Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation

The eight catalytic subunits of the mammalian phosphoinositide-3-OH kinase (PI(3)K) family form the backbone of an evolutionarily conserved signalling pathway; however, the roles of most PI(3)K isoforms in organismal physiology and disease are unknown. To delineate the role of p110alpha, a ubiquitously expressed PI(3)K involved in tyrosine kinase and Ras signalling, here we generated mice carrying a knockin mutation (D933A) that abrogates p110alpha kinase activity. Homozygosity for this kinase-dead p110alpha led to embryonic lethality. Mice heterozygous for this mutation were viable and fertile, but displayed severely blunted signalling via insulin-receptor substrate (IRS) proteins, key mediators of insulin, insulin-like growth factor-1 and leptin action. Defective responsiveness to these hormones led to reduced somatic growth, hyperinsulinaemia, glucose intolerance, hyperphagia and increased adiposity in mice heterozygous for the D933A mutation. This signalling function of p110alpha derives from its highly selective recruitment and activation to IRS signalling complexes compared to p110beta, the other broadly expressed PI(3)K isoform, which did not contribute to IRS-associated PI(3)K activity. p110alpha was the principal IRS-associated PI(3)K in cancer cell lines. These findings demonstrate a critical role for p110alpha in growth factor and metabolic signalling and also suggest an explanation for selective mutation or overexpression of p110alpha in a variety of cancers.     

Isotopic enhancements of 17O and 18O from solar wind particles in the lunar regolith

Differences in isotopic abundances between meteorites and rocks on Earth leave unclear the true composition of the gas out of which the Solar System formed. The Sun should have preserved in its outer layers the original composition, and recent work has indicated that the solar wind is enriched in 16O, relative to Earth, Mars and bulk meteorites. This suggests that self-shielding of CO due to photo-dissociation, which is a well understood process in molecular clouds, also led to evolution in the isotopic abundances in the early Solar System. Here we report measurements of oxygen isotopic abundances in lunar grains that were recently exposed to the solar wind. We find that 16O is underabundant, opposite to an earlier finding based on studies of ancient metal grains. Our result, however, is more difficult to understand within the context of current models, because there is no clear way to make 16O more abundant in Solar System rocks than in the Sun.     

Conjugated action of two species-specific invasion proteins for fetoplacental listeriosis

The ability to cross host barriers is an essential virulence determinant of invasive microbial pathogens. Listeria monocytogenes is a model microorganism that crosses human intestinal and placental barriers, and causes severe maternofetal infections by an unknown mechanism. Several studies have helped to characterize the bacterial invasion proteins InlA and InlB. However, their respective species specificity has complicated investigations on their in vivo role. Here we describe two novel and complementary animal models for human listeriosis: the gerbil, a natural host for L. monocytogenes, and a knock-in mouse line ubiquitously expressing humanized E-cadherin. Using these two models, we uncover the essential and interdependent roles of InlA and InlB in fetoplacental listeriosis, and thereby decipher the molecular mechanism underlying the ability of a microbe to target and cross the placental barrier.     

Semi-annual oscillations in Saturn's low-latitude stratospheric temperatures

Observations of oscillations of temperature and wind in planetary atmospheres provide a means of generalizing models for atmospheric dynamics in a diverse set of planets in the Solar System and elsewhere. An equatorial oscillation similar to one in the Earth's atmosphere has been discovered in Jupiter. Here we report the existence of similar oscillations in Saturn's atmosphere, from an analysis of over two decades of spatially resolved observations of its 7.8-microm methane and 12.2-microm ethane stratospheric emissions, where we compare zonal-mean stratospheric brightness temperatures at planetographic latitudes of 3.6 degrees and 15.5 degrees in both the northern and the southern hemispheres. These results support the interpretation of vertical and meridional variability of temperatures in Saturn's stratosphere as a manifestation of a wave phenomenon similar to that on the Earth and in Jupiter. The period of this oscillation is 14.8 +/- 1.2 terrestrial years, roughly half of Saturn's year, suggesting the influence of seasonal forcing, as is the case with the Earth's semi-annual oscillation.     

Global trends in emerging infectious diseases

Emerging infectious diseases (EIDs) are a significant burden on global economies and public health. Their emergence is thought to be driven largely by socio-economic, environmental and ecological factors, but no comparative study has explicitly analysed these linkages to understand global temporal and spatial patterns of EIDs. Here we analyse a database of 335 EID 'events' (origins of EIDs) between 1940 and 2004, and demonstrate non-random global patterns. EID events have risen significantly over time after controlling for reporting bias, with their peak incidence (in the 1980s) concomitant with the HIV pandemic. EID events are dominated by zoonoses (60.3% of EIDs): the majority of these (71.8%) originate in wildlife (for example, severe acute respiratory virus, Ebola virus), and are increasing significantly over time. We find that 54.3% of EID events are caused by bacteria or rickettsia, reflecting a large number of drug-resistant microbes in our database. Our results confirm that EID origins are significantly correlated with socio-economic, environmental and ecological factors, and provide a basis for identifying regions where new EIDs are most likely to originate (emerging disease 'hotspots'). They also reveal a substantial risk of wildlife zoonotic and vector-borne EIDs originating at lower latitudes where reporting effort is low. We conclude that global resources to counter disease emergence are poorly allocated, with the majority of the scientific and surveillance effort focused on countries from where the next important EID is least likely to originate.     

Investigation on regenerator temperature inhomogeneity in Stirling-type pulse tube cooler

Regenerator is one of the most crucial components to pulse tube cooler (PTC) and thermoacoustic engine. As such regenerator is scaled up to high-power, the thermal and hydrodynamic communication transverse to the acoustic axis gets weaker and weaker. Under this condition, any unsymmetric factor could cause serious instability to the cooler or engine, which degrades their performance. Investigation has been carried out on a high-power two-stage thermal-coupled U-shape Stirling-type PTC. By detailed circumferential temperature measurements along the middle heat exchanger and second stage regen-erator, a kind of temperature inhomogeneity caused by unsymmetric pre-cooling effect of inter-stage thermal bridge was found in the lower part of the regenerator of the PTC. The temperature inhomoge-neity originating from the middle heat exchanger of the second stage regenerator amplified itself in the lower part of the regenerator and then internal streaming formed. The maximal radial temperature dif-ference could reach 30―40 K. Experimental results show that the temperature inhomogeneity intensi-fies with increased pre-cooling power and its direction can be reversed by changing the pre-cooling effect of the first stage PTC to heating effect by using external thermal load. This research shows that it is important to maintain the heating or cooling effects of heat exchangers uniform in high-power re-generative coolers and engines.     

斯特林型脉管制冷机中的回热器温度不均匀性研究

回热器是脉管制冷机和热声热机中的最关键部件之一. 当回热器由中小功率放大到大功率时, 其内垂直于声传播方向的热力和水力联系变弱. 在这种情况下, 任何的非对称因素都可能在制冷机或发动机的回热器内引发严重的不稳定性问题, 从而降低制冷机或发动机的性能. 对一台大功率二级热耦合U型斯特林脉管制冷机进行了实验研究, 通过对中间换热器和回热器周向温度分布进行测量, 发现了一种由级间预冷不对称性引起的回热器温度不均匀性. 观察发现, 回热器周向的温度不均匀性源于第二级回热器的中间换热器, 之后, 这个温度不均匀性在回热器中以内部直流的形式自行放大, 最大径向温差可达30~40 K. 在对第一级冷头外加热负荷并逐步增大热负荷直至把第一级的预冷效应转变为加热效应的过程中, 回热器内的温度不均性逐渐变弱, 最后其方向发生逆转. 本研究证明了在大功率回热式热机中保持换热器加热或冷却作用周向均一的重要性.     

Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer

Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, we detected a single-gene amplification of the ESR1 gene, which encodes estrogen receptor alpha, at 6q25. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein overexpression, compared with 66.6% cancers without ESR1 amplification (P < 0.0001). In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor-expressing cancers without ESR1 amplification (P = 0.023). Notably, we also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers.