A natural allele of Nxf1 suppresses retrovirus insertional mutations

Endogenous retroviruses have shaped the evolution of mammalian genomes. Host genes that control the effects of retrovirus insertions are therefore of great interest. The modifier-of-vibrator-1 locus (Mvb1) controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the Pitpn(vb) tremor mutation and the Eya1(BOR) model of human branchiootorenal syndrome. Positional complementation cloning identifies Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between the mRNA export receptor and pre-mRNA processing. Population structure of the suppressive allele in wild Mus musculus castaneus suggests selective advantage. A congenic Mvb1(CAST) allele is a useful tool for modifying gene expression from existing mutations and could be used to manipulate engineered mutations containing retroviral elements.     

MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability

DNA mismatch repair is important because of its role in maintaining genomic integrity and its association with hereditary non-polyposis colon cancer (HNPCC). To identify new human mismatch repair proteins, we probed nuclear extracts with the conserved carboxy-terminal MLH1 interaction domain. Here we describe the cloning and complete genomic sequence of MLH3, which encodes a new DNA mismatch repair protein that interacts with MLH1. MLH3 is more similar to mismatch repair proteins from yeast, plants, worms and bacteria than to any known mammalian protein, suggesting that its conserved sequence may confer unique functions in mice and humans. Cells in culture stably expressing a dominant-negative MLH3 protein exhibit microsatellite instability. Mlh3 is highly expressed in gastrointestinal epithelium and physically maps to the mouse complex trait locus colon cancer susceptibility I (Ccs1). Although we were unable to identify a mutation in the protein-coding region of Mlh3 in the susceptible mouse strain, colon tumours from congenic Ccs1 mice exhibit microsatellite instability. Functional redundancy among Mlh3, Pms1 and Pms2 may explain why neither Pms1 nor Pms2 mutant mice develop colon cancer, and why PMS1 and PMS2 mutations are only rarely found in HNPCC families.     

A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease

Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species.     

Nitride semiconductors free of electrostatic fields for efficient white light-emitting diodes

Compact solid-state lamps based on light-emitting diodes (LEDs) are of current technological interest as an alternative to conventional light bulbs. The brightest LEDs available so far emit red light and exhibit higher luminous efficiency than fluorescent lamps. If this luminous efficiency could be transferred to white LEDs, power consumption would be dramatically reduced, with great economic and ecological consequences. But the luminous efficiency of existing white LEDs is still very low, owing to the presence of electrostatic fields within the active layers. These fields are generated by the spontaneous and piezoelectric polarization along the [0001] axis of hexagonal group-III nitrides--the commonly used materials for light generation. Unfortunately, as this crystallographic orientation corresponds to the natural growth direction of these materials deposited on currently available substrates. Here we demonstrate that the epitaxial growth of GaN/(Al,Ga)N on tetragonal LiAlO2 in a non-polar direction allows the fabrication of structures free of electrostatic fields, resulting in an improved quantum efficiency. We expect that this approach will pave the way towards highly efficient white LEDs.     

塑造未来——到2030年的科学技术

作者提出美国科学技术未来发展所面临的四大问题，即“我们能否保持美国的科技优势？”“我们能够和应该制定出全国的科技政策吗？”“我们能否培养出一支能迎接到2030年的任务与挑战的训练有素的人员队伍？”“我们的研究机构通用 其科学基础来帮助解决‘非科学的’社会问题吗？”罗斯福在给NSF的创始人万尼瓦尔·布会的信中写道：“新的智力边疆正展现在我们的面前。如果我们能以我们从事战争 的同样的远见、同样的勇敢和同样的勇往直前精神来开拓它们，我们就会创造出更充分和更美好的就业机会以及更富裕和更美满的生活。”     

Membrane curvature and mechanisms of dynamic cell membrane remodelling

Membrane curvature is no longer seen as a passive consequence of cellular activity but an active means to create membrane domains and to organize centres for membrane trafficking. Curvature can be dynamically modulated by changes in lipid composition, the oligomerization of curvature scaffolding proteins and the reversible insertion of protein regions that act like wedges in membranes. There is an interplay between curvature-generating and curvature-sensing proteins during vesicle budding. This is seen during vesicle budding and in the formation of microenvironments. On a larger scale, membrane curvature is a prime player in growth, division and movement.     

The suppression of star formation by powerful active galactic nuclei

The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expelling the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.