• A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin

      McNeilly, A.D.; Williamson, Ritchie; Balfour, D.J.; Stewart, C.A.; Sutherland, C. (2012)
      AIMS/HYPOTHESIS: We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feeding-evoked cognitive deficit by improving insulin sensitivity. METHODS: Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins. RESULTS: HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex. CONCLUSIONS/INTERPRETATION: Metformin prevented the metabolic but not cognitive alterations associated with HF feeding. The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet.
    • A mechanophysical phase transition provides a dramatic example of colour polymorphism: the tribochromism of a substituted tri(methylene)tetrahydrofuran-2-one

      Asiri, A.M.; Heller, H.G.; Hughes, D.S.; Hursthouse, M.B.; Kendrick, John; Leusen, Frank J.J.; Montis, R. (2014)
      Derivatives of fulgides have been shown to have interesting photochromic properties. We have synthesised a number of such derivatives and have found, in some cases, that crystals can be made to change colour on crushing, a phenomenon we have termed "tribochromism". We have studied a number of derivatives by X-ray crystallography, to see if the colour is linked to molecular structure or crystal packing, or both, and our structural results have been supported by calculation of molecular and lattice energies. A number of 5-dicyanomethylene-4-diphenylmethylene-3-disubstitutedmethylene-tetrahydrofuran-2 -one compounds have been prepared and structurally characterised. The compounds are obtained as yellow or dark red crystals, or, in one case, both. In two cases where yellow crystals were obtained, we found that crushing the crystals gave a deep red powder. Structure determinations, including those of the one compound which gave both coloured forms, depending on crystallisation conditions, showed that the yellow crystals contained molecules in which the structure comprised a folded conformation at the diphenylmethylene site, whilst the red crystals contained molecules in a twisted conformation at this site. Lattice energy and molecular conformation energies were calculated for all molecules, and showed that the conformational energy of the molecule in structure IIIa (yellow) is marginally higher, and the conformation thus less stable, than that of the molecule in structure IIIb (red). However, the van der Waals energy for crystal structure IIIa, is slightly stronger than that of structure IIIb - which may be viewed as a hint of a metastable packing preference for IIIa, overcome by the contribution of a more stabilising Coulomb energy to the overall more favourable lattice energy of structure IIIb. Our studies have shown that the crystal colour is correlated with one of two molecular conformations which are different in energy, but that the less stable conformation can be stabilised by its host crystal lattice. Graphical abstractGraphical representation of the structural and colour change in the tribochromic compound (III).
    • A neural hierarchy for illusions of time: duration adaptation precedes multisensory integration

      Heron, James; Hotchkiss, John; Aaen-Stockdale, Craig; Roach, N.W.; Whitaker, David J. (2013)
      Perceived time is inherently malleable. For example, adaptation to relatively long or short sensory events leads to a repulsive aftereffect such that subsequent events appear to be contracted or expanded (duration adaptation). Perceived visual duration can also be distorted via concurrent presentation of discrepant auditory durations (multisensory integration). The neural loci of both distortions remain unknown. In the current study we use a psychophysical approach to establish their relative positioning within the sensory processing hierarchy. We show that audiovisual integration induces marked distortions of perceived visual duration. We proceed to use these distorted durations as visual adapting stimuli yet find subsequent visual duration aftereffects to be consistent with physical rather than perceived visual duration. Conversely, the concurrent presentation of adapted auditory durations with nonadapted visual durations results in multisensory integration patterns consistent with perceived, rather than physical, auditory duration. These results demonstrate that recent sensory history modifies human duration perception prior to the combination of temporal information across sensory modalities and provides support for adaptation mechanisms mediated by duration selective neurons situated in early areas of the visual and auditory nervous system (Aubie, Sayegh, & Faure, 2012; Duysens, Schaafsma, & Orban, 1996; Leary, Edwards, & Rose, 2008).
    • A novel Lozenge gene in silkworm, Bombyx mori regulates the melanization response of hemolymph

      Xu, M.; Wang, X.; Tan, J.; Zhang, K.; Guan, X.; Patterson, Laurence H.; Ding, H.; Cui, H. (2015-11)
      Runt-related (RUNX) transcription factors are evolutionarily conserved either in vertebrate or invertebrate. Lozenge (Lz), a members of RUNX family as well as homologue of AML-1, functions as an important transcription factor regulating the hemocytes differentiation. In this paper, we identified and characterized RUNX family especially Lz in silkworm, which is a lepidopteran model insect. The gene expression analysis illustrated that BmLz was highly expressed in hemocytes throughout the whole development period, and reached a peak in glutonous stage. Over-expression of BmLz in silkworm accelerated the melanization process of hemolymph, and led to instantaneously up-regulation of prophenoloxidases (PPOs), which were key enzymes in the melanization process. Further down-regulation of BmLz expression by RNA interference resulted in the significant delay of melanization reaction of hemolymph. These findings suggested that BmLz regulated the melanization process of hemolymph by inducing PPOs expression, and played a critical role in innate immunity defense in silkworm.
    • A quality by design approach using artificial intelligence techniques to control the critical quality attributes of ramipril tablets manufactured by wet granulation

      Aksu, B.; Paradkar, Anant R.; de Matas, Marcel; Özer, Ö.; Güneri, T.; York, Peter (2013)
      Quality by design (QbD) is an essential part of the modern approach to pharmaceutical quality. This study was conducted in the framework of a QbD project involving ramipril tablets. Preliminary work included identification of the critical quality attributes (CQAs) and critical process parameters (CPPs) based on the quality target product profiles (QTPPs) using the historical data and risk assessment method failure mode and effect analysis (FMEA). Compendial and in-house specifications were selected as QTPPs for ramipril tablets. CPPs that affected the product and process were used to establish an experimental design. The results thus obtained can be used to facilitate definition of the design space using tools such as design of experiments (DoE), the response surface method (RSM) and artificial neural networks (ANNs). The project was aimed at discovering hidden knowledge associated with the manufacture of ramipril tablets using a range of artificial intelligence-based software, with the intention of establishing a multi-dimensional design space that ensures consistent product quality. At the end of the study, a design space was developed based on the study data and specifications, and a new formulation was optimized. On the basis of this formulation, a new laboratory batch formulation was prepared and tested. It was confirmed that the explored formulation was within the design space.
    • A safe, convenient and efficient method for the preparation of heterocyclic N-oxides using urea-hydrogen peroxide

      Rong, Dawen; Phillips, Victoria A.; Rubio, R.S.; Angeles Castro, M.; Wheelhouse, Richard T. (2008)
      A novel, convenient, and high-yielding method has been developed for the preparation of heterocyclic N-oxides. The reaction uses the urea·hydrogen peroxide addition complex as a peroxide source for the in situ generation of trifluoroperacetic acid. The advantages of this method are easy handling of a stable, solid oxidant; high yields and simple removal of excess reagents and by-products.
    • The abandonment of souterrains: evolution, catastrophe or dislocation?

      Armit, Ian (1999)
      This paper considers the evidence for the abandonment of souterrains in that part of east central Scotland characterized by Wainwright as 'southern Pictland'. The evidence suggests that most souterrains here were deliberately destroyed, or at least infilled, and that none seems to have outlasted the early third century AD. The process of destruction seems to have been associated with a significant degree of ritual activity not previously noted. It is postulated that the evidence would allow for a single episode of abandonment (a 'souterrain abandonment horizon'), in the late second or early third century AD, which might be related to a major reorientation of social and political structures, perhaps associated with changes in Roman frontier policy.
    • Aberrant Phenotype in Human Endothelial Cells of Diabetic Origin: Implications for Saphenous Vein Graft Failure?

      Roberts, A.C.; Gohil, J.; Hudson, L.; Connolly, K.; Warburton, P.; Suman, R.; O'Toole, P.; O'Regan, D.J.; Turner, N.A.; Riches-Suman, Kirsten; et al. (2015)
      Type 2 diabetes (T2DM) confers increased risk of endothelial dysfunction, coronary heart disease, and vulnerability to vein graft failure after bypass grafting, despite glycaemic control. This study explored the concept that endothelial cells (EC) cultured from T2DM and nondiabetic (ND) patients are phenotypically and functionally distinct. Cultured human saphenous vein- (SV-) EC were compared between T2DM and ND patients in parallel. Proliferation, migration, and in vitro angiogenesis assays were performed; western blotting was used to quantify phosphorylation of Akt, ERK, and eNOS. The ability of diabetic stimuli (hyperglycaemia, TNF-α, and palmitate) to modulate angiogenic potential of ND-EC was also explored. T2DM-EC displayed reduced migration (~30%) and angiogenesis (~40%) compared with ND-EC and a modest, nonsignificant trend to reduced proliferation. Significant inhibition of Akt and eNOS, but not ERK phosphorylation, was observed in T2DM cells. Hyperglycaemia did not modify ND-EC function, but TNF-α and palmitate significantly reduced angiogenic capacity (by 27% and 43%, resp.), effects mimicked by Akt inhibition. Aberrancies of EC function may help to explain the increased risk of SV graft failure in T2DM patients. This study highlights the importance of other potentially contributing factors in addition to hyperglycaemia that may inflict injury and long-term dysfunction to the homeostatic capacity of the endothelium.
    • Absence of premature senescence in Werner's syndrome keratinocytes

      Ibrahim, B.; Sheerin, A.N.; Jennert-Burston, K.; Bird, Joseph; Massala, M.V.; James, S.E.; Faragher, R.G.A. (2016-10)
      Werner's syndrome (WS) is an autosomal recessive genetic disorder caused by loss of function mutation in wrn and is a useful model of premature in vivo ageing. Cellular senescence is a plausible causal mechanism of mammalian ageing and, at the cellular level, WS fibroblasts show premature senescence resulting from a combination of telomeric attrition and replication fork stalling. Over 90% of WS fibroblast cultures achieve < 20 population doublings (PD) in vitro compared to wild type human fibroblast cultures. It has been proposed that some cell types, capable of proliferation, will fail to show a premature senescence phenotype in response to wrn mutations. To test this hypothesis, human dermal keratinocytes (derived from both WS and wild type patients) were cultured long term. WS Keratinocytes showed a replicative lifespan in excess of 100 population doublings but maintained functional growth arrest mechanisms based on p16 and p53. The karyotype of the cells was superficially normal and the cultures retained markers characteristic of keratinocyte holoclones (stem cells) including p63 expression and telomerase activity. Accordingly we conclude that, in contrast to WS fibroblasts, WS keratinocytes do not demonstrate slow growth rates or features of premature senescence. These findings suggest that the epidermis is among the tissue types that do not display symptoms of premature ageing caused by loss of function of wrn. This is in support that Werner's syndrome is a segmental progeroid syndrome.
    • Absolute Energy Level Positions in CdSe Nanostructures from Potential-Modulated Absorption Spectroscopy (EMAS)

      Spittel, D.; Poppe, J.; Meerbach, C.; Ziegler, C.; Hickey, Stephen G.; Eychmüller, A. (2018)
      Semiconductor nanostructures like CdSe quantum dots and colloidal nanoplatelets exhibit remarkable optical properties, making them interesting for applications in optoelectronics and photocatalysis. For both areas of application a detailed understanding of the electronic structure is essential to achieve highly efficient devices. The electronic structure can be probed using the fact that optical properties of semiconductor nanoparticles are found to be extremely sensitive to the presence of excess charges that can for instance be generated by means of an electrochemical charge transfer via an electrode. Here we present the use of potential modulated absorption spectroscopy (EMAS) as a versatile spectroelectrochemical method to obtain absolute band edge positions of CdSe nanostructures versus a well-defined reference electrode under ambient conditions. In this the spectral properties of the nanoparticles are monitored dependent on an applied electrochemical potential. We developed a bleaching model that yields the lowest electronic state in the conduction band of the nanostructures. A change in the band edge positions caused by quantum confinement is shown both for CdSe quantum dots as well as for colloidal nanoplatelets. In the case of CdSe quantum dots these findings are in good agreement with tight binding calculations. The method presented is not limited to CdSe nanostructures but can be used as a universal tool. Hence, this technique allows the determination of absolute band edge positions of a large variety of materials used in various applications.
    • Accountability in action: how can archaeology make amends?

      Fitzpatrick, Alexandra L. (2021)
      This special issue gathers together a selection of short articles reflecting on the historical construction of inequality and race in the histories of archaeology. The articles also suggest ways in which the discipline might grapple with the—often obvious, sometimes subtle—consequences of that historical process. Solicited via an open call for papers in the summer of 2020 (one made with the aim of speedy publication), the breadth of the topics discussed in the articles reflect how inequality and race have become more prominent research themes within the histories of archaeology in the previous five-to-ten years. At the same time, the pieces show how research can—and should—be connected to attempts to promote social justice and an end to racial discrimination within archaeological practice, the archaeological profession, and the wider worlds with which the discipline interacts. Published at a time when a pandemic has not only swept the world, but also exposed such inequalities further, the special issue represents a positive intervention in what continues to be a contentious issue.
    • Accumulation of quinolinic acid with euro-inflammation: does it mean excitotoxicity?

      Urenjak, Jutta A.; Obrenovitch, Tihomir P. (Kluwer Academic, Plenum Publishers, New York, 2003)
    • Act now to close chemical-weapons loophole

      Shang, Lijun; Crowley, Michael J.A.; Dando, Malcolm R. (2018-10-18)
      As the Fourth Review Conference of the Chemical Weapons Convention meets next month, state parties need to address mounting concerns about the potential development and use of law-enforcement weapons involving chemical agents that act on the central nervous system (CNS).
    • Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation

      Mancini, S.J.; White, A.D.; Bijland, S.; Rutherford, C.; Graham, D.; Richter, E.A.; Viollet, B.; Touyz, R.M.; Palmer, Timothy M.; Salt, I.P. (2017-01-15)
      Inflammation of adipose tissue in obesity is associated with increased IL-1β, IL-6 and TNF-α secretion and proposed to contribute to insulin resistance. AMP-activated protein kinase (AMPK) regulates nutrient metabolism and is reported to have anti-inflammatory actions in adipose tissue, yet the mechanisms underlying this remain poorly characterised. The effect of AMPK activation on cytokine-stimulated proinflammatory signalling was therefore assessed in cultured adipocytes. AMPK activation inhibited IL-1β-stimulated CXCL10 secretion, associated with reduced interleukin-1 receptor associated kinase-4 (IRAK4) phosphorylation and downregulated MKK4/JNK and IKK/IκB/NFκB signalling. AMPK activation inhibited TNF-α-stimulated IKK/IκB/NFκB signalling but had no effect on JNK phosphorylation. The JAK/STAT3 pathway was also suppressed by AMPK after IL-6 stimulation and during adipogenesis. Adipose tissue from AMPKα1−/− mice exhibited increased JNK and STAT3 phosphorylation, supporting suppression of these distinct proinflammatory pathways by AMPK in vivo. The inhibition of multiple pro-inflammatory signalling pathways by AMPK may underlie the reported beneficial effects of AMPK activation in adipose tissue.
    • Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia

      McLean, Samantha L.; Grayson, Ben; Idris, Nagi F.; Lesage, A.S.; Pemberton, D.J.; Mackie, C.; Neill, Joanna C. (2011-04)
      Rationale: Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Aim: To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987. Methods: Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7-days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20 mg/kg; s.c.) or vehicle and were tested in the reversal learning task. In cohort 2, PCP-treated rats received PNU-282987 (10 mg/kg; s.c.) or saline for 15 days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. Results: Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01-0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10 mg/kg (P<0.01) and 20 mg/kg (P<0.001), and in novel object recognition at 10 mg/kg on day 1 (P<0.01) and on day 15 (P<0.001). Conclusions: These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15 day daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.
    • The Activities of Daily Vision Scale for cataract surgery outcomes: re-evaluating validity with Rasch analysis.

      Pesudovs, Konrad; Garamendi, Estibaliz; Keeves, J.P.; Elliott, David B. (2003)
      PURPOSE. The Activities of Daily Vision Scale (ADVS) has been extensively validated by traditional methodology. In the current study, Rasch analysis was used to explore further the validity of the ADVS and to determine whether improvements could be made. METHODS. Forty-three patients with cataract underwent visual acuity (VA) and contrast sensitivity (CS) testing and completed the ADVS. The data were Rasch analyzed and the value of response scale and item reduction explored. A shortened version and the original ADVS were tested for criterion validity by determining correlations with VA and CS. RESULTS. The ADVS data contained nonnormally distributed items and items with ceiling effects and empty response categories. Therefore, items benefited from shortening the response scale, the optimum length being three responses. There was poor targeting of item difficulty to patient ability, because many patients with cataract were sufficiently able that they had no difficulty with many activities. Items were eliminated if the task was too easy or did not fit with the overall concept of visual disability determined by the Rasch model. A reduced ADVS version was established that had adequate precision, equivalent criterion validity, and improved targeting of item difficulty to patient ability, but this version was still not ideal. CONCLUSIONS. Despite careful traditional validation, the ADVS data contained inadequacies exposed by Rasch analysis. Through Rasch scaling, particularly with response scale reduction, the ADVS can be improved, but additional questions seem to be needed to suit the more able, including patients undergoing second eye cataract surgery. There remains a need to develop Rasch-scaled measures of visual disability for use in ophthalmic outcomes research.
    • Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2

      DaSilva, L.L.; Wall, M.J.; de Almeida, Luciana P.; Wauters, S.C.; Januario, Y.C.; Muller, Jurgen; Corrêa, Sonia A.L. (2016-05-04)
      The activity-regulated cytoskeleton-associated (Arc) protein control synaptic strength by facilitating AMPA receptor (AMPAR) endocytosis. Here we demonstrate that Arc targets AMPAR to be internalized through a direct interaction with the clathrin-adaptor protein 2 (AP-2). We show that Arc overexpression overexpression in dissociated hippocampal neurons obtained from C57BL/6 mouse reduces the density of AMPAR GluA1 subunits at the cell surface and reduces the amplitude and rectification of AMPAR-mediated miniature-excitatory postsynaptic currents (mEPSC). Mutations of Arc, that prevent the AP-2 interaction reduce Arc-mediated endocytosis of GluA1 and abolish the reduction in AMPAR-mediated mEPSC amplitude and rectification. Depletion of the AP-2 subunit µ2 blocks the Arc-mediated reduction in mEPSC amplitude, effect that is restored by re-introducing µ2. The Arc/AP-2 interaction plays an important role in homeostatic synaptic scaling as the Arc-dependent decrease in mEPSC amplitude, induced by a chronic increase in neuronal activity, is inhibited by AP-2 depletion. This data provides a mechanism to explain how activity-dependent expression of Arc decisively controls the fate of AMPAR at the cell surface and modulates synaptic strength, via the direct interaction with the endocytic clathrin adaptor AP-2.
    • Activity-Related Skeletal Change in Medieval Humeri: Cross-Sectional and Architectural Alterations.

      Knüsel, Christopher J.; Rhodes, Jill Anne (2005)
      This paper examines humeral cross-sectional properties in two different samples of later medieval date: a group of blade-injured males from the sites of Towton, North Yorkshire, and Fishergate in the City of York, England, and a comparative group of nonblade-injured males also from the site of Fishergate in York. CT image slices were taken of the humeral shaft at 20%, 35%, 50%, 65%, and 80% from the distal end to investigate population differences in levels and patterns of mechanical loading. Bilateral asymmetry is investigated and comparisons are made with different populations of varying activity levels. Architectural changes such as humeral torsion are also investigated to determine the relationship between architectural changes and biomechanical efficiency. Results show significant differences in diaphyseal robusticity between the Towton sample and the comparative population, as well as significant differences in diaphyseal shape both between limbs within the Towton sample and between blade-injured samples. Population differences were also identified in the level of bilateral asymmetry, further demonstrating the differences in movement and activity patterns both between and within samples. These variations may relate to distinctive, more strenuous weapon use and differences in strenuous movement patterns in the two groups.
    • Adaptation minimizes distance-related audiovisual delays

      Heron, James; Whitaker, David J.; McGraw, Paul V.; Horoshenkov, Kirill V. (2007)
      A controversial hypothesis within the domain of sensory research is that observers are able to use visual and auditory distance cues to maintain perceptual synchrony - despite the differential velocities of light and sound. Here we show that observers are categorically unable to utilize such distance cues. Nevertheless, given a period of adaptation to the naturally occurring audiovisual asynchrony associated with each viewing distance, a temporal recalibration mechanism helps to perceptually compensate for the effects of distance-induced auditory delays. These effects demonstrate a novel functionality of temporal recalibration with clear ecological benefits.