Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.     

An initiation site for meiotic crossing-over and gene conversion in the mouse

During meiosis, the reductional segregation of homologous chromosomes at the first meiotic division requires reciprocal exchange (crossing over) between homologs. The number of crossovers is tightly regulated (one to two per homolog in mice), and their distribution in the genome is not random-recombination 'hot' and 'cold' regions can be identified. We developed a molecular assay to study these events directly in mouse germ cells. This analysis was developed with reference to the proteosome subunit beta type 9 (Psmb9, previously called Lmp2) hot-spot region identified through genetic analysis. Here we show that this hot spot is an initiation site of meiotic recombination on the basis of two observations: (i) crossover density is maximal in an interval of 210 bp and decreases on both sides of this region; (ii) a high frequency of gene conversion is found in the region of highest crossover density. We then used this strategy to carry out the first temporal analysis of meiotic recombination in mouse spermatogenesis and demonstrate that crossover events occur during the pachytene stage of meiotic prophase.     

Characterization of a common precursor population for dendritic cells

Dendritic cells (DCs) are essential for the establishment of immune responses against pathogens and tumour cells, and thus have great potential as tools for vaccination and cancer immunotherapy trials. Experimental evidence has led to a dual DC differentiation model, which involves the existence of both myeloid- and lymphoid-derived DCs. But this concept has been challenged by recent reports demonstrating that both CD8- and CD8+ DCs, considered in mice as archetypes of myeloid and lymphoid DCs respectively, can be generated from either lymphoid or myeloid progenitors. The issue of DC physiological derivation therefore remains an open question. Here we report the characterization of a DC-committed precursor population, which has the capacity to generate all the DC subpopulations present in mouse lymphoid organs---including CD8- and CD8+ DCs, as well as the B220+ DC subset---but which is devoid of myeloid or lymphoid differentiation potential. These data support an alternative model of DC development, in which there is an independent, common DC differentiation pathway.     

Optical studies of solid hydrogen to 320 GPa and evidence for black hydrogen

The quest for metallic hydrogen at high pressures represents a longstanding problem in condensed matter physics. Recent calculations have predicted that solid hydrogen should become a molecular metal at pressures above 300 GPa, before transforming into an alkali metal; but the strong quantum nature of the problem makes the predictions difficult. Over a decade ago, an optical study of hydrogen was made using a diamond anvil cell to reach 250 GPa. However, despite many subsequent efforts, quantitative studies at higher pressures have proved difficult and their conclusions controversial. Here we report optical measurements of solid hydrogen up to a pressure of 320 GPa at 100 K. The vibron signature of the H2 molecule persists to at least 316 GPa; no structural changes are detected above 160 GPa, and solid hydrogen is observed to turn completely opaque at 320 GPa. We measure the absorption edge of hydrogen above 300 GPa, observing features characteristic of a direct electronic bandgap. This is at odds with the most recent theoretical calculations that predict much larger direct transition energies and the closure of an indirect gap. We predict that metal hydrogen should be observed at about 450 GPa when the direct gap closes.     

Sequence and analysis of chromosome 2 of Dictyostelium discoideum

The genome of the lower eukaryote Dictyostelium discoideum comprises six chromosomes. Here we report the sequence of the largest, chromosome 2, which at 8 megabases (Mb) represents about 25% of the genome. Despite an A + T content of nearly 80%, the chromosome codes for 2,799 predicted protein coding genes and 73 transfer RNA genes. This gene density, about 1 gene per 2.6 kilobases (kb), is surpassed only by Saccharomyces cerevisiae (one per 2 kb) and is similar to that of Schizosaccharomyces pombe (one per 2.5 kb). If we assume that the other chromosomes have a similar gene density, we can expect around 11,000 genes in the D. discoideum genome. A significant number of the genes show higher similarities to genes of vertebrates than to those of other fully sequenced eukaryotes. This analysis strengthens the view that the evolutionary position of D. discoideum is located before the branching of metazoa and fungi but after the divergence of the plant kingdom, placing it close to the base of metazoan evolution.     

The lipid phosphatase SHIP2 controls insulin sensitivity

Insulin is the primary hormone involved in glucose homeostasis, and impairment of insulin action and/or secretion has a critical role in the pathogenesis of diabetes mellitus. Type-II SH2-domain-containing inositol 5-phosphatase, or 'SHIP2', is a member of the inositol polyphosphate 5-phosphatase family. In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling events mediated by both phosphoinositide-3-OH kinase and Ras/mitogen-activated protein kinase. Here we report the generation of mice lacking the SHIP2 gene. Loss of SHIP2 leads to increased sensitivity to insulin, which is characterized by severe neonatal hypoglycaemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. Adult mice that are heterozygous for the SHIP2 mutation have increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter and increased glycogen synthesis in skeletal muscles. Our results show that SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo.     

N-terminal acetylation in a third protein family of vertebrate alcohol dehydrogenase/retinal reductase found through a 'proteomics' approach in enzyme characterization

A recent finding of a novel class of retinol-active alcohol dehydrogenase (ADH) in frog prompted analysis of this activity in other vertebrate forms. Surprisingly, yet another and still more unrelated ADH was identified in chicken tissues. It was found to be a member of the aldo-keto reductase (AKR) enzyme family, not previously known as an ADH in vertebrates. Its terminal blocking group and the N-terminal segment, not assigned by protein and cDNA structure analysis, were determined by electrospray tandem mass spectrometry after protein isolation by two-dimensional gel electrophoresis. The N terminus is Acetyl-Ala- and the N-terminal segment contains two consecutive Asn residues. The results establish the new ADH enzyme of the AKR family and show the usefulness of combined gel separation and mass spectrometry in enzyme-characterization.     

Mesoscale vertical motion and the size structure of phytoplankton in the ocean

Phytoplankton size structure is acknowledged as a fundamental property determining energy flow through 'microbial' or 'herbivore' pathways. The balance between these two pathways determines the ability of the ecosystem to recycle carbon within the upper layer or to export it to the ocean interior. Small cells are usually characteristic of oligotrophic, stratified ocean waters, in which regenerated ammonium is the only available form of inorganic nitrogen and recycling dominates. Large cells seem to characterize phytoplankton in which inputs of nitrate enter the euphotic layer and exported production is higher. But the size structure of phytoplankton may depend more directly on hydrodynamical forces than on the source of available nitrogen. Here we present an empirical model that relates the magnitude of mesoscale vertical motion to the slope of the size-abundance spectrum of phytoplankton in a frontal ecosystem. Our model indicates that the relative proportion of large cells increases with the magnitude of the upward velocity. This suggests that mesoscale vertical motion-a ubiquitous feature of eddies and unstable fronts-controls directly the size structure of phytoplankton in the ocean.     

Evidence for non-selective preservation of organic matter in sinking marine particles

The sinking of particulate organic matter from ocean surface waters transports carbon to the ocean interior, where almost all is then recycled. The unrecycled fraction of this organic matter can become buried in ocean sediments, thus sequestering carbon and so influencing atmospheric carbon dioxide concentrations. The processes controlling the extensive biodegradation of sinking particles remain unclear, partly because of the difficulty in resolving the composition of the residual organic matter at depth with existing chromatographic techniques. Here, using solid-state 13C NMR spectroscopy, we characterize the chemical structure of organic carbon in both surface plankton and sinking particulate matter from the Pacific Ocean and the Arabian Sea. We found that minimal changes occur in bulk organic composition, despite extensive (>98%) biodegradation, and that amino-acid-like material predominates throughout the water column in both regions. The compositional similarity between phytoplankton biomass and the small remnant of organic matter reaching the ocean interior indicates that the formation of unusual biochemicals, either by chemical recombination or microbial biosynthesis, is not the main process controlling the preservation of particulate organic carbon within the water column at these two sites. We suggest instead that organic matter might be protected from degradation by the inorganic matrix of sinking particles.