ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma

Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.     

The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J

The protein predicted to be defective in individuals with Fanconi anemia complementation group J (FA-J), FANCJ, is a missing component in the Fanconi anemia pathway of genome maintenance. Here we identify pathogenic mutations in eight individuals with FA-J in the gene encoding the DEAH-box DNA helicase BRIP1, also called FANCJ. This finding is compelling evidence that the Fanconi anemia pathway functions through a direct physical interaction with DNA.     

Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion

Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a vaginal microbicide: the application of inhibitory compounds before intercourse. Here, we have evaluated the microbicide concept using the rhesus macaque 'high dose' vaginal transmission model with a CCR5-receptor-using simian-human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus-cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.     

Planning as a means of social change: The Durban Functional Region Forum case

This paper describes a regional planning effort that took place in South Africa that contributed to social change in that country. The Durban Functional Region Forum was created in 1988 with the aim of fostering coordinated long term planning for greater Durban region. It consisted of a range of participants who engaged in a planning process that continued formally until 1995, 7 years after the initial activities. The dominant concern was netative social, economic, and political trends, and the impact they were having on the region. The aim was to develop suggestions on what needed to be done to change the situation around and to initiate action on these suggestions. The forum used a form of interactive planning to support its interactions and was participative in nature. This paper describes background to this process and some of the achievements are examined. The process is described and illustrated in terms of its contribution to progressive social change as defined in the paper.     

A very energetic supernova associated with the gamma-ray burst of 29 March 2003

Over the past five years evidence has mounted that long-duration (>2 s) gamma-ray bursts (GRBs)-the most luminous of all astronomical explosions-signal the collapse of massive stars in our Universe. This evidence was originally based on the probable association of one unusual GRB with a supernova, but now includes the association of GRBs with regions of massive star formation in distant galaxies, the appearance of supernova-like 'bumps' in the optical afterglow light curves of several bursts and lines of freshly synthesized elements in the spectra of a few X-ray afterglows. These observations support, but do not yet conclusively demonstrate, the idea that long-duration GRBs are associated with the deaths of massive stars, presumably arising from core collapse. Here we report evidence that a very energetic supernova (a hypernova) was temporally and spatially coincident with a GRB at redshift z = 0.1685. The timing of the supernova indicates that it exploded within a few days of the GRB, strongly suggesting that core-collapse events can give rise to GRBs, thereby favouring the 'collapsar' model.     

Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts

Homeostasis of self-renewing small intestinal crypts results from neutral competition between Lgr5 stem cells, which are small cycling cells located at crypt bottoms. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells that are known to produce bactericidal products such as lysozyme and cryptdins/defensins. Single Lgr5-expressing stem cells can be cultured to form long-lived, self-organizing crypt-villus organoids in the absence of non-epithelial niche cells. Here we find a close physical association of Lgr5 stem cells with Paneth cells in mice, both in vivo and in vitro. CD24(+) Paneth cells express EGF, TGF-α, Wnt3 and the Notch ligand Dll4, all essential signals for stem-cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells markedly improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells. In colon crypts, CD24(+) cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell.     

Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling

The adult stem cell marker Lgr5 and its relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. We find that conditional deletion of both genes in the mouse gut impairs Wnt target gene expression and results in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition. Mass spectrometry demonstrates that Lgr4 and Lgr5 associate with the Frizzled/Lrp Wnt receptor complex. Each of the four R-spondins, secreted Wnt pathway agonists, can bind to Lgr4, -5 and -6. In HEK293 cells, RSPO1 enhances canonical WNT signals initiated by WNT3A. Removal of LGR4 does not affect WNT3A signalling, but abrogates the RSPO1-mediated signal enhancement, a phenomenon rescued by re-expression of LGR4, -5 or -6. Genetic deletion of Lgr4/5 in mouse intestinal crypt cultures phenocopies withdrawal of Rspo1 and can be rescued by Wnt pathway activation. Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues.     

Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection

There is concern that variola virus, the aetiological agent of smallpox, may be used as a biological weapon. For this reason several countries are now stockpiling (vaccinia virus-based) smallpox vaccine. Although the preventive use of smallpox vaccination has been well documented, little is known about its efficacy when used after exposure to the virus. Here we compare the effectiveness of (1) post-exposure smallpox vaccination and (2) antiviral treatment with either cidofovir (also called HPMPC or Vistide) or with a related acyclic nucleoside phosphonate analogue (HPMPO-DAPy) after lethal intratracheal infection of cynomolgus monkeys (Macaca fascicularis) with monkeypox virus (MPXV). MPXV causes a disease similar to human smallpox and this animal model can be used to measure differences in the protective efficacies of classical and new-generation candidate smallpox vaccines. We show that initiation of antiviral treatment 24 h after lethal intratracheal MPXV infection, using either of the antiviral agents and applying various systemic treatment regimens, resulted in significantly reduced mortality and reduced numbers of cutaneous monkeypox lesions. In contrast, when monkeys were vaccinated 24 h after MPXV infection, using a standard human dose of a currently recommended smallpox vaccine (Elstree-RIVM), no significant reduction in mortality was observed. When antiviral therapy was terminated 13 days after infection, all surviving animals had virus-specific serum antibodies and antiviral T lymphocytes. These data show that adequate preparedness for a biological threat involving smallpox should include the possibility of treating exposed individuals with antiviral compounds such as cidofovir or other selective anti-poxvirus drugs.     

Episodic fresh surface waters in the Eocene Arctic Ocean

It has been suggested, on the basis of modern hydrology and fully coupled palaeoclimate simulations, that the warm greenhouse conditions that characterized the early Palaeogene period (55-45 Myr ago) probably induced an intensified hydrological cycle with precipitation exceeding evaporation at high latitudes. Little field evidence, however, has been available to constrain oceanic conditions in the Arctic during this period. Here we analyse Palaeogene sediments obtained during the Arctic Coring Expedition, showing that large quantities of the free-floating fern Azolla grew and reproduced in the Arctic Ocean by the onset of the middle Eocene epoch (approximately 50 Myr ago). The Azolla and accompanying abundant freshwater organic and siliceous microfossils indicate an episodic freshening of Arctic surface waters during an approximately 800,000-year interval. The abundant remains of Azolla that characterize basal middle Eocene marine deposits of all Nordic seas probably represent transported assemblages resulting from freshwater spills from the Arctic Ocean that reached as far south as the North Sea. The termination of the Azolla phase in the Arctic coincides with a local sea surface temperature rise from approximately 10 degrees C to 13 degrees C, pointing to simultaneous increases in salt and heat supply owing to the influx of waters from adjacent oceans. We suggest that onset and termination of the Azolla phase depended on the degree of oceanic exchange between Arctic Ocean and adjacent seas.