Stuart Cobb

University of Glasgow, Glasgow, Scotland, United Kingdom

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Publications (60)255.2 Total impact

  • Stuart R Cobb

    No preview · Article · Oct 2015 · Nature
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    ABSTRACT: Rett syndrome (RTT) is a neurological disorder that affects females and is caused by loss-of-function mutations in the X-linked gene MECP2. Deletion of Mecp2 in mice results in a constellation of neurological features that resemble those seen in RTT patients. Experiments in mice have demonstrated that restoration of MeCP2, even at adult stages, reverses several aspects of the RTT-like pathology suggesting that the disorder may be inherently treatable. This has provided an impetus to explore several therapeutic approaches targeting RTT at the level of the gene, including gene therapy, activation of MECP2 on the inactive X chromosome and read-through and repair of RTT-causing mutations. Here, we review these different strategies and the challenges of gene-based approaches in RTT.
    No preview · Article · Oct 2015 · Future Neurology
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    ABSTRACT: We have developed a simple wavelength-tunable optical parametric generator (OPG), emitting broadband ultrashort pulses with peak wavelengths at 1530-1790 nm, for nonlinear label-free microscopy. The OPG consists of a periodically poled lithium niobate crystal, pumped at 1064 nm by a ultrafast Yb:fiber laser with high pulse energy. We demonstrate that this OPG can be used for label-free imaging, by third-harmonic generation, of nuclei of brain cells and blood vessels in a >150 μm thick brain tissue section, with very little decay of intensity with imaging depth and no visible damage to the tissue at an incident average power of 15 mW.
    No preview · Article · Aug 2015 · Optics Letters
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    ABSTRACT: This study assessed the anticonvulsant and seizure generation effects of carbamazepine (CBZ), oxcarbazepine (OXC) and eslicarbazepine (S-Lic) in wild-type mice. Electrophysiological recordings were made to discriminate potential cellular and synaptic mechanisms underlying anti- and pro-epileptic actions. The anticonvulsant and pro-convulsant effects were evaluated in the MES, the 6-Hz and the Irwin tests. Whole-cell patch-clamp recordings were used to investigate the effects on fast excitatory and inhibitory synaptic transmission in hippocampal area CA1. The safety window for CBZ, OXC and eslicarbazepine (ED50 value against the MES test and the dose that produces grade 5 convulsions in all mice), was 6.3, 6.0 and 12.5, respectively. At high concentrations the three drugs reduced synaptic transmission. CBZ and OXC enhanced excitatory postsynaptic currents (EPSCs) at low, therapeutically-relevant concentrations. These effects were associated with no change in inhibitory postsynaptic currents (IPSCs) resulting in altered balance between excitation and inhibition. S-Lic had no effect on EPSC or IPSC amplitudes over the same concentration range. The CBZ mediated enhancement of EPSCs was blocked by DPCPX, a selective antagonist, and occluded by CCPA, a selective agonist of the adenosine A1 receptor. Furthermore, reduction of endogenous adenosine by application of the enzyme adenosine deaminase also abolished the CBZ- and OXC-induced increase of EPSCs, indicating that the two drugs act as antagonists at native adenosine receptors. In conclusion, CBZ and OXC possess pro-epileptic actions at clinically-relevant concentrations through the enhancement of excitatory synaptic transmission. S-Lic by comparison has no such effect on synaptic transmission, explaining its lack of seizure exacerbation.
    Full-text · Article · Feb 2015 · Neuropharmacology
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    ABSTRACT: Rett syndrome (RTT) is a genetic disorder characterized by a range of features including cognitive impairment, gait abnormalities and a reduction in purposeful hand skills. Mice harbouring knockout mutations in the Mecp2 gene display many RTT-like characteristics and are central to efforts to find novel therapies for the disorder. As hand stereotypies and gait abnormalities constitute major diagnostic criteria in RTT, it is clear that motor and gait-related phenotypes will be of importance in assessing preclinical therapeutic outcomes. We therefore aimed to assess gait properties over the prodromal phase in a functional knockout mouse model of RTT. In male Mecp2 knockout mice, we observed alterations in stride, coordination and balance parameters at 4 weeks of age, before the onset of other overt phenotypic changes as revealed by observational scoring. These data suggest that gait measures may be used as a robust and early marker of MeCP2-dysfunction in future preclinical therapeutic studies.
    Full-text · Article · Nov 2014 · PLoS ONE
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    ABSTRACT: Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2(stop/y) male mice in which Mecp2 is silenced in all cells and female Mecp2(stop/+) mice in which Mecp2 is silenced in similar to 50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies. (C) 2014 The Authors. Published by Elsevier Inc.
    Full-text · Article · Oct 2014 · Bone
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    ABSTRACT: Cellular activity in the CA1 area of the hippocampus waxes and wanes at theta frequency (4-8Hz) during exploratory behaviour of rats. Perisomatic inhibition onto pyramidal cells tends to be strongest out of phase with pyramidal cell activity, whereas dendritic inhibition is strongest in phase with pyramidal cell activity. Synaptic plasticity also varies across the theta cycle, from strong long-term potentiation (LTP) to long-term-depression (LTD), putatively corresponding to encoding and retrieval phases for information patterns encoded by pyramidal cell activity (Hasselmo et al, 2002a). The mechanisms underpinning the phasic changes in plasticity are not clear, but it is likely that inhibition plays a role by affecting levels of electrical activity and calcium concentration at synapses. We explore the properties of synaptic plasticity during theta at Schaffer collateral synapses on CA1 pyramidal neurons and the influence of spatially and temporally targeted inhibition using a detailed multicompartmental model of the CA1 pyramidal neuron microcircuit and a phenomenological model of synaptic plasticity. The results suggest CA3-CA1 synapses are potentiated on one phase of theta due to high calcium levels provided by paired weak CA3 and layer III entorhinal cortex (EC) inputs even when somatic spiking is inhibited by perisomatic interneuron activity. Weak CA3 inputs alone induce lower calcium transients and result in depression of the CA3-CA1 synapses. These synapses are depressed if activated in phase with dendritic inhibition as strong CA3 inputs alone are not able to cause high calcium in this theta phase even though the CA1 pyramidal neuron shows somatic spiking. Dendritic inhibition acts as a switch that prevents LTP and promotes LTD during the retrieval phases of the theta rhythm in CA1 pyramidal cell. This may be important for not overly reinforcing recalled memories and in forgetting no longer relevant memories. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Sep 2014 · Hippocampus
  • Bruce P Graham · Ausra Saudargiene · Stuart Cobb
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    ABSTRACT: We use a computational model of a hippocampal CA1 pyramidal cell to demonstrate that spine head calcium provides an instantaneous readout at each synapse of the postsynaptic weighted sum of all presynaptic activity impinging on the cell. The form of the readout is equivalent to the functions of weighted, summed inputs used in neural network learning rules. Within a dendritic layer, peak spine head calcium levels are either a linear or sigmoidal function of the number of coactive synapses, with nonlinearity depending on the ability of voltage spread in the dendrites to reach calcium spike threshold. This is strongly controlled by the potassium A-type current, with calcium spikes and the consequent sigmoidal increase in peak spine head calcium present only when the A-channel density is low. Other membrane characteristics influence the gain of the relationship between peak calcium and the number of active synapses. In particular, increasing spine neck resistance increases the gain due to increased voltage responses to synaptic input in spine heads. Colocation of stimulated synapses on a single dendritic branch also increases the gain of the response. Input pathways cooperate: CA3 inputs to the proximal apical dendrites can strongly amplify peak calcium levels due to weak EC input to the distal dendrites, but not so strongly vice versa. CA3 inputs to the basal dendrites can boost calcium levels in the proximal apical dendrites, but the relative electrical compactness of the basal dendrites results in the reverse effect being less significant. These results give pointers as to how to better describe the contributions of pre- and postsynaptic activity in the learning "rules" that apply in these cells. The calcium signal is closer in form to the activity measures used in traditional neural network learning rules than to the spike times used in spike-timing-dependent plasticity.
    No preview · Article · Jul 2014 · Neural Computation
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    ABSTRACT: Numerous experimental models have been developed to reiterate endophenotypes of Rett syndrome, a neurodevelopmental disorder with a multitude of motor, cognitive and vegetative symptoms. Here, female Mecp2Stop mice [1] were characterised at mild symptomatic conditions in tests for anxiety (open field, elevated plus maze) and home cage observation systems for food intake, locomotor activity and circadian rhythms. Aged 8–9 months, Mecp2Stop mice presented with heightened body weight, lower overall activity in the open field, but no anxiety phenotype. Although home cage activity scans conducted in two different observation systems, PhenoMaster and PhenoTyper, confirmed normal circadian activity, they revealed severely compromised habituation to a novel environment in all parameters registered including those derived from a non-linear decay model such as initial exploration maximum, decay half-life of activity and span, as well as plateau. Furthermore, overall activity was significantly reduced in nocturnal periods due to reductions in both fast ambulatory movements, but also a slow lingering. In contrast, light-period activity profiles during which the amount of sleep was highest remained normal in Mecp2Stop mice. These data confirm the slow and progressive development of Rett-like symptoms in female Mecp2Stop mice resulting in a prominent reduction of overall locomotor activity, while circadian rhythms are maintained. Alterations in the time-course of habituation may indicate deficiencies in cognitive processing.
    No preview · Article · May 2013 · Behavioural brain research
  • Stuart R Cobb · Ceri H Davies

    No preview · Article · Feb 2013 · Neuropharmacology
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    ABSTRACT: Rett syndrome (RTT) is a disorder with a pronounced neurological phenotype and is caused mainly by mutations in the X-linked gene MECP2. A common feature of RTT is an abnormal EEG and a propensity for seizures. In the current study we aimed to assess brain network excitability and seizure propensity in a mouse model of RTT. Mice in which Mecp2 expression was silenced (Mecp2(stop/y)) showed a higher seizure score (mean = 6 ± 0.8 compared to 4 ± 0.2 in wild-type, WT) and more rapid seizure onset (median onset = 10 mins in Mecp2(stop/y) and 32 mins in WT) when challenged with the convulsant drug kainic acid (25mg/Kg). Hippocampal slices from Mecp2(stop/y) brain displayed no spontaneous field potential activities under control conditions but showed higher power gamma frequency field potential oscillations compared to WT in response to kainic acid (400 nM) in vitro. Brain slices challenged with the GABA(A) receptor antagonist bicuculline (0.1-10μM) and the potassium channel blocker 4-aminopyridine (1-50μM) also revealed differences between genotypes with hippocampal circuits from Mecp2(stop/y) mouse slices showing enhanced epileptiform burst duration and frequency. In contrast to these network level findings, single cell analysis of pyramidal cells by whole-cell patch clamp recording revealed no detectable differences in synaptic or biophysical properties between MeCP2-containing and MeCP2-deficient neurons. These data support the proposal that loss of MeCP2 alters network level excitability in the brain to promote epileptogenesis.
    Full-text · Article · Dec 2012 · Neuroscience
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    ABSTRACT: Typical Rett syndrome (RTT) is a pediatric disorder caused by loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. The demonstrated reversibility of RTT-like phenotypes in mice suggests that MECP2 gene replacement is a potential therapeutic option in patients. We report improvements in survival and phenotypic severity in Mecp2-null male mice after neonatal intracranial delivery of a single-stranded (ss) AAV9/chicken β-actin (CBA)-MECP2 vector. Median survival was 16.6 weeks for MECP2-treated versus 9.3 weeks for green fluorescent protein (GFP)-treated mice. ssAAV9/CBA-MECP2-treated mice also showed significant improvement in the phenotype severity score, in locomotor function, and in exploratory activity, as well as a normalization of neuronal nuclear volume in transduced cells. Wild-type (WT) mice receiving neonatal injections of the same ssAAV9/CBA-MECP2 vector did not show any significant deficits, suggesting a tolerance for modest MeCP2 overexpression. To test a MECP2 gene replacement approach in a manner more relevant for human translation, a self-complementary (sc) adeno-associated virus (AAV) vector designed to drive MeCP2 expression from a fragment of the Mecp2 promoter was injected intravenously (IV) into juvenile (4-5 weeks old) Mecp2-null mice. While the brain transduction efficiency in juvenile mice was low (~2-4% of neurons), modest improvements in survival were still observed. These results support the concept of MECP2 gene therapy for RTT.Molecular Therapy (2012); doi:10.1038/mt.2012.200.
    Full-text · Article · Sep 2012 · Molecular Therapy
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    Bruce P Graham · Ausra Saudargiene · Stuart Cobb

    Full-text · Article · Jul 2012 · BMC Neuroscience
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    ABSTRACT: Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 display a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. Although routinely classified as a neurodevelopmental disorder, many aspects of the mouse phenotype can be effectively reversed by activation of a quiescent Mecp2 gene in adults. This suggests that absence of Mecp2 during brain development does not irreversibly compromise brain function. It is conceivable, however, that deep-seated neurological defects persist in mice rescued by late activation of Mecp2. To test this possibility, we have quantitatively analysed structural and functional plasticity of the rescued adult male mouse brain. Activation of Mecp2 in ∼70% of neurons reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity. Restoration of Mecp2 expression was also accompanied by a significant improvement in respiratory and sensory-motor functions, including breathing pattern, grip strength, balance beam and rotarod performance. Our findings sustain the view that MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete.
    Full-text · Article · Apr 2012 · Brain
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    V Cutsuridis · S Cobb · Graham BP
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    ABSTRACT: Aim We have developed a microcircuit model of storage and recall in the CA1 area of the hippocampus. Central to this model is the effect of inhibition on pyramidal cell activity and plasticity. Here we look in detail at how inhibition may shape STDP profiles. Recent experimental evidence [1, 2, 3] has reported that the profiles of spike-timing-dependent plasticity (STDP) in the CA1 pyramidal neuron can be classified into two types depending on the location along the stratum radiatum (SR) dendrite: (1) A symmetric STDP profile centered at 0 ms (largest LTP value) with two distinct LTD windows at about ±20ms in the proximal SR dendrite, and (2) an asymmetric one in the distal SR dendrite. Bicuculline application revealed that GABAA is responsible for the symmetry of the STDP curve. We investigate via computer simulations the STDP symmetry-to-asymmetry transition in the proximal SR dendrite. Experiments To investigate the transition of the STDP curve from symmetry to asymmetry in the SR dendrite, we designed the following experimental paradigms: 1. Excitatory spike pairs repeatedly applied to the SR dendrite and soma for 2s (7 times at about 3 Hz) in the presence of a single pre-synaptic GABA spike slid between the interspike interval ∆τ. 2. Spike pairs repeatedly applied to the SR dendrite and soma for 2s (7 times at about 3 Hz) in the presence of a GABA inhibitory spike train presented at 100 Hz (gamma frequency) between the interspike interval . For all experimental paradigms, we varied the conductance of GABA and observed its effects on the amplitude of the proximal SR Ca2+ spike and the STDP curve.
    Full-text · Article · Apr 2012
  • Shih-Ming Weng · Mark E.S. Bailey · Stuart R Cobb
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    ABSTRACT: Rett syndrome (RTT), a neurodevelopmental condition characterized by delayed-onset loss of spoken language and the development of distinctive hand stereotypies, affects approximately 1 in 10,000 live female births. Clinical diagnosis has been based on symptoms such as loss of acquired purposeful hand skills, autistic behaviors, motor dysfunctions, seizure disorders, and gait abnormalities. RTT is a genetic disease and is caused almost exclusively by mutations in the X-linked gene, MECP2, to produce a phenotype that is thought to be primarily of neurological origin. Clinical reports show RTT patients to have a smaller brain volume, especially in the cerebral hemispheres, and alterations in various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, substance P, and various trophic factors. Because of its monogenetic characteristic, disruption of Mecp2 is readily recapitulated in mice to produce a prominent RTT-like phenotype and provide an excellent platform for understanding the pathogenesis of RTT. As shown in human studies, Mecp2 mutants also display subtle alterations in neuronal morphology, including smaller cortical neurons with a higher-packing density and reduced dendritic complexity. Neurophysiological studies in Mecp2-mutant mice consistently report alterations in synaptic function, notably, defects in synaptic plasticity. These data suggest that RTT might be regarded as a synaptopathy (disease of the synapse) and thus potentially amenable to rational therapeutic intervention.
    No preview · Article · Dec 2011 · Pediatrics & Neonatology
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    ABSTRACT: Caspase 3 activation has been linked to the acute neurotoxic effects of central nervous system damage, as in traumatic brain injury or cerebral ischaemia, and also to the early events leading to long-term neurodegeneration, as in Alzheimer's disease. However, the precise mechanisms activating caspase 3 in neuronal injury are unclear. RhoB is a member of the Rho GTPase family that is dramatically induced by cerebral ischaemia or neurotrauma, both in preclinical models and clinically. In the current study, we tested the hypothesis that RhoB might directly modulate caspase 3 activity and apoptotic or necrotic responses in neurons. Over-expression of RhoB in the NG108-15 neuronal cell line or in cultured corticohippocampal neurons elevated caspase 3 activity without inducing overt toxicity. Cultured corticohippocampal neurons from RhoB knockout mice did not show any differences in sensitivity to a necrotic stimulus - acute calcium ionophore exposure - compared with neurons from wild-type mice. However, corticohippocampal neurons lacking RhoB exhibited a reduction in the degree of DNA fragmentation and caspase 3 activation induced by the apoptotic agent staurosporine, in parallel with increased neuronal survival. Staurosporine induction of caspase 9 activity was also suppressed. RhoB knockout mice showed reduced basal levels of caspase 3 activity in the adult brain. These data directly implicate neuronal RhoB in caspase 3 activation and the initial stages of programmed cell death, and suggest that RhoB may represent an attractive target for therapeutic intervention in conditions involving elevated caspase 3 activity in the central nervous system.
    No preview · Article · Nov 2011 · European Journal of Neuroscience

  • No preview · Article · Oct 2011 · Human Gene Therapy
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    Kamal K E Gadalla · Mark E S Bailey · Stuart R Cobb
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    ABSTRACT: Mutations in the X-linked gene MECP2 (methyl CpG-binding protein 2) are the primary cause of the neurodevelopmental disorder RTT (Rett syndrome), and are also implicated in other neurological conditions. The expression product of this gene, MeCP2, is a widely expressed nuclear protein, especially abundant in mature neurons of the CNS (central nervous system). The major recognized consequences of MECP2 mutation occur in the CNS, but there is growing awareness of peripheral effects contributing to the full RTT phenotype. MeCP2 is classically considered to act as a DNA methylation-dependent transcriptional repressor, but may have additional roles in regulating gene expression and chromatin structure. Knocking out Mecp2 function in mice recapitulates many of the overt neurological features seen in RTT patients, and the characteristic postnatally delayed onset of symptoms is accompanied by aberrant neuronal morphology and deficits in synaptic physiology. Evidence that reactivation of endogenous Mecp2 in mutant mice, even at adult stages, can reverse aspects of RTT-like pathology and result in apparently functionally mature neurons has provided renewed hope for patients, but has also provoked discussion about traditional boundaries between neurodevelopmental disorders and those involving dysfunction at later stages. In the present paper we review the neurobiology of MeCP2 and consider the various genetic (including gene therapy), pharmacological and environmental interventions that have been, and could be, developed to attempt phenotypic rescue in RTT. Such approaches are already providing valuable insights into the potential tractability of RTT and related conditions, and are useful pointers for the development of future therapeutic strategies.
    Full-text · Article · Oct 2011 · Biochemical Journal
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    ABSTRACT: Synaptic plasticity is the ability of synaptic connections between neurons to be strengthened or weakened; a process that is central to the information processing within the brain and which plays a particularly important role in enabling higher cognitive processes [1,2]. Its role in disease is becoming increasingly clear across a wide spectrum of CNS disorders. Thus, for example, dysfunctional synaptic plasticity has been reported in neurodegenerative disorders such as Alzheimer's Disease (AD) as well as in schizophrenia and in a range of disorders associated with learning disabilities [3]. Moreover, maladaptive plasticity processes in response to specific external challenges are believed to underlie disorders such as addiction and post-traumatic stress disorder (PTSD). The molecular basis of normal and disease plasticity is rapidly being unravelled such that synaptic plasticity now provides a unique platform from which to launch the hunt for highly innovative drugs to treat CNS disease by either, firstly, rectifying identifiable abnormalities in these processes, or secondly, utilizing these processes as a vehicle to rectify, or bypass, other mechanisms underlying disease. In this respect, recent advances have been made in studying synaptic plasticity in humans at the molecular through to clinical level and these approaches now provide a real opportunity to test synaptic plasticity as a treatment paradigm for a wide variety of CNS disorders.
    Full-text · Article · Jul 2011 · Current Opinion in Pharmacology

Publication Stats

2k Citations
255.20 Total Impact Points


  • 2002-2015
    • University of Glasgow
      • Institute of Neuroscience and Psychology
      Glasgow, Scotland, United Kingdom
  • 2009
    • University of Stirling
      • Department of Computing Science and Mathematics
      Stirling, Scotland, United Kingdom
  • 1999-2004
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2001
    • University of Bristol
      • Centre for Synaptic Plasticity
      Bristol, ENG, United Kingdom