Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.     

Gating of the rapid shade-avoidance response by the circadian clock in plants

The phytochromes are a family of plant photoreceptor proteins that control several adaptive developmental strategies. For example, the phytochromes perceive far-red light (wavelengths between 700 and 800 nm) reflected or scattered from the leaves of nearby vegetation. This provides an early warning of potential shading, and triggers a series of 'shade-avoidance' responses, such as a rapid increase in elongation, by which the plant attempts to overgrow its neighbours. Other, less immediate, responses include accelerated flowering and early production of seeds. However, little is known about the molecular events that connect light perception with increased growth in shade avoidance. Here we show that the circadian clock gates this rapid shade-avoidance response. It is most apparent around dusk and is accompanied by altered expression of several genes. One of these rapidly responsive genes encodes a basic helix-loop-helix protein, PIL1, previously shown to interact with the clock protein TOC1 (ref. 4). Furthermore PIL1 and TOC1 are both required for the accelerated growth associated with the shade-avoidance response.     

城市--生态学最后的前沿阵地

自从产业革命以来，城市便是西方文化中一个奇特的关联到爱与恨的主题。一方面，我们对城市在文明兴起中的重要作用表示敬意；另一方面，我们为城市中连绵的大烟囱、堆积如山的垃圾和漫溢的阴沟而掩住鼻孔，责难它们恰恰是旷野的对立面。美国的哲学家、博物学家亨利·大维·梭罗写道，大自然“孤独地挥舞着，远离人类居住的城镇。”但是如果一位外星人来访，它会不会表示异议？它会不会像观察雨林和珊瑚礁一样，把城市看作是地球上另一个生态系统？它会不会注意到城市里的所有事物最终受制于同样的生物和物理进程，正是这一进程形成了每一处…     

A wide depth distribution of seismic tremors along the northern Cascadia margin

The Cascadia subduction zone is thought to be capable of generating major earthquakes with moment magnitude as large as M(w) = 9 at an interval of several hundred years. The seismogenic portion of the plate interface is mostly offshore and is currently locked, as inferred from geodetic data. However, episodic surface displacements-in the direction opposite to the long-term deformation motions caused by relative plate convergence across a locked interface-are observed about every 14 months with an unusual tremor-like seismic signature. Here we show that these tremors are distributed over a depth range exceeding 40 km within a limited horizontal band. Many occurred within or close to the strong seismic reflectors above the plate interface where local earthquakes are absent, suggesting that the seismogenic process for tremors is fluid-related. The observed depth range implies that tremors could be associated with the variation of stress field induced by a transient slip along the deeper portion of the Cascadia interface or, alternatively, that episodic slip is more diffuse than originally suggested.     

Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.     

Life without myoglobin

Hemoproteins are widely distributed among prokaryotes, unicellular eukaryotes, plants and animals [1]. Myoglobin, a cytoplasmic hemoprotein that is restricted to cardiomyocytes and oxidative skeletal myofibers in vertebrates, has been proposed to facilitate oxygen transport to the mitochondria [1-3]. This cytoplasmic hemoprotein was the first protein to be subjected to definitive structural analysis and has been a subject of long-standing and ongoing interest to biologists [1-3]. Recently, we utilized gene disruption technology to generate mice that are viable and fertile despite a complete absence of myoglobin [4]. This unexpected result led us to reexamine existing paradigms regarding the function of myoglobin in striated muscle.     

Regulation of Arabidopsis cryptochrome 2 by blue-light-dependent phosphorylation

Cryptochromes are blue/ultraviolet-A light receptors that mediate various light responses in plants and animals. But the initial photochemical reaction of cryptochrome is still unclear. For example, although most photoreceptors are known to undergo light-dependent protein modification such as phosphorylation, no blue-light dependent phosphorylation has been reported for a cryptochrome. Arabidopsis cryptochrome 2 (cry2) mediates light regulation of seedling development and photoperiodic flowering. The physiological activity and cellular level of cry2 protein are light-dependent, and protein protein interactions are important for cry2 function. Here we report that cry2 undergoes a blue-light-dependent phosphorylation, and that cry2 phosphorylation is associated with its function and regulation. Our results suggest that, in the absence of light, cry2 remains unphosphorylated, inactive and stable; absorption of blue light induces the phosphorylation of cry2, triggering photomorphogenic responses and eventually degradation of the photoreceptor.     

Should fixed coefficients be re-estimated every period for extrapolation?

This paper demonstrates that forecast accuracy is not necessarily improved when fixed-coefficient models are sequentially re-estimated and used for prediction, after updating the database with the latest observation(s). It is argued that although sequential estimation may minimize the variances of predictors based on some classes of estimators, sequential estimation does not necessarily yield accurate predictions (i.e. predictions that are close to actual realizations). Minimizing the mean squared prediction error about the actual realization is a necessary condition for maximizing the probability that one predictor is more accurate than others. This minimization need not require, and may even exclude, the most recent data. It has been shown by an example that a prediction based on a nonsequential estimate of a stochastically varying coefficient model is superior to predictions based on several sequential estimates of the fixed-coefficient models, including a random walk model.