The McKinsey-Tarski theorem for locally compact ordered spaces

We prove that the modal logic of a crowded locally compact generalized ordered space is S4. This provides a version of the McKinsey–Tarski theorem for generalized ordered spaces. We then utilize this theorem to axiomatize the modal logic of an arbitrary locally compact generalized ordered space

Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.

This is the final version of the article. Available from Nature Publishing Group via the DOI in this record.Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.We are grateful to all of the patients and control subjects who contributed to this study. The authors would like to acknowledge support of the Brain and Behaviour Research Foundation through a NARSAD Young Investigator Grant to TMM and from the UK Medical Research Council (MRC) (grant number MR/K013807/1) to JM. ZK would like to acknowledge funding from the NIH grant (grant number NIMH 1R21MH094771). The Douglas Bell Canada Brain Bank is supported by the FRQS through the Quebec Network on Suicide, Mood Disorders and Related Disorders, and by Brain Canada through an infrastructure grant. We acknowledge Niamh Mullins and Professor Catherine Lewis, King’s College London, for kindly supplying us with the suicide attempt GWAS data

The Birmingham Boron Neutron Capture Therapy (BNCT) project : developments towards selective internal particle therapy

This paper will review progress on two aspects of the Birmingham BNCT project. Firstly on evaluation of the effects of high and low LET radiations when delivered simultaneously, and secondly on attempts to optimise delivery of the boron carrier compound BPA through pharmacokinetic studies. Simultaneous or non-simultaneous irradiations of V79 cells with alpha-particle and X-ray irradiations were performed. Alpha doses of 2 and 2.5 Gy were chosen and the impact on survival when delivered separately or simultaneously with variable doses of X-rays was evaluated. The pharmacokinetics of the delivery of a new formulation of BPA (BPA-mannitol) are being investigated in brain tumour patients through a study with 2 × 2 design featuring intravenous and intracarotid artery infusion of BPA, with or without a mannitol bolus. On the combined effect of low and high LET radiations, a synergistic effect was observed when alpha and X-ray doses are delivered simultaneously. The effect is only present at the 2.5 Gy alpha dose and is a very substantial effect on both the shape of the survival curve and the level of cell killing. This indicates that the alpha component may have the effect of inhibiting the repair of damage from the low LET radiation dose delivered simultaneously. On the pharmacokinetics of BPA, data on the first three cohorts indicate that bioavailability of BPA in brain ECF is increased substantially through the addition of a mannitol bolus, as well as by the use of intracarotid artery route of infusion. In both cases, for some patients the levels after infusion approach those seen in blood, whereas the ECF levels for intravenous infusion without mannitol are typically less than 10% of the blood values

European “freedoms”: a critical analysis

Faced with the present migrant crisis and the dismal record of Europe in protecting vulnerable refugees’ and migrants’ rights, what could be the view of the moral philosopher? The contrast between the principles enshrined in the European Charter of Fundamental Rights and the reality of present policies is shocking, but more scrutiny will show that it is the result of a larger trend towards an understanding of freedom mostly in economic terms, at a time when economists such as Amartya Sen have revised their approach to economic growth and prosperity, noting the central role played by a much richer conception of freedom. The paper will scrutinize these inconsistencies and the conception of the person from which they derive and will provide an alternative and more coherent moral vision that could strengthen the legitimacy of the European Charter, at a time of growing dissatisfaction and so-called democratic deficit. Such a vision could help reconnect the Charter with a conception of the human person as in need not solely of passive legal protection, but also of active promotion of her self-respect and capabilities, and of her aspiration to a valuable life

Long-term effects of gestational nicotine exposure and food-restriction on gene expression in the striatum of adolescent rats

Gestational exposure to environmental toxins such as nicotine may result in detectable gene expression changes in later life. To investigate the direct toxic effects of prenatal nicotine exposure on later brain development, we have used transcriptomic analysis of striatal samples to identify gene expression differences between adolescent Lister Hooded rats exposed to nicotine in utero and controls. Using an additional group of animals matched for the reduced food intake experienced in the nicotine group, we were also able to assess the impact of imposed food-restriction on gene expression profiles. We found little evidence for a role of gestational nicotine exposure on altered gene expression in the striatum of adolescent offspring at a significance level of p0.5|, although we cannot exclude the possibility of nicotine-induced changes in other brain regions, or at other time points. We did, however, find marked gene expression differences in response to imposed food-restriction. Food-restriction resulted in significant group differences for a number of immediate early genes (IEGs) including Fos, Fosb, Fosl2, Arc, Junb, Nr4a1 and Nr4a3. These genes are associated with stress response pathways and therefore may reflect long-term effects of nutritional deprivation on the development of the stress system