PROGRESS IN SCF-SW-XALPHA AB INITIO XANES CALCULATIONS FOR CHROMIUM HEXACARBONYL BASED ON GENERAL NON-MUFFIN-TIN POTENTIALS

We describe progress towards the performance of SCF-SW-Xalpha calculations of photo-absorption cross-sections based on the theory of Natoli et al. for non-muffin-tin potentials. A crucial requirement is the accurate modelling of the electron-molecule potential using spherical harmonic expansions. We describe how this has been achieved and what difficulties are encountered. In the particular case of our model compound, chromium hexacarbonyl, we show what muffin-tin calculations produce and show that we may expect significant improvements from a non-muffin-tin calculation. Finally, we comment on the programming problems involved in these computations

Large well-relaxed models of vitreous silica, coordination numbers and entropy

A Monte Carlo method is presented for the simulation of vitreous silica. Well-relaxed networks of vitreous silica are generated containing up to 300,000 atoms. The resulting networks, quenched under the BKS potential, display smaller bond-angle variations and lower defect concentrations, as compared to networks generated with molecular dynamics. The total correlation functions T(r) of our networks are in excellent agreement with neutron scattering data, provided that thermal effects and the maximum inverse wavelength used in the experiment are included in the comparison. A procedure commonly used in experiments to obtain coordination numbers from scattering data is to fit peaks in rT(r) with a gaussian. We show that this procedure can easily produce incorrect results. Finally, we estimate the configurational entropy of vitreous silica.Comment: 7 pages, 4 figures (two column version to save paper

BioCatalogue: a universal catalogue of web services for the life sciences

The use of Web Services to enable programmatic access to on-line bioinformatics is becoming increasingly important in the Life Sciences. However, their number, distribution and the variable quality of their documentation can make their discovery and subsequent use difficult. A Web Services registry with information on available services will help to bring together service providers and their users. The BioCatalogue (http://www.biocatalogue.org/) provides a common interface for registering, browsing and annotating Web Services to the Life Science community. Services in the BioCatalogue can be described and searched in multiple ways based upon their technical types, bioinformatics categories, user tags, service providers or data inputs and outputs. They are also subject to constant monitoring, allowing the identification of service problems and changes and the filtering-out of unavailable or unreliable resources. The system is accessible via a human-readable ‘Web 2.0’-style interface and a programmatic Web Service interface. The BioCatalogue follows a community approach in which all services can be registered, browsed and incrementally documented with annotations by any member of the scientific community

Roles of P2 receptors in glial cells: focus on astrocytes

Central nervous system glial cells release and respond to nucleotides under both physiological and pathological conditions, suggesting that these molecules play key roles in both normal brain function and in repair after damage. In particular, ATP released from astrocytes activates P2 receptors on astrocytes and other brain cells, allowing a form of homotypic and heterotypic signalling, which also involves microglia, neurons and oligodendrocytes. Multiple P2X and P2Y receptors are expressed by both astrocytes and microglia; however, these receptors are differentially recruited by nucleotides, depending upon specific pathophysiological conditions, and also mediate the long-term trophic changes of these cells during inflammatory gliosis. In astrocytes, P2-receptor-induced gliosis occurs via activation of the extracellular-regulated kinases (ERK) and protein kinase B/Akt pathways and involves induction of inflammatory and anti-inflammatory genes, cyclins, adhesion and antiapoptotic molecules. While astrocytic P2Y1 and P2Y2,4 are primarily involved in short-term calcium-dependent signalling, multiple P2 receptor subtypes seem to cooperate to astrocytic long-term changes. Conversely, in microglia, exposure to inflammatory and immunological stimuli results in differential functional changes of distinct P2 receptors, suggesting highly specific roles in acquisition of the activated phenotype. We believe that nucleotide-induced activation of astrocytes and microglia may originally start as a defence mechanism to protect neurons from cytotoxic and ischaemic insults; dysregulation of this process in chronic inflammatory diseases eventually results in neuronal cell damage and loss. On this basis, full elucidation of the specific roles of P2 receptors in these cells may help exploit the beneficial neuroprotective features of activated glia while attenuating their harmful properties and thus provide the basis for novel neuroprotective strategies that specifically target the purinergic system

MPP+-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine

Guanosine exerts neuroprotective effects in the central nervous system. Apoptosis, a morphological form of programmed cell death, is implicated in the pathophysiology of Parkinson’s disease (PD). MPP+, a dopaminergic neurotoxin, produces in vivo and in vitro cellular changes characteristic of PD, such as cytotoxicity, resulting in apoptosis. Undifferentiated human SH-SY5Y neuroblastoma cells had been used as an in vitro model of Parkinson’s disease. We investigated if extracellular guanosine affected MPP+-induced cytotoxicity and examined the molecular mechanisms mediating its effects. Exposure of neuroblastoma cells to MPP+ (10 μM–5 mM for 24–72 h) induced DNA fragmentation in a time-dependent manner (p < 0.05). Administration of guanosine (100 μM) before, concomitantly with or, importantly, after the addition of MPP+ abolished MPP+-induced DNA fragmentation. Addition of MPP+ (500 μM) to cells increased caspase-3 activity over 72 h (p < 0.05), and this was abolished by pre- or co-treatment with guanosine. Exposure of cells to pertussis toxin prior to MPP+ eliminated the anti-apoptotic effect of guanosine, indicating that this effect is dependent on a Gi protein-coupled receptor, most likely the putative guanosine receptor. The protection by guanosine was also abolished by the selective inhibitor of the enzyme PI-3-K/Akt/PKB (LY294002), confirming that this pathway plays a decisive role in this effect of guanosine. Neither MPP+ nor guanosine had any significant effect on α-synuclein expression. Thus, guanosine antagonizes and reverses MPP+-induced cytotoxicity of neuroblastoma cells via activation of the cell survival pathway, PI-3-K/Akt/PKB. Our results suggest that guanosine may be an effective pharmacological intervention in PD

Guanosine effect on cholesterol efflux and apolipoprotein E expression in astrocytes

The main source of cholesterol in the central nervous system (CNS) is represented by glial cells, mainly astrocytes, which also synthesise and secrete apolipoproteins, in particular apolipoprotein E (ApoE), the major apolipoprotein in the brain, thus generating cholesterol-rich high density lipoproteins (HDLs). This cholesterol trafficking, even though still poorly known, is considered to play a key role in different aspects of neuronal plasticity and in the stabilisation of synaptic transmission. Moreover, cell cholesterol depletion has recently been linked to a reduction in amyloid beta formation. Here we demonstrate that guanosine, which we previously reported to exert several neuroprotective effects, was able to increase cholesterol efflux from astrocytes and C6 rat glioma cells in the absence of exogenously added acceptors. In this effect the phosphoinositide 3 kinase/extracellular signal-regulated kinase 1/2 (PI3K/ERK1/2) pathway seems to play a pivotal role. Guanosine was also able to increase the expression of ApoE in astrocytes, whereas it did not modify the levels of ATP-binding cassette protein A1 (ABCA1), considered the main cholesterol transporter in the CNS. Given the emerging role of cholesterol balance in neuronal repair, these effects provide evidence for a role of guanosine as a potential pharmacological tool in the modulation of cholesterol homeostasis in the brain