Peptido-aminobenzophenones-novel latentiated benzo-1,4-diazepines

Summary It has been shown that cleavage of the N-terminal L-amino acids of a novel series of dipeptide derivatives of 2-aminobenzophenones occurs readily in vivo to give benzo-1,4-diazepines. Such compounds may serve as useful pro-drug forms of minor tranquillizers such as Valium^®.     

Effect of norepinephrine and vasopressin on carotid sinus baroreceptor activity in the anesthetized rabbit

Summary Norepinephrine (NE) 10^–6 M or vasopressin (VP) 12.5 U/ml were injected into the isolated carotid sinus of anesthetized rabbits. The sinus was exposed either to the arterial pressure or to a pressure controlled reservoir. Multifiber and single fiber recordings were made. Both NE and VP increased baroreceptor activity at all sinus pressures but decreased activity in a few fibers. The results are consistent with the drugs having their effects on smooth muscle fibers in the adventitia.Acknowledgments. This work was supported by grants from the Medical Research Council of Canada and the B.C. Heart Foundation. The authors are grateful to J. Sharp and D. Morton for their excellent assistance.     

The genomic and epidemiological dynamics of human influenza A virus

The evolutionary interaction between influenza A virus and the human immune system, manifest as 'antigenic drift' of the viral haemagglutinin, is one of the best described patterns in molecular evolution. However, little is known about the genome-scale evolutionary dynamics of this pathogen. Similarly, how genomic processes relate to global influenza epidemiology, in which the A/H3N2 and A/H1N1 subtypes co-circulate, is poorly understood. Here through an analysis of 1,302 complete viral genomes sampled from temperate populations in both hemispheres, we show that the genomic evolution of influenza A virus is characterized by a complex interplay between frequent reassortment and periodic selective sweeps. The A/H3N2 and A/H1N1 subtypes exhibit different evolutionary dynamics, with diverse lineages circulating in A/H1N1, indicative of weaker antigenic drift. These results suggest a sink-source model of viral ecology in which new lineages are seeded from a persistent influenza reservoir, which we hypothesize to be located in the tropics, to sink populations in temperate regions.     

Distinctively mathematical explanation and the problem of directionality: A quasi-erotetic solution

The increasing preponderance of opinion that some natural phenomena can be explained mathematically has inspired a search for a viable account of distinctively mathematical explanation. Among the desiderata for an adequate account is that it should solve the problem of directionality —the reversals of distinctively mathematical explanations should not count as members among the explanatory fold but any solution must also avoid the exclusion of genuine explanations. In what follows, I introduce and defend what I refer to as a quasi-erotetic solution which provides a remedy to the problem in the form of an additional necessary condition on explanation.     

Natural and unnatural; wild and cultural

Yellowstone National Parks mission and policy can be clarified by analysis of the natural and the unnatural. Nature is a comprehensive word, in some uses excluding nothing; more useful is a contrast distinguishing nature and culture . Specifying ""wild nature"" denotes spontaneous nature absent human influence. Critics claim that the meaning of wild nature, especially of wilderness, is a foil of culture. Pristine nature, often romanticized, is contrasted with a technological and industrial culture. By this account, wilderness is a social construction. Nevertheless, wild nature successfully denotes, outside culture, an evolutionary and ecological natural history, which remains present on the Yellowstone landscape, jeopardized by numerous human influences, including the invasions of exotic species. Natural processes have returned in the past, as when Native Americans left the landscape. Natural processes can be preserved today, because of, rather than in spite of, park management. Over much of the North American landscape nature is managed and at an end. Yellowstone provides an opportunity to encounter and to conserve ""untrammeled"" nature as an end in itself, past, present, and future.     

Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells

Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α(1)-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α(1)-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies.