The marine sponge metabolite mycothiazole: a novel prototype mitochondrial complex I inhibitor.

A natural product chemistry-based approach was applied to discover small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis marine sponge extract yielded mycothiazole (1), a solid tumor selective compound with no known mechanism for its cell line-dependent cytotoxic activity. Compound 1 inhibited hypoxic HIF-1 signaling in tumor cells (IC(50) 1nM) that correlated with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 1 selectively suppresses mitochondrial respiration at complex I (NADH-ubiquinone oxidoreductase). Unlike rotenone, MPP(+), annonaceous acetogenins, piericidin A, and other complex I inhibitors, mycothiazole is a mixed polyketide/peptide-derived compound with a central thiazole moiety. The exquisite potency and structural novelty of 1 suggest that it may serve as a valuable molecular probe for mitochondrial biology and HIF-mediated hypoxic signaling

“A very orderly retreat”: Democratic transition in East Germany, 1989-90

East Germany's 1989-90 democratisation is among the best known of East European transitions, but does not lend itself to comparative analysis, due to the singular way in which political reform and democratic consolidation were subsumed by Germany's unification process. Yet aspects of East Germany's democratisation have proved amenable to comparative approaches. This article reviews the comparative literature that refers to East Germany, and finds a schism between those who designate East Germany's transition “regime collapse” and others who contend that it exemplifies “transition through extrication”. It inquires into the merits of each position and finds in favour of the latter. Drawing on primary and secondary literature, as well as archival and interview sources, it portrays a communist elite that was, to a large extent, prepared to adapt to changing circumstances and capable of learning from “reference states” such as Poland. Although East Germany was the Soviet state in which the positions of existing elites were most threatened by democratic transition, here too a surprising number succeeded in maintaining their position while filing across the bridge to market society. A concluding section outlines the alchemy through which their bureaucratic power was transmuted into property and influence in the “new Germany”

Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes

Purpose of reviewThe purpose of this review is to summarize pathogenic mechanisms and clinical implications of the most illustrative genetic entities of congenital neutropenia syndromes.Recent findingsCongenital neutropenia comprise monogenetic entities with or without additional immunologic and extrahaematopoietic syndromatic features. Continuous careful explorations of known entities such as ELANE, GFI1, HAX1, G6PC3 deficiency and XLN help to define principles controlling differentiation and function of neutrophil granulocytes. Furthermore, the identification of novel genetic defects associated with congenital neutropenia, such as VPS45 deficiency, broadens our understanding of neutrophil biology. Pathogenic mechanisms imply protein and vesicle mistrafficking, endoplasmic reticulum stress, the unfolded protein response, destabilization of the mitochondrial membrane potential, disturbed energy metabolism, dysglycosylation and deregulated actin polymerization.SummaryAdvanced genetic and biochemical techniques have helped to expand our knowledge of congenital neutropenia syndromes. Known and novel genetic entities shed light on fundamental biological processes important for the homeostatis and functioning not only of the neutrophil granulocyte but as well of the entire haematopoietic system. Furthermore, treatment decisions become more tailored and might pave the road towards personalized molecular medicine

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Progress in dark tourism and thanatourism research: An uneasy relationship with heritage tourism

This paper reviews academic research into dark tourism and thanatourism over the 1996–2016 period. The aims of this paper are threefold. First, it reviews the evolution of the concepts of dark tourism and thanatourism, highlighting similarities and differences between them. Second it evaluates progress in 6 key themes and debates. These are: issues of the definition and scope of the concepts; ethical issues associated with such forms of tourism; the political and ideological dimensions of dark tourism and thanatourism; the nature of demand for places of death and suffering; the management of such places; and the methods of research used for investigating such tourism. Third, research gaps and issues that demand fuller scrutiny are identified. The paper argues that two decades of research have not convincingly demonstrated that dark tourism and thanatourism are distinct forms of tourism, and in many ways they appear to be little different from heritage tourism

Novel oxylipins and other bioactive metabolites from marine algae

I have participated in a drug discovery program designed to screen marine algae for inhibitors of cancer-related enzymes, antitumor compounds, antiinflammatory substances, and other agents of potential pharmaceutical utility. Over 1,500 lipid and aqueous extracts of marine plants and animals were surveyed for biomedical potential. Assays designed to screen extracts for new types of marine toxins have served to guide the isolation and identification of biologically active compounds. Extracts of the Oregon marine alga Constantinea simplex were found to contain a mixture of constanolactones, and lactonized cyclopropyl-containing oxylipin metabolites that logically derive from arachidonic and eicosapentaenoic acids. Spectroscopic analysis and chiroptical measurements of the natural products and various synthetically produced derivatives afforded the structures of seven structurally related compounds. Nakienones A-C and nakitriol, a series of reactive cytotoxic metabolites, were isolated from dead and necrotic branches of stony coral (Acropora sp.) which were completely covered with a gray-black mat of cyanobacteria (Synechocystis sp.). Their structures were determined spectroscopically by interpretation of 2D-NMR experiments, including heteronuclear multiple-bond coherence spectroscopy (HMBC) and 2-D nuclear Overhauser exchange spectroscopy (NOESY), and by comparison with model compounds. Bioassay-guided fractionation of the organic extract of a Curacao Lyngbya majuscula organic extract led to the isolation of an extremely potent brine shrimp toxin with antiproliferative activity. The structure of this new thiazoline ring-containing lipid, curacin A, was deduced from spectroscopic information and comparison of products obtained from chemical degradation of the natural product with the same substances prepared by synthesis. Curacin A is an antimitotic agent that inhibits microtubule assembly and the binding of colchicine to tubulin. In addition to curacin A, a potent new ichthyotoxic depsipeptide (antillatoxin), a new malyngamide derivative, and an unusual molluscicidal compound have been isolated from this alga