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    ABSTRACT: Colors distinguishable with trichromatic vision can be defined by a 3D color space, such as red-green-blue or hue-saturation-lightness (HSL) space, but it remains unclear how the cortex represents colors along these dimensions. Using intrinsic optical imaging and electrophysiology, and systematically choosing color stimuli from HSL coordinates, we examined how perceptual colors are mapped in visual area V4 in behaving macaques. We show that any color activates 1-4 separate cortical patches within "globs," millimeter-sized color-preferring modules. Most patches belong to different hue or lightness clusters, in which sequential representations follow the color order in HSL space. Some patches overlap greatly with those of related colors, forming stacks, possibly representing invariable features, whereas few seem positioned irregularly. However, for any color, saturation increases the activity of all its patches. These results reveal how the color map in V4 is organized along the framework of the perceptual HSL space, whereupon different multipatch activity patterns represent different colors. We propose that such distributed and combinatorial representations may expand the encodable color space of small cortical maps and facilitate binding color information to other image features.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2014; 34(1):202-17. DOI:10.1523/JNEUROSCI.4549-12.2014
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    ABSTRACT: The prevalence of lower urinary tract storage disorders such as overactive bladder syndrome (OAB) and urinary incontinence (UI) significantly increase with age. Previous studies have shown alterations in detrusor function and urothelial transmitter release but there are few studies which have investigated how the urothelium and sensory pathways are affected. The aim of this study was to investigate the effect of ageing on urothelial-afferent signaling in the mouse bladder. To this aim, 3 month old control and 24 month old aged male mice were used in this study. In vivo natural voiding behaviour, sensory nerve activity, urothelial cell function, muscle contractility, transmitter release and gene protein expression were measured to identify how all three components of the bladder (neural, contractile and urothelial) were affected by ageing. In aged mice, increased voiding frequency and enhanced low threshold afferent nerve activity was observed suggesting that ageing induces overactivity and hypersensitivity of the bladder. These changes were concurrent with altered ATP and ACh bioavailability, measured as transmitter overflow into the lumen, increased purinergic receptor sensitivity and raised P2X3 receptor expression in the urothelium. Taken together these data suggest that ageing results in aberrant urothelial function, increased afferent mechanosensitivity, increased smooth muscle contractility and changes in gene and protein expression (including P2X3). These data are consistent with the hypothesis that ageing evokes changes in purinergic signalling from the bladder, however further studies are now required to fully validate this idea.
    The Journal of Physiology 12/2013; 592(3). DOI:10.1113/jphysiol.2013.262634
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    ABSTRACT: Angiosarcomas are rare, aggressive vascular tumours known to express vascular endothelial growth factor (VEGF), a key pro-angiogenic growth factor. The aim of this study was to determine the potential effects of vascular-targeted agents for the treatment of angiosarcoma, using two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS), and human dermal microvascular endothelial cells (HuDMECs) for comparison. Protein arrays were used to assess the expression of angiogenesis-related proteins, and potential drug targets were assessed by ELISA and Western blotting. Response to vascular-targeted agents, including bevacizumab an anti-VEGF antibody, axitinib a VEGF-receptor tyrosine kinase inhibitor, everolimus an mTOR inhibitor, selumetinib a MEK inhibitor and vadimezan a vascular-disrupting agent were compared in functional in vitro cellular assays, including viability, differentiation and migration assays. ASM and ISO-HAS cells expressed a broad range of pro-angiogenic growth factors. ASM and ISO-HAS VEGF expression was significantly increased (p = 0.029) compared with HuDMECs. Striking responses were seen to vadimezan with an IC50 of 90 and 150 μg/ml for ASM and ISO-HAS cells, respectively. Selumetinib inhibited ASM with an IC50 of 1,750 ng/ml, but was not effective in ISO-HAS. Everolimus reduced both ASM and ISO-HAS viable cell counts by 20 % (p < 0.001). Minimal responses were observed to bevacizumab and axitinib in assays with ASM and ISO-HAS cells. Further studies are warranted to investigate mTOR inhibitors, MEK inhibitors and vascular-disrupting agents for the treatment of angiosarcoma.
    Cancer Chemotherapy and Pharmacology 11/2013; 73(2). DOI:10.1007/s00280-013-2345-0
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    ABSTRACT: Spontaneous electrical activity generated by developing sensory cells and neurons is crucial for the maturation of neural circuits. The full maturation of mammalian auditory inner hair cells (IHCs) depends on patterns of spontaneous action potentials during a 'critical period' of development. The intrinsic spiking activity of IHCs can be modulated by inhibitory input from cholinergic efferent fibres descending from the brainstem, which transiently innervate immature IHCs. However, it remains unknown whether this transient efferent input to developing IHCs is required for their functional maturation. We used a mouse model that lacks the α9-nicotinic acetylcholine receptor subunit (α9nAChR) in IHCs and another lacking synaptotagmin-2 in the efferent terminals to remove or reduce efferent input to IHCs, respectively. We found that the efferent system is required for the developmental linearization of the Ca(2+)-sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their general cell development. This provides the first direct evidence that the efferent system, by modulating IHC electrical activity, is required for the maturation of the IHC synaptic machinery. The central control of sensory cell development is unique among sensory systems.
    Open Biology 11/2013; 3(11):130163. DOI:10.1098/rsob.130163
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    ABSTRACT: JAK/STAT signalling regulates multiple essential developmental processes including cell proliferation and haematopoiesis while its inappropriate activation is associated with the majority of myeloproliferative neoplasias and numerous cancers. Furthermore, high levels of JAK/STAT pathway signalling have also been associated with enhanced metastatic invasion by cancerous cells. Strikingly, gain-of-function mutations in the single Drosophila JAK homologue, Hopscotch, result in haemocyte neoplasia, inappropriate differentiation and the formation of melanised haemocyte-derived 'tumour' masses; phenotypes that are partly orthologous to human gain-of-function JAK2-associated pathologies. Here we show that Gα73B, a novel JAK/STAT pathway target gene, is necessary for JAK/STAT-mediated tumour formation in flies. In addition, while Gα73Β does not affect haemocyte differentiation, it does regulate haemocyte morphology and motility under non-pathological conditions. We show that Gα73Β is required for constitutive, but not injury-induced, activation of Rho1 and for the localisation of Rho1 into filopodia upon haemocyte activation. Consistent with these results, we also show that Rho1 interacts genetically with JAK/STAT signalling, and that wild-type levels of Rho1 are necessary for tumour formation. Our findings link JAK/STAT transcriptional outputs, Gα73Β activity and Rho1-dependent cytoskeletal rearrangements/cell motility and therefore connect a pathway associated with cancer with a marker indicative of invasiveness. As such, we suggest a mechanism via which JAK/STAT pathway signalling may promote metastasis.
    Journal of Cell Science 10/2013; 127(1). DOI:10.1242/jcs.132852
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    ABSTRACT: Human pluripotent stem cells (PSCs), whether embryonic stem cells or induced PSCs, offer enormous opportunities for regenerative medicine and other biomedical applications once we have developed the ability to harness their capacity for extensive differentiation. Central to this is our ability to identify and characterize such PSC, but this is fraught with potential difficulties that arise from a tension between functional definitions of pluripotency and the more convenient use of 'markers', a problem exacerbated by ethical issues, our lack of knowledge of early human embryonic development, and differences from the mouse paradigm.
    Neuroreport 10/2013; 24. DOI:10.1097/WNR.0000000000000040
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    ABSTRACT: Dystroglycan is frequently lost in adenocarcinoma, but the mechanisms and consequences are poorly understood. We report an analysis of β-dystroglycan in prostate cancer in human tissue samples and in LNCaP cells in vitro. There is progressive loss of β-dystroglycan immunoreactivity from basal and lateral surfaces of prostate epithelia which correlates significantly with increasing Gleason grade. In about half of matched bone metastases there is significant dystroglycan re-expression. In tumour tissue and in LNCaP cells there is also a tyrosine phosphorylation-dependent translocation of β-dystroglycan to the nucleus. Analysis of gene expression data by microarray, reveals that nuclear targeting of β-dystroglycan in LNCaP cells alters the transcription of relatively few genes, the most unregulated being the transcription factor ETV1. These data suggest that proteolysis, tyrosine phosphorylation and translocation of dystroglycan to the nucleus resulting in altered gene transcription could be important mechanisms in the progression of prostate cancer.
    Scientific Reports 09/2013; 3:2792. DOI:10.1038/srep02792
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    ABSTRACT: SNARE complex assembly constitutes a key step in exocytosis that is rendered Ca(2+)-dependent by interactions with synaptotagmin-1. Two putative sites for synaptotagmin binding have recently been identified in SNAP-25 using biochemical methods: one located around the center and another at the C-terminal end of the SNARE bundle. However, it is still unclear whether and how synaptotagmin-1 × SNARE interactions at these sites are involved in regulating fast neurotransmitter release. Here, we have used electrophysiological techniques with high time-resolution to directly investigate the mechanistic ramifications of proposed SNAP-25 × synaptotagmin-1 interaction in mouse chromaffin cells. We demonstrate that the postulated central binding domain surrounding layer zero covers both SNARE motifs of SNAP-25 and is essential for vesicle docking, priming, and fast fusion-triggering. Mutation of this site caused no further functional alterations in synaptotagmin-1-deficient cells, indicating that the central acidic patch indeed constitutes a mechanistically relevant synaptotagmin-1 interaction site. Moreover, our data show that the C-terminal binding interface only plays a subsidiary role in triggering but is required for the full size of the readily releasable pool. Intriguingly, we also found that mutation of synaptotagmin-1 interaction sites led to more pronounced phenotypes in the context of the adult neuronal isoform SNAP-25B than in the embryonic isoform SNAP-25A. Further experiments demonstrated that stronger synaptotagmin-1 × SNAP-25B interactions allow for the larger primed vesicle pool supported by SNAP-25 isoform B. Thus, synaptotagmin-1 × SNARE interactions are not only required for multiple mechanistic steps en route to fusion but also underlie the developmental control of the releasable vesicle pool.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2013; 33(36):14417-14430. DOI:10.1523/JNEUROSCI.1236-13.2013
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    ABSTRACT: Conserved from humans to Drosophila, the JAK/STAT signaling cascade is essential for multiple developmental and homeostatic processes with regulatory molecules controlling pathway activity also highly conserved. Here we characterize the Drosophila JAK/STAT pathway regulator SOCS36E and show that it functions via two independent mechanisms. Firstly we show that Drosophila Elongin B/C and Cullin 5 act via the SOCS-box of SOCS36E, to reduce pathway activity specifically in response to ligand stimulation - a process that involves endocytic trafficking and lysosomal degradation of the Domeless receptor. In addition, SOCS36E also suppresses both stimulated and basal pathway activity via an Elongin/Cullin-independent mechanism which is mediated by the N-terminus of SOCS36E which is required for the physical interaction of SOCS36E with Domeless. Although some human SOCS proteins contain N-terminal kinase inhibitory domains, we do not identify such a region in SOCS36E and propose a model where the N-terminal of SOCS36E blocks access to tyrosine residues in Dome. Our biochemical analysis of a SOCS-family regulator from a lower organism highlights the fundamental conserved roles played by regulatory mechanisms in signal transduction.
    Molecular biology of the cell 07/2013; 24(18). DOI:10.1091/mbc.E13-05-0275
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    ABSTRACT: Genomic abnormalities may accumulate in human embryonic stem cells (hESCs) during in vitro maintenance. Characterization of the mechanisms enabling survival and expansion of abnormal hESCs is important due to consequences of genetic changes for the therapeutic utilization of stem cells. Furthermore, these cells provide an excellent model to study transformation in vitro. We report here that the histone deacetylase proteins, HDAC1 and HDAC2, are increased in karyotypically abnormal hESCs when compared to their normal counterparts. Importantly, similar to many cancer cell lines, we found that HDAC inhibitors repress proliferation of the karyotypically abnormal hESCs, whereas normal cells are more resistant to the treatment. The decreased proliferation correlates with downregulation of HDAC1 and HDAC2 proteins, induction of the proliferation inhibitor, cyclin-dependent kinase inhibitor 1A (CDKN1A), and altered regulation of tumor suppressor protein Retinoblastoma 1 (RB1). Through genome-wide transcriptome analysis we have identified genes with altered expression and responsiveness to HDAC inhibition in abnormal cells. Most of these genes are linked to severe developmental and neurological diseases and cancers. Our results highlight the importance of epigenetic mechanisms in the regulation of genomic stability of hESCs, and provide valuable candidates for targeted and selective growth inhibition of karyotypically abnormal cells.
    Stem Cell Research 07/2013; 11(3):1022-1036. DOI:10.1016/j.scr.2013.07.002
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