Neuroprotective effects of phenolic antioxidant tBHQ associate with inhibition of FoxO3a nuclear translocation and activity

The Forkhead transcription factor, FoxO3a induces genomic death responses in neurones following translocation from the cytosol to the nucleus. Nuclear translocation of FoxO3a is triggered by trophic factor withdrawal, oxidative stress and the stimulation of extrasynaptic NMDA receptors. Receptor activation of phosphatidylinositol 3-kinase (PI3K) – Akt signalling pathways retains FoxO3a in the cytoplasm thereby inhibiting the transcriptional activation of death promoting genes. We hypothesised that phenolic antioxidants such as tert-Butylhydroquinone (tBHQ), which is known to stimulate PI3K-Akt signalling, would inhibit FoxO3a translocation and activity. Treatment of cultured cortical neurones with NMDA increased the nuclear localisation of FoxO3a, reduced the phosphorylation of FoxO3a, increased caspase activity and upregulated Fas ligand expression. In contrast the phenolic antioxidant tBHQ caused retention of FoxO3a in the cytosol coincident with enhanced PI3K- dependent phosphorylation of FoxO3a. tBHQ-induced nuclear exclusion of FoxO3a was associated with reduced FoxO-mediated transcriptional activity. Exposure of neurones to tBHQ inhibited NMDA-induced nuclear translocation of FoxO3a prevented NMDA-induced upregulation of FoxO-mediated transcriptional activity, blocked caspase activation and protected neurones from NMDA-induced excitotoxic death. Collectively, these data suggest that phenolic antioxidants such as tBHQ oppose stress-induced activation of FoxO3a and therefore have potential neuroprotective utility in neurodegeneration.

Probability of survival in a random exchange economy with dependent agents

In this paper I analyze the general equilibrium in a random Walrasian economy. Dependence among agents is introduced in the form of dependency neighborhoods. Under the uncertainty, an agent may fail to survive due to a meager endowment in a particular state (direct effect), as well as due to unfavorable equilibrium price system at which the value of the endowment falls short of the minimum needed for survival (indirect terms-of-trade effect). To illustrate the main result I compute the stochastic limit of equilibrium price and probability of survival of an agent in a large Cobb-Douglas economy.

Two macrocyclic pentaaza compounds containing pyridine evaluated as novel chelating agents in copper(II) and nickel(II) overload

Two pentaaza macrocycles containing pyridine in the backbone, namely 3,6,9,12,18-pentaazabicyclo[12.3.1] octadeca-1(18),14,16-triene ([15]pyN(5)), and 3,6,10,13,19-pentaazabicyclo[13.3.1]nonadeca-1(19),15,17-triene ([16]pyN(5)), were synthesized in good yields. The acid-base behaviour of these compounds was studied by potentiometry at 298.2 K in aqueous solution and ionic strength 0.10 M in KNO3. The protonation sequence of [15]pyN(5) was investigated by H-1 NMR titration that also allowed the determination of protonation constants in D2O. Binding studies of the two ligands with Ca2+, Ni2+, Cu2+, Zn2+, Cd2+, and Pb2+ metal ions were performed under the same experimental conditions. The results showed that all the complexes formed with the 15-membered ligand, particularly those of Cu2+ and especially Ni2+, are thermodynamically more stable than with the larger macrocycle. Cyclic voltammetric data showed that the copper(II) complexes of the two macrocycles exhibited analogous behaviour, with a single quasi-reversible one-electron transfer reduction process assigned to the Cu(II)/Cu(I) couple. The UV-visible-near IR spectroscopic and magnetic moment data of the nickel(II) complexes in solution indicated a tetragonal distorted coordination geometry for the metal centre. X-band EPR spectra of the copper(II) complexes are consistent with distorted square pyramidal geometries. The crystal structure of [Cu([15]pyN(5))](2+) determined by X-ray diffraction showed the copper(II) centre coordinated to all five macrocyclic nitrogen donors in a distorted square pyramidal environment.

Understanding the effects of anesthetic agents on the EEG through neural field theory

Anesthetic and analgesic agents act through a diverse range of pharmacological mechanisms. Existing empirical data clearly shows that such "microscopic" pharmacological diversity is reflected in their "macroscopic" effects on the human electroencephalogram (EEG). Based on a detailed mesoscopic neural field model we theoretically posit that anesthetic induced EEG activity is due to selective parametric changes in synaptic efficacy and dynamics. Specifically, on the basis of physiologically constrained modeling, it is speculated that the selective modification of inhibitory or excitatory synaptic activity may differentially effect the EEG spectrum. Such results emphasize the importance of neural field theories of brain electrical activity for elucidating the principles whereby pharmacological agents effect the EEG. Such insights will contribute to improved methods for monitoring depth of anesthesia using the EEG.

Understanding the transition to seizure by modeling the epileptiform activity of general anesthetic agents

A central difficulty in modeling epileptogenesis using biologically plausible computational and mathematical models is not the production of activity characteristic of a seizure, but rather producing it in response to specific and quantifiable physiologic change or pathologic abnormality. This is particularly problematic when it is considered that the pathophysiological genesis of most epilepsies is largely unknown. However, several volatile general anesthetic agents, whose principle targets of action are quantifiably well characterized, are also known to be proconvulsant. The authors describe recent approaches to theoretically describing the electroencephalographic effects of volatile general anesthetic agents that may be able to provide important insights into the physiologic mechanisms that underpin seizure initiation.

Highly contrasting effects of different climate forcing agents on terrestrial ecosystem services

Many atmospheric constituents besides carbon dioxide (CO2) contribute to global warming, and it is common to compare their influence on climate in terms of radiative forcing, which measures their impact on the planetary energy budget. A number of recent studies have shown that many radiatively active constituents also have important impacts on the physiological functioning of ecosystems, and thus the ‘ecosystem services’ that humankind relies upon. CO2 increases have most probably increased river runoff and had generally positive impacts on plant growth where nutrients are non-limiting, whereas increases in near-surface ozone (O3) are very detrimental to plant productivity. Atmospheric aerosols increase the fraction of surface diffuse light, which is beneficial for plant growth. To illustrate these differences, we present the impact on net primary productivity and runoff of higher CO2, higher near-surface O3, and lower sulphate aerosols, and for equivalent changes in radiative forcing.We compare this with the impact of climate change alone, arising, for example, from a physiologically inactive gas such as methane (CH4). For equivalent levels of change in radiative forcing, we show that the combined climate and physiological impacts of these individual agents vary markedly and in some cases actually differ in sign. This study highlights the need to develop more informative metrics of the impact of changing atmospheric constituents that go beyond simple radiative forcing.

Controlling market power of vertically integrated firms in electricity networks: demand response of aggregator agents

This article reports the results of an experiment that examined how demand aggregators can discipline vertically-integrated firms - generator and distributor-retailer holdings-, which have a high share in wholesale electricity market with uniform price double auction (UPDA). We initially develop a treatment where holding members redistribute the profit based on the imposition of supra-competitive prices, in equal proportions (50%-50%). Subsequently, we introduce a vertical disintegration (unbundling) treatment with holding-s information sharing, where profits are distributed according to market outcomes. Finally, a third treatment is performed to introduce two active demand aggregators, with flexible interruptible loads in real time. We found that the introduction of responsive demand aggregators neutralizes the power market and increases market efficiency, even beyond what is achieved through vertical disintegration.

Power and control: managing agents for international student recruitment in higher education

This multiple case-based study investigates the relationship between recruiting agents and the UK universities who act as their principals. The current extensive use of agents in UK higher education may be seen as an indicator of the financial impact made by international students. The study analyses the practice of agent management and explores the manner in which power and control interact. The study employed semi-structured interviews and group discussions involving up to 6 respondents from each of the 20 UK case institutions. The qualitative data reveal a considerable variation in the manner in which the universities manage their agency relationships. Through the joint consideration of control measures and use of power, five distinctive approaches have been identified. The study also reveals that over-dependence on agents reduces the power of the principal, and consequently, the principal’s ability to exercise control, particularly in highly competitive global and national markets.

Structural complexity in indium selenides prepared using bicyclic amines as structure-directing agents

The synthesis and characterization of five new indium selenides, [C9H17N2]3[In5Se8+x(Se2)1−x] (1–2), [C6H12N2]4[C6H14N2]3[In10Se15(Se2)3] (3), [C6H14N2][(C6H12N2)2NaIn5Se9] (4) and [enH2][NH4][In7Se12] (5), are described. These materials were prepared under solvothermal conditions, using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO) as structure-directing agents. Compounds 1–4 represent the first examples of ribbons in indium selenides, and 4 is the first example of incorporation of an alkali metal complex. Compounds 1, 2 and 4 contain closely related [In5Se8+x(Se2)1−x]3− ribbons which differ only in their content of (Se2)2− anions. These ribbons are interspaced by organic countercations in 1 and 2, while in 4 they are linked by highly unusual [Na(DABCO)2]+ units into a three-dimensional framework. Compound 3 contains complex ribbons, with a long repeating sequence of ca. 36 Å, and 4 is a non-centrosymmetric three-dimensional framework, formed as a consequence of the decomposition of DABCO into ethylenediamine (en) and ammonia.

Segmenting the Italian coffee market: marketing opportunities for economic agents working along the international coffee chain

Globalization, either directly or indirectly (e.g. through structural adjustment reforms), has called for profound changes in the previously existing institutional order. Some changes adversely impacted the production and market environment of many coffee producers in developing countries resulting in more risky and less remunerative coffee transactions. This paper focuses on customization of a tropical commodity, fair-trade coffee, as an approach to mitigating the effects of worsened market conditions for small-scale coffee producers in less developed countries. fair-trade labeling is viewed as a form of “de-commodification” of coffee through product differentiation on ethical grounds. This is significant not only as a solution to the market failure caused by pervasive information asymmetries along the supply chain, but also as a means of revitalizing the agricultural-commodity-based trade of less developed countries (LDCs) that has been languishing under globalization. More specifically, fair-trade is an example of how the same strategy adopted by developed countries’ producers/ processors (i.e. the sequence product differentiation - institutional certification - advertisement) can be used by LDC producers to increase the reputation content of their outputs by transforming them from mere commodities into “decommodified” (i.e. customized and more reputed) goods. The resulting segmentation of the world coffee market makes possible to meet the demand by consumers with preference for this “(ethically) customized” coffee and to transfer a share of the accruing economic rents backward to the Fair-trade coffee producers in LDCs. It should however be stressed that this outcome cannot be taken for granted since investments are needed to promote the required institutional innovations. In Italy FTC is a niche market with very few private brands selling this product. However, an increase of FTC market share could be a big commercial opportunity for farmers in LDCs and other economic agents involved along the international coffee chain. Hence, this research explores consumers’ knowledge of labels promoting quality products, consumption coffee habits, brand loyalty, willingness to pay and market segmentation according to the heterogeneity of preferences for coffee products. The latter was assessed developing a D-efficient design where stimuli refinement was tested during two focus groups.

Exploring quercetin and luteolin derivatives as antiangiogenic agents

The formation of new blood vessels from the pre-existing vasculature (angiogenesis) is a crucial stage in cancer progression and, indeed, angiogenesis inhibitors are now used as anticancer agents, clinically. Here we have explored the potential of flavonoid derivatives as antiangiogenic agents. Specifically, we have synthesised methoxy and 4-thio derivatives of the natural flavones quercetin and luteolin, two of which (4-thio quercetin and 4-thio luteolin) had never been previously reported. Seven of these compounds showed significant (P<0.05) antiangiogenic activity in an in vitro scratch assay. Their activity ranged from an 86% inhibition of the vascular endothelium growth factor (VEGF)-stimulated migration (observed for methoxyquercetin at 10 µM and for luteolin at 1 µM) to a 36% inhibition (for thiomethoxy quercetin at 10 µM). Western blotting studies showed that most (4 out of 7) compounds inhibited phosphorylation of the VEGF receptor-2 (VEGFR2), suggesting that the antiangiogenic activity was due to an interference with the VEGF/VEGFR2 pathway. Molecular modelling studies looking at the affinity of our compounds towards VEGFR and/or VEGF confirmed this hypothesis, and indeed the compound with the highest antiangiogenic activity (methoxyquercetin) showed the highest affinity towards VEGFR and VEGF. As reports from others have suggested that structurally similar compounds can elicit biological responses via a non-specific, promiscuous membrane perturbation, potential interactions of the active compounds with a model lipid bilayer were assessed via DSC. Luteolin and its derivatives did not perturb the model membrane even at concentrations 10 times higher than the biologically active concentration and only subtle interactions were observed for quercetin and its derivatives. Finally, cytotoxicity assessment of these flavonoid derivatives against MCF-7 breast cancer cells demonstrated also a direct anticancer activity albeit at generally higher concentrations than those required for an antiangiogenic effect (10 fold higher for the methoxy analogues). Taken together these results show promise for flavonoid derivatives as antiangiogenic agents.

Synthesis of mucoadhesive thiol-bearing microgels from 2-(acetylthio)ethylacrylate and 2-hydroxyethylmethacrylate: novel drug delivery systems for chemotherapeutic agents to the bladder

Thiol-bearing microgels have been synthesised from copolymerisation of 2-(acetylthio)ethylacrylate and 2-hydroxyethylmethacrylate, and subsequent deprotection using sodium thiomethoxide. The concentration of thiol groups on these microgels could be tailored by use of different molar ratios of the two monomers. These thiol-bearing microgels were shown to adhere to ex vivo porcine urinary bladder, which was correlated with their level of thiolation. By simply mixing solutions of thiol-bearing microgels and doxorubicin, high levels of drug loading into the microgels could be achieved. Thiol-bearing microgels controlled the release of doxorubicin in a time-dependent manner over several hours. These doxorubicin-loaded thiol-bearing microgels could have application in the treatment of early-stage bladder cancers. The method used represents a new ‘bottom-up’ approach for the synthesis of novel mucoadhesive microgels.

'Nature concocts & expels': the agents and processes of recovery from disease in Early Modern England

The ‘golden saying’ in early modern medicine was ‘Nature is the healer of disease’. This article uncovers the meaning and significance of this forgotten axiom by investigating perceptions of the agents and physiological processes of recovery from illness in England, c.1580-1720. Drawing on sources such as medical texts and diaries, it shows that doctors and laypeople attributed recovery to three agents – God, Nature, and the practitioner. While scholars are familiar with the roles of providence and medicine, the vital agency of Nature has been overlooked. In theory, the agents operated in a hierarchy: Nature was ‘God’s instrument’, and the physician, ‘Nature’s servant’; but in practice the power balance was more ambivalent. Nature was depicted both as a housewife who cooked and cleaned the humours, and as a warrior, who defeated the disease. Through exploring these complex dynamics, the article sheds fresh light on concepts of gender, disease, and bodies.