Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice

Syndecan-1 is a cell-surface, heparan-sulphate proteoglycan (HSPG) predominantly expressed by epithelial cells. It binds specifically to many proteins, including oncoproteins. For example, it induces the assembly of a signalling complex between FGF ligands and their cognate receptors. But so far there has been no direct evidence that this proteoglycan contributes to tumorigenesis. Here we have examined the role of syndecan-1 (encoded by Sdc1) during mammary tumour formation in response to the ectopic expression of the proto-oncogene Wnt1. We crossed syndecan-1-deficient mice with transgenic mice that express Wnt1 in mammary gland (TgN(Wnt-1)1Hev; ref. 2). Ectopic Wnt-1 expression induces generalized mammary hyperplasia, followed by the development of solitary tumours (median time 22 weeks). We show that in Sdc1-/- mice, Wnt-1-induced hyperplasia in virgin mammary gland was reduced by 70%, indicating that the Wnt-1 signalling pathway was inhibited. Of the 39 tumours that developed in a test cohort of mice, only 1 evolved in the Sdc1-/- background. In addition, we show that soluble syndecan-1 ectodomain purified from mouse mammary epithelial cells stimulates the activity of a Wnt-1 homologue in a tissue culture assay. Our results provide both genetic and biochemical evidence that syndecan-1 can modulate Wnt signalling, and is critical for Wnt-1-induced tumorigenesis of the mouse mammary gland.     

Effect of stream channel size on the delivery of nitrogen to the Gulf of Mexico

An increase in the flux of nitrogen from the Mississippi river during the latter half of the twentieth century has caused eutrophication and chronic seasonal hypoxia in the shallow waters of the Louisiana shelf in the northern Gulf of Mexico. This has led to reductions in species diversity, mortality of benthic communities and stress in fishery resources. There is evidence for a predominantly anthropogenic origin of the increased nitrogen flux, but the location of the most significant sources in the Mississippi basin responsible for the delivery of nitrogen to the Gulf of Mexico have not been clearly identified, because the parameters influencing nitrogen-loss rates in rivers are not well known. Here we present an analysis of data from 374 US monitor ing stations, including 123 along the six largest tributaries to the Mississippi, that shows a rapid decline in the average first-order rate of nitrogen loss with channel size--from 0.45 day (-1) in small streams to 0.005 day (-1) in the Mississippi river. Using stream depth as an explanatory variable, our estimates of nitrogen-loss rates agreed with values from earlier studies. We conclude that the proximity of sources to large streams and rivers is an important determinant of nitrogen delivery to the estuary in the Mississippi basin, and possibly also in other large river basins.     

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28

Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.     

Evidence for neuromelanin involvement in MPTP-induced neurotoxicity

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces certain clinical, pathological, and neurochemical features of Parkinson's disease. MPTP is metabolized by monoamine oxidase Type B to 1-methyl-4-phenylpyridine (MPP+), which is selectively accumulated by high-affinity uptake mechanisms into dopaminergic neurons. Lyden et al. described low-affinity binding of MPTP to synthetic and retinal melanin. We showed that MPP+ binds to neuromelanin with high affinity, suggesting that in MPTP neurotoxicity, MPP+ enters nigral neurons by the dopamine uptake system and binds to neuromelanin, which serves as a depot, continuously releasing MPP+ until it destroys the cells. This model predicts that agents which compete with MPP+ binding to neuromelanin should partially protect the dopamine neurons from MPTP-induced toxicity. The most potent identified competitor for MPP+ binding to melanin is the antimalarial drug chloroquine, which has a high affinity for melanins. In the present study, chloroquine, administered to monkeys in conventional anti-malarial doses before MPTP, protects them from MPTP-induced parkinsonian motor abnormalities, dopamine depletion in the striatum, and neuropathological changes in the substantia nigra.     

Superconductivity in lithium below 0.4 millikelvin at ambient pressure

Elements in the alkali metal series are regarded as unlikely superconductors because of their monovalent character. A superconducting transition temperature as high as 20 K, recently found in compressed lithium (the lightest alkali element), probably arises from pressure-induced changes in the conduction-electron band structure. Superconductivity at ambient pressure in lithium has hitherto remained unresolved, both theoretically and experimentally. Here we demonstrate that lithium is a superconductor at ambient pressure with a transition temperature of 0.4 mK. As lithium has a particularly simple conduction electron system, it represents an important case for any attempts to classify superconductors and transition temperatures, especially to determine if any non-magnetic configuration can exclude superconductivity down to zero temperature. Furthermore, the combination of extremely weak superconductivity and relatively strong nuclear magnetism in lithium would clearly lead to mutual competition between these two ordering phenomena under suitably prepared conditions.     

Neural substrates of awakening probed with optogenetic control of hypocretin neurons

The neural underpinnings of sleep involve interactions between sleep-promoting areas such as the anterior hypothalamus, and arousal systems located in the posterior hypothalamus, the basal forebrain and the brainstem. Hypocretin (Hcrt, also known as orexin)-producing neurons in the lateral hypothalamus are important for arousal stability, and loss of Hcrt function has been linked to narcolepsy. However, it is unknown whether electrical activity arising from Hcrt neurons is sufficient to drive awakening from sleep states or is simply correlated with it. Here we directly probed the impact of Hcrt neuron activity on sleep state transitions with in vivo neural photostimulation, genetically targeting channelrhodopsin-2 to Hcrt cells and using an optical fibre to deliver light deep in the brain, directly into the lateral hypothalamus, of freely moving mice. We found that direct, selective, optogenetic photostimulation of Hcrt neurons increased the probability of transition to wakefulness from either slow wave sleep or rapid eye movement sleep. Notably, photostimulation using 5-30 Hz light pulse trains reduced latency to wakefulness, whereas 1 Hz trains did not. This study establishes a causal relationship between frequency-dependent activity of a genetically defined neural cell type and a specific mammalian behaviour central to clinical conditions and neurobehavioural physiology.     

Pulsational pair instability as an explanation for the most luminous supernovae

The extremely luminous supernova SN 2006gy (ref. 1) challenges the traditional view that the collapse of a stellar core is the only mechanism by which a massive star makes a supernova, because it seems too luminous by more than a factor of ten. Here we report that the brightest supernovae in the modern Universe arise from collisions between shells of matter ejected by massive stars that undergo an interior instability arising from the production of electron-positron pairs. This 'pair instability' leads to explosive burning that is insufficient to unbind the star, but ejects many solar masses of the envelope. After the first explosion, the remaining core contracts and searches for a stable burning state. When the next explosion occurs, several solar masses of material are again ejected, which collide with the earlier ejecta. This collision can radiate 10(50) erg of light, about a factor of ten more than an ordinary supernova. Our model is in good agreement with the observed light curve for SN 2006gy and also shows that some massive stars can produce more than one supernova-like outburst.     

Hadean diamonds in zircon from Jack Hills, Western Australia

Detrital zircons more than 4 billion years old from the Jack Hills metasedimentary belt, Yilgarn craton, Western Australia, are the oldest identified fragments of the Earth's crust and are unique in preserving information on the earliest evolution of the Earth. Inclusions of quartz, K-feldspar and monazite in the zircons, in combination with an enrichment of light rare-earth elements and an estimated low zircon crystallization temperature, have previously been used as evidence for early recycling of continental crust, leading to the production of granitic melts in the Hadean era. Here we present the discovery of microdiamond inclusions in Jack Hills zircons with an age range from 3,058 +/- 7 to 4,252 +/- 7 million years. These include the oldest known diamonds found in terrestrial rocks, and introduce a new dimension to the debate on the origin of these zircons and the evolution of the early Earth. The spread of ages indicates that either conditions required for diamond formation were repeated several times during early Earth history or that there was significant recycling of ancient diamond. Mineralogical features of the Jack Hills diamonds-such as their occurrence in zircon, their association with graphite and their Raman spectroscopic characteristics-resemble those of diamonds formed during ultrahigh-pressure metamorphism and, unless conditions on the early Earth were unique, imply a relatively thick continental lithosphere and crust-mantle interaction at least 4,250 million years ago.