Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis

Haploinsufficiency of Dll4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis. Mechanistically, it is unclear how the Dll4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that Dll4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing Dll4 with a Dll4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 inhibited tumour growth in several tumour models. Remarkably, antibodies against Dll4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that Dll4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing Dll4 had no discernable impact on intestinal goblet cell differentiation, supporting the idea that Dll4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting Dll4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours.     

A low density of 0.8 g cm(-3) for the Trojan binary asteroid 617 Patroclus

The Trojan population consists of two swarms of asteroids following the same orbit as Jupiter and located at the L4 and L5 stable Lagrange points of the Jupiter-Sun system (leading and following Jupiter by 60 degrees ). The asteroid 617 Patroclus is the only known binary Trojan. The orbit of this double system was hitherto unknown. Here we report that the components, separated by 680 km, move around the system's centre of mass, describing a roughly circular orbit. Using this orbital information, combined with thermal measurements to estimate the size of the components, we derive a very low density of 0.8(- 0.1)+0.2 g cm(-3). The components of 617 Patroclus are therefore very porous or composed mostly of water ice, suggesting that they could have been formed in the outer part of the Solar System.     

Analysis of the DNA sequence and duplication history of human chromosome 15

Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplications in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.     

A voltage-gated proton-selective channel lacking the pore domain

Voltage changes across the cell membrane control the gating of many cation-selective ion channels. Conserved from bacteria to humans, the voltage-gated-ligand superfamily of ion channels are encoded as polypeptide chains of six transmembrane-spanning segments (S1-S6). S1-S4 functions as a self-contained voltage-sensing domain (VSD), in essence a positively charged lever that moves in response to voltage changes. The VSD 'ligand' transmits force via a linker to the S5-S6 pore domain 'receptor', thereby opening or closing the channel. The ascidian VSD protein Ci-VSP gates a phosphatase activity rather than a channel pore, indicating that VSDs function independently of ion channels. Here we describe a mammalian VSD protein (H(V)1) that lacks a discernible pore domain but is sufficient for expression of a voltage-sensitive proton-selective ion channel activity. H(v)1 currents are activated at depolarizing voltages, sensitive to the transmembrane pH gradient, H+-selective, and Zn2+-sensitive. Mutagenesis of H(v)1 identified three arginine residues in S4 that regulate channel gating and two histidine residues that are required for extracellular inhibition of H(v)1 by Zn2+. H(v)1 is expressed in immune tissues and manifests the characteristic properties of native proton conductances (G(vH+)). In phagocytic leukocytes, G(vH+) are required to support the oxidative burst that underlies microbial killing by the innate immune system. The data presented here identify H(v)1 as a long-sought voltage-gated H+ channel and establish H(v)1 as the founding member of a family of mammalian VSD proteins.     

Clarifying the mechanics of DNA strand exchange in meiotic recombination

During meiosis, accurate separation of maternal and paternal chromosomes requires that they first be connected to one another through homologous recombination. Meiotic recombination has many intriguing but poorly understood features that distinguish it from recombination in mitotically dividing cells, and several of these features depend on the meiosis-specific DNA strand exchange protein Dmc1 (disrupted meiotic cDNA1). Many questions about this protein have arisen since its discovery more than a decade ago, but recent genetic and biochemical breakthroughs promise to shed light on the unique behaviours and functions of this central player in the remarkable chromosome dynamics of meiosis.     

Parasite community of the golden cownose ray Rhinoptera steindachneri Evermann and Jenkins 1891 (Chondrichthyes: Myliobatidae), in Acapulco Bay,Guerrero, Mexico

The parasite community of the ray Rhinoptera steindachneri from Acapulco Bay was examined and quantified; analyses were based on the sex of the host and the date of sampling. A total of 171 specimens of R. steindachneri were examined during July–August of 2010, and May and July of 2012. Twenty-one species of parasites were found: three species of Monogenea; eight adult and one larval species of Cestoda; one larval species of Nematoda; five species of Copepoda; two species of Isopoda; and one species of Hirudinea. Cestodes had the greatest species richness (43% of the total species), followed by the copepods (24%). Two species of cestode, Glyphobothrium sp. and Rhinebothrium sp., were collected only from adult rays. At the component community level, species richness showed statistically significant variation between 13 and 16 species, which is similar to previous reports for other species of rays. The parasite component communities and infracommunities of R. steindachneri exhibited similar patterns: high species number and low numerical dominance by a particular species of parasite. The differences of body size of male vs. female rays, and a change in diet and feeding behaviour with the age of R. steindachneri, are likely important factors in the structuring of their parasite communities.