Neuroprotective function for ramified microglia in hippocampal excitotoxicity

<p>Abstract</p> <p>Background</p> <p>Most of the known functions of microglia, including neurotoxic and neuroprotective properties, are attributed to morphologically-activated microglia. Resting, ramified microglia are suggested to primarily monitor their environment including synapses. Here, we show an active protective role of ramified microglia in excitotoxicity-induced neurodegeneration.</p> <p>Methods</p> <p>Mouse organotypic hippocampal slice cultures were treated with <it>N</it>-methyl-D-aspartic acid (NMDA) to induce excitotoxic neuronal cell death. This procedure was performed in slices containing resting microglia or slices that were chemically or genetically depleted of their endogenous microglia.</p> <p>Results</p> <p>Treatment of mouse organotypic hippocampal slice cultures with 10-50 μM <it>N</it>-methyl-D-aspartic acid (NMDA) induced region-specific excitotoxic neuronal cell death with CA1 neurons being most vulnerable, whereas CA3 and DG neurons were affected less. Ablation of ramified microglia severely enhanced NMDA-induced neuronal cell death in the CA3 and DG region rendering them almost as sensitive as CA1 neurons. Replenishment of microglia-free slices with microglia restored the original resistance of CA3 and DG neurons towards NMDA.</p> <p>Conclusions</p> <p>Our data strongly suggest that ramified microglia not only screen their microenvironment but additionally protect hippocampal neurons under pathological conditions. Morphological activation of ramified microglia is thus not required to influence neuronal survival.</p

Equipoise across the patient population: Optimising recruitment to a randomised controlled trial

© 2016 The Author(s). Background: This paper proposes a novel perspective on the value of qualitative research for improving trial design and optimising recruitment. We report findings from a qualitative study set within the OPEN trial, a surgical randomised controlled trial (RCT) comparing two interventions for recurrent bulbar urethral stricture, a common cause of urinary problems in men. Methods: Interviews were conducted with men meeting trial eligibility criteria (n = 19) to explore reasons for accepting or declining participation and with operating urologists (n = 15) to explore trial acceptability. Results: Patients expressed various preferences and understood these in the context of relative severity and tolerability of their symptoms. Accounts suggest a common trajectory of worsening symptoms with a particular window within which either treatment arm would be considered acceptable. Interviews with clinician recruiters found that uncertainty varied between general and specialist sites, which reflect clinicians' relative exposure to different proportions of the patient population. Conclusion: Recruitment post referral, at specialist sites, was challenging due to patient (and clinician) expectations. Trial design, particularly where there are fixed points for recruitment along the care pathway, can enable or constrain the possibilities for effective accrual depending on how it aligns with the optimum point of patient equipoise. Qualitative recruitment investigations, often focussed on information provision and patient engagement, may also look to better understand the target patient population in order to optimise the point at which patients are approached. Trial registration: ISRCTN Registry, ISRCTN98009168. Registered on 29 November 2012

Towards an understanding of contextual features that influence the linguistic formality of British Sign Language users

This paper seeks to understand linguistic formality through the identification and measurement of contextual features. Using an adapted sociometric methodology to combine systemic functional linguistics and sign linguistics, a survey identifies the elements of context that have an effect upon the level of linguistic formality employed by British Sign Language users. The responses of 51 participants are analysed in order to ascertain (i) the level of linguistic formality that would be employed in certain communicative scenarios, and (ii) the contextual features of these scenarios that have an influence on linguistic formality. The results obtained from this study posit that there is an overall agreement shared between British Sign Language users when choosing levels of linguistic formality based on broad contextual description alone. The people involved in the communication and their interpersonal relationships tend to be the biggest influence on the level of formality employed, whereas the topic of the interaction appears to show no significant influence upon linguistic formality on its own. This work contributes further evidence to the importance of studying language within communicative contexts and the importance of formality as an influential factor in linguistic production. It is hoped that this will encourage future studies to derive linguistic data of British Sign Language users, or indee

‘Friends call me racist’: Experiences of repercussions from writing comments on newspaper websites

acceptedVersio

Island survivors: population genetic structure and demography of the critically endangered giant lizard of La Gomera, Gallotia bravoana

Background: The giant lizard of La Gomera (Gallotia bravoana), is an endemic lacertid of this Canary Island that lives confined to a very restricted area of occupancy in a steep cliff, and is catalogued as Critically Endangered by IUCN. We present the first population genetic analysis of the wild population as well as of captive-born individuals (for which paternity data are available) from a recovery center. Current genetic variability, and inferred past demographic changes were determined in order to discern the relative contribution of natural versus human-mediated effects on the observed decline in population size. Results: Genetic analyses indicate that the only known natural population of the species shows low genetic diversity and acts as a single evolutionary unit. Demographic analyses inferred a prolonged decline of the species for at least 230 generations. Depending on the assumed generation time, the onset of the decline was dated between 1200-13000 years ago. Pedigree analyses of captive individuals suggest that reproductive behavior of the giant lizard of La Gomera may include polyandry, multiple paternity and female long-term sperm retention. Conclusions: The current low genetic diversity of G. bravoana is the result of a long-term gradual decline. Because generation time is unknown in this lizard and estimates had large credibility intervals, it is not possible to determine the relative contribution of humans in the collapse of the population. Shorter generation times would favor a stronger influence of human pressure whereas longer generation times would favor a climate-induced origin of the decline. In any case, our analyses show that the wild population has survived for a long period of time with low levels of genetic diversity and a small effective population size. Reproductive behavior may have acted as an important inbreeding avoidance mechanism allowing the species to elude extinction. Overall, our results suggest that the species retains its adaptive potential and could restore its ancient genetic diversity under favorable conditions. Therefore, management of the giant lizard of La Gomera should concentrate efforts on enhancing population growth rates through captive breeding of the species as well as on restoring the carrying capacity of its natural habitat.Spanish Ministry of Education; European Life Project [LIFE 02 NAT-E-008614]; Ministerio de Ciencia e Innovacion [REN 2001- 1514/GLO, CGL 2010-18216]info:eu-repo/semantics/publishedVersio

Static Magnetic Field Exposure Reproduces Cellular Effects of the Parkinson's Disease Drug Candidate ZM241385

This study was inspired by coalescing evidence that magnetic therapy may be a viable treatment option for certain diseases. This premise is based on the ability of moderate strength fields (i.e., 0.1 to 1 Tesla) to alter the biophysical properties of lipid bilayers and in turn modulate cellular signaling pathways. In particular, previous results from our laboratory (Wang et al., BMC Genomics, 10, 356 (2009)) established that moderate strength static magnetic field (SMF) exposure altered cellular endpoints associated with neuronal function and differentiation. Building on this background, the current paper investigated SMF by focusing on the adenosine A(2A) receptor (A(2A)R) in the PC12 rat adrenal pheochromocytoma cell line that displays metabolic features of Parkinson's disease (PD).SMF reproduced several responses elicited by ZM241385, a selective A(2A)R antagonist, in PC12 cells including altered calcium flux, increased ATP levels, reduced cAMP levels, reduced nitric oxide production, reduced p44/42 MAPK phosphorylation, inhibited proliferation, and reduced iron uptake. SMF also counteracted several PD-relevant endpoints exacerbated by A(2A)R agonist CGS21680 in a manner similar to ZM241385; these include reduction of increased expression of A(2A)R, reversal of altered calcium efflux, dampening of increased adenosine production, reduction of enhanced proliferation and associated p44/42 MAPK phosphorylation, and inhibition of neurite outgrowth.When measured against multiple endpoints, SMF elicited qualitatively similar responses as ZM241385, a PD drug candidate. Provided that the in vitro results presented in this paper apply in vivo, SMF holds promise as an intriguing non-invasive approach to treat PD and potentially other neurological disorders

P1 receptors and cytokine secretion

Evidence has accumulated in the last three decades to suggest tissue protection and regeneration by adenosine in multiple different cell types. Adenosine produced in hypoxic or inflamed environments reduces tissue injury and promotes repair by receptor-mediated mechanisms. Among other actions, regulation of cytokine production and secretion by immune cells, astrocytes and microglia (the brain immunocytes) has emerged as a main mechanism at the basis of adenosine effects in diseases characterized by a marked inflammatory component. Many recent studies have highlighted that signalling through A1 and A2A adenosine receptors can powerfully prevent the release of pro-inflammatory cytokines, thus inhibiting inflammation and reperfusion injury. However, the activation of adenosine receptors is not invariably protective of tissues, as signalling through the A2B adenosine receptor has been linked to pro-inflammatory actions which are, at least in part, mediated by increased release of pro-inflammatory cytokines from epithelial cells, astrocytes and fibroblasts. Here, we discuss the multiple actions of P1 receptors on cytokine secretion, by analyzing, in particular, the role of the various adenosine receptor subtypes, the complex reciprocal interplay between the adenosine and the cytokine systems, their pathophysiological significance and the potential of adenosine receptor ligands as new anti-inflammatory agents

Trust-building strategies in corporate discourse:An experimental study

This paper presents a scenario-based experiment designed to test the effects of trust-building strategies, realised in stance-taking acts, which a previous corpus-based study found to be salient features of stakeholder-facing corporate communication. The experiment relies on a between-subjects design in which a target group of subjects are exposed to trust-building strategies while another control group are not. We apply this paradigm to corporate discourse in the form of an About Us webpage produced by a fictitious multinational pharmaceutical company that has been accused by a whistleblower of corporate misconduct. The results of the study show that these strategies are indeed effective in fostering trust in the company and have an indirect positive effect on the perceived credibility of the company’s denial in response to the allegations made by the whistleblower. The strategies are therefore able to mitigate the potential damage caused by public accusations of wrongdoing and help companies insure against future threats to their legitimacy and freedom to operate, as when their behaviour violates, or is said to violate, societal norms and values. Theoretically, the results provide insights into the psychological mechanisms of trust-building and reader response. Methodologically, the study contributes to the growing body of work using experimental methods in CDA by further demonstrating that experimentation can usefully complement more traditional discourse-analytical methods as a form of triangulation