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    ABSTRACT: The atrial volume receptor reflex arc serves to regulate plasma volume. Atrial volume receptors located in the endocardium of the atrial wall undergo mechanical deformation as blood is returned to the atria of the heart. The mechanosensitive channel(s) responsible for regulating plasma volume remain to be determined. Here we report that the TRP channel family members TRPC1 and TRPV4 were expressed in sensory nerve endings in the atrial endocardium. Furthermore, TRPC1 and TRPV4 were coincident with the nerve ending vesicle marker synaptophysin. Calcitonin gene related peptide was exclusively confined to the myo- and epicardium of the atria. The small conductance Ca(2+)-activated K(+) channels (SK2 and SK4) were also present, however there was no relationship between SK and TRP channels. SK2 channels were expressed in nerves in the epicardium, while SK4 channels were in some regions of the endocardium but appeared to be present in epithelial cells rather than sensory endings. In conclusion, we have provided the first evidence for TRPC1 and TRPV4 channels as potential contributors to mechanosensation in the atrial volume receptors.
    Neuroscience 03/2014;
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    ABSTRACT: LINC (Linker of Nucleoskeleton and Cytoskeleton) complex is an evolutionary conserved structure that spans the entire nuclear envelope (NE), and integrates the nuclear interior with the cytoskeleton, in order to support a diverse array of fundamental biological processes. A key component of the LINC complex are nesprins (Nuclear Envelope SPectrin Repeat proteINS) that were initially described as large integral NE proteins. However, nesprin genes are complex and generate many variants, which occupy various sub-cellular compartments suggesting additional functions. Hence, the potential involvement of nesprins in disease has expanded immensely on what we already know. That is, nesprins are implicated in diseases such as: cancer, myopathies, arthrogryposis, neurological disorders and hearing loss. Here we review nesprins by providing an in depth account of their structure, molecular interactions and cellular functions with relevance to their potential roles in disease. Specifically, we speculate about possible pathomechanisms underlying nesprin-associated diseases.
    Seminars in Cell and Developmental Biology 12/2013;
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    ABSTRACT: A pathological feature of heart failure (HF) is abnormal control of the sympathetic nervous system. The paraventricular nucleus of the hypothalamus (PVN) is one of the most important central sites involved in regulating sympathetic tone and is in part responsible for the dysregulation of the sympathetic nervous system evident in HF. Generation of sympathetic tone in response to fluctuations in cardiovascular regulation utilises discrete anatomical pathways and neurochemical modulators. Direct and indirect projections from the PVN-preautonomic neurons innervate the sympathetic preganglionic neurons in the spinal cord, which in turn innervate sympathetic ganglia that give rise to the sympathetic nerves. Preautonomic neurons of the PVN themselves receive an afferent input arising from the nucleus tractus solitarii (NTS) and viscerosensory receptors convey cardiovascular fluctuations to the NTS. The PVN contains excitatory and inhibitory neurons, whose balance determines the sympathetic tone. In non-pathological conditions the tonic inhibition of the PVN-preautonomic neurons is mediated by γ-aminobutyric acid (GABA) and nitric oxide (NO) releasing neurons. In HF, the preautonomic neurons are disinhibited by the actions of the excitatory neurotransmitters glutamate and angiotensin II (ANGII) leading to increased sympathetic activity. A key feature of the disinhibition is a reduction in the bioavailability of NO as a consequence of disrupted CAPON and PIN signalling mechanisms within the neuron. Another critical feature that contributes to increased neuronal excitation within the PVN is the production of proinflammatory cytokines immediately following a myocardial infarction, the activation of the ANGII-type-1 receptor and the production of reactive oxygen species. By examining the changes associated with the sympathetic nervous system pathway we will progress our understanding of sympathetic regulation in HF, identify gaps in our knowledge and suggest new therapeutic strategies.
    Experimental physiology 12/2013;
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    ABSTRACT: We have recently developed a range of synthetic retinoid analogues which include the compounds EC23 and EC19. They are stable on exposure to light and are predicted to be resistant to the normal metabolic processes involved in the inactivation of retinoids in vivo. Based on the position of the terminal carboxylic acid groups in the compounds we suggest that EC23 is a structural analogue of all-trans retinoic acid (ATRA), and EC19 is an analogue of 13-cis retinoic acid. Their effects on the differentiation of pluripotent stem cells has been previously described in vitro and are consistent with this hypothesis. We present herein the first description of the effects of these molecules in vivo. Retinoids were applied to the anterior limb buds of chicken embryos in ovo via ion-exchange beads. We found that retinoid EC23 produces effects on the wing digits similar to ATRA, but does so at two orders of magnitude lower concentration. When larger quantities of EC23 are applied, a novel phenotype is obtained involving production of multiple digit 1s on the anterior limb. This corresponds to differential effects of ATRA and EC23 on sonic hedgehog (shh) expression in the developing limb bud. With EC23 application we also find digit 1 phenotypes similar to thumb duplications described in the clinical literature. EC23 and ATRA are shown to have effects on the entire proximal-distal axis of the limb, including hitherto undescribed effects on the scapula. This includes suppression of expression of the scapula marker Pax1. EC23 also produces effects similar to those of ATRA on the developing face, producing reductions of the upper beak at concentrations two orders of magnitude lower than ATRA. In contrast, EC19, which is structurally very similar to EC23, has novel, less severe effects on the face and rarely alters limb development. EC19 and ATRA are effective at similar concentrations. These results further demonstrate the ability of retinoids to influence embryonic development. Moreover, EC23 represents a useful new tool to investigate developmental processes and probe the mechanisms underlying congenital abnormalities in vertebrates including man.
    Journal of Anatomy 12/2013;
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    ABSTRACT: Artificial epidermis can be reconstituted in vitro by seeding primary epidermal cells (keratinocytes) onto a supportive substrate and then growing the developing skin equivalent at the air-liquid interface. In vitro skin models are widely used to study skin biology and for industrial drug and cosmetic testing. Here, we describe updated methods for growing 3-dimensional skin equivalents using de-vitalized, de-epidermalized dermis (DED) substrates including methods for DED substrate preparation, cell seeding, growth conditions, and fixation procedures.
    Methods in molecular biology (Clifton, N.J.) 11/2013;
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    ABSTRACT: This study describes the development of a functional porous polymer for use as a scaffold to support 3D hepatocyte culture. A high internal phase emulsion (HIPE) is prepared containing the monomers styrene (STY), divinylbenzene (DVB), and 2-ethylhexyl acrylate (EHA) in the external oil phase and the monomer acrylic acid (Aa) in the internal aqueous phase. Upon thermal polymerization with azobisisobutyronitrile (AIBN), the resulting porous polymer (polyHIPE) is found to have an open-cell morphology and a porosity of 89%, both suitable characteristics for 3D cell scaffold applications. X-ray photo-electron spectroscopy reveals that the polyHIPE surface contained 7.5% carboxylic acid functionality, providing a useful substrate for subsequent surface modifications and bio-conjugations. Initial bio-compatibility assessments with human hepatocytes show that the acid functionality does not have any detrimental effect on cell adhesion. It is therefore believed that this material can be a useful precursor scaffold towards 3D substrates that offer tailored surface functionality for enhanced cell adhesion.
    Macromolecular Rapid Communications 11/2013;
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    ABSTRACT: The laboratory mouse is a key animal model for studies of adipose biology, metabolism and disease, yet the developmental changes that occur in tissues and cells that become the adipose layer in mouse skin have received little attention. Moreover, the terminology around this adipose body is often confusing, as frequently no distinction is made between adipose tissue within the skin, and so called subcutaneous fat. Here adipocyte development in mouse dorsal skin was investigated from before birth to the end of the first hair follicle growth cycle. Using Oil Red O staining, immunohistochemistry, quantitative RT-PCR and TUNEL staining we confirmed previous observations of a close spatio-temporal link between hair follicle development and the process of adipogenesis. However, unlike previous studies, we observed that the skin adipose layer was created from cells within the lower dermis. By day 16 of embryonic development (e16) the lower dermis was demarcated from the upper dermal layer, and commitment to adipogenesis in the lower dermis was signalled by expression of FABP4, a marker of adipocyte differentiation. In mature mice the skin adipose layer is separated from underlying subcutaneous adipose tissue by the panniculus carnosus. We observed that the skin adipose tissue did not combine or intermix with subcutaneous adipose tissue at any developmental time point. By transplanting skin isolated from e14.5 mice (prior to the start of adipogenesis), under the kidney capsule of adult mice, we showed that skin adipose tissue develops independently and without influence from subcutaneous depots. This study has reinforced the developmental link between hair follicles and skin adipocyte biology. We argue that because skin adipocytes develop from cells within the dermis and independently from subcutaneous adipose tissue, that it is accurately termed dermal adipose tissue and that, in laboratory mice at least, it represents a separate adipose depot.
    PLoS ONE 10/2013; 8(3):e59811.
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    ABSTRACT: The histamine field has moved on rapidly in the last four years, with expansion in roles and clinical development, particularly in the newest two of four histamine receptors. This themed volume is a testament to this expansion with 16 original and review articles spanning a wide spectrum of histamine-related topics, with therapeutic translational relevance to addiction, dementias, anxiety disorders, cancers, vestibular disorders, migraine and autoimmune disorders. This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1.
    British Journal of Pharmacology 09/2013; 170(1):1-3.
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    ABSTRACT: Understanding the evolution of diversity and the resulting systematics in marine systems is confounded by the lack of clear boundaries in oceanic habitats, especially for highly mobile species like marine mammals. Dolphin populations and sibling species often show differentiation between coastal and offshore habitats, similar to the pelagic/littoral or benthic differentiation seen for some species of fish. Here we test the hypothesis that lineages within the polytypic genus Tursiops track past changes in the environment reflecting ecological drivers of evolution facilitated by habitat release. We used a known recent time point for calibration (the opening of the Bosphorus) and whole mitochondrial genome (mitogenome) sequences for high phylogenetic resolution. The pattern of lineage formation suggested an origin in Australasia and several early divisions involving forms currently inhabiting coastal habitats. Radiation in pelagic environments was relatively recent, and was likely followed by a return to coastal habitat in some regions. The timing of some nodes defining different ecotypes within the genus clustered near the two most recent interglacial transitions. A signal for an increase in diversification was also seen for dates after the last glacial maximum. Together these data suggest the tracking of habitat preference during geographic expansions, followed by transition points reflecting habitat shifts, which were likely associated with periods of environmental change.
    Systematic Biology 08/2013;
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    ABSTRACT: The cause and mechanism of development of Alzheimer's disease (AD) remain unexplained. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, denoted by adrenal cortisol hypersecretion, is a recognised feature of the condition but generally disregarded as causative, due to lack of association between AD and other hypercortisolemic states. However, a meta-analysis of published studies suggests a need for reappraisal. A specific circadian rhythm of cortisol hypersecretion pertains at mild-to-moderate AD stages, entailing increased levels at the circadian peak from a low nadir. This is in contrast to the continuously elevated levels that are characteristic of other hypercortisolemic states, e.g. Cushing's disease or major depression. This previously overlooked detail provides a starting premise here: that equating the form of hypercortisolism in AD with that in other states is inappropriate, as phasic and chronic elevation elicit different neuroendocrine effects. Theoretical implications are discussed in this review. Given the capacity of glucocorticoids and corticotropin-releasing hormone to induce AD-associated pathologies, I suggest a role for circadian cortisol hypersecretion in the initiation of sporadic AD; and propose a temporal mechanism for AD development featuring neuroinflammation-mediated suppression of central glucocorticoid receptor (GR) signaling. This latter may represent a critical phase in AD development, where the density of functional GR is proposed to underlie the "cognitive reserve". Supporting evidence for this mechanism is drawn from the brain regional locations of AD neuropathologies, and from risk factors for AD development (aging, ApoE-4 genotype, and hypertension). Thus, it is argued that basal hypercortisolemia merits further scrutiny regarding AD causation and development.
    Current Alzheimer research 07/2013;
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