Mapping copy number variation by population-scale genome sequencing

Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.     

Forecasting contemporaneous aggregates and the combination of forecasts: The case of the U.K. monetary aggregates

A number of papers in recent years have investigated the problems of forecasting contemporaneously aggregated time series and of combining alternative forecasts of a time series. This paper considers the integration of both approaches within the example of assessing the forecasting performance of models for two of the U.K. monetary aggregates, £M3 and MO. It is found that forecasts from a time series model for aggregate £M3 are superior to aggregated forecasts from individual models fitted to either the components or counterparts of £M3 and that an even better forecast is obtained by forming a linear combination of the three alternatives. For MO, however, aggregated forecasts from its components prove superior to either the forecast from the aggregate itself or from a linear combination of the two.     

GTPase activity of dynamin and resulting conformation change are essential for endocytosis

Dynamin is a large GTPase with a relative molecular mass of 96,000 (Mr 96K) that is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Although its function is apparently essential for scission of newly formed vesicles from the plasma membrane, the nature of dynamin's role in the scission process is still unclear. It has been proposed that dynamin is a regulator (similar to classical G proteins) of downstream effectors. Here we report the analysis of several point mutants of dynamin's GTPase effector (GED) and GTPase domains. We show that oligomerization and GTP binding alone, by dynamin, are not sufficient for endocytosis in vivo. Rather, efficient GTP hydrolysis and an associated conformational change are also required. These data argue that dynamin has a mechanochemical function in vesicle scission.     

Curvature of clathrin-coated pits driven by epsin

Clathrin-mediated endocytosis involves cargo selection and membrane budding into vesicles with the aid of a protein coat. Formation of invaginated pits on the plasma membrane and subsequent budding of vesicles is an energetically demanding process that involves the cooperation of clathrin with many different proteins. Here we investigate the role of the brain-enriched protein epsin 1 in this process. Epsin is targeted to areas of endocytosis by binding the membrane lipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)). We show here that epsin 1 directly modifies membrane curvature on binding to PtdIns(4,5)P(2) in conjunction with clathrin polymerization. We have discovered that formation of an amphipathic alpha-helix in epsin is coupled to PtdIns(4,5)P(2) binding. Mutation of residues on the hydrophobic region of this helix abolishes the ability to curve membranes. We propose that this helix is inserted into one leaflet of the lipid bilayer, inducing curvature. On lipid monolayers epsin alone is sufficient to facilitate the formation of clathrin-coated invaginations.     

Myofibrillar protein degradation after eccentric exercise

Male rats were run downhill for 90 minutes (nonexhaustive). Following the exercise, muscle protein degradation was increased, as determined by urinary 3-methylhistidine. However, minimal changes were observed in the relative percentage of the minor myofibrillar proteins and in the protease calcium activated factor in the long head of the triceps brachii muscle (eccentrically exercised) following the exercise bout.     

Iron and phosphorus co-limit nitrogen fixation in the eastern tropical North Atlantic

The role of iron in enhancing phytoplankton productivity in high nutrient, low chlorophyll oceanic regions was demonstrated first through iron-addition bioassay experiments and subsequently confirmed by large-scale iron fertilization experiments. Iron supply has been hypothesized to limit nitrogen fixation and hence oceanic primary productivity on geological timescales, providing an alternative to phosphorus as the ultimate limiting nutrient. Oceanographic observations have been interpreted both to confirm and refute this hypothesis, but direct experimental evidence is lacking. We conducted experiments to test this hypothesis during the Meteor 55 cruise to the tropical North Atlantic. This region is rich in diazotrophs and strongly impacted by Saharan dust input. Here we show that community primary productivity was nitrogen-limited, and that nitrogen fixation was co-limited by iron and phosphorus. Saharan dust addition stimulated nitrogen fixation, presumably by supplying both iron and phosphorus. Our results support the hypothesis that aeolian mineral dust deposition promotes nitrogen fixation in the eastern tropical North Atlantic.     

The production of molecular positronium

It has been known for many years that an electron and its antiparticle, the positron, may together form a metastable hydrogen-like atom, known as positronium or Ps (ref. 1). In 1946, Wheeler speculated that two Ps atoms may combine to form the di-positronium molecule (Ps2), with a binding energy of 0.4 eV. More recently, this molecule has been studied theoretically; however, because Ps has a short lifetime and it is difficult to obtain low-energy positrons in large numbers, Ps2 has not previously been observed unambiguously. Here we show that when intense positron bursts are implanted into a thin film of porous silica, Ps2 is created on the internal pore surfaces. We found that molecule formation occurs much more efficiently than the competing process of spin exchange quenching, which appears to be suppressed in the confined pore geometry. This result experimentally confirms the existence of the Ps2 molecule and paves the way for further multi-positronium work. Using similar techniques, but with a more intense positron source, we expect to increase the Ps density to the point where many thousands of atoms interact and can undergo a phase transition to form a Bose-Einstein condensate. As a purely leptonic, macroscopic quantum matter-antimatter system this would be of interest in its own right, but it would also represent a milestone on the path to produce an annihilation gamma-ray laser.     

Solidification and crystallization properties of CaO-SiO2-Na2O based mold fluxes

Crystallization properties play an important role in keeping a smooth running of continuous casting process and high surface quality of cast strands. To reduce fluorine pollution in slag, a new type of CaO-SiO₂-Na₂O (CSN) based mold flux was studied. The solidification and crystallization properties, including crystallization temperature, crystallization ratio and solidification mineragraphy, were measured, which were compared with the CaO-SiO₂-CaF₂ (GF) mold flux. The results show that the crystallization performance is equal to the high fluoride mold powder and CSN can be used for peritectic steel grades sensitive to longitudinal cracking in continuous casting.     

Essay review

In the trial of Galileo there is a small but significant discrepancy between the text of his condemnation by the Holy Office and the text of his recantation, which has been generally overlooked or ignored. The offence that he was required to recant was more serious than the one of which he had been found guilty. The most plausible explanation seems to be that the two texts were drawn up independently of each other by the Inquisitors and the Pope respectively, and that the latter wished to deal more harshly with Galileo than the former. There is some independent evidence for this supposition.