Modulation of single Ca2+-dependent K+-channel activity by protein phosphorylation

There is considerable evidence that cyclic AMP can modulate the electrical activity of excitable cells and that protein phosphorylation by the catalytic subunit (CS) of cAMP-dependent protein kinase is a necessary step in these modulatory effects. In analogy to alterations in enzyme activities following phosphorylation, it seems possible that direct phosphorylation of ion-channel proteins may alter their gating properties, giving rise to the observe changes in electrical activity. However, the results obtained so far do not indicate whether it is ion channels themselves that are phosphorylated, or whether phosphorylation is simply an early step in some cascade of events which leads ultimately to modulation of channel activity. The development of single-channel recording techniques has provided a way to investigate this question. Here we describe effects of CS on the activity of individual CA2+-dependent K+ channels from the nervous system of the land snail Helix measured in isolated membrane patches and in artificial phospholipid bilayers. The results demonstrate that cAMP-dependent protein phosphorylation produces long-lasting changes in the activity of individual channels, and indicate that the relevant phosphorylation site is closely associated with the channel.     

The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor

Mammalian Toll-like receptors (TLRs) 3, 7, 8 and 9 initiate immune responses to infection by recognizing microbial nucleic acids; however, these responses come at the cost of potential autoimmunity owing to inappropriate recognition of self nucleic acids. The localization of TLR9 and TLR7 to intracellular compartments seems to have a role in facilitating responses to viral nucleic acids while maintaining tolerance to self nucleic acids, yet the cell biology regulating the transport and localization of these receptors remains poorly understood. Here we define the route by which TLR9 and TLR7 exit the endoplasmic reticulum and travel to endolysosomes in mouse macrophages and dendritic cells. The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. Notably, although both the full-length and cleaved forms of TLR9 are capable of binding ligand, only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids.     

Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity

A common viral immune evasion strategy involves mutating viral surface proteins in order to evade host neutralizing antibodies. Such immune evasion tactics have not previously been intentionally applied to the development of novel viral gene delivery vectors that overcome the critical problem of anti-vector immunity. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens have proved highly immunogenic in preclinical studies but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world. Here we show that rAd5 vectors can be engineered to circumvent anti-Ad5 immunity. We constructed novel chimaeric rAd5 vectors in which the seven short hypervariable regions (HVRs) on the surface of the Ad5 hexon protein were replaced with the corresponding HVRs from the rare adenovirus serotype Ad48. These HVR-chimaeric rAd5 vectors were produced at high titres and were stable through serial passages in vitro. HVR-chimaeric rAd5 vectors expressing simian immunodeficiency virus Gag proved comparably immunogenic to parental rAd5 vectors in naive mice and rhesus monkeys. In the presence of high levels of pre-existing anti-Ad5 immunity, the immunogenicity of HVR-chimaeric rAd5 vectors was not detectably suppressed, whereas the immunogenicity of parental rAd5 vectors was abrogated. These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are focused on epitopes located within the hexon HVRs. Moreover, these studies show that recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy.     

柳杉树轮δ~(13)C与气候要素的分析与应用

<正>对采自气候为非限制性因子地区的柳杉树轮稳定碳同位素比 δ１３ Ｃ进行气候响应分析。用排除法消除大气二氧化碳中δ１３Ｃ的变化对柳杉树轮δ１３Ｃ变化的影响后,建立残差年序列ＲＥ,并结合西天目山气象站的气象记录,分析了树轮δ１３Ｃ年序列对气候要素的响应。结果表明：西天目山地区树轮 δ１３Ｃ的高频振荡与 １１、１２月最高气温的平均值,１、２、３月降水总和以及６、７月降水总和显著相关,在一定程度上反映了东亚季风对该区的影响大小。可见气候非限制性因子地区树轮稳定碳同位素组成年序列同样可以作为气候变化指针。     

Observation of moist convection in Jupiter's atmosphere. Galileo Imaging Team

The energy source driving Jupiter's active meteorology is not understood. There are two main candidates: a poorly understood internal heat source and sunlight. Here we report observations of an active storm system possessing both lightning and condensation of water. The storm has a vertical extent of at least 50 km and a length of about 4,000 km. Previous observations of lightning on Jupiter have revealed both its frequency of occurrence and its spatial distribution, but they did not permit analysis of the detailed cloud structure and its dynamics. The present observations reveal the storm (on the day side of the planet) at the same location and within just a few hours of a lightning detection (on the night side). We estimate that the total vertical transport of heat by storms like the one observed here is of the same order as the planet's internal heat source. We therefore conclude that moist convection-similar to large clusters of thunderstorm cells on the Earth-is a dominant factor in converting heat flow into kinetic energy in the jovian atmosphere.     

A giant thunderstorm on Saturn

Lightning discharges in Saturn's atmosphere emit radio waves with intensities about 10,000 times stronger than those of their terrestrial counterparts. These radio waves are the characteristic features of lightning from thunderstorms on Saturn, which last for days to months. Convective storms about 2,000 kilometres in size have been observed in recent years at planetocentric latitude 35° south (corresponding to a planetographic latitude of 41° south). Here we report observations of a giant thunderstorm at planetocentric latitude 35° north that reached a latitudinal extension of 10,000 kilometres-comparable in size to a 'Great White Spot'-about three weeks after it started in early December 2010. The visible plume consists of high-altitude clouds that overshoot the outermost ammonia cloud layer owing to strong vertical convection, as is typical for thunderstorms. The flash rates of this storm are about an order of magnitude higher than previous ones, and peak rates larger than ten per second were recorded. This main storm developed an elongated eastward tail with additional but weaker storm cells that wrapped around the whole planet by February 2011. Unlike storms on Earth, the total power of this storm is comparable to Saturn's total emitted power. The appearance of such storms in the northern hemisphere could be related to the change of seasons, given that Saturn experienced vernal equinox in August 2009.