• 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.
    • 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.
    • Adaptive gait changes due to spectacle magnification and dioptric blur in older people

      Elliott, David B.; Chapman, Graham J. (2010-02)
      Purpose. A recent study suggested that updated spectacles could increase falls rate in older people. We hypothesized that this may be due to changes in spectacle magnification and this study assessed the effects of spectacle magnification on adaptive gait. Methods. Adaptive gait and visual function was measured in 10 older adults (mean age 77.1 ¿ 4.3 years) with the participants¿ optimal refractive correction and when blurred with +1.00DS, +2.00DS, -1.00DS and -2.00DS lenses. Adaptive gait measurements for the lead and trail foot included foot position before the step, toe clearance of the step edge and foot position on the step. Vision measurements included visual acuity, contrast sensitivity and stereoacuity. Results. The blur lenses led to equal decrements in visual acuity and stereoacuity for the +1.00DS and -1.00DS and the +2.00DS and -2.00DS lenses. However, they had very different effects on adaptive gait compared to the optimal correction: Positive blur lenses led to an increased distance of the feet from the step, increased vertical toe clearance and reduced distance of the lead heel position on the step. Negative lenses led to the opposite of these changes. Conclusion. The adaptive gait changes did not mirror the effects of blur on vision, but were driven by the magnification changes of the lenses. Steps appear closer and larger with positive lenses and further away and smaller with negative ones. Magnification likely explains the mobility problems some older adults have with updated spectacles and after cataract surgery.
    • The addition of stripes (a version of the ‘horizontal-vertical illusion’) increases foot clearance when crossing low-height obstacles

      Foster, Richard J.; Buckley, John G.; Whitaker, David J.; Elliott, David B. (2016)
      Trips over obstacles are one of the main causes of falling in older adults, with vision playing an important role in successful obstacle negotiation. We determined whether a horizontal-vertical illusion, superimposed onto low-height obstacles to create a perceived increase in obstacle height, increased foot clearances during obstacle negotiation thus reducing the likelihood of tripping. Eleven adults (mean ± 1 SD: age 27.3 ± 5.1 years) negotiated obstacles of varying heights (3, 5, 7 cm) with four different appearance conditions; two were obstacles with a horizontal-vertical illusion (vertical stripes of different thickness) superimposed on the front, one was a plain obstacle and the fourth a plain obstacle with a horizontal black line painted on the top edge. Foot clearance parameters were compared across conditions. Both illusions led to a significant increase in foot clearance when crossing the obstacle, compared to the plain condition, irrespective of obstacle height. Superimposing a horizontal-vertical illusion onto low-height obstacles can increase foot clearance, and its use on the floor section of a double-glazing door frame for example may reduce the incidence of tripping in the home.
    • Additions to the Mycota of the Seychelles

      Watling, R.; Seaward, Mark R.D. (2014)
      Eleven species of fungi and one slime-mould are added to the previous list of fungi from Indian Ocean islands made by the authors in 2004. Two other species in the area are confirmed. Our knowledge of fungal distributions in these remote islands is extended and comments are made on some immature collections. This small collection does, however, indicate a palaeotropical element to the mycota with bias towards species found in Southeast Asia, although some have a worldwide distribution.
    • Additive Manufacturing of a Point-of-Care “Polypill:” Fabrication of Concept Capsules of Complex Geometry with Bespoke Release against Cardiovascular Disease

      Pereira, B.C.; Isreb, Abdullah; Isreb, Mohammad; Forbes, R.T.; Oga, E.F.; Alhnan, M.A. (2020-07)
      Polypharmacy is often needed for the management of cardiovascular diseases and is associated with poor adherence to treatment. Hence, highly flexible and adaptable systems are in high demand to accommodate complex therapeutic regimens. A novel design approach is employed to fabricate highly modular 3D printed “polypill” capsules with bespoke release patterns for multiple drugs. Complex structures are devised using combined fused deposition modeling 3D printing aligned with hot-filling syringes. Two unibody highly modular capsule skeletons with four separate compartments are devised: i) concentric format: two external compartments for early release while two inner compartments for delayed release, or ii) parallel format: where nondissolving capsule shells with free-pass corridors and dissolution rate-limiting pores are used to achieve immediate and extended drug releases, respectively. Controlling drug release is achieved through digital manipulation of shell thickness in the concentric format or the size of the rate limiting pores in the parallel format. Target drug release profiles are achieved with variable orders and configurations, hence confirming the modular nature with capacity to accommodate therapeutics of different properties. Projection of the pharmacokinetic profile of this digital system capsules reveal how the developed approach can be applied in dose individualization and achieving multiple desired pharmacokinetic profiles.
    • Addressing inequalities in eye health with subsidies and increased fees for General Ophthalmic Services in socio-economically deprived communities: A sensitivity analysis

      Shickle, D.; Todkill, D.; Chisholm, Catharine M.; Rughani, S.; Griffin, M.; Cassels-Brown, A.; May, H.; Slade, S.V.; Davey, Christopher J. (2015)
      Objectives: Poor knowledge of eye health, concerns about the cost of spectacles, mistrust of optometrists and limited geographical access in socio-economically deprived areas are barriers to accessing regular eye examinations and result in low uptake and subsequent late presentation to ophthalmology clinics. Personal Medical Services (PMS) were introduced in the late 1990s to provide locally negotiated solutions to problems associated with inequalities in access to primary care. An equivalent approach to delivery of optometric services could address inequalities in the uptake of eye examinations. Study design: One-way and multiway sensitivity analyses. Methods: Variations in assumptions were included in the models for equipment and accommodation costs, uptake and length of appointments. The sensitivity analyses thresholds were cost-per-person tested below the GOS1 fee paid by the NHS and achieving break-even between income and expenditure, assuming no cross-subsidy from profits from sales of optical appliances. Results: Cost per test ranged from £24.01 to £64.80 and subsidy required varied from £14,490 to £108,046. Unused capacity utilised for local enhanced service schemes such as glaucoma referral refinement reduced the subsidy needed. Conclusions: In order to support the financial viability of primary eye care in socio-economically deprived communities, income is required from additional subsidies or from sources other than eye examinations, such as ophthalmic or other optometric community services. This would require a significant shift of activity from secondary to primary care locations. The subsidy required could also be justified by the utility gain from earlier detection of preventable sight loss.
    • Adherence to coronary artery disease secondary prevention medicines: exploring modifiable barriers

      Khatib, R.; Marshall, K.; Silcock, Jonathan; Forrest, C.; Hall, A.S. (2019-07)
      Background: Non-adherence to secondary prevention medicines (SPMs) among patients with coronary artery disease (CAD) remains a challenge in clinical practice. This study attempted to identify actual and potential modifiable barriers to adherence that can be addressed in cardiology clinical practice. Methods: This was a cross-sectional, postal survey-based study of the medicines-taking experience of patients with CAD treated at a secondary/tertiary care centre. All participants had been on SPM for ≥3 months. Results: In total, 696 eligible patients were sent the survey and 503 responded (72.3%). The median age was 70 years, and 403 (80.1%) were male; the median number of individual daily doses of all medicines was 6. The rate of non-adherence to at least one SPM was 43.5% (n=219), but 53.3% of reported non-adherence was to only one SPM. Statins contributed to 66.7% and aspirin to 61.7% of overall non-adherence identified by the Single Question (SQ) tool. In 30.8% of non-adherent patients (n=65), this was at least partly intentional. Barriers included forgetfulness (84.9%; n=186), worry that medicines will do more harm than good (33.8%; n=74), feeling hassled about medicines taking (18.7%; n=41), feeling worse when taking medicines (14.2%; n=31) and not being convinced of the benefit of medicines (9.1%; n=20). In a multivariate analysis, modifiable factors associated with overall non-adherence included being prescribed aspirin (OR: 2.22; 95% CI: 1.18 to 4.17), having specific concern about SPM (OR: 1.12; 95% CI: 1.07 to 1.18) and issues with repeat prescriptions (OR: 2.48; 95% CI: 1.26 to 4.90). Different factors were often associated with intentional versus unintentional non-adherence. Conclusions: Using appropriate self-report tools, patients share actual and potential modifiable barriers to adherence that can be addressed in clinical practice. Non-adherence behaviour was selective. Most non-adherence was driven by forgetfulness, concern about the harm caused by SPM and practical barriers.
    • Adipose tissue: a source of stem cells with potential for regenerative therapies for wound healing

      Trevor, Lucy V.; Riches-Suman, Kirsten; Mahajan, A.L.; Thornton, M. Julie (2020-07)
      Interest in adipose tissue is fast becoming a focus of research after many years of being considered as a simple connective tissue. It is becoming increasingly apparent that adipose tissue contains a number of diverse cell types, including adipose-derived stem cells (ASCs) with the potential to differentiate into a number of cell lineages, and thus has significant potential for developing therapies for regenerative medicine. Currently, there is no gold standard treatment for scars and impaired wound healing continues to be a challenge faced by clinicians worldwide. This review describes the current understanding of the origin, different types, anatomical location, and genetics of adipose tissue before discussing the properties of ASCs and their promising applications for tissue engineering, scarring, and wound healing.
    • Adsorption of DNA Fragments at Aqueous Graphite and Au(111) via Integration of Experiment and Simulation

      Hughes, Zak E.; Gang, W.; Drew, K.L.M.; Ciacchi, L.C.; Walsh, T.R. (2017-09-08)
      We combine single molecule force spectroscopy measurements with all-atom metadynamics simulations to investigate the cross-materials binding strength trends of DNA fragments adsorbed at the aqueous graphite C(0001) and Au(111) interfaces. Our simulations predict this adsorption at the level of the nucleobase, nucleoside, and nucleotide. We find that despite challenges in making clear, careful connections between the experimental and simulation data, reasonable consistency between the binding trends between the two approaches and two substrates was evident. On C(0001), our simulations predict a binding trend of dG > dA ≈ dT > dC, which broadly aligns with the experimental trend. On Au(111), the simulation-based binding strength trends reveal stronger adsorption for the purines relative to the pyrimadines, with dG ≈ dA > dT ≈ dC. Moreover, our simulations provide structural insights into the origins of the similarities and differences in adsorption of the nucleic acid fragments at the two interfaces. In particular, our simulation data offer an explanation for the differences observed in the relative binding trend between adenosine and guanine on the two substrates.
    • Advances in antitumor effects of NSAIDs

      Zhang, Z.; Chen, F.; Shang, Lijun (2018-10-15)
      In recent years, the reports on using nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer prevention and treatment have been on the rise. In 2017, the US Preventive Services Working Group issued primary prevention guidelines on the use of NSAIDs, especially aspirin, for cardiovascular disease and colorectal cancer, and formally established the role and status of aspirin in cancer prevention. However, the mechanism of NSAIDs on preventing cancer is still not clear. In this paper, the progress of the application of NSAIDs, especially aspirin, in the prevention and treatment of tumors in recent years is summarized, and new ideas and directions for the follow-up study are also discussed.
    • Advances in archaeomagnetic dating in Britain: New data, new approaches and a new calibration curve

      Batt, Catherine M.; Brown, M.C.; Clelland, Sarah-Jane; Korte, M.; Linford, P.; Outram, Zoe (2017-09)
      Archaeomagnetic dating offers a valuable chronological tool for archaeological investigations, particularly for dating fired material. The method depends on the establishment of a dated record of secular variation of the Earth's magnetic field and this paper presents new and updated archaeomagnetic directional data from the UK and geomagnetic secular variation curves arising from them. The data are taken from publications from the 1950's to the present day; 422 dated entries derived from existing archaeo and geomagnetic databases are re-evaluated and 487 new directions added, resulting in 909 entries with corresponding dates, the largest collection of dated archaeomagnetic directions from a single country. An approach to improving the largest source of uncertainty, the independent dating, is proposed and applied to the British Iron Age, resulting in 145 directions from currently available databases being updated with revised ages and/or uncertainties, and a large scale reassessment of age assignments prior to inclusion into the Magnetic Moments of the Past and GEOMAGIA50 databases. From the significantly improved dataset a new archaeomagnetic dating curve for the UK is derived through the development of a temporally continuous geomagnetic field model, and is compared with previous UK archaeomagnetic dating curves and global field models. The new model, ARCH-UK.1 allows model predictions for any location in the UK with associated uncertainties. It is shown to improve precision and accuracy in archaeomagnetic dating, and to provide new insight into past geomagnetic field changes.
    • Advances in identifying archaeological traces of horn and other keratinous hard tissues

      O'Connor, Sonia A.; Solazzo, C.; Collins, M. (2015)
      Despite being widely utilized in the production of cultural objects, keratinous hard tissues, such as horn, baleen, and tortoiseshell, rarely survive in archaeological contexts unless factors combine to inhibit biodeterioration. Even when these materials do survive, working, use, and diagenetic changes combine to make identification difficult. This paper reviews the chemistry and deterioration of keratin and past approaches to the identification of keratinous archaeological remains. It describes the formation of horn, hoof, baleen, and tortoiseshell and demonstrates how identification can be achieved by combining visual observation under low-power magnification with an understanding of the structure and characteristic deterioration of these materials. It also demonstrates how peptide mass fingerprinting of the keratin can be used to identify keratinous tissues, often to species, even when recognizable structural information has not survived.
    • Agarose Spot as a Comparative Method for in situ Analysis of Simultaneous Chemotactic Responses to Multiple Chemokines

      Ahmed, Mohaned S.A.; Basheer, Haneen A.; Ayuso, J.M.; Ahmet, Djevdet S.; Mazzini, Marco; Patel, Roshan; Shnyder, Steven D.; Vinader, Victoria; Afarinkia, Kamyar (2017-04-21)
      We describe a novel protocol to quantitatively and simultaneously compare the chemotactic responses of cells towards different chemokines. In this protocol, droplets of agarose gel containing different chemokines are applied onto the surface of a Petri dish, and then immersed under culture medium in which cells are suspended. As chemokine molecules diffuse away from the spot, a transient chemoattractant gradient is established across the spots. Cells expressing the corresponding cognate chemokine receptors migrate against this gradient by crawling under the agarose spots towards their centre. We show that this migration is chemokine-specific; meaning that only cells that express the cognate chemokine cell surface receptor, migrate under the spot containing its corresponding chemokine ligand. Furthermore, we show that migration under the agarose spot can be modulated by selective small molecule antagonists present in the cell culture medium.
    • Age Changes in Bone Microstructure - Do They Occur Uniformly?

      Macho, Gabriele A.; Abel, R.; Schutkowski, Holger (2005)
      Age estimations based on conventional multifactorial methods were compared with trends observed in the internal morphology of bones obtained from high-resolution µCT. Specifically, average trabecular thickness and number of trabeculae/mm transect were determined in the non-load-bearing capitate (hand) and the load-bearing navicular (foot). The µCT findings reveal age-related trends but - surprisingly - these correspond only loosely with the ages assigned by conventional ageing methods, and are also not in accordance with what would be predicted from biomechanical considerations: trabeculae tend to be thinner in the (habitually) load-bearing navicular than in the (habitually) non-load-bearing capitate. While the statistically significant correlation between trabecular thickness and number of trabeculae would suggest a compensatory mechanism between these two aspects of microanatomy, they are not correlated with the assigned ages and, importantly, may differ between sexes. Only in females is there an unequivocal trend towards trabecular thickness increase with age. These findings, although unexpected, can be reconciled with recent histological evidence and assumed average activity levels in historical populations. Conversely, changes in trabecular number are less clear-cut and may be due to the lack of very old individuals in the sample. Nevertheless, the trends observed for trabecular thickness, as well as for trabecular number, seem to imply that the higher incidence of osteoporosis in women could be explained from a structural point of view alone.
    • Age estimation [editorial].

      Liversidge, H.M.; Buckberry, Jo; Marquez-Grant, N. (2015-08)
      Assessing and interpreting dental and skeletal age-related changes in both the living and the dead is of interest to a wide range of disciplines (e.g. see Bittles and Collins 1986) including human biology, paediatrics, public health, palaeodemography, archaeology, palaeontology, human evolution, forensic anthropology and legal medicine. ... This special issue of Annals of Human Biology arises from the 55th annual symposium of the Society for the Study of Human Biology in association with the British Association for Biological Anthropological and Osteoarchaeology held in Oxford, UK, from 9–11 December 2014. Only a selection of the presentations are included here which encompass some of the major recent advances in age estimation from the dentition and skeleton.
    • Age Estimation from the Auricular Surface of the Ilium: A Revised Method

      Buckberry, Jo; Chamberlain, A. (2002)
      A revised method for estimating adult age at death using the auricular surface of the ilium has been developed. It is based on the existing auricular surface aging method of Lovejoy et al. ([1985] Am. J. Phys. Anthropol. 68:15-28), but the revised technique is easier to apply, and has low levels of inter- and intraobserver error. The new method records age-related stages for different features of the auricular surface, which are then combined to provide a composite score from which an estimate of age at death is obtained. Blind tests of the method were carried out on a known-age skeletal collection from Christ Church, Spitalfields, London. These tests showed that the dispersion of age at death for a given morphological stage was large, particularly after the first decade of adult life. Statistical analysis showed that the age-related changes in auricular surface are not significantly different for males and females. The scores from the revised method have a slightly higher correlation with age than do the Suchey-Brooks pubic symphysis stages. Considering the higher survival rates of the auricular surface compared with the pubic symphysis, this method promises to be useful for biological anthropology and forensic science.