Spreading-rate dependence of melt extraction at mid-ocean ridges from mantle seismic refraction data

A variety of observations indicate that mid-ocean ridges produce less crust at spreading rates below 20 mm yr(-1) (refs 1-3), reflecting changes in fundamental ridge processes with decreasing spreading rate. The nature of these changes, however, remains uncertain, with end-member explanations being decreasing shallow melting or incomplete melt extraction, each due to the influence of a thicker thermal lid. Here we present results of a seismic refraction experiment designed to study mid-ocean ridge processes by imaging residual mantle structure. Our results reveal an abrupt lateral change in bulk mantle seismic properties associated with a change from slow to ultraslow palaeo-spreading rate. Changes in mantle velocity gradient, basement topography and crustal thickness all correlate with this spreading-rate change. These observations can be explained by variations in melt extraction at the ridge, with a gabbroic phase preferentially retained in the mantle at slower spreading rates. The estimated volume of retained melt balances the approximately 1.5-km difference in crustal thickness, suggesting that changes in spreading rate affect melt-extraction processes rather than total melting.     

The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer

Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2 and MSH6 mutations underlie high-penetrance CRC susceptibility in hereditary nonpolyposis colon cancer (HNPCC), we hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. We looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability (MSI) phenotype. Association studies identified a new MLH1 variant (415G-->C, resulting in the amino acid substitution D132H) in approximately 1.3% of Israeli individuals with CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually do not have the MSI defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G-->C mutation. The new MLH1 variant confers a high risk of CRC and identifies a previously unrecognized mechanism in microsatellite-stable tumors. These studies suggest that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than previously assumed.     

Quantification of modelling uncertainties in a large ensemble of climate change simulations

Comprehensive global climate models are the only tools that account for the complex set of processes which will determine future climate change at both a global and regional level. Planners are typically faced with a wide range of predicted changes from different models of unknown relative quality, owing to large but unquantified uncertainties in the modelling process. Here we report a systematic attempt to determine the range of climate changes consistent with these uncertainties, based on a 53-member ensemble of model versions constructed by varying model parameters. We estimate a probability density function for the sensitivity of climate to a doubling of atmospheric carbon dioxide levels, and obtain a 5-95 per cent probability range of 2.4-5.4 degrees C. Our probability density function is constrained by objective estimates of the relative reliability of different model versions, the choice of model parameters that are varied and their uncertainty ranges, specified on the basis of expert advice. Our ensemble produces a range of regional changes much wider than indicated by traditional methods based on scaling the response patterns of an individual simulation.     

Control of gene expression by a natural metabolite-responsive ribozyme

Most biological catalysts are made of protein; however, eight classes of natural ribozymes have been discovered that catalyse fundamental biochemical reactions. The central functions of ribozymes in modern organisms support the hypothesis that life passed through an 'RNA world' before the emergence of proteins and DNA. We have identified a new class of ribozymes that cleaves the messenger RNA of the glmS gene in Gram-positive bacteria. The ribozyme is activated by glucosamine-6-phosphate (GlcN6P), which is the metabolic product of the GlmS enzyme. Additional data indicate that the ribozyme serves as a metabolite-responsive genetic switch that represses the glmS gene in response to rising GlcN6P concentrations. These findings demonstrate that ribozyme switches may have functioned as metabolite sensors in primitive organisms, and further suggest that modern cells retain some of these ancient genetic control systems.     

Genome rearrangement by replication-directed translocation

Gene order in bacteria is poorly conserved during evolution. For example, although many homologous genes are shared by the proteobacteria Escherichia coli, Haemophilus influenzae and Helicobacter pylori, their relative positions are very different in each genome, except local functional clusters such as operons. The complete sequences of the more closely related bacterial genomes, such as pairs of Chlamydia, H. pylori and Mycobacterium species, now allow identification of the processes and mechanisms involved in genome evolution. Here we provide evidence that a substantial proportion of rearrangements in gene order results from recombination sites that are determined by the positions of the replication forks. Our observations suggest that replication has a major role in directing genome evolution.     

Rom-1 is required for rod photoreceptor viability and the regulation of disk morphogenesis

The homologous membrane proteins Rom-1 and peripherin-2 are localized to the disk rims of photoreceptor outer segments (OSs), where they associate as tetramers and larger oligomers. Disk rims are thought to be critical for disk morphogenesis, OS renewal and the maintenance of OS structure, but the molecules which regulate these processes are unknown. Although peripherin-2 is known to be required for OS formation (because Prph2-/- mice do not form OSs; ref. 6), and mutations in RDS (the human homologue of Prph2) cause retinal degeneration, the relationship of Rom-1 to these processes is uncertain. Here we show that Rom1-/- mice form OSs in which peripherin-2 homotetramers are localized to the disk rims, indicating that peripherin-2 alone is sufficient for both disk and OS morphogenesis. The disks produced in Rom1-/- mice were large, rod OSs were highly disorganized (a phenotype which largely normalized with age) and rod photoreceptors died slowly by apoptosis. Furthermore, the maximal photoresponse of Rom1-/- rod photoreceptors was lower than that of controls. We conclude that Rom-1 is required for the regulation of disk morphogenesis and the viability of mammalian rod photoreceptors, and that mutations in human ROM1 may cause recessive photoreceptor degeneration.     

Regulation of carbamoyl phosphate synthetase by MAP kinase

The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. The rate-limiting step in this pathway is catalysed by carbamoyl phosphate synthetase (CPS II), part of the multifunctional enzyme CAD. Here we describe the regulation of CAD by the mitogen-activated protein (MAP) kinase cascade. When phosphorylated by MAP kinase in vitro or activated by epidermal growth factor in vivo, CAD lost its feedback inhibition (which is dependent on uridine triphosphate) and became more sensitive to activation (which depends upon phosphoribosyl pyrophosphate). Both these allosteric regulatory changes favour biosynthesis of pyrimidines for growth. They were accompanied by increased epidermal growth factor-dependent phosphorylation of CAD in vivo and were prevented by inhibition of MAP kinase. Mutation of a consensus MAP kinase phosphorylation site abolished the changes in CAD allosteric regulation that were stimulated by growth factors. Finally, consistent with an effect of MAP kinase signalling on CPS II activity, epidermal growth factor increased cellular uridine triphosphate and this increase was reversed by inhibition of MAP kinase. Hence these studies may indicate a direct link between activation of the MAP kinase cascade and de novo biosynthesis of pyrimidine nucleotides.     

Effect of aldosterone on mammalian eccrine sweat glands

Zusammenfassung Nachweis, dass Natriumretention bei der menschlichen Temperaturregulation und in den exokrinen Schweissdrüsen der Handflächen von Aldosteron verursacht wird; dies im Unterschied zu den Drüsen in Katzenpfoten, welche charakteristischerweise vom exokrinen Sekretionsprozess des duktalen Ionenwechsels nicht beeinflusst werden und weder auf Aldosteron noch auf Blutung reagieren.