A depletable pool of adenosine in area CA1 of the rat hippocampus

Adenosine plays a major modulatory and neuroprotective role in the mammalian CNS. During cerebral metabolic stress, such as hypoxia or ischemia, the increase in extracellular adenosine inhibits excitatory synaptic transmission onto vulnerable neurons via presynaptic adenosine A1 receptors, thereby reducing the activation of postsynaptic glutamate receptors. Using a combination of extracellular and whole-cell recordings in the CA1 region of hippocampal slices from 12- to 24-d-old rats, we have found that this protective depression of synaptic transmission weakens with repeated exposure to hypoxia, thereby allowing potentially damaging excitation to both persist for longer during oxygen deprivation and recover more rapidly on reoxygenation. This phenomenon is unlikely to involve A1 receptor desensitization or impaired nucleoside transport. Instead, by using the selective A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine and a novel adenosine sensor, we demonstrate that adenosine production is reduced with repeated episodes of hypoxia. Furthermore, this adenosine depletion can be reversed at least partially either by the application of exogenous adenosine, but not by a stable A1 agonist, N6-cyclopentyladenosine, or by endogenous means by prolonged (2 hr) recovery between hypoxic episodes. Given the vital neuroprotective role of adenosine, these findings suggest that depletion of adenosine may underlie the increased neuronal vulnerability to repetitive or secondary hypoxia/ischemia in cerebrovascular disease and head injury

An algorithm for Monte-Carlo time-dependent radiation transfer

A new Monte-Carlo algorithm for calculating time-dependent radiative-transfer under the assumption of LTE is presented. Unlike flux-limited diffusion the method is polychromatic, includes scattering, and is able to treat the optically thick and free-streaming regimes simultaneously. The algorithm is tested on a variety of 1-d and 2-d problems, and good agreement with benchmark solutions is found. The method is used to calculate the time-varying spectral energy distribution from a circumstellar disc illuminated by a protostar whose accretion luminosity is varying. It is shown that the time lag between the optical variability and the infrared variability results from a combination of the photon travel time and the thermal response in the disc, and that the lag is an approximately linear function of wavelength.Comment: 10 pages, 10 figures, accepted for publication by MNRA

Modeling the pore structure of voltage-gated sodium channels in closed, open, and fast-inactivated conformation reveals details of site 1 toxin and local anesthetic binding

In this work molecular modeling was applied to generate homology models of the pore region of the Na v 1.2 and Na v 1.8 isoforms of human voltage-gated sodium channels. The models represent the channels in the resting, open, and fast-inactivated states. The transmembrane portions of the channels were based on the equivalent domains of the closed and open conformation potassium channels KcsA and MthK, respectively. The critical selectivity loops were modeled using a structural template identified by a novel 3D-search technique and subsequently merged with the transmembrane portions. The resulting draft models were used to study the differences of tetrodotoxin binding to the tetrodotoxin-sensitive Na v 1.2 (EC50: 0.012μM) and -insensitive Na v 1.8 (EC50: 60μM) isoforms, respectively. Furthermore, we investigated binding of the local anesthetic tetracaine to Na v 1.8 (EC50: 12.5μM) in resting, conducting, and fast-inactivated state. In accordance with experimental mutagenesis studies, computational docking of tetrodotoxin and tetracaine provided (1) a description of site 1 toxin and local anesthetic binding sites in voltage-gated sodium channels. (2) A rationale for site 1 toxin-sensitivity versus -insensitivity in atomic detail involving interactions of the Na v 1.2 residues F385-I and W943-II. (3) A working hypothesis of interactions between Na v 1.8 in different conformational states and the local anesthetic tetracaine. Figure Tetracaine in complex with Nav1.8 in fast-inactivated form. The ligand is represented in CPK and colored by atom type. Ribbons and amino acids are colored by domain: yellow = domain I, blue = domain II, green = domain III, red = domain IV, pink = inactivation gate. Main interaction partners are shown in CPK. a) Tetracaine bound to the inner vestibule. View along the membrane plane. b) Same view as in a but limited to main interaction partners only. The polar head group of tetracaine interacts with the DEKA-motif residues, its hydrophobic tail with the hydrophobic and mainly aromatic residues of S6-IV and the inactivation gat

“Neuter-ality?” The Irish Defence Forces as an institution of masculinity during the Emergency, 1939-1945

At the very end of the Second World War, the Irish Times, recently freed from wartime censorship constraints, made a rather revealing statement. It critiqued the Irish state’s policy of neutrality as amounting to a ‘policy of national emasculation.’ Clair Wills in her excellent cultural history of the Emergency refers to this view wryly as ‘neuter-ality’- neutrality as something which was inappropriately gendered. It is perhaps easy to see why the paper saw abstention from war as emasculating. As Dudnik, Hagemann and Tosh have argued, war has long been seen as a ‘natural homeland of masculinity.’ Irish historiography has justly focussed on the connection between warfare and masculinity, with significant attention paid to the construction of masculinity during times of violence in Irish history, chiefly the Irish Revolution and the Troubles- for example, in the work of Sikata Banerjee and Aidan Beatty. The history of masculinity in the Second World War has also received ample scholarly attention, as research by Martin Francis, Sonya Rose, and Christina Jarvis has shown. While the experience of belligerent states has, perhaps unsurprisingly, tended to predominate, Christof Dejung’s work on Switzerland demonstrates that masculinity could be easily reconciled with a policy of neutrality. Significantly less research, however, has explored the construction of Irish masculinity, during the Second World War, when the Irish state remained neutral

"Neuter-ality?” The gendered debate over Neutral Ireland’s place in the Second World War

At the very end of the Second World War, the Irish Times newspaper made a rather curious statement. It critiqued the Irish state’s policy of neutrality as amounting to a ‘policy of national emasculation.’ What is particularly notable about this statement is its gendered character. Clair Willis, in her seminal cultural history of neutral Ireland in the Second War suggests that the paper saw the Irish state’s foreign policy as a form of ‘neuter-ality,’: that is to say, something that went against the ‘correct’ gendered order. That the Irish Times might see neutrality in distinctly gendered terms is unsurprising. In the words of Stefan Dudnik and Karen Hagemann and John Tosh, war has long been seen as a ‘natural homeland’ of masculinity. Since the history of masculinities emerged as distinct sub-discipline in the 1990s, the relationship between war and masculinity has attracted significant attention over the past three decades. The Second World War is no exception to this rule, as research by Martin Francis, Lindsey Robb and Sonya Rose has shown. Yet, while the experience of belligerent states has, perhaps unsurprisingly, tended to predominate, Christof Dejung’s work on Switzerland demonstrates that masculinity could be easily reconciled with a policy of neutrality.<br/

"Neuter-ality?” The gendered debate over Neutral Ireland’s place in the Second World War

At the very end of the Second World War, the Irish Times newspaper made a rather curious statement. It critiqued the Irish state’s policy of neutrality as amounting to a ‘policy of national emasculation.’ What is particularly notable about this statement is its gendered character. Clair Willis, in her seminal cultural history of neutral Ireland in the Second War suggests that the paper saw the Irish state’s foreign policy as a form of ‘neuter-ality,’: that is to say, something that went against the ‘correct’ gendered order. That the Irish Times might see neutrality in distinctly gendered terms is unsurprising. In the words of Stefan Dudnik and Karen Hagemann and John Tosh, war has long been seen as a ‘natural homeland’ of masculinity. Since the history of masculinities emerged as distinct sub-discipline in the 1990s, the relationship between war and masculinity has attracted significant attention over the past three decades. The Second World War is no exception to this rule, as research by Martin Francis, Lindsey Robb and Sonya Rose has shown. Yet, while the experience of belligerent states has, perhaps unsurprisingly, tended to predominate, Christof Dejung’s work on Switzerland demonstrates that masculinity could be easily reconciled with a policy of neutrality.<br/