Re-Os isotopic evidence for long-lived heterogeneity and equilibration processes in the Earth's upper mantle

The geochemical composition of the Earth's upper mantle is thought to reflect 4.5 billion years of melt extraction, as well as the recycling of crustal materials. The fractionation of rhenium and osmium during partial melting in the upper mantle makes the Re-Os isotopic system well suited for tracing the extraction of melt and recycling of the resulting mid-ocean-ridge basalt. Here we report osmium isotope compositions of more than 700 osmium-rich platinum-group element alloys derived from the upper mantle. The osmium isotopic data form a wide, essentially gaussian distribution, demonstrating that, with respect to Re-Os isotope systematics, the upper mantle is extremely heterogeneous. As depleted and enriched domains can apparently remain unequilibrated on a timescale of billions of years, effective equilibration seems to require high degrees of partial melting, such as occur under mid-ocean ridges or in back-arc settings, where percolating melts enhance the mobility of both osmium and rhenium. We infer that the gaussian shape of the osmium isotope distribution is the signature of a random mixing process between depleted and enriched domains, resulting from a 'plum pudding' distribution in the upper mantle, rather than from individual melt depletion events.     

Progenitor cell maintenance requires numb and numblike during mouse neurogenesis

Neurons in most regions of the mammalian nervous system are generated over an extended period of time during development. Maintaining sufficient numbers of progenitors over the course of neurogenesis is essential to ensure that neural cells are produced in correct numbers and diverse types. The underlying molecular mechanisms, like those governing stem-cell self-renewal in general, remain poorly understood. We report here that mouse numb and numblike (Nbl), two highly conserved homologues of Drosophila numb, play redundant but critical roles in maintaining neural progenitor cells during embryogenesis, by allowing their progenies to choose progenitor over neuronal fates. In Nbl mutant embryos also conditionally mutant for mouse numb in the nervous system, early neurons emerge in the expected spatial and temporal pattern, but at the expense of progenitor cells, leading to a nearly complete depletion of dividing cells shortly after the onset of neurogenesis. Our findings show that a shared molecular mechanism, with mouse Numb and Nbl as key components, governs the self-renewal of all neural progenitor cells, regardless of their lineage or regional identities.     

The origin of the anomalous superconducting properties of MgB(2)

Magnesium diboride differs from ordinary metallic superconductors in several important ways, including the failure of conventional models to predict accurately its unusually high transition temperature, the effects of isotope substitution on the critical transition temperature, and its anomalous specific heat. A detailed examination of the energy associated with the formation of charge-carrying pairs, referred to as the 'superconducting energy gap', should clarify why MgB(2) is different. Some early experimental studies have indicated that MgB(2) has multiple gaps, but past theoretical studies have not explained from first principles the origin of these gaps and their effects. Here we report an ab initio calculation of the superconducting gaps in MgB(2) and their effects on measurable quantities. An important feature is that the electronic states dominated by orbitals in the boron plane couple strongly to specific phonon modes, making pair formation favourable. This explains the high transition temperature, the anomalous structure in the specific heat, and the existence of multiple gaps in this material. Our analysis suggests comparable or higher transition temperatures may result in layered materials based on B, C and N with partially filled planar orbitals.     

A critical role for the protein tyrosine phosphatase receptor type Z in functional recovery from demyelinating lesions

Several lines of evidence suggest that tyrosine phosphorylation is a key element in myelin formation, differentiation of oligodendrocytes and Schwann cells, and recovery from demyelinating lesions. Multiple sclerosis is a demyelinating disease of the human central nervous system, and studies of experimental demyelination indicate that remyelination in vivo requires the local generation, migration or maturation of new oligodendrocytes, or some combination of these. Failure of remyelination in multiple sclerosis could result from the failure of any of these processes or from the death of oligodendrocytes. Ptprz encodes protein tyrosine phosphatase receptor type Z (Ptpz, also designated Rptpbeta), which is expressed primarily in the nervous system but also in oligodendrocytes, astrocytes and neurons. Here we examine the susceptibility of mice deficient in Ptprz to experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We observe that mice deficient in Ptprz show impaired recovery from EAE induced by myelin oligodendrocyte glycoprotein (MOG) peptide. This sustained paralysis is associated with increased apoptosis of mature oligodendrocytes in the spinal cords of mutant mice at the peak of inflammation. We further demonstrate that expression of PTPRZ1, the human homolog of Ptprz, is induced in multiple sclerosis lesions and that the gene is specifically expressed in remyelinating oligodendrocytes in these lesions. These results support a role for Ptprz in oligodendrocyte survival and in recovery from demyelinating disease.     

Biochemical networking contributes more to genetic buffering in human and mouse metabolic pathways than does gene duplication

During evolution different genes evolve at unequal rates, reflecting the varying functional constraints on phenotype. An important contributor to this variation is genetic buffering, which reduces the potential detrimental effects of mutations. We studied whether gene duplication and redundant metabolic networks affect genetic buffering by comparing the evolutionary rate of 242 human and mouse orthologous genes involved in metabolic pathways. A gene with a redundant network is defined as one for which the structural layout of metabolic pathways provides an alternative metabolic route that can, in principle, compensate for the loss of a protein function encoded by the gene. We found that genes with redundant networks evolve at similar rates as did genes without redundant networks, [corrected] but no significant difference was detected between single-copy genes and gene families. This implies that redundancy in metabolic networks provides significantly more genetic buffering than do gene families. We also found that genes encoding proteins involved in glycolysis and gluconeogenesis showed as a group a distinct pattern of variation, in contrast to genes involved in other pathways. These results suggest that redundant networks provide genetic buffering and contribute to the functional diversification of metabolic pathways.     

Enhancement of the high-magnetic-field critical current density of superconducting MgB2 by proton irradiation

Magnesium diboride, MgB2, has a relatively high superconducting transition temperature, placing it between the families of low- and high-temperature (copper oxide based) superconductors. Supercurrent flow in MgB2 is unhindered by grain boundaries, making it potentially attractive for technological applications in the temperature range 20-30 K. But in the bulk material, the critical current density (Jc) drops rapidly with increasing magnetic field strength. The magnitude and field dependence of the critical current are related to the presence of structural defects that can 'pin' the quantized magnetic vortices that permeate the material, and a lack of natural defects in MgB2 may be responsible for the rapid decline of Jc with increasing field strength. Here we show that modest levels of atomic disorder induced by proton irradiation enhance the pinning of vortices, thereby significantly increasing Jc at high field strengths. We anticipate that either chemical doping or mechanical processing should generate similar levels of disorder, and so achieve performance that is technologically attractive in an economically viable way.     

Phagocytosis and clearance of apoptotic cells is mediated by MER

Apoptosis is fundamental to the development and maintenance of animal tissues and the immune system. Rapid clearance of apoptotic cells by macrophages is important to inhibit inflammation and autoimmune responses against intracellular antigens. Here we report a new function for Mer, a member of the Axl/Mer/Tyro3 receptor tyrosine kinase family. mer(kd) mice with a cytoplasmic truncation of Mer had macrophages deficient in the clearance of apoptotic thymocytes. This was corrected in chimaeric mice reconstituted with bone marrow from wild-type animals. Primary macrophages isolated from mer(kd) mice showed that the phagocytic deficiency was restricted to apoptotic cells and was independent of Fc receptor-mediated phagocytosis or ingestion of other particles. The inability to clear apoptotic cells adequately may be linked to an increased number of nuclear autoantibodies in mer(kd) mice. Thus, the Mer receptor tyrosine kinase seems to be critical for the engulfment and efficient clearance of apoptotic cells. This has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus.     

Interaction of reelin signaling and Lis1 in brain development

Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.