940 research outputs found
TCN 201 selectively blocks GluN2A-containing NMDARs in a GluN1 co-agonist dependent but non-competitive manner
No full textAntagonists that are sufficiently selective to preferentially block GluN2A-containing N-methyl-d-aspartate receptors (NMDARs) over GluN2B-containing NMDARs are few in number. In this study we describe a pharmacological characterization of 3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide (TCN 201), a sulphonamide derivative, that was recently identified from a high-throughput screen as a potential GluN2A-selective antagonist. Using two-electrode voltage-clamp (TEVC) recordings of NMDAR currents from Xenopus laevis oocytes expressing either GluN1/GluN2A or GluN1/GluN2B NMDARs we demonstrate the selective antagonism by TCN 201 of GluN2A-containing NMDARs. The degree of inhibition produced by TCN 201 is dependent on the concentration of the GluN1-site co-agonist, glycine (or d-serine), and is independent of the glutamate concentration. This GluN1 agonist-dependency is similar to that observed for a related GluN2A-selective antagonist, N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide (TCN 213). Schild analysis of TCN 201 antagonism indicates that it acts in a non-competitive manner but its equilibrium constant at GluN1/GluN2A NMDARs indicates TCN 201 is around 30-times more potent than TCN 213. In cortical neurones TCN 201 shows only modest antagonism of NMDAR-mediated currents recorded from young (DIV 9-10) neurones where GluN2B expression predominates. In older cultures (DIV 15-18) or in cultures where GluN2A subunits have been over-expressed TCN 201 gives a strong block that is negatively correlated with the degree of block produced by the GluN2B-selective antagonist, ifenprodil. Nevertheless, while TCN 201 is a potent antagonist it must be borne in mind that its ability to block GluN2A-containing NMDARs is dependent on the GluN1-agonist concentration and is limited by its low solubility
G.E. Stewart Interview - Transcript
No full textG.E. Steward (1906-1979)
G. E. Steward was born near Shreveport, Louisiana and was raised near Longview, Texas. He lost his eyesight when he was twelve and attended the State School for the Blind in Austin. Much of the interview focuses on his relationship with G. P. Bowser, who baptized him in 1931. Steward preached in Abilene, Texas, for three years in the thirties and moved to Memphis in 1936. He served as preacher at the Vance Avenue Church of Christ in Memphis, the Third Ward Church in Houston, and in Oklahoma City before moving to Detroit to the West Side Church. Stewart was a staff writer for the Christian Echo and is the author of Our Pulpit and What the Bible Teaches about Illicit Sex and Homosexuality.
In the interview he talks about his family history and about Bowser. The file consists of information about Steward and includes a term paper and his obituary
Predicting growth rates of interfaces and internal layers in a turbulent boundary layer using a first order jump model
No full textExperimental research is presented on the characteristics of interfaces and internal layers that are present in a turbulent boundary layer (TBL). Both the turbulent non-turbulent interface (T/NT) and internal shear layers are detected in snapshots of the stereo-PIV data. It turns out that the internal layers exhibit similar characteristics compared to the T/NT interface. A theoretical approximation of the large scale boundary layer growth indicates that the correct boundary layer growth can be obtained by employing a modified first order jump model on the conditional statistics. Employing the same framework to the internal shear layers indicates that shear layers tend to move slower in close proximity to the wall, whereas they accelerate when moving away from the wall. Based on previous research it is believed that these internal layers separate large regions of approximately uniform momentum. Hence, boundary entrainment velocities may be interpreted as growth rates of large scale motions in a TBL
Structure and dynamics of turbulent flows over highly permeable walls
No full textHighly porous materials are found in various industrial applications and environmental flows. In previous studies it was found that a turbulent flow along a highly porous wall experiences a higher skin friction as compared to a solid wall with similar surface roughness when the so-called permeability Reynolds number (Re_K) is larger than O(1). The main objective of the present study was to gain understanding of the characteristic structures and auto-generation mechanisms of turbulence for Re_K >> 1. To this purpose the Volume-Averaged Navier-Stokes (VANS) equations were solved in a Direct Numerical Simulation (DNS) of a turbulent flow through a plane channel with an upper solid wall and a lower porous wall at Re_K = 5.91. The DNS results are in good agreement with available Particle Image Velocimetry (PIV) data for the same flow geometry. A linear stochastic estimation technique was used to capture the structure associated with the characteristic ejection event that contributes most to the Reynolds shear stress near the porous wall. This structure is similar to a horseshoe vortex. Contrary to the conventional hairpin vortex found near solid walls, this horseshoe vortex has a significantly higher inclination angle with the wall and its legs are much shorter. The latter is consistent with the observed absence of low and high-speed streaks near highly permeable walls. Next, the auto-generation mechanisms of the horseshoe vortex were studied in another DNS in which the horseshoe vortex was released in the Reynolds-averaged flow field obtained from the former DNS. Two distinct auto-generation mechanisms were observed: (1) the generation of new structures at the upstream end of the horseshoe vortex, which evolve rapidly into a turbulent spot with an arrowhead shape, and (2) the interaction of the horseshoe vortex with spanwise oriented Kelvin-Helmholtz vortex rollers originating from the inflexion point in the mean velocity profile near the porous wall
Scale interaction in a mixing layer: The role of the large-scale gradients
No full textThe interaction between scales is investigated in a turbulent mixing layer. The large-scale amplitude modulation of the small scales already observed in other works depends on the crosswise location. Large-scale positive fluctuations correlate with a stronger activity of the small scales on the low speed-side of the mixing layer, and a reduced activity on the high speed-side. However, from physical considerations we would expect the scales to interact in a qualitatively similar way within the flow and across different turbulent flows. Therefore, instead of the large-scale fluctuations, the large-scale gradients modulation of the small scales has been additionally investigated
Mechanistic investigations into pro-survival and pro-death neuronal Ca2+ signalling pathways
No full textCa2+ is an important second messenger which modulates a variety of signalling pathways in
both excitable and non-excitable cells. In the CNS, Ca2+ plays an important role in neurons
both physiologically and pathologically. Ca2+ influx following synaptic activity, is important
in development, plasticity, redox balance, as well as in neuroprotection, largely through
activation of pro-survival pathways downstream of synaptic NMDAR activation, including
upregulation of antioxidant defences. However, excessive Ca2+ influx in neurons leads to
neuronal damage and excitotoxicity, in which mitochondrial Ca2+ uptake through the
mitochondrial Ca2+ uniporter (Mcu) resulting in mitochondrial dysfunction is a key player.
Excitotoxicity occurs due to glutamate efflux from astrocytes following stroke, traumatic brain
injury and in chronic neurodegenerative diseases, leading to excessive neuronal NMDAR
activation and triggering of its downstream pro-death pathways. This thesis focuses on
understanding the pro-survival and pro-death effects of signalling pathways activated by Ca2+
in neurons, as well as the potential effect of neuronal synaptic activity on influencing
neuroprotective gene transcription in astrocytes.
I investigated the role of AMPK, a master regulator of metabolism, in NMDA excitotoxicity
in cortical neurons as a potential downstream effector of Mcu-dependent excitotoxic death;
and found the deletion of AMPKα1/2 to be neuroprotective against NMDA-mediated
excitotoxicity, however I found AMPK activation to be independent of Mcu. I also
investigated the expression pattern of Mcu and other mitochondrial calcium regulatory genes
(MCRGs), and found MCRGs to be differentially expressed in different neural cells (primary
neurons vs astrocytes), and neuronal subtypes (CA1 vs CA3 region of the hippocampus),
suggesting differing dependence on the various MCRGs in mitochondrial Ca2+ handling in
these cell types. A better functional understanding of these genes will allow for investigation
of their importance in mitochondrial Ca2+ handling, including their potential role in
excitotoxicity.
I next investigated the neuroprotective effects of synaptic activity induced Ca2+ influx,
focusing on antioxidant target genes of Nrf2, a transcription factor and major regulator of
antioxidant genes. I found that unlike astrocytes, neurons express very low levels of Nrf2.
However, synaptic activity increased the expression of several Nrf2 target genes in neurons,
independently of astrocytes and Nrf2. Additionally, I found no effect of synaptic activity on
increasing Nrf2 protein levels, despite previous reports in literature of Nrf2 pathway activation
following synaptic activity. Finally, using RNA-seq I identified a list of genes strongly
upregulated by a known Nrf2 activator in astrocytes, and found no evidence that neuronal
activity triggers expression of these genes independently of neurons, providing further
evidence that neuronal activity does not activate the Nrf2 pathway in astrocytes. This suggests
that synaptic activity via pathways activated by Ca2+ signalling provides neurons with cell-autonomous
antioxidant defences, independently of Nrf2; thus providing a distinct pathway
for antioxidant defences in neurons from the Nrf2 pathway, which is activated in astrocytes
providing neurons with non-cell autonomous antioxidant support.
These results give us further insight into the mechanisms that underlie synaptic and non-synaptic
Ca2+ signalling pathways mediating neuronal survival and death, which could help in
identifying therapeutic targets to combat excitotoxicity and oxidative stress in various
neurological diseases
Theory of spin and lattice wave dynamics excited by focused laser pulses
No full textWe develop a theory of spin wave dynamics excited by ultrafast focused laser pulses in a magnetic film. We take into account both the volume and surface spin wave modes in the presence of applied, dipolar and magnetic anisotropy fields and include the dependence on laser spot exposure size and magnetic damping. We show that the sound waves generated by local heating by an ultrafast focused laser pulse can excite a wide spectrum of spin waves (on top of a dominant magnon-phonon contribution). Good agreement with recent experiments supports the validity of the model.Accepted Author ManuscriptQN/Bauer Grou
Polonais d’origine juive volontaires de la guerre civile en Espagne (1936-1939)
No full textG. E. Sichon article is, first of all, an historical analysis, as the title suggests, of Polish Jews who participate in the International Brigades during the Spanish War. But this is also a major eye-witness account, since the author met most of the important protagonists. The article is illustrated with several of his own photographs, which he has generously given to the BDIC Collection.L’article de Gaby Ersler Sichon est d’abord une analyse historique sur les Polonais d’origine juive dans les Brigades internationales durant la guerre d’Espagne. Mais c’est aussi celle d’un témoin oculaire d’événements dont il a connu personnellement les protagonistes. L’article est illustré de photographies qu’il a prises, provenant d’un corpus généreusement déposé à la BDIC.Sichon G.e. Polonais d’origine juive volontaires de la guerre civile en Espagne (1936-1939). In: Matériaux pour l'histoire de notre temps, n°73, 2004. pp. 44-48
Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis
No full textMolecular, genetic and pathological evidence suggests that deficits in GABAergic parvalbumin-positive interneurons contribute to schizophrenia pathophysiology through alterations in the brain's excitation-inhibition balance that result in impaired behaviour and cognition. Although the factors that trigger these deficits are diverse, there is increasing evidence that they converge on a common pathological hub that involves NMDA receptor hypofunction and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology
Autotraduttori polacchi del Novecento: un saggio di ricognizione
No full text20th-Century Polish Self-Translators: a Reconnaissance Survey
Twentieth-Century Polish literature provides surprisingly many examples of writers who
happened to become translators of their own works, such as Stanisław Przybyszewski
(German), Tadeusz Rittner (German), Wacław Sieroszewski (Russian), Bruno Jasieński
(Russian), Stanisław Ignacy Witkiewicz (French), Debora Vogel (Yiddish), Stanisław Kubicki
(German), Stefan Themerson (English), Maria Kuncewiczowa (English), Stanisław
Barańczak (English), Witold Gombrowicz (Spanish), Czesław Miłosz (English) and many
others. The author of this paper aims first of all to draw attention to the practice of selftranslation
by Polish writers, which turns out to be much more widespread than the number
of studies devoted to it would suggest. The paper is intended as a sort of preliminary reconnaissance
of the field of analysis, leading to the realization of its real dimensions, of the kind
of issues it involves, of its constants and variants. Three periods are highlighted, when selftranslation
is practiced in different contexts: before the World War I the keyword explaining
the recourse to self-translation is expropriation (Poland is deprived of state sovereignty,
bilingualism is imposed by the invaders), between the Wars it is experiment, and after World
War II it is exile. An outline of each self-translator’s activity is traced, including an analysis
of self-translation’s motivations (internal factors and external factors), directionality (from
and into which language, unidirectional or bidirectional), frequency (occasional, repeated
or usual) and degree of authoriality (alone or in collaboration)
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