Positional cloning of a novel gene influencing asthma from chromosome 2q14

Asthma is a common disease in children and young adults. Four separate reports have linked asthma and related phenotypes to an ill-defined interval between 2q14 and 2q32 (refs. 1-4), and two mouse genome screens have linked bronchial hyper-responsiveness to the region homologous to 2q14 (refs. 5,6). We found and replicated association between asthma and the D2S308 microsatellite, 800 kb distal to the IL1 cluster on 2q14. We sequenced the surrounding region and constructed a comprehensive, high-density, single-nucleotide polymorphism (SNP) linkage disequilibrium (LD) map. SNP association was limited to the initial exons of a solitary gene of 3.6 kb (DPP10), which extends over 1 Mb of genomic DNA. DPP10 encodes a homolog of dipeptidyl peptidases (DPPs) that cleave terminal dipeptides from cytokines and chemokines, and it presents a potential new target for asthma therapy.     

Female choice selects for a viability-based male trait in pheasants

Recent theory on sexual selection suggests that females in species without paternal care choose mates by their secondary sexual characters because these indicate genotypic quality which will be transmitted to the offspring. These ideas are not yet empirically supported as data quantifying the relationship between female mate choice and female reproductive success are lacking. Only in one case, in Colias butterflies, has it been demonstrated unequivocally that females choose 'good genotypes' as mates and there is only one study, on Drosophila, demonstrating that mate choice increases one component of offspring fitness. Spur length of male pheasants (Phasianus colchicus) correlates with various fitness-related properties. We here present the first experimental field data showing that female pheasants select mates on the basis of male spur length and that female mate choice correlates with female reproductive success.     

Transfection of the CD8 gene enhances T-cell recognition

Antibodies against CD8 or CD4 antigens can prevent T-cell functions induced by T-cell targets. As CD8 or CD4 antibodies can also initiate negative signals in T cells in the absence of appropriate targets it is not clear whether CD8 and CD4 molecules are directly involved in the interaction of T cells with their targets. In previous experiments we have introduced the T-cell receptor alpha- and beta-chain genes from a CD8-positive cytolytic T cell specific for the antigen fluorescein (FL) and the H-2D molecule of the major histocompatibility complex (MHC) into a CD8-negative recipient cell. The CD8-positive donor cell lysed both FL-conjugated fibroblasts and lymphoblasts, which express relatively high and low amounts of H-2D molecules, respectively. In contrast the CD8-negative transfectant lysed FL-conjugated fibroblasts only. Here we show that recognition of FL-conjugated lymphoblasts by the transfectant is enhanced by supertransfecting it with the CD8 gene.     

Imaging of apoptotic HeLa cells by using scanning near-field optical microscopy

By using scanning near-field optical microscopy (SNOM), HeLa cells in apoptosis process are imaged with a higher optical resolution beyond the diffraction limit. Since SNOM provides both topographic and transmitted light intensity information of a cell, it can correlate the structural characteristics and optical properties with the spatial position of the apoptotic cells. Wavelength imaging by using near-field spectroscopy shows that there is a great difference in light propagation and absorption in the cell. This unique technique can be applied to the super high resolution imaging of different components in the cell. The observations by near-field optical imaging and near-field spectroscopy indicate an inhomogeneous aggregation of the inner structure in the apoptotic HeLa cells and the change of transmission intensity of light with the apoptosis status.     

Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes

N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca2(+)-permeable cation channels which are blocked by extracellular Mg2(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg2(+) block and a decrease in Ca2(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.     

Efficient mapping of mendelian traits in dogs through genome-wide association

With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with approximately 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only approximately 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of approximately 100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health.     

Inability of CD8 alpha' polypeptides to associate with p56lck correlates with impaired function in vitro and lack of expression in vivo

T-cell accessory molecules, particularly CD4 and CD8, seem to be involved in the control of T-cell activation by antigen. Precisely how such molecules operate is not fully understood, but evidence to date suggests a dual role, as receptors binding ligands on stimulator cells and by direct or indirect involvement in intracellular signalling events. In mouse, truncated 'tailless' CD8 molecules occur naturally (CD8 alpha' polypeptides) and although they are expressed on the surface of thymocytes, they are not expressed on the surface of mature T cells. In this study, we show that truncated CD8 molecules are impaired in their ability to interact with the protein tyrosine kinase, p56lck, and have decreased ability to restore immune responsiveness in vitro. Our data support a dual function for CD8 molecules correlated with expression of external domains and cytoplasmic domains, respectively. Both functions appear to be critical for a competent immune system in vivo.     

An exceptionally bright flare from SGR 1806-20 and the origins of short-duration gamma-ray bursts

Soft-gamma-ray repeaters (SGRs) are galactic X-ray stars that emit numerous short-duration (about 0.1 s) bursts of hard X-rays during sporadic active periods. They are thought to be magnetars: strongly magnetized neutron stars with emissions powered by the dissipation of magnetic energy. Here we report the detection of a long (380 s) giant flare from SGR 1806-20, which was much more luminous than any previous transient event observed in our Galaxy. (In the first 0.2 s, the flare released as much energy as the Sun radiates in a quarter of a million years.) Its power can be explained by a catastrophic instability involving global crust failure and magnetic reconnection on a magnetar, with possible large-scale untwisting of magnetic field lines outside the star. From a great distance this event would appear to be a short-duration, hard-spectrum cosmic gamma-ray burst. At least a significant fraction of the mysterious short-duration gamma-ray bursts may therefore come from extragalactic magnetars.     

Relaxor ferroelectricity and colossal magnetocapacitive coupling in ferromagnetic CdCr2S4

Materials in which magnetic and electric order coexist--termed 'multiferroics' or 'magnetoelectrics'--have recently become the focus of much research. In particular, the simultaneous occurrence of ferromagnetism and ferroelectricity, combined with an intimate coupling of magnetization and polarization via magnetocapacitive effects, holds promise for new generations of electronic devices. Here we present measurements on a simple cubic spinel compound with unusual, and potentially useful, magnetic and electric properties: it shows ferromagnetic order coexisting with relaxor ferroelectricity (a ferroelectric cluster state with a smeared-out phase transition), both having sizable ordering temperatures and moments. Close to the ferromagnetic ordering temperature, the magnetocapacitive coupling (characterized by a variation of the dielectric constant in an external magnetic field) reaches colossal values, approaching 500 per cent. We attribute the relaxor properties to geometric frustration, which is well known for magnetic moments but here is found to impede long-range order of the structural degrees of freedom that drive the formation of the ferroelectric state.