has also been observed by experiment.

  2. Sodium Dependent Multivitamin Transporter (SMVT): A Potential Target for Drug Delivery

    PubMed Central

    Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Mitra, Ashim K.

    2015-01-01

    Sodium dependent multivitamin transporter (SMVT; product of the SLC5A6 gene) is an important transmembrane protein responsible for translocation of vitamins and other essential cofactors such as biotin, pantothenic acid and lipoic acid. Hydropathy plot (Kyte-Dolittle algorithm) revealed that human SMVT protein consists of 635 amino acids and 12 transmembrane domains with both amino and carboxyl termini oriented towards the cytoplasm. SMVT is expressed in various tissues such as placenta, intestine, brain, liver, lung, kidney, cornea, retina and heart. This transporter displays broad substrate specificity and excellent capacity for utilization in drug delivery. Drug absorption is often limited by the presence of physiological (epithelial tight junctions), biochemical (efflux transporters and enzymatic degradation) and chemical (size, lipophilicity, molecular weight, charge, etc.) barriers. These barriers may cause many potential therapeutics to be dropped from the preliminary screening portfolio and subsequent entry into the market. Transporter targeted delivery has become a powerful approach to deliver drugs to target tissues because of the ability of the transporter to translocate the drug to intracellular organelles at a higher rate. This review highlights studies employing SMVT transporter as a target for drug delivery to improve bioavailability and investigate the feasibility of developing SMVT targeted drug delivery systems. PMID:22420308

  3. Quark-mass dependence of the three-flavor QCD phase diagram at zero and imaginary chemical potential: Model prediction

    SciTech Connect

    Sasaki, Takahiro; Sakai, Yuji; Yahiro, Masanobu; Kouno, Hiroaki

    2011-11-01

    We draw the three-flavor phase diagram as a function of light- and strange-quark masses for both zero and imaginary quark-number chemical potential, using the Polyakov-loop extended Nambu-Jona-Lasinio model with an effective four-quark vertex depending on the Polyakov loop. The model prediction is qualitatively consistent with 2+1 flavor lattice QCD prediction at zero chemical potential and with degenerate three-flavor lattice QCD prediction at imaginary chemical potential.

  4. Developmental switch in the kinase dependency of long-term potentiation depends on expression of GluA4 subunit-containing AMPA receptors

    PubMed Central

    Luchkina, Natalia V.; Huupponen, Johanna; Clarke, Vernon R. J.; Coleman, Sarah K.; Keinänen, Kari; Taira, Tomi; Lauri, Sari E.

    2014-01-01

    The AMPA-receptor subunit GluA4 is expressed transiently in CA1 pyramidal neurons at the time synaptic connectivity is forming, but its physiological significance is unknown. Here we show that GluA4 expression is sufficient to alter the signaling requirements of long-term potentiation (LTP) and can fully explain the switch in the LTP kinase dependency from PKA to Ca2+/calmodulin-dependent protein kinase II during synapse maturation. At immature synapses, activation of PKA leads to a robust potentiation of AMPA-receptor function via the mobilization of GluA4. Analysis of GluA4-deficient mice indicates that this mechanism is critical for neonatal PKA-dependent LTP. Furthermore, lentiviral expression of GluA4 in CA1 neurons conferred a PKA-dependent synaptic potentiation and LTP regardless of the developmental stage. Thus, GluA4 defines the signaling requirements for LTP and silent synapse activation during a critical period of synapse development. PMID:24599589

  5. Maximum Diastolic Potential of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Depends Critically on IKr

    PubMed Central

    Goodrow, Robert J.; Wu, Yuesheng; Cordeiro, Jonathan M.; Nesterenko, Vladislav V.; Barajas-Martínez, Héctor; Hu, Dan; Urrutia, Janire; Desai, Mayurika; Treat, Jacqueline A.; Sachinidis, Agapios; Antzelevitch, Charles

    2012-01-01

    Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) hold promise for therapeutic applications. To serve these functions, the hiPSC-CM must recapitulate the electrophysiologic properties of native adult cardiomyocytes. This study examines the electrophysiologic characteristics of hiPSC-CM between 11 and 121 days of maturity. Embryoid bodies (EBs) were generated from hiPS cell line reprogrammed with Oct4, Nanog, Lin28 and Sox2. Sharp microelectrodes were used to record action potentials (AP) from spontaneously beating clusters (BC) micro-dissected from the EBs (n = 103; 37°C) and to examine the response to 5 µM E-4031 (n = 21) or BaCl2 (n = 22). Patch-clamp techniques were used to record IKr and IK1 from cells enzymatically dissociated from BC (n = 49; 36°C). Spontaneous cycle length (CL) and AP characteristics varied widely among the 103 preparations. E-4031 (5 µM; n = 21) increased Bazett-corrected AP duration from 291.8±81.2 to 426.4±120.2 msec (p<0.001) and generated early afterdepolarizations in 8/21 preparations. In 13/21 BC, E-4031 rapidly depolarized the clusters leading to inexcitability. BaCl2, at concentrations that selectively block IK1 (50–100 µM), failed to depolarize the majority of clusters (13/22). Patch-clamp experiments revealed very low or negligible IK1 in 53% (20/38) of the cells studied, but presence of IKr in all (11/11). Consistent with the electrophysiological data, RT-PCR and immunohistochemistry studies showed relatively poor mRNA and protein expression of IK1 in the majority of cells, but robust expression of IKr. In contrast to recently reported studies, our data point to major deficiencies of hiPSC-CM, with remarkable diversity of electrophysiologic phenotypes as well as pharmacologic responsiveness among beating clusters and cells up to 121 days post-differentiation (dpd). The vast majority have a maximum diastolic potential that depends critically on IKr due to the absence of IK1. Thus

  6. Modeling and experiments to explain the potential dependency of an UHSS to hydrogen environment assisted cracking

    NASA Astrophysics Data System (ADS)

    Kehler, Beth A.

    Modern ultra high strength steels have been developed with outstanding combinations of strength and fracture toughness but lack intrinsic corrosion resistance. Such steels are used by the military for aircraft components such as landing gears but require coatings and cathodic protection which can lead to various rates of hydrogen production depending on material, geometry, and electro(chemistry). The susceptibility of such steels to internal hydrogen embrittlement (IHE) and hydrogen environment embrittlement (HEE) limits their use in marine environments. The objective of this research is to develop the understanding necessary to design coated ultra high strength steels that resist HEE when stressed in marine environments. The cause of HEE is the establishment of high diffusible hydrogen concentrations (CH,diff) at the crack tip. There is a window of applied potentials (Eapplied) where susceptibility to HEE is reduced because CH,diff is reduced. However, Eapplied itself does not yield insight as to the exact conditions at the crack tip. Ohmic potential drop and electrochemical/chemical reactions in the crack can lead to a significantly different environment at the crack tip than on the surface. The issues that hinder understanding of HEE center on the capability to quantify and ultimately predict crack tip hydrogen concentrations (C H,Tip) relative to critical concentrations that trigger fracture as a function of Eapplied. CH,tip was characterized using a multi-pronged approach. Scaling laws were developed to enable measurements of E and pH in a scaled-up crack as a function of the scaling parameter, x2/G and Eapplied . Such measurements were correlated with CH,diff using an experimentally determined hydrogen uptake law based on first order absorption laws and trapping theory. CH,diff values were then used as inputs into existing micromechanical models for KTH and da/dtII to predict cracking susceptibility. The scientific contributions of this work include the

  7. Lipogenic potential of liver from morbidly obese patients with and without non-insulin-dependent diabetes

    SciTech Connect

    Barakat, H.A.; McLendon, V.D.; Carpenter, J.W.; Marks, R.H.; Legett, N.; O'Brien, K.; Caro, J.F. )

    1991-03-01

    Intra-abdominal liver biopsies were obtained during surgery from fasted obese patients with non-insulin-dependent diabetes mellitus (NIDDM), obese normoglycemic controls, and lean controls. Lipid synthesis was studied in freshly isolated hepatocytes and liver homogenates from the three groups of subjects. Incorporation of 3H2O into the lipids of hepatocytes was determined in the absence and presence of insulin (0.1 mumol/L). The activities of five enzymes involved in fatty acid synthesis, and the incorporation of 14C-glycerol-3-phosphate into lipids were determined in liver homogenates. Basal lipid synthesis by hepatocytes was not different in the three groups of patients. Insulin stimulated lipogenesis by 8% +/- 30% in the lean controls, 33% +/- 8% in the obese controls and 17% +/- 6% in the NIDDM patients. No significant differences in the activities of the five enzymes that are involved in de novo fatty acid synthesis among the three groups of patients were observed. Similarly, incorporation of 14C-glycerol-3-phosphate by liver homogenates, in the presence of saturating or submaximal concentrations of fatty acids, did not differ among the three groups. These results show that under the experimental conditions of this study, including the fasted state of the patients, the basal capacity of liver of NIDDM patients to synthesize fatty acids or glycerides is the same as that of liver from obese and lean controls. Thus, it is likely that an increase in fatty acid flux into a liver with normal lipogenic potential may contribute to the increased synthesis of triglycerides by the liver of these patients in vivo.

  8. Time and Frequency-Dependent Modulation of Local Field Potential Synchronization by Deep Brain Stimulation

    PubMed Central

    McCracken, Clinton B.; Kiss, Zelma H. T.

    2014-01-01

    High-frequency electrical stimulation of specific brain structures, known as deep brain stimulation (DBS), is an effective treatment for movement disorders, but mechanisms of action remain unclear. We examined the time-dependent effects of DBS applied to the entopeduncular nucleus (EP), the rat homolog of the internal globus pallidus, a target used for treatment of both dystonia and Parkinson’s disease (PD). We performed simultaneous multi-site local field potential (LFP) recordings in urethane-anesthetized rats to assess the effects of high-frequency (HF, 130 Hz; clinically effective), low-frequency (LF, 15 Hz; ineffective) and sham DBS delivered to EP. LFP activity was recorded from dorsal striatum (STR), ventroanterior thalamus (VA), primary motor cortex (M1), and the stimulation site in EP. Spontaneous and acute stimulation-induced LFP oscillation power and functional connectivity were assessed at baseline, and after 30, 60, and 90 minutes of stimulation. HF EP DBS produced widespread alterations in spontaneous and stimulus-induced LFP oscillations, with some effects similar across regions and others occurring in a region- and frequency band-specific manner. Many of these changes evolved over time. HF EP DBS produced an initial transient reduction in power in the low beta band in M1 and STR; however, phase synchronization between these regions in the low beta band was markedly suppressed at all time points. DBS also enhanced low gamma synchronization throughout the circuit. With sustained stimulation, there were significant reductions in low beta synchronization between M1-VA and STR-VA, and increases in power within regions in the faster frequency bands. HF DBS also suppressed the ability of acute EP stimulation to induce beta oscillations in all regions along the circuit. This dynamic pattern of synchronizing and desynchronizing effects of EP DBS suggests a complex modulation of activity along cortico-BG-thalamic circuits underlying the therapeutic effects

  9. POTENTIATION OF INHIBITION WITH PERFORANT PATH KINDLING: AN NMDA-DEPENDENT PROCESS

    EPA Science Inventory

    Kindling produces a long lasting enhancement of excitatory and inhibitory neurotransmission. Both long-term potentiation and kindling-induced potentiation of hippocampal excitatory neurotransmission are suppressed by N-methyl-d-aspartate (NMDA) antagonists. We have previously rep...

  10. Dilepton production as a useful probe of quark gluon plasma with temperature dependent chemical potential quark mass

    NASA Astrophysics Data System (ADS)

    Kumar, Yogesh; Singh, S. Somorendro

    2016-07-01

    We extend the previous study of dilepton production using [S. Somorendro Singh and Y. Kumar, Can. J. Phys. 92 (2014) 31] based on a simple quasiparticle model of quark-gluon plasma (QGP). In this model, finite value of quark mass uses temperature dependent chemical potential the so-called Temperature Dependent Chemical Potential Quark Mass (TDCPQM). We calculate dilepton production in the relevant range of mass region. It is observed that the production rate is marginally enhanced from the earlier work. This is due to the effect of TDCPQM and its effect is highly significant in the production of dilepton.

  11. Vector Constants of Motion for Time-Dependent Kepler and Isotropic Harmonic Oscillator Potentials

    NASA Astrophysics Data System (ADS)

    Ritter, O. M.; Santos, F. C.; Tort, A. C.

    2001-06-01

    A method of obtaining vector constants of motion for time-independent as well as time-dependent central fields is discussed. Some well-established results are rederived in this alternative way and new ones obtained.

  12. Potential-dependent sum frequency generation study of 5-methylbenzotriazole on polycrystalline copper, platinum, and gold.

    PubMed

    Romero, Casey; Baldelli, Steven

    2006-06-22

    In situ sum frequency generation vibrational spectroscopy, at varied potentials and polarization combinations, was performed on polycrystalline copper, polycrystalline platinum, and polycrystalline gold samples in 0.5 M HClO4 with 50 mM 5-methylbenzotriazole (5-methylBTAH) added. These studies were performed to determine the orientation of 5-methylBTAH on the surface at different potentials. For copper surfaces, orientation of the molecule on the surface is not affected by potential within the potential window studied (-500 to -100 mV vs saturated calomel electrode (SCE)). Sum frequency generation spectra of 5-methylBTAH on platinum show a change in orientation over the potential range studied (-250 to 750 mV vs SCE). The orientation of the methyl group tilts more toward the plane of the interface as the potential is scanned in the positive direction. This orientation change is correlated to hydrogen coadsorption on the platinum surface at low potentials. 5-Methylbenzotriazole lies in the surface plane or does not orient on gold at lower potentials but the orientation is tilted toward normal at more positive potentials over the potential range studied (-500 to 900 mV vs SCE). To compliment these results, cyclic voltammetry and electrochemical impedance spectroscopy measurements were performed. Cyclic voltammograms of copper show that addition of 5-methylBTAH protects the surface from copper dissolution, increasing the electrochemical window by 450 mV. Cyclic voltammetry of 5-methylBTAH on platinum showed a partial blockage of adsorbed hydrogen and also prevented the adsorption of oxygenated species at 450-600 mV. Cyclic voltammetry on gold shows that 5-methylBTAH blocks oxide formation for 400 mV thus increasing the electrochemical window. Electrochemical impedance spectroscopy has been performed to determine the potential of zero charge of 5-methylBTAH on copper. PMID:16800498

  13. Context-dependent symbioses and their potential roles in wildlife diseases

    PubMed Central

    Daskin, Joshua H.; Alford, Ross A.

    2012-01-01

    It is well known in ecology, evolution and medicine that both the nature (commensal, parasitic and mutualistic) and outcome (symbiont fitness, survival) of symbiotic interactions are often context-dependent. Less is known about the importance of context-dependence in symbioses involved in wildlife disease. We review variable symbioses, and use the amphibian disease chytridiomycosis to demonstrate how understanding context-dependence can improve the understanding and management of wildlife diseases. In chytridiomycosis, the host–pathogen interaction is context-dependent; it is strongly affected by environmental temperature. Skin bacteria can also modify the interaction; some bacteria reduce amphibians' susceptibility to chytridiomycosis. Augmentation of protective microbes is being considered as a possible management tool, but informed application of bioaugmentation requires understanding of how the interactions between host, beneficial bacteria and pathogen depend upon environmental context. The community-level response of the amphibian skin microbiota to environmental conditions may explain the relatively narrow range of environmental conditions in which past declines have occurred. Environmental context affects virulence and the protection provided by mutualists in other host–pathogen systems, including threatened bats and corals. Increased focus on context-dependence in interactions between wildlife and their symbionts is likely to be crucial to the future investigation and management of emerging diseases of wildlife. PMID:22237907

  14. Are distance-dependent statistical potentials considering three interacting bodies superior to two-body statistical potentials for protein structure prediction?

    PubMed

    Ghomi, Hamed Tabatabaei; Thompson, Jared J; Lill, Markus A

    2014-10-01

    Distance-based statistical potentials have long been used to model condensed matter systems, e.g. as scoring functions in differentiating native-like protein structures from decoys. These scoring functions are based on the assumption that the total free energy of the protein can be calculated as the sum of pairwise free energy contributions derived from a statistical analysis of pair-distribution functions. However, this fundamental assumption has been challenged theoretically. In fact the free energy of a system with N particles is only exactly related to the N-body distribution function. Based on this argument coarse-grained multi-body statistical potentials have been developed to capture higher-order interactions. Having a coarse representation of the protein and using geometric contacts instead of pairwise interaction distances renders these models insufficient in modeling details of multi-body effects. In this study, we investigated if extending distance-dependent pairwise atomistic statistical potentials to corresponding interaction functions that are conditional on a third interacting body, defined as quasi-three-body statistical potentials, could model details of three-body interactions. We also tested if this approach could improve the predictive capabilities of statistical scoring functions for protein structure prediction. We analyzed the statistical dependency between two simultaneous pairwise interactions and showed that there is surprisingly little if any dependency of a third interacting site on pairwise atomistic statistical potentials. Also the protein structure prediction performance of these quasi-three-body potentials is comparable with their corresponding two-body counterparts. The scoring functions developed in this study showed better or comparable performances compared to some widely used scoring functions for protein structure prediction. PMID:25212727

  15. ACUTE SULFOLANE EXPOSURE PRODUCES TEMPERATURE-INDEPENDENT AND DEPENDENT CHANGES IN VISUAL EVOKED POTENTIALS

    EPA Science Inventory

    The report describes the consequences of acute exposure to sulfolane upon the visual system, as measured using flash evoked potential (FEPs) and pattern reversal evoked potentials (PREPs). A single injection of either 1/2 or 1/4, but not 1/8 the i.p. LD50 (1600 mg/kg) produced si...

  16. Sustained Exocytosis after Action Potential-Like Stimulation at Low Frequencies in Mouse Chromaffin Cells Depends on a Dynamin-Dependent Fast Endocytotic Process

    PubMed Central

    Moya-Díaz, José; Álvarez, Yanina D.; Montenegro, Mauricio; Bayonés, Lucas; Belingheri, Ana V.; González-Jamett, Arlek M.; Cárdenas, Ana M.; Marengo, Fernando D.

    2016-01-01

    Under basal conditions the action potential firing rate of adrenal chromaffin cells is lower than 0.5 Hz. The maintenance of the secretory response at such frequencies requires a continuous replenishment of releasable vesicles. However, the mechanism that allows such vesicle replenishment remains unclear. Here, using membrane capacitance measurements on mouse chromaffin cells, we studied the mechanism of replenishment of a group of vesicles released by a single action potential-like stimulus (APls). The exocytosis triggered by APls (ETAP) represents a fraction (40%) of the immediately releasable pool, a group of vesicles highly coupled to voltage dependent calcium channels. ETAP was replenished with a time constant of 0.73 ± 0.11 s, fast enough to maintain synchronous exocytosis at 0.2–0.5 Hz stimulation. Regarding the mechanism involved in rapid ETAP replenishment, we found that it depends on the ready releasable pool; indeed depletion of this vesicle pool significantly delays ETAP replenishment. On the other hand, ETAP replenishment also correlates with a dynamin-dependent fast endocytosis process (τ = 0.53 ± 0.01 s). In this regard, disruption of dynamin function markedly inhibits the fast endocytosis and delays ETAP replenishment, but also significantly decreases the synchronous exocytosis during repetitive APls stimulation at low frequencies (0.2 and 0.5 Hz). Considering these findings, we propose a model in where both the transfer of vesicles from ready releasable pool and fast endocytosis allow rapid ETAP replenishment during low stimulation frequencies. PMID:27507935

  17. Sustained Exocytosis after Action Potential-Like Stimulation at Low Frequencies in Mouse Chromaffin Cells Depends on a Dynamin-Dependent Fast Endocytotic Process.

    PubMed

    Moya-Díaz, José; Álvarez, Yanina D; Montenegro, Mauricio; Bayonés, Lucas; Belingheri, Ana V; González-Jamett, Arlek M; Cárdenas, Ana M; Marengo, Fernando D

    2016-01-01

    Under basal conditions the action potential firing rate of adrenal chromaffin cells is lower than 0.5 Hz. The maintenance of the secretory response at such frequencies requires a continuous replenishment of releasable vesicles. However, the mechanism that allows such vesicle replenishment remains unclear. Here, using membrane capacitance measurements on mouse chromaffin cells, we studied the mechanism of replenishment of a group of vesicles released by a single action potential-like stimulus (APls). The exocytosis triggered by APls (ETAP) represents a fraction (40%) of the immediately releasable pool, a group of vesicles highly coupled to voltage dependent calcium channels. ETAP was replenished with a time constant of 0.73 ± 0.11 s, fast enough to maintain synchronous exocytosis at 0.2-0.5 Hz stimulation. Regarding the mechanism involved in rapid ETAP replenishment, we found that it depends on the ready releasable pool; indeed depletion of this vesicle pool significantly delays ETAP replenishment. On the other hand, ETAP replenishment also correlates with a dynamin-dependent fast endocytosis process (τ = 0.53 ± 0.01 s). In this regard, disruption of dynamin function markedly inhibits the fast endocytosis and delays ETAP replenishment, but also significantly decreases the synchronous exocytosis during repetitive APls stimulation at low frequencies (0.2 and 0.5 Hz). Considering these findings, we propose a model in where both the transfer of vesicles from ready releasable pool and fast endocytosis allow rapid ETAP replenishment during low stimulation frequencies. PMID:27507935

  18. The APP-Interacting Protein FE65 is Required for Hippocampus-Dependent Learning and Long-Term Potentiation

    ERIC Educational Resources Information Center

    Wang, Yan; Zhang, Ming; Moon, Changjong; Hu, Qubai; Wang, Baiping; Martin, George; Sun, Zhongsheng; Wang, Hongbing

    2009-01-01

    FE65 is expressed predominantly in the brain and interacts with the C-terminal domain of [beta]-amyloid precursor protein (APP). We examined hippocampus-dependent memory and in vivo long-term potentiation (LTP) at the CA1 synapses with isoform-specific FE65 knockout (p97FE65[superscript -/-]) mice. When examined using the Morris water maze,…

  19. Isolation of Bacteria Whose Growth Is Dependent on High Levels of CO2 and Implications of Their Potential Diversity▿ †

    PubMed Central

    Ueda, Kenji; Tagami, Yudai; Kamihara, Yuka; Shiratori, Hatsumi; Takano, Hideaki; Beppu, Teruhiko

    2008-01-01

    Although some bacteria require an atmosphere with high CO2 levels for their growth, CO2 is not generally supplied to conventional screening cultures. Here, we isolated 84 bacterial strains exhibiting high-CO2 dependence. Their phylogenetic affiliations imply that high-CO2 culture has potential as an effective method to isolate unknown microorganisms. PMID:18487395

  20. The force dependence of isometric and concentric potentiation in mouse muscle with and without skeletal myosin light chain kinase.

    PubMed

    Gittings, William; Aggarwal, Harish; Stull, James T; Vandenboom, Rene

    2015-01-01

    The isometric potentiation associated with myosin phosphorylation is force dependent. The purpose of this study was to assess the influence of a pre-existing period of isometric force on the concentric force potentiation displayed by mouse muscles with and without the ability to phosphorylate myosin. We tested isometric (ISO) and concentric (CON) potentiation, as well as concentric potentiation after isometric force (ISO-CON), in muscles from wild-type (WT) and skeletal myosin light chain kinase-deficient (skMLCK(-/-)) mice. A conditioning stimulus increased (i.e., potentiated) mean concentric force in the ISO-CON and CON conditions to 1.31 ± 0.02 and 1.35 ± 0.02 (WT) and to 1.19 ± 0.02 and 1.21 ± 0.01 (skMLCK(-/-)) of prestimulus levels, respectively (data n = 6-8, p < 0.05). No potentiation of mean isometric force was observed in either genotype. The potentiation of mean concentric force was inversely related to relative tetanic force level (P/Po) in both genotypes. Moreover, concentric potentiation varied greatly within each contraction type and was negatively correlated with unpotentiated force in both genotypes. Thus, although no effect of pre-existing force was observed, strong and inverse relationships between concentric force potentiation and unpotentiated concentric force may suggest an influence of attached and force-generating crossbridges on potentiation magnitude in both WT and skMLCK(-/-) muscles. PMID:25412230

  1. Impact parameter dependent potentials and average transverse momentum in inclusive DIS

    NASA Astrophysics Data System (ADS)

    Alhalholy, Tareq; Burkardt, Matthias

    2016-06-01

    We exploit a connection between the Coulomb/Eikonal phase and the charge distribution in the transverse plane for a transversely polarized nucleon. The known deformation of the charge density in impact parameter space translates into an asymmetry in the Coulomb/Eikonal phase (or the impact parameter electromagnetic potential). The asymmetry in the transverse potential implies an azimuthal asymmetry in the scattering cross section of the scattered electrons in inclusive DIS. We use the transverse potential to calculate the average transverse momentum of the scattered electrons. The sign of the calculated average transverse momentum for a neutron target is consistent with recent Jefferson Lab data.

  2. Entrance Channel Mass Asymmetry Effects in Sub-Barrier Fusion Dynamics by Using Energy Dependent Woods-Saxon Potential

    NASA Astrophysics Data System (ADS)

    Manjeet Singh, Gautam

    2015-12-01

    The present article highlights the inconsistency of static Woods-Saxon potential and the applicability of energy dependent Woods-Saxon potential to explore the fusion dynamics of {}4822Ti+58,60,6428Ni, {}4622Ti+{}6428Ni,{}5022Ti+{}6028Ni, and {}199F+9341Nb reactions leading to formation of different Sn-isotopes via different entrance channels. Theoretical calculations based upon one-dimensional Wong formula obtained by using static Woods-Saxon potential unable to provide proper explanation for sub-barrier fusion enhancement of these projectile-target combinations. However, the predictions of one-dimensional Wong formula based upon energy dependent Woods-Saxon potential model (EDWSP model) accurately describe the observed fusion dynamics of these systems wherein the significantly larger value of diffuseness parameter ranging from a = 0.85 fm to a = 0.97 fm is required to address the experimental data in whole range of energy. Therefore, the energy dependence in nucleus-nucleus potential simulates the influence of the nuclear structure degrees of freedom of the colliding pairs. Supported by Dr. D.S. Kothari Post-Doctoral Fellowship Scheme sponsored by University Grants Commission (UGC), New Delhi, India

  3. The dependence of potential well formation on the magnetic field strength and electron injection current in a polywell device

    SciTech Connect

    Cornish, S. Gummersall, D.; Carr, M.; Khachan, J.

    2014-09-15

    A capacitive probe has been used to measure the plasma potential in a polywell device in order to observe the dependence of potential well formation on magnetic field strength, electron injection current, and polywell voltage bias. The effectiveness of the capacitive probe in a high energy electron plasma was determined by measuring the plasma potential of a planar diode with an axial magnetic field. The capacitive probe was translated along the axis of one of the field coils of the polywell, and the spatial profile of the potential well was measured. The confinement time of electrons in the polywell was estimated with a simple analytical model which used the experimentally observed potential well depths, as well as a simulation of the electron trajectories using particle orbit theory.

  4. Surface and zeta-potentials of silver halide single crystals: pH-dependence in comparison to particle systems.

    PubMed

    Selmani, Atiða; Lützenkirchen, Johannes; Kallay, Nikola; Preočanin, Tajana

    2014-06-18

    We have carried out surface and zeta-potential measurements on AgCl and AgBr single crystals. As for particle systems we find that, surprisingly and previously unnoted, the zeta-potential exhibits pH-dependence, while the surface potential does not. A possible interpretation of these observations is the involvement of water ions in the interfacial equilibria and in particular, stronger affinity of the hydroxide ion compared to the proton. The pH-dependence of the zeta-potential can be suppressed at sufficiently high silver concentrations, which agrees with previous measurements in particle systems where no pH-dependence was found at high halide ion concentrations. The results suggest a subtle interplay between the surface potential determining the halide and silver ion concentrations, and the water ions. Whenever the charge due to the halide and silver ions is sufficiently high, the influence of the proton/hydroxide ion on the zeta-potential vanishes. This might be related to the water structuring at the relevant interfaces which should be strongly affected by the surface potential. Another interesting observation is accentuation of the assumed water ion effect on the zeta-potential at the flat single crystal surfaces compared to the corresponding silver halide colloids. Previous generic MD simulations have indeed predicted that hydroxide ion adsorption is accentuated on flat/rigid surfaces. A thermodynamic model for AgI single crystals was developed to describe the combined effects of iodide, silver and water ions, based on two independently previously published models for AgI (that only consider constituent and background electrolyte ions) and inert surfaces (that only consider water and background electrolyte ions). The combined model correctly predicts all the experimentally observed trends. PMID:24863080

  5. Theoretical approach for optical response in electrochemical systems: Application to electrode potential dependence of surface-enhanced Raman scattering

    SciTech Connect

    Iida, Kenji; Noda, Masashi; Nobusada, Katsuyuki

    2014-09-28

    We propose a theoretical approach for optical response in electrochemical systems. The fundamental equation to be solved is based on a time-dependent density functional theory in real-time and real-space in combination with its finite temperature formula treating an electrode potential. Solvation effects are evaluated by a dielectric continuum theory. The approach allows us to treat optical response in electrochemical systems at the atomistic level of theory. We have applied the method to surface-enhanced Raman scattering (SERS) of 4-mercaptopyridine on an Ag electrode surface. It is shown that the SERS intensity has a peak as a function of the electrode potential. Furthermore, the real-space computational approach facilitates visualization of variation of the SERS intensity depending on an electrode potential.

  6. Quantization of time-dependent singular potential systems in one-dimension by using the Nikiforov-Uvarov method

    NASA Astrophysics Data System (ADS)

    Menouar, Salah; Choi, Jeong Ryeol

    2015-10-01

    The technique for quantizing simple static systems can be extended to more generalized systems that involve time-dependent parameters. In this work, a particle with linearly increasing mass that is bound by a time-dependent singular potential, which is composed of an inverse quadratic potential and a Coulomb-like potential, is quantized by using the Nikiforov-Uvarov method together with the invariant operator method and the unitary transformation method. The Nikiforov-Uvarov method is an alternative method for solving the Schrödinger equation on the basis of a particular mathematical technique that reduces second-order differential equations to generalized hypergeometric ones. The exact wave functions of the system are identified, and their properties are addressed in detail.

  7. Frequency dependent activation of a slow N-methyl-D-aspartate-dependent excitatory postsynaptic potential in turtle cerebellum by mossy fibre afferents.

    PubMed

    Larson-Prior, L J; Morrison, P D; Bushey, R M; Slater, N T

    1995-08-01

    The synaptic responses of turtle cerebellar Purkinje cells to stimulation of localized mossy fibre systems have been studied by use of intrasomatic and intradendritic recordings in a brainstem-cerebellum preparation in vitro. Activation of mossy fibre inputs from the spinocerebellar pathway evoked fast, disynaptic postsynaptic potentials which were graded in amplitude with stimulus intensity and elicited at latencies consistent with those reported for peripheral nerve stimulation. Repetitive activation (50-100 Hz, 2-10 stimuli) of both spinocerebellar and trigeminocerebellar pathways evoked a slow, long-lasting excitatory postsynaptic potential regardless of whether single stimuli resulted in excitatory, inhibitory, or no postsynaptic responses. This slow potential was capable of triggering dendritic pacemaker discharges in recorded Purkinje cells in addition to volleys of simple spikes when activated at or near resting membrane potential. The fast excitatory synaptic potentials evoked by spinocerebellar stimulation were blocked by the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, consistent with the hypothesis that they are mediated by activation of ionotropic glutamate receptors of the alpha-amino-3-hydroxy-5-methylisox-azole-4-proprionic acid subtype at the mossy fibre-granule cell synapse and the subsequent parallel fibre-Purkinje cell synapse. The slow excitatory synaptic potential evoked by repetitive stimulation of either the spinocerebellar tract or trigeminal nerve was blocked by DL-2-amino-5-phosphonvalerate, indicating that this potential is primarily dependent upon N-methyl-D-aspartate receptors at the mossy fibre-granule cell synapse for its expression. This slow potential was reversibly potentiated by L-2-amino-4-phosphonobutyrate and bicuculline; the metabotropic glutamate antagonist (+)-alpha-methyl-4-carboxyphenylglycine did not block this potentiation. The ability of mossy fibre inputs to drive long, slow excitatory events in

  8. Pulsed magnetic stimulation modifies amplitude of action potentials in vitro via ionic channels-dependent mechanism.

    PubMed

    Ahmed, Zaghloul; Wieraszko, Andrzej

    2015-07-01

    This paper investigates the influence of pulsed magnetic fields (PMFs) on amplitude of evoked, compound action potential (CAP) recorded from the segments of sciatic nerve in vitro. PMFs were applied for 30 min at frequency of 0.16 Hz and intensity of 15 mT. In confirmation of our previous reports, PMF exposure enhanced amplitude of CAPs. The effect persisted beyond PMF activation period. As expected, CAP amplitude was attenuated by antagonists of sodium channel, lidocaine, and tetrodotoxin. Depression of the potential by sodium channels antagonists was reversed by subsequent exposure to PMFs. The effect of elevated potassium concentration and veratridine on the action potential was modified by exposure to PMFs as well. Neither inhibitors of protein kinase C and protein kinase A, nor known free radicals scavengers had any effects on PMF action. Possible mechanisms of PMF action are discussed. PMID:25884360

  9. Iontophoresis From a Micropipette into a Porous Medium Depends on the ζ-Potential of the Medium

    PubMed Central

    Guy, Yifat; Faraji, Amir H.; Gavigan, Colleen A.; Strein, Timothy G.; Weber, Stephen G.

    2012-01-01

    Iontophoresis uses electricity to deliver solutes into living tissue. Often, iontophoretic ejections from micropipettes into brain tissue are confined to millisecond pulses for highly localized delivery, but longer pulses are common. As hippocampal tissue has a ζ-potential of approximately –22 mV, we hypothesized that, in the presence of the electric field resulting from the iontophoretic current, electroosmotic flow in the tissue would carry solutes considerably farther than diffusion alone. A steady state solution to this mass transport problem predicts a spherically symmetrical solute concentration profile with the characteristic distance of the profile depending on the ζ-potential of the medium, the current density at the tip, the tip size and the solute electrophoretic mobility and diffusion coefficient. Of course, the ζ-potential of the tissue is defined by immobilized components of the extracellular matrix as well as cell-surface functional groups. As such, it cannot be changed at will. Therefore, the effect of the ζ-potential of the porous medium on ejections is examined using poly(acrylamide-co-acrylic acid) hydrogels with various magnitudes of ζ-potential, including that similar to hippocampal brain tissue. We demonstrated that nearly neutral fluorescent dextran (3 and 70 kD) solute penetration distance in the hydrogels and OHSCs depends on the magnitude of the applied current, solute properties, and, in the case of the hydrogels, the ζ-potential of the matrix. Steady state solute ejection profiles can be predicted semi-quantitatively. PMID:22264102

  10. Why does high T sub c sometimes depend on oxidation; An investigation of Madelung Potentials

    SciTech Connect

    Tan, N.X.; Bourdillon, A.J. )

    1990-03-10

    Some high temperature superconductors require atmospheres of oxygen for the formation of the superconducting phase, and others do not. The former corrode more easily and includes the doped compound (La{sub 1.5}Ba{sub 0.5}) CuO{sub 4}. In the latter class, Cu ions inhabit sites with large ionic potential, which apparently allows the formation of high charge states such as Cu(d8) or CuO{sup +}. In this paper an elementary code was used to examine potentials on a number of defect sites. Thus a high charge state on polyvalent Cu is a feature common to both types of superconductors.

  11. Dependence of the 16O+16O nuclear potential on nuclear incompressibility

    NASA Astrophysics Data System (ADS)

    Hossain, S.; Tariq, A. S. B.; Nilima, Athoy; Islam, M. Sujan; Majumder, R.; Sayed, M. A.; Billah, M. M.; Azad, M. M. B.; Uddin, M. A.; Reichstein, I.; Malik, F. B.; Basak, A. K.

    2015-06-01

    Nonmonotonic (NM) nucleus-nucleus potentials from the energy-density functional (EDF) theory including the Pauli principle have been considered for the nuclear incompressibility K in the range 188-266 MeV. The experimental cross sections of the 16O+16O elastic scattering over the 31-350 MeV incident energies have been analyzed in the optical model using the NM potentials. Sensitivity of K on the elastic scattering data is studied and its value for infinite cold nuclear matter deduced to be 222 ±5 MeV .

  12. [Regulation of potential-dependant calcium channels by 5-HT1B serotonin receptors in various populations of hippocampal cells].

    PubMed

    Kononov, A V; Ivanov, S V; Zinchenko, V P

    2013-01-01

    Metabotropic serotonin receptors of 5HT1-type in brain neurons participate in regulation of such human emotional states as aggression, fear and dependence on alcohol. Activated presynaptic 5-HT1B receptors suppress the Ca2+ influx through the potential-dependent calcium channels in certain neurons. The Ca2+ influx into the cells has been measured by increase of calcium ions concentration in cytoplasm in reply to the depolarization caused by 35mM KC1. Using system of image analysis in hippocampal cells culture we found out that Ca2+-signals to depolarization oin various populations of neurons differed in form, speed and amplitude. 5HT1B receptor agonists in 86 +/- 3 % of neurons slightly suppressed the activity of potential-dependent calcium channels. Two minor cell populations (5-8 % of cells each) were found out, that strongly differed in Ca2+ signal desensitization. Calcium signal caused by depolarization in one cells population differed in characteristic delay and high rate of decay. 5HT1B receptor agonists strongly inhibited the amplitude of the Ca2+ response on KCl only in this population of neurons. The calcium signal in second cell population differed by absence desensitization and smaller amplitude which constantly increased during depolarization. 5HT 1 B receptor agonists increased the calcium response amplitude to depolarization in this population of neurons. Thus we show various sensitivity of potential-dependent calcium channels of separate neurons to 5HTB1 receptor agonist. PMID:23659057

  13. Direction-dependent spectral sensitivity and interaural spectral difference in a dolphin: evoked potential study.

    PubMed

    Supin AYa; Popov, V V

    1993-06-01

    Sensitivity and interaural intensity difference (IID) dependence on sound frequency and direction was measured in an Amazon river dolphin Inia geoffrensis by recording the auditory nerve evoked response from the body surface. The maximal sensitivity in the horizontal plane was found when the sound direction was 5 degrees to 10 degrees ipsilateral to the recorded ear; the direction dependence of sensitivity was more pronounced at higher frequencies than at lower ones. The IID reached its peak at small azimuthal angles (7.5 degrees to 15 degrees) and higher sound frequencies (100 kHz), or at large azimuthal angles (30 degrees to 45 degrees) and lower sound frequencies (20 to 30 kHz). Each sound direction featured its specific pattern of spectral sensitivity and of interaural spectral difference. The interaural spectral difference fluctuated within a range of more than 20 dB depending on sound direction. The data indicate that interaural intensity as well as spectral difference may be cues for binaural localization of sound direction by dolphins. PMID:8326074

  14. Molecular wave function and effective adiabatic potentials calculated by extended multi-configuration time-dependent Hartree-Fock method

    NASA Astrophysics Data System (ADS)

    Kato, Tsuyoshi; Ide, Yoshihiro; Yamanouchi, Kaoru

    2015-12-01

    We first calculate the ground-state molecular wave function of 1D model H2 molecule by solving the coupled equations of motion formulated in the extended multi-configuration time-dependent Hartree-Fock (MCTDHF) method by the imaginary time propagation. From the comparisons with the results obtained by the Born-Huang (BH) expansion method as well as with the exact wave function, we observe that the memory size required in the extended MCTDHF method is about two orders of magnitude smaller than in the BH expansion method to achieve the same accuracy for the total energy. Second, in order to provide a theoretical means to understand dynamical behavior of the wave function, we propose to define effective adiabatic potential functions and compare them with the conventional adiabatic electronic potentials, although the notion of the adiabatic potentials is not used in the extended MCTDHF approach. From the comparison, we conclude that by calculating the effective potentials we may be able to predict the energy differences among electronic states even for a time-dependent system, e.g., time-dependent excitation energies, which would be difficult to be estimated within the BH expansion approach.

  15. Molecular wave function and effective adiabatic potentials calculated by extended multi-configuration time-dependent Hartree-Fock method

    SciTech Connect

    Kato, Tsuyoshi; Ide, Yoshihiro; Yamanouchi, Kaoru

    2015-12-31

    We first calculate the ground-state molecular wave function of 1D model H{sub 2} molecule by solving the coupled equations of motion formulated in the extended multi-configuration time-dependent Hartree-Fock (MCTDHF) method by the imaginary time propagation. From the comparisons with the results obtained by the Born-Huang (BH) expansion method as well as with the exact wave function, we observe that the memory size required in the extended MCTDHF method is about two orders of magnitude smaller than in the BH expansion method to achieve the same accuracy for the total energy. Second, in order to provide a theoretical means to understand dynamical behavior of the wave function, we propose to define effective adiabatic potential functions and compare them with the conventional adiabatic electronic potentials, although the notion of the adiabatic potentials is not used in the extended MCTDHF approach. From the comparison, we conclude that by calculating the effective potentials we may be able to predict the energy differences among electronic states even for a time-dependent system, e.g., time-dependent excitation energies, which would be difficult to be estimated within the BH expansion approach.

  16. The Potential Energy Density in Transverse String Waves Depends Critically on Longitudinal Motion

    ERIC Educational Resources Information Center

    Rowland, David R.

    2011-01-01

    The question of the correct formula for the potential energy density in transverse waves on a taut string continues to attract attention (e.g. Burko 2010 "Eur. J. Phys." 31 L71), and at least three different formulae can be found in the literature, with the classic text by Morse and Feshbach ("Methods of Theoretical Physics" pp 126-127) stating…

  17. Large diffuse halos in time-dependent space-charge potentials with colored noise

    SciTech Connect

    Courtlandt Bohn and Ioannis V. Sideris

    2003-05-22

    We explore the potential impact of colored noise on space-charge-induced halo formation. By coupling particle orbits to parametric resonance, colored noise due to space-charge fluctuations and/or imperfections in the beamline can eject particles to much larger amplitudes than would be inferred from parametric resonance alone.

  18. LIFE-STAGE DEPENDENT DOSIMETRY AND POTENTIAL IMPACTS ON RISK ASSESSMENT APPROACHES

    EPA Science Inventory

    Increasingly reproductive and developmental toxicity studies are utilized in assessing the potential for adverse affects in pregnant women, nursing infants, and children. These studies largely have been utilized based upon the dose to the mother due to the complexity of describi...

  19. TEMPERATURE-DEPENDENT CHANGES IN VISUAL EVOKED POTENTIALS OF RATS (JOURNAL VERSION)

    EPA Science Inventory

    The effects of alterations in body temperature on flash and pattern reversal evoked potential (FEPs and PREPs) were examined in hooded rats whose thermoregulatory capacity was compromised with lesions of the preoptic/anterior hypothalamic area and/or cold restraint. Body temperat...

  20. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

    PubMed

    Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

    2016-06-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  1. Volume dependence of the long-range two-body potentials in various color channels by lattice QCD

    SciTech Connect

    Nakagawa, Y.; Toki, H.; Nakamura, A.; Saito, T.

    2008-02-01

    We study the color-dependent confining forces between two quarks by the quenched lattice simulations of Coulomb gauge QCD. The color-singlet and color-antitriplet instantaneous potentials yield attractive forces. The ratio of the string tensions obtained from them is approximately 2, and these tensions have little volume dependence. Meanwhile, the color-octet and color-sextet channels give a minor contribution to the two-quark system. We finally find that the infrared self-energy of the color-nonsinglet channels diverges in the infinite volume limit; however, the degree of the divergence on the finite lattice can be understood in terms of color factors.

  2. On the Josephson effect in a Bose-Einstein condensate subject to a density-dependent gauge potential

    NASA Astrophysics Data System (ADS)

    Edmonds, M. J.; Valiente, M.; Öhberg, P.

    2013-07-01

    We investigate the coherent dynamics of a Bose-Einstein condensate in a double well, subject to a density-dependent gauge potential. Further, we derive the nonlinear Josephson equations that allow us to understand the many-body system in terms of a classical Hamiltonian that describes the motion of a nonrigid pendulum with an initial angular offset. Finally we analyse the phase-space trajectories of the system, and describe how the self-trapping is affected by the presence of an interacting gauge potential.

  3. [The potential role of childhood ADHD in the development of heroin dependence at a young age].

    PubMed

    Szilágyi, Agnes; Barta, Csaba; Boór, Krisztina; Székely, Anna; Demetrovics, Zsolt; Csorba, József; Kalász, Huba; Sasvári-Székely, Mária

    2007-06-01

    Several studies suggested a possible link between substance use disorder and attention deficit hyperactivity syndrome (ADHD). The ADHD Rating Scale (ADHD-RS) completed by parents is a tool for diagnosing ADHD in childhood. We adapted this questionnaire for a self-report retrospective scale to estimate the presence of childhood ADHD symptoms in adults. This retrospective questionnaire was completed by 121 heroin dependent patients and 85 age- and sex-matched healthy controls. The ADHD Rating Scale Retrospective Questionnaire is a novel tool for assessing ADHD symptoms that demonstrated high validity. Our results showed strong gender difference in the prevalence of ADHD symptoms, since male subjects obtained higher mean scores of both attention-deficit and hyperactivity scales than females in both the control and the heroin dependent population. Besides, mean score of both scales were higher in the clinical population as a higher portion of substance abusers reported symptoms of childhood ADHD than controls. These results support the hypothesis that untreated childhood ADHD could be a risk factor for developing substance use disorder. PMID:17970529

  4. Analysis of proton scattering of stable and exotic light nuclei using an energy-dependent microscopic optical potential

    NASA Astrophysics Data System (ADS)

    Maridi, H. M.; Farag, M. Y. H.; Esmael, E. H.

    2016-01-01

    The proton elastic scattering off the 9,10,11,12Be isotopes at a wide energy range from 3 to 200 MeV/nucleon is analyzed using the optical model with the partial-wave expansion method. The microscopic optical potential (OP) is taken within the single-folding model. The density- and isospin-dependent M3YParis nucleon-nucleon (NN) interaction is used for the real part and the NN-scattering amplitude of the highenergy approximation for the imaginary one. The cross-section data are reproduced well at energies up to 100 MeV/nucleon by use of the partial-wave expansion. For higher energies, the eikonal approximation is successfully used. The volume integrals of the OP parts have systematic energy dependencies and they can be parameterized as functions of energy. From these parametrization, an energy-dependent OP can be obtained.

  5. Complex absorbing potential based Lorentzian fitting scheme and time dependent quantum transport

    SciTech Connect

    Xie, Hang Kwok, Yanho; Chen, GuanHua; Jiang, Feng; Zheng, Xiao

    2014-10-28

    Based on the complex absorbing potential (CAP) method, a Lorentzian expansion scheme is developed to express the self-energy. The CAP-based Lorentzian expansion of self-energy is employed to solve efficiently the Liouville-von Neumann equation of one-electron density matrix. The resulting method is applicable for both tight-binding and first-principles models and is used to simulate the transient currents through graphene nanoribbons and a benzene molecule sandwiched between two carbon-atom chains.

  6. Nonlinear pressure dependence of the interaction potential of dense protein solutions.

    PubMed

    Schroer, Martin A; Markgraf, Jonas; Wieland, D C Florian; Sahle, Christoph J; Möller, Johannes; Paulus, Michael; Tolan, Metin; Winter, Roland

    2011-04-29

    The influence of pressure on the structure and protein-protein interaction potential of dense protein solutions was studied and analyzed using small-angle x-ray scattering in combination with a liquid state theoretical approach. The structural as well as the interaction parameters of dense lysozyme solutions are affected by pressure in a nonlinear way. The structural properties of water lead to a modification of the protein-protein interactions below 4 kbar, which might have significant consequences for the stability of proteins in extreme natural environments. PMID:21635065

  7. Topological phases of two-component bosons in species-dependent artificial gauge potentials

    NASA Astrophysics Data System (ADS)

    Wu, Ying-Hai; Shi, Tao

    2016-08-01

    We study bosonic atoms with two internal states in artificial gauge potentials whose strengths are different for the two components. A series of topological phases for such systems is proposed using the composite fermion theory and the parton construction. It is found in exact diagonalization that some of the proposed states may be realized for simple contact interaction between bosons. The ground states and low-energy excitations of these states are modeled using trial wave functions. The effective field theories for these states are also constructed and reveal some interesting properties.

  8. Dynamic dependence of interaction potentials for keV atoms at metal surfaces

    SciTech Connect

    Schueller, A.; Adamov, G.; Wethekam, S.; Maass, K.; Mertens, A.; Winter, H.

    2004-05-01

    He and N atoms are scattered with keV energies under a grazing angle of incidence from clean and flat Ag(111) and Al(111) surfaces. For incidence along low index crystallographic directions in the surface plane, atomic projectiles are steered by rows of atoms (''axial surface channeling'') giving rise to characteristic rainbows in their angular distribution. From the analysis of this effect we derive effective scattering potentials which reveal pronounced dynamical effects. We attribute our observation to the embedding energy for penetration of atoms in the electron gas of a metal.

  9. Chemomimetic biocatalysis: exploiting the synthetic potential of cofactor-dependent enzymes to create new catalysts.

    PubMed

    Prier, Christopher K; Arnold, Frances H

    2015-11-11

    Despite the astonishing breadth of enzymes in nature, no enzymes are known for many of the valuable catalytic transformations discovered by chemists. Recent work in enzyme design and evolution, however, gives us good reason to think that this will change. We describe a chemomimetic biocatalysis approach that draws from small-molecule catalysis and synthetic chemistry, enzymology, and molecular evolution to discover or create enzymes with non-natural reactivities. We illustrate how cofactor-dependent enzymes can be exploited to promote reactions first established with related chemical catalysts. The cofactors can be biological, or they can be non-biological to further expand catalytic possibilities. The ability of enzymes to amplify and precisely control the reactivity of their cofactors together with the ability to optimize non-natural reactivity by directed evolution promises to yield exceptional catalysts for challenging transformations that have no biological counterparts. PMID:26502343

  10. Proline transport in Leishmania donovani amastigotes: dependence on pH gradients and membrane potential.

    PubMed

    Glaser, T A; Mukkada, A J

    1992-03-01

    Amastigotes of Leishmania donovani develop and multiply within the acidic phagolysosomes of mammalian macrophages. Isolated amastigotes are acidophilic; they catabolize substrates and synthesize macromolecules optimally at pH 5.5. Substrate transport in amastigotes has not been characterized. Here we show that amastigotes exhibit an uphill transport of proline (active transport) with an acid pH optimum (pH 5.5). It is dependent upon metabolic energy and is driven by proton motive force. Agents which selectively disturb the component forces of proton motive force, such as carbonyl cyanide chlorophenylhydrazone, nigericin and valinomycin, inhibit proline transport. Transport is sensitive to dicyclohexylcarbodiimide and insensitive to ouabain, demonstrating the involvement of a proton ATPase in the maintenance of proton motive force. It is suggested that the plasma membrane pH gradient probably makes the greatest contribution to proton motive force that drives substrate transport in the amastigote stage. PMID:1533014

  11. A study on temperature dependent vestibular potential: effect of long lasting thermal stimulus and aminoglycoside agent.

    PubMed

    Suzuki, M; Kadir, A; Takamoto, M; Hayashi, N; Harada, Y

    1997-03-01

    Effect of temperature changes on the vestibular receptor was studied using isolated posterior semicircular canals (PSC) of bull frogs. Cupula was removed from the crista. PSC was placed in the inner compartment of the double chamber. Warm or cool water was filled in the outer compartment to change the temperature of the inner compartment. Changes of the spontaneous discharge were recorded from the ampullary nerve. When cooled, the discharge temporarily increased, followed by a gradual decrease. When warmed, it temporarily decreased and then increased, forming response curves of a mirror image. After addition of streptomycin, the temperature dependent response disappeared. These results suggest that the semicircular canal receptor is activated by direct temperature effects. PMID:9105453

  12. Potential Biological Functions of Cytochrome P450 Reductase-dependent Enzymes in Small Intestine

    PubMed Central

    D'Agostino, Jaime; Ding, Xinxin; Zhang, Peng; Jia, Kunzhi; Fang, Cheng; Zhu, Yi; Spink, David C.; Zhang, Qing-Yu

    2012-01-01

    NADPH-cytochrome P450 reductase (POR) is essential for the functioning of microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. The biological roles of the POR-dependent enzymes in the intestine have not been defined, despite the wealth of knowledge on the biochemical properties of the various oxygenases. In this study, cDNA microarray analysis revealed significant changes in gene expression in enterocytes isolated from the small intestine of intestinal epithelium-specific Por knock-out (named IE-Cpr-null) mice compared with that observed in wild-type (WT) littermates. Gene ontology analyses revealed significant changes in terms related to P450s, transporters, cholesterol biosynthesis, and, unexpectedly, antigen presentation/processing. The genomic changes were confirmed at either mRNA or protein level for selected genes, including those of the major histocompatibility complex class II (MHC II). Cholesterol biosynthetic activity was greatly reduced in the enterocytes of the IE-Cpr-null mice, as evidenced by the accumulation of the lanosterol metabolite, 24-dihydrolanosterol. However, no differences in either circulating or enterocyte cholesterol levels were observed between IE-Cpr-null and WT mice. Interestingly, the levels of the cholesterol precursor farnesyl pyrophosphate and its derivative geranylgeranyl pyrophosphate were also increased in the enterocytes of the IE-Cpr-null mice. Furthermore, the expression of STAT1 (signal transducer and activator of transcription 1), a downstream target of geranylgeranyl pyrophosphate signaling, was enhanced. STAT1 is an activator of CIITA, the class II transactivator for MHC II expression; CIITA expression was concomitantly increased in IE-Cpr-null mice. Overall, these findings provide a novel and mechanistic link between POR-dependent enzymes and the expression of MHC II genes in the small intestine. PMID:22453923

  13. Global analysis and parametric dependencies for potential unintended hydrogen-fuel releases

    SciTech Connect

    Harstad, Kenneth; Bellan, Josette

    2006-01-01

    Global, simplified analyses of gaseous-hydrogen releases from a high-pressure vessel and liquid-hydrogen pools are conducted for two purposes: (1) establishing order-of-magnitude values of characteristic times and (2) determining parametric dependencies of these characteristic times on the physical properties of the configuration and on the thermophysical properties of hydrogen. According to the ratio of the characteristic release time to the characteristic mixing time, two limiting configurations are identified: (1) a rich cloud exists when this ratio is much smaller than unity, and (2) a jet exists when this ratio is much larger than unity. In all cases, it is found that the characteristic release time is proportional to the total released mass and inversely proportional to a characteristic area. The approximate size, convection velocity, and circulation time of unconfined burning-cloud releases scale with the cloud mass at powers 1/3, 1/6, and 1/6, respectively, multiplied by an appropriately dimensional constant; the influence of cross flow can only be important if its velocity exceeds that of internal convection. It is found that the fireball lifetime is approximately the maximum of the release time and thrice the convection-associated characteristic time. Transition from deflagration to detonation can occur only if the size of unconfined clouds exceeds by a factor of O(10) that of a characteristic detonation cell, which ranges from 0.015 m under stoichiometric conditions to approximately 1 m under extreme rich/lean conditions. For confined vapor pockets, transition occurs only for pocket sizes larger than the cell size. In jets, the release time is inversely proportional to the initial vessel pressure and has a square root dependence on the vessel temperature. Jet velocities are a factor of 10 larger than convective velocities in fireballs and combustion is possible only in the subsonic, downstream region where entrainment may occur.

  14. In vivo therapeutic potential of mesenchymal stromal cells depends on the source and the isolation procedure.

    PubMed

    Bortolotti, Francesca; Ukovich, Laura; Razban, Vahid; Martinelli, Valentina; Ruozi, Giulia; Pelos, Barbara; Dore, Franca; Giacca, Mauro; Zacchigna, Serena

    2015-03-10

    Over the last several years, mesenchymal stromal cells (MSCs) have been isolated from different tissues following a variety of different procedures. Here, we comparatively assess the ex vivo and in vivo properties of MSCs isolated from either adipose tissue or bone marrow by different purification protocols. After MSC transplantation into a mouse model of hindlimb ischemia, clinical and histological analysis revealed that bone marrow MSCs purified on adhesive substrates exerted the best therapeutic activity, preserving tissue viability and promoting formation of new arterioles without directly transdifferentiating into vascular cells. In keeping with these observations, these cells abundantly expressed cytokines involved in vessel maturation and cell retention. These findings indicate that the choice of MSC source and purification protocol is critical in determining the therapeutic potential of these cells and warrant the standardization of an optimal MSC isolation procedure in order to select the best conditions to move forward to more effective clinical experimentation. PMID:25660405

  15. Serum cyclin-dependent kinase 9 is a potential biomarker of atherosclerotic inflammation

    PubMed Central

    Han, Yeming; Zhao, Shanshan; Gong, Yaoqin; Hou, Guihua

    2016-01-01

    Atherosclerotic coronary artery disease (CAD) is one of the most prevalent diseases worldwide. Atherosclerosis was considered to be the single most important contributor to CAD. In this study, a distinct serum protein expression pattern in CAD patients was demonstrated by proteomic analysis with two-dimensional gel electrophoresis coupled with mass spectrometry. In particular, CDK9 was found to be highly elevated in serum, monocytes and artery plaque samples of CAD patients. Furthermore, there was high infiltration of CD14+ monocytes/macrophages within artery plaques correlated with the expression of CDK9. Moreover, Flavopiridol (CDK9 inhibitor) could inhibit THP-1 cell (monocytic acute leukemia cell line) proliferation by targeting CDK9. Altogether, These findings indicate that CDK9 represent an important role for inflammation in the pathogenesis of atherosclerosis. It may be a potential biomarker of atherosclerotic inflammation and offer insights into the pathophysiology and targeted therapy for atherosclerotic CAD. PMID:26636538

  16. The potential for indirect effects between co-flowering plants via shared pollinators depends on resource abundance, accessibility and relatedness.

    PubMed

    Carvalheiro, Luísa Gigante; Biesmeijer, Jacobus Christiaan; Benadi, Gita; Fründ, Jochen; Stang, Martina; Bartomeus, Ignasi; Kaiser-Bunbury, Christopher N; Baude, Mathilde; Gomes, Sofia I F; Merckx, Vincent; Baldock, Katherine C R; Bennett, Andrew T D; Boada, Ruth; Bommarco, Riccardo; Cartar, Ralph; Chacoff, Natacha; Dänhardt, Juliana; Dicks, Lynn V; Dormann, Carsten F; Ekroos, Johan; Henson, Kate S E; Holzschuh, Andrea; Junker, Robert R; Lopezaraiza-Mikel, Martha; Memmott, Jane; Montero-Castaño, Ana; Nelson, Isabel L; Petanidou, Theodora; Power, Eileen F; Rundlöf, Maj; Smith, Henrik G; Stout, Jane C; Temitope, Kehinde; Tscharntke, Teja; Tscheulin, Thomas; Vilà, Montserrat; Kunin, William E

    2014-11-01

    Co-flowering plant species commonly share flower visitors, and thus have the potential to influence each other's pollination. In this study we analysed 750 quantitative plant-pollinator networks from 28 studies representing diverse biomes worldwide. We show that the potential for one plant species to influence another indirectly via shared pollinators was greater for plants whose resources were more abundant (higher floral unit number and nectar sugar content) and more accessible. The potential indirect influence was also stronger between phylogenetically closer plant species and was independent of plant geographic origin (native vs. non-native). The positive effect of nectar sugar content and phylogenetic proximity was much more accentuated for bees than for other groups. Consequently, the impact of these factors depends on the pollination mode of plants, e.g. bee or fly pollinated. Our findings may help predict which plant species have the greatest importance in the functioning of plant-pollination networks. PMID:25167890

  17. Dependence of electrostatic potential distribution of Al2O3/Ge structure on Al2O3 thickness

    NASA Astrophysics Data System (ADS)

    Wang, Xiaolei; Xiang, Jinjuan; Wang, Wenwu; Zhao, Chao; Zhang, Jing

    2016-09-01

    Electrostatic potential distribution of Al2O3/Ge structure is investigated vs. Al2O3 thickness by X-ray photoelectron spectroscopy (XPS). The electrostatic potential distribution is found to be Al2O3 thickness dependent. This interesting phenomenon is attributed to the appearance of gap states on Al2O3 surface (GSAl2O3) and its higher charge neutrality level (CNL) compared with the CNL of gap states at Al2O3/Ge interface (GSAl2O3/Ge), leading to electron transfer from GSAl2O3 to GSAl2O3/Ge. In the case of thicker Al2O3, fewer electrons transfer from GSAl2O3 to GSAl2O3/Ge, resulting in a larger potential drop across Al2O3 and XPS results.

  18. Dependency of global primary bioenergy crop potentials in 2050 on food systems, yields, biodiversity conservation and political stability

    PubMed Central

    Erb, Karl-Heinz; Haberl, Helmut; Plutzar, Christoph

    2012-01-01

    The future bioenergy crop potential depends on (1) changes in the food system (food demand, agricultural technology), (2) political stability and investment security, (3) biodiversity conservation, (4) avoidance of long carbon payback times from deforestation, and (5) energy crop yields. Using a biophysical biomass-balance model, we analyze how these factors affect global primary bioenergy potentials in 2050. The model calculates biomass supply and demand balances for eleven world regions, eleven food categories, seven food crop types and two livestock categories, integrating agricultural forecasts and scenarios with a consistent global land use and NPP database. The TREND scenario results in a global primary bioenergy potential of 77 EJ/yr, alternative assumptions on food-system changes result in a range of 26–141 EJ/yr. Exclusion of areas for biodiversity conservation and inaccessible land in failed states reduces the bioenergy potential by up to 45%. Optimistic assumptions on future energy crop yields increase the potential by up to 48%, while pessimistic assumptions lower the potential by 26%. We conclude that the design of sustainable bioenergy crop production policies needs to resolve difficult trade-offs such as food vs. energy supply, renewable energy vs. biodiversity conservation or yield growth vs. reduction of environmental problems of intensive agriculture. PMID:23576836

  19. Urinary Bladder-Relaxant Effect of Kurarinone Depending on Potentiation of Large-Conductance Ca2+-Activated K+ Channels.

    PubMed

    Lee, Sojung; Chae, Mee Ree; Lee, Byoung-Cheol; Kim, Yong-Chul; Choi, Jae Sue; Lee, Sung Won; Cheong, Jae Hoon; Park, Chul-Seung

    2016-08-01

    The large-conductance calcium-activated potassium channel (BKCa channel) plays critical roles in smooth muscle relaxation. In urinary bladder smooth muscle, BKCa channel activity underlies the maintenance of the resting membrane potential and repolarization of the spontaneous action potential triggering the phasic contraction. To identify novel BKCa channel activators, we screened a library of natural compounds using a cell-based fluorescence assay and a hyperactive mutant BKCa channel (Lee et al., 2013). From 794 natural compounds, kurarinone, a flavanone from Sophora flavescens, strongly potentiated BKCa channels. When treated from the extracellular side, this compound progressively shifted the conductance-voltage relationship of BKCa channels to more negative voltages and increased the maximum conductance in a dose-dependent manner. Whereas kurarinone strongly potentiated the homomeric BKCa channel composed of only the α subunit, its effects were much smaller on heteromeric channels coassembled with auxiliary β subunits. Although the activation kinetics was not altered significantly, the deactivation of BKCa channels was dramatically slowed by kurarinone treatment. At the single-channel level, kurarinone increased the open probability of the BKCa channel without affecting its single-channel conductance. Kurarinone potently relaxed acetylcholine-induced contraction of rat bladder smooth muscle and thus decreased the micturition frequency of rats with overactive bladder symptoms. These results indicate that kurarinone can directly potentiate BKCa channels and demonstrate the therapeutic potentials of kurarinone and its derivatives for developing antioveractive bladder medications and supplements. PMID:27251362

  20. Dependence Potential of the Synthetic Cannabinoids JWH-073, JWH-081, and JWH-210: In Vivo and In Vitro Approaches.

    PubMed

    Cha, Hye Jin; Lee, Kwang-Wook; Song, Min-Ji; Hyeon, Yang-Jin; Hwang, Ji-Young; Jang, Choon-Gon; Ahn, Joon-Ik; Jeon, Seol-Hee; Kim, Hyun-Uk; Kim, Young-Hoon; Seong, Won-Keun; Kang, Hoil; Yoo, Han Sang; Jeong, Ho-Sang

    2014-07-01

    Synthetic cannabinoids (CBs) such as the JWH series have caused social problems concerning their abuse liability. Because the JWH series produces euphoric and hallucinogenic effects, they have been distributed illegally under street names such as "Spice" and "Smoke". Many countries including Korea have started to schedule some of the JWH series compounds as controlled substances, but there are a number of JWH series chemicals that remain uncontrolled by law. In this study, three synthetic CBs with different binding affinities to the CB1 receptor (JWH-073, 081, and 210) and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) were evaluated for their potential for psychological dependence. The conditioned place preference test (unbiased method) and self-administration test (fixed ratio of 1) using rodents were conducted. Ki values of the three synthetic cannabinoids were calculated as supplementary data using a receptor binding assay and overexpressed CB1 protein membranes to compare dependence potential with CB1 receptor binding affinity. All mice administered JWH-073, 081, or 210 showed significantly increased time spent at unpreferred space in a dose-dependence manner in the conditioned place preference test. In contrast, all tested substances except Δ(9)-THC showed aversion phenomenon at high doses in the conditioned place preference test. The order of affinity to the CB1 receptor in the receptor binding assay was JWH-210 > JWH-081 > JWH-073, which was in agreement with the results from the conditioned place preference test. However, no change in self-administration was observed. These findings suggest the possibility to predict dependence potential of synthetic CBs through a receptor binding assay at the screening level. PMID:25143817

  1. Potentiation of NF-κB-dependent transcription and inflammatory mediator release by histamine in human airway epithelial cells

    PubMed Central

    Holden, N S; Gong, W; King, E M; Kaur, M; Giembycz, M A; Newton, R

    2007-01-01

    Background and purpose: In asthma, histamine contributes to bronchoconstriction, vasodilatation and oedema, and is associated with the late phase response. The current study investigates possible inflammatory effects of histamine acting on nuclear factor κB (NF-κB)-dependent transcription and cytokine release. Experimental approach: Using BEAS-2B bronchial epithelial cells, NF-κB-dependent transcription and both release and mRNA expression of IL-6 and IL-8 were examined by reporter assay, ELISA and quantitative RT-PCR. Histamine receptors were detected using qualitative RT-PCR and function examined using selective agonists and antagonists. Key results: Addition of histamine to TNFα-stimulated BEAS-2B cells maximally potentiated NF-κB-dependent transcription 1.8 fold, whereas IL-6 and IL-8 protein release were enhanced 7.3- and 2.7-fold respectively. These responses were, in part, NF-κB-dependent and were associated with 2.6- and 1.7-fold enhancements of IL-6 and IL-8 mRNA expression. The H1 receptor antagonist, mepyramine, caused a rightward shift in the concentration-response curves of TNFα-induced NF-κB-dependent transcription (pA2=9.91) and release of IL-6 (pA2=8.78) and IL-8 (pA2=8.99). Antagonists of histamine H2, H3 and H4 receptors were without effect. Similarly, H3 and H4 receptor agonists did not affect TNFα-induced NF-κB-dependent transcription, or IL-6 and IL-8 release at concentrations below 10 μM. The anti-inflammatory glucocorticoid, dexamethasone, inhibited the histamine enhanced NF-κB-dependent transcription and IL-6 and IL-8 release. Conclusions and implications: Potentiation of NF-κB-dependent transcription and inflammatory cytokine release by histamine predominantly involves receptors of the H1 receptor subtype. These data support an anti-inflammatory role for H1 receptor antagonists by preventing the transcription and release of pro-inflammatory cytokines. PMID:17891168

  2. Eye color: A potential indicator of alcohol dependence risk in European Americans.

    PubMed

    Sulovari, Arvis; Kranzler, Henry R; Farrer, Lindsay A; Gelernter, Joel; Li, Dawei

    2015-07-01

    In archival samples of European-ancestry subjects, light-eyed individuals have been found to consume more alcohol than dark-eyed individuals. No published population-based studies have directly tested the association between alcohol dependence (AD) and eye color. We hypothesized that light-eyed individuals have a higher prevalence of AD than dark-eyed individuals. A mixture model was used to select a homogeneous sample of 1,263 European-Americans and control for population stratification. After quality control, we conducted an association study using logistic regression, adjusting for confounders (age, sex, and genetic ancestry). We found evidence of association between AD and blue eye color (P = 0.0005 and odds ratio = 1.83 (1.31-2.57)), supporting light eye color as a risk factor relative to brown eye color. Network-based analyses revealed a statistically significant (P = 0.02) number of genetic interactions between eye color genes and AD-associated genes. We found evidence of linkage disequilibrium between an AD-associated GABA receptor gene cluster, GABRB3/GABRG3, and eye color genes, OCA2/HERC2, as well as between AD-associated GRM5 and pigmentation-associated TYR. Our population-phenotype, network, and linkage disequilibrium analyses support association between blue eye color and AD. Although we controlled for stratification we cannot exclude underlying occult stratification as a contributor to this observation. Although replication is needed, our findings suggest that eye pigmentation information may be useful in research on AD. Further characterization of this association may unravel new AD etiological factors. © 2015 Wiley Periodicals, Inc. PMID:25921801

  3. Synthesis of an enzyme-dependent prodrug and evaluation of its potential for colon targeting

    PubMed Central

    Pang, Yi-Nuo; Zhang, Yan; Zhang, Zhi-Rong

    2002-01-01

    AIM: To synthesize dexamethasone-succinate-dextran (DSD) conjugate and to evaluate the potentiality of DSD for the treatment of inflammatory bowel diseases. METHODS: Dexamethasone was attached to dextran (average molecular weight = 70400 Dalton) using succinate anhydride in an anhydrous environment catalyzed by 4-dimethylaminopyridine and 1,1’-carbonyldiimidazole. The chemical structure of DSD was identified by UV, IR and NMR, and the in vivo drug release behavior of this prodrug was investigated after oral administration of DSD suspension. RESULTS: The DSD conjugate was obtained in two steps and the content of dexamethasone in DSD was 11.28%. The dextran prodrug was stable in rat stomach and small intestine and negligibly absorbed from these tracts. Four to nine hours after the oral administration, most of the prodrug (> 95%) had moved to the cecum and colon, and was easily hydrolyzed by an endodextranase. Recover of dexamethasone from colon and cecum after administration of DSD conjugate was 6-12 folds higher than the recovery after administration of unmodified dexamethasone (t = 2.74, P < 0.05). The preferential release of free dexamethasone in cecum and colon over that in the small intestine was statistically significant (t = 2.27, P < 0.05). CONCLUSION: The results of this study indicate that dextran conjugates may be useful in selectively delivering glucocorticoids to the colon. PMID:12378641

  4. Potentiation of swim analgesia by D-amino acids in mice is genotype dependent.

    PubMed

    Panocka, I; Sadowski, B

    1990-12-01

    The effect of combined treatment with 125 mg/kg of D-phenylalanine plus 125 mg/kg of D-leucine (IP) on magnitude and duration of analgesia caused by 3 min swim at 20 degrees C was studied in mouse lines selectively bred for 20 generations toward high and low level of stress-induced analgesia. The D-amino acids administered 30 min prior to swimming increased postswim tail-flick latencies and prolonged antinociception more in the high analgesia line (HA) than in concomitantly bred unselected controls, but were not effective in the low analgesia line (LA). The potentiation of swim analgesia by D-amino acids was prevented by simultaneous administration of 1 mg/kg of naloxone hydrochloride which, given alone, antagonized the analgesia more in the HA line than in controls, but not in the LA line. The results are interpreted in terms of genetic differentiation of opioidergic transmission in the selectively bred mouse lines. PMID:2093164

  5. Age dependent changes of distractibility and reorienting of attention revisited: an event-related potential study.

    PubMed

    Berti, Stefan; Grunwald, Martin; Schröger, Erich

    2013-01-23

    Adults of three age groups (18-27, 39-45, and 59-66 years) performed an auditory duration discrimination task with short (200 ms) or long (400 ms) sinusoidal tones. Performance was highly accurate and reaction times were on the same level in all groups, indicating no differences in auditory duration processing. Task irrelevant rare changes of the frequency of the stimuli were introduced to check whether the subjects, firstly, were distracted by changes in the environment while focusing on the task relevant information (indicated by prolonged responses), and, secondly, could re-focus on the relevant task after distraction. The results show that a distraction effect is present in all groups. Importantly, the 59-66 years group showed a behavioral distraction effect nearly twice as high as the other groups. The event-related brain potentials (ERPs) show mismatch negativity (MMN), P3a, and reorienting negativity (RON) elicited by deviants which are present in all groups. Aging effects on these ERP components were observable in all three components but a revealed a weak significant effect for the MMN only. Taken together, the behavioral and ERP results suggest that the function of balancing the processing of task irrelevant changes in the stimulation while focusing on task relevant information is effective during adulthood until the 7th decade of life. PMID:23159833

  6. The ozone depletion potentials on halocarbons: Their dependence of calculation assumptions

    NASA Technical Reports Server (NTRS)

    Karol, Igor L.; Kiselev, Andrey A.

    1994-01-01

    The concept of Ozone Depletion Potential (ODP) is widely used in the evaluation of numerous halocarbons and of their replacement effects on ozone, but the methods, assumptions and conditions used in ODP calculations have not been analyzed adequately. In this paper a model study of effects on ozone of the instantaneous releases of various amounts of CH3CCl3 and of CHF2Cl (HCFC-22) for several compositions of the background atmosphere are presented, aimed at understanding connections of ODP values with the assumptions used in their calculations. To facilitate the ODP computation in numerous versions for the long time periods after their releases, the above rather short-lived gases and the one-dimensional radiative photochemical model of the global annually averaged atmospheric layer up to 50 km height are used. The variation of released gas global mass from 1 Mt to 1 Gt leads to ODP value increase with its stabilization close to the upper bound of this range in the contemporary atmosphere. The same variations are analyzed for conditions of the CFC-free atmosphere of 1960's and for the anthropogenically loaded atmosphere in the 21st century according to the known IPCC 'business as usual' scenario. Recommendations for proper ways of ODP calculations are proposed for practically important cases.

  7. Time-Dependent Effect of Encapsulating Alginate Hydrogel on Neurogenic Potential

    PubMed Central

    Razavi, Shahnaz; Khosravizadeh, Zahra; Bahramian, Hamid; Kazemi, Mohammad

    2015-01-01

    Objective Due to the restricted potential of neural stem cells for regeneration of central nervous system (CNS) after injury, providing an alternative source for neural stem cells is essential. Adipose derived stem cells (ADSCs) are multipotent cells with properties suitable for tissue engineering. In addition, alginate hydrogel is a biocompatible polysaccharide polymer that has been used to encapsulate many types of cells. The aim of this study was to assess the proliferation rate and level of expression of neural markers; NESTIN, glial fibrillary acidic protein (GFAP) and microtubule-associated protein 2 (MAP2) in encapsulated human ADSCs (hADSCs) 10 and14 days after neural induction. Materials and Methods In this experimental study, ADSCs isolated from human were cultured in neural induction media and seeded into alginate hydrogel. The rate of proliferation and differentiation of encapsulated cells were evaluated by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay, immunocytoflourescent and realtime reverse transcriptase polymerase chain reaction (RT-PCR) analyzes 10 and 14 days after induction. Results The rate of proliferation of encapsulated cells was not significantly changed with time passage. The expression of NESTIN and GFAP significantly decreased on day 14 relative to day 10 (P<0.001) but MAP2 expression was increased. Conclusion Alginate hydrogel can promote the neural differentiation of encapsulated hADSCs with time passage. PMID:26199909

  8. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

    PubMed Central

    Lu, Simin; Kanekura, Kohsuke; Hara, Takashi; Mahadevan, Jana; Spears, Larry D.; Oslowski, Christine M.; Martinez, Rita; Yamazaki-Inoue, Mayu; Toyoda, Masashi; Neilson, Amber; Blanner, Patrick; Brown, Cris M.; Semenkovich, Clay F.; Marshall, Bess A.; Hershey, Tamara; Umezawa, Akihiro; Greer, Peter A.; Urano, Fumihiko

    2014-01-01

    Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases. PMID:25422446

  9. Dynamics of matter-wave solitons in Bose-Einstein condensates with time-dependent scattering length and complex potentials

    NASA Astrophysics Data System (ADS)

    Kengne, Emmanuel; Shehou, Abdourahman; Lakhssassi, Ahmed

    2016-03-01

    We investigate the dynamics of matter-wave solitons in the one-dimensional (1-D) Gross-Pitaevskii (GP) equation describing Bose-Einstein condensates (BECs) with time-dependent scattering length in varying trapping potentials with feeding/loss term. By performing a modified lens-type transformation, we reduce the GP equation into a classical nonlinear Schrödinger (NLS) equation with distributed coefficients and find its integrable condition. Under the integrable condition, we apply the generalized Jacobian elliptic function method (GJEFM) and present exact analytical solutions which describe the propagation of a bright and dark solitons in BECs. Their stability is examined using analytic method. The obtained exact solutions show that the amplitude of bright and dark solitons depends on the scattering length, while their motion and the total number of BEC atoms depend on the external trapping potential. Our results also shown that the loss of atoms can dominate the aggregation of atoms by the attractive interaction, and thus the peak density can decrease in time despite that the strength of the attractive interaction is increased.

  10. Generation of matter-wave solitons of the Gross-Pitaevskii equation with a time-dependent complicated potential

    SciTech Connect

    Mohamadou, Alidou; Wamba, Etienne; Kofane, Timoleon C.; Doka, Serge Y.; Ekogo, Thierry B.

    2011-08-15

    We examine the generation of bright matter-wave solitons in the Gross-Pitaevskii equation describing Bose-Einstein condensates with a time-dependent complex potential, which is composed of a repulsive parabolic background potential and a gravitational field. By performing a modified lens-type transformation, an explicit expression for the growth rate of a purely growing modulational instability is presented and analyzed. We point out the effects of the gravitational field, as well as of the parameter related to the feeding or loss of atoms in the condensate, on the instability growth rate. It is evident from numerical simulations that the feeding with atoms and the magnetic trap have opposite effects on the dynamics of the system. It is shown that the feeding or loss parameter can be well used to control the instability domain. Our study shows that the gravitational field changes the condensate trail of the soliton trains during the propagation. We also perform a numerical analysis to solve the Gross-Pitaevskii equation with a time-dependent complicated potential. The numerical results on the effect of both the gravitational field and the parameter of feeding or loss of atoms in the condensate agree well with predictions of the linear stability analysis. Another result of the present work is the modification of the background wave function in the Thomas-Fermi approximation during the numerical simulations.

  11. A plant alkaloid, veratridine, potentiates cancer chemosensitivity by UBXN2A-dependent inhibition of an oncoprotein, mortalin-2

    PubMed Central

    Abdullah, Ammara; Sane, Sanam; Branick, Kate A.; Freeling, Jessica L.; Wang, Hongmin; Zhang, Dong; Rezvani, Khosrow

    2015-01-01

    Veratridine (VTD), an alkaloid derived from the Liliaceae plant shows anti-tumor effects; however, its molecular targets have not been thoroughly studied. Using a high-throughput drug screen, we found that VTD enhances transactivation of UBXN2A, resulting in upregulation of UBXN2A in the cytoplasm, where UBXN2A binds and inhibits the oncoprotein mortalin-2 (mot-2). VTD-treated cancer cells undergo cell death in UBXN2A- and mot-2-dependent manners. The cytotoxic function of VTD is grade-dependent, and the combined treatment with a sub-optimal dose of the standard chemotherapy, 5-Fluorouracil (5-FU) and etoposide, demonstrated a synergistic effect, resulting in higher therapeutic efficacy. VTD influences the CD44+ stem cells, possibly through UBXN2A-dependent inhibition of mot-2. The VTD-dependent expression of UBXN2A is a potential candidate for designing novel strategies for colon cancer treatment because: 1) In 50% of colon cancer patients, UBXN2A protein levels in tumor tissues are significantly lower than those in the adjacent normal tissues. 2) Cytoplasmic expression of the mot-2 protein is very low in non-cancerous cells; thus, VTD can produce tumor-specific toxicity while normal cells remain intact. 3) Finally, VTD or its modified analogs offer a valuable adjuvant chemotherapy strategy to improve the efficacy of 5-FU-based chemotherapy for colon cancer patients harboring WT-p53. PMID:26188124

  12. Dependence of Na+ pump current on external monovalent cations and membrane potential in rabbit cardiac Purkinje cells.

    PubMed Central

    Bielen, F V; Glitsch, H G; Verdonck, F

    1991-01-01

    1. The effect of membrane potential and various extracellular monovalent cations on the Na+ pump current (Ip) was studied on isolated, single Purkinje cells of the rabbit heart by means of whole-cell recording. 2. Ip was identified as current activated by external K+ or its congeners NH4+ and Tl+. The current was blocked by dihydroouabain (1-5 x 10(-4) M) over the whole range of membrane potentials tested. 3. In Na(+)-containing solution half-maximum Ip activation (K0.5) occurred at 0.4 mM-Tl+, 1.9 mM-K+ and 5.7 mM-NH4+ (holding potential, -20 mV). 4. The pump current (Ip)-voltage (V) relationship of the cells in Na(+)-containing media with K+ or its congeners at the tested concentrations greater than K0.5 displayed a steep positive slope at negative membrane potentials between -120 and -20 mV. Little voltage dependence of Ip was observed at more positive potentials up to +40 mV. At even more positive potentials Ip measured at 2 and 5.4 mM-K+ decreased. 5. Lowering the concentration of K+ or its congeners below the K0.5 value in Na(+)-containing solution induced a region of negative slope of the Ip-V curve at membrane potentials positive to -20 mV. 6. The shape of the Ip-V relationship remained unchanged when the K+ concentration (5.4 mM) of the Na(+)-containing medium was replaced by NH4+ or Tl+ concentrations of similar potency to activate Ip (20 mM-NH4+ or 2 mM-Tl+). 7. In Na(+)-free, choline-containing solution half-maximum Ip activation occurred at 0.13 mM-K+ (holding potential, -20 mV). 8. At negative membrane potentials the positive slope of the Ip-V curve was flatter in Na(+)-free than in Na(+)-containing media. A reduced voltage dependence of Ip persisted, regardless of whether choline ions or Li+ were used as a Na+ substitute. 9. Lowering the K+ concentration of the Na(+)-free, choline-containing solution to 0.05 mM evoked an extended region of negative slope in the Ip-V relationship at membrane potentials between -40 and +60 mV. 10. It is concluded that

  13. Time-dependent self-trapping of Bose-Einstein condensates in a double-well potential

    SciTech Connect

    Cui, B.; Wang, L. C.; Yi, X. X.

    2010-12-15

    Based on the mean-field approximation and a phase-space analysis, we discuss the dynamics of Bose-Einstein condensates (BECs) in a double-well potential. The condensates are found to be trapped in the time-dependent eigenstates of the effective Hamiltonian; we refer to this effect as time-dependent self-trapping of BECs. By comparison of this self-trapping with the adiabatic evolution, we find that adiabatic evolution beyond the traditional adiabatic condition can be achieved in BECs. Furthermore, the population imbalance of the BECs in the wells can be controlled by manipulating the atom-atom couplings and the driving field. The fixed points for the system are also calculated and discussed.

  14. Excited-state nuclear forces on adiabatic potential-energy surfaces by time-dependent density-functional theory

    NASA Astrophysics Data System (ADS)

    Haruyama, Jun; Suzuki, Takahiro; Hu, Chunping; Watanabe, Kazuyuki

    2012-01-01

    We present a simple and computationally efficient method to calculate excited-state nuclear forces on adiabatic potential-energy surfaces (APES) from linear-response time-dependent density-functional theory within a real-space framework. The Casida ansatz, which has been validated for computing first-order nonadiabatic couplings in previous studies, was applied to the calculation of the excited-state forces. Our method is validated by the consistency of results in the lower excited states, which reproduce well those obtained by the numerical derivative of each APES. We emphasize the usefulness of this technique by demonstrating the excited-state molecular-dynamics simulation.

  15. Frequency-dependent streaming potential of porous media: Experimental measurement of Ottawa sand, Lochaline sand and quartz glass beads

    NASA Astrophysics Data System (ADS)

    Glover, Paul; Walker, Emilie; Ruel, Jean; Yagout, Fuad

    2013-04-01

    High quality frequency-dependent streaming potential coefficient measurements have been made upon Ottawa sand, Lochaline sand and glass bead packs using a new apparatus that is based on an electro-magnetic drive. The apparatus operates in the range 1 Hz to 1 kHz with samples of 25.4mm diameter up to 150 mm long. The results have been analysed using theoretical models that are either (i) based upon vibrational mechanics, (ii) treat the geological material as a bundle of capillary tubes, or (iii) treat the material as a porous medium. In each case we have considered the real and imaginary parts of the complex streaming potential coefficient as well as its magnitude. It is clear from the results that the complex streaming potential coefficient does not follow a Debye-type behaviour, differing from the Debye-type behaviour most markedly for frequencies above the transition frequency. The best fit to all the data was provided by the Pride (1994) model and its simplification by Walker and Glover (2010), which is satisfying as this model was conceived for porous media rather than capillary tube bundles. Theory predicts that the transition frequency is related to the inverse square of the effective pore radius. Values for the transition frequency were derived from each of the models for each sample and were found to be in good agreement with those expected from the independently measured effective pore radius of each material. The fit to the Pride model for all four samples was also found to be consistent with the independently measured steady-state permeability, while the value of the streaming potential coefficient in the low-frequency limit was found to be in good agreement with steady-state streaming potential coefficient data measured using a steady-state streaming potential rig as well as the corpus of steady-state determinations for quartz-based samples existing in the literature.

  16. Cathodic Potential Dependence of Electrochemical Reduction of SiO2 Granules in Molten CaCl2

    NASA Astrophysics Data System (ADS)

    Yang, Xiao; Yasuda, Kouji; Nohira, Toshiyuki; Hagiwara, Rika; Homma, Takayuki

    2016-05-01

    As part of an ongoing fundamental study to develop a new process for producing solar-grade silicon, this paper examines the effects of cathodic potential on reduction kinetics, current efficiency, morphology, and purity of Si product during electrolysis of SiO2 granules in molten CaCl2 at 1123 K (850 °C). SiO2 granules were electrolyzed potentiostatically at different cathodic potentials (0.6, 0.8, 1.0, and 1.2 V vs Ca2+/Ca). The reduction kinetics was evaluated based on the growth of the reduced Si layer and the current behavior during electrolysis. The results suggest that a more negative cathodic potential is favorable for faster reduction. Current efficiencies in 60 minutes are greater than 65 pct at all the potentials examined. Si wires with sub-micron diameters are formed, and their morphologies show little dependence on the cathodic potential. The impurities in the Si product can be controlled at low level. The rate-determining step for the electrochemical reduction of SiO2 granules in molten CaCl2 changes with time. At the initial stage of electrolysis, the electron transfer is the rate-determining step. At the later stage, the diffusion of O2- ions is the rate-determining step. The major cause of the decrease in reduction rate with increasing electrolysis time is the potential drop from the current collector to the reaction front due to the increased contact resistance among the reduced Si particles.

  17. Expression of a mitochondrial progesterone receptor in human spermatozoa correlates with a progestin-dependent increase in mitochondrial membrane potential.

    PubMed

    Tantibhedhyangkul, J; Hawkins, K C; Dai, Q; Mu, K; Dunn, C N; Miller, S E; Price, T M

    2014-11-01

    The hyperactivation of human spermatozoa necessary for fertilization requires a substantial increase in cellular energy production. The factors responsible for increasing cellular energy remain poorly defined. This article proposes a role for a novel mitochondrial progesterone receptor (PR-M) in modulation of mitochondrial activity. Basic science studies demonstrate a 38 kDa protein with western blot analysis, consistent with PR-M; whereas imaging studies with confocal and immunoelectron microscopy demonstrate a PR on the mitochondria. Treatment with a PR-specific progestin shows increased mitochondrial membrane potential, not related to induction of an acrosome reaction. The increase in mitochondrial membrane potential was inhibited by a specific PR antagonist, but not affected by an inhibitor to the progesterone-dependent Catsper voltage-activated channel. In conclusion, these studies suggest expression of a novel mitochondrial PR in human spermatozoa with a progestin-dependent increase in mitochondrial activity. This mechanism may serve to enhance cellular energy production as the spermatozoa traverse the female genital tract being exposed to increasing concentrations of progesterone. PMID:25187426

  18. Posttetanic potentiation critically depends on an enhanced Ca2+ sensitivity of vesicle fusion mediated by presynaptic PKC

    PubMed Central

    Korogod, Natalya; Lou, Xuelin; Schneggenburger, Ralf

    2007-01-01

    Activity-dependent enhancement of transmitter release is a common form of presynaptic plasticity, but the underlying signaling mechanisms have remained largely unknown, perhaps because of the inaccessibility of most CNS nerve terminals. Here we investigated the signaling steps that underlie posttetanic potentiation (PTP), a form of presynaptic plasticity found at many CNS synapses. Direct whole-cell recordings from the large calyx of Held nerve terminals with the perforated patch-clamp technique showed that PTP was not mediated by changes in the presynaptic action potential waveform. Ca2+ imaging revealed a slight increase of the presynaptic Ca2+ transient during PTP (≈15%), which, however, was too small to explain a large part of PTP. The presynaptic PKC pathway was critically involved in PTP because (i) PTP was occluded by activation of PKC with phorbol esters, and (ii) PTP was largely (by approximately two-thirds) blocked by the PKC inhibitors, Ro31-8220 or bisindolylmaleimide. Activation of PKC during PTP most likely acts directly on the presynaptic release machinery, because in presynaptic Ca2+ uncaging experiments, activation of PKC by phorbol ester greatly increased the Ca2+ sensitivity of vesicle fusion in a Ro31-8220-sensitive manner (≈300% with small Ca2+ uncaging stimuli), but only slightly increased presynaptic voltage-gated Ca2+ currents (≈15%). We conclude that a PKC-dependent increase in the Ca2+ sensitivity of vesicle fusion is a key step in the enhancement of transmitter release during PTP. PMID:17884983

  19. Brownian motion in time-dependent logarithmic potential: Exact results for dynamics and first-passage properties.

    PubMed

    Ryabov, Artem; Berestneva, Ekaterina; Holubec, Viktor

    2015-09-21

    The paper addresses Brownian motion in the logarithmic potential with time-dependent strength, U(x, t) = g(t)log(x), subject to the absorbing boundary at the origin of coordinates. Such model can represent kinetics of diffusion-controlled reactions of charged molecules or escape of Brownian particles over a time-dependent entropic barrier at the end of a biological pore. We present a simple asymptotic theory which yields the long-time behavior of both the survival probability (first-passage properties) and the moments of the particle position (dynamics). The asymptotic survival probability, i.e., the probability that the particle will not hit the origin before a given time, is a functional of the potential strength. As such, it exhibits a rather varied behavior for different functions g(t). The latter can be grouped into three classes according to the regime of the asymptotic decay of the survival probability. We distinguish 1. the regular (power-law decay), 2. the marginal (power law times a slow function of time), and 3. the regime of enhanced absorption (decay faster than the power law, e.g., exponential). Results of the asymptotic theory show good agreement with numerical simulations. PMID:26395697

  20. pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development.

    PubMed

    Zhang, L; Wu, F; Lee, S C; Zhao, H; Zhang, L

    2014-08-01

    Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated. PMID:24733008

  1. Variability in projected elevation dependent warming in boreal midlatitude winter in CMIP5 climate models and its potential drivers

    NASA Astrophysics Data System (ADS)

    Rangwala, Imtiaz; Sinsky, Eric; Miller, James R.

    2016-04-01

    The future rate of climate change in mountains has many potential human impacts, including those related to water resources, ecosystem services, and recreation. Analysis of the ensemble mean response of CMIP5 global climate models (GCMs) shows amplified warming in high elevation regions during the cold season in boreal midlatitudes. We examine how the twenty-first century elevation-dependent response in the daily minimum surface air temperature [d(ΔTmin)/dz] varies among 27 different GCMs during winter for the RCP 8.5 emissions scenario. The focus is on regions within the northern hemisphere mid-latitude band between 27.5°N and 40°N, which includes both the Rocky Mountains and the Tibetan Plateau/Himalayas. We find significant variability in d(ΔTmin)/dz among the individual models ranging from 0.16 °C/km (10th percentile) to 0.97 °C/km (90th percentile), although nearly all of the GCMs (24 out of 27) show a significant positive value for d(ΔTmin)/dz. To identify some of the important drivers associated with the variability in d(ΔTmin)/dz during winter, we evaluate the co-variance between d(ΔTmin)/dz and the differential response of elevation-based anomalies in different climate variables as well as the GCMs' spatial resolution, their global climate sensitivity, and their elevation-dependent free air temperature response. We find that d(ΔTmin)/dz has the strongest correlation with elevation-dependent increases in surface water vapor, followed by elevation-dependent decreases in surface albedo, and a weak positive correlation with the GCMs' free air temperature response.

  2. Recombinant NAD-dependent SIR-2 Protein of Leishmania donovani: Immunobiochemical Characterization as a Potential Vaccine against Visceral Leishmaniasis

    PubMed Central

    Baharia, Rajendra K; Tandon, Rati; Sharma, Tanuj; Suthar, Manish K; Das, Sanchita; Siddiqi, Mohammad Imran; Saxena, Jitendra Kumar; Sunder, Shyam; Dube, Anuradha

    2015-01-01

    Background The development of a vaccine conferring long-lasting immunity remains a challenge against visceral leishmaniasis (VL). Immunoproteomic characterization of Leishmania donovani proteins led to the identification of a novel protein NAD+-dependent Silent Information regulatory-2 (SIR2 family or sirtuin) protein (LdSir2RP) as one of the potent immunostimulatory proteins. Proteins of the SIR2 family are characterized by a conserved catalytic domain that exerts unique NAD-dependent deacetylase activity. In the present study, an immunobiochemical characterization of LdSir2RP and further evaluation of its immunogenicity and prophylactic potential was done to assess for its possible involvement as a vaccine candidate against leishmaniasis. Methodology/Principal Findings LdSir2RP was successfully cloned, expressed and purified. The gene was present as a monomeric protein of ~45 kDa and further established by the crosslinking experiment. rLdSir2RP shown cytosolic localization in L. donovani and demonstrating NAD+-dependent deacetylase activity. Bioinformatic analysis also confirmed that LdSir2RP protein has NAD binding domain. The rLdSir2RP was further assessed for its cellular response by lymphoproliferative assay and cytokine ELISA in cured Leishmania patients and hamsters (Mesocricetus auratus) in comparison to soluble Leishmania antigen and it was observed to stimulate the production of IFN-γ, IL-12 and TNF-α significantly but not the IL-4 and IL-10. The naïve hamsters when vaccinated with rLdSir2RP alongwith BCG resisted the L. donovani challenge to the tune of ~75% and generated strong IL-12 and IFN-γ mediated Th1 type immune response thereof. The efficacy was further supported by remarkable increase in IgG2 antibody level which is indicative of Th1 type of protective response. Further, with a possible implication in vaccine design against VL, identification of potential T-cell epitopes of rLdSir2RP was done using computational approach. Conclusion

  3. Raft-Dependent Endocytosis of Autocrine Motility Factor/Phosphoglucose Isomerase: A Potential Drug Delivery Route for Tumor Cells

    PubMed Central

    Kojic, Liliana D.; Wiseman, Sam M.; Ghaidi, Fariba; Joshi, Bharat; Nedev, Hinyu; Saragovi, H. Uri; Nabi, Ivan R.

    2008-01-01

    Background Autocrine motility factor/phosphoglucose isomerase (AMF/PGI) is the extracellular ligand for the gp78/AMFR receptor overexpressed in a variety of human cancers. We showed previously that raft-dependent internalization of AMF/PGI is elevated in metastatic MDA-435 cells, but not metastatic, caveolin-1-expressing MDA-231 cells, relative to non-metastatic MCF7 and dysplastic MCF10A cells suggesting that it might represent a tumor cell-specific endocytic pathway. Methodology/Principal Findings Similarly, using flow cytometry, we demonstrate that raft-dependent endocytosis of AMF/PGI is increased in metastatic HT29 cancer cells expressing low levels of caveolin-1 relative to metastatic, caveolin-1-expressing, HCT116 colon cells and non-metastatic Caco-2 cells. Therefore, we exploited the raft-dependent internalization of AMF/PGI as a potential tumor-cell specific targeting mechanism. We synthesized an AMF/PGI-paclitaxel conjugate and found it to be as efficient as free paclitaxel in inducing cytotoxicity and apoptosis in tumor cells that readily internalize AMF/PGI compared to tumor cells that poorly internalize AMF/PGI. Murine K1735-M1 and B16-F1 melanoma cells internalize FITC-conjugated AMF/PGI and are acutely sensitive to AMF/PGI-paclitaxel mediated cytotoxicity in vitro. Moreover, following in vivo intratumoral injection, FITC-conjugated AMF/PGI is internalized in K1735-M1 tumors. Intratumoral injection of AMF/PGI-paclitaxel induced significantly higher tumor regression compared to free paclitaxel, even in B16-F1 cells, known to be resistant to taxol treatment. Treatment with AMF/PGI-paclitaxel significantly prolonged the median survival time of tumor bearing mice. Free AMF/PGI exhibited a pro-survival role, reducing the cytotoxic effect of both AMF/PGI-paclitaxel and free paclitaxel suggesting that AMF/PGI-paclitaxel targets a pathway associated with resistance to chemotherapeutic agents. AMF/PGI-FITC uptake by normal murine spleen and thymus cells was

  4. Nitric Oxide Is Required for L-Type Ca2+ Channel-Dependent Long-Term Potentiation in the Hippocampus

    PubMed Central

    Pigott, Beatrice M.; Garthwaite, John

    2016-01-01

    Nitric oxide (NO) has long been implicated in the generation of long-term potentiation (LTP) and other types of synaptic plasticity, a role for which the intimate coupling between NMDA receptors (NMDARs) and the neuronal isoform of NO synthase (nNOS) is likely to be instrumental in many instances. While several types of synaptic plasticity depend on NMDARs, others do not, an example of which is LTP triggered by opening of L-type voltage-gated Ca2+ channels (L-VGCCs) in postsynaptic neurons. In CA3-CA1 synapses in the hippocampus, NMDAR-dependent LTP (LTPNMDAR) appears to be primarily expressed postsynaptically whereas L-VGCC-dependent LTP (LTPL−VGCC), which often coexists with LTPNMDAR, appears mainly to reflect enhanced presynaptic transmitter release. Since NO is an excellent candidate as a retrograde messenger mediating post-to-presynaptic signaling, we sought to determine if NO functions in LTPL−VGCC in mouse CA3-CA1 synapses. When elicited by a burst type of stimulation with NMDARs and the associated NO release blocked, LTPL−VGCC was curtailed by inhibition of NO synthase or of the NO-receptor guanylyl cyclase to the same extent as occurred with inhibition of L-VGCCs. Unlike LTPNMDAR at these synapses, LTPL−VGCC was unaffected in mice lacking endothelial NO synthase, implying that the major source of the NO is neuronal. Transient delivery of exogenous NO paired with tetanic synaptic stimulation under conditions of NMDAR blockade resulted in a long-lasting potentiation that was sensitive to inhibition of NO-receptor guanylyl cyclase but was unaffected by inhibition of L-VGCCs. The results indicate that NO, acting through its second messenger cGMP, plays an unexpectedly important role in L-VGCC-dependent, NMDAR-independent LTP, possibly as a retrograde messenger generated in response to opening of postsynaptic L-VGCCs and/or as a signal acting postsynaptically, perhaps to facilitate changes in gene expression. PMID:27445786

  5. pH-Dependent Reduction Potentials and Proton-Coupled Electron Transfer Mechanisms in Hydrogen-Producing Nickel Molecular Electrocatalysts

    SciTech Connect

    Horvath, Samantha; Fernandez, Laura; Appel, Aaron M.; Hammes-Schiffer, Sharon

    2013-04-01

    The nickel-based Ph Bz 2 2 P N electrocatalysts, which are comprised of a nickel atom and two 1,5-dibenzyl-3,7-diphenyl-1,5-diaza-3,7-diphosphacyclooctane ligands, have been shown to effectively catalyze H2 production in acetonitrile. Recent electrochemical experiments revealed a linear dependence of the NiII/I reduction potential on pH, suggesting a proton-coupled electron transfer (PCET) reaction. In the proposed mechanism, the catalytic cycle begins with a PCET process involving electrochemical electron transfer to the nickel center and intermolecular proton transfer from an acid to the pendant amine ligand. This paper presents quantum mechanical calculations of this PCET process to examine the thermodynamics of the sequential mechanisms, in which either the electron or the proton transfers first (ET–PT and PT–ET, respectively), and the concerted mechanism (EPT). The favored mechanism depends on a balance among many factors, including the acid strength, association free energy for the acid–catalyst complex, PT free energy barrier, and ET reduction potential. The ET reduction potential is less negative after PT, favoring the PT–ET mechanism, and the association free energy is less positive after reduction, favoring the ET–PT mechanism. The calculations, along with analysis of the experimental data, indicate that the sequential ET–PT mechanism is favored for weak acids because of the substantial decrease in the association free energy after reduction. For strong acids, however, the PT–ET mechanism may be favored because the association free energy is somewhat smaller and PT is more thermodynamically favorable. The concerted mechanism could also occur, particularly for intermediate acid strengths. In the context of the entire catalytic cycle for H2 production, the initial PCET process involving intermolecular PT has a more negative reduction potential than the subsequent PCET process involving intramolecular PT. As a result, the second PCET should

  6. Kappa-opioid receptor signaling in the striatum as a potential modulator of dopamine transmission in cocaine dependence.

    PubMed

    Trifilieff, Pierre; Martinez, Diana

    2013-01-01

    Cocaine addiction is accompanied by a decrease in striatal dopamine signaling, measured as a decrease in dopamine D2 receptor binding as well as blunted dopamine release in the striatum. These alterations in dopamine transmission have clinical relevance, and have been shown to correlate with cocaine-seeking behavior and response to treatment for cocaine dependence. However, the mechanisms contributing to the hypodopaminergic state in cocaine addiction remain unknown. Here we review the positron emission tomography (PET) imaging studies showing alterations in D2 receptor binding potential and dopamine transmission in cocaine abusers and their significance in cocaine-seeking behavior. Based on animal and human studies, we propose that the kappa receptor/dynorphin system, because of its impact on dopamine transmission and upregulation following cocaine exposure, could contribute to the hypodopaminergic state reported in cocaine addiction, and could thus be a relevant target for treatment development. PMID:23760592

  7. VDAC electronics: 3. VDAC-Creatine kinase-dependent generation of the outer membrane potential in respiring mitochondria.

    PubMed

    Lemeshko, Victor V

    2016-07-01

    Mitochondrial energy in cardiac cells has been reported to be channeled into the cytosol through the intermembrane contact sites formed by the adenine nucleotide translocator, creatine kinase and VDAC. Computational analysis performed in this study showed a high probability of the outer membrane potential (OMP) generation coupled to such a mechanism of energy channeling in respiring mitochondria. OMPs, positive inside, calculated at elevated concentrations of creatine are high enough to restrict ATP release from mitochondria, to significantly decrease the apparent K(m,ADP) for state 3 respiration and to maintain low concentrations of Ca(2+) in the mitochondrial intermembrane space. An inhibition by creatine of Ca(2+)-induced swelling of isolated mitochondria and other protective effects of creatine reported in the literature might be explained by generated positive OMP. We suggest that VDAC-creatine kinase-dependent generation of OMP represents a novel physiological factor controlling metabolic state of mitochondria, cell energy channeling and resistance to death. PMID:27085978

  8. Limits on the dependence of the fine-structure constant on gravitational potential from white-dwarf spectra.

    PubMed

    Berengut, J C; Flambaum, V V; Ong, A; Webb, J K; Barrow, John D; Barstow, M A; Preval, S P; Holberg, J B

    2013-07-01

    We propose a new probe of the dependence of the fine-structure constant α on a strong gravitational field using metal lines in the spectra of white-dwarf stars. Comparison of laboratory spectra with far-UV astronomical spectra from the white-dwarf star G191-B2B recorded by the Hubble Space Telescope Imaging Spectrograph gives limits of Δα/α=(4.2±1.6)×10(-5) and (-6.1±5.8)×10(-5) from FeV and NiV spectra, respectively, at a dimensionless gravitational potential relative to Earth of Δφ≈5×10(-5). With better determinations of the laboratory wavelengths of the lines employed these results could be improved by up to 2 orders of magnitude. PMID:23862989

  9. Cordycepin Decreases Compound Action Potential Conduction of Frog Sciatic Nerve In Vitro Involving Ca (2+) -Dependent Mechanisms.

    PubMed

    Yao, Li-Hua; Yu, Hui-Min; Xiong, Qiu-Ping; Sun, Wei; Xu, Yan-Liang; Meng, Wei; Li, Yu-Ping; Liu, Xin-Ping; Yuan, Chun-Hua

    2015-01-01

    Cordycepin has been widely used in oriental countries to maintain health and improve physical performance. Compound nerve action potential (CNAP), which is critical in signal conduction in the peripheral nervous system, is necessary to regulate physical performance, including motor system physiological and pathological processes. Therefore, regulatory effects of cordycepin on CNAP conduction should be elucidated. In this study, the conduction ability of CNAP in isolated frog sciatic nerves was investigated. Results revealed that cordycepin significantly decreased CNAP amplitude and conductive velocity in a reversible and concentration-dependent manner. At 50 mg/L cordycepin, CNAP amplitude and conductive velocity decreased by 62.18 ± 8.06% and 57.34% ± 6.14% compared with the control amplitude and conductive velocity, respectively. However, the depressive action of cordycepin on amplitude and conductive velocity was not observed in Ca(2+)-free medium or in the presence of Ca(2+) channel blockers (CdCl2/LaCl3). Pretreatment with L-type Ca(2+) channel antagonist (nifedipine/deltiazem) also blocked cordycepin-induced responses; by contrast, T-type and P-type Ca(2+) channel antagonists (Ni(2+)) failed to block such responses. Therefore, cordycepin decreased the conduction ability of CNAP in isolated frog sciatic nerves via L-type Ca(2+) channel-dependent mechanism. PMID:26078886

  10. Inhibition of the MAPK/ERK cascade: a potential transcription-dependent mechanism for the amnesic effect of anesthetic propofol.

    PubMed

    Fibuch, Eugene E; Wang, John Q

    2007-03-01

    Intravenous anesthetics are known to cause amnesia, but the underlying molecular mechanisms remain elusive. To identify a possible molecular mechanism, we recently turned our attention to a key intracellular signaling pathway organized by a family of mitogen-activated protein kinases (MAPKs). As a prominent synapse-to-nucleus superhighway, MAPKs couple surface glutamate receptors to nuclear transcriptional events essential for the development and/or maintenance of different forms of synaptic plasticity (long-term potentiation and long-term depression) and memory formation. To define the role of MAPK-dependent transcription in the amnesic property of anesthetics, we conducted a series of studies to examine the effect of a prototype intravenous anesthetic propofol on the MAPK response to N-methyl-D-aspartate receptor (NMDAR) stimulation in hippocampal neurons. Our results suggest that propofol possesses the ability to inhibit NMDAR-mediated activation of a classic subclass of MAPKs, extracellular signal-regulated protein kinase 1/2 (ERK1/2). Concurrent inhibition of transcriptional activity also occurs as a result of inhibited responses of ERK1/2 to NMDA. These findings provide first evidence for an inhibitory modulation of the NMDAR-MAPK pathway by an intravenous anesthetic and introduce a new avenue to elucidate a transcription-dependent mechanism processing the amnesic effect of anesthetics. PMID:17592535

  11. Replication-Dependent Radiosensitization of Human Glioma Cells by Inhibition of Poly(ADP-Ribose) Polymerase: Mechanisms and Therapeutic Potential

    SciTech Connect

    Dungey, Fiona A.; Loeser, Dana A.; Chalmers, Anthony J.

    2008-11-15

    Purpose: Current treatments for glioblastoma multiforme are inadequate and limited by the radiation sensitivity of normal brain. Because glioblastoma multiforme are rapidly proliferating tumors within nondividing normal tissue, the therapeutic ratio might be enhanced by combining radiotherapy with a replication-specific radiosensitizer. KU-0059436 (AZD2281) is a potent and nontoxic inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) undergoing a Phase II clinical trial as a single agent. Methods and Materials: Based on previous observations that the radiosensitizing effects of PARP inhibition are more pronounced in dividing cells, we investigated the mechanisms underlying radiosensitization of human glioma cells by KU-0059436, evaluating the replication dependence of this effect and its therapeutic potential. Results: KU-0059436 increased the radiosensitivity of four human glioma cell lines (T98G, U373-MG, UVW, and U87-MG). Radiosensitization was enhanced in populations synchronized in S phase and abrogated by concomitant exposure to aphidicolin. Sensitization was further enhanced when the inhibitor was combined with a fractionated radiation schedule. KU-0059436 delayed repair of radiation-induced DNA breaks and was associated with a replication-dependent increase in {gamma}H2AX and Rad51 foci. Conclusion: The results of our study have shown that KU-0059436 increases radiosensitivity in a replication-dependent manner that is enhanced by fractionation. A mechanism is proposed whereby PARP inhibition increases the incidence of collapsed replication forks after ionizing radiation, generating persistent DNA double-strand breaks. These observations indicate that KU-0059436 is likely to enhance the therapeutic ratio achieved by radiotherapy in the treatment of glioblastoma multiforme. A Phase I clinical trial is in development.

  12. Cell-Context Dependent TCF/LEF Expression and Function: Alternative Tales of Repression, De-Repression and Activation Potentials

    PubMed Central

    Mao, Catherine D; Byers, Stephen W.

    2012-01-01

    Wnt signaling controls cell specification and fate during development and adult tissue homeostasis by converging on a small family of DNA binding factors, the T-cell factor/lymphoid enhancer factor (TCF/LEF) family. In response to Wnt signals, TCF/LEF members undergo a transcriptional switch from repression to activation mediated in part by nuclear β-catenin binding and recruitment of co-activator complexes. In mammals, the specificity and fine tuning of this transcriptional switch is also achieved by the cell-context-dependent expression of four members (TCF7, TCF7L1, TCF7L2, and LEF1) and numerous variants, which display differential DNA binding affinity and specificity, repression strength, activation potential, and regulators. TCF7/LEF1 variants are generated by alternative promoters, alternative exon cassettes, and alternative donor/acceptor splicing sites, allowing combinatorial insertion/exclusion of modular functional and regulatory domains. In this review we present mounting evidence for the interdependency of TCF7/LEF1 variant expression and functions with cell lineage and cell state. We also illustrate how the p53 and nuclear receptor family of transcription factors, known to control cell fate and to inhibit Wnt signaling, may participate in the fine tuning of TCF7/LEF1 repression/activation potentials. PMID:22111711

  13. D1 dopamine receptor-induced cyclic AMP-dependent protein kinase phosphorylation and potentiation of striatal glutamate receptors.

    PubMed

    Price, C J; Kim, P; Raymond, L A

    1999-12-01

    Dopamine receptor activation regulates cyclic AMP levels and is critically involved in modulating neurotransmission in the striatum. Others have shown that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate receptor-mediated current is potentiated by cyclic AMP-dependent protein kinase (PKA) activation. We made whole-cell patch clamp recordings from cultured striatal neurons and tested whether D1-type dopamine receptor activation affected AMPA receptor-mediated currents. After a 5-min exposure to the D1 agonist SKF 81297 (1 microM), kainate-evoked current amplitude was enhanced in approximately 75% of cells to 121+/-2.5% of that recorded prior to addition of drug. This response was inhibited by the D1 antagonist SCH 23390 and mimicked by activators of PKA. Moreover, by western blot analysis using an antibody specific for the phosphorylated PKA site Ser845 of GluR1, we observed a marked increase in phosphorylated GluR1 following a 10-min exposure of striatal neurons to 1 microM SKF 81297. Our data demonstrate that activation of D1-type dopamine receptors on striatal neurons promotes phosphorylation of AMPA receptors by PKA as well as potentiation of current amplitude. These results elucidate one mechanism by which dopamine can modulate neurotransmission in the striatum. PMID:10582604

  14. The timing of phasic transmitter release is Ca2+-dependent and lacks a direct influence of presynaptic membrane potential

    PubMed Central

    Felmy, Felix; Neher, Erwin; Schneggenburger, Ralf

    2003-01-01

    Ca2+ influx through voltage-gated Ca2+ channels and the resulting elevation of intracellular Ca2+ concentration, [Ca2+]i, triggers transmitter release in nerve terminals. However, it is controversial whether in addition to the opening of Ca2+ channels, membrane potential directly affects transmitter release. Here, we assayed the influence of membrane potential on transmitter release at the calyx of Held nerve terminals. Transmitter release was evoked by presynaptic Ca2+ uncaging, or by presynaptic Ca2+ uncaging paired with presynaptic voltage-clamp depolarizations to +80 mV, under pharmacological block of voltage-gated Ca2+ channels. Such a change in membrane potential did not alter the Ca2+ dependence of transmitter release rates or synaptic delays. We also found, by varying the amount of Ca2+ influx during Ca2+ tail-currents, that the time course of phasic transmitter release is not invariant to changes in release probability. Rather, the time difference between peak Ca2+ current and peak transmitter release became progressively shorter with increasing Ca2+ current amplitude. When this time difference was plotted as a function of the estimated local [Ca2+]i at the sites of vesicle fusion, a slope of ≈100 μs per 10 μM [Ca2+]i was found, in reasonable agreement with a model of cooperative Ca2+ binding and vesicle fusion. Thus, the amplitude and time course of the [Ca2+]i signal at the sites of vesicle fusion controls the timing and the amount of transmitter release, both under conditions of brief periods of Ca2+ influx, as well as during step-like elevations of [Ca2+]i produced by Ca2+ uncaging. PMID:14630950

  15. The timing of phasic transmitter release is Ca2+-dependent and lacks a direct influence of presynaptic membrane potential.

    PubMed

    Felmy, Felix; Neher, Erwin; Schneggenburger, Ralf

    2003-12-01

    Ca2+ influx through voltage-gated Ca2+ channels and the resulting elevation of intracellular Ca2+ concentration, [Ca2+]i, triggers transmitter release in nerve terminals. However, it is controversial whether in addition to the opening of Ca2+ channels, membrane potential directly affects transmitter release. Here, we assayed the influence of membrane potential on transmitter release at the calyx of Held nerve terminals. Transmitter release was evoked by presynaptic Ca2+ uncaging, or by presynaptic Ca2+ uncaging paired with presynaptic voltage-clamp depolarizations to +80 mV, under pharmacological block of voltage-gated Ca2+ channels. Such a change in membrane potential did not alter the Ca2+ dependence of transmitter release rates or synaptic delays. We also found, by varying the amount of Ca2+ influx during Ca2+ tail-currents, that the time course of phasic transmitter release is not invariant to changes in release probability. Rather, the time difference between peak Ca2+ current and peak transmitter release became progressively shorter with increasing Ca2+ current amplitude. When this time difference was plotted as a function of the estimated local [Ca2+]i at the sites of vesicle fusion, a slope of approximately 100 micros per 10 microM [Ca2+]i was found, in reasonable agreement with a model of cooperative Ca2+ binding and vesicle fusion. Thus, the amplitude and time course of the [Ca2+]i signal at the sites of vesicle fusion controls the timing and the amount of transmitter release, both under conditions of brief periods of Ca2+ influx, as well as during step-like elevations of [Ca2+]i produced by Ca2+ uncaging. PMID:14630950

  16. Overdamped motion of interacting particles in general confining potentials: time-dependent and stationary-state analyses

    NASA Astrophysics Data System (ADS)

    Ribeiro, M. S.; Nobre, F. D.; Curado, E. M. F.

    2012-12-01

    By comparing numerical and analytical results, it is shown that a system of interacting particles under overdamped motion is very well described by a nonlinear Fokker-Planck equation, which can be associated with nonextensive statistical mechanics. The particle-particle interactions considered are repulsive, motivated by three different physical situations: (i) modified Bessel function, commonly used in vortex-vortex interactions, relevant for the flux-front penetration in disordered type-II superconductors; (ii) Yukawa-like forces, useful for charged particles in plasma, or colloidal suspensions; (iii) derived from a Gaussian potential, common in complex fluids, like polymer chains dispersed in a solvent. Moreover, the system is subjected to a general confining potential, φ( x) = ( α| x| z )/ z ( α > 0 , z > 1), so that a stationary state is reached after a sufficiently long time. Recent numerical and analytical investigations, considering interactions of type (i) and a harmonic confining potential ( z = 2), have shown strong evidence that a q-Gaussian distribution, P( x,t), with q = 0, describes appropriately the particle positions during their time evolution, as well as in their stationary state. Herein we reinforce further the connection with nonextensive statistical mechanics, by presenting numerical evidence showing that: (a) in the case z = 2, different particle-particle interactions only modify the diffusion parameter D of the nonlinear Fokker-Planck equation; (b) for z ≠ 2, all cases investigated fit well the analytical stationary solution P st( x), given in terms of a q-exponential (with the same index q = 0) of the general external potential φ( x). In this later case, we propose an approximate time-dependent P( x,t) (not known analytically for z ≠ 2), which is in very good agreement with the simulations for a large range of times, including the approach to the stationary state. The present work suggests that a wide variety of physical phenomena

  17. Potential Role for Extracellular Glutathione-Dependent Ferric Reductase in Utilization of Environmental and Host Ferric Compounds by Histoplasma capsulatum

    PubMed Central

    Timmerman, Michelle M.; Woods, Jon P.

    2001-01-01

    The mammalian host specifically limits iron during Histoplasma capsulatum infection, and fungal acquisition of iron is essential for productive infection. H. capsulatum expresses several iron acquisition mechanisms under iron-limited conditions in vitro. These components include hydroxamate siderophores, extracellular glutathione-dependent ferric reductase enzyme, extracellular nonproteinaceous ferric reductant(s), and cell surface ferric reducing agent(s). We examined the relationship between these mechanisms and a potential role for the extracellular ferric reductase in utilization of environmental and host ferric compounds through the production of free, soluble Fe(II). Siderophores and ferric reducing agents were coproduced under conditions of iron limitation. The H. capsulatum siderophore dimerum acid and the structurally similar basidiomycete siderophore rhodotorulic acid acted as substrates for the ferric reductase, and rhodotorulic acid removed Fe(III) bound by transferrin. The mammalian Fe(III)-binding compounds hemin and transferrin served both as substrates for the ferric reductase and as iron sources for yeast-phase growth at neutral pH. In the case of transferrin, there was a correlation between the level of iron saturation and efficacy for both of these functions. Our data are not consistent with an entirely pH-dependent mechanism of iron acquisition from transferrin, as has been suggested to occur in the macrophage phagolysosome. The foreign siderophore ferrioxamine B also acted as a substrate for the ferric reductase, while the foreign siderophore ferrichrome did not. Both ferrioxamine and ferrichrome served as iron sources for yeast- and mold-phase growth, the latter presumably by some other acquisition mechanism(s). PMID:11705947

  18. Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

    PubMed Central

    Kaneko, Atsushi; Omiya, Yuji; Ohbuchi, Katsuya; Ohno, Nagisa; Yamamoto, Masahiro

    2013-01-01

    The functional roles of transient receptor potential (TRP) channels in the gastrointestinal tract have garnered considerable attention in recent years. We previously reported that daikenchuto (TU-100), a traditional Japanese herbal medicine, increased intestinal blood flow (IBF) via adrenomedullin (ADM) release from intestinal epithelial (IE) cells (Kono T et al. J Crohns Colitis 4: 161–170, 2010). TU-100 contains multiple TRP activators. In the present study, therefore, we examined the involvement of TRP channels in the ADM-mediated vasodilatatory effect of TU-100. Rats were treated intraduodenally with the TRP vanilloid type 1 (TRPV1) agonist capsaicin (CAP), the TRP ankyrin 1 (TRPA1) agonist allyl-isothiocyanate (AITC), or TU-100, and jejunum IBF was evaluated using laser-Doppler blood flowmetry. All three compounds resulted in vasodilatation, and the vasodilatory effect of TU-100 was abolished by a TRPA1 antagonist but not by a TRPV1 antagonist. Vasodilatation induced by AITC and TU-100 was abrogated by anti-ADM antibody treatment. RT-PCR and flow cytometry revealed that an IEC-6 cell line originated from the small intestine and purified IE cells expressed ADM and TRPA1 but not TRPV1. AITC increased ADM release in IEC cells remarkably, while CAP had no effect. TU-100 and its ingredient 6-shogaol (6SG) increased ADM release dose-dependently, and the effects were abrogated by a TRPA1 antagonist. 6SG showed similar TRPA1-dependent vasodilatation in vivo. These results indicate that TRPA1 in IE cells may play an important role in controlling bowel microcirculation via ADM release. Epithelial TRPA1 appears to be a promising target for the development of novel strategies for the treatment of various gastrointestinal disorders. PMID:23275609

  19. Hemolytic potential of miltefosine is dependent on cell concentration: Implications for in vitro cell cytotoxicity assays and pharmacokinetic data.

    PubMed

    Alonso, Lais; Alonso, Antonio

    2016-06-01

    Miltefosine possesses antiparasitic, antibacterial, antifungal and antitumor activities; however, its mechanism of action is not well established. In the current work, the miltefosine concentrations required to achieve 50% hemolysis in PBS were shown to vary from 600 μM using 5×10(9) cells/mL to ~2.9 μM for ~5×10(6) cells/mL. This cell concentration-dependent hemolytic potential was described using an equation that included the membrane-water partition coefficient (K) and miltefosine concentrations in the cell membrane (cm) and aqueous medium (cw) as variables. The best-fit values for the 50% hemolysis data were log K=4.68, cm=110.8 mM, and cw=2.3 μM. Hemolysis measurements in whole blood were used to determine the erythrocyte membrane-plasma partition coefficient of miltefosine (Log KM/P=1.77). Additionally, miltefosine concentration in whole blood was found to be ~86% of that in plasma. Previously reported clinical pharmacokinetics data indicate that the plasma concentration of miltefosine peaks at ~90 μg/mL when treating visceral leishmaniasis. Using this concentration, which corresponds to ~77 μg/mL miltefosine in whole blood, we found only 2.8% hemolysis. Significant hemolysis (5.4%) was observed only after doubling the concentration to 180 μg/mL. Recently reported data indicate that miltefosine inhibitory concentrations in Leishmania are also dependent on cell concentration. The biophysical parameters assessed in the current study indicated that this type of response is associated with the accumulation of the drug in the cell membrane, which becomes damaged when critical drug concentrations are reached. PMID:26947181

  20. Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents

    PubMed Central

    Leitch, AE; Haslett, C; Rossi, AG

    2009-01-01

    The cyclin-dependent kinase inhibitor (CDKi) drugs such as R-roscovitine have emerged as potential anti-inflammatory, pharmacological agents that can influence the resolution of inflammation. Usually, once an inciting inflammatory stimulus has been eliminated, resolution proceeds by prompt, safe removal of dominant inflammatory cells. This is accomplished by programmed cell death (apoptosis) of prominent effector, inflammatory cells typified by the neutrophil. Apoptosis of neutrophils ensures that toxic neutrophil granule contents are securely packaged in apoptotic bodies and expedites phagocytosis by professional phagocytes such as macrophages. A panel of CDKi drugs have been shown to promote neutrophil apoptosis in a concentration- and time-dependent manner and the archetypal CDKi drug, R-roscovitine, overrides the anti-apoptotic effects of powerful survival factors [including lipopolysaccharide (LPS) and granulocyte macrophage-colony stimulating factor (GM-CSF)]. Inflammatory cell longevity and survival signalling is integral to the inflammatory process and any putative anti-inflammatory agent must unravel a complex web of redundancy in order to be effective. CDKi drugs have also been demonstrated to have significant effects on other cell types including lymphocytes and fibroblasts indicating that they may have pleiotropic anti-inflammatory, pro-resolution activity. In keeping with this, CDKi drugs like R-roscovitine have been reported to be efficacious in resolving established animal models of neutrophil-dominant and lymphocyte-driven inflammation. However, the mechanism of action behind these powerful effects has not yet been fully elucidated. CDKs play an integral role in the regulation of the cell cycle but are also recognized as participants in processes such as apoptosis and transcriptional regulation. Neutrophils have functional CDKs, are transcriptionally active and demonstrate augmented apoptosis in response to CDKi drugs, while lymphocyte proliferation

  1. Formulation and in vitro evaluation of polymeric enteric nanoparticles as dermal carriers with pH-dependent targeting potential.

    PubMed

    Sahle, Fitsum Feleke; Balzus, Benjamin; Gerecke, Christian; Kleuser, Burkhard; Bodmeier, Roland

    2016-09-20

    pH-sensitive nanoparticles which release in a controlled fashion on the skin or dissolve in the hair follicle could significantly improve treatment effectiveness and make transfollicular drug delivery a success. Dexamethasone-loaded Eudragit® L 100 nanoparticles were prepared by nanoprecipitation from an organic drug-polymer solution. Their toxicity potential was assessed using isolated human fibroblasts. pH-dependent swelling and erosion kinetics of the nanoparticles were investigated by dynamic light scattering and viscosity measurements and its effect on drug release was assessed in vitro with Franz diffusion cells. Stable, 100-550nm-sized dexamethasone-loaded Eudragit® L 100 nanoparticles with drug loading capacity and entrapment efficiency as high as 8.3% and 85%, respectively, were obtained by using polyvinyl alcohol as a stabilizer and ethanol as organic solvent. The nanoparticles showed little or no toxicity on isolated normal human fibroblasts. Dexamethasone existed in the nanoparticles as solid solution or in amorphous form. The nanoparticles underwent extensive swelling and slow drug release in media with a low buffer capacity (as low as 10mM) and a higher pH or at a pH close to the dissolution pH of the polymer (pH6) and a higher buffer capacity. In 40mM buffer and above pH6.8, the nanoparticles eroded fast or dissolved completely and thus released the drug rapidly. pH-sensitive nanoparticles which potentially release in a controlled manner on the stratum corneum but dissolve in the hair follicle could be prepared. PMID:27393341

  2. Density-dependent groundwater flow and dissolution potential along a salt diapir in the Transylvanian Basin, Romania

    NASA Astrophysics Data System (ADS)

    Zechner, Eric; Danchiv, Alex; Dresmann, Horst; Mocuţa, Marius; Huggenberger, Peter; Scheidler, Stefan; Wiesmeier, Stefan; Popa, Iulian; Zlibut, Alexandru; Zamfirescu, Florian

    2016-04-01

    Salt diapirs and the surrounding sediments are often involved in a variety of human activities, such as salt mining, exploration and storage of hydrocarbons, and also storage of radioactive waste material. The presence of highly soluble evaporitic rocks, a complex tectonic setting related to salt diapirsm, and human activities can lead to significant environmental problems, e.g. land subsidence, sinkhole development, salt cavern collapse, and contamination of water resources with brines. In the Transylvanian town of Ocna Mures. rock salt of a near-surface diapir has been explored since the Roman ages in open excavations, and up to the 20th century in galleries and with solution mining. Most recently, in 2010 a sudden collapse in the adjacent Quaternary unconsolidated sediments led to the formation of a 70-90m wide salt lake with a max. depth of 23m. Over the last 3 years a Romanian-Swiss research project has led to the development of 3D geological and hydrogeological information systems in order to improve knowledge on possible hazards related to uncontrolled salt dissolution. One aspect which has been investigated is the possibility of density-driven flow along permeable subvertical zones next to the salt dome, and the potential for subsaturated groundwater to dissolve the upper sides of the diapir. Structural 3D models of the salt diapir, the adjacent basin sediments, and the mining galleries, led to the development of 2D numerical vertical density-dependent models of flow and transport along the diapir. Results show that (1) increased rock permeability due to diapirsm, regional tectonic thrusting and previous dissolution, and (2) more permeable sandstone layers within the adjacent basin sediments may lead to freshwater intrusion towards the top of the diapir, and, therefore, to increased potential for salt dissolution.

  3. Higher diet-dependent renal acid load associates with higher glucocorticoid secretion and potentially bioactive free glucocorticoids in healthy children.

    PubMed

    Esche, Jonas; Shi, Lijie; Sánchez-Guijo, Alberto; Hartmann, Michaela F; Wudy, Stefan A; Remer, Thomas

    2016-08-01

    Metabolic acidosis induces elevated glucocorticoid (GC) levels. However, the influence of less strong daily acid loads on GCs is largely unexplored. To investigate this, we studied whether higher acid loads in children, fully within the normal range of habitual diets, associate with endogenous GCs. In a specific quasi-experimental design, we examined 200 6- to 10-year-old healthy participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study equally divided to either high or low 24-hour renal net acid excretion. Major urinary GC metabolites were analyzed by gas chromatography-mass spectrometry to assess daily adrenal GC secretion and metabolites of tissue cortisol catabolism (6β-hydroxycortisol and 20α-dihydrocortisol). Liquid chromatography-mass spectrometry was used to quantify urinary free cortisol and cortisone. After confounder adjustment, significant positive associations were unmasked for urinary potential renal acid load and net acid excretion with adrenal GC secretion, free cortisone, free cortisone plus cortisol, 6β-hydroxycortisol, and 20α-dihydrocortisol. An inverse association emerged for an enzymatic marker (5β-reductase) of irreversible GC inactivation. Our data suggest that existing moderate elevations in diet-dependent acid loads suffice to raise GCs and affect cortisol metabolism. Thus, potential detrimental effects of high acid loading appear to be mediated, in part, by increased GC activity via increased GC secretion and/or reduced GC inactivation. Higher cortisone levels, directly available for intracrine activation to cortisol may play a special role. PMID:27165611

  4. Energy dependence of the optical potentials for the 9Be +208Pb and 9Be +209Bi systems at near-Coulomb-barrier energies

    NASA Astrophysics Data System (ADS)

    Gómez Camacho, A.; Yu, N.; Zhang, H. Q.; Gomes, P. R. S.; Jia, H. M.; Lubian, J.; Lin, C. J.

    2015-04-01

    We analyze the energy dependence of the interacting optical potential, at near barrier energies, for two systems involving the weakly bound projectile 9Be and the heavy 208Pb and 209Bi targets, by the simultaneous fit of elastic scattering angular distributions and fusion excitation functions. The approach used consists of dividing the optical potential into two parts. A short-range potential VF+i WF that is responsible for fusion, and a superficial potential VDR+i WDR for direct reactions. It is found, for both systems studied, that the fusion imaginary potential WF presents the usual threshold anomaly (TA) observed in tightly bound systems, whereas the direct reaction imaginary potential WDR shows a breakup threshold anomaly (BTA) behavior. Both potentials satisfy the dispersion relation. The direct reaction polarization potential predominates over the fusion potential and so a net overall behavior is found to follow the BTA phenomenon.

  5. Orbital-dependent second-order scaled-opposite-spin correlation functionals in the optimized effective potential method

    SciTech Connect

    Grabowski, Ireneusz Śmiga, Szymon; Buksztel, Adam; Fabiano, Eduardo; Teale, Andrew M.; Sala, Fabio Della

    2014-07-14

    The performance of correlated optimized effective potential (OEP) functionals based on the spin-resolved second-order correlation energy is analysed. The relative importance of singly- and doubly- excited contributions as well as the effect of scaling the same- and opposite- spin components is investigated in detail comparing OEP results with Kohn–Sham (KS) quantities determined via an inversion procedure using accurate ab initio electronic densities. Special attention is dedicated in particular to the recently proposed scaled-opposite–spin OEP functional [I. Grabowski, E. Fabiano, and F. Della Sala, Phys. Rev. B 87, 075103 (2013)] which is the most advantageous from a computational point of view. We find that for high accuracy, a careful, system dependent, selection of the scaling coefficient is required. We analyse several size-extensive approaches for this selection. Finally, we find that a composite approach, named OEP2-SOSh, based on a post-SCF rescaling of the correlation energy can yield high accuracy for many properties, being comparable with the most accurate OEP procedures previously reported in the literature but at substantially reduced computational effort.

  6. Aryl hydrocarbon receptor–dependent enrichment of a megakaryocytic precursor with a high potential to produce proplatelets

    PubMed Central

    Brouard, Nathalie; Mallo, Lea; Receveur, Nicolas; Mangin, Pierre; Eckly, Anita; Bieche, Ivan; Tarte, Karin; Gachet, Christian; Lanza, François

    2016-01-01

    The mechanisms regulating megakaryopoiesis and platelet production (thrombopoiesis) are still incompletely understood. Identification of a progenitor with enhanced thrombopoietic capacity would be useful to decipher these mechanisms and to improve our capacity to produce platelets in vitro. Differentiation of peripheral blood CD34+ cells in the presence of bone marrow–human mesenchymal stromal cells (MSCs) enhanced the production of proplatelet-bearing megakaryocytes (MKs) and platelet-like elements. This was accompanied by enrichment in a MK precursor population exhibiting an intermediate level of CD41 positivity while maintaining its expression of CD34. Following sorting and subculture with MSCs, this CD34+CD41low population was able to efficiently generate proplatelet-bearing MKs and platelet-like particles. Similarly, StemRegenin 1 (SR1), an antagonist of the aryl hydrocarbon receptor (AhR) transcription factor known to maintain CD34 expression of progenitor cells, led to an enriched CD34+CD41low fraction and to an increased capacity to generate proplatelet-producing MKs and platelet-like elements ultrastructurally and functionally similar to circulating platelets. The effect of MSCs, like that of SR1, appeared to be mediated by an AhR-dependent mechanism because both culture conditions resulted in repression of its downstream effector CYP1B1. This newly described isolation of a precursor exhibiting strong MK potential could be exploited to study normal and abnormal thrombopoiesis and for in vitro platelet production. PMID:26966088

  7. Vorticity vector-potential method for 3D viscous incompressible flows in time-dependent curvilinear coordinates

    NASA Astrophysics Data System (ADS)

    Chen, Yu; Xie, Xilin

    2016-05-01

    E and Liu [J. Comput. Phys. 138 (1997) 57-82] put forward a finite difference method for 3D viscous incompressible flows in the vorticity-vector potential formulation on non-staggered grids. In this paper, we will extend this method to the case of flows in the presence of a deformable surface. By use of two kinds of surface differential operators, the implementation of boundary conditions on a plane is generalized to a curved smooth surface with given velocity distribution, whether this be an inflow/outflow interface or a curved wall. To deal with the irregular and varying physical domain, time-dependent curvilinear coordinates are constructed and the corresponding tensor analysis is adopted in deriving the component form of the governing equations. Therefore, the equations can be discretized and solved in a regular and fixed parametric domain. Numerical results are presented for a 3D lid-driven cavity with a deforming surface and a 3D duct flow with a deforming boundary. A new way to validate numerical simulations is proposed based on an expression for the rate-of-strain tensor on a deformable surface.

  8. pH-dependent cross-linking of catechols through oxidation via Fe(3+) and potential implications for mussel adhesion.

    PubMed

    Fullenkamp, Dominic E; Barrett, Devin G; Miller, Dusty R; Kurutz, Josh W; Messersmith, Phillip B

    2014-01-01

    The mussel byssus is a remarkable attachment structure that is formed by injection molding and rapid in-situ hardening of concentrated solutions of proteins enriched in the catecholic amino acid 3,4-dihydroxy-L-phenylalanine (DOPA). Fe(3+), found in high concentrations in the byssus, has been speculated to participate in redox reactions with DOPA that lead to protein polymerization, however direct evidence to support this hypothesis has been lacking. Using small molecule catechols, DOPA-containing peptides, and native mussel foot proteins, we report the first direct observation of catechol oxidation and polymerization accompanied by reduction of Fe(3+) to Fe(2+). In the case of the small molecule catechol, we identified two dominant dimer species and characterized their connectivities by nuclear magnetic resonance (NMR), with the C6-C6 and C5-C6 linked species as the major and minor products, respectively. For the DOPA-containing peptide, we studied the pH dependence of the reaction and demonstrated that catechol polymerization occurs readily at low pH, but is increasingly diminished in favor of metal-catechol coordination interactions at higher pH. Finally, we demonstrate that Fe(3+) can induce cross-links in native byssal mussel proteins mefp-1 and mcfp-1 at acidic pH. Based on these findings, we discuss the potential implications to the chemistry of mussel adhesion. PMID:25243062

  9. Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade

    PubMed Central

    Gainey, Melanie A.; Tatavarty, Vedakumar; Nahmani, Marc; Lin, Heather; Turrigiano, Gina G.

    2015-01-01

    Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to changes in synapse number and strength. Scaling up in response to action-potential blockade is accomplished through increased synaptic accumulation of GluA2-containing AMPA receptors (AMPAR), but the receptor trafficking steps that drive this process remain largely obscure. Here, we show that the AMPAR-binding protein glutamate receptor-interacting protein-1 (GRIP1) is essential for regulated synaptic AMPAR accumulation during scaling up. Synaptic abundance of GRIP1 was enhanced by activity deprivation, directly increasing synaptic GRIP1 abundance through overexpression increased the amplitude of AMPA miniature excitatory postsynaptic currents (mEPSCs), and shRNA-mediated GRIP1 knockdown prevented scaling up of AMPA mEPSCs. Furthermore, knockdown and replace experiments targeting either GRIP1 or GluA2 revealed that scaling up requires the interaction between GRIP1 and GluA2. Finally, GRIP1 synaptic accumulation during scaling up did not require GluA2 binding. Taken together, our data support a model in which activity-dependent trafficking of GRIP1 to synaptic sites drives the forward trafficking and enhanced synaptic accumulation of GluA2-containing AMPAR during synaptic scaling up. PMID:26109571

  10. Temperature-dependent evaluation of Nd:LiCAF optical properties as potential vacuum ultraviolet laser material

    NASA Astrophysics Data System (ADS)

    Minami, Yuki; Arita, Ren; Cadatal-Raduban, Marilou; Pham, Minh Hong; Empizo, Melvin John Fernandez; Luong, Mui Viet; Hori, Tatsuhiro; Takabatake, Masahiro; Fukuda, Kazuhito; Mori, Kazuyuki; Yamanoi, Kohei; Shimizu, Toshihiko; Sarukura, Nobuhiko; Fukuda, Kentaro; Kawaguchi, Noriaki; Yokota, Yuui; Yoshikawa, Akira

    2016-08-01

    We investigate the temperature-dependent optical properties of Nd3+-doped LiCaAlF6 (Nd:LiCAF) in the vacuum ultraviolet (VUV) region. The 172-nm absorption edge does not seem to experience any significant blue shift as temperature is decreased from room temperature down to 30 K. This is confirmed by excitation spectra for the same temperature range. Several energy levels in the excited state configuration are observed. Based on these energy levels, the dominant emission peak at 177 nm is assigned to the allowed dipole transition from the 4f25d configuration of Nd3+ and the 4I11/2 level of the 4f3 ground state configuration. The position of the dominant 177-nm emission peak appears to be fixed across the temperature range considered. Our results suggest that the spectral overlap between the excitation and emission spectra should not increase as temperature is raised, possibly making Nd:LiCAF a potential VUV laser gain medium operating at room temperature.

  11. Analytical solitonlike solutions and the dynamics of ultracold Fermi gases in a time-dependent three-dimensional harmonic potential

    NASA Astrophysics Data System (ADS)

    Wang, Ying; Luo, Guosen; Zhou, Yu; Hang, Chao

    2015-09-01

    We present a theoretical study of solitonlike solutions and their dynamics of ultracold superfluid Fermi gases trapped in a time-dependent three-dimensional (3D) harmonic potential with gain or loss. The 3D analytical solitonlike solutions are obtained without introducing any additional integrability constraints used elsewhere. The propagation of both bright- and dark-soliton-like solutions is investigated. We show that the amplitudes of dark-soliton-like solutions exhibit periodic oscillation, whereas those of the bright-soliton-like ones do not show such behavior. Moreover, we highlight that the oscillation periods of dark-soliton-like solutions predicted by our approach are matched very well with those observed in a recent experiment carried out by Yefsah et al. [T. Yefsah, A. T. Sommer, M. J. H. Ku, L. W. Cheuk, W. Ji, W. S. Bakr, and M. W. Zwierlein, Nature (London) 499, 426 (2013), 10.1038/nature12338] in both Bose-Einstein condensation and unitarity regimes.

  12. Analytical solitonlike solutions and the dynamics of ultracold Fermi gases in a time-dependent three-dimensional harmonic potential.

    PubMed

    Wang, Ying; Luo, Guosen; Zhou, Yu; Hang, Chao

    2015-09-01

    We present a theoretical study of solitonlike solutions and their dynamics of ultracold superfluid Fermi gases trapped in a time-dependent three-dimensional (3D) harmonic potential with gain or loss. The 3D analytical solitonlike solutions are obtained without introducing any additional integrability constraints used elsewhere. The propagation of both bright- and dark-soliton-like solutions is investigated. We show that the amplitudes of dark-soliton-like solutions exhibit periodic oscillation, whereas those of the bright-soliton-like ones do not show such behavior. Moreover, we highlight that the oscillation periods of dark-soliton-like solutions predicted by our approach are matched very well with those observed in a recent experiment carried out by Yefsah et al. [T. Yefsah, A. T. Sommer, M. J. H. Ku, L. W. Cheuk, W. Ji, W. S. Bakr, and M. W. Zwierlein, Nature (London) 499, 426 (2013)NATUAS0028-083610.1038/nature12338] in both Bose-Einstein condensation and unitarity regimes. PMID:26465543

  13. Aryl hydrocarbon receptor-dependent enrichment of a megakaryocytic precursor with a high potential to produce proplatelets.

    PubMed

    Strassel, Catherine; Brouard, Nathalie; Mallo, Lea; Receveur, Nicolas; Mangin, Pierre; Eckly, Anita; Bieche, Ivan; Tarte, Karin; Gachet, Christian; Lanza, François

    2016-05-01

    The mechanisms regulating megakaryopoiesis and platelet production (thrombopoiesis) are still incompletely understood. Identification of a progenitor with enhanced thrombopoietic capacity would be useful to decipher these mechanisms and to improve our capacity to produce platelets in vitro. Differentiation of peripheral blood CD34(+) cells in the presence of bone marrow-human mesenchymal stromal cells (MSCs) enhanced the production of proplatelet-bearing megakaryocytes (MKs) and platelet-like elements. This was accompanied by enrichment in a MK precursor population exhibiting an intermediate level of CD41 positivity while maintaining its expression of CD34. Following sorting and subculture with MSCs, this CD34(+)CD41(low) population was able to efficiently generate proplatelet-bearing MKs and platelet-like particles. Similarly, StemRegenin 1 (SR1), an antagonist of the aryl hydrocarbon receptor (AhR) transcription factor known to maintain CD34 expression of progenitor cells, led to an enriched CD34(+)CD41(low) fraction and to an increased capacity to generate proplatelet-producing MKs and platelet-like elements ultrastructurally and functionally similar to circulating platelets. The effect of MSCs, like that of SR1, appeared to be mediated by an AhR-dependent mechanism because both culture conditions resulted in repression of its downstream effector CYP1B1. This newly described isolation of a precursor exhibiting strong MK potential could be exploited to study normal and abnormal thrombopoiesis and for in vitro platelet production. PMID:26966088

  14. Surface-Facet-Dependent Phonon Deformation Potential in Individual Strained Topological Insulator Bi2Se3 Nanoribbons.

    PubMed

    Yan, Yuan; Zhou, Xu; Jin, Han; Li, Cai-Zhen; Ke, Xiaoxing; Van Tendeloo, Gustaaf; Liu, Kaihui; Yu, Dapeng; Dressel, Martin; Liao, Zhi-Min

    2015-10-27

    Strain is an important method to tune the properties of topological insulators. For example, compressive strain can induce superconductivity in Bi2Se3 bulk material. Topological insulator nanostructures are the superior candidates to utilize the unique surface states due to the large surface to volume ratio. Therefore, it is highly desirable to monitor the local strain effects in individual topological insulator nanostructures. Here, we report the systematical micro-Raman spectra of single strained Bi2Se3 nanoribbons with different thicknesses and different surface facets, where four optical modes are resolved in both Stokes and anti-Stokes Raman spectral lines. A striking anisotropy of the strain dependence is observed in the phonon frequency of strained Bi2Se3 nanoribbons grown along the ⟨112̅0⟩ direction. The frequencies of the in-plane Eg(2) and out-of-plane A1g(1) modes exhibit a nearly linear blue-shift against bending strain when the nanoribbon is bent along the ⟨112̅0⟩ direction with the curved {0001} surface. In this case, the phonon deformation potential of the Eg(2) phonon for 100 nm-thick Bi2Se3 nanoribbon is up to 0.94 cm(–1)/%, which is twice of that in Bi2Se3 bulk material (0.52 cm(–1)/%). Our results may be valuable for the strain modulation of individual topological insulator nanostructures. PMID:26365014

  15. pH-dependent cross-linking of catechols through oxidation via Fe3+ and potential implications for mussel adhesion

    PubMed Central

    Fullenkamp, Dominic E.; Barrett, Devin G.; Miller, Dusty R.; Kurutz, Josh W.; Messersmith, Phillip B.

    2014-01-01

    The mussel byssus is a remarkable attachment structure that is formed by injection molding and rapid in-situ hardening of concentrated solutions of proteins enriched in the catecholic amino acid 3,4-dihydroxy-L-phenylalanine (DOPA). Fe3+, found in high concentrations in the byssus, has been speculated to participate in redox reactions with DOPA that lead to protein polymerization, however direct evidence to support this hypothesis has been lacking. Using small molecule catechols, DOPA-containing peptides, and native mussel foot proteins, we report the first direct observation of catechol oxidation and polymerization accompanied by reduction of Fe3+ to Fe2+. In the case of the small molecule catechol, we identified two dominant dimer species and characterized their connectivities by nuclear magnetic resonance (NMR), with the C6-C6 and C5-C6 linked species as the major and minor products, respectively. For the DOPA-containing peptide, we studied the pH dependence of the reaction and demonstrated that catechol polymerization occurs readily at low pH, but is increasingly diminished in favor of metal-catechol coordination interactions at higher pH. Finally, we demonstrate that Fe3+ can induce cross-links in native byssal mussel proteins mefp-1 and mcfp-1 at acidic pH. Based on these findings, we discuss the potential implications to the chemistry of mussel adhesion. PMID:25243062

  16. Strong-field ionization rates of linear polyenes simulated with time-dependent configuration interaction with an absorbing potential

    SciTech Connect

    Krause, Pascal; Schlegel, H. Bernhard

    2014-11-07

    The strong field ionization rates for ethylene, trans 1,3-butadiene, and trans,trans 1,3,5-hexatriene have been calculated using time-dependent configuration interaction with single excitations and a complex absorbing potential (TDCIS-CAP). The calculations used the aug-cc-pVTZ basis set with a large set of diffuse functions (3 s, 2 p, 3 d, and 1 f) on each atom. The absorbing boundary was placed 3.5 times the van der Waals radius from each atom. The simulations employed a seven-cycle cosine squared pulse with a wavelength of 800 nm. Ionization rates were calculated for intensities ranging from 0.3 × 10{sup 14} W/cm{sup 2} to 3.5 × 10{sup 14} W/cm{sup 2}. Ionization rates along the molecular axis increased markedly with increasing conjugation length. By contrast, ionization rates perpendicular to the molecular axis were almost independent of the conjugation length.

  17. Strong-field ionization rates of linear polyenes simulated with time-dependent configuration interaction with an absorbing potential.

    PubMed

    Krause, Pascal; Schlegel, H Bernhard

    2014-11-01

    The strong field ionization rates for ethylene, trans 1,3-butadiene, and trans,trans 1,3,5-hexatriene have been calculated using time-dependent configuration interaction with single excitations and a complex absorbing potential (TDCIS-CAP). The calculations used the aug-cc-pVTZ basis set with a large set of diffuse functions (3 s, 2 p, 3 d, and 1 f) on each atom. The absorbing boundary was placed 3.5 times the van der Waals radius from each atom. The simulations employed a seven-cycle cosine squared pulse with a wavelength of 800 nm. Ionization rates were calculated for intensities ranging from 0.3 × 10(14) W/cm(2) to 3.5 × 10(14) W/cm(2). Ionization rates along the molecular axis increased markedly with increasing conjugation length. By contrast, ionization rates perpendicular to the molecular axis were almost independent of the conjugation length. PMID:25381499

  18. Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1

    PubMed Central

    Pareek, Tej K.; Keller, Jason; Kesavapany, Sashi; Agarwal, Nitin; Kuner, Rohini; Pant, Harish C.; Iadarola, Michael J.; Brady, Roscoe O.; Kulkarni, Ashok B.

    2007-01-01

    Transient receptor potential vanilloid 1 (TRPV1), a ligand-gated cation channel highly expressed in small-diameter sensory neurons, is activated by heat, protons, and capsaicin. The phosphorylation of TRPV1 provides a versatile regulation of intracellular calcium levels and is critical for TRPV1 function in responding to a pain stimulus. We have previously reported that cyclin-dependent kinase 5 (Cdk5) activity regulates nociceptive signaling. In this article we report that the Cdk5-mediated phosphorylation of TRPV1 at threonine-407 can modulate agonist-induced calcium influx. Inhibition of Cdk5 activity in cultured dorsal root ganglia neurons resulted in a significant reduction of TRPV1-mediated calcium influx, and this effect could be reversed by restoring Cdk5 activity. Primary nociceptor-specific Cdk5 conditional-knockout mice showed reduced TRPV1 phosphorylation, resulting in significant hypoalgesia. Thus, the present study indicates that Cdk5-mediated TRPV1 phosphorylation is important in the regulation of pain signaling. PMID:17194758

  19. Serotonergic Dysfunction in Patients with Bipolar Disorder Assessed by the Loudness Dependence of the Auditory Evoked Potential

    PubMed Central

    Lee, Kyung-Sang; Park, Young-Min

    2012-01-01

    Objective The loudness dependence of the auditory evoked potential (LDAEP) is suggested to be a marker of serotonin system function. This study explored the LDAEP of multiple mood statuses (depression, mania, and euthymia) and its clinical implication in bipolar disorder patients. Methods A total of 89 subjects, comprising 35 patients with bipolar disorder, 32 patients with schizophrenia, and 22 healthy controls were evaluated. The bipolar disorder cases comprised 10 depressed patients, 15 patients with mania, and 10 euthymic patients. The N1/P2 peak-to-peak amplitudes were measured at 5 stimulus intensities, and the LDAEP was calculated as the slope of the linear regression. Both cortical and source LDAEP values were calculated. Results LDAEP varied according to mood statuses, and was significantly stronger in cases of euthymia, depression, and mania. Cortical LDAEP was significantly stronger in patients with bipolar euthymia compared with schizophrenia, stronger in bipolar depression than in schizophrenia, stronger in healthy controls than in schizophrenia patients, and stronger in healthy controls than in patients with bipolar mania. Source LDAEP was significantly stronger in patients with bipolar euthymia, bipolar depression, and bipolar mania compared with schizophrenia, stronger in bipolar euthymia than in bipolar mania. Psychotic features weakened the source LDAEP relative to nonpsychotic features. The severity of the depressive symptom was negatively correlated with source LDAEP. Conclusion These findings suggest that the serotonin activity of patients with bipolar disorder may vary according to mood status. A longitudinal follow-up study should be pursued using drug-naive subjects. PMID:22993531

  20. Agonist-dependence of functional properties for common nonsynonymous variants of human transient receptor potential vanilloid 1.

    PubMed

    Wang, Sen; Joseph, John; Diatchenko, Luda; Ro, Jin Y; Chung, Man-Kyo

    2016-07-01

    Transient receptor potential vanilloid 1 (TRPV1) is a polymodal receptor activated by capsaicin, heat, and acid, which plays critical roles in thermosensation and pain. In addition, TRPV1 also contributes to multiple pathophysiological states in respiratory, cardiovascular, metabolic, and renal systems. These contributions are further supported by evidence that variations in the human TRPV1 (hTRPV1) gene are associated with various physiological and pathological phenotypes. However, it is not well understood how the variations in hTRPV1 affect channel functions. In this study, we examined functional consequences of amino acid variations of hTRPV1 induced by 5 nonsynonymous single-nucleotide polymorphisms (SNPs) that most commonly exist in the human population. Using electrophysiological assays in HEK293 cells, we examined 9 parameters: activation, Ca permeation, and desensitization after activation by capsaicin, acid, and heat. Our results demonstrated that the 5 SNPs differentially affected functional properties of hTRPV1 in an agonist-dependent manner. Based upon the directionality of change of each phenotype and cumulative changes in each SNP, we classified the 5 SNPs into 3 presumptive functional categories: gain of function (hTRPV1 Q85R, P91S, and T469I), loss of function (I585V), and mixed (M315I). These results reveal a spectrum of functional variation among common hTRPV1 polymorphisms in humans and may aid mechanistic interpretation of phenotypes associated with nonsynonymous hTRPV1 SNPs under pathophysiological conditions. PMID:26967694

  1. Vanishing rainbows near orbiting and the energy dependence of rainbow scattering - Relation to properties of the potential. [molecular beam scattering cross sections

    NASA Technical Reports Server (NTRS)

    Greene, E. F.; Hall, R. B.; Mason, E. A.

    1975-01-01

    The energy threshold behavior of elastic rainbow scattering near the transition to orbiting is derived. Analysis of the energy dependence of the rainbow angle shows that the full range from high energies down to orbiting can be fitted with two parameters. Thus, measurements of the rainbow angle can give essentially only two pieces of information about the potential. For potentials of common shapes, such measurements are sensitive to regions of the potential just beyond the minimum and give information about the shape of the potential in this range. However, neither a minimum nor a point of inflection in the potential is necessary for rainbow scattering.

  2. Communication: Rigorous quantum dynamics of O + O{sub 2} exchange reactions on an ab initio potential energy surface substantiate the negative temperature dependence of rate coefficients

    SciTech Connect

    Li, Yaqin; Sun, Zhigang E-mail: dawesr@mst.edu; Jiang, Bin; Guo, Hua E-mail: dawesr@mst.edu; Xie, Daiqian; Dawes, Richard E-mail: dawesr@mst.edu

    2014-08-28

    The kinetics and dynamics of several O + O{sub 2} isotope exchange reactions have been investigated on a recently determined accurate global O{sub 3} potential energy surface using a time-dependent wave packet method. The agreement between calculated and measured rate coefficients is significantly improved over previous work. More importantly, the experimentally observed negative temperature dependence of the rate coefficients is for the first time rigorously reproduced theoretically. This negative temperature dependence can be attributed to the absence in the new potential energy surface of a submerged “reef” structure, which was present in all previous potential energy surfaces. In addition, contributions of rotational excited states of the diatomic reactant further accentuate the negative temperature dependence.

  3. Role of membrane potential in endothelium-dependent relaxation of guinea-pig coronary arterial smooth muscle.

    PubMed

    Parkington, H C; Tonta, M A; Coleman, H A; Tare, M

    1995-04-15

    1. Membrane potential and tension were measured simultaneously in ring segments of main coronary artery of guinea-pigs. The synthetic thromboxane A2 analogue U46619 depolarized the tissues from -58 +/- 2 to -40 +/- 1 mV and increased tension by 12 +/- 1 mN mm-1. Nitric oxide (NO) and Iloprost, the stable analogue of prostacyclin, evoked hyperpolarization and relaxation. 2. The concentration of NO required to evoke half-maximal hyperpolarization (EC50 of 2 x 10(-5) M) was 40-fold higher than that which was required to induce relaxation (EC50 of 5 x 10(-7) M). The EC50 for Iloprost-induced hyperpolarization (3 x 10(-8) M) was similar to that for relaxation (4 x 10(-8) M). 3. Glibenclamide (10(-6) M) abolished the hyperpolarization in response to both NO and Iloprost but was without effect on the amplitudes of the relaxations over the complete concentration-response curves. 4. Acetylcholine evoked concentration-dependent hyperpolarization and relaxation in the presence of N omega-nitro-L-arginine methyl ester (NAME; 10(-5) M) and indomethacin (10(-6) M), and these responses were attributed to endothelium-derived hyperpolarizing factor (EDHF). The hyperpolarization produced by EDHF always preceded relaxation, and relaxation never occurred at concentrations of acetylcholine that were insufficient to evoke hyperpolarization. 5. The concentration-hyperpolarization and concentration-relaxation curves in response to acetylcholine were not affected by glibenclamide or barium (1-3 mM) but were shifted to the right 4- and 5-fold, respectively, by 1 mM tetraethylammonium. The hyperpolarization and relaxation evoked by acetylcholine were also reduced in a parallel manner when the potassium concentration in the superfusate was increased. 6. Hyperpolarizing current steps, applied to spiral strips of coronary artery denuded of endothelium and depolarized and constricted with U46619, caused relaxation. The relationship between hyperpolarization and relaxation evoked electronically

  4. Maximum diastolic potential of human induced pluripotent stem cell-derived cardiomyocytes depends critically on I(Kr).

    PubMed

    Doss, Michael Xavier; Di Diego, José M; Goodrow, Robert J; Wu, Yuesheng; Cordeiro, Jonathan M; Nesterenko, Vladislav V; Barajas-Martínez, Héctor; Hu, Dan; Urrutia, Janire; Desai, Mayurika; Treat, Jacqueline A; Sachinidis, Agapios; Antzelevitch, Charles

    2012-01-01

    Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) hold promise for therapeutic applications. To serve these functions, the hiPSC-CM must recapitulate the electrophysiologic properties of native adult cardiomyocytes. This study examines the electrophysiologic characteristics of hiPSC-CM between 11 and 121 days of maturity. Embryoid bodies (EBs) were generated from hiPS cell line reprogrammed with Oct4, Nanog, Lin28 and Sox2. Sharp microelectrodes were used to record action potentials (AP) from spontaneously beating clusters (BC) micro-dissected from the EBs (n = 103; 37°C) and to examine the response to 5 µM E-4031 (n = 21) or BaCl(2) (n = 22). Patch-clamp techniques were used to record I(Kr) and I(K1) from cells enzymatically dissociated from BC (n = 49; 36°C). Spontaneous cycle length (CL) and AP characteristics varied widely among the 103 preparations. E-4031 (5 µM; n = 21) increased Bazett-corrected AP duration from 291.8±81.2 to 426.4±120.2 msec (p<0.001) and generated early afterdepolarizations in 8/21 preparations. In 13/21 BC, E-4031 rapidly depolarized the clusters leading to inexcitability. BaCl(2), at concentrations that selectively block I(K1) (50-100 µM), failed to depolarize the majority of clusters (13/22). Patch-clamp experiments revealed very low or negligible I(K1) in 53% (20/38) of the cells studied, but presence of I(Kr) in all (11/11). Consistent with the electrophysiological data, RT-PCR and immunohistochemistry studies showed relatively poor mRNA and protein expression of I(K1) in the majority of cells, but robust expression of I(Kr.) In contrast to recently reported studies, our data point to major deficiencies of hiPSC-CM, with remarkable diversity of electrophysiologic phenotypes as well as pharmacologic responsiveness among beating clusters and cells up to 121 days post-differentiation (dpd). The vast majority have a maximum diastolic potential that depends critically on I(Kr) due to the

  5. Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress.

    PubMed

    Shi, Y; Yang, Y; Hoang, B; Bardeleben, C; Holmes, B; Gera, J; Lichtenstein, A

    2016-02-25

    Protein translation is inhibited by the unfolded protein response (UPR)-induced eIF-2α phosphorylation to protect against endoplasmic reticulum (ER) stress. In addition, we found additional inhibition of protein translation owing to diminished mTORC1 (mammalian target of rapamycin complex1) activity in ER-stressed multiple myeloma (MM) cells. However, c-myc protein levels and myc translation was maintained. To ascertain how c-myc was maintained, we studied myc IRES (internal ribosome entry site) function, which does not require mTORC1 activity. Myc IRES activity was upregulated in MM cells during ER stress induced by thapsigargin, tunicamycin or the myeloma therapeutic bortezomib. IRES activity was dependent on upstream MAPK (mitogen-activated protein kinase) and MNK1 (MAPK-interacting serine/threonine kinase 1) signaling. A screen identified hnRNP A1 (A1) and RPS25 as IRES-binding trans-acting factors required for ER stress-activated activity. A1 associated with RPS25 during ER stress and this was prevented by an MNK inhibitor. In a proof of principle, we identified a compound that prevented binding of A1 to the myc IRES and specifically inhibited myc IRES activity in MM cells. This compound, when used alone, was not cytotoxic nor did it inhibit myc translation or protein expression. However, when combined with ER stress inducers, especially bortezomib, a remarkable synergistic cytotoxicity ensued with associated inhibition of myc translation and expression. These results underscore the potential for targeting A1-mediated myc IRES activity in MM cells during ER stress. PMID:25961916

  6. The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy.

    PubMed

    Smilansky, Angela; Dangoor, Liron; Nakdimon, Itay; Ben-Hail, Danya; Mizrachi, Dario; Shoshan-Barmatz, Varda

    2015-12-25

    The voltage-dependent anion channel 1 (VDAC1), found in the mitochondrial outer membrane, forms the main interface between mitochondrial and cellular metabolisms, mediates the passage of a variety of molecules across the mitochondrial outer membrane, and is central to mitochondria-mediated apoptosis. VDAC1 is overexpressed in post-mortem brains of Alzheimer disease (AD) patients. The development and progress of AD are associated with mitochondrial dysfunction resulting from the cytotoxic effects of accumulated amyloid β (Aβ). In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in Aβ cell penetration and cell death induction. Aβ directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated Aβ interacted with bilayer-reconstituted VDAC1 and increased its conductance ∼ 2-fold. Incubation of cells with Aβ resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented Aβ cellular entry and Aβ-induced mitochondria-mediated apoptosis. Likewise, silencing VDAC1 expression by specific siRNA prevented Aβ entry into the cytosol as well as Aβ-induced toxicity. Finally, the mode of Aβ-mediated action involves detachment of mitochondria-bound hexokinase, induction of VDAC1 oligomerization, and cytochrome c release, a sequence of events leading to apoptosis. As such, we suggest that Aβ-mediated toxicity involves mitochondrial and plasma membrane VDAC1, leading to mitochondrial dysfunction and apoptosis induction. The VDAC1-N-Ter peptide targeting Aβ cytotoxicity is thus a potential new therapeutic strategy for AD treatment. PMID:26542804

  7. Caspase Dependent Programmed Cell Death in Developing Embryos: A Potential Target for Therapeutic Intervention against Pathogenic Nematodes

    PubMed Central

    Mohapatra, Alok Das; Kumar, Sunil; Satapathy, Ashok Kumar; Ravindran, Balachandran

    2011-01-01

    Background Successful embryogenesis is a critical rate limiting step for the survival and transmission of parasitic worms as well as pathology mediated by them. Hence, blockage of this important process through therapeutic induction of apoptosis in their embryonic stages offers promise for developing effective anti-parasitic measures against these extra cellular parasites. However, unlike in the case of protozoan parasites, induction of apoptosis as a therapeutic approach is yet to be explored against metazoan helminth parasites. Methodology/Principal Findings For the first time, here we developed and evaluated flow cytometry based assays to assess several conserved features of apoptosis in developing embryos of a pathogenic filarial nematode Setaria digitata, in-vitro as well as ex-vivo. We validated programmed cell death in developing embryos by using immuno-fluorescence microscopy and scoring expression profile of nematode specific proteins related to apoptosis [e.g. CED-3, CED-4 and CED-9]. Mechanistically, apoptotic death of embryonic stages was found to be a caspase dependent phenomenon mediated primarily through induction of intracellular ROS. The apoptogenicity of some pharmacological compounds viz. DEC, Chloroquine, Primaquine and Curcumin were also evaluated. Curcumin was found to be the most effective pharmacological agent followed by Primaquine while Chloroquine displayed minimal effect and DEC had no demonstrable effect. Further, demonstration of induction of apoptosis in embryonic stages by lipid peroxidation products [molecules commonly associated with inflammatory responses in filarial disease] and demonstration of in-situ apoptosis of developing embryos in adult parasites in a natural bovine model of filariasis have offered a framework to understand anti-fecundity host immunity operational against parasitic helminths. Conclusions/Significance Our observations have revealed for the first time, that induction of apoptosis in developing embryos can

  8. A self-consistent, microenvironment modulated screened coulomb potential approximation to calculate pH-dependent electrostatic effects in proteins.

    PubMed

    Mehler, E L; Guarnieri, F

    1999-07-01

    An improved approach is presented for calculating pH-dependent electrostatic effects in proteins using sigmoidally screened Coulomb potentials (SCP). It is hypothesized that a key determinant of seemingly aberrant behavior in pKa shifts is due to the properties of the unique microenvironment around each residue. To help demonstrate this proposal, an approach is developed to characterize the microenvironments using the local hydrophobicity/hydrophilicity around each residue of the protein. The quantitative characterization of the microenvironments shows that the protein is a complex mosaic of differing dielectric regions that provides a physical basis for modifying the dielectric screening functions: in more hydrophobic microenvironments the screening decreases whereas the converse applies to more hydrophilic regions. The approach was applied to seven proteins providing more than 100 measured pKa values and yielded a root mean square deviation of 0.5 between calculated and experimental values. The incorporation of the local hydrophobicity characteristics into the algorithm allowed the resolution of some of the more intractable problems in the calculation of pKa. Thus, the divergent shifts of the pKa of Glu-35 and Asp-66 in hen egg white lysozyme, which are both about 90% buried, was correctly predicted. Mechanistically, the divergence occurs because Glu-35 is in a hydrophobic microenvironment, while Asp-66 is in a hydrophilic microenvironment. Furthermore, because the calculation of the microenvironmental effects takes very little CPU time, the computational speed of the SCP formulation is conserved. Finally, results from different crystal structures of a given protein were compared, and it is shown that the reliability of the calculated pKa values is sufficient to allow identification of conformations that may be more relevant for the solution structure. PMID:10388736

  9. Exploring the Antibacterial and Antifungal Potential of Jellyfish-Associated Marine Fungi by Cultivation-Dependent Approaches

    PubMed Central

    Yue, Yang; Yu, Huahua; Li, Rongfeng; Xing, Ronge; Liu, Song; Li, Pengcheng

    2015-01-01

    Fungi isolated from marine invertebrates are of considerable importance as new promising sources of unique secondary metabolites with significant biomedical potential. However, the cultivable fungal community harbored in jellyfish was less investigated. In this work, we seek to recover symbiotic fungi from different tissues of jellyfish Nemopilema nomurai. A total of seven morphotypes were isolated, which were assigned into four genera (Aspergillus, Cladosporium, Purpureocillium, and Tilletiopsis) from two phyla (Ascomycota and Basidiomycota) by comparing the rDNA-ITS sequences with the reference sequences in GenBank. The most fungi were found in the inner tissues of subumbrella. Two of the cultivation-independent procedures, changing media type and co-cultivation, were employed to maximize the complexity of metabolites. Thus, thirteen EtOAc gum were obtained and fingerprinted by High Performance Liquid Chromatography (HPLC) equipped with a photodiode array (PDA) detector. Antibacterial and antifungal activities of these complex mixtures were tested against a panel of bacterial and fungal pathogens. The antimicrobial results showed that all of the 13 EtOAc extracts displayed different levels of antibacterial activity, three of which exhibited strong to significant antibacterial activity to the bacterial pathogens Staphylococcus aureus and Salmonella entrica. Antifungal activity indicated that the EtOAc extracts from pure culture of Aspergillus versicolor and co-culture of A. versicolor and Tilletiopsis sp. in rice media were promising for searching new compounds, with the maximal mycelial growth inhibition of 82.32% ± 0.61% for Rhizoctonia solani and 48.41% ± 11.02% for Botrytis cinerea at 200 μg/ml, respectively. This study is the first report on the antibacterial and antifungal activity of jellyfish-associated fungi and allows the first sight into cultivable fungal community residing in jellyfish. Induced metabolites by cultivation-dependent approaches

  10. 2100-MHz electromagnetic fields have different effects on visual evoked potentials and oxidant/antioxidant status depending on exposure duration.

    PubMed

    Hidisoglu, Enis; Kantar Gok, Deniz; Er, Hakan; Akpinar, Deniz; Uysal, Fatma; Akkoyunlu, Gokhan; Ozen, Sukru; Agar, Aysel; Yargicoglu, Piraye

    2016-03-15

    The purpose of the present study was to investigate the duration effects of 2100-MHz electromagnetic field (EMF) on visual evoked potentials (VEPs) and to assess lipid peroxidation (LPO), nitric oxide (NO) production and antioxidant status of EMF exposed rats. Rats were randomized to following groups: Sham rats (S1 and S10) and rats exposed to 2100-MHz EMF (E1 and E10) for 2h/day for 1 or 10 weeks, respectively. At the end of experimental periods, VEPs were recorded under anesthesia. Brain thiobarbituric acid reactive substances (TBARS) and 4-hydroxy-2-nonenal (4-HNE) levels were significantly decreased in the E1 whereas increased in the E10 compared with their control groups. While brain catalase (CAT), glutathione peroxidase (GSH-Px) activities and NO and glutathione (GSH) levels were significantly increased in the E1, reduction of superoxide dismutase (SOD) activity was detected in the same group compared with the S1. Conversely, decreased CAT, GSH-Px activities and NO levels were observed in the E10 compared with the S10. Latencies of all VEP components were shortened in the E1 compared with the S1, whereas latencies of all VEP components, except P1, were prolonged in the E10 compared with the S10. There was a positive correlation between all VEP latencies and brain TBARS and 4-HNE values. Consequently, it could be concluded that different effects of EMFs on VEPs depend on exposure duration. In addition, our results indicated that short-term EMF could provide protective effects, while long-term EMF could have an adverse effect on VEPs and oxidant/antioxidant status. PMID:26776477

  11. A Context-Dependent View on the Linguistic Interdependence Hypothesis: Language Use and SES as Potential Moderators

    ERIC Educational Resources Information Center

    Prevoo, Mariëlle J. L.; Malda, Maike; Emmen, Rosanneke A. G.; Yeniad, Nihal; Mesman, Judi

    2015-01-01

    The linguistic interdependence hypothesis states that the development of skills in a second language (L2) partly depends on the skill level in the first language (L1). It has been suggested that the theory lacked attention for differential interdependence. In this study we test what we call the hypothesis of context-dependent linguistic…

  12. Two strictly polyphosphate-dependent gluco(manno)kinases from diazotrophic Cyanobacteria with potential to phosphorylate hexoses from polyphosphates.

    PubMed

    Albi, Tomás; Serrano, Aurelio

    2015-05-01

    The single-copy genes encoding putative polyphosphate-glucose phosphotransferases (PPGK, EC 2.7.1.63) from two nitrogen-fixing Cyanobacteria, Nostoc sp. PCC7120 and Nostoc punctiforme PCC73102, were cloned and functionally characterized. In contrast to their actinobacterial counterparts, the cyanobacterial PPGKs have shown the ability to phosphorylate glucose using strictly inorganic polyphosphates (polyP) as phosphoryl donors. This has proven to be an economically attractive reagent in contrast to the more costly ATP. Cyanobacterial PPGKs had a higher affinity for medium-long-sized polyP (greater than ten phosphoryl residues). Thus, longer polyP resulted in higher catalytic efficiency. Also in contrast to most their homologs in Actinobacteria, both cyanobacterial PPGKs exhibited a modest but significant polyP-mannokinase activity as well. Specific activities were in the range of 180-230 and 2-3 μmol min(-1) mg(-1) with glucose and mannose as substrates, respectively. No polyP-fructokinase activity was detected. Cyanobacterial PPGKs required a divalent metal cofactor and exhibited alkaline pH optima (approx. 9.0) and a remarkable thermostability (optimum temperature, 45 °C). The preference for Mg(2+) was noted with an affinity constant of 1.3 mM. Both recombinant PPGKs are homodimers with a subunit molecular mass of ca. 27 kDa. Based on database searches and experimental data from Southern blots and activity assays, closely related PPGK homologs appear to be widespread among unicellular and filamentous mostly nitrogen-fixing Cyanobacteria. Overall, these findings indicate that polyP may be metabolized in these photosynthetic prokaryotes to yield glucose (or mannose) 6-phosphate. They also provide evidence for a novel group-specific subfamily of strictly polyP-dependent gluco(manno)kinases with ancestral features and high biotechnological potential, capable of efficiently using polyP as an alternative and cheap source of energy-rich phosphate instead of costly ATP

  13. Avoidance of a potential tracheoinnominate fistula by innominate artery re-implantation in a four year old girl with tracheostomy dependence and Pfeiffer syndrome.

    PubMed

    Olson, Michael D; Boesch, R Paul; Duncan, Audra A; Cofer, Shelagh A

    2016-02-01

    A 4 year old tracheostomy dependent girl with Pfeiffer syndrome was noted on bronchoscopy to have a pulsatile tracheostomal mass. CT chest angiography was consistent with the innominate artery crossing anterior to the trachea and superior to the sternal notch. The patient underwent reimplantation of the innominate artery via a median sternotomy approach. Tracheoinnominate fistula is a potentially devastating complication of tracheostomy. We report discovery of a near tracheoinnominate fistula in order to highlight the importance of regular interval surveillance endoscopy in tracheostomy dependent children and to discuss a preventative surgical intervention employed in prevention of this potentially devastating complication. PMID:26810298

  14. Self-augmentation of the lengthening of repolarization is related to the shape of the cardiac action potential: implications for reverse rate dependency

    PubMed Central

    Virág, László; Acsai, Károly; Hála, Ottó; Zaza, Antonio; Bitay, Miklós; Bogáts, Gábor; Papp, Julius Gy; Varró, András

    2009-01-01

    Background and purpose: The aims of the present work were to study the mechanism of the reverse rate dependency of different interventions prolonging cardiac action potential duration (APD). Experimental approach: The reverse rate-dependent lengthening effect of APD-prolonging interventions and the possible involvement of IKr (rapid component of the delayed rectifier potassium current) and IK1 (inward rectifier potassium current) were studied by using the standard microelectrode and the whole-cell patch-clamp techniques in dog multicellular ventricular preparations and in myocytes isolated from undiseased human and dog hearts. Key results: All applied drugs – dofetilide (1 µmol·L−1), BaCl2 (10 µmol·L−1), BAY-K-8644 (1 µmol·L−1), veratrine (1 µg·mL−1) – lengthened APD in a reverse rate-dependent manner regardless of their mode of action, suggesting that reverse rate dependency may not represent a specific mechanism of APD prolongation. The E-4031-sensitive current (IKr) and the Ba2+-sensitive current (IK1) were recorded during repolarizing voltage ramps having various steepness and also during action potential waveforms with progressively prolonged APD. Gradually delaying repolarization results in smaller magnitude of IKr and IK1 currents at an isochronal phase of the pulses. This represents a positive feedback mechanism, which appears to contribute to the reverse rate-dependent prolongation of action potentials. Conclusions and implications: Action potential configuration may influence the reverse rate-dependent APD prolongation due to the intrinsic properties of IKr and IK1 currents. Drugs lengthening repolarization by decreasing repolarizing outward, or increasing depolarizing inward, currents are expected to cause reverse rate-dependent APD lengthening with high probability, regardless of which current they modify. PMID:19226285

  15. INTERPRETATION OF THE CANCER RESPONSE TO POTENTIAL RENTAL CARCINOGENS IN THE TSC2 KNOCKOUT (EKER) RAT IS DEPENDENT ON LENGTH OF TREATMENT.

    EPA Science Inventory

    INTERPRETATION OF THE CANCER RESPONSE TO POTENTIAL RENAL CARCINOGENS IN THE TSC2 KNOCKOUT (EKER) RAT IS DEPENDENT ON LENGTH OF TREATMENT.

    Genetically increasing the function of oncogenes or knocking out the function of a tumor supressor gene has dramatically increased the...

  16. Learning-Dependent Potentiation in the Vibrissal Motor Cortex Is Closely Related to the Acquisition of Conditioned Whisker Responses in Behaving Mice

    ERIC Educational Resources Information Center

    Delgado-Garcia, Jose Maria; Troncoso, Julieta; Munera, Alejandro

    2007-01-01

    The role of the primary motor cortex in the acquisition of new motor skills was evaluated during classical conditioning of vibrissal protraction responses in behaving mice, using a trace paradigm. Conditioned stimulus (CS) presentation elicited a characteristic field potential in the vibrissal motor cortex, which was dependent on the synchronized…

  17. Quantization of time-dependent non-central singular potential systems in three dimensions by using the Nikiforov-Uvarov method

    NASA Astrophysics Data System (ADS)

    Menouar, Salah; Choi, Jeong Ryeol

    2016-02-01

    Quantum solutions of a time-dependent Hamiltonian for the motion of a time-varying mass subjected to time-dependent singular potentials in three dimensions are investigated. A time-dependent inverse quadratic potential and a Coulomb-like potential are considered as the components of the singular potential of the system. Because the Hamiltonian is a function of time, special techniques for deriving quantum solutions of the system are necessary. A quadratic invariant operator is introduced, and its eigenstates are derived using the Nikiforov-Uvarov method together with a unitary transformation method. The Nikiforov-Uvarov method enables us to solve the eigenvalue equations of the invariant operator, which are second-order linear diffierential equations, by reducing the original equation to a hypergeometric type. According to the invariant operator theory, the wave functions of the system are represented in terms of the eigenstates obtained in such a way. The difference of the wave functions from the eigenstates of the invariant operator is that the wave functions have time-dependent phases while the eigenstates do not. By determining the phases of the wave functions via the help of the Schr¨odinger equation, we identify the full wave functions of the system and address their physical implications.

  18. Comment on 'Wave functions for a Duffin-Kemmer-Petiau particle in a time-dependent potential' [J. Math. Phys. 48, 073515 (2007)

    SciTech Connect

    Castro, L. B.; Castro, A. S. de

    2010-03-15

    It is shown that the paper 'Wave functions for a Duffin-Kemmer-Petiau particle in a time-dependent potential' by Merad and Bensaid [J. Math. Phys. 48, 073515 (2007)] is not correct in using inadvertently a non-Hermitian Hamiltonian in a formalism that does require Hermitian Hamiltonians.

  19. Dynamic subnuclear relocalization of WRKY40, a potential new mechanism of ABA-dependent transcription factor regulation

    PubMed Central

    Geilen, Katja; Böhmer, Maik

    2015-01-01

    The phytohormone ABA plays a major role during plant development, e.g. seed maturation and seed germination, and during adaptation to abiotic stresses like stomatal aperture regulation. The three closely related WRKY transcription factors WRKY18, WRKY40 and WRKY60 function in ABA signal transduction. We recently demonstrated that WRKY18 and WRKY40 but not WRKY60 localize to nuclear bodies in A. thaliana mesophyll protoplasts. WRKY40, a negative regulator of ABA-dependent inhibition of seed germination, relocalizes from PNBs to the nucleoplasm in the presence of ABA in a dynamic and phosphorylation-dependent manner. We propose that subnuclear relocalization of WRKY40 might constitute a new regulatory mechanism of ABA-dependent modulation of transcription factor activity. PMID:26479147

  20. Dynamic subnuclear relocalization of WRKY40, a potential new mechanism of ABA-dependent transcription factor regulation.

    PubMed

    Geilen, Katja; Böhmer, Maik

    2015-01-01

    The phytohormone ABA plays a major role during plant development, e.g. seed maturation and seed germination, and during adaptation to abiotic stresses like stomatal aperture regulation. The three closely related WRKY transcription factors WRKY18, WRKY40 and WRKY60 function in ABA signal transduction. We recently demonstrated that WRKY18 and WRKY40 but not WRKY60 localize to nuclear bodies in A. thaliana mesophyll protoplasts. WRKY40, a negative regulator of ABA-dependent inhibition of seed germination, relocalizes from PNBs to the nucleoplasm in the presence of ABA in a dynamic and phosphorylation-dependent manner. We propose that subnuclear relocalization of WRKY40 might constitute a new regulatory mechanism of ABA-dependent modulation of transcription factor activity. PMID:26479147

  1. Control of nanoscale friction on gold in an ionic liquid by a potential-dependent ionic lubricant layer.

    PubMed

    Sweeney, James; Hausen, Florian; Hayes, Robert; Webber, Grant B; Endres, Frank; Rutland, Mark W; Bennewitz, Roland; Atkin, Rob

    2012-10-12

    The lubricating properties of an ionic liquid on gold surfaces can be controlled through application of an electric potential to the sliding contact. A nanotribology approach has been used to study the frictional behavior of 1-butyl-1-methylpyrrolidinium tris(pentafluoroethyl) trifluorophosphate ([Py(1,4)]FAP) confined between silica colloid probes or sharp silica tips and a Au(111) substrate using atomic force microscopy. Friction forces vary with potential because the composition of a confined ion layer between the two surfaces changes from cation-enriched (at negative potentials) to anion-enriched (at positive potentials). This offers a new approach to tuning frictional forces reversibly at the molecular level without changing the substrates, employing a self-replenishing boundary lubricant of low vapor pressure. PMID:23102330

  2. Control of Nanoscale Friction on Gold in an Ionic Liquid by a Potential-Dependent Ionic Lubricant Layer

    NASA Astrophysics Data System (ADS)

    Sweeney, James; Hausen, Florian; Hayes, Robert; Webber, Grant B.; Endres, Frank; Rutland, Mark W.; Bennewitz, Roland; Atkin, Rob

    2012-10-01

    The lubricating properties of an ionic liquid on gold surfaces can be controlled through application of an electric potential to the sliding contact. A nanotribology approach has been used to study the frictional behavior of 1-butyl-1-methylpyrrolidinium tris(pentafluoroethyl) trifluorophosphate ([Py1,4]FAP) confined between silica colloid probes or sharp silica tips and a Au(111) substrate using atomic force microscopy. Friction forces vary with potential because the composition of a confined ion layer between the two surfaces changes from cation-enriched (at negative potentials) to anion-enriched (at positive potentials). This offers a new approach to tuning frictional forces reversibly at the molecular level without changing the substrates, employing a self-replenishing boundary lubricant of low vapor pressure.

  3. Host sex-dependent growth of potential Thy-1+ lymphoma cells that appear in the thymus of X-irradiated NFS mice

    SciTech Connect

    Mori, N.; Takamori, Y. )

    1990-01-01

    During the course of studies designed to detect potentially leukemic cells in radiation lymphomagenesis, using an opposite-sex (male----female) transplantation assay method, we previously found that potential Thy-1- lymphoma cells are generated in the bone marrow of NFS mice exposed to a split-dose irradiation (1.7 Gy X 4), while potential Thy-1+ lymphoma cells are not detectable. In this report, using a (female----male) intrathymic transplantation assay system we show that potential Thy-1+ lymphoma cells were generated in the thymus of female NFS mice exposed to split-dose irradiation, and reconfirm that such cells were not detected in the (male----female) transplantation system. These results demonstrate that the detection of potential Thy-1+ lymphoma cells strictly depends on the transplantation system.

  4. In skeletal muscle the relaxation of the resting membrane potential induced by K(+) permeability changes depends on Cl(-) transport.

    PubMed

    Geukes Foppen, R J

    2004-01-01

    In resting skeletal muscle the potassium permeability is determined by the permeability of the inwardly potassium rectifier. Continuous resting membrane potential measurements are done to follow the relaxation of the membrane potential upon changes in potassium permeability. Inhibition of the inwardly potassium rectifier, by extracellular application of 80 microM Ba(2+), causes the cell to depolarize with mean time constants as follows: in control 127+/-7 s ( n=23), in the presence of bumetanide, as an inhibitor of the Na(+)/K(+)/2Cl(-) cotransporter, 182+/-23 s ( n=7), in hypertonic media (340 mosmol/kg) 90.4+/-5 s ( n=7) and in reduced chloride medium 64+/-8 s ( n=5). The depolarizing relaxation of the membrane potential induced by reduction of extracellular potassium produces similar results. These time constants are at least three orders of magnitude slower than the time constants reported in the literature for the inhibition of the inwardly potassium rectifier. Chloride transport affects the relaxation of the membrane potential. A further characterization of chloride transport is done by following the relaxation of the membrane potential upon application of chloride transport modulators. It is argued that the electroneutral cotransporter, for which a flux was preliminarily estimated of 13.4 pmol cm(-2) s(-1), has a considerable role in the processes related to the resting membrane potential. PMID:14648122

  5. POTENTIATING AND PROTECTIVE EFFECTS OF ASCORBATE ON OXIDATIVE STRESS DEPENDS UPON DIETARY IRON CONCENTRATION FED TO C3H MICE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ascorbic acid (AA) is an antioxidant that in the presence of iron and hydrogen peroxide increases the production of hydroxyl radicals in vitro. Whether AA has similar pro-oxidant properties in vivo may depend upon the relative balance of iron and ascorbic acid concentrations. In this study, C3H mice...

  6. Kohn–Sham approach to quantum electrodynamical density-functional theory: Exact time-dependent effective potentials in real space

    PubMed Central

    Flick, Johannes; Ruggenthaler, Michael; Appel, Heiko; Rubio, Angel

    2015-01-01

    The density-functional approach to quantum electrodynamics extends traditional density-functional theory and opens the possibility to describe electron–photon interactions in terms of effective Kohn–Sham potentials. In this work, we numerically construct the exact electron–photon Kohn–Sham potentials for a prototype system that consists of a trapped electron coupled to a quantized electromagnetic mode in an optical high-Q cavity. Although the effective current that acts on the photons is known explicitly, the exact effective potential that describes the forces exerted by the photons on the electrons is obtained from a fixed-point inversion scheme. This procedure allows us to uncover important beyond-mean-field features of the effective potential that mark the breakdown of classical light–matter interactions. We observe peak and step structures in the effective potentials, which can be attributed solely to the quantum nature of light; i.e., they are real-space signatures of the photons. Our findings show how the ubiquitous dipole interaction with a classical electromagnetic field has to be modified in real space to take the quantum nature of the electromagnetic field fully into account. PMID:26627715

  7. Kohn-Sham approach to quantum electrodynamical density-functional theory: Exact time-dependent effective potentials in real space.

    PubMed

    Flick, Johannes; Ruggenthaler, Michael; Appel, Heiko; Rubio, Angel

    2015-12-15

    The density-functional approach to quantum electrodynamics extends traditional density-functional theory and opens the possibility to describe electron-photon interactions in terms of effective Kohn-Sham potentials. In this work, we numerically construct the exact electron-photon Kohn-Sham potentials for a prototype system that consists of a trapped electron coupled to a quantized electromagnetic mode in an optical high-Q cavity. Although the effective current that acts on the photons is known explicitly, the exact effective potential that describes the forces exerted by the photons on the electrons is obtained from a fixed-point inversion scheme. This procedure allows us to uncover important beyond-mean-field features of the effective potential that mark the breakdown of classical light-matter interactions. We observe peak and step structures in the effective potentials, which can be attributed solely to the quantum nature of light; i.e., they are real-space signatures of the photons. Our findings show how the ubiquitous dipole interaction with a classical electromagnetic field has to be modified in real space to take the quantum nature of the electromagnetic field fully into account. PMID:26627715

  8. Nitric oxide-dependent long-term depression but not endocannabinoid-mediated long-term potentiation is crucial for visual recognition memory

    PubMed Central

    Tamagnini, Francesco; Barker, Gareth; Warburton, E Clea; Burattini, Costanza; Aicardi, Giorgio; Bashir, Zafar I

    2013-01-01

    Synaptic plasticity in perirhinal cortex is essential for recognition memory. Nitric oxide and endocannabinoids (eCBs), which are produced in the postsynaptic cell and act on the presynaptic terminal, are implicated in mechanisms of long-term potentiation (LTP) and long-term depression (LTD) in other brain regions. In this study, we examine these two retrograde signalling cascades in perirhinal cortex synaptic plasticity and in visual recognition memory in the rat. We show that inhibition of NO-dependent signalling prevented both carbachol- and activity (5 Hz)-dependent LTD but not activity (100 Hz theta burst)-dependent LTP in the rat perirhinal cortex in vitro. In contrast, inhibition of the eCB-dependent signalling prevented LTP but not the two forms of LTD in vitro. Local administration into perirhinal cortex of the nitric oxide synthase inhibitor NPA (2 μm) disrupted acquisition of long-term visual recognition memory. In contrast, AM251 (10 μm), a cannabinoid receptor 1 antagonist, did not impair visual recognition memory. The results of this study demonstrate dissociation between putative retrograde signalling mechanisms in LTD and LTP in perirhinal cortex. Thus, LTP relies on cannabinoid but not NO signalling, whilst LTD relies on NO- but not eCB-dependent signalling. Critically, these results also establish, for the first time, that NO- but not eCB-dependent signalling is important in perirhinal cortex-dependent visual recognition memory. PMID:23671159

  9. Learning-dependent potentiation in the vibrissal motor cortex is closely related to the acquisition of conditioned whisker responses in behaving mice

    PubMed Central

    Troncoso, Julieta; Múnera, Alejandro; Delgado-García, José María

    2007-01-01

    The role of the primary motor cortex in the acquisition of new motor skills was evaluated during classical conditioning of vibrissal protraction responses in behaving mice, using a trace paradigm. Conditioned stimulus (CS) presentation elicited a characteristic field potential in the vibrissal motor cortex, which was dependent on the synchronized firing of layer V pyramidal cells. CS-evoked and other event-related potentials were particular cases of a motor cortex oscillatory state related to the increased firing of pyramidal neurons and to vibrissal activities. Along conditioning sessions, but not during pseudoconditioning, CS-evoked field potentials and unitary pyramidal cell responses grew with a time-course similar to the percentage of vibrissal conditioned responses (CRs), and correlated significantly with CR parameters. High-frequency stimulation of barrel cortex afferents to the vibrissal motor cortex mimicked CS-related potentials growth, suggesting that the latter process was due to a learning-dependent potentiation of cortico-cortical synaptic inputs. This potentiation seemed to enhance the efficiency of cortical commands to whisker-pad intrinsic muscles, enabling the generation of acquired motor responses. PMID:17272653

  10. Does Silent Reading Speed in Normal Adult Readers Depend on Early Visual Processes? Evidence from Event-Related Brain Potentials

    ERIC Educational Resources Information Center

    Korinth, Sebastian Peter; Sommer, Werner; Breznitz, Zvia

    2012-01-01

    Little is known about the relationship of reading speed and early visual processes in normal readers. Here we examined the association of the early P1, N170 and late N1 component in visual event-related potentials (ERPs) with silent reading speed and a number of additional cognitive skills in a sample of 52 adult German readers utilizing a Lexical…

  11. Corticosterone Time-Dependently Modulates [beta]-Adrenergic Effects on Long-Term Potentiation in the Hippocampal Dentate Gyrus

    ERIC Educational Resources Information Center

    Pu, Zhenwei; Krugers, Harm J.; Joels, Marian

    2007-01-01

    Previous experiments in the hippocampal CA1 area have shown that corticosterone can facilitate long-term potentiation (LTP) in a rapid non-genomic fashion, while the same hormone suppresses LTP that is induced several hours after hormone application. Here, we elaborated on this finding by examining whether corticosterone exerts opposite effects on…

  12. A Protein Synthesis and Nitric Oxide-Dependent Presynaptic Enhancement in Persistent Forms of Long-Term Potentiation

    ERIC Educational Resources Information Center

    Johnstone, Victoria P. A.; Raymond, Clarke R.

    2011-01-01

    Long-term potentiation (LTP) is an important process underlying learning and memory in the brain. At CA3-CA1 synapses in the hippocampus, three discrete forms of LTP (LTP1, 2, and 3) can be differentiated on the basis of maintenance and induction mechanisms. However, the relative roles of pre- and post-synaptic expression mechanisms in LTP1, 2,…

  13. Activity-Dependent Calpain Activation Plays a Critical Role in Synaptic Facilitation and Post-Tetanic Potentiation

    ERIC Educational Resources Information Center

    Khoutorsky, Arkady; Spira, Micha E.

    2009-01-01

    Synaptic facilitation and post-tetanic potentiation (PTP) are believed to necessitate active regeneration of the release machinery and supply of synaptic vesicles to a ready-releasable site. The prevailing hypothesis assumes that synapsins play pivotal roles in these processes. Using a cholinergic synapse formed between cultured "Aplysia" neurons…

  14. Type II PKAs are anchored to mature insulin secretory granules in INS-1 β-cells and required for cAMP-dependent potentiation of exocytosis.

    PubMed

    Villalpando, Sabrina; Cazevieille, Chantal; Fernandez, Anne; Lamb, Ned J; Hani, El-Habib

    2016-06-01

    Specificity of the cAMP-dependent protein kinase (PKA) pathway relies on an extremely sophisticated compartmentalization mechanism of the kinase within a given cell, based on high-affinity binding of PKA tetramer pools to different A-Kinase Anchoring Proteins (AKAPs). We and others have previously shown that AKAPs-dependent PKA subcellular targeting is a requisite for optimal cAMP-dependent potentiation of insulin exocytosis. We thus hypothesized that a PKA pool may directly anchor to the secretory compartment to potentiate insulin exocytosis. Here, using immunofluorescence analyses combined to subcellular fractionations and purification of insulin secretory granules (ISGs), we identified discrete subpools of type II PKAs, RIIα and RIIβ PKAs, along with the catalytic subunit, physically associated with ISGs within pancreatic insulin-secreting β-cells. Ultrastructural analysis of native rodent β-cells confirmed in vivo the occurrence of PKA on dense-core ISGs. Isoform-selective disruption of binding of PKAs to AKAPs reinforced the requirement of type II PKA isoforms for cAMP potentiation of insulin exocytosis. This granular localization of PKA was of critical importance since siRNA-mediated depletion of either RIIα or RIIβ PKAs resulted in a significant reduction of cAMP-dependent potentiation of insulin release. The present work provides evidence for a previously unrecognized pool of type II PKAs physically anchored to the β-cell ISGs compartment and supports a non-redundant function for type II PKAs during cAMP potentiation of exocytosis. PMID:26898328

  15. Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol

    PubMed Central

    Epstein, David H.; Preston, Kenzie L.; Jasinski, Donald R.

    2010-01-01

    Assessment of abuse potential of opioid analgesics has a long history in both laboratory animals and humans. This article reviews the methods used in animals and in humans and then presents the data collected in the evaluation of tramadol, an atypical centrally acting opioid analgesic approved for marketing in the United States in 1998. Finally, data on the abuse of tramadol from postmarketing surveillance and case reports are presented. The consistency between animal and human study results and the predictive value of both are discussed. Overall, there was substantial agreement between animal and human data, with each having predictive value. Nonetheless, it is suggested that abuse-potential screening of new medications would benefit from an organized, integrated cross-species program. PMID:16497429

  16. A new ab initio potential energy surface for the NeCO complex with the vibrational coordinate dependence

    PubMed Central

    Wang, Zhongquan; Feng, Eryin; Yu, Haijun; Zhang, Chunzao; Du, Jianming

    2011-01-01

    A new high quality three-dimensional potential energy surface for the Ne–CO van der Waals complex is developed using the CCSD(T) method and avqz/avqz+33221 basis set. The ab initio calculation is performed in a total of 1365 configurations with supermolecule method. There is a single global minimum located in a nearly T-shaped geometry. The global minimum energy is −49.4090 cm−1 at Re =6.40a0 and θe =82.5° for V00 . Using the three-dimensional potential energy surface, we have calculated bound rovibrational energy levels up to J = 10 including the Coriolis coupling terms. Compared with the experimental transition frequencies, the theoretical results are in good agreement with the experimental results. PMID:21241112

  17. Dependence of the 0.7 anomaly on the curvature of the potential barrier in quantum wires

    NASA Astrophysics Data System (ADS)

    Smith, L. W.; Al-Taie, H.; Lesage, A. A. J.; Sfigakis, F.; See, P.; Griffiths, J. P.; Beere, H. E.; Jones, G. A. C.; Ritchie, D. A.; Hamilton, A. R.; Kelly, M. J.; Smith, C. G.

    2015-06-01

    Ninety-eight one-dimensional channels defined using split gates fabricated on a GaAs/AlGaAs heterostructure are measured during one cooldown at 1.4 K. The devices are arranged in an array on a single chip and are individually addressed using a multiplexing technique. The anomalous conductance feature known as the "0.7 structure" is studied using statistical techniques. The ensemble of data shows that the 0.7 anomaly becomes more pronounced and occurs at lower values as the curvature of the potential barrier in the transport direction decreases. This corresponds to an increase in the effective length of the device. The 0.7 anomaly is not strongly influenced by other properties of the conductance related to density. The curvature of the potential barrier appears to be the primary factor governing the shape of the 0.7 structure at a given T and B .

  18. Coupling of nuclear quadrupole and octupole degrees of freedom in an angular momentum dependent potential of two deformation variables

    SciTech Connect

    Minkov, N.; Yotov, P.; Drenska, S.; Scheid, W.; Bonatsos, Dennis; Lenis, D.; Petrellis, D.

    2006-04-26

    We propose a collective rotation-vibration Hamiltonian of nuclei in which the axial quadrupole {beta}2 and octupole {beta}3 variables are coupled through the centrifugal interaction. We consider that the system oscillates between positive and negative {beta}3-values by rounding a potential core in the ({beta}2,{beta}3)- space. We examine the effect of the 'rounding' in the structure of the spectrum.

  19. Bound and Scattering State of Position Dependent Mass Klein-Gordon Equation with Hulthen Plus Deformed-Type Hyperbolic Potential

    NASA Astrophysics Data System (ADS)

    Ikot, A. N.; Obong, H. P.; Abbey, T. M.; Zare, S.; Ghafourian, M.; Hassanabadi, H.

    2016-05-01

    In this article we use supersymmetry quantum mechanics and factorization methods to study the bound and scattering state of Klein-Gordon equation with deformed Hulthen plus deformed hyperbolical potential for arbitrary state in D-dimensions. The analytic relativistic bound state eigenvalues and the scattering phase factor are found in closed form. We report on the numerical results for the bound state energy in D-dimensions.

  20. Time-dependent reversal of long-term potentiation by brief cooling shocks in rat hippocampal slices.

    PubMed

    Bittar, P; Muller, D

    1993-08-27

    Using a recording chamber built with peltier elements, we studied the effects of fast and brief reductions in temperature on synaptic transmission and plasticity in area CA1 of rat hippocampal slices. Cooling shocks consisted of a drop in temperature from 33 degrees C to 30 degrees C, 27 degrees C or 24 degrees C for 2-5 min. Equilibrium to the new temperature was reached in about 30 s. During these cooling episodes, marked modifications of the size and time course of synaptic responses were observed. Changing the temperature for 4-5 min from 33 degrees C to 24 degrees C resulted in a 75% reduction in amplitude and 158% prolongation of the rise time of excitatory postsynaptic potentials (EPSPs). These changes were followed by a complete recovery of synaptic transmission. This recovery was very fast for the EPSP rise time (about 30 s), but much slower for the amplitude or initial slope (20-30 min). This slow recovery was correlated with changes in size of the presynaptic fiber volley, thereby indicating transient modifications of cell excitability. Application of cooling episodes of 4-5 min from 33 degrees C to 24 degrees C during the first 20 min that followed induction of long-term potentiation resulted in a complete reversal of synaptic potentiation. The LTP abolished by a cooling shock could be reinstated by re-applying high frequency trains. Several sequential induction/abolition effects could thus be obtained. In contrast, cooling episodes applied later than 25 min after LTP induction did not affect synaptic potentiation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8396492

  1. Malonate induces cell death via mitochondrial potential collapse and delayed swelling through an ROS-dependent pathway

    PubMed Central

    Fernandez-Gomez, Francisco J; Galindo, Maria F; Gómez-Lázaro, Maria; Yuste, Victor J; Comella, Joan X; Aguirre, Norberto; Jordán, Joaquín

    2005-01-01

    Herein we study the effects of the mitochondrial complex II inhibitor malonate on its primary target, the mitochondrion. Malonate induces mitochondrial potential collapse, mitochondrial swelling, cytochrome c (Cyt c) release and depletes glutathione (GSH) and nicotinamide adenine dinucleotide coenzyme (NAD(P)H) stores in brain-isolated mitochondria. Although, mitochondrial potential collapse was almost immediate after malonate addition, mitochondrial swelling was not evident before 15 min of drug presence. This latter effect was blocked by cyclosporin A (CSA), Ruthenium Red (RR), magnesium, catalase, GSH and vitamin E. Malonate added to SH-SY5Y cell cultures produced a marked loss of cell viability together with the release of Cyt c and depletion of GSH and NAD(P)H concentrations. All these effects were not apparent in SH-SY5Y cells overexpressing Bcl-xL. When GSH concentrations were lowered with buthionine sulphoximine, cytoprotection afforded by Bcl-xL overexpression was not evident anymore. Taken together, all these data suggest that malonate causes a rapid mitochondrial potential collapse and reactive oxygen species production that overwhelms mitochondrial antioxidant capacity and leads to mitochondrial swelling. Further permeability transition pore opening and the subsequent release of proapoptotic factors such as Cyt c could therefore be, at least in part, responsible for malonate-induced toxicity. PMID:15655518

  2. A Multiple Scattering Theory Approach to Solving the Time-Dependent Schrödinger Equation with an Asymmetric Rectangular Potential

    NASA Astrophysics Data System (ADS)

    Los, Victor F.; Los, Nicholas V.

    2016-04-01

    The exact expressions for an energy-dependent Green function (resolvent), space-time propagator and time-dependent solution for the wave function Ψ(r, t) of a particle moving in the presence of an asymmetric rectangular well/barrier potential are obtained. It is done by applying to this problem the multiple scattering theory (MST), which is different from previous such approaches by using the localized at the potential jumps effective potentials responsible for transmission through and reflection from the considered rectangular potential. This approach (alternative to the path-integral one) enables considering these processes from a particle (rather than a wave) point of view. The solution for the wave function describes these quantum phenomena as a function of time and is related to the fundamental issues (such as measuring time) of quantum mechanics. It is presented in terms of integrals of elementary functions and is a sum of the forward- and backward-moving components of the wave packet. The relative contribution of these components and their interference as well as of the potential asymmetry to the probability density |Ψ(x, t)|2 and particle dwell time is considered and numerically visualized for narrow and broad energy (momentum) distributions of the initial Gaussian wave packet. It is shown that in the case of a broad initial wave packet, the quantum mechanical counterintuitive effect of the influence of the backward-moving components on the considered quantities becomes significant.

  3. Prevalence of unidirectional Na+-dependent adenosine transport and altered potential for adenosine generation in diabetic cardiac myocytes.

    PubMed

    Podgorska, M; Kocbuch, K; Grden, M; Szutowicz, A; Pawelczyk, T

    2006-05-01

    Adenosine is an important physiological regulator of the cardiovascular system. The goal of our study was to assess the expression level of nucleoside transporters (NT) in diabetic rat cardiomyocytes and to examine the activities of adenosine metabolizing enzymes. Isolated rat cardiomyocytes displayed the presence of detectable amounts of mRNA for ENT1, ENT2, CNT1, and CNT2. Overall adenosine (10 microM) transport in cardiomyocytes isolated from normal rat was 36 pmol/mg/min. The expression level of equilibrative transporters (ENT1, ENT2) decreased and of concentrative transporters (CNT1, CNT2) increased in myocytes isolated from diabetic rat. Consequently, overall adenosine transport decreased by 30%, whereas Na(+)-dependent adenosine uptake increased 2-fold, and equilibrative transport decreased by 60%. The activity ratio of AMP deaminase/5'-nucleotidase in cytosol of normal cardiomyocytes was 11 and increased to 15 in diabetic cells. The activity of ecto-5'-nucleotidase increased 2-fold in diabetic cells resulting in a rise of the activity ratio of ecto-5'-nucleotidase/adenosine deaminase from 28 to 56.These results indicate that in rat cardiomyocytes diabetes alters activities of adenosine metabolizing enzymes in such a way that conversion of AMP to IMP is favored in the cytosolic compartment, whereas the capability to produce adenosine extracellularly is increased. This is accompanied by an increased unidirectional Na(+)-dependent uptake of adenosine and significantly reduced bidirectional adenosine transport. PMID:16369729

  4. The phosphatidylserine receptor from Hydra is a nuclear protein with potential Fe(II) dependent oxygenase activity

    PubMed Central

    Cikala, Mihai; Alexandrova, Olga; David, Charles N; Pröschel, Matthias; Stiening, Beate; Cramer, Patrick; Böttger, Angelika

    2004-01-01

    Background Apoptotic cell death plays an essential part in embryogenesis, development and maintenance of tissue homeostasis in metazoan animals. The culmination of apoptosis in vivo is the phagocytosis of cellular corpses. One morphological characteristic of cells undergoing apoptosis is loss of plasma membrane phospholipid asymmetry and exposure of phosphatidylserine on the outer leaflet. Surface exposure of phosphatidylserine is recognised by a specific receptor (phosphatidylserine receptor, PSR) and is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. Results We have cloned the PSR receptor from Hydra in order to investigate its function in this early metazoan. Bioinformatic analysis of the Hydra PSR protein structure revealed the presence of three nuclear localisation signals, an AT-hook like DNA binding motif and a putative 2-oxoglutarate (2OG)-and Fe(II)-dependent oxygenase activity. All of these features are conserved from human PSR to Hydra PSR. Expression of GFP tagged Hydra PSR in hydra cells revealed clear nuclear localisation. Deletion of one of the three NLS sequences strongly diminished nuclear localisation of the protein. Membrane localisation was never detected. Conclusions Our results suggest that Hydra PSR is a nuclear 2-oxoglutarate (2OG)-and Fe(II)-dependent oxygenase. This is in contrast with the proposed function of Hydra PSR as a cell surface receptor involved in the recognition of apoptotic cells displaying phosphatidylserine on their surface. The conservation of the protein from Hydra to human infers that our results also apply to PSR from higher animals. PMID:15193161

  5. Transcriptional Expression of Myelin Basic Protein in Oligodendrocytes Depends on Functional Syntaxin 4: a Potential Correlation with Autocrine Signaling

    PubMed Central

    Bijlard, Marjolein; Klunder, Bert; de Jonge, Jenny C.; Nomden, Anita; Tyagi, Sanjay; de Vries, Hans; Hoekstra, Dick

    2014-01-01

    Myelination of axons by oligodendrocytes is essential for saltatory nerve conduction. To form myelin membranes, a coordinated synthesis and subsequent polarized transport of myelin components are necessary. Here, we show that as part of the mechanism to establish membrane polarity, oligodendrocytes exploit a polarized distribution of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) machinery components syntaxins 3 and 4, localizing to the cell body and the myelin membrane, respectively. Our data further reveal that the expression of myelin basic protein (MBP), a myelin-specific protein that is synthesized “on site” after transport of its mRNA, depends on the correct functioning of the SNARE machinery, which is not required for mRNA granule assembly and transport per se. Thus, downregulation and overexpression of syntaxin 4 but not syntaxin 3 in oligodendrocyte progenitor cells but not immature oligodendrocytes impeded MBP mRNA transcription, thereby preventing MBP protein synthesis. The expression and localization of another myelin-specific protein, proteolipid protein (PLP), was unaltered. Strikingly, conditioned medium obtained from developing oligodendrocytes was able to rescue the block of MBP mRNA transcription in syntaxin 4-downregulated cells. These findings indicate that the initiation of the biosynthesis of MBP mRNA relies on a syntaxin 4-dependent mechanism, which likely involves activation of an autocrine signaling pathway. PMID:25512606

  6. Transcriptional expression of myelin basic protein in oligodendrocytes depends on functional syntaxin 4: a potential correlation with autocrine signaling.

    PubMed

    Bijlard, Marjolein; Klunder, Bert; de Jonge, Jenny C; Nomden, Anita; Tyagi, Sanjay; de Vries, Hans; Hoekstra, Dick; Baron, Wia

    2015-02-01

    Myelination of axons by oligodendrocytes is essential for saltatory nerve conduction. To form myelin membranes, a coordinated synthesis and subsequent polarized transport of myelin components are necessary. Here, we show that as part of the mechanism to establish membrane polarity, oligodendrocytes exploit a polarized distribution of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) machinery components syntaxins 3 and 4, localizing to the cell body and the myelin membrane, respectively. Our data further reveal that the expression of myelin basic protein (MBP), a myelin-specific protein that is synthesized "on site" after transport of its mRNA, depends on the correct functioning of the SNARE machinery, which is not required for mRNA granule assembly and transport per se. Thus, downregulation and overexpression of syntaxin 4 but not syntaxin 3 in oligodendrocyte progenitor cells but not immature oligodendrocytes impeded MBP mRNA transcription, thereby preventing MBP protein synthesis. The expression and localization of another myelin-specific protein, proteolipid protein (PLP), was unaltered. Strikingly, conditioned medium obtained from developing oligodendrocytes was able to rescue the block of MBP mRNA transcription in syntaxin 4-downregulated cells. These findings indicate that the initiation of the biosynthesis of MBP mRNA relies on a syntaxin 4-dependent mechanism, which likely involves activation of an autocrine signaling pathway. PMID:25512606

  7. On a relativistic particle and a relativistic position-dependent mass particle subject to the Klein-Gordon oscillator and the Coulomb potential

    NASA Astrophysics Data System (ADS)

    Vitória, R. L. L.; Furtado, C.; Bakke, K.

    2016-07-01

    The relativistic quantum dynamics of an electrically charged particle subject to the Klein-Gordon oscillator and the Coulomb potential is investigated. By searching for relativistic bound states, a particular quantum effect can be observed: a dependence of the angular frequency of the Klein-Gordon oscillator on the quantum numbers of the system. The meaning of this behaviour of the angular frequency is that only some specific values of the angular frequency of the Klein-Gordon oscillator are permitted in order to obtain bound state solutions. As an example, we obtain both the angular frequency and the energy level associated with the ground state of the relativistic system. Further, we analyse the behaviour of a relativistic position-dependent mass particle subject to the Klein-Gordon oscillator and the Coulomb potential.

  8. Fixed conditions for achieving the real-valued partition function of one-dimensional Gross-Pitaevskii equation coupled with time-dependent potential

    SciTech Connect

    Prayitno, T. B.

    2014-03-24

    We have imposed the conditions in order to preserve the real-valued partition function in the case of onedimensional Gross-Pitaevskii equation coupled by time-dependent potential. In this case we have solved the Gross-Pitaevskii equation by means of the time-dependent perturbation theory by extending the previous work of Kivshar et al. [Phys. Lett A 278, 225–230 (2001)]. To use the method, we have treated the equation as the macroscopic quantum oscillator and found that the expression of the partition function explicitly has complex values. In fact, we have to choose not only the appropriate functions but also the suitable several values of the potential to keep the real-valued partition function.

  9. Calcium-Permeable AMPA Receptors Mediate the Induction of the Protein Kinase A-Dependent Component of Long-Term Potentiation in the Hippocampus

    PubMed Central

    Park, Pojeong; Sanderson, Thomas M.; Amici, Mascia; Choi, Sun-Lim; Bortolotto, Zuner A.; Zhuo, Min

    2016-01-01

    Two forms of NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) at hippocampal CA1 synapses can be distinguished based on their sensitivity to inhibitors of protein kinase A (PKA). The PKA-dependent form requires multiple episodes of high-frequency stimulation (HFS) or theta burst stimuli (TBS) with a spacing between episodes in the order of minutes. To investigate the mechanism by which spaced episodes induce the PKA-dependent form of LTP, we have compared, in interleaved experiments, spaced (s) and compressed (c) TBS protocols in the rat CA1 synapses. We find that LTP induced by sTBS, but not that induced by cTBS, involves the insertion of calcium-permeable (CP) AMPARs, as assessed using pharmacological and electrophysiological criteria. Furthermore, a single TBS when paired with rolipram [4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one], to activate PKA, generates an LTP that also involves the insertion of CP-AMPARs. These data demonstrate that the involvement of CP-AMPARs in LTP is critically determined by the timing of the induction trigger and is associated specifically with the PKA-dependent form of LTP. SIGNIFICANCE STATEMENT Long-term potentiation is a family of synaptic mechanisms that are believed to be important for learning and memory. Two of the most extensively studied forms are triggered by the synaptic activation of NMDA receptors and expressed by changes in AMPA receptor function. They can be distinguished on the basis of their requirement for activation of a protein kinase, PKA. We show that the PKA-dependent form also involves the transient insertion of calcium-permeable AMPA receptors. These results have implications for relating synaptic plasticity to learning and memory and suggest a specific linkage between PKA activation and the rapid synaptic insertion of calcium-permeable AMPA receptors during long-term potentiation. PMID:26758849

  10. Dynamics of vector solitons in two-component Bose-Einstein condensates with time-dependent interactions and harmonic potential

    NASA Astrophysics Data System (ADS)

    Zhou, Zheng; Yu, Hui-You; Yan, Jia-Ren

    2010-01-01

    We present two kinds of exact vector-soliton solutions for coupled nonlinear Schrödinger equations with time-varying interactions and time-varying harmonic potential. Using the variational approach, we investigate the dynamics of the vector solitons. It is found that the two bright solitons oscillate about slightly and pass through each other around the equilibration state which means that they are stable under our model. At the same time, we obtain the opposite situation for dark-dark solitons.

  11. Expression, purification, crystallization and preliminary crystallographic study of a potential metal-dependent hydrolase with cyclase activity from Thermoanaerobacter tengcongensis

    PubMed Central

    Liu, Sen; Wu, Guangteng; Huang, Qichen; Lai, Luhua; Tang, Youqi; Unno, Hideaki; Kusunoki, Masami

    2005-01-01

    The putative metal-dependent hydrolase gene TTE1006 from Thermoanaerobacter tengcongensis strain MB4T (T = type strain; Genbank accession No. AE008691) was heterologously expressed in Escherichia coli. The 205-amino-acid gene product was purified and crystallized. The crystal used for data collection belongs to space group P21, with unit-cell parameters a = 85.2, b = 62.1, c = 172.4 Å, β = 104.2°. Using a synchrotron-radiation source, the resolution limit of the data reached 1.87 Å. Eight molecules were estimated to be present in the asymmetric unit, with a solvent content of 48%. Structure determination is ongoing using the multiple-wavelength anomalous diffraction (MAD) method and also the molecular-replacement (MR) method. PMID:16508100

  12. G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1

    PubMed Central

    Ferdaoussi, M.; Bergeron, V.; Zarrouki, B.; Kolic, J.; Cantley, J.; Fielitz, J.; Olson, E. N.; Prentki, M.; Biden, T.; MacDonald, P. E.

    2013-01-01

    Aims/hypothesis Activation of the G protein-coupled receptor (GPR)40 by long-chain fatty acids potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, and GPR40 agonists are in clinical development for type 2 diabetes therapy. GPR40 couples to the G protein subunit Gαq/11 but the signalling cascade activated down-stream is unknown. This study aimed to determine the mechanisms of GPR40-dependent potentiation of GSIS by fatty acids. Methods Insulin secretion in response to glucose, oleate or diacylglycerol (DAG) was assessed in dynamic perifusions and static incubations in islets from wild-type (WT) and Gpr40−/− mice. Depolymerisation of filamentous actin (F-actin) was visualised by phalloidin staining and epifluorescence. Pharmacological and molecular approaches were used to ascertain the roles of protein kinase D (PKD) and protein kinase C delta in GPR40-mediated potentiation of GSIS. Results Oleate potentiates the second phase of GSIS, and this effect is largely dependent upon GPR40. Accordingly, oleate induces rapid F-actin remodelling in WT but not in Gpr40−/− islets. Exogenous DAG potentiates GSIS in both WT and Gpr40−/− islets. Oleate induces PKD phosphorylation at residues Ser-744/748 and Ser-916 in WT but not Gpr40−/− islets. Importantly, oleate-induced F-actin depolymerisation and potentiation of GSIS are lost upon pharmacological inhibition of PKD1 or deletion of Prkd1. Conclusions/interpretation We conclude that the signalling cascade downstream of GPR40 activation by fatty acids involves activation of PKD1, F-actin depolymerisation and potentiation of second-phase insulin secretion. These results provide important information on the mechanisms of action of GPR40, a novel drug target for type 2 diabetes. PMID:22820510

  13. Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

    PubMed Central

    Chen, Songcang; Grigsby, Christopher L.; Law, Christopher S.; Ni, Xiping; Nekrep, Nada; Olsen, Keith; Humphreys, Michael H.; Gardner, David G.

    2009-01-01

    In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum- and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity. However, the mechanism of its regulation and the physiological role of hypertonicity-induced SGK1 gene expression remain unclear. Here, we identified a tonicity-responsive enhancer (TonE) upstream of the rat Sgk1 transcriptional start site. The transcription factor NFAT5 associated with TonE in a tonicity-dependent fashion in cultured rat renal medullary cells, and selective blockade of NFAT5 activity resulted in suppression of the osmotic induction of the Sgk1 promoter. In vivo, water restriction of rats or mice led to increased urine osmolality, increased Sgk1 expression, increased expression of the type A natriuretic peptide receptor (NPR-A), and dehydration natriuresis. In cultured rat renal medullary cells, siRNA-mediated Sgk1 knockdown blocked the osmotic induction of natriuretic peptide receptor 1 (Npr1) gene expression. Furthermore, Npr1–/– mice were resistant to dehydration natriuresis, which suggests that Sgk1-dependent activation of the NPR-A pathway may contribute to this response. Collectively, these findings define a specific mechanistic pathway for the osmotic regulation of Sgk1 gene expression and suggest that Sgk1 may play an important role in promoting the physiological response of the kidney to elevations in extracellular tonicity. PMID:19436108

  14. A numerical study of geometry dependent errors in velocity, temperature, and density measurements from single grid planar retarding potential analyzers

    SciTech Connect

    Davidson, R. L.; Earle, G. D.; Heelis, R. A.; Klenzing, J. H.

    2010-08-15

    Planar retarding potential analyzers (RPAs) have been utilized numerous times on high profile missions such as the Communications/Navigation Outage Forecast System and the Defense Meteorological Satellite Program to measure plasma composition, temperature, density, and the velocity component perpendicular to the plane of the instrument aperture. These instruments use biased grids to approximate ideal biased planes. These grids introduce perturbations in the electric potential distribution inside the instrument and when unaccounted for cause errors in the measured plasma parameters. Traditionally, the grids utilized in RPAs have been made of fine wires woven into a mesh. Previous studies on the errors caused by grids in RPAs have approximated woven grids with a truly flat grid. Using a commercial ion optics software package, errors in inferred parameters caused by both woven and flat grids are examined. A flat grid geometry shows the smallest temperature and density errors, while the double thick flat grid displays minimal errors for velocities over the temperature and velocity range used. Wire thickness along the dominant flow direction is found to be a critical design parameter in regard to errors in all three inferred plasma parameters. The results shown for each case provide valuable design guidelines for future RPA development.

  15. Pigment epithelium-derived factor: clinical significance in estrogen-dependent tissues and its potential in cancer therapy

    PubMed Central

    Franco-Chuaire, María Liliana; Ramírez-Clavijo, Sandra; Chuaire-Noack, Lilian

    2015-01-01

    Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the family of non-inhibitory serpins. The broad spectrum of PEDF biological activity is evident when considering its effects in promoting cell survival and proliferation, as well as its antiangiogenic, antitumor, and anti-metastatic properties. Although the structural domains of the PEDF gene that mediate such diverse effects and their mechanisms of action have not been completely elucidated, there is a large body of evidence describing their diverse range of activities; this evidence combined with the regulation of PEDF expression by sex steroids and their receptors have led to the idea that PEDF is not only a diagnostic and prognostic marker for certain diseases such as cancer, but is also a potential therapeutic target. In this manner, this paper aims to generally review the regulation of PEDF expression and PEDF interactions, as well as the findings that relate PEDF to the role of estrogens and estrogen receptors. In addition, this manuscript will review major advances toward potential therapeutic applications of PEDF. PMID:26523216

  16. Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: An in vitro study

    PubMed Central

    Ghosh, Chaitali; Hossain, Mohammad; Spriggs, Addison; Ghosh, Arnab; Grant, Gerald A.; Marchi, Nicola; Perucca, Emilio; Janigro, Damir

    2015-01-01

    SUMMARY Objective Drug toxicity is a hurdle to drug development and to clinical translation of basic research. Antiepileptic drugs such as carbamazepine (CBZ) and selective serotonin reuptake inhibitors such as sertraline (SRT) are commonly co-prescribed to patients with epilepsy and comorbid depression. Because SRT may interfere with cytochrome P450 (CYP) enzyme activity and CYPs have been implicated in the conversion of CBZ to reactive cytotoxic metabolites, we investigated in vitro models to determine whether SRT affects the neurotoxic potential of CBZ and the mechanisms involved. Methods Human fetal brain-derived dopaminergic neurons, human brain microvascular endothelial cells (HBMECs), and embryonic kidney (HEK) cells were used to evaluate cytotoxicity of CBZ and SRT individually and in combination. Nitrite and glutathione (GSH) levels were measured with drug exposure. To validate the role of CYP3A4 in causing neurotoxicity, drug metabolism was compared to cell death in HEK CYP3A4 overex-pressed and cells pretreated with the CYP3A4 inhibitor ketoconazole. Results In all cellular systems tested, exposure to CBZ (127 μM) or SRT (5 μM) alone caused negligible cytotoxicity. By contrast CBZ, tested at a much lower concentration (17 μM) in combination with SRT (5 μM), produced prominent cytotoxicity within 15 min exposure. In neurons and HBMECs, cytotoxicity was associated with increased nitrite levels, suggesting involvement of free radicals as a pathogenetic mechanism. Pretreatment of HBMECs with reduced GSH or with the GSH precursor N-acetyl-L-cysteine prevented cytotoxic response. In HEK cells, the cytotoxic response to the CBZ + SRT combination correlated with the rate of CBZ biotransformation and production of 2-hydroxy CBZ, further suggesting a causative role of reactive metabolites. In the same system, cytotoxicity was potentiated by overexpression of CYP3A4, and prevented by CYP3A4 inhibitor. Significance These results demonstrate an unexpected

  17. Semi-exact solutions to position-dependent mass Schrödinger problem with a class of hyperbolic potential V0tanh(ax)

    NASA Astrophysics Data System (ADS)

    Dong, Shishan; Sun, Guo-Hua; Falaye, B. J.; Dong, Shi-Hai

    2016-05-01

    In this work we report the semi-exact solutions of the position-dependent mass Schrödinger equation (PDMSE) with a class of hyperbolic potential V0tanh(a x). The terminology of semi-exact solutions arises from the fact that the wave functions of this quantum system can be expressed by confluent Heun functions, but the energy levels cannot be obtained analytically. The potential V(z) obtained by some canonical transformations essentially keeps invariant when the potential parameter v is replaced by - v . The properties of the wave functions depending on v are also illustrated graphically. We find that the quasi-symmetric and quasi-antisymmetric wave functions that appear only for very small v are violated completely when v becomes large. This arises from the fact that the parity, which is almost a defined symmetry for very small v, is completely violated for large v. We also notice that the energy level ɛ1 decreases and the ɛ_{6-8} ones increase with the increasing potential parameter v, respectively, while the ɛ_{2-5} ones first increase and then decrease with increasing v.

  18. Length and sequence dependent accumulation of simple sequence repeats in vertebrates: potential role in genome organization and regulation.

    PubMed

    Ramamoorthy, Senthilkumar; Garapati, Hita Sony; Mishra, Rakesh Kumar

    2014-11-10

    Simple sequence repeats (SSRs) or microsatellites are tandemly repeated short DNA sequence motifs found to be abundant in higher eukaryotes. Enrichment of SSRs with increasing genome complexity points to a positive selection and their functional relevance. We analyzed genomes of 24 organisms to find features that may help understand the functional relevance of SSRs. Of the 501 possible SSRs, only 73 show length specific enrichment. We also noticed that ~45 bp is the optimum length for a majority of them particularly in the human genome. Finally, we observed non-random distribution of ACG and CCG, enriched around transcriptional start sites (TSSs) in several species. Taken together, these results suggest that SSRs are functionally relevant with potential regulatory role. We propose that such repeats are evolving under positive selection pressure like any other functional element in the genome. PMID:25172211

  19. In Vivo Therapeutic Potential of Mesenchymal Stromal Cells Depends on the Source and the Isolation Procedure

    PubMed Central

    Bortolotti, Francesca; Ukovich, Laura; Razban, Vahid; Martinelli, Valentina; Ruozi, Giulia; Pelos, Barbara; Dore, Franca; Giacca, Mauro; Zacchigna, Serena

    2015-01-01

    Summary Over the last several years, mesenchymal stromal cells (MSCs) have been isolated from different tissues following a variety of different procedures. Here, we comparatively assess the ex vivo and in vivo properties of MSCs isolated from either adipose tissue or bone marrow by different purification protocols. After MSC transplantation into a mouse model of hindlimb ischemia, clinical and histological analysis revealed that bone marrow MSCs purified on adhesive substrates exerted the best therapeutic activity, preserving tissue viability and promoting formation of new arterioles without directly transdifferentiating into vascular cells. In keeping with these observations, these cells abundantly expressed cytokines involved in vessel maturation and cell retention. These findings indicate that the choice of MSC source and purification protocol is critical in determining the therapeutic potential of these cells and warrant the standardization of an optimal MSC isolation procedure in order to select the best conditions to move forward to more effective clinical experimentation. PMID:25660405

  20. Effects of rotation on the sleep state-dependent midlatency auditory evoked P50 potential in the human

    NASA Technical Reports Server (NTRS)

    Dornhoffer, John L.; Mamiya, N.; Bray, P.; Skinner, Robert D.; Garcia-Rill, Edgar

    2002-01-01

    Sopite syndrome, characterized by loss of initiative, sensitivity to normally innocuous sensory stimuli, and impaired concentration amounting to a sensory gating deficit, is commonly associated with Space Motion Sickness (SMS). The amplitude of the P50 potential is a measure of level of arousal, and a paired-stimulus paradigm can be used to measure sensory gating. We used the rotary chair to elicit the sensory mismatch that occurs with SMS by overstimulating the vestibular apparatus. The effects of rotation on the manifestation of the P50 midlatency auditory evoked response were then assessed as a measure of arousal and distractibility. Results showed that rotation-induced motion sickness produced no change in the level of arousal but did produce a significant deficit in sensory gating, indicating that some of the attentional and cognitive deficits observed with SMS may be due to distractibility induced by decreased habituation to repetitive stimuli.

  1. Effects of some hypoxic cell radiosensitizers on the decay of potentially lethal oxygen-dependent damage in fully hydrated spores.

    PubMed Central

    Tallentire, A.; Stratford, I. J.; Maughan, R. L.; Michael, B. D.

    1978-01-01

    Using a stopped-flow mixing and pulsed irradiation apparatus, a study has been made of the decay, to a harmless form, of radiation-induced species that would otherwise be lethal to spores on contact with oxygen. Aqueous suspensions of Bacillus megaterium spores were irradiated with electrons for approximately 1 s; at various times after irradiation oxygen in solution was added. As the interval between anoxic irradiation and introduction of oxygen increased, the fraction of spores surviving increased. This change in survival reflects the decay of potentially lethal species. The presence of electron-affinic radiosensitizers during irradiation enhanced the decay rate of this damage, the greatest enhancement being seen with sensitizers of the highest electron affinity. In contrast, the nitroxyl-free radical sensitizer TAN fixed the radiation-induced damage so that no increase in survival, and hence no decay, was seen. PMID:98174

  2. An environment-dependent interatomic potential for silicon carbide: calculation of bulk properties, high-pressure phases, point and extended defects, and amorphous structures.

    PubMed

    Lucas, G; Bertolus, M; Pizzagalli, L

    2010-01-27

    An interatomic potential has been developed to describe interactions in silicon, carbon and silicon carbide, based on the environment-dependent interatomic potential (EDIP) (Bazant et al 1997 Phys. Rev. B 56 8542). The functional form of the original EDIP has been generalized and two sets of parameters have been proposed. Tests with these two potentials have been performed for many properties of SiC, including bulk properties, high-pressure phases, point and extended defects, and amorphous structures. One parameter set allows us to keep the original EDIP formulation for silicon, and is shown to be well suited for modelling irradiation-induced effects in silicon carbide, with a very good description of point defects and of the disordered phase. The other set, including a new parametrization for silicon, has been shown to be efficient for modelling point and extended defects, as well as high-pressure phases. PMID:21386297

  3. Peroxidase-dependent metabolism of benzene's phenolic metabolites and its potential role in benzene toxicity and carcinogenicity.

    PubMed Central

    Smith, M T; Yager, J W; Steinmetz, K L; Eastmond, D A

    1989-01-01

    The metabolism of two of benzene's phenolic metabolites, phenol and hydroquinone, by peroxidase enzymes has been studied in detail. Studies employing horseradish peroxidase and human myeloperoxidase have shown that in the presence of hydrogen peroxide phenol is converted to 4,4'-diphenoquinone and other covalent binding metabolites, whereas hydroquinone is converted solely to 1,4-benzoquinone. Surprisingly, phenol stimulates the latter conversion rather than inhibiting it, an effect that may play a role in the in vivo myelotoxicity of benzene. Indeed, repeated coadministration of phenol and hydroquinone to B6C3F1 mice results in a dramatic and significant decrease in bone marrow cellularity similar to that observed following benzene exposure. A mechanism of benzene-induced myelotoxicity is therefore proposed in which the accumulation and interaction of phenol and hydroquinone in the bone marrow and the peroxidase-dependent formation of 1,4-benzoquinone are important components. This mechanism may also be responsible, at least in part, for benzene's genotoxic effects, as 1,4-benzoquinone has been shown to damage DNA and is shown here to induce multiple micronuclei in human lymphocytes. Secondary activation of benzene's phenol metabolites in the bone marrow may therefore play an important role in benzene's myelotoxic and carcinogenic effects. PMID:2551665

  4. Dependence of trends in and sensitivity of drought over China (1961-2013) on potential evaporation model

    NASA Astrophysics Data System (ADS)

    Zhang, Jie; Sun, Fubao; Xu, Jijun; Chen, Yaning; Sang, Yan-Fang; Liu, Changming

    2016-01-01

    The Palmer Drought Severity Index (PDSI) can lead to controversial results in assessing droughts responding to global warming. Here we assess recent changes in the droughts over China (1961-2013) using the PDSI with two different estimates, i.e., the Thornthwaite (PDSI_th) and Penman-Monteith (PDSI_pm) approaches. We found that droughts have become more severe in the PDSI_th but slightly lessened in the PDSI_pm estimate. To quantify and interpret the different responses in the PDSI_th and PDSI_pm, we designed numerical experiments and found that drying trend of the PDSI_th responding to the warming alone is 3.4 times higher than that of the PDSI_pm, and the latter was further compensated by decreases in wind speed and solar radiation causing the slightly wetting in the PDSI_pm. Interestingly, we found that interbasin difference in the PDSI_th and PDSI_pm responses to the warming alone tends to be larger in warmer basins, exponentially depending on mean temperature.

  5. Synthesis, pH-Dependent, and Plasma Stability of Meropenem Prodrugs for Potential Use Against Drug-Resistant Tuberculosis

    PubMed Central

    Teitelbaum, Aaron M.; Meissner, Anja; Harding, Ryan A.; Wong, Christopher A.; Aldrich, Courtney C.; Remmel, Rory P.

    2013-01-01

    Meropenem, a broad-spectrum parenteral β-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem’s short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem. PMID:23845282

  6. Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: potential role of NMDA receptor-dependent BDNF signaling.

    PubMed

    Neal, April P; Stansfield, Kirstie H; Worley, Paul F; Thompson, Richard E; Guilarte, Tomás R

    2010-07-01

    Lead (Pb(2+)) exposure is known to affect presynaptic neurotransmitter release in both in vivo and cell culture models. However, the precise mechanism by which Pb(2+) impairs neurotransmitter release remains unknown. In the current study, we show that Pb(2+) exposure during synaptogenesis in cultured hippocampal neurons produces the loss of synaptophysin (Syn) and synaptobrevin (Syb), two proteins involved in vesicular release. Pb(2+) exposure also increased the number of presynaptic contact sites. However, many of these putative presynaptic contact sites lack Soluble NSF attachment protein receptor complex proteins involved in vesicular exocytosis. Analysis of vesicular release using FM 1-43 dye confirmed that Pb(2+) exposure impaired vesicular release and reduced the number of fast-releasing sites. Because Pb(2+) is a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, we tested the hypothesis that NMDAR inhibition may be producing the presynaptic effects. We show that NMDAR inhibition by aminophosphonovaleric acid mimics the presynaptic effects of Pb(2+) exposure. NMDAR activity has been linked to the signaling of the transsynaptic neurotrophin brain-derived neurotrophic factor (BDNF), and we observed that both the cellular expression of proBDNF and release of BDNF were decreased during the same period of Pb(2+) exposure. Furthermore, exogenous addition of BDNF rescued the presynaptic effects of Pb(2+). We suggest that the presynaptic deficits resulting from Pb(2+) exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling. PMID:20375082

  7. Hypoglycemic Effect of Aquatic Extract of Stevia in Pancreas of Diabetic Rats: PPARγ-dependent Regulation or Antioxidant Potential

    PubMed Central

    Assaei, Raheleh; Mokarram, Pooneh; Dastghaib, Sanaz; Darbandi, Sara; Darbandi, Mahsa; Zal, Fatemeh; Akmali, Masoumeh; Ranjbar Omrani, Gholam Hossein

    2016-01-01

    Background: Traditional medicines with anti-diabetic effects are considered suitable supplements to treat diabetes. Among medicinal herbs, Stevia Rebaudiana Bertoni is famous for its sweet taste and beneficial effect in regulation of glucose. However, little is known about the exact mechanism of stevia in pancreatic tissue. Therefore, this study investigated the possible effects of stevia on pancreas in managing hyperglycemia seen in streptozotocin-induced Sprague-Dawley rats. Methods: Sprague-Dawley rats were divided into four groups including normoglycemic, diabetic and two more diabetic groups in which, one was treated with aquatic extract of stevia (400 mg/kg) and the other with pioglitazone (10 mg/kg) for the period of 28 days. After completion of the experimental duration, rats were dissected; blood samples and pancreas were further used for detecting biochemical and histopathological changes. FBS, TG, cholestrol, HDL, LDL, ALT and AST levels were measured in sera. Moreover, MDA (malondialdehyde) level, catalase activity, levels of insulin and PPARγ mRNA expression were also measured in pancreatic tissue. Results: Aquatic extract of stevia significantly reduced the FBS, triglycerides, MDA, ALT, AST levels and normalized catalase activity in treated rats compared with diabetic rats (p<0.05). In addition to this, stevia surprisingly, increased PPARγ and insulin mRNA levels in treated rats (p<0.05). Furthermore, stevia compensated for the histopathological damage in diabetic rats. Conclusion: It is concluded that stevia acts on pancreatic tissue to elevate the insulin level and exerts beneficial anti-hyperglycemic effects through the PPARγ-dependent mechanism and stevia’s antioxidant properties. PMID:27141265

  8. Formation of reactive nitrogen species at biologic heme centers: a potential mechanism of nitric oxide-dependent toxicity.

    PubMed Central

    Casella, Luigi; Monzani, Enrico; Roncone, Raffaella; Nicolis, Stefania; Sala, Alberto; De Riso, Antonio

    2002-01-01

    The peroxidase-catalyzed nitration of tyrosine derivatives by nitrite and hydrogen peroxide has been studied in detail using the enzymes lactoperoxidase (LPO) from bovine milk and horseradish peroxidase (HRP). The results indicate the existence of two competing pathways, in which the nitrating species is either nitrogen dioxide or peroxynitrite. The first pathway involves one-electron oxidation of nitrite by the classical peroxidase intermediates compound I and compound II, whereas in the second pathway peroxynitrite is generated by reaction between enzyme-bound nitrite and hydrogen peroxide. The two mechanisms can be simultaneously operative, and their relative importance depends on the reagent concentrations. With HRP the peroxynitrite pathway contributes significantly only at relatively high nitrite concentrations, but for LPO this represents the main pathway even at relatively low (pathophysiological) nitrite concentrations and explains the high efficiency of the enzyme in the nitration. Myoglobin and hemoglobin are also active in the nitration of phenolic compounds, albeit with lower efficiency compared with peroxidases. In the case of myoglobin, endogenous nitration of the protein has been shown to occur in the absence of substrate. The main nitration site is the heme, but a small fraction of nitrated Tyr146 residue has been identified upon proteolytic digestion and high-performance liquid chromatography/mass spectrometry analysis of the peptide fragments. Preliminary investigation of the nitration of tryptophan derivatives by the peroxidase/nitrite/hydrogen peroxide systems shows that a complex pattern of isomeric nitration products is produced, and this pattern varies with nitrite concentration. Comparative experiments using chemical nitrating agents indicate that at low nitrite concentrations, the enzymatic nitration produces a regioisomeric mixture of nitrotryptophanyl derivatives resembling that obtained using nitrogen dioxide, whereas at high nitrite

  9. Biliary Elimination of Pemetrexed Is Dependent on Mrp2 in Rats: Potential Mechanism of Variable Response in Nonalcoholic Steatohepatitis.

    PubMed

    Dzierlenga, Anika L; Clarke, John D; Klein, David M; Anumol, Tarun; Snyder, Shane A; Li, HongYu; Cherrington, Nathan J

    2016-08-01

    Hepatic multidrug resistance-associated protein 2 (MRP2) provides the biliary elimination pathway for many xenobiotics. Disruption of this pathway contributes to retention of these compounds and may ultimately lead to adverse drug reactions. MRP2 mislocalization from the canalicular membrane has been observed in nonalcoholic steatohepatitis (NASH), the late stage of nonalcoholic fatty liver disease, which is characterized by fat accumulation, oxidative stress, inflammation, and fibrosis. MRP2/Mrp2 mislocalization is observed in both human NASH and the rodent methionine and choline-deficient (MCD) diet model, but the extent to which it impacts overall transport capacity of MRP2 is unknown. Pemetrexed is an antifolate chemotherapeutic indicated for non-small cell lung cancer, yet its hepatobiliary elimination pathway has yet to be determined. The purpose of this study was to quantify the loss of Mrp2 function in NASH using an obligate Mrp2 transport substrate. To determine whether pemetrexed is an obligate Mrp2 substrate, its cumulative biliary elimination was compared between wild-type and Mrp2(-/-) rats. No pemetrexed was detected in the bile of Mrp2(-/-) rats, indicating pemetrexed is completely reliant on Mrp2 function for biliary elimination. Comparing the biliary elimination of pemetrexed between MCD and control animals identified a transporter-dependent decrease in biliary excretion of 60% in NASH. This study identifies Mrp2 as the exclusive biliary elimination mechanism for pemetrexed, making it a useful in vivo probe substrate for Mrp2 function, and quantifying the loss of function in NASH. This mechanistic feature may provide useful insight into the impact of NASH on interindividual variability in response to pemetrexed. PMID:27233293

  10. Novel analogues of chlormethiazole are neuroprotective in four cellular models of neurodegeneration by a mechanism with variable dependence on GABAA receptor potentiation

    PubMed Central

    VandeVrede, Lawren; Tavassoli, Ehsan; Luo, Jia; Qin, Zhihui; Yue, Lan; Pepperberg, David R; Thatcher, Gregory R

    2014-01-01

    Background and Purpose: Chlormethiazole (CMZ), a clinical sedative/anxiolytic agent, did not reach clinical efficacy in stroke trials despite neuroprotection demonstrated in numerous animal models. Using CMZ as a lead compound, neuroprotective methiazole (MZ) analogues were developed, and neuroprotection and GABAA receptor dependence were studied. Experimental Approach: Eight MZs were selected from a novel library, of which two were studied in detail. Neuroprotection, glutamate release, intracellular calcium and response to GABA blockade by picrotoxin were measured in rat primary cortical cultures using four cellular models of neurodegeneration. GABA potentiation was assayed in oocytes expressing the α1β2γ2 GABAA receptor. Key Results: Neuroprotection against a range of insults was retained even with substantial chemical modification. Dependence on GABAA receptor activity was variable: at the extremes, neuroprotection by GN-28 was universally sensitive to picrotoxin, while GN-38 was largely insensitive. In parallel, effects on extracellular glutamate and intracellular calcium were associated with GABAA dependence. Consistent with these findings, GN-28 potentiated α1β2γ2 GABAA function, whereas GN-38 had a weak inhibitory effect. Neuroprotection against moderate dose oligomeric Aβ1–42 was also tolerant to structural changes. Conclusions and Implications: The results support the concept that CMZ does not contain a single pharmacophore, rather that broad-spectrum neuroprotection results from a GABAA-dependent mechanism represented by GN-28, combined with a mechanism represented in GN-38 that shows the least dependence on GABAA receptors. These findings allow further refinement of the neuroprotective pharmacophore and investigation into secondary mechanisms that will assist in identifying MZ-based compounds of use in treating neurodegeneration. PMID:24116891

  11. Opposing effects of PSD-93 and PSD-95 on long-term potentiation and spike timing-dependent plasticity

    PubMed Central

    Carlisle, Holly J; Fink, Ann E; Grant, Seth G N; O'Dell, Thomas J

    2008-01-01

    The membrane-associated guanylate kinases (MAGUKs) PSD-95, PSD-93 and SAP102 are thought to have crucial roles in both AMPA receptor trafficking and formation of NMDA receptor-associated signalling complexes involved in synaptic plasticity. While PSD-95, PSD-93, and SAP102 appear to have similar roles in AMPA receptor trafficking, it is not known whether these MAGUKs also have functionally similar roles in synaptic plasticity. To explore this issue we examined several properties of basal synaptic transmission in the hippocampal CA1 region of PSD-93 and PSD-95 mutant mice and compared the ability of a number of different synaptic stimulation protocols to induce long-term potentiation (LTP) and long-term depression (LTD) in these mutants. We find that while both AMPA and NMDA receptor-mediated synaptic transmission are normal in PSD-93 mutants, PSD-95 mutant mice exhibit clear deficits in AMPA receptor-mediated transmission. Moreover, in contrast to the facilitation of LTP induction and disruption of LTD observed in PSD-95 mutant mice, PSD-93 mutant mice exhibit deficits in LTP and normal LTD. Our results suggest that PSD-95 has a unique role in AMPA receptor trafficking at excitatory synapses in the hippocampus of adult mice and indicate that PSD-93 and PSD-95 have essentially opposite roles in LTP, perhaps because these MAGUKs form distinct NMDA receptor signalling complexes that differentially regulate the induction of LTP by different patterns of synaptic activity. PMID:18936077

  12. Charged black holes in string-inspired gravity II. Mass inflation and dependence on parameters and potentials

    SciTech Connect

    Hansen, Jakob; Yeom, Dong-han

    2015-09-07

    We investigate the relation between the existence of mass inflation and model parameters of string-inspired gravity models. In order to cover various models, we investigate a Brans-Dicke theory that is coupled to a U(1) gauge field. By tuning a model parameter that decides the coupling between the Brans-Dicke field and the electromagnetic field, we can make both of models such that the Brans-Dicke field is biased toward strong or weak coupling directions after gravitational collapses. We observe that as long as the Brans-Dicke field is biased toward any (strong or weak) directions, there is no Cauchy horizon and no mass inflation. Therefore, we conclude that to induce a Cauchy horizon and mass inflation inside a charged black hole, either there is no bias of the Brans-Dicke field as well as no Brans-Dicke hair outside the horizon or such a biased Brans-Dicke field should be well trapped and controlled by a potential.

  13. Retinoids induce cellular senescence in breast cancer cells by RAR-β dependent and independent pathways: Potential clinical implications (Review)

    PubMed Central

    SHILKAITIS, ANNE; GREEN, ALBERT; CHRISTOV, KONSTANTIN

    2015-01-01

    Most studies on cellular senescence (CS) have been performed in vitro by employing cytotoxic agents, irradiation, chromatin and telomerase modulators or by activating certain oncogenes. All these approaches usually lead to DNA damage, gene instability and/or chromatin alterations that primarily affect p53-p21 signaling. Little is known on whether retinoids and rexinoids, which are cell differentiation agents, can also induce CS in vitro and in vivo, and which molecular mechanisms are involved in promoting the senescent phenotype. We reviewed the recent publications on CS induced by retinoids and rexinoids in ER+ and ER− breast cancer cell lines and in corresponding animal models of mammary carcinogenesis which simulate those of human breast cancer. The role of retinoic acid receptors β2 and 5 (RARβ2 and RARβ5) and of receptor independent genes involved in mediating the senescence program of retinoids and rexinoids in ER+ and ER− breast cancer cells is discussed. Potential strategists for clinical implication of CS as biomarker of prognosis and of response to treatment with retinoids, rexinoids and with other cell differentiation and antitumor agents are outlined. PMID:25997921

  14. Transient receptor potential vanilloid 4-dependent calcium influx and ATP release in mouse and rat gastric epithelia

    PubMed Central

    Mihara, Hiroshi; Suzuki, Nobuhiro; Boudaka, Ammar Abdullkader; Muhammad, Jibran Sualeh; Tominaga, Makoto; Tabuchi, Yoshiaki; Sugiyama, Toshiro

    2016-01-01

    AIM: To explore the expression of transient receptor potential vanilloid 4 (TRPV4) and its physiological meaning in mouse and rat gastric epithelia. METHODS: RT-PCR and immunochemistry were used to detect TRPV4 mRNA and protein expression in mouse stomach and a rat normal gastric epithelial cell line (RGE1-01), while Ca2+-imaging and electrophysiology were used to evaluate TRPV4 channel activity. ATP release was measured by a luciferin-luciferase assay. Gastric emptying was also compared between WT and TRPV4 knockout mice. RESULTS: TRPV4 mRNA and protein were detected in mouse tissues and RGE1-01 cells. A TRPV4-specific agonist (GSK1016790A) increased intracellular Ca2+ concentrations and/or evoked TRPV4-like current activities in WT mouse gastric epithelial cells and RGE1-01 cells, but not TRPV4KO cells. GSK1016790A or mechanical stimuli induced ATP release from RGE1-01 cells while TRPV4 knockout mice displayed delayed gastric emptying in vivo. CONCLUSION: TRPV4 is expressed in mouse and rat gastric epithelium and contributes to ATP release and gastric emptying. PMID:27350729

  15. Topographic Roughness of Hawaiian Volcanic Terrains: A Scale-Dependent Analysis of a Potential Mars Landing Site Analog

    NASA Astrophysics Data System (ADS)

    Morris, A. R.; Anderson, F.; Mouginis-Mark, P.; Haldemann, A.

    2006-12-01

    The roughness of a natural surface is often defined by the topography of the surface at scales of a few tens of meters or less and can be quantitatively described by self-affine, or fractal, statistics. To ensure the safety of rovers and scientific instruments on Mars, these scales are of critical importance during landing site selection and rover traverse operations. Published work on terrestrial and Martian topography datasets has demonstrated that statistical values such as the Hurst exponent can be used in conjunction with other statistical measures such as RMS slope to understand the relationship between scale-dependent roughness characteristics and the morphology of a surface. We seek to understand the effects of dataset resolution on the interpretation of various volcanic surfaces on Kilauea volcano, with applications to rover traverse navigation on remote, planetary surfaces. Extensive Light Detection and Ranging (LiDAR) coverage of the summit of Kilauea volcano, Hawaii, (30 cm posting, 1 m DEM, 2 cm vertical resolution) provides an opportunity for simulating higher resolution Martian topography data such as will be obtained from photoclinometry and stereo imaging using the High Resolution Imaging Science Experiment (HiRISE) camera on Mars Reconnaissance Orbiter (MRO). Using the method of calculating fractal statistics described in detail by previous authors, we develop two-dimensional maps of the Hurst exponent of Martian analog flows in Hawaii to understand the effects of limited resolution topographic and imaging data on the interpretation of volcanic features on the surface of Mars. In addition to the LiDAR data, we use high resolution topographic data generated from controlled stereo imaging of volcanic surfaces within Kilauea caldera to provide a detailed view of sub-meter surface roughness of the young volcanic terrains covered by the LiDAR data. To obtain the stereo data, we moved a 12.8 mega- pixel digital camera, pointed perpendicular to the

  16. Simultaneous evaluation of substrate-dependent oxygen consumption rates and mitochondrial membrane potential by TMRM and safranin in cortical mitochondria

    PubMed Central

    Chowdhury, Subir Roy; Djordjevic, Jelena; Albensi, Benedict C.; Fernyhough, Paul

    2015-01-01

    Mitochondrial membrane potential (mtMP) is critical for maintaining the physiological function of the respiratory chain to generate ATP. The present study characterized the inter-relationship between mtMP, using safranin and tetramethyl rhodamine methyl ester (TMRM), and mitochondrial respiratory activity and established a protocol for functional analysis of mitochondrial bioenergetics in a multi-sensor system. Coupled respiration was decreased by 27 and 30–35% in the presence of TMRM and safranin respectively. Maximal respiration was higher than coupled with Complex I- and II-linked substrates in the presence of both dyes. Safranin showed decreased maximal respiration at a higher concentration of carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP) compared with TMRM. FCCP titration revealed that maximal respiration in the presence of glutamate and malate was not sustainable at higher FCCP concentrations as compared with pyruvate and malate. Oxygen consumption rate (OCR) and mtMP in response to mitochondrial substrates were higher in isolated mitochondria compared with tissue homogenates. Safranin exhibited higher sensitivity to changes in mtMP than TMRM. This multi-sensor system measured mitochondrial parameters in the brain of transgenic mice that model Alzheimer's disease (AD), because mitochondrial dysfunction is believed to be a primary event in the pathogenesis of AD. The coupled and maximal respiration of electron transport chain were decreased in the cortex of AD mice along with the mtMP compared with age-matched controls. Overall, these data demonstrate that safranin and TMRM are suitable for the simultaneous evaluation of mtMP and respiratory chain activity using isolated mitochondria and tissue homogenate. However, certain care should be taken concerning the selection of appropriate substrates and dyes for specific experimental circumstances. PMID:26647379

  17. Acute but not chronic metabolic acidosis potentiates the acetylcholine-induced reduction in blood pressure: an endothelium-dependent effect.

    PubMed

    Celotto, A C; Ferreira, L G; Capellini, V K; Albuquerque, A A S; Rodrigues, A J; Evora, P R B

    2016-02-01

    Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 μM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control. PMID:26648089

  18. Membrane potential and Ca2+ concentration dependence on pressure and vasoactive agents in arterial smooth muscle: A model.

    PubMed

    Karlin, Arthur

    2015-07-01

    Arterial smooth muscle (SM) cells respond autonomously to changes in intravascular pressure, adjusting tension to maintain vessel diameter. The values of membrane potential (Vm) and sarcoplasmic Ca(2+) concentration (Ca(in)) within minutes of a change in pressure are the results of two opposing pathways, both of which use Ca(2+) as a signal. This works because the two Ca(2+)-signaling pathways are confined to distinct microdomains in which the Ca(2+) concentrations needed to activate key channels are transiently higher than Ca(in). A mathematical model of an isolated arterial SM cell is presented that incorporates the two types of microdomains. The first type consists of junctions between cisternae of the peripheral sarcoplasmic reticulum (SR), containing ryanodine receptors (RyRs), and the sarcolemma, containing voltage- and Ca(2+)-activated K(+) (BK) channels. These junctional microdomains promote hyperpolarization, reduced Ca(in), and relaxation. The second type is postulated to form around stretch-activated nonspecific cation channels and neighboring Ca(2+)-activated Cl(-) channels, and promotes the opposite (depolarization, increased Ca(in), and contraction). The model includes three additional compartments: the sarcoplasm, the central SR lumen, and the peripheral SR lumen. It incorporates 37 protein components. In addition to pressure, the model accommodates inputs of α- and β-adrenergic agonists, ATP, 11,12-epoxyeicosatrienoic acid, and nitric oxide (NO). The parameters of the equations were adjusted to obtain a close fit to reported Vm and Ca(in) as functions of pressure, which have been determined in cerebral arteries. The simulations were insensitive to ± 10% changes in most of the parameters. The model also simulated the effects of inhibiting RyR, BK, or voltage-activated Ca(2+) channels on Vm and Ca(in). Deletion of BK β1 subunits is known to increase arterial-SM tension. In the model, deletion of β1 raised Ca(in) at all pressures, and these

  19. Plug-in hybrid electric vehicles : How does one determine their potential for reducing U.S. oil dependence?

    SciTech Connect

    Vyas, A.; Santini, D.; Duoba, M.; Alexander, M.; Energy Systems; EPRI

    2008-09-01

    Estimation of the potential of plug-in hybrid electric vehicles (PHEV's) ability to reduce U.S. gasoline use is difficult and complex. Although techniques have been proposed to estimate the vehicle kilometers of travel (VKT) that can be electrified, these methods may be inadequate and/or inappropriate for early market introduction circumstances. Factors that must be considered with respect to the PHEV itself include (1) kWh battery storage capability; (2) kWh/km depletion rate of the vehicle (3) liters/km use of gasoline (4) average daily kilometers driven (5) annual share of trips exceeding the battery depletion distance (6) driving cycle(s) (7) charger location [i.e. on-board or off-board] (8) charging rate. Each of these factors is actually a variable, and many interact. Off the vehicle, considerations include (a) primary overnight charging spot [garage, carport, parking garage or lot, on street], (b) availability of primary and secondary charging locations [i.e. dwellings, workplaces, stores, etc] (c) time of day electric rates (d) seasonal electric rates (e) types of streets and highways typically traversed during most probable trips depleting battery charge [i.e. city, suburban, rural and high vs. low density]; (f) cumulative trips per day from charger origin (g) top speeds and peak acceleration rates required to make usual trips. Taking into account PHEV design trade-off possibilities (kW vs. kWh of battery, in particular), this paper attempts to extract useful information relating to these topics from the 2001 National Household Travel Survey (NHTS), and the 2005 American Housing Survey (AHS). Costs per kWh of PHEVs capable of charge depleting (CD) all-electric range (CDE, or AER) vs. those CD in 'blended' mode (CDB) are examined. Lifetime fuel savings of alternative PHEV operating/utilization strategies are compared to battery cost estimates.

  20. Transient receptor potential vanilloid 4 (TRPV4)-dependent calcium influx and ATP release in mouse oesophageal keratinocytes

    PubMed Central

    Mihara, Hiroshi; Boudaka, Ammar; Sugiyama, Toshiro; Moriyama, Yoshinori; Tominaga, Makoto

    2011-01-01

    Abstract Gastro-oesophageal reflux disease (GERD) is a multi-factorial disease that may involve oesophageal hypersensitivity to mechanical or heat stimulus as well as acids. Intraganglionic laminar endings (IGLEs) are the most prominent terminal structures of oesophageal vagal mechanosensitive afferents and may modulate mechanotransduction via purinergic receptors. Transient receptor potential channel vanilloid 4 (TRPV4) can detect various stimuli such as warm temperature, stretch and some chemicals, including 4α-phorbol 12,13-didecanoate (4α-PDD) and GSK1016790A. TRPV4 is expressed in many tissues, including renal epithelium, skin keratinocytes and urinary bladder epithelium, but its expression and function in the oesophagus is poorly understood. Here, we show anatomical and functional TRPV4 expression in mouse oesophagus and its involvement in ATP release. TRPV4 mRNA and protein were detected in oesophageal keratinocytes. Several known TRPV4 activators (chemicals, heat and stretch stimulus) increased cytosolic Ca2+ concentrations in cultured WT keratinocytes but not in TRPV4 knockout (KO) cells. Moreover, the TRPV4 agonist GSK1016790A and heat stimulus evoked TRPV4-like current responses in isolated WT keratinocytes, but not in TRPV4KO cells. GSK1016790A and heat stimulus also significantly increased ATP release from WT oesophageal keratinocytes compared to TRPV4KO cells. The vesicle-trafficking inhibitor brefeldin A (BFA) inhibited the ATP release. This ATP release could be mediated by the newly identified vesicle ATP transporter, VNUT, which is expressed by oesophageal keratinocytes at the mRNA and protein levels. In conclusion, in response to heat, chemical and possibly mechanical stimuli, TRPV4 contributes to ATP release in the oesophagus. Thus, TRPV4 could be involved in oesophageal mechano- and heat hypersensitivity. PMID:21540339

  1. Acute but not chronic metabolic acidosis potentiates the acetylcholine-induced reduction in blood pressure: an endothelium-dependent effect

    PubMed Central

    Celotto, A.C.; Ferreira, L.G.; Capellini, V.K.; Albuquerque, A.A.S.; Rodrigues, A.J.; Evora, P.R.B.

    2015-01-01

    Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 μM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control. PMID:26648089

  2. Simultaneous evaluation of substrate-dependent oxygen consumption rates and mitochondrial membrane potential by TMRM and safranin in cortical mitochondria.

    PubMed

    Chowdhury, Subir Roy; Djordjevic, Jelena; Albensi, Benedict C; Fernyhough, Paul

    2016-01-01

    Mitochondrial membrane potential (mtMP) is critical for maintaining the physiological function of the respiratory chain to generate ATP. The present study characterized the inter-relationship between mtMP, using safranin and tetramethyl rhodamine methyl ester (TMRM), and mitochondrial respiratory activity and established a protocol for functional analysis of mitochondrial bioenergetics in a multi-sensor system. Coupled respiration was decreased by 27 and 30-35% in the presence of TMRM and safranin respectively. Maximal respiration was higher than coupled with Complex I- and II-linked substrates in the presence of both dyes. Safranin showed decreased maximal respiration at a higher concentration of carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP) compared with TMRM. FCCP titration revealed that maximal respiration in the presence of glutamate and malate was not sustainable at higher FCCP concentrations as compared with pyruvate and malate. Oxygen consumption rate (OCR) and mtMP in response to mitochondrial substrates were higher in isolated mitochondria compared with tissue homogenates. Safranin exhibited higher sensitivity to changes in mtMP than TMRM. This multi-sensor system measured mitochondrial parameters in the brain of transgenic mice that model Alzheimer's disease (AD), because mitochondrial dysfunction is believed to be a primary event in the pathogenesis of AD. The coupled and maximal respiration of electron transport chain were decreased in the cortex of AD mice along with the mtMP compared with age-matched controls. Overall, these data demonstrate that safranin and TMRM are suitable for the simultaneous evaluation of mtMP and respiratory chain activity using isolated mitochondria and tissue homogenate. However, certain care should be taken concerning the selection of appropriate substrates and dyes for specific experimental circumstances. PMID:26647379

  3. Calcium-dependence of Donnan potentials in glycerinated rabbit psoas muscle in rigor, at and beyond filament overlap; a role for titin in the contractile process.

    PubMed

    Coomber, S J; Bartels, E M; Elliott, G F

    2011-07-01

    In glycerinated rabbit psoas muscle, Donnan potential measurements demonstrated that the net electric charge on the actin-myosin matrix undergoes a sharp switch-like transition at pCa(50) = 6.8. The potentials are 2 mV less negative at the lower pCa(2+) (P < 0.001). If ATP is present, the muscle contracts and breaks the microelectrode. Therefore the rigor state was studied. There is no reason to suppose a priori that a similar voltage switch does not occur during contraction, however. Calcium dependence is still apparent in muscles stretched beyond overlap (sarcomere length>3.8 μm) and is also seen in the gap filaments between the A- and I-band ends; further stretching abolishes the dependence. These experiments strongly suggest that calcium dependence is controlled initially by the titin component, and that this control is lost when titin filaments break. We suppose that that effect is mediated by the titin kinase in the M-line region and may involve the extensible PEVK region of titin. There is great interest in the electric charge on proteins in muscle within the structural system. We suggest how changes in these charges may control the calcium activation process. We also suggest some simple experimental approaches that could clarify these effects. PMID:21663965

  4. Nuclear magnetic resonance chemical shifts with the statistical average of orbital-dependent model potentials in Kohn-Sham density functional theory

    NASA Astrophysics Data System (ADS)

    Poater, Jordi; van Lenthe, Erik; Baerends, Evert Jan

    2003-05-01

    In this paper, an orbital-dependent Kohn-Sham exchange-correlation potential, the so-called statistical average of (model) orbital potentials, is applied to the calculation of nuclear magnetic resonance chemical shifts of a series of simple molecules containing H, C, N, O, and F. It is shown that the use of this model potential leads to isotropic chemical shifts which are substantially improved over both local and gradient-corrected functionals, especially for nitrogen and oxygen atoms. This improvement in the chemical shift calculations can be attributed to the increase in the gap between highest occupied and lowest unoccupied orbitals, thus correcting the excessively large paramagnetic contributions, which have been identified to give deficient chemical shifts with both the local-density approximation and with gradient-corrected functionals. This is in keeping with the improvement by the statitical average of orbital model potentials for response properties in general and for excitation energies in particular. The present results are comparable in accuracy to those previously reported with self-interaction corrected functionals by Patchovskii et al., but still inferior to those obtained with accurate Kohn-Sham potentials by Wilson and Tozer. However, the present approach is computationally expedient and routinely applicable to all systems, requiring virtually the same computational effort as local-density and generalized-gradient calculations.

  5. Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer

    PubMed Central

    Casneuf, Tineke; Axel, Amy E; King, Peter; Alvarez, John D; Werbeck, Jillian L; Verhulst, Tinne; Verstraeten, Karin; Hall, Brett M; Sasser, A Kate

    2016-01-01

    engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of hMSC expressing human IL-6 and estrogen. Conclusion Given the established role for IL-6 in ERα-positive breast cancer, these data demonstrate the potential for anti-IL-6 therapeutics in breast cancer. PMID:26893580

  6. A position-dependent mass model for the Thomas–Fermi potential: Exact solvability and relation to δ-doped semiconductors

    SciTech Connect

    Schulze-Halberg, Axel; García-Ravelo, Jesús; Pacheco-García, Christian; Juan Peña Gil, José

    2013-06-15

    We consider the Schrödinger equation in the Thomas–Fermi field, a model that has been used for describing electron systems in δ-doped semiconductors. It is shown that the problem becomes exactly-solvable if a particular effective (position-dependent) mass distribution is incorporated. Orthogonal sets of normalizable bound state solutions are constructed in explicit form, and the associated energies are determined. We compare our results with the corresponding findings on the constant-mass problem discussed by Ioriatti (1990) [13]. -- Highlights: ► We introduce an exactly solvable, position-dependent mass model for the Thomas–Fermi potential. ► Orthogonal sets of solutions to our model are constructed in closed form. ► Relation to delta-doped semiconductors is discussed. ► Explicit subband bottom energies are calculated and compared to results obtained in a previous study.

  7. Temperature dependence of the absorbance of alkaline solutions of 4-nitrophenyl phosphate--a potential source of error in the measurement of alkaline phosphatase activity.

    PubMed

    Burtis, C A; Seibert, L E; Baird, M A; Sampson, E J

    1977-09-01

    The absorbance of an alkaline solution of 4-nitrophenyl phosphate is a function of temperature. Quantitative evaluation of this phenomenon indicates that it (a) depends on the concentration of the compound and is independent of source, buffer concentration, and pH above 9.0; (b) is reversible; (c) is not a result of alkaline hydrolysis or 4-nitrophenol contamination; and (d) correlates with a temperature-induced shift of its absorbance spectrum. The phenomenon may represent a potential analytical problem in methods for alkaline phosphatase in which this compound is the substrate. If thermal equilibrium is not reached and maintained during an alkaline phosphatase assay, the thermochromic response will be included in the measured rate. The magnitude of this error depends on the thermal response and control characteristics of each particular instrument and the reaction conditions under which such an analysis is performed. PMID:19164

  8. Perspectives of optical lattices with state-dependent tunneling in approaching quantum magnetism in the presence of the external harmonic trapping potential

    NASA Astrophysics Data System (ADS)

    Sotnikov, Andrii

    2016-03-01

    We study theoretically potential advantages of two-component mixtures in optical lattices with state-dependent tunneling for approaching long-range-order phases and detecting easy-axis antiferromagnetic correlations. While we do not find additional advantages of mixtures with large hopping imbalance for approaching quantum magnetism in a harmonic trap, it is shown that a nonzero difference in hopping amplitudes remains highly important for a proper symmetry breaking in the pseudospin space for the single-site-resolution imaging and can be advantageously used for a significant increase of the signal-to-noise ratio and thus detecting long-range easy-axis antiferromagnetic correlations in the corresponding experiments.

  9. Microscopic study of the Sn132,124+Zr96 reactions: Dynamic excitation energy, energy-dependent heavy-ion potential, and capture cross section

    NASA Astrophysics Data System (ADS)

    Oberacker, V. E.; Umar, A. S.; Maruhn, J. A.; Reinhard, P.-G.

    2010-09-01

    We study reactions between neutron-rich Sn132 nucleus and Zr96 within a dynamic microscopic theory at energies in the vicinity of the ion-ion potential barrier peak, and we compare the properties to those of the stable system Sn124+Zr96. The calculations are carried out on a three-dimensional lattice using the density-constrained time-dependent Hartree-Fock method. In particular, we calculate the dynamic excitation energy E*(t) during the initial stages of the collision. The barrier heights and widths of the heavy-ion potential increase substantially with Ec.m. energy. The capture cross sections for the two reactions are of similar magnitude, but the interaction barrier for the neutron-rich system is found to be significantly (9 MeV) lower. A comparison with recently measured data is given.

  10. Dopamine Modulates Spike Timing-Dependent Plasticity and Action Potential Properties in CA1 Pyramidal Neurons of Acute Rat Hippocampal Slices

    PubMed Central

    Edelmann, Elke; Lessmann, Volkmar

    2011-01-01

    Spike timing-dependent plasticity (STDP) is a cellular model of Hebbian synaptic plasticity which is believed to underlie memory formation. In an attempt to establish a STDP paradigm in CA1 of acute hippocampal slices from juvenile rats (P15–20), we found that changes in excitability resulting from different slice preparation protocols correlate with the success of STDP induction. Slice preparation with sucrose containing ACSF prolonged rise time, reduced frequency adaptation, and decreased latency of action potentials in CA1 pyramidal neurons compared to preparation in conventional ASCF, while other basal electrophysiological parameters remained unaffected. Whereas we observed prominent timing-dependent long-term potentiation (t-LTP) to 171 ± 10% of controls in conventional ACSF, STDP was absent in sucrose prepared slices. This sucrose-induced STDP deficit could not be rescued by stronger STDP paradigms, applying either more pre- and/or postsynaptic stimuli, or by a higher stimulation frequency. Importantly, slice preparation with sucrose containing ACSF did not eliminate theta-burst stimulation induced LTP in CA1 in field potential recordings in our rat hippocampal slices. Application of dopamine (for 10–20 min) to sucrose prepared slices completely rescued t-LTP and recovered action potential properties back to levels observed in ACSF prepared slices. Conversely, acute inhibition of D1 receptor signaling impaired t-LTP in ACSF prepared slices. No similar restoring effect for STDP as seen with dopamine was observed in response to the β-adrenergic agonist isoproterenol. ELISA measurements demonstrated a significant reduction of endogenous dopamine levels (to 61.9 ± 6.9% of ACSF values) in sucrose prepared slices. These results suggest that dopamine signaling is involved in regulating the efficiency to elicit STDP in CA1 pyramidal neurons. PMID:22065958

  11. Direct observation of bias-dependence potential distribution in metal/HfO{sub 2} gate stack structures by hard x-ray photoelectron spectroscopy under device operation

    SciTech Connect

    Yamashita, Y.; Yoshikawa, H.; Kobayashi, K.; Chikyo, T.

    2014-01-28

    Although gate stack structures with high-k materials have been extensively investigated, there are some issues to be solved for the formation of high quality gate stack structures. In the present study, we employed hard x-ray photoelectron spectroscopy in operating devices. This method allows us to investigate bias dependent electronic states, while keeping device structures intact. Using this method, we have investigated electronic states and potential distribution in gate metal/HfO{sub 2} gate stack structures under device operation. Analysis of the core levels shifts as a function of the bias voltage indicated that a potential drop occurred at the Pt/HfO{sub 2} interface for a Pt/HfO{sub 2} gate structure, while a potential gradient was not observed at the Ru/HfO{sub 2} interface for a Ru/HfO{sub 2} gate structure. Angle resolved photoelectron spectroscopy revealed that a thicker SiO{sub 2} layer was formed at the Pt/HfO{sub 2} interface, indicating that the origin of potential drop at Pt/HfO{sub 2} interface is formation of the thick SiO{sub 2} layer at the interface. The formation of the thick SiO{sub 2} layer at the metal/high-k interface might concern the Fermi level pinning, which is observed in metal/high-k gate stack structures.

  12. Hypergravity within a critical period impacts on the maturation of somatosensory cortical maps and their potential for use-dependent plasticity in the adult.

    PubMed

    Zennou-Azogui, Yoh'i; Catz, Nicolas; Xerri, Christian

    2016-06-01

    We investigated experience-dependent plasticity of somatosensory maps in rat S1 cortex during early development. We analyzed both short- and long-term effects of exposure to 2G hypergravity (HG) during the first 3 postnatal weeks on forepaw representations. We also examined the potential of adult somatosensory maps for experience-dependent plasticity after early HG rearing. At postnatal day 22, HG was found to induce an enlargement of cortical zones driven by nail displacements and a contraction of skin sectors of the forepaw map. In these remaining zones serving the skin, neurons displayed expanded glabrous skin receptive fields (RFs). HG also induced a bias in the directional sensitivity of neuronal responses to nail displacement. HG-induced map changes were still found after 16 wk of housing in normogravity (NG). However, the glabrous skin RFs recorded in HG rats decreased to values similar to that of NG rats, as early as the end of the first week of housing in NG. Moreover, the expansion of the glabrous skin area and decrease in RF size normally induced in adults by an enriched environment (EE) did not occur in the HG rats, even after 16 wk of EE housing in NG. Our findings reveal that early postnatal experience critically and durably shapes S1 forepaw maps and limits their potential to be modified by novel experience in adulthood. PMID:26888103

  13. Temperature-dependent development, cold tolerance, and potential distribution of Cricotopus lebetis (Diptera: Chironomidae), a tip miner of Hydrilla verticillata (Hydrocharitaceae).

    PubMed

    Stratman, Karen N; Overholt, William A; Cuda, James P; Mukherjee, A; Diaz, R; Netherland, Michael D; Wilson, Patrick C

    2014-01-01

    A chironomid midge, Cricotopus lebetis (Sublette) (Diptera: Chironomidae), was discovered attacking the apical meristems of Hydrilla verticillata (L.f. Royle) in Crystal River, Citrus Co., Florida in 1992. The larvae mine the stems of H. verticillata and cause basal branching and stunting of the plant. Temperature-dependent development, cold tolerance, and the potential distribution of the midge were investigated. The results of the temperature-dependent development study showed that optimal temperatures for larval development were between 20 and 30°C, and these data were used to construct a map of the potential number of generations per year of C. lebetis in Florida. Data from the cold tolerance study, in conjunction with historical weather data, were used to generate a predicted distribution of C. lebetis in the United States. A distribution was also predicted using an ecological niche modeling approach by characterizing the climate at locations where C. lebetis is known to occur and then finding other locations with similar climate. The distributions predicted using the two modeling approaches were not significantly different and suggested that much of the southeastern United States was climatically suitable for C. lebetis. PMID:25347841

  14. A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface.

    PubMed

    de Jong, Rob N; Beurskens, Frank J; Verploegen, Sandra; Strumane, Kristin; van Kampen, Muriel D; Voorhorst, Marleen; Horstman, Wendy; Engelberts, Patrick J; Oostindie, Simone C; Wang, Guanbo; Heck, Albert J R; Schuurman, Janine; Parren, Paul W H I

    2016-01-01

    IgG antibodies can organize into ordered hexamers on cell surfaces after binding their antigen. These hexamers bind the first component of complement C1 inducing complement-dependent target cell killing. Here, we translated this natural concept into a novel technology platform (HexaBody technology) for therapeutic antibody potentiation. We identified mutations that enhanced hexamer formation and complement activation by IgG1 antibodies against a range of targets on cells from hematological and solid tumor indications. IgG1 backbones with preferred mutations E345K or E430G conveyed a strong ability to induce conditional complement-dependent cytotoxicity (CDC) of cell lines and chronic lymphocytic leukemia (CLL) patient tumor cells, while retaining regular pharmacokinetics and biopharmaceutical developability. Both mutations potently enhanced CDC- and antibody-dependent cellular cytotoxicity (ADCC) of a type II CD20 antibody that was ineffective in complement activation, while retaining its ability to induce apoptosis. The identified IgG1 Fc backbones provide a novel platform for the generation of therapeutics with enhanced effector functions that only become activated upon binding to target cell-expressed antigen. PMID:26736041

  15. A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface

    PubMed Central

    Verploegen, Sandra; Strumane, Kristin; van Kampen, Muriel D.; Voorhorst, Marleen; Horstman, Wendy; Engelberts, Patrick J.; Oostindie, Simone C.; Wang, Guanbo; Heck, Albert J. R.; Schuurman, Janine; Parren, Paul W. H. I.

    2016-01-01

    IgG antibodies can organize into ordered hexamers on cell surfaces after binding their antigen. These hexamers bind the first component of complement C1 inducing complement-dependent target cell killing. Here, we translated this natural concept into a novel technology platform (HexaBody technology) for therapeutic antibody potentiation. We identified mutations that enhanced hexamer formation and complement activation by IgG1 antibodies against a range of targets on cells from hematological and solid tumor indications. IgG1 backbones with preferred mutations E345K or E430G conveyed a strong ability to induce conditional complement-dependent cytotoxicity (CDC) of cell lines and chronic lymphocytic leukemia (CLL) patient tumor cells, while retaining regular pharmacokinetics and biopharmaceutical developability. Both mutations potently enhanced CDC- and antibody-dependent cellular cytotoxicity (ADCC) of a type II CD20 antibody that was ineffective in complement activation, while retaining its ability to induce apoptosis. The identified IgG1 Fc backbones provide a novel platform for the generation of therapeutics with enhanced effector functions that only become activated upon binding to target cell–expressed antigen. PMID:26736041

  16. UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1).

    PubMed

    Kemp, Michael G; Lindsey-Boltz, Laura A; Sancar, Aziz

    2015-05-01

    The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders. PMID:25792739

  17. Action Potentials are required for nitric oxide dependent LTP in CA1 neurons of adult GluR1 knockout and Wild-type mice

    PubMed Central

    Phillips, Keith G.; Hardingham, Neil R.; Fox, Kevin

    2009-01-01

    Neocortical LTP consists of both pre- and postsynaptic components that rely on nitric oxide (NO) and GluR1 respectively. In this study, we found that hippocampal LTP, induced by theta-burst stimulation in mature (> 8 week old) GluR1 knockout mice was almost entirely NO-dependent and involved both the α splice variant of NO synthase-1 (αNOS-1) and the NO synthase-3 (NOS-3) isoforms of NO synthase. Theta-burst induced LTP was also partly NO-dependent in wild-type mice, and made up approximately 50% of the potentiation 2 hours post-tetanus. Theta-burst stimulation reliably produced postsynaptic spikes including a high probability of complex spikes. Inhibition of postsynaptic somatic spikes with intracellular QX314 or local TTX application prevented LTP in the GluR1 knockout mice and also blocked the NO-component of LTP in wild-types. We conclude that theta-burst stimulation is particularly well suited to producing the somatic postsynaptic spikes required for NO-dependent LTP. PMID:19109486

  18. Mutation of light-dependent phosphorylation sites of the Drosophila transient receptor potential-like (TRPL) ion channel affects its subcellular localization and stability.

    PubMed

    Cerny, Alexander C; Oberacker, Tina; Pfannstiel, Jens; Weigold, Sebastian; Will, Carina; Huber, Armin

    2013-05-31

    The Drosophila phototransduction cascade terminates in the opening of the ion channel transient receptor potential (TRP) and TRP-like (TRPL). Contrary to TRP, TRPL undergoes light-dependent subcellular trafficking between rhabdomeric photoreceptor membranes and an intracellular storage compartment, resulting in long term light adaptation. Here, we identified in vivo phosphorylation sites of TRPL that affect TRPL stability and localization. Quantitative mass spectrometry revealed a light-dependent change in the TRPL phosphorylation pattern. Mutation of eight C-terminal phosphorylation sites neither affected multimerization of the channels nor the electrophysiological response of flies expressing the mutated channels. However, these mutations resulted in mislocalization and enhanced degradation of TRPL after prolonged dark-adaptation. Mutation of subsets of the eight C-terminal phosphorylation sites also led to a reduction of TRPL content and partial mislocalization in the dark. This suggests that a light-dependent switch in the phosphorylation pattern of the TRPL channel mediates stable expression of TRPL in the rhabdomeres upon prolonged dark-adaptation. PMID:23592784

  19. Mutation of Light-dependent Phosphorylation Sites of the Drosophila Transient Receptor Potential-like (TRPL) Ion Channel Affects Its Subcellular Localization and Stability*

    PubMed Central

    Cerny, Alexander C.; Oberacker, Tina; Pfannstiel, Jens; Weigold, Sebastian; Will, Carina; Huber, Armin

    2013-01-01

    The Drosophila phototransduction cascade terminates in the opening of the ion channel transient receptor potential (TRP) and TRP-like (TRPL). Contrary to TRP, TRPL undergoes light-dependent subcellular trafficking between rhabdomeric photoreceptor membranes and an intracellular storage compartment, resulting in long term light adaptation. Here, we identified in vivo phosphorylation sites of TRPL that affect TRPL stability and localization. Quantitative mass spectrometry revealed a light-dependent change in the TRPL phosphorylation pattern. Mutation of eight C-terminal phosphorylation sites neither affected multimerization of the channels nor the electrophysiological response of flies expressing the mutated channels. However, these mutations resulted in mislocalization and enhanced degradation of TRPL after prolonged dark-adaptation. Mutation of subsets of the eight C-terminal phosphorylation sites also led to a reduction of TRPL content and partial mislocalization in the dark. This suggests that a light-dependent switch in the phosphorylation pattern of the TRPL channel mediates stable expression of TRPL in the rhabdomeres upon prolonged dark-adaptation. PMID:23592784

  20. Hartree potential dependent exchange functional.

    PubMed

    Constantin, Lucian A; Fabiano, Eduardo; Della Sala, Fabio

    2016-08-28

    We introduce a novel non-local ingredient for the construction of exchange density functionals: the reduced Hartree parameter, which is invariant under the uniform scaling of the density and represents the exact exchange enhancement factor for one- and two-electron systems. The reduced Hartree parameter is used together with the conventional meta-generalized gradient approximation (meta-GGA) semilocal ingredients (i.e., the electron density, its gradient, and the kinetic energy density) to construct a new generation exchange functional, termed u-meta-GGA. This u-meta-GGA functional is exact for the exchange of any one- and two-electron systems, is size-consistent and non-empirical, satisfies the uniform density scaling relation, and recovers the modified gradient expansion derived from the semiclassical atom theory. For atoms, ions, jellium spheres, and molecules, it shows a good accuracy, being often better than meta-GGA exchange functionals. Our construction validates the use of the reduced Hartree ingredient in exchange-correlation functional development, opening the way to an additional rung in the Jacob's ladder classification of non-empirical density functionals. PMID:27586907

  1. Antibody-Dependent NK Cell Activation Is Associated with Late Kidney Allograft Dysfunction and the Complement-Independent Alloreactive Potential of Donor-Specific Antibodies.

    PubMed

    Legris, Tristan; Picard, Christophe; Todorova, Dilyana; Lyonnet, Luc; Laporte, Cathy; Dumoulin, Chloé; Nicolino-Brunet, Corinne; Daniel, Laurent; Loundou, Anderson; Morange, Sophie; Bataille, Stanislas; Vacher-Coponat, Henri; Moal, Valérie; Berland, Yvon; Dignat-George, Francoise; Burtey, Stéphane; Paul, Pascale

    2016-01-01

    Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs). The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR) of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK) cells as innate immune effectors of antibody-dependent cellular cytotoxicity (ADCC), but few studies have investigated their alloreactive potential in the context of solid organ transplantation. Our study aimed to investigate the potential contribution of the antibody-dependent alloreactive function of NK cells to kidney graft dysfunction. We first conducted an observational study to investigate whether the cytotoxic function of NK cells is associated with chronic allograft dysfunction. The NK-Cellular Humoral Activation Test (NK-CHAT) was designed to evaluate the recipient and antibody-dependent reactivity of NK cells against allogeneic target cells. The release of CD107a/Lamp1(+) cytotoxic granules, resulting from the recognition of rituximab-coated B cells by NK cells, was analyzed in 148 kidney transplant recipients (KTRs, mean graft duration: 6.2 years). Enhanced ADCC responsiveness was associated with reduced graft function and identified as an independent risk factor predicting a decline in the estimated glomerular filtration rate over a 1-year period (hazard ratio: 2.83). In a second approach, we used the NK-CHAT to reveal the cytotoxic potential of circulating alloantibodies in vitro. The level of CD16 engagement resulting from the in vitro recognition of serum-coated allogeneic B cells or splenic cells was further identified as a specific marker of DSA-induced ADCC. The NK-CHAT scoring of sera obtained from 40 patients at the time of transplant biopsy was associated with ABMR diagnosis. Our findings indicate that despite the administration of

  2. Antibody-Dependent NK Cell Activation Is Associated with Late Kidney Allograft Dysfunction and the Complement-Independent Alloreactive Potential of Donor-Specific Antibodies

    PubMed Central

    Legris, Tristan; Picard, Christophe; Todorova, Dilyana; Lyonnet, Luc; Laporte, Cathy; Dumoulin, Chloé; Nicolino-Brunet, Corinne; Daniel, Laurent; Loundou, Anderson; Morange, Sophie; Bataille, Stanislas; Vacher-Coponat, Henri; Moal, Valérie; Berland, Yvon; Dignat-George, Francoise; Burtey, Stéphane; Paul, Pascale

    2016-01-01

    Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs). The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR) of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK) cells as innate immune effectors of antibody-dependent cellular cytotoxicity (ADCC), but few studies have investigated their alloreactive potential in the context of solid organ transplantation. Our study aimed to investigate the potential contribution of the antibody-dependent alloreactive function of NK cells to kidney graft dysfunction. We first conducted an observational study to investigate whether the cytotoxic function of NK cells is associated with chronic allograft dysfunction. The NK-Cellular Humoral Activation Test (NK-CHAT) was designed to evaluate the recipient and antibody-dependent reactivity of NK cells against allogeneic target cells. The release of CD107a/Lamp1+ cytotoxic granules, resulting from the recognition of rituximab-coated B cells by NK cells, was analyzed in 148 kidney transplant recipients (KTRs, mean graft duration: 6.2 years). Enhanced ADCC responsiveness was associated with reduced graft function and identified as an independent risk factor predicting a decline in the estimated glomerular filtration rate over a 1-year period (hazard ratio: 2.83). In a second approach, we used the NK-CHAT to reveal the cytotoxic potential of circulating alloantibodies in vitro. The level of CD16 engagement resulting from the in vitro recognition of serum-coated allogeneic B cells or splenic cells was further identified as a specific marker of DSA-induced ADCC. The NK-CHAT scoring of sera obtained from 40 patients at the time of transplant biopsy was associated with ABMR diagnosis. Our findings indicate that despite the administration of

  3. Single-Nucleotide Polymorphisms in Corticotropin Releasing Hormone Receptor 1 Gene (CRHR1) Are Associated With Quantitative Trait of Event-Related Potential and Alcohol Dependence

    PubMed Central

    Chen, Andrew C. H.; Manz, Niklas; Tang, Yongqiang; Rangaswamy, Madhavi; Almasy, Laura; Kuperman, Samuel; Nurnberger, John; O’Connor, Sean J.; Edenberg, Howard J.; Schuckit, Marc A.; Tischfield, Jay; Foroud, Tatiana; Bierut, Laura J.; Rohrbaugh, John; Rice, John P.; Goate, Alison; Hesselbrock, Victor; Porjesz, Bernice

    2011-01-01

    Background Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis. Methods We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons. Results Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene. Conclusions Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders. PMID:20374216

  4. Incorporating cold-air pooling into downscaled climate models increases potential refugia for snow-dependent species within the Sierra Nevada Ecoregion, CA

    USGS Publications Warehouse

    Curtis, Jennifer A.; Flint, Lorraine E.; Flint, Alan L.; Lundquist, Jessica D.; Hudgens, Brian; Boydston, Erin E.; Young, Julie K.

    2014-01-01

    We present a unique water-balance approach for modeling snowpack under historic, current and future climates throughout the Sierra Nevada Ecoregion. Our methodology uses a finer scale (270 m) than previous regional studies and incorporates cold-air pooling, an atmospheric process that sustains cooler temperatures in topographic depressions thereby mitigating snowmelt. Our results are intended to support management and conservation of snow-dependent species, which requires characterization of suitable habitat under current and future climates. We use the wolverine (Gulo gulo) as an example species and investigate potential habitat based on the depth and extent of spring snowpack within four National Park units with proposed wolverine reintroduction programs. Our estimates of change in spring snowpack conditions under current and future climates are consistent with recent studies that generally predict declining snowpack. However, model development at a finer scale and incorporation of cold-air pooling increased the persistence of April 1st snowpack. More specifically, incorporation of cold-air pooling into future climate projections increased April 1st snowpack by 6.5% when spatially averaged over the study region and the trajectory of declining April 1st snowpack reverses at mid-elevations where snow pack losses are mitigated by topographic shading and cold-air pooling. Under future climates with sustained or increased precipitation, our results indicate a high likelihood for the persistence of late spring snowpack at elevations above approximately 2,800 m and identify potential climate refugia sites for snow-dependent species at mid-elevations, where significant topographic shading and cold-air pooling potential exist.

  5. Incorporating cold-air pooling into downscaled climate models increases potential refugia for snow-dependent species within the Sierra Nevada Ecoregion, CA.

    PubMed

    Curtis, Jennifer A; Flint, Lorraine E; Flint, Alan L; Lundquist, Jessica D; Hudgens, Brian; Boydston, Erin E; Young, Julie K

    2014-01-01

    We present a unique water-balance approach for modeling snowpack under historic, current and future climates throughout the Sierra Nevada Ecoregion. Our methodology uses a finer scale (270 m) than previous regional studies and incorporates cold-air pooling, an atmospheric process that sustains cooler temperatures in topographic depressions thereby mitigating snowmelt. Our results are intended to support management and conservation of snow-dependent species, which requires characterization of suitable habitat under current and future climates. We use the wolverine (Gulo gulo) as an example species and investigate potential habitat based on the depth and extent of spring snowpack within four National Park units with proposed wolverine reintroduction programs. Our estimates of change in spring snowpack conditions under current and future climates are consistent with recent studies that generally predict declining snowpack. However, model development at a finer scale and incorporation of cold-air pooling increased the persistence of April 1st snowpack. More specifically, incorporation of cold-air pooling into future climate projections increased April 1st snowpack by 6.5% when spatially averaged over the study region and the trajectory of declining April 1st snowpack reverses at mid-elevations where snow pack losses are mitigated by topographic shading and cold-air pooling. Under future climates with sustained or increased precipitation, our results indicate a high likelihood for the persistence of late spring snowpack at elevations above approximately 2,800 m and identify potential climate refugia sites for snow-dependent species at mid-elevations, where significant topographic shading and cold-air pooling potential exist. PMID:25188379

  6. Incorporating Cold-Air Pooling into Downscaled Climate Models Increases Potential Refugia for Snow-Dependent Species within the Sierra Nevada Ecoregion, CA

    PubMed Central

    Curtis, Jennifer A.; Flint, Lorraine E.; Flint, Alan L.; Lundquist, Jessica D.; Hudgens, Brian; Boydston, Erin E.; Young, Julie K.

    2014-01-01

    We present a unique water-balance approach for modeling snowpack under historic, current and future climates throughout the Sierra Nevada Ecoregion. Our methodology uses a finer scale (270 m) than previous regional studies and incorporates cold-air pooling, an atmospheric process that sustains cooler temperatures in topographic depressions thereby mitigating snowmelt. Our results are intended to support management and conservation of snow-dependent species, which requires characterization of suitable habitat under current and future climates. We use the wolverine (Gulo gulo) as an example species and investigate potential habitat based on the depth and extent of spring snowpack within four National Park units with proposed wolverine reintroduction programs. Our estimates of change in spring snowpack conditions under current and future climates are consistent with recent studies that generally predict declining snowpack. However, model development at a finer scale and incorporation of cold-air pooling increased the persistence of April 1st snowpack. More specifically, incorporation of cold-air pooling into future climate projections increased April 1st snowpack by 6.5% when spatially averaged over the study region and the trajectory of declining April 1st snowpack reverses at mid-elevations where snow pack losses are mitigated by topographic shading and cold-air pooling. Under future climates with sustained or increased precipitation, our results indicate a high likelihood for the persistence of late spring snowpack at elevations above approximately 2,800 m and identify potential climate refugia sites for snow-dependent species at mid-elevations, where significant topographic shading and cold-air pooling potential exist. PMID:25188379

  7. Culture-dependent and culture-independent characterization of potentially functional biphenyl-degrading bacterial community in response to extracellular organic matter from Micrococcus luteus

    PubMed Central

    Su, Xiao-Mei; Liu, Yin-Dong; Hashmi, Muhammad Zaffar; Ding, Lin-Xian; Shen, Chao-Feng

    2015-01-01

    Biphenyl (BP)-degrading bacteria were identified to degrade various polychlorinated BP (PCB) congers in long-term PCB-contaminated sites. Exploring BP-degrading capability of potentially useful bacteria was performed for enhancing PCB bioremediation. In the present study, the bacterial composition of the PCB-contaminated sediment sample was first investigated. Then extracellular organic matter (EOM) from Micrococcus luteus was used to enhance BP biodegradation. The effect of the EOM on the composition of bacterial community was investigated by combining with culture-dependent and culture-independent methods. The obtained results indicate that Proteobacteria and Actinobacteria were predominant community in the PCB-contaminated sediment. EOM from M. luteus could stimulate the activity of some potentially difficult-to-culture BP degraders, which contribute to significant enhancement of BP biodegradation. The potentially difficult-to-culture bacteria in response to EOM addition were mainly Rhodococcus and Pseudomonas belonging to Gammaproteobacteria and Actinobacteria respectively. This study provides new insights into exploration of functional difficult-to-culture bacteria with EOM addition and points out broader BP/PCB degrading, which could be employed for enhancing PCB-bioremediation processes. PMID:25675850

  8. Net electron-phonon scattering rates in InN/GaN multiple quantum wells: The effects of an energy dependent acoustic deformation potential

    SciTech Connect

    Xia, H. Patterson, R.; Feng, Y.; Shrestha, S.; Conibeer, G.

    2014-08-11

    The rates of charge carrier relaxation by phonon emission are of substantial importance in the field of hot carrier solar cell, primarily in investigation of mechanisms to slow down hot carrier cooling. In this work, energy and momentum resolved deformation potentials relevant to electron-phonon scattering are computed for wurtzite InN and GaN as well as an InN/GaN multiple quantum well (MQW) superlattice using ab-initio methods. These deformation potentials reveal important features such as discontinuities across the electronic bandgap of the materials and variations over tens of eV. The energy dependence of the deformation potential is found to be very similar for wurtzite nitrides despite differences between the In and Ga pseudopotentials and their corresponding electronic band structures. Charge carrier relaxation by this mechanism is expected to be minimal for electrons within a few eV of the conduction band edge. However, hole scattering at energies more accessible to excitation by solar radiation is possible between heavy and light hole states. Moderate reductions in overall scattering rates are observed in MQW relative to the bulk nitride materials.

  9. Pathways to decoding the clinical potential of stress response FOXO-interaction networks for Huntington's disease: of gene prioritization and context dependence.

    PubMed

    Parmentier, Frédéric; Lejeune, François-Xavier; Neri, Christian

    2013-01-01

    The FOXO family of transcription factors is central to the regulation of organismal longevity and cellular survival. Several studies have indicated that FOXO factors lie at the center of a complex network of upstream pathways, cofactors and downstream targets (FOXO-interaction networks), which may have developmental and post-developmental roles in the regulation of chronic-stress response in normal and diseased cells. Noticeably, FOXO factors are important for the regulation of proteotoxicity and neuron survival in several models of neurodegenerative disease, suggesting that FOXO-interaction networks may have therapeutic potential. However, the status of FOXO-interaction networks in neurodegenerative disease remains largely unknown. Systems modeling is anticipated to provide a comprehensive assessment of this question. In particular, interrogating the context-dependent variability of FOXO-interaction networks could predict the clinical potential of cellular-stress response genes and aging regulators for tackling brain and peripheral pathology in neurodegenerative disease. Using published transcriptomic data obtained from murine models of Huntington's disease (HD) and post-mortem brains, blood samples and induced-pluripotent-stem cells from HD carriers as a case example, this review briefly highlights how the biological status and clinical potential of FOXO-interaction networks for HD may be decoded by developing network and entropy based feature selection across heterogeneous datasets. PMID:23781200

  10. Culture-dependent and culture-independent characterization of potentially functional biphenyl-degrading bacterial community in response to extracellular organic matter from Micrococcus luteus.

    PubMed

    Su, Xiao-Mei; Liu, Yin-Dong; Hashmi, Muhammad Zaffar; Ding, Lin-Xian; Shen, Chao-Feng

    2015-05-01

    Biphenyl (BP)-degrading bacteria were identified to degrade various polychlorinated BP (PCB) congers in long-term PCB-contaminated sites. Exploring BP-degrading capability of potentially useful bacteria was performed for enhancing PCB bioremediation. In the present study, the bacterial composition of the PCB-contaminated sediment sample was first investigated. Then extracellular organic matter (EOM) from Micrococcus luteus was used to enhance BP biodegradation. The effect of the EOM on the composition of bacterial community was investigated by combining with culture-dependent and culture-independent methods. The obtained results indicate that Proteobacteria and Actinobacteria were predominant community in the PCB-contaminated sediment. EOM from M. luteus could stimulate the activity of some potentially difficult-to-culture BP degraders, which contribute to significant enhancement of BP biodegradation. The potentially difficult-to-culture bacteria in response to EOM addition were mainly Rhodococcus and Pseudomonas belonging to Gammaproteobacteria and Actinobacteria respectively. This study provides new insights into exploration of functional difficult-to-culture bacteria with EOM addition and points out broader BP/PCB degrading, which could be employed for enhancing PCB-bioremediation processes. PMID:25675850

  11. Net electron-phonon scattering rates in InN/GaN multiple quantum wells: The effects of an energy dependent acoustic deformation potential

    NASA Astrophysics Data System (ADS)

    Xia, H.; Patterson, R.; Feng, Y.; Shrestha, S.; Conibeer, G.

    2014-08-01

    The rates of charge carrier relaxation by phonon emission are of substantial importance in the field of hot carrier solar cell, primarily in investigation of mechanisms to slow down hot carrier cooling. In this work, energy and momentum resolved deformation potentials relevant to electron-phonon scattering are computed for wurtzite InN and GaN as well as an InN/GaN multiple quantum well (MQW) superlattice using ab-initio methods. These deformation potentials reveal important features such as discontinuities across the electronic bandgap of the materials and variations over tens of eV. The energy dependence of the deformation potential is found to be very similar for wurtzite nitrides despite differences between the In and Ga pseudopotentials and their corresponding electronic band structures. Charge carrier relaxation by this mechanism is expected to be minimal for electrons within a few eV of the conduction band edge. However, hole scattering at energies more accessible to excitation by solar radiation is possible between heavy and light hole states. Moderate reductions in overall scattering rates are observed in MQW relative to the bulk nitride materials.

  12. Rhesus macaque model of chronic opiate dependence and neuro-AIDS: longitudinal assessment of auditory brainstem responses and visual evoked potentials

    PubMed Central

    Riazi, Mariam; Marcario, Joanne K; Samson, Frank K.; Kenjale, Himanshu; Adany, Istvan; Staggs, Vincent; Ledford, Emily; Marquis, Janet; Narayan, Opendra; Cheney, Paul D.

    2013-01-01

    Our work characterizes the effects of opiate (morphine) dependence on auditory brainstem and visual evoked responses in a rhesus macaque model of neuro-AIDS utilizing a chronic continuous drug delivery paradigm. The goal of this study was to clarify whether morphine is protective, or if it exacerbates simian immunodeficiency virus (SIV) related systemic and neurological disease. Our model employs a macrophage tropic CD4/CCR5 co-receptor virus, SIVmac239 (R71/E17), which crosses the blood brain barrier shortly after inoculation and closely mimics the natural disease course of human immunodeficiency virus (HIV) infection. The cohort was divided into 3 groups: morphine only, SIV only, and SIV + morphine. Evoked potential (EP) abnormalities in sub-clinically infected macaques were evident as early as eight weeks post-inoculation. Prolongations in EP latencies were observed in SIV-infected macaques across all modalities. Animals with the highest CSF viral loads and clinical disease showed more abnormalities than those with sub-clinical disease, confirming our previous work (Raymond et al, 1998, 1999, 2000). Although some differences were observed in auditory and visual evoked potentials in morphine treated compared to untreated SIV-infected animals, the effects were relatively small and not consistent across evoked potential type. However, morphine treated animals with subclinical disease had a clear tendency toward higher virus loads in peripheral and CNS tissues (Marcario et al., 2008) suggesting that if had been possible to follow all animals to end-stage disease, a clearer pattern of evoked potential abnormality might have emerged. PMID:19283490

  13. CD8(+) T cells sabotage their own memory potential through IFN-γ-dependent modification of the IL-12/IL-15 receptor α axis on dendritic cells.

    PubMed

    Kohlhapp, Frederick J; Zloza, Andrew; O'Sullivan, Jeremy A; Moore, Tamson V; Lacek, Andrew T; Jagoda, Michael C; McCracken, James; Cole, David J; Guevara-Patiño, José A

    2012-04-15

    CD8(+) T cell responses have been shown to be regulated by dendritic cells (DCs) and CD4(+) T cells, leading to the tenet that CD8(+) T cells play a passive role in their own differentiation. In contrast, by using a DNA vaccination model, to separate the events of vaccination from those of CD8(+) T cell priming, we demonstrate that CD8(+) T cells, themselves, actively limit their own memory potential through CD8(+) T cell-derived IFN-γ-dependent modification of the IL-12/IL-15Rα axis on DCs. Such CD8(+) T cell-driven cytokine alterations result in increased T-bet and decreased Bcl-2 expression, and thus decreased memory progenitor formation. These results identify an unrecognized role for CD8(+) T cells in the regulation of their own effector differentiation fate and a previously uncharacterized relationship between the balance of inflammation and memory formation. PMID:22430740

  14. pH-Dependent biodegradable silica nanotubes derived from Gd(OH)3 nanorods and their potential for oral drug delivery and MR imaging.

    PubMed

    Hu, Kuo-Wei; Hsu, Kang-Che; Yeh, Chen-Sheng

    2010-09-01

    We report a pH dependence of degradable silica nanotubes, which dissolved to the biodegradation product monosilicic acid, Si(OH)(4). The silica nanotubes, potentially acting as oral-based administration carriers, were resistant to dissolution in the extreme acidic condition of pH 1, but degraded quickly at pH 8, and the degradation rate can be tuned by tailoring the thickness of silica nanotubes with thicker nanotubes dissolving more slowly. Because Gd(OH)(3) nanorods were used as templates, the silica nanotubes could be further developed as MR imaging contrast agents as well as drugs carriers. The released Gd(3+) ions resulting from the etching of Gd(OH)(3) nanorods were chelated by the pre-modified DOTA, yielding Gd-DOTA complexes grafted onto silica nanotubes. The Gd-DOTA grafted silica nanotubes loaded with doxorubicin revealed enhanced T(1) imaging contrast and anticancer activity. PMID:20542331

  15. The Contribution of Ionic Currents to Rate-Dependent Action Potential Duration and Pattern of Reentry in a Mathematical Model of Human Atrial Fibrillation

    PubMed Central

    Lee, Young-Seon; Hwang, Minki; Song, Jun-Seop; Li, Changyong; Joung, Boyoung; Sobie, Eric A.; Pak, Hui-Nam

    2016-01-01

    Persistent atrial fibrillation (PeAF) in humans is characterized by shortening of action potential duration (APD) and attenuation of APD rate-adaptation. However, the quantitative influences of particular ionic current alterations on rate-dependent APD changes, and effects on patterns of reentry in atrial tissue, have not been systematically investigated. Using mathematical models of human atrial cells and tissue and performing parameter sensitivity analysis, we evaluated the quantitative contributions to action potential (AP) shortening and APD rate-adaptation of ionic current remodeling seen with PeAF. Ionic remodeling in PeAF was simulated by reducing L-type Ca2+ channel current (ICaL), increasing inward rectifier K+ current (IK1) and modulating five other ionic currents. Parameter sensitivity analysis, which quantified how each ionic current influenced APD in control and PeAF conditions, identified interesting results, including a negative effect of Na+/Ca2+ exchange on APD only in the PeAF condition. At high pacing rate (2 Hz), electrical remodeling in IK1 alone accounts for the APD reduction of PeAF, but at slow pacing rate (0.5 Hz) both electrical remodeling in ICaL alone (-70%) and IK1 alone (+100%) contribute equally to the APD reduction. Furthermore, AP rate-adaptation was affected by IKur in control and by INaCa in the PeAF condition. In a 2D tissue model, a large reduction (-70%) of ICaL becomes a dominant factor leading to a stable spiral wave in PeAF. Our study provides a quantitative and unifying understanding of the roles of ionic current remodeling in determining rate-dependent APD changes at the cellular level and spatial reentry patterns in tissue. PMID:26964092

  16. Biophysical Insights into How Spike Threshold Depends on the Rate of Membrane Potential Depolarization in Type I and Type II Neurons

    PubMed Central

    Yi, Guo-Sheng; Wang, Jiang; Tsang, Kai-Ming; Wei, Xi-Le; Deng, Bin

    2015-01-01

    Dynamic spike threshold plays a critical role in neuronal input-output relations. In many neurons, the threshold potential depends on the rate of membrane potential depolarization (dV/dt) preceding a spike. There are two basic classes of neural excitability, i.e., Type I and Type II, according to input-output properties. Although the dynamical and biophysical basis of their spike initiation has been established, the spike threshold dynamic for each cell type has not been well described. Here, we use a biophysical model to investigate how spike threshold depends on dV/dt in two types of neuron. It is observed that Type II spike threshold is more depolarized and more sensitive to dV/dt than Type I. With phase plane analysis, we show that each threshold dynamic arises from the different separatrix and K+ current kinetics. By analyzing subthreshold properties of membrane currents, we find the activation of hyperpolarizing current prior to spike initiation is a major factor that regulates the threshold dynamics. The outward K+ current in Type I neuron does not activate at the perithresholds, which makes its spike threshold insensitive to dV/dt. The Type II K+ current activates prior to spike initiation and there is a large net hyperpolarizing current at the perithresholds, which results in a depolarized threshold as well as a pronounced threshold dynamic. These predictions are further attested in several other functionally equivalent cases of neural excitability. Our study provides a fundamental description about how intrinsic biophysical properties contribute to the threshold dynamics in Type I and Type II neurons, which could decipher their significant functions in neural coding. PMID:26083350

  17. Increases in reactive oxygen species enhance vascular endothelial cell migration through a mechanism dependent on the transient receptor potential melastatin 4 ion channel.

    PubMed

    Sarmiento, Daniela; Montorfano, Ignacio; Cerda, Oscar; Cáceres, Mónica; Becerra, Alvaro; Cabello-Verrugio, Claudio; Elorza, Alvaro A; Riedel, Claudia; Tapia, Pablo; Velásquez, Luis A; Varela, Diego; Simon, Felipe

    2015-03-01

    A hallmark of severe inflammation is reactive oxygen species (ROS) overproduction induced by increased inflammatory mediators secretion. During systemic inflammation, inflammation mediators circulating in the bloodstream interact with endothelial cells (ECs) raising intracellular oxidative stress at the endothelial monolayer. Oxidative stress mediates several pathological functions, including an exacerbated EC migration. Because cell migration critically depends on calcium channel-mediated Ca(2+) influx, the molecular identification of the calcium channel involved in oxidative stress-modulated EC migration has been the subject of intense investigation. The transient receptor potential melastatin 4 (TRPM4) protein is a ROS-modulated non-selective cationic channel that performs several cell functions, including regulating intracellular Ca(2+) overload and Ca(2+) oscillation. This channel is expressed in multiple tissues, including ECs, and contributes to the migration of certain immune cells. However, whether the TRPM4 ion channel participates in oxidative stress-mediated EC migration is not known. Herein, we investigate whether oxidative stress initiates or enhances EC migration and study the role played by the ROS-modulated TRPM4 ion channel in oxidative stress-mediated EC migration. We demonstrate that oxidative stress enhances, but does not initiate, EC migration in a dose-dependent manner. Notably, we demonstrate that the TRPM4 ion channel is critical in promoting H2O2-enhanced EC migration. These results show that TRPM4 is a novel pharmacological target for the possible treatment of severe inflammation and other oxidative stress-mediated inflammatory diseases. PMID:24518820

  18. Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome.

    PubMed

    Martin, Henry G S; Lassalle, Olivier; Brown, Jonathan T; Manzoni, Olivier J

    2016-05-01

    The most common inherited monogenetic cause of intellectual disability is Fragile X syndrome (FXS). The clinical symptoms of FXS evolve with age during adulthood; however, neurophysiological data exploring this phenomenon are limited. TheFmr1knockout (Fmr1KO) mouse models FXS, but studies in these mice of prefrontal cortex (PFC) function are underrepresented, and aging linked data are absent. We studied synaptic physiology and activity-dependent synaptic plasticity in the medial PFC ofFmr1KO mice from 2 to 12 months. In young adultFmr1KO mice, NMDA receptor (NMDAR)-mediated long-term potentiation (LTP) is intact; however, in 12-month-old mice this LTP is impaired. In parallel, there was an increase in the AMPAR/NMDAR ratio and a concomitant decrease of synaptic NMDAR currents in 12-month-oldFmr1KO mice. We found that acute pharmacological blockade of mGlu5receptor in 12-month-oldFmr1KO mice restored a normal AMPAR/NMDAR ratio and LTP. Taken together, the data reveal an age-dependent deficit in LTP inFmr1KO mice, which may correlate to some of the complex age-related deficits in FXS. PMID:25750254

  19. Potential effects of climate change on inland glacial lakes and implications for lake-dependent biota in Wisconsin: final report April 2013

    USGS Publications Warehouse

    Meyer, Michael W.; Walker, John F.; Kenow, Kevin P.; Rasmussen, Paul W.; Garrison, Paul J.; Hanson, Paul C.; Hunt, Randall J.

    2013-01-01

    F statewide, and an increase in precipitation of 1”–2”. However, summer precipitation in the northern part of the state is expected to be less and winter precipitation will be greater. By the end of the 21st century, the magnitude of changes in temperature and precipitation are expected to intensify. Such climatic changes have altered, and would further alter hydrological, chemical, and physical properties of inland lakes. Lake-dependent wildlife sensitive to changes in water quality, are particularly susceptible to lake quality-associated habitat changes and are likely to suffer restrictions to current breeding distributions under some climate change scenarios. We have selected the common loon (Gavia immer) to serve as a sentinel lake-dependent piscivorous species to be used in the development of a template for linking primary lake-dependent biota endpoints (e.g., decline in productivity and/or breeding range contraction) to important lake quality indicators. In the current project, we evaluate how changes in freshwater habitat quality (specifically lake clarity) may impact common loon lake occupancy in Wisconsin under detailed climate-change scenarios. In addition, we employ simple land-use/land cover and habitat scenarios to illustrate the potential interaction of climate and land-use/land cover effects. The methods employed here provide a template for studies where integration of physical and biotic models is used to project future conditions under various climate and land use change scenarios. Findings presented here project the future conditions of lakes and loons within an important watershed in northern Wisconsin – of importance to water resource managers and state citizens alike.

  20. Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential.

    PubMed

    Xiao, Dong; Lew, Karen L; Zeng, Yan; Xiao, Hui; Marynowski, Stanley W; Dhir, Rajiv; Singh, Shivendra V

    2006-11-01

    The present study was undertaken to gain insights into the molecular mechanism of apoptosis induction by phenethyl isothiocyanate (PEITC), which is a cancer chemopreventive constituent of cruciferous vegetables, using PC-3 human prostate cancer cells as a model. The PEITC-induced cell death in PC-3 cells was associated with disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria to the cytosol and generation of reactive oxygen species (ROS), which were blocked in the presence of a combined mimetic of superoxide dismutase and catalase (Euk134). Ectopic expression of Bcl-xL, whose protein level is reduced markedly on treatment of PC-3 cells with PEITC, conferred partial protection against PEITC-induced apoptosis only at higher drug concentrations (>10 microM). Administration of 12 micromol PEITC/day (Monday through Friday) by oral gavage significantly retarded growth of PC-3 xenografts in athymic mice. For instance, 31 days after the initiation of PEITC administration, the average tumor volume in control mice (721 +/- 153 mm3) was approximately 2-fold higher compared with mice receiving 12 micromol PEITC/day. The PEITC-mediated inhibition of PC-3 xenograft growth was associated with induction of Bax and Bid proteins. In conclusion, the present study indicates that the PEITC-induced apoptosis in PC-3 cells is mediated by ROS-dependent disruption of the mitochondrial membrane potential and regulated by Bax and Bid. PMID:16774948

  1. An Eight-Degree-of-Freedom, Time-Dependent Quantum Dynamics Study for the H₂+C₂H Reaction on a New Modified potential Energy Surface

    SciTech Connect

    Wang, Dunyou; Huo, Winifred M.

    2007-10-21

    An eight dimensional time-dependent quantum dynamics wavepacket approach is performed for the study of the H₂+C₂H ! H + C₂H₂ reaction system on a new modified potential energy surface (PES) [Chem. Phys. Lett. 409, 249 (2005)]. This new potential energy surface is obtained by modifying Wang and Bowman's old PES [ J. Chem. Phys. 101, 8646 (1994)] based on the new ab initio calculation. This new modified PES has a much lower transition state barrier height at 2.29 kcal/mol than Wang and Bowman's old PES at 4.3 kcal/mol. This study shows the reactivity for this diatom-triatom reaction system is enchanced by vibrational excitations of H₂; whereas, the vibrational excitations of C₂H only have a small effect on the reactivity. Furthermore, the bending excitations of C₂H, comparing to the ground state reaction probability, hinder the reactivity. The comparison of the rate constant between this calculation and experimental results agree with each other very well. This comparison indicates that the new modified PES corrects the large barrier height problem in Wang and Bowman's old PES.

  2. C-type lectin-like molecule-1 (CLL1)-targeted TRAIL augments the tumoricidal activity of granulocytes and potentiates therapeutic antibody-dependent cell-mediated cytotoxicity

    PubMed Central

    Wiersma, Valerie R; de Bruyn, Marco; Shi, Ce; Gooden, Marloes JM; Wouters, Maartje CA; Samplonius, Douwe F; Hendriks, Djoke; Nijman, Hans W; Wei, Yunwei; Zhou, Jin; Helfrich, Wijnand; Bremer, Edwin

    2015-01-01

    The therapeutic effect of anti-cancer monoclonal antibodies stems from their capacity to opsonize targeted cancer cells with subsequent phagocytic removal, induction of antibody-dependent cell-mediated cytotoxicity (ADCC) or induction of complement-mediated cytotoxicity (CDC). The major immune effector cells involved in these processes are natural killer (NK) cells and granulocytes. The latter and most prevalent blood cell population contributes to phagocytosis, but is not effective in inducing ADCC. Here, we report that targeted delivery of the tumoricidal protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to granulocyte marker C-type lectin-like molecule-1 (CLL1), using fusion protein CLL1:TRAIL, equips granulocytes with high levels of TRAIL. Upon CLL1-selective binding of this fusion protein, granulocytes acquire additional TRAIL-mediated cytotoxic activity that, importantly, potentiates antibody-mediated cytotoxicity of clinically used therapeutic antibodies (e.g., rituximab, cetuximab). Thus, CLL1:TRAIL could be used as an adjuvant to optimize the clinical potential of anticancer antibody therapy by augmenting tumoricidal activity of granulocytes. PMID:25760768

  3. Redox probing study of the potential dependence of charge transport through Li2O2

    SciTech Connect

    Knudsen, Kristian B.; Luntz, Alan C.; Jensen, Søren H.; Vegge, Tejs; Hjelm, Johan

    2015-11-20

    In the field of energy storage devices the pursuit for cheap, high energy density, reliable secondary batteries is at the top of the agenda. The Li–O2 battery is one of the possible technologies that, in theory, should be able to close the gap, which exists between the present state-of-the-art Li-ion technologies and the demand placed on batteries by technologies such as electrical vehicles. Here we present a redox probing study of the charge transfer across the main deposition product lithium peroxide, Li2O2, in the Li–O2 battery using outer-sphere redox shuttles. The change in heterogeneous electron transfer exchange rate as a function of the potential and the Li2O2 layer thickness (~depth-of-discharge) was determined using electrochemical impedance spectroscopy. In addition, the attenuation of the electron transfer exchange rate with film thickness is dependent on the probing potential, providing evidence that hole transport is the dominant process for charge transfer through Li2O2 and showing that the origin of the sudden death observed upon discharge is due to charge transport limitations.

  4. Antihepatocellular Carcinoma Potential of Tetramethylpyrazine Induces Cell Cycle Modulation and Mitochondrial-Dependent Apoptosis: Regulation of p53 Signaling Pathway in HepG2 Cells In Vitro.

    PubMed

    Bi, Lei; Yan, Xiaojing; Chen, Weiping; Gao, Jing; Qian, Lei; Qiu, Shuang

    2016-06-01

    Tetramethylpyrazine (TMP) was originally isolated from a traditional Chinese herbal medicine, Ligusticum chuanxiong In the present study, TMP exhibits potent antitumor activities in vitro. However, the molecular mechanisms remain to be defined. Hence, this study aims to investigate the antiproliferative and apoptotic effects of TMP on HepG2 and elucidate the underlying mechanisms. Analyses using Cell Counting Kit-8 and real-time cell analyzer indicated that TMP significantly inhibited HepG2 cell proliferation. We also observed that TMP induced cell cycle arrest at the G0/G1 checkpoint and apoptosis, using flow cytometry and high-content screening. Furthermore, our results predicted that TMP could directly decrease mitochondrial membrane potential (Δψm), increase the release of cytochrome c, and increase caspase activation, indicating that mitochondrial pathway apoptosis could be the mechanism for TMP within HepG2 cells. Moreover, TMP altered expression of p53 and the Bcl-2/Bax protein ratio, which revealed that TMP induced cell cycle arrest and caspase-dependent mitochondrial apoptosis in HepG2 cells in vitro. These studies provided mechanistic insights into the antitumor properties of TMP, which may be explored as a potential option for treatment of hepatocellular carcinoma. PMID:27179035

  5. A novel inward-rectifying K+ current with a cell-cycle dependence governs the resting potential of mammalian neuroblastoma cells.

    PubMed Central

    Arcangeli, A; Bianchi, L; Becchetti, A; Faravelli, L; Coronnello, M; Mini, E; Olivotto, M; Wanke, E

    1995-01-01

    1. Human and murine neuroblastoma cell lines were used to investigate, by the whole-cell patch-clamp technique, the properties of a novel inward-rectifying K+ current (IIR) in the adjustment of cell resting potential (Vrest), which was in the range -40 to -20 mV. 2. When elicited from a holding potential of 0 mV, IIR was completely inactivated with time constants ranging from 13 ms at -140 mV to 4.5 s at -50 mV. The steady-state inactivation curve (h(V)) was found to be independent of [Na+]o and [K+]o (2-80 mM) and could be fitted to a Boltzmann curve with a steep slope factor of 5-6, and a V1/2 around Vrest. Divalent ion-free extracellular solutions shifted h(V) to the left by about 28 mV. 3. Peak chord conductance, whose maximal value was approximately proportional to the square root of [K+]o, could be fitted to a Boltzmann curve independently of [K+]o, with a V1/2 value around -48 mV and a slope factor of 18. Extracellular Cs+ and Ba2+ blocked the IIR in a concentration- and voltage-dependent manner, but Ba2+ was less effective than it is on classical inward-rectifier channels. 4. Under control culture conditions the values of Vrest and V1/2 of h(V) varied widely among cells. The knowledge of V1/2 proved crucial or the theoretical prediction of Vrest. After cell synchronization in the G0-G1 phase of the cell cycle, or at the G1-S boundaries, the cells reduced their variability of h(V). The same occurred after cell synchronization in G1 by treatment with retinoic acid. 5. The experimental data could be fitted to a classical model of an inward rectifier, after removing the dependence of conductance activation on (V-EK), and incorporating an inactivation with an intrinsic voltage dependence. Moreover, the model predicts, for this novel inward rectifier and in contrast with the classical inward rectifier, the incapacity of maintaining, in physiological media, a Vrest more negative than -35 to -40 mV, which is an important feature of cancer cells. PMID:8847640

  6. Evaluation of potential implication of membrane estrogen binding sites on ERE-dependent transcriptional activity and intracellular estrogen receptor-alpha regulation in MCF-7 breast cancer cells.

    PubMed

    Seo, Hye Sook; Leclercq, Guy

    2002-01-01

    The potential involvement of membrane estrogen binding sites in the induction of ERE-dependent transcriptional activity as well as in the regulation of intracellular estrogen receptor alpha (ER-alpha) level under estradiol (E2) stimulation was investigated. Our approach relied upon the use of two DCC-treated E2-BSA (bovine serum albumin) solutions (E2-6-BSA and E2-17-BSA). The absence of detectable free E2 in these solutions was established. Both E2-BSA conjugates led to a transient dose-dependent stimulation of the expression of ERE-luciferase (LUC) reporter gene in MVLN cells (MCF-7 cells stably transfected with a pVit-tk-LUC reporter plasmid), a property not recorded with free E2, which maintained enhanced transcriptional activity during the whole experiment. A very low concentration of E2 (10 pM) synergistically acted with E2-BSA conjugates. Hence, ERE-dependent transcriptional activity induced by these conjugates appeared to result from their known interactions with membrane estrogen binding sites. Anti-estrogens (AEs: 4-OH-TAM and RU 58,668), which antagonize genomic ER responses, abrogated the luciferase activity induced by E2-BSA conjugates, confirming a potential relationship between membrane-related signals and intracellular ER. Moreover, induction of luciferase was recorded when the cells were exposed to IBMX (3-isobutyl-1-methylxanthine) and cyclic nucleotides (cAMP/cGMP), suggesting the implication of the latter in the signal transduction pathway leading to the expression of the reporter gene. Growth factors (IGF-I, EGF and TGF-alpha) also slightly stimulated luciferase and synergistically acted with 10 pM E2, or 1 microM E2-BSA conjugates, in agreement with the concept of a cross-talk between steroids and peptides acting on the cell membrane. Remarkably, E2-BSA conjugates, IBMX and all investigated growth factors failed to down-regulate intracellular ER in MCF-7 cells, indicating the need for a direct intracellular interaction of the ligand with the

  7. A Primary Cortical Input to Hippocampus Expresses a Pathway-Specific and Endocannabinoid-Dependent Form of Long-Term Potentiation

    PubMed Central

    Wang, Weisheng; Jia, Yousheng; Pham, Danielle T.; Karsten, Carley A.; Merrill, Collin B.; Gall, Christine M.; Piomelli, Daniele

    2016-01-01

    Abstract The endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), a key modulator of synaptic transmission in mammalian brain, is produced in dendritic spines and then crosses the synaptic junction to depress neurotransmitter release. Here we report that 2-AG-dependent retrograde signaling also mediates an enduring enhancement of glutamate release, as assessed with independent tests, in the lateral perforant path (LPP), one of two cortical inputs to the granule cells of the dentate gyrus. Induction of this form of long-term potentiation (LTP) involved two types of glutamate receptors, changes in postsynaptic calcium, and the postsynaptic enzyme that synthesizes 2-AG. Stochastic optical reconstruction microscopy confirmed that CB1 cannabinoid receptors are localized presynaptically to LPP terminals, while the inhibition or knockout of the receptors eliminated LPP-LTP. Suppressing the enzyme that degrades 2-AG dramatically enhanced LPP potentiation, while overexpressing it produced the opposite effect. Priming with a CB1 agonist markedly reduced the threshold for LTP. Latrunculin A, which prevents actin polymerization, blocked LPP-LTP when applied extracellularly but had no effect when infused postsynaptically into granule cells, indicating that critical actin remodeling resides in the presynaptic compartment. Importantly, there was no evidence for the LPP form of potentiation in the Schaffer-commissural innervation of field CA1 or in the medial perforant path. Peripheral injections of compounds that block or enhance LPP-LTP had corresponding effects on the formation of long-term memory for cues conveyed to the dentate gyrus by the LPP. Together, these results indicate that the encoding of information carried by a principal hippocampal afferent involves an unusual, regionally differentiated form of plasticity. PMID:27517090

  8. Age-Dependent Switch of the Role of Serotonergic 5-HT1A Receptors in Gating Long-Term Potentiation in Rat Visual Cortex In Vivo

    PubMed Central

    Gagolewicz, Peter J.; Dringenberg, Hans C.

    2016-01-01

    The rodent primary visual cortex (V1) is densely innervated by serotonergic axons and previous in vitro work has shown that serotonin (5-HT) can modulate plasticity (e.g., long-term potentiation (LTP)) at V1 synapses. However, little work has examined the effects of 5-HT on LTP under in vivo conditions. We examined the role of 5-HT on LTP in V1 elicited by theta burst stimulation (TBS) of the lateral geniculate nucleus in urethane-anesthetized (adult and juvenile) rats. Thalamic TBS consistently induced potentiation of field postsynaptic potentials (fPSPs) recorded in V1. While 5-HT application (0.1–10 mM) itself did not alter LTP levels, the broad-acting 5-HT receptor antagonists methiothepin (1 mM) resulted in a clear facilitation of LTP in adult animals, an effect that was mimicked by the selective 5-HT1A receptor antagonist WAY 100635 (1 mM). Interestingly, in juvenile rats, WAY 100635 application inhibited LTP, indicative of an age-dependent switch in the role of 5-HT1A receptors in gating V1 plasticity. Analyses of spontaneous electrocorticographic (ECoG) activity in V1 indicated that the antagonist-induced LTP enhancement was not related to systematic changes in oscillatory activity in V1. Together, these data suggest a facilitating role of 5-HT1A receptor activation on LTP in the juvenile V1, which switches to a tonic, inhibitory influence in adulthood. PMID:27247804

  9. A Primary Cortical Input to Hippocampus Expresses a Pathway-Specific and Endocannabinoid-Dependent Form of Long-Term Potentiation.

    PubMed

    Wang, Weisheng; Trieu, Brian H; Palmer, Linda C; Jia, Yousheng; Pham, Danielle T; Jung, Kwang-Mook; Karsten, Carley A; Merrill, Collin B; Mackie, Ken; Gall, Christine M; Piomelli, Daniele; Lynch, Gary

    2016-01-01

    The endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), a key modulator of synaptic transmission in mammalian brain, is produced in dendritic spines and then crosses the synaptic junction to depress neurotransmitter release. Here we report that 2-AG-dependent retrograde signaling also mediates an enduring enhancement of glutamate release, as assessed with independent tests, in the lateral perforant path (LPP), one of two cortical inputs to the granule cells of the dentate gyrus. Induction of this form of long-term potentiation (LTP) involved two types of glutamate receptors, changes in postsynaptic calcium, and the postsynaptic enzyme that synthesizes 2-AG. Stochastic optical reconstruction microscopy confirmed that CB1 cannabinoid receptors are localized presynaptically to LPP terminals, while the inhibition or knockout of the receptors eliminated LPP-LTP. Suppressing the enzyme that degrades 2-AG dramatically enhanced LPP potentiation, while overexpressing it produced the opposite effect. Priming with a CB1 agonist markedly reduced the threshold for LTP. Latrunculin A, which prevents actin polymerization, blocked LPP-LTP when applied extracellularly but had no effect when infused postsynaptically into granule cells, indicating that critical actin remodeling resides in the presynaptic compartment. Importantly, there was no evidence for the LPP form of potentiation in the Schaffer-commissural innervation of field CA1 or in the medial perforant path. Peripheral injections of compounds that block or enhance LPP-LTP had corresponding effects on the formation of long-term memory for cues conveyed to the dentate gyrus by the LPP. Together, these results indicate that the encoding of information carried by a principal hippocampal afferent involves an unusual, regionally differentiated form of plasticity. PMID:27517090

  10. Structure-based characterization of the binding of peptide to the human endophilin-1 Src homology 3 domain using position-dependent noncovalent potential analysis.

    PubMed

    Fu, Chunjiang; Wu, Gang; Lv, Fenglin; Tian, Feifei

    2012-05-01

    Many protein-protein interactions are mediated by a peptide-recognizing domain, such as WW, PDZ, or SH3. In the present study, we describe a new method called position-dependent noncovalent potential analysis (PDNPA), which can accurately characterize the nonbonding profile between the human endophilin-1 Src homology 3 (hEndo1 SH3) domain and its peptide ligands and quantitatively predict the binding affinity of peptide to hEndo1 SH3. In this procedure, structure models of diverse peptides in complex with the hEndo1 SH3 domain are constructed by molecular dynamics simulation and a virtual mutagenesis protocol. Subsequently, three noncovalent interactions associated with each position of the peptide ligand in the complexed state are analyzed using empirical potential functions, and the resulting potential descriptors are then correlated with the experimentally measured affinity on the basis of 1997 hEndo1 SH3-binding peptides with known activities, using linear partial least squares regression (PLS) and the nonlinear support vector machine (SVM). The results suggest that: (i) the electrostatics appears to be more important than steric properties and hydrophobicity in the formation of the hEndo1 SH3-peptide complex; (ii) P(-4) of the core decapeptide ligand with the sequence pattern P(-6)P(-5)P(-4)P(-3)P(-2)P(-1)P(0)P(1)P(2)P(3) is the most important position in terms of determining both the stability and specificity of the architecture of the complex, and; (iii) nonlinear SVM appears to be more effective than linear PLS for accurately predicting the binding affinity of a peptide ligand to hEndo1 SH3, whereas PLS models are straightforward and easy to interpret as compared to those built by SVM. PMID:21947444

  11. Combination of blood oxygen level–dependent functional magnetic resonance imaging and visual evoked potential recordings for abnormal visual cortex in two types of amblyopia

    PubMed Central

    Wang, Xinmei; Cui, Dongmei; Zheng, Ling; Yang, Xiao; Yang, Hui

    2012-01-01

    Purpose To elucidate the different neuromechanisms of subjects with strabismic and anisometropic amblyopia compared with normal vision subjects using blood oxygen level–dependent functional magnetic resonance imaging (BOLD-fMRI) and pattern-reversal visual evoked potential (PR-VEP). Methods Fifty-three subjects, age range seven to 12 years, diagnosed with strabismic amblyopia (17 cases), anisometropic amblyopia (20 cases), and normal vision (16 cases), were examined using the BOLD-fMRI and PR-VEP of UTAS-E3000 techniques. Cortical activation by binocular viewing of reversal checkerboard patterns was examined in terms of the calcarine region of interest (ROI)-based and spatial frequency–dependent analysis. The correlation of cortical activation in fMRI and the P100 amplitude in VEP were analyzed using the SPSS 12.0 software package. Results In the BOLD-fMRI procedure, reduced areas and decreased activation levels were found in Brodmann area (BA) 17 and other extrastriate areas in subjects with amblyopia compared with the normal vision group. In general, the reduced areas mainly resided in the striate visual cortex in subjects with anisometropic amblyopia. In subjects with strabismic amblyopia, a more significant cortical impairment was found in bilateral BA 18 and BA 19 than that in subjects with anisometropic amblyopia. The activation by high-spatial-frequency stimuli was reduced in bilateral BA 18 and 19 as well as BA 17 in subjects with anisometropic amblyopia, whereas the activation was mainly reduced in BA 18 and BA 19 in subjects with strabismic amblyopia. These findings were further confirmed by the ROI-based analysis of BA 17. During spatial frequency–dependent VEP detection, subjects with anisometropic amblyopia had reduced sensitivity for high spatial frequency compared to subjects with strabismic amblyopia. The cortical activation in fMRI with the calcarine ROI-based analysis of BA 17 was significantly correlated with the P100 amplitude in VEP

  12. Direct autocrine inhibition and cAMP-dependent potentiation of single L-type Ca2+ channels in bovine chromaffin cells.

    PubMed

    Carabelli, V; Hernández-Guijo, J M; Baldelli, P; Carbone, E

    2001-04-01

    Using the cell-attached recording configuration, we found that in adult bovine chromaffin cells there exists a direct membrane-delimited inhibition of single Bay K-modified L-channels mediated by opioids and ATP locally released in the recording pipette. This autocrine modulation is mediated by pertussis toxin (PTX)-sensitive G-proteins and causes a 50 % decrease of the open channel probability (Po) and an equivalent percentage increase of null sweeps at +10 mV with no changes to the activation kinetics, single channel conductance and mean open time. The decrease in Po is mainly due to an increase in the occurrence and duration of slow closed times (> 40 ms). Addition of purinergic and opioidergic antagonists (suramin and naloxone) or cell pre-treatment with PTX removes the inhibition while addition of ATP and opioids inside the pipette, but not outside, mimics the effect. Strong pre-pulses (+150 mV, 280 ms) followed by short repolarizations are unable to remove the inhibition at test potential (+10 mV). Increasing the level of cAMP by either direct application of 8-(4-chlorophenylthio)-cAMP (8-CPT-cAMP) or mixtures of forskolin and 1-methyl-3-isobutylxanthine (IBMX) potentiates the activity of L-channels by increasing the mean open time and decreasing the mean closed time and percentage of null sweeps. The cAMP-induced potentiation occurs regardless of whether the G-protein-mediated inhibition is activated by ATP and opioids or inactivated by PTX. Protein kinase inhibitors (H7 and H89) prevent the effects of cAMP without altering the basal autocrine modulation associated with PTX-sensitive G-proteins. Our results provide new evidence for the coexistence of two distinct modulations that may converge on the same neuroendocrine L-channel: a direct G-protein-dependent inhibition and a cAMP-mediated potentiation, which may work in combination to regulate Ca2+ entry during neurosecretion. PMID:11283226

  13. Direct autocrine inhibition and cAMP-dependent potentiation of single L-type Ca2+ channels in bovine chromaffin cells

    PubMed Central

    Carabelli, Valentina; Hernández-Guijo, Jesús M; Baldelli, Pietro; Carbone, Emilio

    2001-01-01

    Using the cell-attached recording configuration, we found that in adult bovine chromaffin cells there exists a direct membrane-delimited inhibition of single Bay K-modified L-channels mediated by opioids and ATP locally released in the recording pipette. This autocrine modulation is mediated by pertussis toxin (PTX)-sensitive G-proteins and causes a 50 % decrease of the open channel probability (Po) and an equivalent percentage increase of null sweeps at +10 mV with no changes to the activation kinetics, single channel conductance and mean open time. The decrease in Po is mainly due to an increase in the occurrence and duration of slow closed times (> 40 ms). Addition of purinergic and opioidergic antagonists (suramin and naloxone) or cell pre-treatment with PTX removes the inhibition while addition of ATP and opioids inside the pipette, but not outside, mimics the effect. Strong pre-pulses (+150 mV, 280 ms) followed by short repolarizations are unable to remove the inhibition at test potential (+10 mV). Increasing the level of cAMP by either direct application of 8-(4-chlorophenylthio)-cAMP (8-CPT-cAMP) or mixtures of forskolin and 1-methyl-3-isobutylxanthine (IBMX) potentiates the activity of L-channels by increasing the mean open time and decreasing the mean closed time and percentage of null sweeps. The cAMP-induced potentiation occurs regardless of whether the G-protein-mediated inhibition is activated by ATP and opioids or inactivated by PTX. Protein kinase inhibitors (H7 and H89) prevent the effects of cAMP without altering the basal autocrine modulation associated with PTX-sensitive G-proteins. Our results provide new evidence for the coexistence of two distinct modulations that may converge on the same neuroendocrine L-channel: a direct G-protein-dependent inhibition and a cAMP-mediated potentiation, which may work in combination to regulate Ca2+ entry during neurosecretion. PMID:11283226

  14. Alternative splicing at C terminus of Ca(V)1.4 calcium channel modulates calcium-dependent inactivation, activation potential, and current density.

    PubMed

    Tan, Gregory Ming Yeong; Yu, Dejie; Wang, Juejin; Soong, Tuck Wah

    2012-01-01

    The Ca(V)1.4 voltage-gated calcium channel is predominantly expressed in the retina, and mutations to this channel have been associated with human congenital stationary night blindness type-2. The L-type Ca(V)1.4 channel displays distinct properties such as absence of calcium-dependent inactivation (CDI) and slow voltage-dependent inactivation (VDI) due to the presence of an autoinhibitory domain (inhibitor of CDI) in the distal C terminus. We hypothesized that native Ca(V)1.4 is subjected to extensive alternative splicing, much like the other voltage-gated calcium channels, and employed the transcript scanning method to identify alternatively spliced exons within the Ca(V)1.4 transcripts isolated from the human retina. In total, we identified 19 alternative splice variations, of which 16 variations have not been previously reported. Characterization of the C terminus alternatively spliced exons using whole-cell patch clamp electrophysiology revealed a splice variant that exhibits robust CDI. This splice variant arose from the splicing of a novel alternate exon (43*) that can be found in 13.6% of the full-length transcripts screened. Inclusion of exon 43* inserts a stop codon that truncates half the C terminus. The Ca(V)1.4 43* channel exhibited robust CDI, a larger current density, a hyperpolarized shift in activation potential by ∼10 mV, and a slower VDI. Through deletional experiments, we showed that the inhibitor of CDI was responsible for modulating channel activation and VDI, in addition to CDI. Calcium currents in the photoreceptors were observed to exhibit CDI and are more negatively activated as compared with currents elicited from heterologously expressed full-length Ca(V)1.4. Naturally occurring alternative splice variants may in part contribute to the properties of the native Ca(V)1.4 channels. PMID:22069316

  15. Homology Modeling of NAD+-Dependent DNA Ligase of the Wolbachia Endosymbiont of Brugia malayi and Its Drug Target Potential Using Dispiro-Cycloalkanones

    PubMed Central

    Shrivastava, Nidhi; Nag, Jeetendra K.; Pandey, Jyoti; Tripathi, Rama Pati; Shah, Priyanka; Siddiqi, Mohammad Imran

    2015-01-01

    Lymphatic filarial nematodes maintain a mutualistic relationship with the endosymbiont Wolbachia. Depletion of Wolbachia produces profound defects in nematode development, fertility, and viability and thus has great promise as a novel approach for treating filarial diseases. NAD+-dependent DNA ligase is an essential enzyme of DNA replication, repair, and recombination. Therefore, in the present study, the antifilarial drug target potential of the NAD+-dependent DNA ligase of the Wolbachia symbiont of Brugia malayi (wBm-LigA) was investigated using dispiro-cycloalkanone compounds. Dispiro-cycloalkanone specifically inhibited the nick-closing and cohesive-end ligation activities of the enzyme without inhibiting human or T4 DNA ligase. The mode of inhibition was competitive with the NAD+ cofactor. Docking studies also revealed the interaction of these compounds with the active site of the target enzyme. The adverse effects of these inhibitors were observed on adult and microfilarial stages of B. malayi in vitro, and the most active compounds were further monitored in vivo in jirds and mastomys rodent models. Compounds 1, 2, and 5 had severe adverse effects in vitro on the motility of both adult worms and microfilariae at low concentrations. Compound 2 was the best inhibitor, with the lowest 50% inhibitory concentration (IC50) (1.02 μM), followed by compound 5 (IC50, 2.3 μM) and compound 1 (IC50, 2.9 μM). These compounds also exhibited the same adverse effect on adult worms and microfilariae in vivo (P < 0.05). These compounds also tremendously reduced the wolbachial load, as evident by quantitative real-time PCR (P < 0.05). wBm-LigA thus shows great promise as an antifilarial drug target, and dispiro-cycloalkanone compounds show great promise as antifilarial lead candidates. PMID:25845868

  16. Genetic knockout of the α7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner.

    PubMed

    Freund, Ronald K; Graw, Sharon; Choo, Kevin S; Stevens, Karen E; Leonard, Sherry; Dell'Acqua, Mark L

    2016-08-01

    Reduced α7 nicotinic acetylcholine receptor (nAChR) function is linked to impaired hippocampal-dependent sensory processing and learning and memory in schizophrenia. While knockout of the Chrna7 gene encoding the α7nAChR on a C57/Bl6 background results in changes in cognitive measures, prior studies found little impact on hippocampal synaptic plasticity in these mice. However, schizophrenia is a multi-genic disorder where complex interactions between specific genetic mutations and overall genetic background may play a prominent role in determining phenotypic penetrance. Thus, we compared the consequences of knocking out the α7nAChR on synaptic plasticity in C57/Bl6 and C3H mice, which differ in their basal α7nAChR expression levels. Homozygous α7 deletion in C3H mice, which normally express higher α7nAChR levels, resulted in impaired long-term potentiation (LTP) at hippocampal CA1 synapses, while C3H α7 heterozygous mice maintained robust LTP. In contrast, homozygous α7 deletion in C57 mice, which normally express lower α7nAChR levels, did not alter LTP, as had been previously reported for this strain. Thus, the threshold of Chrna7 expression required for LTP may be different in the two strains. Measurements of auditory gating, a hippocampal-dependent behavioral paradigm used to identify schizophrenia-associated sensory processing deficits, was abnormal in C3H α7 knockout mice confirming that auditory gating also requires α7nAChR expression. Our studies highlight the importance of genetic background on the regulation of synaptic plasticity and could be relevant for understanding genetic and cognitive heterogeneity in human studies of α7nAChR dysfunction in mental disorders. PMID:27233215

  17. The potential for gene flow in a dependent lineage system of a harvester ant: fair meiosis in the F1 generation.

    PubMed

    Curry, Meghan M; Wheeler, Diana E; Yang, Kimberly; Anderson, Kirk E

    2010-01-01

    We investigated the potential for gene flow in a dependent lineage (DL) system of the harvester ant Pogonomyrmex. Each DL system is composed of 2 reproductively isolated lineages that are locked in an obligate mutualism. The genetic components that produce the worker phenotype are acquired by hybridizing with the partner lineage. In the mating flight, queens of both lineages mate with multiple males from each lineage. During colony growth and reproduction, eggs fertilized by partner-lineage sperm produce F(1) hybrid workers with interlineage genomes, whereas eggs fertilized by same-lineage sperm result in the development of new queens with intralineage genomes. New males are typically produced from unfertilized eggs laid by the pure-lineage queen but in her absence may be produced by interlineage F(1) workers. We investigated the potential for interlineage gene flow in this system using 2 classes of lineage-specific nuclear markers to identify hybrid genome combinations. We confirmed the production of viable interlineage F(1) reproductive females in field colonies, the occurrence of which is associated with the relative frequencies of each lineage in the population: interlineage F(1) queens occurred only in the rare lineage of the population with dramatically skewed lineage frequencies. In laboratory colonies, we detected fair meiosis in interlineage F(1) workers leading to the production of viable and haploid interlineage F(2) males. We conclude that the genomes of each lineage recombine freely, suggesting that extrinsic postzygotic selection maintains the integrity of each lineage genome. We compare our findings with those of the H1/H2 DL system. PMID:20022894

  18. First-passage-time statistics of a Brownian particle driven by an arbitrary unidimensional potential with a superimposed exponential time-dependent drift

    NASA Astrophysics Data System (ADS)

    Urdapilleta, Eugenio

    2015-12-01

    In one-dimensional systems, the dynamics of a Brownian particle are governed by the force derived from a potential as well as by diffusion properties. In this work, we obtain the first-passage-time statistics of a Brownian particle driven by an arbitrary potential with an exponential temporally decaying superimposed field up to a prescribed threshold. The general system analyzed here describes the sub-threshold signal integration of integrate-and-fire neuron models, of any kind, supplemented by an adaptation-like current, whereas the first-passage-time corresponds to the declaration of a spike. Following our previous studies, we base our analysis on the backward Fokker-Planck equation and study the survival probability and the first-passage-time density function in the space of the initial condition. By proposing a series solution we obtain a system of recurrence equations, which given the specific structure of the exponential time-dependent drift, easily admit a simpler Laplace representation. Naturally, the present general derivation agrees with the explicit solution we found previously for the Wiener process in (2012 J. Phys. A: Math. Theor. 45 185001). However, to demonstrate the generality of the approach, we further explicitly evaluate the first-passage-time statistics of the underlying Ornstein-Uhlenbeck process. To test the validity of the series solution, we extensively compare theoretical expressions with the data obtained from numerical simulations in different regimes. As shown, agreement is precise whenever the series is truncated at an appropriate order. Beyond the fact that both the Wiener and Ornstein-Uhlenbeck processes have a direct interpretation in the context of neuronal models, given their ubiquity in different fields, our present results will be of interest in other settings where an additive state-independent temporal relaxation process is being developed as the particle diffuses.

  19. Size and site dependent biological hazard potential of particulate matters collected from different heights at the vicinity of a building construction.

    PubMed

    Li, Huaqiong; Fang, Crystal Hay Yu; Shi, Wenxiong; Gurusamy, Subramaniam; Li, Shuzhou; Krishnan, Manoj N; George, Saji

    2015-11-01

    Although building constructions are a recurring part of urbanization, the health risk of particulate matters (PM) originating from such activities have seldom been subjected to detailed studies. We sought to characterize the relative risk of air borne PM collected from different heights (ground and top floor) of a building adjacent to a building under early phase of construction. We determined the physico-chemical properties such as size and shape, elemental composition and surface charge of the PM. The oxidative stress dependent cytotoxic and pro-inflammatory responses were assessed in BEAS-2B and RAW 264.7 cell lines using high-content-screening platforms. In comparison to top floor, the total mass of PM collected from ground floor was two-three folds higher and the mass fraction was dominated by PM20-35. Elemental analysis showed abundance of Si, Al, K, Ca and Fe in bigger PM while for PM0.25-0.5 it was mostly constituted by C and crystals rich in S and K. PM caused NFκB activation, secretion of pro-inflammatory cytokines and cytotoxicity wherein PM0.25-0.5 was the most potent among the tested PM. Estimated exposure level and lung burden together with the data on hazard potential were used for developing a MATLAB based risk-assessment model which suggested that the potential for health risk is relatively higher at the ground floor. Our studies demonstrated differences in, relative abundance of PM, their physicochemical and biological properties collected from different heights adjacent to a construction site and showed that relative health risk is higher at the ground floor. PMID:26253280

  20. Redox potential of quinones in photosynthetic reaction centers from Rhodobacter sphaeroides: dependence on protonation of Glu-L212 and Asp-L213.

    PubMed

    Ishikita, Hiroshi; Morra, Giulia; Knapp, Ernst-Walter

    2003-04-01

    The absolute values of the one-electron redox potentials of the two quinones (Q(A) and Q(B)) in bacterial photosynthetic reaction centers from Rhodobacter sphaeroides were calculated by evaluating the electrostatic energies from the solution of the linearized Poisson-Boltzmann equation at pH 7.0. The redox potential for Q(A) was calculated to be between -173 and -160 mV, which is close to the lowest measured values that are assumed to refer to nonequilibrated protonation patterns in the redox state Q(A)(-). The redox potential of quinone Q(B) is found to be about 160-220 mV larger for the light-exposed than for the dark-adapted structure. These values of the redox potentials are obtained if Asp-L213 is nearly protonated (probability 0.75-1.0) before and after electron transfer from Q(A) to Q(B), while Glu-L212 is partially protonated (probability 0.6) in the initial state Q(A)(-)Q(B)(0) and fully protonated in the final state Q(A)(0)Q(B)(-). Conversely, if the charge state of the quinones is varied from Q(A)(-)Q(B)(0) to Q(A)(0)Q(B)(-) corresponding to the electron transfer from Q(A) to Q(B), Asp-L213 remains protonated, while Glu-L212 changes its protonation state from 0.15 H(+) to fully protonated. In agreement with results from FTIR spectra, there is proton uptake at Glu-L212 going along with the electron transfer, whereas Asp-L213 does not change its protonation state. However, in our simulations Asp-L213 is considered to be protonated rather than ionized as deduced from FTIR spectra. The calculated redox potential of Q(A) shows little dependence on the charge state of Asp-L213, which is due to a strong coupling with the protonation state of Asp-M17 but increases by 50 mV if Glu-L212 changes from the ionized to the protonated charge state. Both are in agreement with fluorescence measurements observing the decay of SP(+)Q(A)(-) in a wide pH regime. The computed difference in redox potential of Q(B) in the light-exposed and dark-adapted structure was traced back

  1. Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system.

    PubMed

    Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Giampà, Carmela; Di Mauro, Michela; Mazzocchetti, Petra; Costa, Cinzia; Di Filippo, Massimiliano; Grassi, Silvarosa; Pettorossi, Vito Enrico; Calabresi, Paolo

    2015-01-01

    17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson's disease. PMID:26074768

  2. Coupled 3D Time-Dependent Wave-Packet Approach in Hyperspherical Coordinates: The D(+)+H2 Reaction on the Triple-Sheeted DMBE Potential Energy Surface.

    PubMed

    Ghosh, Sandip; Sahoo, Tapas; Adhikari, Satrajit; Sharma, Rahul; Varandas, António J C

    2015-12-17

    We implement a coupled three-dimensional (3D) time-dependent wave packet formalism for the 4D reactive scattering problem in hyperspherical coordinates on the accurate double many body expansion (DMBE) potential energy surface (PES) for the ground and first two singlet states (1(1)A', 2(1)A', and 3(1)A') to account for nonadiabatic processes in the D(+) + H2 reaction for both zero and nonzero values of the total angular momentum (J). As the long-range interactions in D(+) + H2 contribute significantly due to nonadiabatic effects, the convergence profiles of reaction probabilities for the reactive noncharge transfer (RNCT), nonreactive charge transfer (NRCT), and reactive charge transfer (RCT) processes are shown for different collisional energies with respect to the helicity (K) and total angular momentum (J) quantum numbers. The total and state-to-state cross sections are presented as a function of the collision energy for the initial rovibrational state v = 0, j = 0 of the diatom, and the calculated cross sections compared with other theoretical and experimental results. PMID:26436891

  3. 2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: potential role in the regulation of aging process.

    PubMed

    Salminen, Antero; Kauppinen, Anu; Kaarniranta, Kai

    2015-10-01

    Recent studies have revealed that the members of an ancient family of nonheme Fe(2+)/2-oxoglutarate-dependent dioxygenases (2-OGDO) are involved in the functions associated with the aging process. 2-Oxoglutarate and O2 are the obligatory substrates and Fe(2+) a cofactor in the activation of 2-OGDO enzymes, which can induce the hydroxylation of distinct proteins and the demethylation of DNA and histones. For instance, ten-eleven translocation 1-3 (TET1-3) are the demethylases of DNA, whereas Jumonji C domain-containing histone lysine demethylases (KDM2-7) are the major epigenetic regulators of chromatin landscape, known to be altered with aging. The functions of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD1-3) as well as those of collagen hydroxylases are associated with age-related degeneration. Moreover, the ribosomal hydroxylase OGFOD1 controls mRNA translation, which is known to decline with aging. 2-OGDO enzymes are the sensors of energy metabolism, since the Krebs cycle intermediate 2-oxoglutarate is an activator whereas succinate and fumarate are the potent inhibitors of 2-OGDO enzymes. In addition, O2 availability and iron redox homeostasis control the activities of 2-OGDO enzymes in tissues. We will briefly elucidate the catalytic mechanisms of 2-OGDO enzymes and then review the potential functions of the above-mentioned 2-OGDO enzymes in the control of the aging process. PMID:26118662

  4. Cholinergic Partition Cells and Lamina X Neurons Induce a Muscarinic-Dependent Short-Term Potentiation of Commissural Glutamatergic Inputs in Lumbar Motoneurons

    PubMed Central

    Bertrand, Sandrine S.; Cazalets, Jean-René

    2011-01-01

    Acetylcholine and the activation of muscarinic receptors influence the activity of neural networks generating locomotor behavior in the mammalian spinal cord. Using electrical stimulations of the ventral commissure, we show that commissural muscarinic (CM) depolarizations could be induced in lumbar motoneurons. We provide a detailed electrophysiological characterization of the muscarinic receptors and the membrane conductance involved in these responses. Activation of the CM terminals, originating from lamina X neurons and partition cells, induced a pathway-specific short-term potentiation (STP) of commissural glutamatergic inputs in motoneurons. This STP is occluded in the presence of the muscarinic antagonist atropine. During fictive locomotion, the activation of the commissural pathways transiently enhanced the motor output in a muscarinic-dependent manner. This study describes for the first time a novel regulatory mechanism of synaptic strength in spinal locomotor networks. Such cellular mechanisms would endow the locomotor central pattern generators with adaptive processes needed to generate appropriate synaptic inputs to motoneurons during different motor tasks. PMID:22069380

  5. Relationship between Serotonergic Dysfunction Based on Loudness Dependence of Auditory-Evoked Potentials and Suicide in Patients with Major Depressive Disorder

    PubMed Central

    2015-01-01

    The relationship between suicidality and the loudness dependence of auditory-evoked potentials (LDAEP) remains controversial. This article reviews the literature related to the LDAEP and suicide in patients with major depressive disorder, and suggests future research directions. Serotonergic dysfunction in suicidality seems to be more complicated than was originally thought. Studies of suicide based on the LDAEP have produced controversial results, but it is possible that these are due to differences in study designs and the smallness of samples. For example, some studies have evaluated suicide ideation and the LDAEP, while others have evaluated suicide attempts and the LDAEP. Furthermore, some of the latter studies enrolled acute suicide attempters, while others enrolled those with the history of previous suicide attempts, irrespective of whether these were acute or chronic. Thus, a more robust study design is needed in future studies, for example by evaluating the LDAEP immediately after a suicide attempt rather than in those with a history of suicide attempts and suicide ideation in order to reduce bias. Moreover, genuine suicide attempt, self-injurious behaviors, and faked suicide attempt need to be discriminated in the future. PMID:26508951

  6. Relationship between Serotonergic Dysfunction Based on Loudness Dependence of Auditory-Evoked Potentials and Suicide in Patients with Major Depressive Disorder.

    PubMed

    Park, Young-Min

    2015-10-01

    The relationship between suicidality and the loudness dependence of auditory-evoked potentials (LDAEP) remains controversial. This article reviews the literature related to the LDAEP and suicide in patients with major depressive disorder, and suggests future research directions. Serotonergic dysfunction in suicidality seems to be more complicated than was originally thought. Studies of suicide based on the LDAEP have produced controversial results, but it is possible that these are due to differences in study designs and the smallness of samples. For example, some studies have evaluated suicide ideation and the LDAEP, while others have evaluated suicide attempts and the LDAEP. Furthermore, some of the latter studies enrolled acute suicide attempters, while others enrolled those with the history of previous suicide attempts, irrespective of whether these were acute or chronic. Thus, a more robust study design is needed in future studies, for example by evaluating the LDAEP immediately after a suicide attempt rather than in those with a history of suicide attempts and suicide ideation in order to reduce bias. Moreover, genuine suicide attempt, self-injurious behaviors, and faked suicide attempt need to be discriminated in the future. PMID:26508951

  7. Conformational Temperature-Dependent Behavior of a Histone H2AX: A Coarse-Grained Monte Carlo Approach Via Knowledge-Based Interaction Potentials

    PubMed Central

    Fritsche, Miriam; Pandey, Ras B.; Farmer, Barry L.; Heermann, Dieter W.

    2012-01-01

    Histone proteins are not only important due to their vital role in cellular processes such as DNA compaction, replication and repair but also show intriguing structural properties that might be exploited for bioengineering purposes such as the development of nano-materials. Based on their biological and technological implications, it is interesting to investigate the structural properties of proteins as a function of temperature. In this work, we study the spatial response dynamics of the histone H2AX, consisting of 143 residues, by a coarse-grained bond fluctuating model for a broad range of normalized temperatures. A knowledge-based interaction matrix is used as input for the residue-residue Lennard-Jones potential. We find a variety of equilibrium structures including global globular configurations at low normalized temperature (), combination of segmental globules and elongated chains (), predominantly elongated chains (), as well as universal SAW conformations at high normalized temperature (). The radius of gyration of the protein exhibits a non-monotonic temperature dependence with a maximum at a characteristic temperature () where a crossover occurs from a positive (stretching at ) to negative (contraction at ) thermal response on increasing . PMID:22442661

  8. Measuring the magnetic-field-dependent chemical potential of a low-density three-dimensional electron gas in n -GaAs and extracting its magnetic susceptibility

    NASA Astrophysics Data System (ADS)

    Roy Choudhury, Aditya N.; Venkataraman, V.

    2016-01-01

    We report the magnetic-field-dependent shift of the electron chemical potential in bulk, n -type GaAs at room temperature. A transient voltage of ˜100 μ V was measured across a Au-Al2O3 -GaAs metal-oxide-semiconductor capacitor in a pulsed magnetic field of ˜6 T . Several spurious voltages larger than the signal that had plagued earlier researchers performing similar experiments were carefully eliminated. The itinerant magnetic susceptibility of GaAs is extracted from the experimentally measured data for four different doping densities, including one as low as 5 ×1015cm-3 . Though the susceptibility in GaAs is dominated by Landau-Peierls diamagnetism, the experimental technique demonstrated can be a powerful tool for extracting the total free carrier magnetization of any electron system. The method is also virtually independent of the carrier concentration and is expected to work better in the nondegenerate limit. Such experiments had been successfully performed in two-dimensional electron gases at cryogenic temperatures. However, an unambiguous report on having observed this effect in any three-dimensional electron gas has been lacking. We highlight the 50 year old literature of various trials and discuss the key details of our experiment that were essential for its success. The technique can be used to unambiguously yield only the itinerant part of the magnetic susceptibility of complex materials such as magnetic semiconductors and hexaborides, and thus shed light on the origin of ferromagnetism in such systems.

  9. Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system

    PubMed Central

    Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Giampà, Carmela; Di Mauro, Michela; Mazzocchetti, Petra; Costa, Cinzia; Di Filippo, Massimiliano; Grassi, Silvarosa; Pettorossi, Vito Enrico; Calabresi, Paolo

    2015-01-01

    17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson’s disease. PMID:26074768

  10. Analysis of Stress Effect on (110)-Oriented Single-Gate SOI nMOSFETs Using a Silicon-Thickness-Dependent Deformation Potential.

    PubMed

    Choi, S; Sun, W; Lee, I; Shin, H

    2016-05-01

    The stress effect in uniaxially strained (100)- and (110)-oriented single-gate (SG) silicon-on-insulator (SOI) n-type metal-oxide-semiconductor field-effect transistors (MOSFETs) was analyzed. A model of a silicon-thickness-dependent deformation potential (D(as_T(si))) was used for accurate calculation of mobility using a Schrödinger-Poisson solver. The simulation results obtained using the D(ac_T(si)) model exhibited excellent agreement with the measured mobility for both strained and unstrained conditions. The enhancements in electron mobility under conditions of longitudinal tensile strain were analyzed as a function of the silicon thickness and strain. As the silicon thickness decreased, the mobility enhancement in (100) SG MOSFETs reached a peak, whereas it diminished in (110) SG MOSFETs. As the strain increased, mobility enhancement increased in the (110) case, whereas it saturated in the (100) case. Therefore, larger mobility enhancement in the (110) orientation is expected. These differences in enhancement between the (100) and (110) cases resulted from differences in the quantization mass, which affect the energy difference between the 1st subbands of two-fold and four-fold degenerate valleys, as well as occupancy change. PMID:27483890

  11. Region- and age-dependent reductions of hippocampal long-term potentiation and NMDA to AMPA ratio in a genetic model of Alzheimer's disease.

    PubMed

    Tozzi, Alessandro; Sclip, Alessandra; Tantucci, Michela; de Iure, Antonio; Ghiglieri, Veronica; Costa, Cinzia; Di Filippo, Massimiliano; Borsello, Tiziana; Calabresi, Paolo

    2015-01-01

    To characterize the mechanisms underlying region- and age-dependent hippocampal synaptic dysfunction in Alzheimer's disease, we used transgenic CRND8 mice, expressing the Swedish-Indiana APP mutation. In 2-month-old mice, no β-amyloid plaques deposition, but the presence of soluble oligomers, were found in CA1 area but not in dentate gyrus (DG). At this age, long-term potentiation (LTP) was reduced selectively in CA1. In 6-month-old mice, the presence of soluble oligomers was accompanied by accumulation of β-amyloid plaques and decreased LTP in CA1 and DG regions. In both regions, the loss of LTP was linked to reduced N-methyl-D-aspartate (NMDA) to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) current ratio. The acetylcholine-esterase inhibitor, neostigmine rescued LTP in CA1 area at early stage of the disease but not after plaques deposition. Conversely, the NMDA receptor antagonist memantine restored LTP selectively in DG at later stages of the disease. Both these effects were associated with a normalization of the NMDA to AMPA ratio. The association between the recovery of LTP and the normalization of the NMDA to AMPA ratio provides information on new possible therapeutic strategies in Alzheimer's disease. PMID:25104560

  12. Analysis of stress-induced mobility enhancement on (100)-oriented single- and double-gate n-MOSFETs using silicon-thickness-dependent deformation potential

    NASA Astrophysics Data System (ADS)

    Choi, Sujin; Sun, Wookyung; Shin, Hyungsoon

    2015-04-01

    The stress effect in uniaxially strained single- and double-gate silicon-on-insulator n-type metal oxide-semiconductor field effect transistors (MOSFETs) with a (100) wafer orientation is analyzed. A model of silicon-thickness-dependent deformation potential ({{D}ac\\_{{TSi}}}) is introduced to accurately calculate the mobility using a Schrödinger-Poisson solver. Simulation results using the {{D}ac\\_{{TSi}}} model exhibit excellent agreement with the measured mobility for both the unstrained and strained conditions. Electron mobility enhancements with longitudinal and transverse tensile stress conditions are simulated as a function of silicon thickness. The mobility enhancement in the single-gate case has one peak point, whereas it produces two peak points in the double-gate case. An in-depth analysis reveals that this phenomenon results from the hump in the energy difference between the Δ2 and Δ4 valleys, which in turn results from the volume inversion in the double gate.

  13. A novel gelatin-based micro-cavitary hydrogel for potential application in delivery of anchorage dependent cells: A study with vasculogenesis model.

    PubMed

    Leong, Wenyan; Fan, Changjiang; Wang, Dong-An

    2016-10-01

    Hydrogels have been widely regarded as promising tissue engineering scaffolds and cell delivery vehicles, however, their inherent submicron- or nano-scale polymer networks severely inhibit the settlement of anchorage dependent cells (ADCs). Here, using endothelial progenitor outgrowth cells (EPOCs) as the typical ADCs, a gelatin-based micro-cavitary gel (namely Gel-MCG) is developed with gelatin-methacrylate and gelatin microspheres as precursor and porogens, respectively, to promote cellular focal adhesion and functions. The introduction of micro-cavitary structures within the Gel-MCG improves its physical properties as well as creates numerous gel-microcavity interfaces within gel-based matrices. Compared with conventional gelatin gel (Gel-G) scaffold, the Gel-MCG provides more suitable microenvironments for EPOCs' attachment, spreading, and proliferation, and then which leads to enhanced endothelial differentiation and vascularization as demonstrated by higher expressions of endothelial markers. The Gel-MCG system shows great potential as vehicle for the delivery of ADCs in tissue engineering. PMID:27371893

  14. Calcium Input Potentiates the Transforming Growth Factor (TGF)-β1-dependent Signaling to Promote the Export of Inorganic Pyrophosphate by Articular Chondrocyte*

    PubMed Central

    Cailotto, Frederic; Reboul, Pascal; Sebillaud, Sylvie; Netter, Patrick; Jouzeau, Jean-Yves; Bianchi, Arnaud

    2011-01-01

    Transforming growth factor (TGF)-β1 stimulates extracellular PPi (ePPi) generation and promotes chondrocalcinosis, which also occurs secondary to hyperparathyroidism-induced hypercalcemia. We previously demonstrated that ANK was up-regulated by TGF-β1 activation of ERK1/2 and Ca2+-dependent protein kinase C (PKCα). Thus, we investigated mechanisms by which calcium could affect ePPi metabolism, especially its main regulating proteins ANK and PC-1 (plasma cell membrane glycoprotein-1). We stimulated articular chondrocytes with TGF-β1 under extracellular (eCa2+) or cytosolic Ca2+ (cCa2+) modulations. We studied ANK, PC-1 expression (quantitative RT-PCR, Western blotting), ePPi levels (radiometric assay), and cCa2+ input (fluorescent probe). Voltage-operated Ca2+-channels (VOC) and signaling pathways involved were investigated with selective inhibitors. Finally, Ank promoter activity was evaluated (gene reporter). TGF-β1 elevated cCa2+ and ePPi levels (by up-regulating Ank and PC-1 mRNA/proteins) in an eCa2+ dose-dependent manner. TGF-β1 effects were suppressed by cCa2+ chelation or L- and T-VOC blockade while being mostly reproduced by ionomycin. In the same experimental conditions, the activation of Ras, the phosphorylation of ERK1/2 and PKCα, and the stimulation of Ank promoter activity were affected similarly. Activation of SP1 (specific protein 1) and ELK-1 (Ets-like protein-1) transcription factors supported the regulatory role of Ca2+. SP1 or ELK-1 overexpression or blockade experiments demonstrated a major contribution of ELK-1, which acted synergistically with SP1 to activate Ank promoter in response to TGF-β1. TGF-β1 promotes input of eCa2+ through opening of L- and T-VOCs, to potentiate ERK1/2 and PKCα signaling cascades, resulting in an enhanced activation of Ank promoter and ePPi production in chondrocyte. PMID:21471198

  15. The membrane-tubulating potential of amphiphysin 2/BIN1 is dependent on the microtubule-binding cytoplasmic linker protein 170 (CLIP-170).

    PubMed

    Meunier, Brigitte; Quaranta, Muriel; Daviet, Laurent; Hatzoglou, Anastassia; Leprince, Corinne

    2009-02-01

    Amphiphysins are BIN-amphiphysin-RVS (BAR) domain-containing proteins that influence membrane curvature in sites such as T-tubules in muscular cells, endocytic pits in neuronal as well as non-neuronal cells, and possibly cytoplasmic endosomes. This effect on lipid membranes is fulfilled by diverse amphiphysin 2/BIN1 isoforms, generated by alternative splicing and showing distinct structural and functional properties. In this study, our goal was to characterize the functional role of a ubiquitously expressed amphiphysin 2/BIN1 by the characterization of new molecular partners. We performed a two-hybrid screen with an isoform of amphiphysin 2/BIN1 expressed in HeLa cells. We identified CLIP-170 as an amphiphysin 2/BIN1-interacting molecule. CLIP-170 is a plus-end tracking protein involved in microtubule (MT) stability and recruitment of dynactin. The binding between amphiphysin 2/BIN1 and CLIP-170 is dependent on the N-terminal part of amphiphysin 2 (mostly the BAR domain) and an internal coiled-coil region of CLIP-170. This partnership was confirmed by GST pull-down assay and by co-immunoprecipitation in HeLa cells that express endogenous amphiphysin 2 (mostly isoforms 6, 9 and 10). When overexpressed in HeLa cells, amphiphysin 2/BIN1 leads to the formation of intracellular tubules which can closely align with MTs. After MT depolymerization by nocodazole, amphiphysin 2-stained tubules disappear, and reappear after nocodazole washout. Furthermore, depletion of CLIP-170 by RNAi induced a decrease in the proportion of cells with amphiphysin 2-stained tubules and an increase in the proportion of cells with no tubules. This result suggests the existence of a mechanistic link between the two types of tubules, which is likely to involve the +TIP protein, CLIP-170. Amphiphysin 2/BIN1 may be an anchoring point on membranes for CLIP-170, and consequently for MT. Then, the pushing force of polymerizing MT could help amphiphysin 2/BIN1 in its tubulation potential. We propose

  16. An empirical dependence of frequency in the oscillatory sorption of H2 and D2 in Pd on the first ionization potential of noble gases.

    PubMed

    Lalik, Erwin

    2011-08-14

    Oscillatory heat evolution in sorption of H(2) and D(2) in Pd can be induced by an admixture of ~10 vol.% of an inert gas (He, Ne, Ar, Kr, or N(2)) to either isotope prior to its contact with palladium powder. The oscillations are represented in the form of a calorimetric time series, recorded using a gas flow-through microcalorimeter at the temperatures of 75 °C for D(2) and 106 °C for H(2). For both D(2) and H(2), the oscillation parameters change as a function of the kind of inert gas used: the amplitude increases and the frequency decreases in passing from He to Kr. An empirical dependence of the oscillation frequencies observed for various admixtures and normalized with respect to Kr has been found. Accordingly, the frequency is a function of a product of the first ionization potential and the square root of atomic mass of the inert gas (He, Ne, Ar, Kr, or N(2)). On the other hand, invariance of the thermal effects of sorption is evident from the integrated areas under the calorimetric time series yielding the molar heats of sorption conserved, irrespective of the inert gas admixture. A novel calibration procedure has been devised in order to deal with an instability of calibration factor arising in desorption of H(2) and D(2) from Pd. A method of dynamic calibration factor made it possible to obtain a good agreement between the heats of sorption and desorption of both H(2) and D(2) within individual sorption-desorption cycles for all inert gas admixtures. PMID:21842944

  17. Phase dependency of long-term potentiation induction during the intermittent bursts of carbachol-induced β oscillation in rat hippocampal slices

    PubMed Central

    Nishimura, Motoshi; Nakatsuka, Hiroki; Natsume, Kiyohisa

    2012-01-01

    The rodent hippocampus possesses theta (θ) and beta (β) rhythms, which occur intermittently as bursts. Both rhythms are related to spatial memory processing in a novel environment. θ rhythm is related to spatial memory encoding process. β rhythm is related to the match/mismatch process. In the match/mismatch process, rodent hippocampus detects a representation matching sensory inputs of the current place among the retrieved internal representations of places. Long-term synaptic potentiation (LTP) is induced in both processes. The cholinergic agent carbachol induces intermittent θ and β oscillations in in vitro slices similar to in vivo bursts. LTP is facilitated during the generation of θ oscillation, suggesting that the facilitation of LTP is dependent upon the phases of intermittent burst (burst phases) of the oscillation. However, whether this is the case for β oscillation has not yet been studied. In the present study, LTP-inducing θ-burst stimulation was administered at the different burst phases of carbachol-induced β oscillations (CIBO), and the synaptic changes were measured at CA3-CA3 pyramidal cell synapses (CA3 synapse) and at CA3-CA1 pyramidal cell synapses (CA1 synapse). At the CA3 synapse, the largest magnitude of LTP was induced at the late burst phases of CIBO. At the CA1 synapse, LTP was induced only at the late burst phases. Modulation of LTP was suppressed when CIBO was blocked by the application of atropine at both synapses. The results suggest that the bursts of hippocampal β rhythm can determine the optimal temporal period for completing with the match/mismatch process.

  18. Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential

    PubMed Central

    Antoine, Thomas; Fisher, Nicholas; Amewu, Richard; O'Neill, Paul M.; Ward, Stephen A.; Biagini, Giancarlo A.

    2014-01-01

    Objectives Artemisinin and artemisinin semi-synthetic derivatives (collectively known as endoperoxides) are first-line antimalarials for the treatment of uncomplicated and severe malaria. Endoperoxides display very fast killing rates and are generally recalcitrant to parasite resistance development. These key pharmacodynamic features are a result of a complex mechanism of action, the details of which lack consensus. Here, we report on the primary physiological events leading to parasite death. Methods Parasite mitochondrial (ΔΨm) and plasma membrane (ΔΨp) electrochemical potentials were measured using real-time single-cell imaging following exposure to pharmacologically relevant concentrations of endoperoxides (artemisinin, dihydroartemisinin, artesunate and the synthetic tetraoxane RKA182). In addition, mitochondrial electron transport chain components NADH:quinone oxidoreductase (alternative complex I), bc1 (complex III) and cytochrome oxidase (complex IV) were investigated to determine their functional sensitivity to the various endoperoxides. Results Parasite exposure to endoperoxides resulted in rapid depolarization of parasite ΔΨm and ΔΨp. The rate of depolarization was decreased in the presence of a reactive oxygen species (ROS) scavenger and Fe3+ chelators. Depolarization of ΔΨm by endoperoxides is not believed to be through the inhibition of mitochondrial electron transport chain components, owing to the lack of significant inhibition when assayed directly. Conclusions The depolarization of ΔΨm and ΔΨp is shown to be mediated via the generation of ROS that are initiated by iron bioactivation of endoperoxides and/or catalysed by iron-dependent oxidative stress. These data are discussed in the context of current hypotheses concerning the mode of action of endoperoxides. PMID:24335485

  19. A dynamic transmission model with age-dependent infectiousness and reactivation for cytomegalovirus in the United States: Potential impact of vaccination strategies on congenital infection.

    PubMed

    Hogea, Cosmina; Dieussaert, Ilse; Van Effelterre, Thierry; Guignard, Adrienne; Mols, Johann

    2015-01-01

    We present an age-structured dynamic transmission model for cytomegalovirus (CMV) in the United States, based on natural history and available data, primarily aiming to combine the available qualitative and quantitative knowledge toward more complex modeling frameworks to better reflect the underlying biology and epidemiology of the CMV infection. The model structure explicitly accounts for primary infections, reactivations and re-infections. Duration of infectiousness and likelihood of reactivation were both assumed to be age-dependent, and natural reduction in the re-infection risk following primary infection was included. We used an empirical social contact matrix (POLYMOD-based) as support for CMV transmission between different age groups. The baseline model reproduced well the age-stratified seroprevalence data (National Health and Nutrition Examination Survey III) used for calibration. The model was further used to explore the potential impact of hypothetical vaccination on reducing congenital CMV infection under various vaccine profiles and vaccination scenarios. Our preliminary model-based simulations suggested that while infant vaccination may represent an attractive way to reduce congenital CMV infection over time, adolescent female vaccination with an adequate routine booster platform may, under certain conditions, provide an alternative. However, for such tools to be considered toward actual decision-making, enhanced validations based on additional studies and data would be further necessary. The modeling framework presented in this paper was designed to be sufficiently general and flexible, such that it can allow for further adaptations to reflect new knowledge or data that may become available in the future. PMID:25984886

  20. N-Acetyl Cysteine Mediates Protection from 2-Hydroxyethyl Methacrylate Induced Apoptosis via Nuclear Factor Kappa B–Dependent and Independent Pathways: Potential Involvement of JNK

    PubMed Central

    Paranjpe, Avina; Cacalano, Nicholas A.; Hume, Wyatt R.; Jewett, Anahid

    2009-01-01

    The mechanisms by which resin based materials induce adverse effects in patients have not been completely elucidated. Here we show that 2-hydroxyethyl methacrylate (HEMA) induces apoptotic cell death in oral keratinocytes. Functional loss and cell death induced by HEMA was significantly inhibited in the presence of N-acetyl cysteine (NAC) treatment. NAC also prevented HEMA mediated decrease in vascular endothelial growth factor secretion. The protective effect of NAC was partly related to its ability to induce NF-κB in the cells, since HEMA mediated inhibition of nuclear NF-κB expression and function was significantly blocked in the presence of NAC treatment. Moreover, blocking of nuclear translocation of NF-κB in oral keratinocytes sensitized these cells to HEMA mediated apoptosis. In addition, since NAC was capable of rescuing close to 50% of NF-κB knockdown cells from HEMA mediated cell death, there is, therefore, an NF-κB independent pathway of protection from HEMA mediated cell death by NAC. NAC mediated prevention of HEMA induced cell death in NF-κB knockdown cells was correlated with a decreased induction of c-Jun N-terminal kinase (JNK) activity since NAC inhibited HEMA mediated increase in JNK levels. Furthermore, the addition of a pharmacologic JNK inhibitor to HEMA treated cells prevented cell death and restored NF-κB knockdown cell function significantly. Therefore, NAC protects oral keratinocytes from the toxic effects of HEMA through NF-κB dependent and independent pathways. Moreover, our data suggest the potential involvement of JNK pathway in NAC mediated protection. PMID:19176594

  1. A dynamic transmission model with age-dependent infectiousness and reactivation for cytomegalovirus in the United States: Potential impact of vaccination strategies on congenital infection

    PubMed Central

    Hogea, Cosmina; Dieussaert, Ilse; Van Effelterre, Thierry; Guignard, Adrienne; Mols, Johann

    2015-01-01

    We present an age-structured dynamic transmission model for cytomegalovirus (CMV) in the United States, based on natural history and available data, primarily aiming to combine the available qualitative and quantitative knowledge toward more complex modeling frameworks to better reflect the underlying biology and epidemiology of the CMV infection. The model structure explicitly accounts for primary infections, reactivations and re-infections. Duration of infectiousness and likelihood of reactivation were both assumed to be age-dependent, and natural reduction in the re-infection risk following primary infection was included. We used an empirical social contact matrix (POLYMOD-based) as support for CMV transmission between different age groups. The baseline model reproduced well the age-stratified seroprevalence data (National Health and Nutrition Examination Survey III) used for calibration. The model was further used to explore the potential impact of hypothetical vaccination on reducing congenital CMV infection under various vaccine profiles and vaccination scenarios. Our preliminary model-based simulations suggested that while infant vaccination may represent an attractive way to reduce congenital CMV infection over time, adolescent female vaccination with an adequate routine booster platform may, under certain conditions, provide an alternative. However, for such tools to be considered toward actual decision-making, enhanced validations based on additional studies and data would be further necessary. The modeling framework presented in this paper was designed to be sufficiently general and flexible, such that it can allow for further adaptations to reflect new knowledge or data that may become available in the future. PMID:25984886

  2. Sex differences in the role of transient receptor potential (TRP) channels in endothelium-dependent vasorelaxation in porcine isolated coronary arteries.

    PubMed

    Wong, Pui San; Roberts, Richard E; Randall, Michael D

    2015-03-01

    Endothelial and smooth muscle Transient Receptor Potential (TRP) channels contribute to regulation of vascular tone. We have previously reported sex differences in the endothelial function in porcine isolated coronary arteries (PCAs). The present study examined the role of TRP channels in endothelium-dependent and H2O2-induced vasorelaxations in male and female PCAs. Distal PCAs were mounted in a wire myograph and precontracted with U46619. Concentration-response curves to bradykinin, H2O2 and A23187 were constructed in the presence of TRP channel antagonists with or without L-NAME and indomethacin to inhibit NO synthase and cyclooxygenase respectively. 2-APB (TRPC & TRPM antagonist) inhibited the maximum relaxation (Rmax) of the bradykinin-induced vasorelaxation and abolished the EDH-type response in PCAs from both sexes. SKF96365 (TRPC antagonist) inhibited the Rmax of bradykinin-induced vasorelaxation in males, and inhibited Rmax of the EDH-type response in both sexes. Pyr3 (TRPC3 antagonist) inhibited both the NO and EDH components of the bradykinin-induced vasorelaxation in males, but not females. RN1734 (TRPV4 antagonist) reduced the potency of the NO component of the bradykinin-induced vasorelaxation in females only, but inhibited the Rmax of the EDH-type component in both sexes. 2-APB, SKF96365 and RN1734 all reduced the H2O2-induced vasorelaxation, whereas Pyr3 had no effect. No differences in expression level of TRPC3 and TRPV4 between sexes were detected using Western blot. Present study demonstrated a clear sex differences in the role TRP channels where TRPC3 play a role in the NO- and EDH-type response in males and TRPV4 play a role in the NO-mediated response in females. PMID:25620134

  3. Effects of repetitive TMS on visually evoked potentials and EEG in the anaesthetized cat: dependence on stimulus frequency and train duration

    PubMed Central

    Aydin-Abidin, Selcen; Moliadze, Vera; Eysel, Ulf T; Funke, Klaus

    2006-01-01

    Repetitive transcranial magnetic stimulation (rTMS) has been shown to alter cortical excitability that lasts beyond the duration of rTMS application itself. High-frequency rTMS leads primarily to facilitation, whereas low-frequency rTMS leads to inhibition of the treated cortex. However, the contribution of rTMS train duration is less clear. In this study, we investigated the effects of nine different rTMS protocols, including low and high frequencies, as well as short and long applications (1, 3 and 10 Hz applied for 1, 5 and 20 min), on visual cortex excitability in anaesthetized and paralysed cats by means of visual evoked potential (VEP) and electroencephalography (EEG) recordings. Our results show that 10 Hz rTMS applied for 1 and 5 min significantly enhanced early VEP amplitudes, while 1 and 3 Hz rTMS applied for 5 and 20 min significantly reduced them. No significant changes were found after 1 and 3 Hz rTMS applied for only 1 min, and 10 Hz rTMS applied for 20 min. EEG activity was only transiently (<20 s) affected, with increased delta activity after 1 and 3 Hz rTMS applied for 1 or 5 min. These findings indicate that the effects of rTMS on cortical excitability depend on the combination of stimulus frequency and duration (or total number of stimuli): short high-frequency trains seem to be more effective than longer trains, and low-frequency rTMS requires longer applications. Changes in the spectral composition of the EEG were not correlated to changes in VEP size. PMID:16690713

  4. Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

    PubMed Central

    Zhang, Meili; Mathews Griner, Lesley A.; Ju, Wei; Duveau, Damien Y.; Guha, Rajarshi; Petrus, Michael N.; Wen, Bernard; Maeda, Michiyuki; Shinn, Paul; Ferrer, Marc; Conlon, Kevin D.; Bamford, Richard N.; O’Shea, John J.; Thomas, Craig J.; Waldmann, Thomas A.

    2015-01-01

    Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1–encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokine-dependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients’ PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL. PMID:26396258

  5. Alpha synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases

    PubMed Central

    Martin, Zane S.; Neugebauer, Volker; Dineley, Kelly T.; Kayed, Rakez; Zhang, Wenru; Reese, Lindsay C.; Taglialatela, Giulio

    2011-01-01

    Intracellular deposition of fibrillar aggregates of alpha synuclein (αSyn) characterizes neurodegenerative diseases such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, recent evidence indicates that small αSyn oligomeric aggregates that precede fibril formation may be the most neurotoxic species and can be found extracellularly. This new evidence has changed the view of pathological αSyn aggregation from a self-contained cellular phenomenon to an extracellular event and prompted investigation of the putative effects of extracellular αSyn oligomers. Here, we report that extracellular application of αSyn oligomers detrimentally impacts neuronal welfare and memory function. We found that oligomeric αSyn increased intracellular Ca2+ levels, induced calcineurin (CaN) activity, decreased cAMP response element binding protein (CREB) transcriptional activity and resulted in calcineurin-dependent death of human neuroblastoma cells. Similarily, CaN induction and CREB inhibition were observed when αSyn oligomers were applied to organotypic brain slices, which opposed hippocampal long-term potentiation (LTP). Furthermore, αSyn oligomers induced CaN, inhibited CREB and evoked memory impairments in mice that received acute intracerebroventricular injections. Notably, all these events were reversed by pharmacological inhibition of CaN. Moreover, we found decreased active calcineurin (CaN) and reduced levels of phosphorylated CREB in autopsy brain tissue from patients affected by DLB, which is characterized by deposition of αSyn aggregates and progressive cognitive decline. These results indicate that exogenously-applied αSyn oligomers impact neuronal function and produce memory deficits through mechanisms that involve CaN activation. PMID:22060133

  6. BODY TEMPERATURE-DEPENDENT AND INDEPENDENT ACTIONS OF CHLORDIMEFORM ON VISUAL EVOKED POTENTIALS AND AXONAL TRANSPORT IN OPTIC SYSTEM OF RAT

    EPA Science Inventory

    Pattern reversal evoked potentials (PREPs), flash evoked potentials (FEPs), optic nerve axonal transport, and body temperature were measured in hooded rats treated with either saline or the formamidine insecticide/acaricide, chlordimeform (CDM). Rats receiving CDM had low body te...

  7. Cytoskeleton-Dependent Transport as a Potential Target for Interfering with Post-transcriptional HuR mRNA Regulons.

    PubMed

    Eberhardt, Wolfgang; Badawi, Amel; Biyanee, Abhiruchi; Pfeilschifter, Josef

    2016-01-01

    The ubiquitous mRNA binding protein human antigen R (HuR), a member of the embryonal lethal abnormal vision protein family has a critical impact on the post-transcriptional control of AU-rich element bearing mRNA regulons implied in inflammation, senescence, and carcinogenesis. HuR in addition to mRNA stability can affect many other aspects of mRNA processing including splicing, polyadenylation, translation, modulation of miRNA repression, and intracellular mRNA trafficking. Since many of the identified HuR mRNA targets ("HuR mRNA regulons") encode tumor-related proteins, HuR is not only discussed as an useful biomarker but also as promising therapeutic target for treatment of various human cancers. HuR which is most abundantly localized in the nucleus is translocated to the cytoplasm which is fundamental for most of the described HuR functions on target mRNAs. Accordingly, an elevation in cytoplasmic HuR was found in many tumors and correlated with a high grade of malignancy and a poor prognosis of patients. Therefore, direct interference with the intracellular trafficking of HuR offers an attractive approach to intervene with pathologically deregulated HuR functions. Data from several laboratories implicate that the integrity of the cytoskeleton is critical for HuR-mediated intracellular mRNA localization and translation. This review will particularly focus on drugs which have proven a direct inhibitory effect on HuR translocation. Based on the results from those studies, we will also discuss on the principle value of targeting cytoskeleton-dependent transport of HuR by natural or synthetic inhibitors as a potential therapeutic avenue for interfering with dysregulated post-transcriptional HuR mRNA regulons and related tumor cell functions. In spite of that, interfering with cytoplasmic HuR transport could highlight a so far underestimated action of microtubule inhibitors clinically used for cancer chemotherapy. PMID:27582706

  8. Cytoskeleton-Dependent Transport as a Potential Target for Interfering with Post-transcriptional HuR mRNA Regulons

    PubMed Central

    Eberhardt, Wolfgang; Badawi, Amel; Biyanee, Abhiruchi; Pfeilschifter, Josef

    2016-01-01

    The ubiquitous mRNA binding protein human antigen R (HuR), a member of the embryonal lethal abnormal vision protein family has a critical impact on the post-transcriptional control of AU-rich element bearing mRNA regulons implied in inflammation, senescence, and carcinogenesis. HuR in addition to mRNA stability can affect many other aspects of mRNA processing including splicing, polyadenylation, translation, modulation of miRNA repression, and intracellular mRNA trafficking. Since many of the identified HuR mRNA targets (“HuR mRNA regulons”) encode tumor-related proteins, HuR is not only discussed as an useful biomarker but also as promising therapeutic target for treatment of various human cancers. HuR which is most abundantly localized in the nucleus is translocated to the cytoplasm which is fundamental for most of the described HuR functions on target mRNAs. Accordingly, an elevation in cytoplasmic HuR was found in many tumors and correlated with a high grade of malignancy and a poor prognosis of patients. Therefore, direct interference with the intracellular trafficking of HuR offers an attractive approach to intervene with pathologically deregulated HuR functions. Data from several laboratories implicate that the integrity of the cytoskeleton is critical for HuR-mediated intracellular mRNA localization and translation. This review will particularly focus on drugs which have proven a direct inhibitory effect on HuR translocation. Based on the results from those studies, we will also discuss on the principle value of targeting cytoskeleton-dependent transport of HuR by natural or synthetic inhibitors as a potential therapeutic avenue for interfering with dysregulated post-transcriptional HuR mRNA regulons and related tumor cell functions. In spite of that, interfering with cytoplasmic HuR transport could highlight a so far underestimated action of microtubule inhibitors clinically used for cancer chemotherapy. PMID:27582706

  9. Assessment of the allergenic potential of transgenic wheat (Triticum aestivum) with reduced levels of omega-5 gliadins, the major sensitizing allergen in wheat-dependent exercise-induced anaphylaxis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The omega-5 gliadins are the major sensitizing allergens in wheat-dependent exercise-induced anaphylaxis (WDEIA). In this study, two-dimensional immunoblot analysis was used to assess the allergenic potential of two transgenic wheat lines in which omega-5 gliadin genes were silenced by RNA interfe...

  10. Dopamine D1/D5 receptor modulates state-dependent switching of soma-dendritic Ca2+ potentials via differential protein kinase A and C activation in rat prefrontal cortical neurons.

    PubMed

    Young, Clint E; Yang, Charles R

    2004-01-01

    To determine the nature of dopamine modulation of dendritic Ca2+ signaling in layers V-VI prefrontal cortex (PFC) neurons, whole-cell Ca2+ potentials were evoked after blockade of Na+ and K+ channels. Soma-dendritic Ca2+ spikes evoked by suprathreshold depolarizing pulses, which could be terminated by superimposed brief intrasomatic hyperpolarizing pulses, are blocked by the L-type Ca2+ channel antagonist nimodipine (1 microM). The D1/D5 receptor agonist dihydrexidine (DHX) (0.01-10 microM; 5 min) or R-(+)SKF81291 (10 microM) induced a prolonged (>30 min) dose-dependent peak suppression of these Ca2+ spikes. This effect was dependent on [Ca2+]i- and protein kinase C (PKC)-dependent mechanisms because [Ca2+]i chelation by BAPTA or inhibition of PKC by bisindolymaleimide (BiM1), but not inhibition of [Ca2+]i release with heparin or Xestospongin C, prevented the D1-mediated suppression of Ca2+ spikes. Depolarizing pulses subthreshold to activating a Ca2+ spike evoked a nimodipine-sensitive Ca2+ "hump" potential. D1/D5 stimulation induced an N-[2-((o-bromocinamyl)amino)ethyl]-5-isoquinolinesulfonamide (H-89)- or internal PKA inhibitory peptide[5-24]-sensitive (PKA-dependent) transient (approximately 7 min) potentiation of the hump potential to full Ca2+ spike firing. Furthermore, application of DHX in the presence of the PKC inhibitor BiM1 or internal PKC inhibitory peptide[19-36] resulted in persistent firing of full Ca2+ spike bursts, suggesting that a D1/D5-PKA mechanism switches subthreshold Ca2+ hump potential to fire full Ca2+ spikes, which are eventually turned off by a D1/D5-Ca2+-dependent PKC mechanism. This depolarizing state-dependent, D1/D5-activated, bi-directional switching of soma-dendritic L-type Ca2+ channels via PKA-dependent potentiation and PKC-dependent suppression may provide spatiotemporal regulation of synaptic integration and plasticity in PFC. PMID:14715933

  11. Dielectric-dependent screened Hartree-Fock exchange potential and Slater-formula with Coulomb-hole interaction for energy band structure calculations.

    PubMed

    Shimazaki, Tomomi; Nakajima, Takahito

    2014-09-21

    We previously reported a screened Hartree-Fock (HF) exchange potential for energy band structure calculations [T. Shimazaki and Y. Asai, J. Chem. Phys. 130, 164702 (2009); T. Shimazaki and Y. Asai, J. Chem. Phys. 132, 224105 (2010)]. In this paper, we discuss the Coulomb-hole (COH) interaction and screened Slater-formula and determine the energy band diagrams of several semiconductors, such as diamond, silicon, AlAs, AlP, GaAs, GaP, and InP, based on the screened HF exchange potential and Slater-formula with COH interaction, to demonstrate the adequacy of those theoretical concepts. The screened HF exchange potential and Slater-formula are derived from a simplified dielectric function and, therefore, include the dielectric constant in their expressions. We also present a self-consistent calculation technique to automatically determine the dielectric constant, which is incorporated into each self-consistent field step. PMID:25240347

  12. Dielectric-dependent screened Hartree-Fock exchange potential and Slater-formula with Coulomb-hole interaction for energy band structure calculations

    NASA Astrophysics Data System (ADS)

    Shimazaki, Tomomi; Nakajima, Takahito

    2014-09-01

    We previously reported a screened Hartree-Fock (HF) exchange potential for energy band structure calculations [T. Shimazaki and Y. Asai, J. Chem. Phys. 130, 164702 (2009); T. Shimazaki and Y. Asai, J. Chem. Phys. 132, 224105 (2010)]. In this paper, we discuss the Coulomb-hole (COH) interaction and screened Slater-formula and determine the energy band diagrams of several semiconductors, such as diamond, silicon, AlAs, AlP, GaAs, GaP, and InP, based on the screened HF exchange potential and Slater-formula with COH interaction, to demonstrate the adequacy of those theoretical concepts. The screened HF exchange potential and Slater-formula are derived from a simplified dielectric function and, therefore, include the dielectric constant in their expressions. We also present a self-consistent calculation technique to automatically determine the dielectric constant, which is incorporated into each self-consistent field step.

  13. Dependence of the Hall Coefficient on a length of rectangular quantum wires with infinitely high potential under the influence of a Laser Radiation

    NASA Astrophysics Data System (ADS)

    Thu Huong, Nguyen; Quang Bau, Nguyen; Hung, Le Thai; Hung, Dao Manh

    2016-06-01

    The Hall coefficient (HC) of a strong electromagnetic wave (EMW) caused by confined electrons in a rectangular quantum wire (RQW) is theoretically studied by using the quantum kinetic equation for electrons. The problem is considered in the case of electrons - acoustic phonons scattering. Wave function and energy spectrum in a RQW are different from those in a cylindrical quantum wire (CQW) or two dimensional systems (2D). Therefore analytical expressions for the HC in a RQW is obtained, different from CQW or 2D. Numerical calculations are carried out with a specific GaAs/GaAsAl RQW to show clearly the dependence of HC on a length Lx (Ly) RQW with different low temperature values. We can see that the length Lx (Ly) increases in value within the domain that HC increases. The HC reaches a peak before slightly decreases when the length Lx (Ly) continues going up. However, the HC depends on the radius and the length of CQW and wire size of RQW Lx and Ly at different values of temperatures; this is the fundamental difference between CQW and RQW. If the length Lx (Ly) continues to increase, the HC remains constant. It means that HC is no longer dependent on the length of quantum wires (This behavior is similar to the case of the independence of the HC on the length in bulk semiconductor).

  14. Static versus energy-dependent nucleus-nucleus potential for description of sub-barrier fusion dynamics of {}_{8}^{16}O+{}^{112,116,120}\\!\\!\\!\\!\\!\\!{}_{50}Sn reactions

    NASA Astrophysics Data System (ADS)

    Manjeet Singh, Gautam

    2015-11-01

    The static and energy-dependent nucleus-nucleus potentials are simultaneously used along with the Wong formula for exploration of fusion dynamics of {}816O+{}112,116,120{}50Sn reactions. The role of internal structure degrees of freedom of colliding pairs, such as inelastic surface vibrations, are examined within the context of coupled channel calculations performed using the code CCFULL. Theoretical calculations based on the static Woods-Saxon potential along with the one-dimensional Wong formula fail to address the fusion data of {}816O+{}112,116,120{}50Sn reactions. Such discrepancies can be removed if one uses couplings to internal structure degrees of freedom of colliding nuclei. However, the energy-dependent Woods-Saxon potential model (EDWSP model) accurately describes the sub-barrier fusion enhancement of {}816O+{}112,116,120{}50Sn reactions. Therefore, in sub-barrier fusion dynamics, energy dependence in the nucleus-nucleus potential governs barrier modification effects in a closely similar way to that of the coupled channel approach. Supported by Dr. D. S. Kothari Post-Doctoral Fellowship Scheme sponsored by University Grants Commission (UGC), New Delhi, India

  15. The adiabatic energy change of plasma electrons and the frame dependence of the cross-shock potential at collisionless magnetosonic shock waves

    NASA Technical Reports Server (NTRS)

    Goodrich, C. C.; Scudder, J. D.

    1984-01-01

    The adiabatic energy gain of electrons in the stationary electric and magnetic field structure of collisionless shock waves was examined analytically in reference to conditions of the earth's bow shock. The study was performed to characterize the behavior of electrons interacting with the cross-shock potential. A normal incidence frame (NIF) was adopted in order to calculate the reversible energy change across a time stationary shock, and comparisons were made with predictions made by the de Hoffman-Teller (HT) model (1950). The electron energy gain, about 20-50 eV, is demonstrated to be consistent with a 200-500 eV potential jump in the bow shock quasi-perpendicular geometry. The electrons lose energy working against the solar wind motional electric field. The reversible energy process is close to that modeled by HT, which predicts that the motional electric field vanishes and the electron energy gain from the electric potential is equated to the ion energy loss to the potential.

  16. High-momenta estimates for the Klein-Gordon equation: long-range magnetic potentials and time-dependent inverse scattering

    NASA Astrophysics Data System (ADS)

    Ballesteros, Miguel; Weder, Ricardo

    2016-04-01

    The study of obstacle scattering for the Klein-Gordon equation in the presence of long-range magnetic potentials is addressed. Previous results of the authors are extended to the long-range case and the results the authors previously proved for high-momenta long-range scattering for the Schrödinger equation are brought to the relativistic scenario. It is shown that there are important differences between relativistic and non-relativistic scattering concerning the long range. In particular, it is proven that the electric potential can be recovered without assuming the knowledge of the long-range part of the magnetic potential, which has to be supposed in the non-relativistic case. The electric potential and the magnetic field are recovered from the high-momenta limit of the scattering operator, as well as fluxes modulo 2π around the handles of the obstacle. Moreover, it is proven that for every \\hat{{v}}\\in {{{S}}}2, {A}∞ (\\hat{{v}})+{A}∞ (-\\hat{{v}}) can be reconstructed, where {A}∞ is the long-range part of the magnetic potential. A simple formula for the high-momenta limit of the scattering operator is given in terms of magnetic fluxes over handles of the obstacle and long-range magnetic fluxes at infinity, that are introduced in this paper. The appearance of these long-range magnetic fluxes is a new effect in scattering theory. Research partially supported by the project PAPIIT-DGAPA UNAM IN102215.

  17. Investigation of temperature dependence of neutron yield and electron screening potential for the d(d, n){sup 3}He reaction proceeding in deuterides ZrD{sub 2} and TiD{sub 2}

    SciTech Connect

    Bystritsky, V. M.; Bystritskii, Vit. M.; Dudkin, G. N.; Filipowicz, M.; Gazi, S.; Huran, J.; Kobzev, A. P.; Mesyats, G. A.; Nechaev, B. A.; Padalko, V. N.; Parzhitskii, S. S.; Pen'kov, F. M.; Philippov, A. V.; Kaminskii, V. L.; Tuleushev, Yu. Zh.; Wozniak, J.

    2012-08-15

    The temperature dependence of the enhancement factor for the dd reaction proceeding in TiD{sub 2} and ZrD{sub 2} is investigated. The experiments were carried out at the Hall pulsed ion accelerator (INP, Polytechnic University, Tomsk, Russia) in the deuteron energy interval 7.0-12.0 keV and at temperatures ranging from 20 to 200 Degree-Sign C. The values obtained for the electron screening potentials indicate that the dd reaction enhancement factor does not depend on the target temperature in the range 20-200 Degree-Sign C. This result contradicts the conclusions drawn by the LUNA Collaboration from their work.

  18. Functional heart diagnosis by the visualization of time-dependent potential deviation and topologic map-based shape analysis from high-resolution ECG

    NASA Astrophysics Data System (ADS)

    Schulz-Bruenken, Barbara; Pelikan, Erich

    1996-04-01

    Our work focuses on functional heart analysis during acute myocardial infarction based on time-sequence data derived with a high-resolution ECG technique. This data stream can be interpreted as a sequence of potential deviation images. The analysis is performed by both visualizing the potential deviation onto the thorax as well as by shape analysis of the underlying ECG signals using a topologic map. The algorithm deals with the measurement of similarity between different pathological signal types. In contrast to other techniques, the whole ECG signal, coded as a feature vector, is used as input for the self-organizing map. The results show that this approach is suitable for handling unsharp class transitions common to the medical domain.

  19. Dependence on channel potential structures of I-V characteristics in InAlAs/InGaAs pseudomorphic high electron mobility transistors

    NASA Astrophysics Data System (ADS)

    Maeda, Narihiko; Ito, Hiroshi; Enoki, Takatomo; Ishii, Yasunobu

    1997-02-01

    We have systematically examined the relationship between channel potential structures and dc device performances in the InP-based pseudomorphic high electron mobility transistors, in order to obtain a guideline for improving the channel potential structures. Based on the self-consistent calculation of the quantum states in the channel, we have designed and fabricated several pseudomorphic devices with different channel potential structures where the quantum states were systematically changed. By comparing the I-V characteristics in terms of the transconductance, the drain conductance, and the shape of the I-V curve, we have successfully extracted information on the states of channel electrons under actual device operation. Not only the design for the ground state but also that for the excited states has been shown to be important for improving the transconductance. The drain conductance was shown to improve by reducing the total channel thickness, probably due to the enhanced recombination of electrons and holes. One of the channel designs, 20 Å In0.53Ga0.47As/30 Å InAs/70 Å In0.7Ga0.3As, was shown to yield a high transconductance of 1240 mS/mm and a low drain conductance of 40 mS/mm simultaneously, for a 0.7 μm gate length device.

  20. Age-dependent acceleration of ischemic injury in endothelial nitric oxide synthase-deficient mice: potential role of impaired VEGF receptor 2 expression.

    PubMed

    Qian, Hu Sheng; de Resende, Micheline Monterio; Beausejour, Christian; Huw, Ling-Yuh; Liu, Perry; Rubanyi, Gabor M; Kauser, Katalin

    2006-04-01

    Morbidity and mortality of peripheral arterial occlusive disease significantly increases with age, often exhibiting more severe disease pathology and decreased treatment effectiveness. Therapeutic angiogenesis with angiogenic growth factors may represent a valuable treatment option for the severely ill, older adult patient population. Aging is considered an independent cardiovascular risk factor, but pathomechanistically it is not well understood. Diminished endothelial nitric oxide (EDNO) production has been considered as a major contributor to the aging process. To investigate the effect of age on postischemic revascularization independent of changes in EDNO, we used endothelial nitric oxide synthase-deficient (ecNOS-KO) mice. We found an age-dependent acceleration in ischemic injury following unilateral femoral artery ligation in these animals compared to C57BL/J6 mice. Postischemic revascularization, quantified by measuring von Willebrand factor expression, was significantly impaired, suggesting that factors other than progressive EDNO deterioration are also involved in the age-dependent severe disease phenotype. Ischemia led to an increase in the expression of vascular endothelial growth factor receptor-2, KDR, in younger ecNOS-KO; however, this increase in KDR expression was absent in the older animals. Lack of increased KDR expression may provide a mechanistic explanation for the severe ischemic injury and perhaps can be used as a clinical marker to identify severe, vascular endothelial growth factor refractory patient population. PMID:16680073

  1. Soil type-dependent effects of a potential biocontrol inoculant on indigenous bacterial communities in the rhizosphere of field-grown lettuce.

    PubMed

    Schreiter, Susanne; Ding, Guo-Chun; Grosch, Rita; Kropf, Siegfried; Antweiler, Kai; Smalla, Kornelia

    2014-12-01

    Bacterial biocontrol strains used as an alternative to chemical fungicides may influence bacterial communities in the rhizosphere and effects might differ depending on the soil type. Here we present baseline data on the effects of Pseudomonas jessenii RU47 on the bacterial community composition in the rhizosphere of lettuce grown in diluvial sand, alluvial loam and loess loam at the same field site. 16S rRNA gene fragments amplified from total community DNA were analyzed by denaturing gradient gel electrophoresis (DGGE) and pyrosequencing. DGGE fingerprints revealed that in three consecutive years (2010-2012) RU47 had a slight but statistically significant effect on the bacterial community composition in one (2010), two (2011) or all the three soils (2012). However, these effects were much less pronounced compared with the influence of soil types. Additional pyrosequence analysis of samples from 2011 showed that significant changes in bacterial community compositions in response to RU47 inoculation occurred only in alluvial loam. Different taxonomic groups responded to the RU47 application depending on the soil type. Most remarkable was the increased relative abundance of OTUs belonging to the genera Bacillus and Paenibacillus in alluvial loam. Pyrosequencing allowed side-effects of the application of bacterial inoculants into the rhizosphere to be identified. PMID:25244497

  2. Assessing potentially time-dependent treatment effect from clinical trials and observational studies for survival data, with applications to the Women's Health Initiative combined hormone therapy trial

    PubMed Central

    Yang, Song; Prentice, Ross L.

    2015-01-01

    For risk and benefit assessment in clinical trials and observational studies with time-to-event data, the Cox model has usually been the model of choice. When the hazards are possibly non-proportional, a piece-wise Cox model over a partition of the time axis may be considered. Here we propose to analyze clinical trials or observational studies with time-to-event data using a certain semiparametric model. The model allows for a time-dependent treatment effect. It includes the important proportional hazards model as a sub-model, and can accommodate various patterns of time-dependence of the hazard ratio. After estimation of the model parameters using a pseudo-likelihood approach, simultaneous confidence intervals for the hazard ratio function are established using a Monte Carlo method to assess the time-varying pattern of the treatment effect. To assess the overall treatment effect, estimated average hazard ratio and its confidence intervals are also obtained. The proposed methods are applied to data from the Women's Health Initiative. To compare the WHI clinical trial and observational study, we use the propensity score in building the regression model. Compared to the piece-wise Cox model, the proposed model yields a better model fit and does not require partitioning of the time axis. PMID:25689356

  3. Development of a potential stationary-phase specific gene expression system by engineering of SigB-dependent cg3141 promoter in Corynebacterium glutamicum.

    PubMed

    Kim, Min Jeong; Yim, Sung Sun; Choi, Jae Woong; Jeong, Ki Jun

    2016-05-01

    Corynebacterium glutamicum is a non-pathogenic, non-sporulating Gram-positive soil bacterium that has been used for the industrial production of various proteins and chemicals. To achieve enhanced and economical production of target molecules, the development of strong auto-inducible promoters is desired, which can be activated without expensive inducers and has significant advantages for industrial-scale use. Here, we developed a stationary-phase gene expression system by engineering a sigma factor B (SigB)-dependent promoter that can be activated during the transition phase between exponential and stationary growth phases in C. glutamicum. First, the inducibilities of three well-known SigB-dependent promoters were examined using super-folder green fluorescent protein as a reporter protein, and we found that promoter of cg3141 (P cg3141 ) exhibited the highest inducibility. Next, a synthetic promoter library was constructed by randomizing the flanking and space regions of P cg3141 , and the stationary-phase promoters exhibiting high strengths were isolated via FACS-based high-throughput screening. The isolated synthetic promoter (P4-N14) showed a 3.5-fold inducibility and up to 20-fold higher strength compared to those of the original cg3141 promoter. Finally, the use of the isolated P4-N14 for fed-batch cultivation was verified with the production of glutathione S-transferase as a model protein in a lab-scale (5-L) bioreactor. PMID:26782746

  4. Gender-Specific Potential Inhibitory Role of Ca2+/Calmodulin Dependent Protein Kinase Phosphatase (CaMKP) in Pressure-Overloaded Mouse Heart

    PubMed Central

    Prévilon, Miresta; Pezet, Mylène; Vinet, Laurent; Mercadier, Jean-Jacques; Rouet-Benzineb, Patricia

    2014-01-01

    Background Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP) has been proposed as a potent regulator of multifunctional Ca2+/calmodulin-dependent protein kinases (i.e., CaMKII). The CaMKII-dependent activation of myocyte enhancer factor 2 (MEF2) disrupts interactions between MEF2-histone deacetylases (HDACs), thereby de-repressing downstream gene transcription. Whether CaMKP modulates the CaMKII- MEF2 pathway in the heart is unknown. Here, we investigated the molecular and functional consequences of left ventricular (LV) pressure overload in the mouse of both genders, and in particular we evaluated the expression levels and localization of CaMKP and its association with CaMKII-MEF2 signaling. Methodology and Principal Findings Five week-old B6D1/F1 mice of both genders underwent a sham-operation or thoracic aortic constriction (TAC). Thirty days later, TAC was associated with pathological LV hypertrophy characterized by systolic and diastolic dysfunction. Gene expression was assessed by real-time PCR. Fetal gene program re-expression comprised increased RNA levels of brain natriuretic peptide and alpha-skeletal actin. Mouse hearts of both genders expressed both CaMKP transcript and protein. Activation of signalling pathways was studied by Western blot in LV lysates or subcellular fractions (nuclear and cytoplasmic). TAC was associated with increased CaMKP expression in male LVs whereas it tended to be decreased in females. The DNA binding activity of MEF2 was determined by spectrophotometry. CaMKP compartmentalization differed according to gender. In male TAC mice, nuclear CaMKP was associated with inactive CaMKII resulting in less MEF2 activation. In female TAC mice, active CaMKII (phospho-CaMKII) detected in the nuclear fraction, was associated with a strong MEF2 transcription factor-binding activity. Conclusions/Significance Gender-specific CaMKP compartmentalization is associated with CaMKII-mediated MEF2 activation in pressure-overloaded hearts

  5. Size-dependent characterisation of historical gold mine wastes to examine human pathways of exposure to arsenic and other potentially toxic elements.

    PubMed

    Martin, Rachael; Dowling, Kim; Pearce, Dora C; Florentine, Singarayer; Bennett, John W; Stopic, Attila

    2016-10-01

    Abandoned historical gold mining wastes often exist as geographically extensive, unremediated, and poorly contained deposits that contain elevated levels of As and other potentially toxic elements (PTEs). One of the key variables governing human exposure to PTEs in mine waste is particle size. By applying a size-resolved approach to mine waste characterisation, this study reports on the proportions of mine waste relevant to human exposure and mobility, as well as their corresponding PTE concentrations, in four distinct historical mine wastes from the gold province in Central Victoria, Australia. To the best of our knowledge, such a detailed investigation and comparison of historical mining wastes has not been conducted in this mining-affected region. Mass distribution analysis revealed notable proportions of waste material in the readily ingestible size fraction (≤250 µm; 36.1-75.6 %) and the dust size fraction (≤100 µm; 5.9-45.6 %), suggesting a high potential for human exposure and dust mobilisation. Common to all mine waste types were statistically significant inverse trends between particle size and levels of As and Zn. Enrichment of As in the finest investigated size fraction (≤53 µm) is of particular concern as these particles are highly susceptible to long-distance atmospheric transport. Human populations that reside in the prevailing wind direction from a mine waste deposit may be at risk of As exposure via inhalation and/or ingestion pathways. Enrichment of PTEs in the finer size fractions indicates that human health risk assessments based on bulk contaminant concentrations may underestimate potential exposure intensities. PMID:26537592

  6. Dependences of Q-branch integrated intensity of linear-molecule pendular spectra on electric-field strength and rotational temperature and its potential applications

    PubMed Central

    Deng, Min; Wang, Hailing; Wang, Qin; Yin, Jianping

    2016-01-01

    We calculate the pendular-state spectra of cold linear molecules, and investigated the dependences of “Q-branch” integrated intensity of pendular spectra on both electric-field strength and molecular rotation-temperature. A new multi-peak structure in the “Q-branch” spectrum is appearing when the Stark interaction strength ω = μE/B equal to or larger than the critical value. Our study shows that the above results can be used not only to measure the electric-field vector and its spatial distribution in some electrostatic devices, such as the Stark decelerator, Stark velocity filter and electrostatic trap and so on, but also to survey the orientation degree of cold linear molecules in a strong electrostatic field. PMID:27231057

  7. Dependences of Q-branch integrated intensity of linear-molecule pendular spectra on electric-field strength and rotational temperature and its potential applications.

    PubMed

    Deng, Min; Wang, Hailing; Wang, Qin; Yin, Jianping

    2016-01-01

    We calculate the pendular-state spectra of cold linear molecules, and investigated the dependences of "Q-branch" integrated intensity of pendular spectra on both electric-field strength and molecular rotation-temperature. A new multi-peak structure in the "Q-branch" spectrum is appearing when the Stark interaction strength ω = μE/B equal to or larger than the critical value. Our study shows that the above results can be used not only to measure the electric-field vector and its spatial distribution in some electrostatic devices, such as the Stark decelerator, Stark velocity filter and electrostatic trap and so on, but also to survey the orientation degree of cold linear molecules in a strong electrostatic field. PMID:27231057

  8. Dependences of Q-branch integrated intensity of linear-molecule pendular spectra on electric-field strength and rotational temperature and its potential applications

    NASA Astrophysics Data System (ADS)

    Deng, Min; Wang, Hailing; Wang, Qin; Yin, Jianping

    2016-05-01

    We calculate the pendular-state spectra of cold linear molecules, and investigated the dependences of “Q-branch” integrated intensity of pendular spectra on both electric-field strength and molecular rotation-temperature. A new multi-peak structure in the “Q-branch” spectrum is appearing when the Stark interaction strength ω = μE/B equal to or larger than the critical value. Our study shows that the above results can be used not only to measure the electric-field vector and its spatial distribution in some electrostatic devices, such as the Stark decelerator, Stark velocity filter and electrostatic trap and so on, but also to survey the orientation degree of cold linear molecules in a strong electrostatic field.

  9. MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models.

    PubMed

    Gu, Juan J; Hernandez-Ilizaliturri, Francisco J; Mavis, Cory; Czuczman, Natalie M; Deeb, George; Gibbs, John; Skitzki, Joseph J; Patil, Ritesh; Czuczman, Myron S

    2013-11-01

    To further develop therapeutic strategies targeting the proteasome system, we studied the antitumor activity and mechanisms of action of MLN2238, a reversible proteasome inhibitor, in preclinical lymphoma models. Experiments were conducted in rituximab-chemotherapy-sensitive cell lines, rituximab-chemotherapy-resistant cell lines (RRCL), and primary B-cell lymphoma cells. Cells were exposed to MLN2238 or caspase-dependent inhibitors, and differences in cell viability, alterations in apoptotic protein levels, effects on cell cycle, and the possibility of synergy when combined with chemotherapeutic agents were evaluated. MLN2238 showed more potent dose-dependent and time-dependent cytotoxicity and inhibition of cell proliferation in lymphoma cells than bortezomib. Our data suggest that MLN2238 can induce caspase-independent cell death in RRCL. MLN2238 (and to a much lesser degree bortezomib) reduced RRCL S phase and induced cell cycle arrest in the G2/M phase. Exposure of rituximab-chemotherapy-sensitive cell lines and RRCL to MLN2238 potentiated the cytotoxic effects of gemcitabine, doxorubicin, and paclitaxel and overcame resistance to chemotherapy in RRCL. MLN2238 is a potent proteasome inhibitor active in rituximab-chemotherapy-sensitive and rituximab-chemotherapy-resistant cell models and potentiates the antitumor activity of chemotherapy agents and has the potential of becoming an effective therapeutic agent in the treatment of therapy-resistant B-cell lymphoma. PMID:23995855

  10. G1-checkpoint function including a cyclin-dependent kinase 2 regulatory pathway as potential determinant of 7-hydroxystaurosporine (UCN-01)-induced apoptosis and G1-phase accumulation.

    PubMed

    Akiyama, T; Sugiyama, K; Shimizu, M; Tamaoki, T; Akinaga, S

    1999-12-01

    7-Hydroxystaurosporine (UCN-01), which was originally identified as a protein kinase C selective inhibitor, is currently in clinical trials as an anti-cancer drug. We previously showed that UCN-01 induced preferential G1-phase accumulation in tumor cells and this effect was associated with the retinoblastoma (Rb) protein and its regulatory factors, such as cyclin-dependent kinase 2 (CDK2) and CDK inhibitors p21Cip1/WAF1 and p27Kip1. We demonstrate here that G1-phase accumulation was induced by UCN-01 in Rb-proficient cell lines (WiDr and HCT116 human colon carcinomas and WI-38 human lung fibroblast), and it was accompanied by dephosphorylation of Rb. In addition, UCN-01-induced G1-phase accumulation was also demonstrated in a Rb-defective cell line (Saos-2 human osteosarcoma), but not in a simian virus 40 (SV40)-transformed cell line (WI-38 VA13). Apoptosis was induced by UCN-01 in the two Rb-deficient cell lines, but not in the other Rb-proficient cell lines. These observations suggest that G1-checkpoint function might be important for cell survival during UCN-01 treatment. In addition, there may be a UCN-01-responsive factor in the G1-checkpoint machinery other than Rb which is targeted by SV40. Further studies revealed a correlation between UCN-01-induced G1-phase accumulation and reduction of cellular CDK2 kinase activity. This reduction was strictly dependent on down-regulation of the Thr160-phosphorylated form of CDK2 protein, and coincided in part with up-regulation of p27Kip1, but it was independent of the level of the p21Cip1/WAF1 protein. These results suggest that G1-checkpoint function, including a CDK2-regulatory pathway, may be a significant determinant of the sensitivity of tumor cells to UCN-01. PMID:10665655

  11. UDP-glucose is a potential intracellular signal molecule in the control of expression of sigma S and sigma S-dependent genes in Escherichia coli.

    PubMed Central

    Böhringer, J; Fischer, D; Mosler, G; Hengge-Aronis, R

    1995-01-01

    The sigma S subunit of RNA polymerase is the master regulator of a regulatory network that controls stationary-phase induction as well as osmotic regulation of many genes in Escherichia coli. In an attempt to identify additional regulatory components in this network, we have isolated Tn10 insertion mutations that in trans alter the expression of osmY and other sigma S-dependent genes. One of these mutations conferred glucose sensitivity and was localized in pgi (encoding phosphoglucose isomerase). pgi::Tn10 strains exhibit increased basal levels of expression of osmY and otsBA in exponentially growing cells and reduced osmotic inducibility of these genes. A similar phenotype was also observed for pgm and galU mutants, which are deficient in phosphoglucomutase and UDP-glucose pyrophosphorylase, respectively. This indicates that the observed effects on gene expression are related to the lack of UDP-glucose (or a derivative thereof), which is common to all three mutants. Mutants deficient in UDP-galactose epimerase (galE mutants) and trehalose-6-phosphate synthase (otsA mutants) do not exhibit such an effect on gene expression, and an mdoA mutant that is deficient in the first step of the synthesis of membrane-derived oligosaccharides, shows only a partial increase in the expression of osmY. We therefore propose that the cellular content of UDP-glucose serves as an internal signal that controls expression of osmY and other sigma S-dependent genes. In addition, we demonstrate that pgi, pgm, and galU mutants contain increased levels of sigma S during steady-state growth, indicating that UDP-glucose interferes with the expression of sigma S itself. PMID:7814331

  12. Spatial distribution of infectious stages of the nematode Syngamus trachea within pheasant (Phasianus colchicus) release pens on estates in the South West of England: Potential density dependence?

    PubMed

    Gethings, O J; Sage, R B; Leather, S R

    2015-09-15

    The spatial distribution of the infectious stages of parasites with a direct life cycle is one of the most important factors influencing infectious disease dynamics, and acquisition rates will generally increase as the contact time between parasite and host increases. For animal species that are constrained by feeding opportunities, one might expect disease patterns to be highly skewed within confined systems. The aim of the present study was to identify to what extent, if any, eggs of avian parasites are aggregated within the release pen, and to evaluate what effect, if any, this aggregation had on the distribution of the adult stages within the host species. The abundance of Syngamus trachea eggs were highly aggregated within pens, with high levels of contamination driven by a combination of feeder placement, soil moisture and host-mediated heterogeneities in immuno-competence. The log mean and log variance of egg abundance was highly linear (R(2)=0.97-0.99), with an estimated slope (b) of between 1.79 and 1.97 for individual sites, and 2.11 when sites were combined, which indicated aggregation relative to an estimated Poisson slope of unity. Although the placement of feeders and environmental moisture could be contributing to parasite aggregation, density-dependent processes appear to be ensuring the population does not become too over or under-dispersed, in order to maintain the transmission-virulence equilibrium. To the best of our knowledge, this is the first paper to explicitly demonstrate the high spatial aggregation of eggs around feeding sites and the first to suggest possible density-dependent regulatory mechanisms stabilising disease dynamics between S. trachea and ring necked Pheasants (Phasianus colchicus). PMID:26220022

  13. Experimental and Computational Analysis of the Solvent-Dependent O2/Li(+)-O2(-) Redox Couple: Standard Potentials, Coupling Strength, and Implications for Lithium-Oxygen Batteries.

    PubMed

    Kwabi, David G; Bryantsev, Vyacheslav S; Batcho, Thomas P; Itkis, Daniil M; Thompson, Carl V; Shao-Horn, Yang

    2016-02-24

    Understanding and controlling the kinetics of O2 reduction in the presence of Li(+)-containing aprotic solvents, to either Li(+)-O2(-) by one-electron reduction or Li2 O2 by two-electron reduction, is instrumental to enhance the discharge voltage and capacity of aprotic Li-O2 batteries. Standard potentials of O2 /Li(+)-O2(-) and O2/O2(-) were experimentally measured and computed using a mixed cluster-continuum model of ion solvation. Increasing combined solvation of Li(+) and O2(-) was found to lower the coupling of Li(+)-O2(-) and the difference between O2/Li(+)-O2(-) and O2/O2(-) potentials. The solvation energy of Li(+) trended with donor number (DN), and varied greater than that of O2 (-) ions, which correlated with acceptor number (AN), explaining a previously reported correlation between Li(+)-O2(-) solubility and DN. These results highlight the importance of the interplay between ion-solvent and ion-ion interactions for manipulating the energetics of intermediate species produced in aprotic metal-oxygen batteries. PMID:26822277

  14. Mechanistic Explanation of the pH Dependence and Onset Potentials for Hydrocarbon Products from Electrochemical Reduction of CO on Cu (111).

    PubMed

    Xiao, Hai; Cheng, Tao; Goddard, William A; Sundararaman, Ravishankar

    2016-01-20

    Energy and environmental concerns demand development of more efficient and selective electrodes for electrochemical reduction of CO2 to form fuels and chemicals. Since Cu is the only pure metal exhibiting reduction to form hydrocarbon chemicals, we focus here on the Cu (111) electrode. We present a methodology for density functional theory calculations to obtain accurate onset electrochemical potentials with explicit constant electrochemical potential and pH effects using implicit solvation. We predict the atomistic mechanisms underlying electrochemical reduction of CO, finding that (1) at acidic pH, the C1 pathway proceeds through COH to CHOH to form CH4 while C2 (C3) pathways are kinetically blocked; (2) at neutral pH, the C1 and C2 (C3) pathways share the COH common intermediate, where the branch to C-C coupling is realized by a novel CO-COH pathway; and (3) at high pH, early C-C coupling through adsorbed CO dimerization dominates, suppressing the C1 pathways by kinetics, thereby boosting selectivity for multi-carbon products. PMID:26716884

  15. The dose-dependent toxicological effects and potential perturbation on the neurotransmitter secretion in brain following intranasal instillation of copper nanoparticles.

    PubMed

    Zhang, Lili; Bai, Ru; Liu, Ying; Meng, Li; Li, Bai; Wang, Liming; Xu, Ligeng; Le Guyader, Laurent; Chen, Chunying

    2012-08-01

    Increasing production and application of metallic nanomaterials are likely to result in the release of these particles into the environment. These released nanoparticles may enter into the lungs and the central nervous system (CNS) directly through inhalation, which therefore poses a potential risk to human health. Herein, we focus on the systemic toxicity and potential influence on the neurotransmitter secretion of intranasally instilled copper nanoparticles (23.5 nm) at three different doses. Copper nanoparticle-exposed mice exhibit pathological lesions at different degrees in certain tissues and especially in lung tissue as revealed by histopathology and transmission electron microscopy (TEM) observations. Inductively-coupled plasma mass spectrometry (ICP-MS) results show that the liver, lung and olfactory bulb are the main tissues in which the copper concentrations increased significantly after exposure to a higher level of Cu nanoparticles (40 mg/kg of body weight). The secretion levels of various neurotransmitters changed as well in some brain regions, especially in the olfactory bulb. Our results indicate that the intranasally instilled copper nanoparticles not only cause the lesions where the copper accumulates, but also affect the neurotransmitter levels in the brain. PMID:21657985

  16. Correlated parameters in the quasi-classical treatment of atomic ground states using effective momentum dependent potentials for molecular dynamics simulation of strongly coupled plasmas

    NASA Astrophysics Data System (ADS)

    Verboncoeur, John; Dharuman, Gautham; Christlieb, Andrew; Murillo, Michael

    2015-11-01

    Ground state energies and configurations of N, F, Ne, Al, S, Ar and Ca are obtained using a quasi-classical treatment with Kirschbaum-Wilets potentials. The effect of phase space parameters on the ground state energy is studied in detail and compared with Hartree-Fock values. The phase space parameters that resulted in ground state energies comparable to Hartree-Fock values are found to be correlated and follow a pattern with atomic number which led to identifying a predictive capability in the model. The change in ground state configurations for different phase space parameters is studied and correlated with the corresponding change in ground state energies. Work supported by Air Force Office of Scientific Research (AFOSR).

  17. 17β-estradiol potentiates endothelium-dependent nitric oxide- and hyperpolarization-mediated relaxations in blood vessels of male but not female apolipoprotein-E deficient mice.

    PubMed

    Kong, Billy W C; Vanhoutte, Paul M; Man, Ricky Y K; Leung, Susan W S

    2015-08-01

    The present study investigated the influence of gender on the changes underlying endothelial dysfunction in hyperlipidemia during aging. Isometric tension in rings (with endothelium) of the aortae and superior mesenteric arteries from apolipoprotein-E deficient mice was determined in wire myographs. Nitric oxide (NO)- and endothelium-dependent hyperpolarization (EDH)-mediated relaxations were smaller in the aortae and mesenteric arteries of 32weeks old males than eight weeks old males. In females, NO- and EDH-mediated relaxations were impaired only at 84weeks of age. The levels of reactive oxygen species were elevated in the blood vessels of 32weeks old males, but not females. Acute in vitro treatment with 17β-estradiol and apocynin improved NO- and EDH-mediated relaxations in 32weeks old males but not in 84weeks old males. Relaxations to SKA-31, activator of intermediate (IKCa) and small (SKCa) conductance calcium-activated potassium channels, were attenuated in the mesenteric arteries of 32weeks old males. Such impairment was restored by acute treatment with apocynin. These findings suggest that male hyperlipidemic mice develop endothelial dysfunction at an earlier age than females. This endothelial dysfunction is associated with impaired NO bioavailability and reduced IKCa and SKCa activity. Apocynin and 17β-estradiol restore the endothelial function only in younger male animals but not in older male or female animals. PMID:25869512

  18. The TP0796 Lipoprotein of Treponema pallidum Is a Bimetal-dependent FAD Pyrophosphatase with a Potential Role in Flavin Homeostasis*

    PubMed Central

    Deka, Ranjit K.; Brautigam, Chad A.; Liu, Wei Z.; Tomchick, Diana R.; Norgard, Michael V.

    2013-01-01

    Treponema pallidum, an obligate parasite of humans and the causative agent of syphilis, has evolved the capacity to exploit host-derived metabolites for its survival. Flavin-containing compounds are essential cofactors that are required for metabolic processes in all living organisms, and riboflavin is a direct precursor of the cofactors FMN and FAD. Unlike many pathogenic bacteria, Treponema pallidum cannot synthesize riboflavin; we recently described a flavin-uptake mechanism composed of an ABC-type transporter. However, there is a paucity of information about flavin utilization in bacterial periplasms. Using a discovery-driven approach, we have identified the TP0796 lipoprotein as a previously uncharacterized Mg2+-dependent FAD pyrophosphatase within the ApbE superfamily. TP0796 probably plays a central role in flavin turnover by hydrolyzing exogenously acquired FAD, yielding AMP and FMN. Biochemical and structural investigations revealed that the enzyme has a unique bimetal Mg2+ catalytic center. Furthermore, the pyrophosphatase activity is product-inhibited by AMP, indicating a possible role for this molecule in modulating FMN and FAD levels in the treponemal periplasm. The ApbE superfamily was previously thought to be involved in thiamine biosynthesis, but our characterization of TP0796 prompts a renaming of this superfamily as a periplasmic flavin-trafficking protein (Ftp). TP0796 is the first structurally and biochemically characterized FAD pyrophosphate enzyme in bacteria. This new paradigm for a bacterial flavin utilization pathway may prove to be useful for future inhibitor design. PMID:23447540

  19. Extracellular Dopamine Potentiates Mn-Induced Oxidative Stress, Lifespan Reduction, and Dopaminergic Neurodegeneration in a BLI-3–Dependent Manner in Caenorhabditis elegans

    PubMed Central

    Benedetto, Alexandre; Au, Catherine; Avila, Daiana Silva; Milatovic, Dejan; Aschner, Michael

    2010-01-01

    Parkinson's disease (PD)-mimicking drugs and pesticides, and more recently PD-associated gene mutations, have been studied in cell cultures and mammalian models to decipher the molecular basis of PD. Thus far, a dozen of genes have been identified that are responsible for inherited PD. However they only account for about 8% of PD cases, most of the cases likely involving environmental contributions. Environmental manganese (Mn) exposure represents an established risk factor for PD occurrence, and both PD and Mn-intoxicated patients display a characteristic extrapyramidal syndrome primarily involving dopaminergic (DAergic) neurodegeneration with shared common molecular mechanisms. To better understand the specificity of DAergic neurodegeneration, we studied Mn toxicity in vivo in Caenorhabditis elegans. Combining genetics and biochemical assays, we established that extracellular, and not intracellular, dopamine (DA) is responsible for Mn-induced DAergic neurodegeneration and that this process (1) requires functional DA-reuptake transporter (DAT-1) and (2) is associated with oxidative stress and lifespan reduction. Overexpression of the anti-oxidant transcription factor, SKN-1, affords protection against Mn toxicity, while the DA-dependency of Mn toxicity requires the NADPH dual-oxidase BLI-3. These results suggest that in vivo BLI-3 activity promotes the conversion of extracellular DA into toxic reactive species, which, in turn, can be taken up by DAT-1 in DAergic neurons, thus leading to oxidative stress and cell degeneration. PMID:20865164

  20. An updated evolutionary study of Flaviviridae NS3 helicase and NS5 RNA-dependent RNA polymerase reveals novel invariable motifs as potential pharmacological targets.

    PubMed

    Papageorgiou, Louis; Loukatou, Styliani; Sofia, Kossida; Maroulis, Dimitrios; Vlachakis, Dimitrios

    2016-06-21

    The rate of Flaviviridae family virus infections worldwide has increased dramatically in the last few years. In addition, infections caused by arthropod vector viruses including Hepatitis C, West Nile, Dengue fever, Yellow fever and Japanese encephalitis are emerging throughout the world. Based on a recent taxon update, the Flaviviridae family comprises four main genera; Flavivirus, Hepacivirus, Pestivirus and a recent genus Pegivirus. Although the new scientific classification plays a key role in providing useful information about the relationships between viruses, many new documented viruses remain unclassified. Furthermore, based on the different results of several studies the classification is unclear. In an effort to provide more insights into the classification of viruses, a holistic evolutionary study of the two viral enzymes NS3 helicase and NS5 RNA-dependent RNA polymerase (RdRp) has been conducted in this study. These two viral enzymes are very crucial for the inhibition of viruses due to the fact that they are involved in the survival, proliferation and transmission of viruses. The main goal of this study is the presentation of two novel updated phylogenetic trees of the enzymes NS3 helicase and NS5 RdRp as a reliable phylogeny "map" to correlate the information of the closely related viruses and identify new possible targets for the Flaviviridae family virus inhibition. Despite the earliest trials for drugs against Flaviviridae related viruses, no antiviral drug vaccine has been available to date. Therefore there is an urgent need for research towards the development of efficient antiviral agents. PMID:26864387

  1. Musical practice and cognitive aging: two cross-sectional studies point to phonemic fluency as a potential candidate for a use-dependent adaptation

    PubMed Central

    Fauvel, Baptiste; Groussard, Mathilde; Mutlu, Justine; Arenaza-Urquijo, Eider M.; Eustache, Francis; Desgranges, Béatrice; Platel, Hervé

    2014-01-01

    Because of permanent use-dependent brain plasticity, all lifelong individuals' experiences are believed to influence the cognitive aging quality. In older individuals, both former and current musical practices have been associated with better verbal skills, visual memory, processing speed, and planning function. This work sought for an interaction between musical practice and cognitive aging by comparing musician and non-musician individuals for two lifetime periods (middle and late adulthood). Long-term memory, auditory-verbal short-term memory, processing speed, non-verbal reasoning, and verbal fluencies were assessed. In Study 1, measures of processing speed and auditory-verbal short-term memory were significantly better performed by musicians compared with controls, but both groups displayed the same age-related differences. For verbal fluencies, musicians scored higher than controls and displayed different age effects. In Study 2, we found that lifetime period at training onset (childhood vs. adulthood) was associated with phonemic, but not semantic, fluency performances (musicians who had started to practice in adulthood did not perform better on phonemic fluency than non-musicians). Current frequency of training did not account for musicians' scores on either of these two measures. These patterns of results are discussed by setting the hypothesis of a transformative effect of musical practice against a non-causal explanation. PMID:25346684

  2. Transcriptome and proteome analysis of tyrosine kinase inhibitor treated canine mast cell tumour cells identifies potentially kit signaling-dependent genes

    PubMed Central

    2012-01-01

    Background Canine mast cell tumour proliferation depends to a large extent on the activity of KIT, a tyrosine kinase receptor. Inhibitors of the KIT tyrosine kinase have recently been introduced and successfully applied as a therapeutic agent for this tumour type. However, little is known on the downstream target genes of this signaling pathway and molecular changes after inhibition. Results Transcriptome analysis of the canine mast cell tumour cell line C2 treated for up to 72 hours with the tyrosine kinase inhibitor masitinib identified significant changes in the expression levels of approximately 3500 genes or 16% of the canine genome. Approximately 40% of these genes had increased mRNA expression levels including genes associated with the pro-proliferative pathways of B- and T-cell receptors, chemokine receptors, steroid hormone receptors and EPO-, RAS and MAP kinase signaling. Proteome analysis of C2 cells treated for 72 hours identified 24 proteins with changed expression levels, most of which being involved in gene transcription, e.g. EIA3, EIA4, TARDBP, protein folding, e.g. HSP90, UCHL3, PDIA3 and protection from oxidative stress, GSTT3, SELENBP1. Conclusions Transcriptome and proteome analysis of neoplastic canine mast cells treated with masitinib confirmed the strong important and complex role of KIT in these cells. Approximately 16% of the total canine genome and thus the majority of the active genes were significantly transcriptionally regulated. Most of these changes were associated with reduced proliferation and metabolism of treated cells. Interestingly, several pro-proliferative pathways were up-regulated, which may represent attempts of masitinib treated cells to activate alternative pro-proliferative pathways. These pathways may contain hypothetical targets for a combination therapy with masitinib to further improve its therapeutic effect. PMID:22747577

  3. Xyn11E from Paenibacillus barcinonensis BP-23: a LppX-chaperone-dependent xylanase with potential for upgrading paper pulps.

    PubMed

    Valenzuela, Susana V; Diaz, Pilar; Pastor, F I Javier

    2014-07-01

    A new xylanase from Paenibacillus barcinonensis BP-23, Xyn11E, has been identified and characterized. Xyn11E has been cloned and heterologously expressed in Escherichia coli. It is a single-domain xylanase belonging to the family 11 of glycosyl hydrolases (GH11) with a predicted molecular weight of 20.652 kDa and an isoelectric point (pI) of 8.7. Substrate specificity, kinetic properties, and mode of action of the purified xylanase were characterized. Xyn11E exhibited high activity toward branched xylans, being beechwood xylan the preferred substrate. The optimum pH and temperature of the purified enzyme were 6.5 and 50 °C, respectively. Catalytic constants were determined on beechwood xylan, on which Xyn11E showed a Km of 12.98 mg/ml and a Vmax of 3,023 U/mg. The enzyme hydrolyzed long xylooligosaccharides, while oligomers shorter than xylotetraose were not degraded. Products released from glucuronoxylans were shorter than those liberated from cereal arabinoxylans. The xylanase was dependent on P. barcinonensis BP-23 LppX for its expression in an active form. Coexpression of Xyn11E with E. coli chaperones could not replace the need of LppX, which seems to act as a specific chaperone for Xyn11E correct folding. Activity of the enzyme on bleached pulps was evaluated. Xyn11E liberated reducing sugars from ECF and TCF pulps from eucalyptus, sisal, and flax, which makes it a good candidate for the enzymatic-assisted production of high-cellulose-content pulps from paper-grade pulps. PMID:24549767

  4. Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier.

    PubMed

    Li, Huiqing; Edie, Sarah; Klinedinst, Donna; Jeong, Jun Seop; Blackshaw, Seth; Maslen, Cheryl L; Reeves, Roger H

    2016-06-01

    Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of >100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1 No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models. PMID:27029737

  5. Inhibition of EGFR pathway signaling and the metastatic potential of breast cancer cells by PA-MSHA mediated by type 1 fimbriae via a mannose-dependent manner.

    PubMed

    Liu, Z-B; Hou, Y-F; Zhu, J; Hu, D-L; Jin, W; Ou, Z-L; Di, G-H; Wu, J; Shen, Z-Z; Shao, Z-M

    2010-05-20

    To identify more therapeutic targets and clarify the detailed mechanisms of Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA) on breast cancer cells both in vitro and in vivo. PA-MSHA was administered to epidermal growth factor receptor (EGFR)-positive human breast cancer cell lines MDA-MB-231HM and MDA-MB-468 in vitro and to mice bearing tumor xenografts. The mannose cocultured test was used to detect the effect of mannose on PA-MSHA-induced cell proliferation, cell cycle arrest, apoptosis, and EGFR pathway signaling. We found that cells stimulated with PA-MSHA exhibited a downregulation of EGFR signaling. The addition of mannose partially inhibited the PA-MSHA-stimulated cell anti-proliferative effect, cell apoptosis, cell cycle arrest, activation of apoptosis-associated caspases, and even downregulation of the EGFR signaling pathway. In vivo, PA-MSHA treatment significantly suppressed mammary tumorigenesis in xenografts in mice and decreased lung metastasis in MDA-MB-231HM cell-transplanted mice. Tumor sample analyses confirmed inhibition of the EGFR pathway in the PA-MSHA-treated mice. In conclusion, this study showed that the involvement of the mannose-mediated EGFR pathway has a critical function in the preclinical rationale for the development of PA-MSHA for the treatment of human breast cancer. It also suggests the potentially beneficial use of PA-MSHA in adjuvant therapy for breast tumors with EGFR overexpression. PMID:20228837

  6. Temperature dependence of the electrode potential of a cobalt-based redox couple in ionic liquid electrolytes for thermal energy harvesting.

    PubMed

    He, Jiangjing; Al-Masri, Danah; MacFarlane, Douglas R; Pringle, Jennifer M

    2016-08-15

    Increasing the application of technologies for harvesting waste heat could make a significant contribution to sustainable energy production. Thermoelectrochemical cells are one such emerging technology, where the thermal response of a redox couple in an electrolyte is used to generate a potential difference across a cell when a temperature gradient exists. The unique physical properties of ionic liquids make them ideal for application as electrolytes in these devices. One of the keys to utilizing these media in efficient thermoelectrochemical cells is achieving high Seebeck coefficients, Se: the thermodynamic quantity that determines the magnitude of the voltage achieved per unit temperature difference. Here, we report the Se and cell performance of a cobalt-based redox couple in a range of different ionic liquids, to investigate the influence of the nature of the IL on the thermodynamics and cell performance of the redox system. The results reported include the highest Se to-date for an IL-based electrolyte. The effect of diluting the different ILs with propylene carbonate is also reported, which results in a significant increase in the output powers and current densities of the device. PMID:27200437

  7. A novel dithiocarbamate analogue with potentially decreased ALDH inhibition has copper-dependent proteasome-inhibitory and apoptosis-inducing activity in human breast cancer cells

    PubMed Central

    Wang, Fei; Zhai, Shumei; Liu, Xiaojun; Li, Liwen; Wu, Shirley; Dou, Q. Ping; Yan, Bing

    2013-01-01

    Dithiocarbamates are a class of sulfur-based metal-chelating compounds with various applications in medicine. We reported previously that certain members of dithiocarbamates, such as diethyldithiocarbamate, disulfiram (DSF) and pyrrolidine dithiocarbamate (PDTC), were able to bind with tumor cellular copper to inhibit tumor growth through the inhibition of proteasome activity and induction of cancer cell apoptosis. Since the DSF is an irreversible inhibitor of aldehyde dehydrogenase (ALDH), its ALDH-inhibitory activity might potentially affect its usefulness as an anti-cancer drug. For the purpose of selecting potent anti-cancer compounds that are not ALDH inhibitors and mapping out preliminary structure–activity relationship trends for these novel compounds, we synthesized a series of PDTC analogues and chose three novel compounds to study their ALDH-inhibitory activity, proteasome-inhibitory activity as well as the cancer cell apoptosis-inducing activity. The results showed that compared to DSF, compound 9 has less ALDH inhibition activity, and the in vitro results also proved the positive effects of 9-Cu in proteasome inhibition and apoptosis induction in breast cancer cells, suggesting that 9 as a lead compound could be developed into a novel proteasome inhibitor anti-cancer drug. PMID:21035945

  8. Diverse Mechanisms of Sp1-Dependent Transcriptional Regulation Potentially Involved in the Adaptive Response of Cancer Cells to Oxygen-Deficient Conditions

    PubMed Central

    Koizume, Shiro; Miyagi, Yohei

    2015-01-01

    The inside of a tumor often contains a hypoxic area caused by a limited supply of molecular oxygen due to aberrant vasculature. Hypoxia-inducible factors (HIFs) are major transcription factors that are required for cancer cells to adapt to such stress conditions. HIFs, complexed with the aryl hydrocarbon receptor nuclear translocator, bind to and activate target genes as enhancers of transcription. In addition to this common mechanism, the induction of the unfolded protein response and mTOR signaling in response to endoplasmic reticulum stress is also known to be involved in the adaptation to hypoxia conditions. Sp1 is a ubiquitously-expressed transcription factor that plays a vital role in the regulation of numerous genes required for normal cell function. In addition to the well-characterized stress response mechanisms described above, increasing experimental evidence suggests that Sp1 and HIFs collaborate to drive gene expression in cancer cells in response to hypoxia, thereby regulating additional adaptive responses to cellular oxygen deficiency. However, these characteristics of Sp1 and their biological merits have not been summarized. In this review, we will discuss the diverse mechanisms of transcriptional regulation by Sp1 and their potential involvement in the adaptive response of cancer cells to hypoxic tumor microenvironments. PMID:26703734

  9. Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II–dependent manner

    PubMed Central

    le Duc, Quint; Shi, Quanming; Blonk, Iris; Sonnenberg, Arnoud

    2010-01-01

    Cell surface receptors integrate chemical and mechanical cues to regulate a wide range of biological processes. Integrin complexes are the mechanotransducers between the extracellular matrix and the actomyosin cytoskeleton. By analogy, cadherin complexes may function as mechanosensors at cell–cell junctions, but this capacity of cadherins has not been directly demonstrated. Furthermore, the molecular composition of the link between E-cadherin and actin, which is needed to sustain such a function, is unresolved. In this study, we describe nanomechanical measurements demonstrating that E-cadherin complexes are functional mechanosensors that transmit force between F-actin and E-cadherin. Imaging experiments reveal that intercellular forces coincide with vinculin accumulation at actin-anchored cadherin adhesions, and nanomechanical measurements show that vinculin potentiates the E-cadherin mechanosensory response. These investigations directly demonstrate the mechanosensory capacity of the E-cadherin complex and identify a novel function for vinculin at cell–cell junctions. These findings have implications for barrier function, morphogenesis, cell migration, and invasion and may extend to all soft tissues in which classical cadherins regulate cell–cell adhesion. PMID:20584916

  10. Activation of CaMKII and ERK1/2 contributes to the time-dependent potentiation of Ca2+ response elicited by repeated application of capsaicin in rat DRG neurons

    PubMed Central

    Daugherty, Stephanie L.; de Groat, William C.

    2011-01-01

    When capsaicin is applied repeatedly to dorsal root ganglion (DRG) neurons for brief periods (10–15 s) at short intervals (5–10 min), the evoked responses rapidly decline, a phenomenon termed tachyphylaxis. In addition to this phenomenon, the present study using Ca2+ imaging revealed that repeated application of capsaicin to rat dissociated DRG neurons at longer intervals (20–40 min) or during multiple applications at short intervals elicited an enhancement of the responses, termed potentiation. The potentiation occurred in 50–60% of the capsaicin-responsive cells, on average representing a 20- to 30% increase in the peak amplitude of the Ca2+ signal, and was maximal at a 40-min application interval. An analysis of the mechanisms underlying potentiation revealed that it was suppressed by block of Ca2+/calmodulin-dependent protein kinase II (CaMKII) with 5 μM KN-93 or block of the activation of extracellular signal-regulated kinase (ERK) 1/2 with 2 μM U-0126. Lowering the extracellular Ca2+ concentration from 2 to 1 mM or pretreatment with deltamethrin (1 μM), which blocks calcineurin and tachyphylaxis, enhanced potentiation. Potentiation was not affected by: 1) inhibition of protein kinase C or protein kinase A, 2) block of the three subtypes of neurokinin receptors, or 3) block of the trafficking of transient receptor potential V1 channel to the membrane. These results indicate that the potentiation is a slowly developing Ca2+-modulated process that is mediated by a complex intracellular signaling pathway involving activation of CaMKII and ERK1/2. Potentiation may be an important peripheral autosensitization mechanism that occurs independently of the pronociceptive effects of inflammatory mediators and neurotrophic factors. PMID:21178121

  11. Dimerization of melanocortin receptor 1 (MC1R) and MC5R creates a ligand-dependent signal modulation: Potential participation in physiological color change in the flounder.

    PubMed

    Kobayashi, Yuki; Hamamoto, Akie; Takahashi, Akiyoshi; Saito, Yumiko

    2016-05-01

    Vertebrates produce α-melanocyte-stimulating hormone (α-MSH), which contains an N-terminal acetyl group, and desacetyl-α-MSH, which does not contain an N-terminal acetyl group. In teleosts and amphibians, α-MSH-related peptides stimulate pigment dispersion via melanocortin receptors 1-5 (MC1R-MC5R), which are members of the G-protein-coupled receptor (GPCR) family. We previously reported an interesting phenomenon associated with physiological color changes in the skin of a flatfish, barfin flounder (bf). Specifically, pigments in xanthophores expressing only the bfMC5R gene were dispersed by both α-MSH and desacetyl-α-MSH, whereas those in melanophores expressing both the bfMC1R and bfMC5R genes were dispersed by desacetyl-α-MSH, but not by α-MSH. In this study, we examined whether heterodimers of bfMC1R and bfMC5R can act as significant inhibitory receptors for the N-terminal acetylation of α-MSH in mammalian Chinese hamster ovary cells. Immunofluorescence analyses showed that bfMC1R and bfMC5R were localized together at the plasma membrane when expressed in the same cells. Indeed, after coexpression of Flag-bfMC1R and HA-bfMC5R, immunoprecipitation with anti-Flag antibodies resulted in the presence of anti-HA immunoreactivity in the precipitate, and vice versa. Importantly, cyclic AMP assays showed that cotransfection of bfMC1R with bfMC5R inhibited the cyclic AMP accumulation induced by α-MSH to a greater extent than that observed after transfection of bfMC1R alone. Of note, this inhibitory response was not caused by desacetyl-α-MSH. Thus, we show a ligand-dependent signaling through functional heterodimerization of MC1R and MC5R in mammalian cells. The ligand-selective receptor complex also provide the first mechanistic implication that may play a role in the control of color change in teleosts. PMID:27080548

  12. Neuregulin-1 Regulates Cell Adhesion via an ErbB2/Phosphoinositide-3 Kinase/Akt-Dependent Pathway: Potential Implications for Schizophrenia and Cancer

    PubMed Central

    Kanakry, Christopher G.; Li, Zhen; Nakai, Yoko; Sei, Yoshitatsu; Weinberger, Daniel R.

    2007-01-01

    Background Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1α-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer. Methodology/Principal Findings Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1α induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1α-induced migration (r2 = 0.61). NRG1α-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/Akt1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1α-induced adhesion (p = 0.0002). In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1α-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063). Conclusion/Significance Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion. PMID:18159252

  13. Strong anticancer potential of nano-triterpenoid from Phytolacca decandra against A549 adenocarcinoma via a Ca(2+)-dependent mitochondrial apoptotic pathway.

    PubMed

    Das, Jayeeta; Das, Sreemanti; Paul, Avijit; Samadder, Asmita; Khuda-Bukhsh, Anisur Rahman

    2014-06-01

    We isolated a triterpenoid from an ethanolic extract of Phytolacca decandra and nanoencapsulated it with biodegradable nontoxic polymers of poly(lactide-co-glycolide) to examine if the nanoform of this hitherto unexplored betulinic-acid derivative (NdBA) could produce a stronger anticancer effect by rendering better drug bioavailability and targeted delivery than the nonencapsulated betulinic-acid derivative (dBA). The nanoparticles were characterized with the help of physicochemical and morphological studies involving dynamic light scattering and atomic force microscopy. A549 cancer cells were exposed to NdBA and dBA at the IC50 doses of 50 μg/mL and 100 μg/mL, respectively. Mitochondrial dysfunction-mediated apoptosis was determined by examining the changes in the intracellular calcium content, the reactive oxygen species accumulation, the cytochrome c release, the upregulation of Bcl-2-associated-X protein (Bax) and caspase 3, the downregulation of B cell lymphoma 2, and the mitochondrial membrane potential (ΔΨm) depolarization. Apoptosis was also verified by acridine orange staining observed under fluorescence microscopy and annexin V-fluorescein isothiocyanate/propidium iodide staining through flow cytometric studies. The levels of intracellular adenosine triphosphate/adenosine diphosphate ratio decreased, and the ATPase activity increased more strikingly in A549 cells exposed to NdBA than in A549 cells exposed to dBA. Overall results showed that both drugs directly target the mitochondrial oxidative phosphorylation system, with NdBA having a stronger effect, indicating NdBA to be a better candidate for the development of an anticancer drug for use against lung adenocarcinomas. PMID:24929458

  14. Susceptibility to acidification of groundwater-dependent wetlands affected by water level declines, and potential risk to an early-breeding amphibian species.

    PubMed

    Serrano, L; Díaz-Paniagua, C; Gómez-Rodríguez, C; Florencio, M; Marchand, M-A; Roelofs, J G M; Lucassen, E C H E T

    2016-11-15

    Eggs of the Western spadefoot toad (Pelobates cultripes) reached a 100% mortality in all 29 clutches deposited at a pH below 5.0 in a temporary pond of the Doñana National Park (SW Spain) throughout the wet season of 2006-2007. A similar trend was detected in a neighbouring pond. The proximity of these two ponds to a groundwater pumping area (<1.5km), prompted us to elucidate the possible links between the reduction in pond hydroperiod over past decades (1989-2008) and the decrease of groundwater pH-buffering capacity. The average hydroperiod had decreased by 4months since 1998-99 in the pond where the extensive egg mortality had occurred. The total alkalinity, and the Mg(2+)concentration had also significantly declined in the shallow water-table since 1998-99, from an average of 8.56 to 0.32meql(-1), and of 3.57 to 1.15meql(-1), respectively. This decline of the shallow groundwater buffering capacity could turn this pond more susceptible to the inorganic acidity associated with pyrite oxidation as the sediment S content was often above 0.03%. The initial ratio of S/Ca+Mg in the summer dry sediment was a good predictor of pore-water pH on re-wetting after desiccation (r(2)=0.802, p<0.01). Therefore, this ratio can give some anticipation to mitigate the impact of acidity on toad hatching before these temporary ponds are reflooded on the next wet season. Our results suggest that the long-term damage to pond water levels can trigger a potential risk of soil acidification in the presence of iron-sulphide minerals. PMID:27476729

  15. Impact of potential large-scale and medium-scale irrigation on the West African Monsoon and its dependence on location of irrigated area

    NASA Astrophysics Data System (ADS)

    Eltahir, E. A. B.; IM, E. S.

    2014-12-01

    This study investigates the impact of potential large-scale (about 400,000 km2) and medium-scale (about 60,000 km2) irrigation on the climate of West Africa using the MIT Regional Climate Model. A new irrigation module is implemented to assess the impact of location and scheduling of irrigation on rainfall distribution over West Africa. A control simulation (without irrigation) and various sensitivity experiments (with irrigation) are performed and compared to discern the effects of irrigation location, size and scheduling. In general, the irrigation-induced surface cooling due to anomalously wet soil tends to suppress moist convection and rainfall, which in turn induces local subsidence and low level anti-cyclonic circulation. These local effects are dominated by a consistent reduction of local rainfall over the irrigated land, irrespective of its location. However, the remote response of rainfall distribution to irrigation exhibits a significant sensitivity to the latitudinal position of irrigation. The low-level northeasterly flow associated with anti-cyclonic circulation centered over the irrigation area can enhance the extent of low level convergence through interaction with the prevailing monsoon flow, leading to significant increase in rainfall. Despite much reduced forcing of irrigation water, the medium-scale irrigation seems to draw the same response as large-scale irrigation, which supports the robustness of the response to irrigation in our modeling system. Both large-scale and medium-scale irrigation experiments show that an optimal irrigation location and scheduling exists that would lead to a more efficient use of irrigation water. The approach of using a regional climate model to investigate the impact of location and size of irrigation schemes may be the first step in incorporating land-atmosphere interactions in the design of location and size of irrigation projects. However, this theoretical approach is still in early stages of development and

  16. The L-type voltage-dependent calcium channel long-term potentiation is higher in the dorsal compared with the ventral associational/commissural CA3 hippocampal synapses.

    PubMed

    Moschovos, Christos; Papatheodoropoulos, Costas

    2016-05-01

    The diversification between dorsal (DH) and ventral (VH) hippocampus includes the different ability to support NMDA receptor-dependent long-term synaptic potentiation (LTP). In this study, we assessed the ability of associational/commissural connections in the CA3 hippocampal field to show NMDA receptor-independent LTP. We found that high-frequency stimulation under blockade of NMDA receptors induced greater LTP in DH (40.7±8.5%) than in VH (17.1±4.6%). The blocker of L-type voltage-dependent calcium channels (VDCC) nifedipine prevented the induction of LTP. We hypothesize that the different ability for VDCC-LTP between DH and VH might have important implications in the memory-related information processing performed by the circuits of the two hippocampal segments. PMID:26541214

  17. A hybrid model for low pressure inductively coupled plasmas combining a fluid model for electrons with a plasma-potential-dependent energy distribution and a fluid-Monte Carlo model for ions

    NASA Astrophysics Data System (ADS)

    Mouchtouris, S.; Kokkoris, G.

    2016-04-01

    A hybrid plasma model is utilized for the simulation of inductively coupled plasmas (ICPs). It consists of a plasma fluid model coupling fluid with Maxwell’s equations and a Monte Carlo (MC) particle tracing model utilized for the calculation of the ion mobility in high electrostatic fields (sheaths). The model is applied to low pressure Argon plasma in the gaseous electronics conference (GEC) reference cell. Following measurements of electron energy distribution function (EEDF) in low pressure ICPs, a three-temperature EEDF is considered; it is formulated with a generalized equation and depends on the local plasma potential. The use of a predefined formula for the EEDF entails a low computational cost: All parameters affected by the EEDF are calculated as functions of the plasma potential and the mean electron energy once and before the solution of the model. The model results are validated by a comparison with spatially resolved (on axial and radial distance) measurements of electron density, electron temperature, and plasma potential. Both the calculation of the ion mobility by the MC model and the consideration of the three-temperature EEDF are critical for the accuracy of the model results. The very good agreement of the model results with the measurements and the low computational cost in combination with the flexibility of the code utilized for the numerical solution manifest the potential of the hybrid plasma model for the simulation of low pressure ICPs.

  18. A case of etizolam dependence

    PubMed Central

    Gupta, Sumit; Garg, Bhavuk

    2014-01-01

    Etizolam is a thienodiazepine anxiolytic which is said to have lower dependence potential than other benzodiazepines. We report a case of etizolam dependence in a young male with social anxiety disorder and moderate depression. This case report highlights the fact that the same caution be exercised while prescribing etizolam with respect to its potential to cause dependence as with any other benzodiazepine. PMID:25538342

  19. A case of etizolam dependence.

    PubMed

    Gupta, Sumit; Garg, Bhavuk

    2014-01-01

    Etizolam is a thienodiazepine anxiolytic which is said to have lower dependence potential than other benzodiazepines. We report a case of etizolam dependence in a young male with social anxiety disorder and moderate depression. This case report highlights the fact that the same caution be exercised while prescribing etizolam with respect to its potential to cause dependence as with any other benzodiazepine. PMID:25538342

  20. Proton transfer dynamics at the membrane/water interface: dependence on the fixed and mobile pH buffers, on the size and form of membrane particles, and on the interfacial potential barrier.

    PubMed

    Cherepanov, Dmitry A; Junge, Wolfgang; Mulkidjanian, Armen Y

    2004-02-01

    Crossing the membrane/water interface is an indispensable step in the transmembrane proton transfer. Elsewhere we have shown that the low dielectric permittivity of the surface water gives rise to a potential barrier for ions, so that the surface pH can deviate from that in the bulk water at steady operation of proton pumps. Here we addressed the retardation in the pulsed proton transfer across the interface as observed when light-triggered membrane proton pumps ejected or captured protons. By solving the system of diffusion equations we analyzed how the proton relaxation depends on the concentration of mobile pH buffers, on the surface buffer capacity, on the form and size of membrane particles, and on the height of the potential barrier. The fit of experimental data on proton relaxation in chromatophore vesicles from phototropic bacteria and in bacteriorhodopsin-containing membranes yielded estimates for the interfacial potential barrier for H(+)/OH(-) ions of approximately 120 meV. We analyzed published data on the acceleration of proton equilibration by anionic pH buffers and found that the height of the interfacial barrier correlated with their electric charge ranging from 90 to 120 meV for the singly charged species to >360 meV for the tetra-charged pyranine. PMID:14747306

  1. Temperature dependence of the HO{sub 2} + ClO reaction. 1. Reaction kinetics by pulsed photolysis-ultraviolet absorption and ab initio studies of the potential surface

    SciTech Connect

    Nickolaisen, S.L.; Roehl, C.M.; Blakeley, L.K.; Friedl, R.R.; Francisco, J.S.; Liu, R.; Sander, S.P.

    2000-01-20

    The kinetics of the HO{sub 2} + ClO reaction was studied using the flash photolysis/ultraviolet absorption technique over the temperature range 203--364 K and pressure range 50--700 Torr of N{sub 2}. In contrast to previous work, the temperature dependence displayed linear Arrhenius behavior over the entire temperature range. Ab initio calculations of intermediates and transition states have been carried out on the singlet and triplet potential energy surfaces. These calculations show that the reaction proceeds mainly through the ClO-HO{sub 2} complex on the triplet surface; however, collisionally stabilized HOOOCl formed on the singlet surface will possess an appreciable lifetime due to large barriers toward decomposition to HCl and HOCl. Termolecular rate calculations using ab initio parameters lead to a strong collision rate constant for HOOOCl formation. This intermediate may be important under both laboratory and atmospheric conditions.

  2. Buprenorphine for opioid dependence.

    PubMed

    Ling, Walter

    2009-05-01

    As a treatment agent for opioid dependence, buprenorphine is a nearly ideal medication at our current stage of medication development. Unlike methadone, buprenorphine dosage can be rapidly adjusted with minimal potential for inducing severe consequences. In addition to its intrinsic safety, buprenorphine's relatively low abuse liability in the combination product (i.e., with naloxone as Suboxone) makes it even more acceptable in regulatory quarters as well as to prescribing physicians. The approval of buprenorphine as a pharmacotherapy for opioid dependence returns to physicians the ability to treat their opioid-dependent patients with an effective opioid-based treatment for the first time in nearly 100 years. Buprenorphine is an opioid, however, and potential for misuse remains, even in combination with naloxone. Whether buprenorphine will be increasingly accepted as a treatment for opioid-dependent patients depends on clinicians recognizing the advantages of its uniquely useful properties while still heeding the need to manage their patients' therapy with reasonable vigilance. PMID:19402772

  3. Charge-transfer correction for improved time-dependent local density approximation excited-state potential energy curves: Analysis within the two-level model with illustration for H2 and LiH

    NASA Astrophysics Data System (ADS)

    Casida, Mark E.; Gutierrez, Fabien; Guan, Jingang; Gadea, Florent-Xavier; Salahub, Dennis; Daudey, Jean-Pierre

    2000-11-01

    Time-dependent density-functional theory (TDDFT) is an increasingly popular approach for calculating molecular excitation energies. However, the TDDFT lowest triplet excitation energy, ωT, of a closed-shell molecule often falls rapidly to zero and then becomes imaginary at large internuclear distances. We show that this unphysical behavior occurs because ωT2 must become negative wherever symmetry breaking lowers the energy of the ground state solution below that of the symmetry unbroken solution. We use the fact that the ΔSCF method gives a qualitatively correct first triplet excited state to derive a "charge-transfer correction" (CTC) for the time-dependent local density approximation (TDLDA) within the two-level model and the Tamm-Dancoff approximation (TDA). Although this correction would not be needed for the exact exchange-correlation functional, it is evidently important for a correct description of molecular excited state potential energy surfaces in the TDLDA. As a byproduct of our analysis, we show why TDLDA and LDA ΔSCF excitation energies are often very similar near the equilibrium geometries. The reasoning given here is fairly general and it is expected that similar corrections will be needed in the case of generalized gradient approximations and hybrid functionals.

  4. Transient Receptor Potential Channel Opening Releases Endogenous Acetylcholine, which Contributes to Endothelium-Dependent Relaxation Induced by Mild Hypothermia in Spontaneously Hypertensive Rat but Not Wistar-Kyoto Rat Arteries.

    PubMed

    Zou, Q; Leung, S W S; Vanhoutte, P M

    2015-08-01

    Mild hypothermia causes endothelium-dependent relaxations, which are reduced by the muscarinic receptor antagonist atropine. The present study investigated whether endothelial endogenous acetylcholine contributes to these relaxations. Aortic rings of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats were contracted with prostaglandin F2 α and exposed to progressive mild hypothermia (from 37 to 31°C). Hypothermia induced endothelium-dependent, Nω-nitro-l-arginine methyl ester-sensitive relaxations, which were reduced by atropine, but not by mecamylamine, in SHR but not in WKY rat aortae. The responses in SHR aortae were also reduced by acetylcholinesterase (the enzyme responsible for acetylcholine degradation), bromoacetylcholine (inhibitor of acetylcholine synthesis), hemicholinium-3 (inhibitor of choline uptake), and vesamicol (inhibitor of acetylcholine release). The mild hypothermia-induced relaxations in both SHR and WKY rat aortae were inhibited by AMTB [N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide; the transient receptor potential (TRP) M8 inhibitor]; only those in SHR aortae were inhibited by HC-067047 [2-methyl-1-[3-(4-morpholinyl)propyl]-5-phenyl-N-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide; TRPV4 antagonist] while those in WKY rat aortae were reduced by HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; TRPA1 antagonist]. The endothelial uptake of extracellular choline and release of cyclic guanosine monophosphate was enhanced by mild hypothermia and inhibited by HC-067047 in SHR but not in WKY rat aortae. Compared with WKY rats, the SHR preparations expressed similar levels of acetylcholinesterase and choline acetyltransferase, but a lesser amount of vesicular acetylcholine transporter, located mainly in