Recognition of bacterial glycosphingolipids by natural killer T cells

Natural killer T (NKT) cells constitute a highly conserved T lymphocyte subpopulation that has the potential to regulate many types of immune responses through the rapid secretion of cytokines. NKT cells recognize glycolipids presented by CD1d, a class I-like antigen-presenting molecule. They have an invariant T-cell antigen receptor (TCR) alpha-chain, but whether this invariant TCR recognizes microbial antigens is still controversial. Here we show that most mouse and human NKT cells recognize glycosphingolipids from Sphingomonas, Gram-negative bacteria that do not contain lipopolysaccharide. NKT cells are activated in vivo after exposure to these bacterial antigens or bacteria, and mice that lack NKT cells have a marked defect in the clearance of Sphingomonas from the liver. These data suggest that NKT cells are T lymphocytes that provide an innate-type immune response to certain microorganisms through recognition by their antigen receptor, and that they might be useful in providing protection from bacteria that cannot be detected by pattern recognition receptors such as Toll-like receptor 4.     

Probable observation of a supersolid helium phase

When liquid (4)He is cooled below 2.176 K, it undergoes a phase transition-Bose-Einstein condensation-and becomes a superfluid with zero viscosity. Once in such a state, it can flow without dissipation even through pores of atomic dimensions. Although it is intuitive to associate superflow only with the liquid phase, it has been proposed theoretically that superflow can also occur in the solid phase of (4)He. Owing to quantum mechanical fluctuations, delocalized vacancies and defects are expected to be present in crystalline solid (4)He, even in the limit of zero temperature. These zero-point vacancies can in principle allow the appearance of superfluidity in the solid. However, in spite of many attempts, such a 'supersolid' phase has yet to be observed in bulk solid (4)He. Here we report torsional oscillator measurements on solid helium confined in a porous medium, a configuration that is likely to be more heavily populated with vacancies than bulk helium. We find an abrupt drop in the rotational inertia of the confined solid below a certain critical temperature. The most likely interpretation of the inertia drop is entry into the supersolid phase. If confirmed, our results show that all three states of matter-gas, liquid and solid-can undergo Bose-Einstein condensation.     

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.     

Sequencing of a rice centromere uncovers active genes

Centromeres are the last frontiers of complex eukaryotic genomes, consisting of highly repetitive sequences that resist mapping, cloning and sequencing. The centromere of rice Chromosome 8 (Cen8) has an unusually low abundance of highly repetitive satellite DNA, which allowed us to determine its sequence. A region of approximately 750 kb in Cen8 binds rice CENH3, the centromere-specific H3 histone. CENH3 binding is contained within a larger region that has abundant dimethylation of histone H3 at Lys9 (H3-Lys9), consistent with Cen8 being embedded in heterochromatin. Fourteen predicted and at least four active genes are interspersed in Cen8, along with CENH3 binding sites. The retrotransposons located in and outside of the CENH3 binding domain have similar ages and structural dynamics. These results suggest that Cen8 may represent an intermediate stage in the evolution of centromeres from genic regions, as in human neocentromeres, to fully mature centromeres that accumulate megabases of homogeneous satellite arrays.     

Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells

Antagonistic activities of glucagon and insulin control metabolism in mammals, and disruption of this balance underlies diabetes pathogenesis. Insulin-producing cells (IPCs) in the brain of insects such as Drosophila also regulate serum glucose, but it remains unclear whether insulin is the sole hormonal regulator of glucose homeostasis and whether mechanisms of glucose-sensing and response in IPCs resemble those in pancreatic islets. Here we show, by targeted cell ablation, that Drosophila corpora cardiaca (CC) cells of the ring gland are also essential for larval glucose homeostasis. Unlike IPCs, CC cells express Drosophila cognates of sulphonylurea receptor (Sur) and potassium channel (Ir), proteins that comprise ATP-sensitive potassium channels regulating hormone secretion by islets and other mammalian glucose-sensing cells. They also produce adipokinetic hormone, a polypeptide with glucagon-like functions. Glucose regulation by CC cells is impaired by exposure to sulphonylureas, drugs that target the Sur subunit. Furthermore, ubiquitous expression of an akh transgene reverses the effect of CC ablation on serum glucose. Thus, Drosophila CC cells are crucial regulators of glucose homeostasis and they use glucose-sensing and response mechanisms similar to islet cells.     

Genome sequence of the Brown Norway rat yields insights into mammalian evolution

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.     

A resource for large-scale RNA-interference-based screens in mammals

Gene silencing by RNA interference (RNAi) in mammalian cells using small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) has become a valuable genetic tool. Here, we report the construction and application of a shRNA expression library targeting 9,610 human and 5,563 mouse genes. This library is presently composed of about 28,000 sequence-verified shRNA expression cassettes contained within multi-functional vectors, which permit shRNA cassettes to be packaged in retroviruses, tracked in mixed cell populations by means of DNA 'bar codes', and shuttled to customized vectors by bacterial mating. In order to validate the library, we used a genetic screen designed to report defects in human proteasome function. Our results suggest that our large-scale RNAi library can be used in specific, genetic applications in mammals, and will become a valuable resource for gene analysis and discovery.     

Derivation of embryonic germ cells and male gametes from embryonic stem cells

Egg and sperm cells (gametes) of the mouse are derived from a founder population of primordial germ cells that are set aside early in embryogenesis. Primordial germ cells arise from the proximal epiblast, a region of the early mouse embryo that also contributes to the first blood lineages of the embryonic yolk sac. Embryonic stem cells differentiate in vitro into cystic structures called embryoid bodies consisting of tissue lineages typical of the early mouse embryo. Because embryoid bodies sustain blood development, we reasoned that they might also support primordial germ cell formation. Here we isolate primordial germ cells from embryoid bodies, and derive continuously growing lines of embryonic germ cells. Embryonic germ cells show erasure of the methylation markers (imprints) of the Igf2r and H19 genes, a property characteristic of the germ lineage. We show that embryoid bodies support maturation of the primordial germ cells into haploid male gametes, which when injected into oocytes restore the somatic diploid chromosome complement and develop into blastocysts. Our ability to derive germ cells from embryonic stem cells provides an accessible in vitro model system for studies of germline epigenetic modification and mammalian gametogenesis.     

Assessing the forecasting accuracy of alternative nominal exchange rate models: the case of long memory

This paper presents an autoregressive fractionally integrated moving‐average (ARFIMA) model of nominal exchange rates and compares its forecasting capability with the monetary structural models and the random walk model. Monthly observations are used for Canada, France, Germany, Italy, Japan and the United Kingdom for the period of April 1973 through December 1998. The estimation method is Sowell's (1992) exact maximum likelihood estimation. The forecasting accuracy of the long‐memory model is formally compared to the random walk and the monetary models, using the recently developed Harvey, Leybourne and Newbold (1997) test statistics. The results show that the long‐memory model is more efficient than the random walk model in steps‐ahead forecasts beyond 1 month for most currencies and more efficient than the monetary models in multi‐step‐ahead forecasts. This new finding strongly suggests that the long‐memory model of nominal exchange rates be studied as a viable alternative to the conventional models. Copyright © 2006 John Wiley & Sons, Ltd.