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  • Organometallic iridium arene compounds: the effects of C-donor ligands on anticancer activity

    Lord, Rianne M.; McGowan, P.C. (2019)
    In the past decade, libraries of iridium organometallic arene compounds have expanded rapidly, with the majority of their applications aimed towards effective catalysts and potential anti-cancer drug candidates. Researchers have begun to adapt the traditional “piano-stool” structures to include different bidentate ligands, ancillary ligands and extend the aromaticity and functionality of the arene substituent, all in the hope to optimize their activities and allow the determination of structure activity relationships. Many of the complexes incorporate N- and O-donor ligands, but more recently, these structures have been expanded to include C-donor ligands such as cyclometalated bidentate ligands and N-heterocyclic carbenes. This mini-review highlights the recent and ongoing research in C-donor iridium arene complexes, and discusses their importance as potential anticancer drugs.
  • Inactivation of apaziquone by haematuria: implications for the design of phase III clinical trials against non-muscle invasive bladder cancer

    Phillips, Roger M.; Loadman, Paul M.; Reddy, G. (2019-06)
    Purpose: Despite positive responses in phase II clinical trials, the bioreductive prodrug apaziquone failed to achieve statistically significant activity in non-muscle invasive bladder cancer in phase III trials. Apaziquone was administered shortly after transurethral resection and here we test the hypothesis that haematuria inactivates apaziquone. Methods: HPLC analysis was used to determine the ability of human whole blood to metabolise apaziquone ex vivo. An in vitro model of haematuria was developed and the response of RT112 and EJ138 cells following a 1-h exposure to apaziquone was determined in the presence of urine plus or minus whole blood or lysed whole blood. Results: HPLC analysis demonstrated that apaziquone is metabolised by human whole blood with a half-life of 78.6±23.0 min. As a model for haematuria, incubation of cells in media containing up to 75% buffered (pH 7.4) urine and 25% whole blood was not toxic to cells for a 1-h exposure period. Whole blood (5% v/v) significantly (p<0.01) reduced the potency of apaziquone in this experimental model. Lysed whole blood also significantly (p<0.05) reduced cell growth, although higher concentrations were required to achieve an effect (15% v/v). Conclusions: The results of this study demonstrate that haematuria can reduce the potency of apaziquone in this experimental model. These findings impact upon the design of further phase III clinical trials and strongly suggest that apaziquone should not be administered immediately after transurethral resection of non-muscle invasive bladder cancer when haematuria is common.
  • Excavations at Old Scatness, Shetland. Volume 3: The Post-medieval township

    Dockrill, Stephen J.; Bond, Julie M.; Turner, V.E.; Brown, L.D.; Bashford, D.J.; Cussans, Julia E.; Nicholson, R.A. (Shetland Heritage Publications, 2019)
  • Perceived time is spatial frequency dependent

    Aaen-Stockdale, Craig; Hotchkiss, John; Heron, James; Whitaker, David J. (2011-06-01)
    We investigated whether changes in low-level image characteristics, in this case spatial frequency, were capable of generating a well-known expansion in the perceived duration of an infrequent “oddball” stimulus relative to a repeatedly-presented “standard” stimulus. Our standard and oddball stimuli were Gabor patches that differed from each other in spatial frequency by two octaves. All stimuli were equated for visibility. Rather than the expected “subjective time expansion” found in previous studies, we obtained an equal and opposite expansion or contraction of perceived time dependent upon the spatial frequency relationship of the standard and oddball stimulus. Subsequent experiments using equi-visible stimuli reveal that mid-range spatial frequencies (ca. 2 c/deg) are consistently perceived as having longer durations than low (0.5 c/deg) or high (8 c/deg) spatial frequencies, despite having the same physical duration. Rather than forming a fixed proportion of baseline duration, this bias is constant in additive terms and implicates systematic variations in visual persistence across spatial frequency. Our results have implications for the widely cited finding that auditory stimuli are judged to be longer in duration than visual stimuli.
  • The MK2 cascade regulates mGluR-dependent synaptic plasticity and reversal learning

    Privitera, Lucia; Hogg, Ellen L.; Gaestel, M.; Wall, M.J.; Corrêa, Sonia A.L. (2019-09-01)
    The ability to either erase or update the memories of a previously learned spatial task is an essential process that is required to modify behaviour in a changing environment. Current evidence suggests that the neural representation of such cognitive flexibility involves the balancing of synaptic potentiation (acquisition of memories) with synaptic depression (modulation and updating previously acquired memories). Here we demonstrate that the p38 MAPK/MAPK-activated protein kinase 2 (MK2) cascade is required to maintain the precise tuning of long-term potentiation and long-term depression at CA1 synapses of the hippocampus which is correlated with efficient reversal learning. Using the MK2 knockout (KO) mouse, we show that mGluR-LTD, but not NMDAR-LTD, is markedly impaired in mice aged between 4 and 5 weeks (juvenile) to 7 months (mature adult). Although the amplitude of LTP was the same as in wildtype mice, priming of LTP by the activation of group I metabotropic receptors was impaired in MK2 KO mice. Consistent with unaltered LTP amplitude and compromised mGluR-LTD, MK2 KO mice had intact spatial learning when performing the Barnes maze task, but showed specific deficits in selecting the most efficient combination of search strategies to perform the task reversal. Findings from this study suggest that the mGluR-p38-MK2 cascade is important for cognitive flexibility by regulating LTD amplitude and the priming of LTP.
  • A bridge too far: is a degree the right path?

    Binns, Carole L. (2019-03-07)
    Studies of graduate destinations generally report positive outcomes for working-class graduates, particularly professionally validated programmes such as pharmacy or social work, which offer specific career pathways. However, I know of working-class graduates with good degrees from good institutions who are in relatively menial positions in the leisure and retail sector. It is as if such students are unable to move beyond working-class jobs and embrace the middle-class careers that a degree should unlock.
  • Effect before cause: supramodal recalibration of sensorimotor timing

    Heron, James; Hanson, James Vincent Michael; Whitaker, David J. (2009)
    Our motor actions normally generate sensory events, but how do we know which events were self generated and which have external causes? Here we use temporal adaptation to investigate the processing stage and generality of our sensorimotor timing estimates. Methodology/Principal Findings: Adaptation to artificially-induced delays between action and event can produce a startling percept¿upon removal of the delay it feels as if the sensory event precedes its causative action. This temporal recalibration of action and event occurs in a quantitatively similar manner across the sensory modalities. Critically, it is robust to the replacement of one sense during the adaptation phase with another sense during the test judgment. Conclusions/Significance: Our findings suggest a high-level, supramodal recalibration mechanism. The effects are well described by a simple model which attempts to preserve the expected synchrony between action and event, but only when causality indicates it is reasonable to do so. We further demonstrate that this model successfully characterises related adaptation data from outside the sensorimotor domain.
  • A matter of months: High precision migration chronology of a Bronze Age female

    Frei, K.M.; Villa, C.; Jorkov, M.L.; Allentoft, M.E.; Kaul, F.; Ethelberg, P.; Reiter, S.S.; Wilson, Andrew S.; Taube, M.; Olsen, J.; Lynnerup, N.; Willerslev, E.; Kristiansen, K.; Frei, R. (2017-06-05)
    Establishing the age at which prehistoric individuals move away from their childhood residential location holds crucial information about the socio dynamics and mobility patterns in ancient societies. We present a novel combination of strontium isotope analyses performed on the over 3000 year old “Skrydstrup Woman” from Denmark, for whom we compiled a highly detailed month-scale model of her migration timeline. When combined with physical anthropological analyses this timeline can be related to the chronological age at which the residential location changed. We conducted a series of high-resolution strontium isotope analyses of hard and soft human tissues and combined these with anthropological investigations including CT-scanning and 3D visualizations. The Skrydstrup Woman lived during a pan-European period characterized by technical innovation and great social transformations stimulated by long-distance connections; consequently she represents an important part of both Danish and European prehistory. Our multidisciplinary study involves complementary biochemical, biomolecular and microscopy analyses of her scalp hair. Our results reveal that the Skrydstrup Woman was between 17–18 years old when she died, and that she moved from her place of origin -outside present day Denmark- to the Skrydstrup area in Denmark 47 to 42 months before she died. Hence, she was between 13 to 14 years old when she migrated to and resided in the area around Skrydstrup for the rest of her life. From an archaeological standpoint, this one-time and one-way movement of an elite female during the possible “age of marriageability” might suggest that she migrated with the aim of establishing an alliance between chiefdoms. Consequently, this detailed multidisciplinary investigation provides a novel tool to reconstruct high resolution chronology of individual mobility with the perspective of studying complex patterns of social and economic interaction in prehistory.
  • From Macro to Micro: Multi-scalar Digital Approaches at the Sculptor’s Cave, North-East Scotland

    Büster, Lindsey; Armit, Ian; Evans, Adrian A.; Sparrow, Thomas; Kershaw, Rachael; Wilson, Andrew S. (2019-02-08)
    Excavations in the 1920s and 1970s at the Sculptor’s Cave, North-East Scotland, revealed that the site was used for mortuary rituals during the Late Bronze Age (c. 1100–800 BC) and Roman Iron Age (late first to fourth centuries AD), whilst a series of Pictish symbols carved into its entrance walls suggest that the cave’s importance continued into the Early Medieval Period. A new programme of analysis has utilised advanced 3D digital documentation and 3D metrology (specifically, 3D laser scanning) to enable this inaccessible site to be appreciated by wider audiences and analysed remotely. Detailed in situ recording of the Pictish symbols was undertaken using macro-level structured light scanning and the high-fidelity digital models blended with terrestrial laser scan data of the cave interior to show the location and detail of the carvings. This chapter examines the value of emerging digital approaches in the analysis, presentation and management of the Sculptor’s Cave, from the elucidation of additional carved details and the monitoring of surface degradation, to the dissemination of this difficult-to-access site to the wider public via online platforms.
  • Interactions of a zwitterionic thiophene-based conjugated polymer with surfactants

    Costa, T.; de Azevedo, D.; Stewart, Beverly; Knaapila, M.; Valente, A.J.M.; Kraft, M.; Scherf, U.; Burrows, H.D. (2015-12-15)
    In this paper we investigate the optical and structural properties of a zwitterionic poly[3-(N-(4-sulfonato-1-butyl)-N,N-diethylammonium)hexyl-2,5-thiophene] (P3SBDEAHT) conjugated polyelectrolyte (CPE) and its interaction in water with surfactants, using absorption, photoluminescence (PL), electrical conductivity, molecular dynamics simulations (MDS) and small-angle X-ray scattering (SAXS). Different surfactants were studied to evaluate the effect of the head group and chain length on the self-assembly. PL data emphasize the importance of polymer–surfactant electrostatic interactions in the formation of complexes. Nevertheless, conductivity and MDS data have shown that nonspecific interactions also play an important role. These seem to be responsible for the spatial position of the surfactant tail in the complex and, eventually, for breaking-up P3SBDEAHT aggregates. SAXS measurements on P3SBDEAHT-zwitterionic cocamidopropyl betaine (CAPB) surfactant complexes showed a specific structural organization of the system. The CAPB surfactant promotes a structural transition from pure P3SBDEAHT 3-dimensional aggregates (radius of gyration ∼85 Å) to thick cylindrical aggregates (∼20 Å) where all CAPB molecules are associated with the polymer. For molar ratios (in terms of the polymer repeat unit) >1 the SAXS interference maximum of the complexes resembles that of pure CAPB thus suggesting ongoing phase segregation in the formation of a “pure” CAPB phase.
  • Incorporation of a Cationic Conjugated Polyelectrolyte CPE within an Aqueous Poly(vinyl alcohol) Sol

    Knaapila, M.; Stewart, Beverly; Costa, T.; Rogers, S.E.; Pragana, J.; Fonseca, S.M.; Valente, A.J.M.; Ramos, M.L.; Murtinho, D.; Costa Pereira, J.; Mallavia, R.; Burrows, H.D. (2016-11-16)
    We report on a multiscale polymer-within-polymer structure of the cationic conjugated polyelectrolyte poly{[9,9-bis(6′-N,N,N-trimethylammonium)hexyl]fluorene–phenylene} (HTMA-PFP) in aqueous poly(vinyl alcohol) (PVA) sol. Molecular dynamics simulations and small-angle neutron scattering (SANS) data show that HTMA-PFP forms aggregates in water but becomes entangled by PVA (with a 1:1 molar ratio of HTMA-PFP to PVA) and eventually immersed in PVA clusters (with the ratio 1:4). This is attributed to the hydrophobic–hydrophilic balance. Contrast variation data with regular and deuterated PVA support a rigid body model, where HTMA-PFP is confined as locally isolated, but closely located, chains within PVA clusters, which alter correlation distances within the system. These results are supported by enhanced photoluminescence (PL) and ionic conductivity which, together with a red-shift in UV/vis absorption spectra, indicate the breakup of HTMA-PFP aggregates upon PVA addition.
  • Multiple spatial frequency channels in human visual perceptual memory

    Nemes, Vanda A.; Whitaker, David J.; Heron, James; McKeefry, Declan J. (2011-12-08)
    Current models of short-term visual perceptual memory invoke mechanisms that are closely allied to low-level perceptual discrimination mechanisms. The purpose of this study was to investigate the extent to which human visual perceptual memory for spatial frequency is based upon multiple, spatially tuned channels similar to those found in the earliest stages of visual processing. To this end we measured how performance on a delayed spatial frequency discrimination paradigm was affected by the introduction of interfering or ‘memory masking’ stimuli of variable spatial frequency during the delay period. Masking stimuli were shown to induce shifts in the points of subjective equality (PSE) when their spatial frequencies were within a bandwidth of 1.2 octaves of the reference spatial frequency. When mask spatial frequencies differed by more than this value, there was no change in the PSE from baseline levels. This selective pattern of masking was observed for different spatial frequencies and demonstrates the existence of multiple, spatially tuned mechanisms in visual perceptual memory. Memory masking effects were also found to occur for horizontal separations of up to 6 deg between the masking and test stimuli and lacked any orientation selectivity. These findings add further support to the view that low-level sensory processing mechanisms form the basis for the retention of spatial frequency information in perceptual memory. However, the broad range of transfer of memory masking effects across spatial location and other dimensions indicates more long range, long duration interactions between spatial frequency channels that are likely to rely contributions from neural processes located in higher visual areas.
  • Adaptation reveals multi-stage coding of visual duration

    Heron, James; Fulcher, Corinne; Collins, Howard; Whitaker, David J.; Roach, N.W. (2019-02-28)
    In conflict with historically dominant models of time perception, recent evidence suggests that the encoding of our environment’s temporal properties may not require a separate class of neurons whose raison d'être is the dedicated processing of temporal information. If true, it follows that temporal processing should be imbued with the known selectivity found within non-temporal neurons. In the current study, we tested this hypothesis for the processing of a poorly understood stimulus parameter: visual event duration. We used sensory adaptation techniques to generate duration aftereffects: bidirectional distortions of perceived duration. Presenting adapting and test durations to the same vs different eyes utilises the visual system’s anatomical progression from monocular, pre-cortical neurons to their binocular, cortical counterparts. Duration aftereffects exhibited robust inter-ocular transfer alongside a small but significant contribution from monocular mechanisms. We then used novel stimuli which provided duration information that was invisible to monocular neurons. These stimuli generated robust duration aftereffects which showed partial selectivity for adapt-test changes in retinal disparity. Our findings reveal distinct duration encoding mechanisms at monocular, depth-selective and depthinvariant stages of the visual hierarchy.
  • ‘Not All That Is White Is Lime’—White Substances from Archaeological Burial Contexts: Analyses and Interpretations

    Schotsmans, Eline M.J.; Toksoy-Köksal, F.; Bretterl, Rhea C.; Bessou, M.; Corbineau, R.; Lingle, A.M.; Bouquin, D.; Blanchard, P.; Becker, K.; Castex, D.; Knüsel, C.J.; Wilson, Andrew S.; Chapoulie, R. (2019)
    Archaeological burial contexts may include a variety of white substances, but few analyses have been published. This study reports on the physico‐chemical characterization of such residues from seven archaeological sites. It is often assumed that white materials from burial contexts are lime. Our findings demonstrate that they can be gypsum, calcite (chalk), aragonite, brushite, degraded metal, natural (gum) resins or synthetic polymer–based products. These may be present as the result of diagenetic processes, funerary practices or modern contamination. This paper provides an analytical approach for the holistic investigation of white materials encountered in burial contexts.
  • Keeping the dead close: grief and bereavement in the treatment of skulls from the Neolithic Middle East

    Croucher, Karina T. (2018)
    Theories of Continuing Bonds, and more recently, the Dual Process of Grieving, have provided new ways of understanding the bereavement process, and have influenced current practice for counsellors, end-oflife care practitioners and other professionals. This paper uses these theories in a new way, exploring their relevance to archaeological interpretation, with particular reference to the phenomenon of the plastering of skulls of the deceased in the Neolithic of Southwest Asia (the Middle East/Near East), suggesting that traditional archaeological interpretations, which focus on concepts of status and social organisation, may be missing a more basic reaction to grief and a desire to keep the dead close for longer.
  • Medication-related risk factors and its association with repeated hospital admissions in frail elderly: A case control study

    Cheong, V-Lin; Sowter, J.; Scally, Andy J.; Hamilton, N.; Ali, A.; Silcock, J. (2019)
    Repeated hospital admissions are prevalent in older people. The role of medication in repeated hospital admissions has not been widely studied. The hypothesis that medication-related risk factors for initial hospital admissions were also associated with repeated hospital admissions was generated. To examine the association between medication-related risk factors and repeated hospital admissions in older people living with frailty. A retrospective case-control study was carried out with 200 patients aged ≥75 years with unplanned medical admissions into a large teaching hospital in England between January and December 2015. Demographic, clinical, and medication-related data were obtained from review of discharge summaries. Statistical comparisons were made between patients with 3 or more hospital admissions during the study period (cases) and those with 2 or fewer admissions (controls). Regressions were performed to establish independent predictors of repeated hospital admissions. Participants had a mean age of 83.8 years (SD 5.68) and 65.5% were female. There were 561 admission episodes across the sample, with the main reasons for admissions recorded as respiratory problems (25%) and falls (17%). Univariate logistic regression revealed five medication-related risks to be associated with repeated hospital admissions: Hyper-polypharmacy (defined as taking ≥10 medications) (OR 2.50, p < 0.005); prescription of potentially inappropriate medications (PIMs) (OR 1.89; p < 0.05); prescription of a diuretic (OR 1.87; p < 0.05); number of high risk medication (OR 1.29; p < 0.05) and the number of 'when required' medication (OR 1.20; p < 0.05). However, the effects of these risk factors became insignificant when comorbid disease was adjusted for in a multivariable model. Medication-related risk factors may play an important role in future repeated admission risk prediction models. The modifiable nature of medication-related risks factors highlights a real opportunity to improve health outcomes.
  • Insight into the Mechanism of Formation of Channel Hydrates via Templating

    Stokes, S.P.; Seaton, Colin C.; Eccles, K.S.; Maguire, A.R.; Lawrence, S.E. (2014-01-22)
    Cocrystallization of modafinil, (1), and 1,4-diiodotetrafluorobenzene, (2), in toluene leads to the formation of a metastable modafinil channel hydrate containing an unusual hydrogen bonded dimer motif involving the modafinil molecules that is not seen in anhydrous forms of modafinil. Computational methodologies utilizing bias drift-free differential evolution optimization have been developed and applied to a series of molecular clusters and multicomponent crystals in the modafinil/water and modafinil/water/additive systems for the additive molecules (2) or toluene. These calculations show the channel hydrate is less energetically stable than the anhydrous modafinil but more stable than a cocrystal involving (1) and (2). This provides theoretical evidence for the observed instability of the channel hydrate. The mechanism for formation of the channel hydrate is found to proceed via templating of the modafinil molecules with the planar additive molecules, allowing the formation of the unusual hydrogen-bonded modafinil dimer. It is envisaged that the additive is then replaced by water molecules to form the channel hydrate. The formation of the channel hydrate is more likely in the presence of (2) compared to toluene due to the destabilizing effect of the larger iodine molecules protruding into neighboring modafinil clusters.
  • Controlled Release of Carbon Monoxide from a Pseudo Electron- Deficient Organometallic Complex

    Pitto-Barry, Anaïs; Barry, Nicolas P.E. (2018-11-16)
    A 16-electron iridium organometallic is reacted with carbon monoxide to form an 18-electron CO-adduct. This CO-adduct is stable for weeks in the solid state, but quickly reverts to its parent 16-e complex in tetrahydrofuran solution, releasing CO(g). Using a simple methodology, we show that this gas can subsequently be used to perform a carbonylation reaction on another molecule.
  • Biocatalytically Triggered Co‐Assembly of Two‐Component Core/Shell Nanofibers

    Abul-Haija, Y.M.; Roy, S.; Frederix, P.W.J.M.; Javid, Nadeem; Jayawarna, V.; Ulijn, R.V. (2014-03-05)
    For the development of applications and novel uses for peptide nanostructures, robust routes for their surface functionalization, that ideally do not interfere with their self‐assembly properties, are required. Many existing methods rely on covalent functionalization, where building blocks are appended with functional groups, either pre‐ or post‐assembly. A facile supramolecular approach is demonstrated for the formation of functionalized nanofibers by combining the advantages of biocatalytic self‐assembly and surfactant/gelator co‐assembly. This is achieved by enzymatically triggered reconfiguration of free flowing micellar aggregates of pre‐gelators and functional surfactants to form nanofibers that incorporate and display the surfactants’ functionality at the surface. Furthermore, by varying enzyme concentration, the gel stiffness and supramolecular organization of building blocks can be varied.
  • Temperature-dependent structure and dynamics of highly-branched poly(N -isopropylacrylamide) in aqueous solution

    Al-Baradi, A.M.; Rimmer, Stephen; Carter, S.R.; de Silva, J.P.; King, S.M.; Maccarini, M.; Farago, B.; Noirez, L.; Geoghegan, M. (2018-02)
    Small-angle neutron scattering (SANS) and neutron spin-echo (NSE) have been used to investigate the temperature-dependent solution behaviour of highly-branched poly(N-isopropylacrylamide) (HB-PNIPAM). SANS experiments have shown that water is a good solvent for both HB-PNIPAM and a linear PNIPAM control at low temperatures where the small angle scattering is described by a single correlation length model. Increasing the temperature leads to a gradual collapse of HB-PNIPAM until above the lower critical solution temperature (LCST), at which point aggregation occurs, forming disperse spherical particles of up to 60 nm in diameter, independent of the degree of branching. However, SANS from linear PNIPAM above the LCST is described by a model that combines particulate structure and a contribution from solvated chains. NSE was used to study the internal and translational solution dynamics of HB-PNIPAM chains below the LCST. Internal HB-PNIPAM dynamics is described well by the Rouse model for non-entangled chains.

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