Effect of thiamine analogs on the electrical activity of the rabbit vagus nerve

Zusammenfassung Der Einfluss einer Anzahl Thiamin-analoga auf die elektrische Aktivität des Vagus wurde untersucht. Das Äthylanalogon des Pyrithiamins hatte mindestens die zehnfache Wirkung des Pyrithiamins auf die Erhöhung der Amplitude des Aktionspotentials. Die Resultate stimmen gut überein mit der Fähigkeit dieser Antimetabolite, in vivo Polyneuritis hervorzurufen.

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This work was supported by grants from the US Public Health Service, Merck, Sharp and Dohme, and The Burroughs Wellcome Company.     

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.     

Kant's universal conception of natural history

Scholars often draw attention to the remarkably individual and progressive character of Kant's Universal Natural History and Theory of the Heavens (1755). What is less often noted, however, is that Kant's project builds on several transformations that occurred in natural science during the seventeenth and eighteenth centuries. Without contextualising Kant's argument within these transformations, the full sense of Kant's achievement remains unseen. This paper situates Kant's essay within the analogical form of Newtonianism developed by a diverse range of naturalists including Georges Buffon, Albrecht von Haller and Thomas Wright. It argues that Kant's universal conception of natural history can be viewed within the free-thinking and anti-clerical movement associated with Buffon. This does not mean, however, that it breaks from the methodological rules of Newtonianism. The claim of this paper is that Kant's essay contributes to the transformation of natural history from a logical system of classification to an explanation for the physical diversity of natural products according to laws.     

A Bayesian Approach to Modelling the Observed Bovine Spongiform Encephalopathy Epidemic

The threat of Bovine Spongiform Encephalopathy (BSE) to humans was realized in March 1996, when the Spongiform Encephalopathy Advisory Committee (SEAC) reported to the government that the most likely explanation of the new variant Creutsfeldt–Jakob Disease (nvCJD) in humans was exposure to the BSE agent. To assess the potential risk of nvCJD, it is necessary to understand the development of the BSE epidemic within the cattle population. This paper reports on work undertaken to model the observed BSE epidemic in the UK using established Bayesian methodology. © 1997 John Wiley & Sons, Ltd.     

The mental wealth of nations

Countries must learn how to capitalize on their citizens' cognitive resources if they are to prosper, both economically and socially. Early interventions will be key.     

Observations on the reproduction and embryology of the Lahontan tui chub, Gila bicolor, in Walker Lake, Nevada

Various aspects of the reproduction and embryology of Walker Lake Lahontan tui chub, Gila bicolor , were investigated during the spring–summer period of 1976, 1977, and 1981. Tui chub were found to spawn in littoral regions of the lake beginning in late May or early June. Early in the season male chub substantially outnumbered females over the spawning grounds, with a normal 1:1 sex ratio gradually approached as the season progressed. The developmental period between fertilization to hatch-out was shortened by increases in water temperature. Selected stages of embryonic development are described from egg fertilization through post-hatch.     

A semiconductor source of triggered entangled photon pairs

Entangled photon pairs are an important resource in quantum optics, and are essential for quantum information applications such as quantum key distribution and controlled quantum logic operations. The radiative decay of biexcitons-that is, states consisting of two bound electron-hole pairs-in a quantum dot has been proposed as a source of triggered polarization-entangled photon pairs. To date, however, experiments have indicated that a splitting of the intermediate exciton energy yields only classically correlated emission. Here we demonstrate triggered photon pair emission from single quantum dots suggestive of polarization entanglement. We achieve this by tuning the splitting to zero, through either application of an in-plane magnetic field or careful control of growth conditions. Entangled photon pairs generated 'on demand' have significant fundamental advantages over other schemes, which can suffer from multiple pair emission, or require post-selection techniques or the use of photon-number discriminating detectors. Furthermore, control over the pair generation time is essential for scaling many quantum information schemes beyond a few gates. Our results suggest that a triggered entangled photon pair source could be implemented by a simple semiconductor light-emitting diode.