Complex Propagation Patterns Characterize Human Cortical Activity during Slow-Wave Sleep

Cortical electrical activity during nonrapid eye movement (non-REM) sleep is dominated by slow-wave activity (SWA). At larger spatial scales (similar to 2-30 cm), investigated by scalp EEG recordings, SWA has been shown to propagate globally over wide cortical regions as traveling waves, which has been proposed to serve as a temporal framework for neural plasticity. However, whether SWA dynamics at finer spatial scales also reflects the orderly propagation has not previously been investigated in humans. To reveal the local, finer spatial scale (similar to 1-6 cm) patterns of SWA propagation during non-REM sleep, electrocorticographic (ECoG) recordings were conducted from subdurally implanted electrode grids and a nonlinear correlation technique [mutual information (MI)] was implemented. MI analysis revealed spatial maps of correlations between cortical areas demonstrating SWA propagation directions, speed, and association strength. Highest correlations, indicating significant coupling, were detected during the initial positive-going deflection of slow waves. SWA propagated predominantly between adjacent cortical areas, albeit spatial noncontinuities were also frequently observed. MI analysis further uncovered significant convergence and divergence patterns. Areas receiving the most convergent activity were similar to those with high divergence rate, while reciprocal and circular propagation of SWA was also frequent. We hypothesize that SWA is characterized by distinct attributes depending on the spatial scale observed. At larger spatial scales, the orderly SWA propagation dominates; at the finer scale of the ECoG recordings, non-REM sleep is characterized by complex SWA propagation patterns

The technologies of isolation: apocalypse and self in Kurosawa Kiyoshi's Kairo

In this investigation of the Japanese film Kairo, I contemplate how the horrors present in the film relate to the issue of self, by examining a number of interlocking motifs. These include thematic foci on disease and technology which are more intimately and inwardly focused that the film's conclusion first appears to suggest. The true horror here, I argue, is ontological: centred on the self and its divorcing from the exterior world, especially founded in an increased use of and reliance on communicative technologies. I contend that these concerns are manifested in Kairo by presenting the spread of technology as disease-like, infecting the city and the individuals who are isolated and imprisoned by their urban environment. Finally, I investigate the meanings of the apocalypse, expounding how it may be read as hopeful for the future rather than indicative of failure or doom

Hyperexcitability of the network contributes to synchronization processes in the human epileptic neocortex.

Interictal activity is a hallmark in epilepsy diagnostics and is linked to neuronal hypersynchrony. Little is known about perturbations in human epileptic neocortical microcircuits, and their role in generating pathological synchronies. To explore hyperexcitability of the human epileptic network, and its contribution to convulsive activity, we investigated an in vitro model of synchronous burst activity spontaneously occurring in postoperative tissue slices derived from patients with or without preoperative clinical and electrographic manifestations of epileptic activity. Human neocortical slices generated two types of synchronies. Interictal-like discharges (classified as epileptiform events) emerged only in epileptic samples, and were hypersynchronous bursts characterized by considerably elevated levels of excitation. Synchronous population activity was initiated both in epileptic and non-epileptic tissue, with a significantly lower degree of excitability and synchrony, and could not be linked to epilepsy. However, in pharmacoresistant epileptic tissue, higher percentage of slices exhibited population activity, with higher local field potential gradient amplitudes. More intracellularly recorded neurons received depolarizing synaptic potentials, discharging more reliably during the events. Light and electron microscopic examinations showed slightly lower neuron densities, and higher densities of excitatory synapses in the human epileptic neocortex. Our data suggest that human neocortical microcircuits retain their functionality and plasticity in vitro, and can generate two significantly different synchronies. We propose that population bursts might not be pathological events while interictal-like discharges may reflect the epileptogenicity of the human cortex. Our results show that hyperexcitability characterizes the human epileptic neocortical network, and that it is closely related to the emergence of synchronies. This article is protected by copyright. All rights reserved

Home Defence and the Sandys Defence White Paper, 1957

Long understood as the key document in Britain's Cold War history, the Duncan Sandys Defence White Paper of 1957 nevertheless has a largely forgotten context: home defence. This article argues that understanding this context allows important new conclusions to be drawn concerning the drafting, presentation and the reception of the document and the deterrent strategy it expounded. It argues that the Paper failed to establish a new doctrine for civil defence which reconciled the policy with the wider deterrent strategy. In doing this, the Paper presented a muddled policy to the public: one which failed to justify the reductions in civil defence provision but which stressed the destructive power of thermonuclear weapons. This had the effect of encouraging the critics of the government's nuclear strategy to flag up the absence of adequate civil defence measures and highlight the 'admission' that there was no defence against the hydrogen bomb

Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection

Chagas' disease is caused by infection with the parasite Trypanosoma cruzi. We report that infected, but not uninfected, human endothelial cells (ECs) released thromboxane A2 (TXA2). Physical chromatography and liquid chromatography-tandem mass spectrometry revealed that TXA2 is the predominant eicosanoid present in all life stages of T. cruzi. Parasite-derived TXA2 accounts for up to 90% of the circulating levels of TXA2 in infected wild-type mice, and perturbs host physiology. Mice in which the gene for the TXA2 receptor (TP) has been deleted, exhibited higher mortality and more severe cardiac pathology and parasitism (fourfold) than WT mice after infection. Conversely, deletion of the TXA2 synthase gene had no effect on survival or disease severity. TP expression on somatic cells, but not cells involved in either acquired or innate immunity, was the primary determinant of disease progression. The higher intracellular parasitism observed in TP-null ECs was ablated upon restoration of TP expression. We conclude that the host response to parasite-derived TXA2 in T. cruzi infection is possibly an important determinant of mortality and parasitism. A deeper understanding of the role of TXA2 may result in novel therapeutic targets for a disease with limited treatment options

Induction of Stable Drug Resistance in Human Breast Cancer Cells Using a Combinatorial Zinc Finger Transcription Factor Library

Combinatorial libraries of artificial zinc-finger transcription factors (ZF-TFs) provide a robust tool for inducing and understanding various functional components of the cancer phenotype. Herein, we utilized combinatorial ZF-TF library technology to better understand how breast cancer cells acquire resistance to fulvestrant, a clinically important anti-endocrine therapeutic agent. From a diverse collection of nearly 400,000 different ZF-TFs, we isolated six ZF-TF library members capable of inducing stable, long-term anti-endocrine drug-resistance in two independent estrogen receptor-positive breast cancer cell lines. Comparative gene expression profile analysis of the six different ZF-TF-transduced breast cancer cell lines revealed five distinct clusters of differentially expressed genes. One cluster was shared among all 6 ZF-TF-transduced cell lines and therefore constituted a common fulvestrant-resistant gene expression signature. Pathway enrichment-analysis of this common fulvestrant resistant signature also revealed significant overlap with gene sets associated with an estrogen receptor-negative-like state and with gene sets associated with drug resistance to different classes of breast cancer anti-endocrine therapeutic agents. Enrichment-analysis of the four remaining unique gene clusters revealed overlap with myb-regulated genes. Finally, we also demonstrated that the common fulvestrant-resistant signature is associated with poor prognosis by interrogating five independent, publicly available human breast cancer gene expression datasets. Our results demonstrate that artificial ZF-TF libraries can be used successfully to induce stable drug-resistance in human cancer cell lines and to identify a gene expression signature that is associated with a clinically relevant drug-resistance phenotype

Systematic Bias in Genomic Classification Due to Contaminating Non-neoplastic Tissue in Breast Tumor Samples

Abstract Background Genomic tests are available to predict breast cancer recurrence and to guide clinical decision making. These predictors provide recurrence risk scores along with a measure of uncertainty, usually a confidence interval. The confidence interval conveys random error and not systematic bias. Standard tumor sampling methods make this problematic, as it is common to have a substantial proportion (typically 30-50%) of a tumor sample comprised of histologically benign tissue. This "normal" tissue could represent a source of non-random error or systematic bias in genomic classification. Methods To assess the performance characteristics of genomic classification to systematic error from normal contamination, we collected 55 tumor samples and paired tumor-adjacent normal tissue. Using genomic signatures from the tumor and paired normal, we evaluated how increasing normal contamination altered recurrence risk scores for various genomic predictors. Results Simulations of normal tissue contamination caused misclassification of tumors in all predictors evaluated, but different breast cancer predictors showed different types of vulnerability to normal tissue bias. While two predictors had unpredictable direction of bias (either higher or lower risk of relapse resulted from normal contamination), one signature showed predictable direction of normal tissue effects. Due to this predictable direction of effect, this signature (the PAM50) was adjusted for normal tissue contamination and these corrections improved sensitivity and negative predictive value. For all three assays quality control standards and/or appropriate bias adjustment strategies can be used to improve assay reliability. Conclusions Normal tissue sampled concurrently with tumor is an important source of bias in breast genomic predictors. All genomic predictors show some sensitivity to normal tissue contamination and ideal strategies for mitigating this bias vary depending upon the particular genes and computational methods used in the predictor

Toward a geography of black internationalism: Bayard Rustin, nonviolence and the promise of Africa

This article charts the trip made by civil rights leader Bayard Rustin to West Africa in 1952, and examines the unpublished ‘Africa Program’ which he subsequently presented to leading American pacifists. I situate Rustin’s writings within the burgeoning literature on black internationalism which, despite its clear geographical registers, geographers themselves have as yet made only a modest contribution towards. The article argues that within this literature there remains a tendency to romanticize cross-cultural connections in lieu of critically interrogating their basic, and often competing, claims. I argue that closer attention to the geographies of black internationalism, however, allows us to shape a more diverse and practiced sense of internationalist encounter and exchange. The article reconstructs the multiplicity of Rustin’s black internationalist geographies which drew eclectically from a range of Pan-African, American and pacifist traditions. Though each of these was profoundly racialized, they conceptualized race in distinctive ways and thereby had differing understandings of what constituted the international as a geographical arena. By blending these forms of internationalism Rustin was able to promote a particular model of civil rights which was characteristically internationalist in outlook, nonviolent in principle and institutional in composition; a model which in selective and uneven ways continues to shape our understanding of the period

US hegemony and the origins of Japanese nuclear power : the politics of consent

This paper deploys the Gramscian concepts of hegemony and consent in order to explore the process whereby nuclear power was brought to Japan. The core argument is that nuclear power was brought to Japan as a consequence of US hegemony. Rather than a simple manifestation of one state exerting material ‘power over' another, bringing nuclear power to Japan involved a series of compromises worked out within and between state and civil society in both Japan and the USA. Ideologies of nationalism, imperialism and modernity underpinned the process, coalescing in post-war debates about the future trajectory of Japanese society, Japan's Cold War alliance with the USA and the role of nuclear power in both. Consent to nuclear power was secured through the generation of a psychological state in the public mind combining the fear of nuclear attack and the hope of unlimited consumption in a nuclear-fuelled post-modern world