Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells

The classical view of neural plate development held that it arises from the ectoderm, after its separation from the mesodermal and endodermal lineages. However, recent cell-lineage-tracing experiments indicate that the caudal neural plate and paraxial mesoderm are generated from common bipotential axial stem cells originating from the caudal lateral epiblast. Tbx6 null mutant mouse embryos which produce ectopic neural tubes at the expense of paraxial mesoderm must provide a clue to the regulatory mechanism underlying this neural versus mesodermal fate choice. Here we demonstrate that Tbx6-dependent regulation of Sox2 determines the fate of axial stem cells. In wild-type embryos, enhancer N1 of the neural primordial gene Sox2 is activated in the caudal lateral epiblast, and the cells staying in the superficial layer sustain N1 activity and activate Sox2 expression in the neural plate. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer N1 before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer N1 activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes. An enhancer-N1-specific deletion mutation introduced into Tbx6 mutant embryos prevented this Sox2 activation in the mesodermal compartment and subsequent development of ectopic neural tubes, indicating that Tbx6 regulates Sox2 via enhancer N1. Tbx6-dependent repression of Wnt3a in the paraxial mesodermal compartment is implicated in this regulatory process. Paraxial mesoderm-specific misexpression of a Sox2 transgene in wild-type embryos resulted in ectopic neural tube development. Thus, Tbx6 represses Sox2 by inactivating enhancer N1 to inhibit neural development, and this is an essential step for the specification of paraxial mesoderm from the axial stem cells.     

Earliest evidence of mammalian social behaviour in the basal Tertiary of Bolivia

The vast majority of Mesozoic and early Cenozoic metatherian mammals (extinct relatives of modern marsupials) are known only from partial jaws or isolated teeth, which give insight into their probable diets and phylogenetic relationships but little else. The few skulls known are generally crushed, incomplete or both, and associated postcranial material is extremely rare. Here we report the discovery of an exceptionally large number of almost undistorted, nearly complete skulls and skeletons of a stem-metatherian, Pucadelphys andinus, in the early Palaeocene epoch of Tiupampa in Bolivia. These give an unprecedented glimpse into early metatherian morphology, evolutionary relationships and, especially, ecology. The remains of 35 individuals have been collected, with 22 of these represented by nearly complete skulls and associated postcrania. These individuals were probably buried in a single catastrophic event, and so almost certainly belong to the same population. The preservation of multiple adult, sub-adult and juvenile individuals in close proximity (<1?m(2)) is indicative of gregarious social behaviour or at least a high degree of social tolerance and frequent interaction. Such behaviour is unknown in living didelphids, which are highly solitary and have been regarded, perhaps wrongly, as the most generalized living marsupials. The Tiupampan P.?andinus population also exhibits strong sexual dimorphism, which, in combination with gregariousness, suggests strong male-male competition and polygyny. Our study shows that social interactions occurred in metatherians as early as the basal Palaeocene and that solitary behaviour may not be plesiomorphic for Metatheria as a whole.     

Isolation in east Senegal of a yellow fever virus strain from a pool of Aedes belonging to the subgenus Diceromyia]

During an epidemiological survey of yellow fever in Eastern Senegal, one strain of yellow fever virus was isolated in December 1976 from wild Mosquitoes. This first isolate obtained in nature from Aedes subgenus Diceromyia shows the primordial part these vectors may have in the area studied. It corroborates the existence of a selvatic focus of yellow fever in this region. It also gives information on the transmission cycle in a dry area.     

How serious is the modifiable areal unit problem for analysis of English census data?

Population data are often collected or presented for geographical areas which may have little or no connection to the processes generating the data. Such areal units are termed 'modifiable'. However analysis undertaken on such data is not independent of how these areal units are configured. Indeed, Openshaw (1984) and others have shown that the results of statistical analysis may differ wildly according to the scale and pattern of the areal units used. This phenomenon is called the modifiable areal unit problem (MAUP). It is clear that the MAUP exists, but far from clear about how often it occurs, how often it affects the conclusions from empirical data analysis, and in what contexts it makes most (or least) difference. British census data are well suited for investigating these issues, being available for different geographies which neatly nest within each other, and for a range of different variables of interest to central and local government and to many academic disciplines. This article is concerned with bivariate correlations (using Pearson's r) between pairs of variables. The aim is to see if any variables seem particularly liable to display MAUP effects, and if so, why. The conclusion is that MAUP in many cases makes little or no difference to the results, but there are some variable pairs where the effect is substantial.     

Origin of Saturn's rings and inner moons by mass removal from a lost Titan-sized satellite

The origin of Saturn's rings has not been adequately explained. The current rings are more than 90 to 95 per cent water ice, which implies that initially they were almost pure ice because they are continually polluted by rocky meteoroids. In contrast, a half-rock, half-ice mixture (similar to the composition of many of the satellites in the outer Solar System) would generally be expected. Previous ring origin theories invoke the collisional disruption of a small moon, or the tidal disruption of a comet during a close passage by Saturn. These models are improbable and/or struggle to account for basic properties of the rings, including their icy composition. Saturn has only one large satellite, Titan, whereas Jupiter has four large satellites; additional large satellites probably existed originally but were lost as they spiralled into Saturn. Here I report numerical simulations of the tidal removal of mass from a differentiated, Titan-sized satellite as it migrates inward towards Saturn. Planetary tidal forces preferentially strip material from the satellite's outer icy layers, while its rocky core remains intact and is lost to collision with the planet. The result is a pure ice ring much more massive than Saturn's current rings. As the ring evolves, its mass decreases and icy moons are spawned from its outer edge with estimated masses consistent with Saturn's ice-rich moons interior to and including Tethys.     

A redox switch in angiotensinogen modulates angiotensin release

Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1?? resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4?? structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.     

Whole-genome sequence of Schistosoma haematobium

Schistosomiasis is a neglected tropical disease caused by blood flukes (genus Schistosoma; schistosomes) and affecting 200 million people worldwide. No vaccines are available, and treatment relies on one drug, praziquantel. Schistosoma haematobium has come into the spotlight as a major cause of urogenital disease, as an agent linked to bladder cancer and as a predisposing factor for HIV/AIDS. The parasite is transmitted to humans from freshwater snails. Worms dwell in blood vessels and release eggs that become embedded in the bladder wall to elicit chronic immune-mediated disease and induce squamous cell carcinoma. Here we sequenced the 385-Mb genome of S. haematobium using Illumina-based technology at 74-fold coverage and compared it to sequences from related parasites. We included genome annotation based on function, gene ontology, networking and pathway mapping. This genome now provides an unprecedented resource for many fundamental research areas and shows great promise for the design of new disease interventions.