Activation of Nrf2-Regulated Glutathione Pathway Genes by Ischemic Preconditioning

Prophylactic pharmacological activation of astrocytic gene expression driven by the transcription factor Nrf2 boosts antioxidant defences and protects against neuronal loss in ischemia and other disease models. However, the role of Nrf2 in mediating endogenous neuroprotective responses is less clear. We recently showed that Nrf2 is activated by mild oxidative stress in both rodent and human astrocytes. Moreover, brief exposure to ischemic conditions was found to activate Nrf2 both in vivo and in vitro, and this was found to contribute to neuroprotective ischemic preconditioning. Here we show that transient ischemic conditions in vitro and in vivo cause an increase in the expression of Nrf2 target genes associated with the glutathione pathway, including those involved in glutathione biosynthesis and cystine uptake. Taken together, these studies indicate that astrocytic Nrf2 may represent an important mediator of endogenous neuroprotective preconditioning pathways

The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults

It is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that the toxicity of NMDAR-mediated Ca(2+) influx is differentially controlled by the cytoplasmic C-terminal domains of GluN2B (CTD(2B)) and GluN2A (CTD(2A)). Studying the effects of acute expression of GluN2A/2B-based chimeric subunits with reciprocal exchanges of their CTDs revealed that CTD(2B) enhances NMDAR toxicity, compared to CTD(2A). Furthermore, the vulnerability of forebrain neurons in vitro and in vivo to NMDAR-dependent Ca(2+) influx is lowered by replacing the CTD of GluN2B with that of GluN2A by targeted exon exchange in a mouse knockin model. Mechanistically, CTD(2B) exhibits stronger physical/functional coupling to the PSD-95-nNOS pathway, which suppresses protective CREB activation. Dependence of NMDAR excitotoxicity on the GluN2 CTD subtype can be overcome by inducing high levels of NMDAR activity. Thus, the identity (2A versus 2B) of the GluN2 CTD controls the toxicity dose-response to episodes of NMDAR activity

Galaxy Zoo: Are Bars Responsible for the Feeding of Active Galactic Nuclei at 0.2 < z < 1.0?

We present a new study investigating whether active galactic nuclei (AGN) beyond the local universe are preferentially fed via large-scale bars. Our investigation combines data from Chandra and Galaxy Zoo: Hubble (GZH) in the AEGIS, COSMOS, and GOODS-S surveys to create samples of face-on, disc galaxies at 0.2 < z < 1.0. We use a novel method to robustly compare a sample of 120 AGN host galaxies, defined to have 10^42 erg/s < L_X < 10^44 erg/s, with inactive control galaxies matched in stellar mass, rest-frame colour, size, Sersic index, and redshift. Using the GZH bar classifications of each sample, we demonstrate that AGN hosts show no statistically significant enhancement in bar fraction or average bar likelihood compared to closely-matched inactive galaxies. In detail, we find that the AGN bar fraction cannot be enhanced above the control bar fraction by more than a factor of two, at 99.7% confidence. We similarly find no significant difference in the AGN fraction among barred and non-barred galaxies. Thus we find no compelling evidence that large-scale bars directly fuel AGN at 0.2<z<1.0. This result, coupled with previous results at z=0, implies that moderate-luminosity AGN have not been preferentially fed by large-scale bars since z=1. Furthermore, given the low bar fractions at z>1, our findings suggest that large-scale bars have likely never directly been a dominant fueling mechanism for supermassive black hole growth.Comment: 13 pages, 5 figures, 2 tables, accepted by MNRA

Banking from Leeds, not London: regional strategy and structure at the Yorkshire Bank, 1859–1952

Industrial philanthropist Edward Akroyd created the Yorkshire Penny Savings Bank in 1859. Despite competition from the Post Office Savings Bank after 1861 and a serious reserve problem in 1911, it sustained his overall strategy to become a successful regional bank. Using archival and contemporary sources to build on recent scholarship illustrating how savings banks were integrated into local economies and the complementary roles of philanthropy and paternalism, we analyse an English regional bank's strategy, including an assessment of strategic innovation, ownership changes and management structure. This will demonstrate that the founder's vision continued, even though the 1911 crisis radically altered both strategy and structure

Stellar populations of barred quiescent galaxies

International audienceSelecting centrally quiescent galaxies from the Sloan Digital Sky Survey (SDSS) to create high signal-to-noise ratio (greater than or similar to 100 angstrom(-1)) stacked spectra with minimal emission-line contamination, we accurately and precisely model the central stellar populations of barred and unbarred quiescent disk galaxies. By splitting our sample by redshift, we can use the fixed size of the SDSS fiber to model the stellar populations at different radii within galaxies. At 0.02 \textless z \textless 0.04, the SDSS fiber radius corresponds to approximate to 1 kpc, which is the typical half-light radii of both classical bulges and disky pseudobulges. Assuming that the SDSS fiber primarily covers the bulges at these redshifts, our analysis shows that there are no significant differences in the stellar populations, i.e., stellar age, [Fe/H], [Mg/Fe], and [N/Fe], of the bulges of barred versus unbarred quiescent disk galaxies. Modeling the stellar populations at different redshift intervals from z = 0.020 to z = 0.085 at fixed stellar masses produces an estimate of the stellar population gradients out to about half the typical effective radius of our sample, assuming null evolution over this approximate to 1 Gyr epoch. We find that there are no noticeable differences in the slopes of the azimuthally averaged gradients of barred versus unbarred quiescent disk galaxies. These results suggest that bars are not a strong influence on the chemical evolution of quiescent disk galaxies

Suppression of the intrinsic apoptosis pathway by sinaptic activity

Synaptic activity promotes resistance to diverse apoptotic insults, the mechanism behind which is incompletely understood. We show here that a coordinated downregulation of core components of the intrinsic apoptosis pathway by neuronal activity forms a key part of the underlying mechanism. Activity-dependent protection against apoptotic insults is associated with inhibition of cytochrome c release in most but not all neurons, indicative of anti-apoptotic signaling both upstream and downstream of this step. We find that enhanced firing activity suppresses expression of the proapoptotic BH3-only member gene Puma in a NMDA receptor-dependent, p53-independent manner. Puma expression is sufficient to induce cytochrome c loss and neuronal apoptosis. Puma deficiency protects neurons against apoptosis and also occludes the protective effect of synaptic activity, while blockade of physiological NMDA receptor activity in the developing mouse brain induces neuronal apoptosis that is preceded by upregulation of Puma. However, enhanced activity can also confer resistance to Puma-induced apoptosis, acting downstream of cytochrome c release. This mechanism is mediated by transcriptional suppression of apoptosome components Apaf-1 and procaspase-9, and limiting caspase-9 activity, since overexpression of procaspase-9 accelerates the rate of apoptosis in active neurons back to control levels. Synaptic activity does not exert further significant anti-apoptotic effects downstream of caspase-9 activation, since an inducible form of caspase-9 overrides the protective effect of synaptic activity, despite activity-induced transcriptional suppression of caspase-3. Thus, suppression of apoptotic gene expression may synergize with other activity-dependent events such as enhancement of antioxidant defenses to promote neuronal survival

Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone

Characterization and petrologic interpretation of olivine-rich basalts at Gusev Crater, Mars

Rocks on the floor of Gusev crater are basalts of uniform composition and mineralogy. Olivine, the only mineral to have been identified or inferred from data by all instruments on the Spirit rover, is especially abundant in these rocks. These picritic basalts are similar in many respects to certain Martian meteorites (olivine-phyric shergottites). The olivine megacrysts in both have intermediate compositions, with modal abundances ranging up to 20&ndash;30%. Associated minerals in both include low-calcium and highcalcium pyroxenes, plagioclase of intermediate composition, iron-titanium-chromium oxides, and phosphate. These rocks also share minor element trends, reflected in their nickel-magnesium and chromium-magnesium ratios. Gusev basalts and shergottites appear to have formed from primitive magmas produced by melting an undepleted mantle at depth and erupted without significant fractionation. However, apparent differences between Gusev rocks and shergottites in their ages, plagioclase abundances, and volatile contents preclude direct correlation. Orbital determinations of global olivine distribution and compositions by thermal emission spectroscopy suggest that olivine-rich rocks may be widespread. Because weathering under acidic conditions preferentially attacks olivine and disguises such rocks beneath alteration rinds, picritic basalts formed from primitive magmas may even be a common component of the Martian crust formed during ancient and recent times.Additional co-authors: PR Christensen, BC Clark, JA Crisp, DJ DesMarais, T Economou, JD Farmer, W Farrand, A Ghosh, M Golombek, S Gorevan, R Greeley, VE Hamilton, JR Johnson, BL Joliff, G Klingelhöfer, AT Knudson, S McLennan, D Ming, JE Moersch, R Rieder, SW Ruff, PA de Souza Jr, SW Squyres, H Wnke, A Wang, A Yen, J Zipfe

Galaxy Zoo: Are bars responsible for the feeding of active galactic nuclei at 0.2<z<1.0?

We present a new study investigating whether active galactic nuclei (AGN) beyond the local universe are preferentially fed via large-scale bars. Our investigation combines data from Chandra and Galaxy Zoo: Hubble (GZH) in the AEGIS (All-wavelength Extended Groth strip International Survey), COSMOS (Cosmological Evolution Survey), and (Great Observatories Origins Deep Survey-South) GOODS-S surveys to create samples of face-on, disc galaxies at 0.21, our findings suggest that large-scale bars have likely never directly been a dominant fuelling mechanism for supermassive black hole growt

‘Remembering as Forgetting’: Organizational commemoration as a politics of recognition

This paper considers the politics of how organizations remember their past through commemorative settings and artefacts. Although these may be seen as ‘merely’ a backdrop to organizational activity, they form part of the lived experience of organizational spaces that its members enact on a daily basis as part of their routes and routines. The main concern of the paper is with how commemoration is bound up in the reflection and reproduction of hierarchies of organizational recognition. Illustrated with reference to two commemorative settings, the paper explores how organizations perpetuate a narrow set of symbolic ideals attributing value to particular forms of organizational membership while appearing to devalue others. In doing so, they communicate values that undermine attempts to achieve equality and inclusion. Developing a recognition-based critique of this process, the discussion emphasizes how commemorative settings and practices work to reproduce established patterns of exclusion and marginalization. To this end, traditional forms of commemorative portraiture that tend to close off difference are contrasted with a memorial garden, in order to explore the potential for an alternative, recognition-based ethics of organizational commemoration that is more open to the Other