• Association of anthropometric measures across the life-course with refractive error and ocular biometry at age 15 years

      Bruce, A.; Ghorbani Mojarrad, Neema; Santorelli, G. (2020-07-08)
      Background A recent Genome-wide association meta-analysis (GWAS) of refractive error reported shared genetics with anthropometric traits such as height, BMI and obesity. To explore a potential relationship with refractive error and ocular structure we performed a life-course analysis including both maternal and child characteristics using data from the Avon Longitudinal Study of Parents and Children cohort. Methods Measures collected across the life-course were analysed to explore the association of height, weight, and BMI with refractive error and ocular biometric measures at age 15 years from 1613children. The outcome measures were the mean spherical equivalent (MSE) of refractive error (dioptres), axial length (AXL; mm), and radius of corneal curvature (RCC; mm). Potential confounding variables; maternal age at conception, maternal education level, parental socio-economic status, gestational age, breast-feeding, and gender were adjusted for within each multi-variable model. Results Maternal height was positively associated with teenage AXL (0.010 mm; 95% CI: 0.003, 0.017) and RCC (0.005 mm; 95% CI: 0.003, 0.007), increased maternal weight was positively associated with AXL (0.004 mm; 95% CI: 0.0001, 0.008). Birth length was associated with an increase in teenage AXL (0.067 mm; 95% CI: 0.032, 0.10) and flatter RCC (0.023 mm; 95% CI: 0.013, 0.034) and increasing birth weight was associated with flatter RCC (0.005 mm; 95% CI: 0.0003, 0.009). An increase in teenage height was associated with a lower MSE (− 0.007 D; 95% CI: − 0.013, − 0.001), an increase in AXL (0.021 mm; 95% CI: 0.015, 0.028) and flatter RCC (0.008 mm; 95% CI: 0.006, 0.010). Weight at 15 years was associated with an increase in AXL (0.005 mm; 95% CI: 0.001, 0.009). Conclusions At each life stage (pre-natal, birth, and teenage) height and weight, but not BMI, demonstrate an association with AXL and RCC measured at age 15 years. However, the negative association between refractive error and an increase in height was only present at the teenage life stage. Further research into the growth pattern of ocular structures and the development of refractive error over the life-course is required, particularly at the time of puberty.
    • Astigmatism and Pseudoaccommodation in Pseudophakic Eyes

      Serra, Pedro M.F.N.; Chisholm, Catharine M.; Cox, Michael J. (22/08/2010)
      Advanced IOLs with circumferential zones of different power provide pseudoaccommodation. We investigated the potential for power variation with meridian, namely astigmatism, to provide pseudo-accommodation. With appropriate power and axis orientations, acceptable pseudo-accommodation can be achieved.
    • Astrocytes grown in Alvetex® 3 dimensional scaffolds retain a non-reactive phenotype

      Ugbode, Christopher I.; Hirst, W.D.; Rattray, Marcus (2016)
      Protocols which permit the extraction of primary astrocytes from either embryonic or postnatal mice are well established however astrocytes in culture are different to those in the mature CNS. Three dimensional (3D) cultures, using a variety of scaffolds may enable better phenotypic properties to be developed in culture. We present data from embryonic (E15) and postnatal (P4) murine primary cortical astrocytes grown on coated coverslips or a 3D polystyrene scaffold, Alvetex. Growth of both embryonic and postnatal primary astrocytes in the 3D scaffold changed astrocyte morphology to a mature, protoplasmic phenotype. Embryonic-derived astrocytes in 3D expressed markers of mature astrocytes, namely the glutamate transporter GLT-1 with low levels of the chondroitin sulphate proteoglycans, NG2 and SMC3. Embroynic astrocytes derived in 3D show lower levels of markers of reactive astrocytes, namely GFAP and mRNA levels of LCN2, PTX3, Serpina3n and Cx43. Postnatal-derived astrocytes show few protein changes between 2D and 3D conditions. Our data shows that Alvetex is a suitable scaffold for growth of astrocytes, and with appropriate choice of cells allows the maintenance of astrocytes with the properties of mature cells and a non-reactive phenotype.
    • Astrocytic Transporters in Alzheimer’s disease

      Ugbode, Christopher I.; Yuhan, H.; Whalley, B.J.; Peers, C.; Rattray, Marcus; Dallas, M. (2017)
      Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer’s disease. These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease modifying therapies for Alzheimer’s disease, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of Alzheimer’s disease. A small number of the four hundred transporter superfamilies’ are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in Alzheimer’s disease. Here we review the current evidence for six astrocytic transporter subfamilies involved in Alzheimer’s disease, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling Alzheimer’s disease.
    • Asymmetric Crystal Growth of Resorcinol from the Vapor Phase: Surface reconstruction and conformational change are the Culprits.

      Anwar, Jamshed; Chatchawalsaisin, Jittima; Kendrick, John (2009-07-28)
      The growth of crystals of a-resorcinol from the vapor phase is asymmetric along the polar axis. By means of molecular-dynamics simulations, the slower growth at the (011) polar surface is traced back to conformational change of the molecule and to surface reconstruction, which may be a general phenomenon in polar crystals.
    • Asymmetric propagation of spreading depression along the anteroposterior axis of the cerebral cortex in mice.

      Obrenovitch, Tihomir P.; Godukhin, O.V. (2001)
      The purpose of this study was to ascertain whether or not spreading depression (CSD) propagates symmetrically along the anteroposterior axis of the cortex of mice, and to determine where CSD should be elicited to achieve a uniform exposure of the cortex to this phenomenon. Experiments were performed in halothane-anesthetized mice, with three different locations aligned 1.5 mm from the midline used for either KCl elicitation of CSD or the recording of its propagation. Our results demonstrated that, at least in the mouse cortex, CSD propagated much more effectively from posterior to anterior regions than in the opposite direction. This feature was due to a different efficacy of propagation in the two opposite directions, and not to a reduced susceptibility of occipital regions to CSD elicitation. Heterogeneous CSD propagation constitutes a potential pitfall for neurochemical studies of post-CSD changes in mice, as brain tissue samples collected for this purpose should be uniformly exposed to CSD. Occipital sites for CSD induction are clearly optimal for this purpose. If CSD propagation is confirmed to be more effective from posterior to anterior regions in other species, this may be relevant to the pathophysiology of classical migraine because the most frequent aura symptoms (i.e., visual disturbances) originate in the occipital cortex.
    • Asymmetric vitreomacular traction and symmetrical full thickness macular hole formation

      Woon, W.H.; Greig, D.; Savage, M.D.; Wilson, M.C.T.; Grant, Colin A.; Bishop, F.; Mokete, B. (2015)
      BACKGROUND: A Full Thickness Macular Hole (FTMH) is often associated with vitreomacular traction, and this can be asymmetric with vitreomacular traction on one side of the hole but not the other. In cross-section, the elevated retinal rim around a developed FTMH is seen as a drawbridge elevation, and this drawbridge elevation may be used as a measure of morphological change. Examination of the drawbridge elevation of the retinal rim in FTMH with asymmetric vitreomacular traction may help to clarify the role of vitreomacular traction in the development of FTMH. METHOD: Cases of FTMH were identified with an initial OCT scan showing vitreomacular traction on one side of the hole only and that had a follow-up OCT scan showing progression of the hole. A tangent to the retinal surface at a distance of 700 microns from the axis of the hole was used as a marker of the drawbridge elevation of the retinal rim around the macular hole. Comparisons of the drawbridge elevation and change in drawbridge elevation between the sides with and without initial vitreomacular traction were made. RESULTS: There was no significant difference between the drawbridge elevation, or change in drawbridge elevation, on the side of the hole with initial vitreomacular traction compared to the side without initial traction. CONCLUSION: There is some intrinsic mechanism within the retina to link the morphological changes on the two sides of a FTMH. A bistable hypothesis of FTMH formation and closure is postulated to explain this linkage.
    • Asymmetries between achromatic and chromatic extraction of 3D motion signals

      Kaestner, M.; Maloney, R.T.; Wailes-Newson, K.H.; Bloj, Marina; Harris, J.M.; Morland, A.B.; Wade, A.R. (2019-07)
      Motion in depth (MID) can be cued by high-resolution changes in binocular disparity over time (CD), and low-resolution interocular velocity differences (IOVD). Computational differences between these two mechanisms suggest that they may be implemented in visual pathways with different spatial and temporal resolutions. Here, we used fMRI to examine how achromatic and S-cone signals contribute to human MID perception. Both CD and IOVD stimuli evoked responses in a widespread network that included early visual areas, parts of the dorsal and ventral streams, and motion-selective area hMT+. Crucially, however, we measured an interaction between MID type and chromaticity. fMRI CD responses were largely driven by achromatic stimuli, but IOVD responses were better driven by isoluminant S-cone inputs. In our psychophysical experiments, when S-cone and achromatic stimuli were matched for perceived contrast, participants were equally sensitive to the MID in achromatic and S-cone IOVD stimuli. In comparison, they were relatively insensitive to S-cone CD. These findings provide evidence that MID mechanisms asymmetrically draw on information in precortical pathways. An early opponent motion signal optimally conveyed by the S-cone pathway may provide a substantial contribution to the IOVD mechanism.
    • Asynchrony adaptation reveals neural population code for audio-visual timing

      Roach, N.W.; Heron, James; Whitaker, David J.; McGraw, Paul V. (2011)
      The relative timing of auditory and visual stimuli is a critical cue for determining whether sensory signals relate to a common source and for making inferences about causality. However, the way in which the brain represents temporal relationships remains poorly understood. Recent studies indicate that our perception of multisensory timing is flexible--adaptation to a regular inter-modal delay alters the point at which subsequent stimuli are judged to be simultaneous. Here, we measure the effect of audio-visual asynchrony adaptation on the perception of a wide range of sub-second temporal relationships. We find distinctive patterns of induced biases that are inconsistent with the previous explanations based on changes in perceptual latency. Instead, our results can be well accounted for by a neural population coding model in which: (i) relative audio-visual timing is represented by the distributed activity across a relatively small number of neurons tuned to different delays; (ii) the algorithm for reading out this population code is efficient, but subject to biases owing to under-sampling; and (iii) the effect of adaptation is to modify neuronal response gain. These results suggest that multisensory timing information is represented by a dedicated population code and that shifts in perceived simultaneity following asynchrony adaptation arise from analogous neural processes to well-known perceptual after-effects.
    • Atom-economical chemoselective synthesis of furocoumarins via cascade palladium catalyzed oxidative aloxylation of 4-oxohydrocoumarins and alkenes

      Tan, X.; Zhao, H.; Pan, Y.; Wu, Na (Anna); Wang, H.; Chen, Z. (2015-01)
      A novel and efficient procedure for the synthesis of furo[3,2-c] coumarins from readily available 4-oxohydrocoumarins and alkenes in the presence of a catalytic amount of Pd(CF3COO)2 has been developed. Atom-economical characteristics and mild conditions of this method are in accord with the concept of modern green chemistry.
    • Attention regulates the plasticity of multisensory timing

      Heron, James; Roach, N.W.; Whitaker, David J.; Hanson, James Vincent Michael (2010)
      Evidence suggests than human time perception is likely to reflect an ensemble of recent temporal experience. For example, prolonged exposure to consistent temporal patterns can adaptively realign the perception of event order, both within and between sensory modalities (e.g. Fujisaki et al., 2004 Nat. Neurosci., 7, 773-778). In addition, the observation that 'a watched pot never boils' serves to illustrate the fact that dynamic shifts in our attentional state can also produce marked distortions in our temporal estimates. In the current study we provide evidence for a hitherto unknown link between adaptation, temporal perception and our attentional state. We show that our ability to use recent sensory history as a perceptual baseline for ongoing temporal judgments is subject to striking top-down modulation via shifts in the observer's selective attention. Specifically, attending to the temporal structure of asynchronous auditory and visual adapting stimuli generates a substantial increase in the temporal recalibration induced by these stimuli. We propose a conceptual framework accounting for our findings whereby attention modulates the perceived salience of temporal patterns. This heightened salience allows the formation of audiovisual perceptual 'objects', defined solely by their temporal structure. Repeated exposure to these objects induces high-level pattern adaptation effects, akin to those found in visual and auditory domains (e.g. Leopold & Bondar (2005) Fitting the Mind to the World: Adaptation and Aftereffects in High-Level Vision. Oxford University Press, Oxford, 189-211; Schweinberger et al. (2008) Curr. Biol., 18, 684-688).
    • Attraction of flashes to moving dots.

      Yilmaz, O.; Tripathy, Srimant P.; Patel, S.S.; Ogmen, Haluk (2007)
      Motion is known to distort visual space, producing illusory mislocalizations for flashed objects. Previously, it has been shown that when a stationary bar is flashed in the proximity of a moving stimulus, the position of the flashed bar appears to be shifted in the direction of nearby motion. A model consisting of predictive projections from the sub-system that processes motion information onto the sub-system that processes position information can explain this illusory position shift of a stationary flashed bar in the direction of motion. Based on this model of motion¿position interactions, we predict that the perceived position of a flashed stimulus should also be attracted towards a nearby moving stimulus. In the first experiment, observers judged the perceived vertical position of a flash with respect to two horizontally moving dots of unequal contrast. The results of this experiment were in agreement with our prediction of attraction towards the high contrast dot. We obtained similar findings when the moving dots were replaced by drifting gratings of unequal contrast. In control experiments, we found that neither attention nor eye movements can account for this illusion. We propose that the visual system uses predictive influences from the motion processing sub-system on the position processing sub-system to overcome the temporal limitations of the position processing system.
    • Audiovisual time perception is spatially specific

      Heron, James; Roach, N.W.; Hanson, James Vincent Michael; McGraw, Paul V.; Whitaker, David J. (2012)
      Our sensory systems face a daily barrage of auditory and visual signals whose arrival times form a wide range of audiovisual asynchronies. These temporal relationships constitute an important metric for the nervous system when surmising which signals originate from common external events. Internal consistency is known to be aided by sensory adaptation: repeated exposure to consistent asynchrony brings perceived arrival times closer to simultaneity. However, given the diverse nature of our audiovisual environment, functionally useful adaptation would need to be constrained to signals that were generated together. In the current study, we investigate the role of two potential constraining factors: spatial and contextual correspondence. By employing an experimental design that allows independent control of both factors, we show that observers are able to simultaneously adapt to two opposing temporal relationships, provided they are segregated in space. No such recalibration was observed when spatial segregation was replaced by contextual stimulus features (in this case, pitch and spatial frequency). These effects provide support for dedicated asynchrony mechanisms that interact with spatially selective mechanisms early in visual and auditory sensory pathways.
    • Auditory ossicles: a potential biomarker for maternal and infant health in utero

      Leskovar, T.; Beaumont, Julia; Lisic, N.; McGalliard, S. (Taylor and Francis, 2019)
      Background: Carbon (δ13C) and nitrogen (δ15N) isotope ratios of collagen from teeth and bone are used to study human nutrition and health. As bones are constantly remodelling throughout life, isotopic values of bone collagen represent an average of several years. In contrast, human teeth do not remodel and their primary dentine contains only the isotopic data from the time of formation. In contrast to all other bones, human auditory ossicles also appear not to remodel. As they develop in utero and finish formation in the first 2 years of life, their collagen should also represent isotopic values of these two relatively short periods. Aim: By comparing δ13C and δ15N data from ossicles and incremental dentine, this study aims to investigate how two developmental periods of the ossicles, in utero and the first 2 years of life, reflect in collagen obtained from the ossicles. Subject and methods: Ossicle and tooth samples of 12 individuals aged 0.5 ± 0.4 years to 13 ± 1 years from the nineteenth century St. Peter’s burial ground in Blackburn were collected and processed to obtain bulk bone and incremental dentine collagen which was measured for δ13C and δ15N. Results: Averaged δ13C and δ15N of ossicles are lower when compared to every age group except after 3 years of age. Average offset between ossicles and dentine of different groups ranges from 0.4–0.9‰ for δ13C and from 0.3–0.9‰ for δ15N, with highest counterbalance at birth and after the first 5 months after birth. Conclusions: There appears to be a systematic offset between the dentine and ossicle data. It seems that the second phase of development does not influence the isotopic values of collagen significantly and the data we are obtaining from ossicles represents the in utero period.
    • Auristatin PYE, a novel synthetic derivative of dolastatin 10, is highly effective in human colon tumour models.

      Shnyder, Steven D.; Cooper, Patricia A.; Millington, Nicola J.; Pettit, G.R.; Bibby, Michael C. (2007)
      Despite promising early data, the natural product dolastatin 10 has not been successful as a single agent in phase II clinical trials. Herein the mechanism of action and efficacy of a synthetic analogue, auristatin PYE, was investigated in 2 human colon adenocarcinoma models, DLD-1 and COLO 205. In vivo efficacy was assessed in subcutaneous xenografts following intravenous administration. Mechanistic studies investigated effects of auristatin PYE on microtubule disruption using immunocytochemistry, whilst cell cycle effects were studied using flow cytometry. Possible effects on tumour functional blood vasculature were assessed in tumour-bearing mice. Auristatin PYE was less potent in vitro than dolastatin 10, but was significantly more effective (p<0.01) in vivo against both tumours. Significant effects on tumour blood vasculature were seen, with optimal shutdown at 6-h post-treatment. Extensive necrosis became more evident over time after treatment. Auristatin PYE caused severe disruption of normal microtubule structure at concentrations and times comparable with the IC50 data, and also instigated a G2/M cell cycle block. Auristatin PYE was more effective in the DLD-1 and COLO 205 models than dolastatin 10, with anti-tumour effects mediated through vascular shutdown. These data suggest that auristatin PYE has good potential as an anti-cancer agent.
    • Australopithecus anamensis: a finite element approach to studying functional adaptations in extinct hominins.

      Macho, Gabriele A.; Shimizu, D.; Jiang, Y.; Spears, I.R. (2005)
      Australopithecus anamensis is the stem species of all later hominins and exhibits the suite of characters traditionally associated with hominins, i.e., bipedal locomotion when on the ground, canine reduction, and thick-enameled teeth. The functional consequences of its thick enamel are, however, unclear. Without appropriate structural reinforcement, these thick-enameled teeth may be prone to failure. This article investigates the mechanical behavior of A. anamensis enamel and represents the first in a series that will attempt to determine the functional adaptations of hominin teeth. First, the microstructural arrangement of enamel prisms in A anamensis teeth was reconstructed using recently developed software and was compared with that of extant hominoids. Second, a finite-element model of a block of enamel containing one cycle of prism deviation was reconstructed for Homo, Pan, Gorilla, and A. anamensis and the behavior of these tissues under compressive stress was determined. Despite similarities in enamel microstructure between A. anamensis and the African great apes, the structural arrangement of prismatic enamel in A. anamensis appears to be more effective in load dissipation under these compressive loads. The findings may imply that this hominin species was well adapted to puncture crushing and are in some respects contrary to expectations based on macromorphology of teeth. Taking together, information obtained from both finite-element analyses and dental macroanatomy leads us to suggest that A. anamensis was probably adapted for habitually consuming a hard-tough diet. However, additional tests are needed to understand the functional adaptations of A. anamensis teeth fully.
    • Authenticity of long curated historical hair samples - the case of Newton's hair

      Wilson, Andrew S.; Richards, Michael P.; Gilbert, M.T.P. (2004)
    • Autocrine catecholamine biosynthesis and the b- adrenoceptor signal is present in Human Epidermal Melanocytes

      Schallreuter, Karin U.; Gillbro, Johanna M.; Hibberts, Nigel A.; Marles, Lee K. (2009-07-13)
      Earlier it has been shown that human proliferating/undifferentiated basal keratinocytes hold the full capacity for autocrine catecholamine synthesis/degradation and express b2-adrenoceptors (b2-AR). In this report, we show that human melanocytes also express all of the mRNA and enzymes for autocrine synthesis of norepinephrine but fail to produce epinephrine. So far, it was established that human melanocytes express b1-AR which are induced by norepinephrine yielding the inosine triphosphate diacylglycerol signal. The presence of catecholamine synthesis and the b2-AR signal escaped definition at that time. Using RT-PCR, immunofluorescence and radioligand binding with the b2-AR antagonist (-)-[3H]CGP 12177, we show here that human melanocytes express functional b2-AR (4230 receptors per cell) with a Bmax at 129.3 and a KD of 3.19 nM but lack b1-AR expression. 2-AR stimulation with epinephrine 10-6 M and salbutamol 10-6¿10-5 M yielded a strong cyclic adenosine monophospate (cAMP) response in association with upregulated melanin production. Taken together these results indicate that the biosynthesis and release of epinephrine (10-6 M) by surrounding keratinocytes can provide the cAMP response leading to melanogenesis in melanocytes via the b2-AR signal. Moreover, the discovery of this catecholaminergic cAMP response in melanocytes adds a new source for this important second messenger in melanogenesis.
    • Autologous cell therapy for aged human skin: A randomized, placebo-controlled, phase-I study

      Grether-Beck, S.; Marini, A.; Jaenicke, T.; Goessens-Rück, P.; McElwee, Kevin J.; Hoffman, R.; Krutmann, J. (2020-01)
      Introduction: Skin ageing involves senescent fibroblast accumulation, disturbance in extracellular matrix (ECM) homeostasis, and decreased collagen synthesis. Objective: to assess a cell therapy product for aged skin (RCS-01; verum) consisting of ~25 × 106 cultured, autologous cells derived from anagen hair follicle non-bulbar dermal sheath (NBDS). Methods: For each subject in the verum group, 4 areas of buttock skin were injected intradermally 1 or 3 times at monthly intervals with RCS-01, cryomedium, or needle penetration without injection; in the placebo group RCS-01 was replaced by cryomedium. The primary endpoint was assessment of local adverse event profiles. As secondary endpoints, expression of genes related to ECM homeostasis was assessed in biopsies from randomly selected volunteers in the RCS-01 group taken 4 weeks after the last injection. ­Results: Injections were well tolerated with no severe adverse events reported 1 year after the first injection. When compared with placebo-treated skin, a single treatment with RCS-01 resulted in a significant upregulation of TGFβ1, CTGF, COL1A1, COL1A2, COL3A1, and lumican mRNA expression. Limitations: The cohort size was insufficient for dose ­ranging evaluation and subgroup analyses of efficacy. Conclusions: RCS-01 therapy is well tolerated and associated with a gene expression response consistent with an improvement of ECM homeostasis.
    • AwareCare: development and validation of an observational measure of awareness in people with severe dementia

      Clare, L.; Whitaker, R.; Quinn, Catherine; Jelley, H.; Hoare, Z.; Woods, B.; Downs, Murna G.; Wilson, B.A. (2012)
      Signs of sensory and perceptual awareness can be observed in people with very severe dementia, and may be influenced by the extent to which the environment offers appropriate stimulation. We developed an observational tool, AwareCare, which care staff can use to identify signs of awareness in residents with very severe dementia, based on the concept of the Wessex Head Injury Matrix (WHIM). Using WHIM items as a guide, and following focus groups with care staff and family members, an expert panel identified 28 environmental stimuli and 35 response categories for the initial version of AwareCare. After baseline assessments of cognition, well-being and quality of life were taken, 40 residents were observed individually for 30 minutes on 5 occasions. Based on the observational data, 10 stimulus categories and 14 response categories were identified for further analysis and formed the final version of AwareCare. All participants showed awareness to varying degrees. Social stimuli elicited the most responses. Greater awareness was associated with better cognitive function, self-care, mobility, and responsiveness, but not with proxy-rated quality of life. Understanding the nature of awareness in this group is an important element in ensuring appropriate levels of interaction and stimulation, and hence enhancing quality of care.