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Dataset in support of the Southampton doctoral thesis 'Haemoglobin neurotoxicity, haptoglobin scavenging and synaptic function in subarachnoid haemorrhage'
No full textFile of all experimental data analysed for the thesis: Haemoglobin Neurotoxicity, Haptoglobin Scavenging and Synaptic Function in Subarachnoid Haemorrhage.</span
Haemoglobin neurotoxicity, haptoglobin scavenging and synaptic function in subarachnoid haemorrhage
No full textDuring subarachnoid haemorrhage, blood spreads into the subarachnoid space and surrounding tissues. Slow release of haemoglobin (Hb) from red blood cell lysis causes oxidative damage and cell death. High rates of disability and cognitive decline in SAH survivors is attributed to loss of neurons and functional connections during secondary brain injury. Haptoglobin (Hp) sequesters free Hb for clearance, but this scavenging system is overwhelmed in a haemorrhage. Hp infusion has been shown to attenuate cytotoxic effects of haemoglobin on neurons in both in vitro and in vivo models of SAH, and other haemorrhagic conditions. The functional effects of clinically relevant and sub-lethal Hb concentrations on surviving neurons, and whether cellular function can be protected with Hp treatment, remain unclear.In this thesis, the effects of a one week exposure to Hb are analysed in primary hippocampal neuron cultures. Our results demonstrate reduced ATP levels and neurite beading at a range of concentrations of haemolysate. At a sub-lethal concentration of 10 μM free Hb, which is the average Hb peak in the CSF after SAH in humans, intrinsic membrane properties are normal. However, we found a reduction in AMPA receptor-mediated current amplitude in the absence of presynaptic alterations, indicating fewer AMPA receptors at the synapse, and an overall reduction in GluA1 subunit expression. By scavenging one-third of free Hb with Hp in vitro, synaptic AMPA receptor impairment can be partially rescued and is indistinguishable from control, indicating that functional rescue can be achieved by Hp even without 1:1 stoichiometric neutralization of Hb. At higher concentrations of free Hb, higher levels of saturation with Hp can protect from ATP deficits and neurite beading. Hp in itself does not alter pre- or post-synaptic measures of synaptic neurotransmission, and has no effect on intrinsic membrane properties at 10μM. Our data highlight a role for Hb in modifying synaptic function after SAH, which may link to impaired cognition or plasticity, and the potential of haptoglobin as a therapy for subarachnoid haemorrhage
Functional effects of haemoglobin can be rescued by haptoglobin in an in vitro model of subarachnoid haemorrhage
No full textDuring subarachnoid haemorrhage, a blood clot forms in the subarachnoid space releasing extracellular haemoglobin (Hb), which causes oxidative damage and cell death in surrounding tissues. High rates of disability and cognitive decline in SAH survivors are attributed to loss of neurons and functional connections during secondary brain injury. Haptoglobin sequesters Hb for clearance, but this scavenging system is overwhelmed after a haemorrhage. Whilst exogenous haptoglobin application can attenuate cytotoxicity of Hb in vitro and in vivo, the functional effects of sub-lethal Hb concentrations on surviving neurons and whether cellular function can be protected with haptoglobin treatment remain unclear. Here we use cultured neurons to investigate neuronal health and function across a range of Hb concentrations to establish the thresholds for cellular damage and investigate synaptic function. Hb impairs ATP concentrations and cytoskeletal structure. At clinically relevant but sub-lethal Hb concentrations, we find that synaptic AMPAR-driven currents are reduced, accompanied by a reduction in GluA1 subunit expression. Haptoglobin co-application can prevent these deficits by scavenging free Hb to reduce it to sub-threshold concentrations and does not need to be present at stoichiometric amounts to achieve efficacy. Haptoglobin itself does not impair measures of neuronal health and function at any concentration tested. Our data highlight a role for Hb in modifying synaptic function in surviving neurons, which may link to impaired cognition or plasticity after SAH and support the development of haptoglobin as a therapy for subarachnoid haemorrhage. (Figure presented.)</p
A luminescence-based reporter to study tau secretion reveals overlapping mechanisms for the release of healthy and pathological tau
No full textIn Alzheimer’s disease, tau pathology is thought to spread via a prion-like manner along connected neuronal networks. For this to occur, the usually cytosolic tau protein must be secreted via an unconventional mechanism prior to uptake into the connected neuron. While secretion of healthy and pathological tau has been documented, it remains under-investigated whether this occurs via overlapping or distinct processes. Here, we established a sensitive bioluminescence-based assay to assess mechanisms underlying the secretion of pseudohyperphosphorylated and wild-type tau in cultured murine hippocampal neurons. We found that under basal conditions, both wild-type and mutant tau are secreted, with mutant tau being more robustly secreted. Pharmacological stimulation of neuronal activity led to a modest increase of wild-type and mutant tau secretion, whereas inhibition of activity had no effect. Interestingly, inhibition of heparin sulfate proteoglycan (HSPG) biosynthesis drastically decreased secretion of both wild-type and mutant tau without affecting cell viability. This shows that native and pathological tau share release mechanisms; both activity-dependent and non-activity-dependent secretion of tau is facilitated by HSPGs
Vagus Nerve Stimulation as a Potential Therapy in Early Alzheimer's Disease: A Review.
No full textCognitive dysfunction in Alzheimer's disease (AD) is caused by disturbances in neuronal circuits of the brain underpinned by synapse loss, neuronal dysfunction and neuronal death. Amyloid beta and tau protein cause these pathological changes and enhance neuroinflammation, which in turn modifies disease progression and severity. Vagal nerve stimulation (VNS), activation of the locus coeruleus (LC), results in the release of catecholamines in the hippocampus and neocortex, which can enhance synaptic plasticity and reduce inflammatory signalling. Vagal nerve stimulation has shown promise to enhance cognitive ability in animal models. Research in rodents has shown that VNS can have positive effects on basal synaptic function and synaptic plasticity, tune inflammatory signalling, and limit the accumulation of amyloid plaques. Research in humans with invasive and non-invasive VNS devices has shown promise for the modulation of cognition. However, the direct stimulation of the vagus nerve afforded with the invasive procedure carries surgical risks. In contrast, non-invasive VNS has the potential to be a broadly available therapy to manage cognitive symptoms in early AD, however, the magnitude and specificity of its effects remains to be elucidated, and the non-inferiority of the effects of non-invasive VNS as compared with invasive VNS still needs to be established. Ongoing clinical trials with healthy individuals and patients with early AD will provide valuable information to clarify the potential benefits of non-invasive VNS in cognition and AD. Whether invasive or non-invasive VNS can produce a significant improvement on memory function and whether its effects can modify the progression of AD will require further investigation
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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