Structural insights into phosphoinositide 3-kinase catalysis and signalling

Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases that function both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PI3Ks are dual-specificity enzymes with a lipid kinase activity which phosphorylates phosphoinositides at the 3-hydroxyl, and a protein kinase activity. The products of PI3K-catalysed reactions, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), PtdIns(3,4)P2 and PtdIns(3)P, are second messengers in a variety of signal transduction pathways, including those essential to cell proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle trafficking. Here we report the 2.2 A X-ray crystallographic structure of the catalytic subunit of PI3Kgamma, the class I enzyme that is activated by heterotrimeric G-protein betagamma subunits and Ras. PI3Kgamma has a modular organization centred around a helical-domain spine, with C2 and catalytic domains positioned to interact with phospholipid membranes, and a Ras-binding domain placed against the catalytic domain where it could drive allosteric activation of the enzyme.     

Structural basis for selective recognition of ESCRT-III by the AAA ATPase Vps4

The AAA+ ATPases are essential for various activities such as membrane trafficking, organelle biogenesis, DNA replication, intracellular locomotion, cytoskeletal remodelling, protein folding and proteolysis. The AAA ATPase Vps4, which is central to endosomal traffic to lysosomes, retroviral budding and cytokinesis, dissociates ESCRT complexes (the endosomal sorting complexes required for transport) from membranes. Here we show that, of the six ESCRT--related subunits in yeast, only Vps2 and Did2 bind the MIT (microtubule interacting and transport) domain of Vps4, and that the carboxy-terminal 30 residues of the subunits are both necessary and sufficient for interaction. We determined the crystal structure of the Vps2 C terminus in a complex with the Vps4 MIT domain, explaining the basis for selective ESCRT-III recognition. MIT helices alpha2 and alpha3 recognize a (D/E)xxLxxRLxxL(K/R) motif, and mutations within this motif cause sorting defects in yeast. Our crystal structure of the amino-terminal domain of an archaeal AAA ATPase of unknown function shows that it is closely related to the MIT domain of Vps4. The archaeal ATPase interacts with an archaeal ESCRT-III-like protein even though these organisms have no endomembrane system, suggesting that the Vps4/ESCRT-III partnership is a relic of a function that pre-dates the divergence of eukaryotes and Archaea.     

Can forecasters forecast successfully? Evidence from UK betting markets

This paper investigates the performance of professional racetrack forecasting services in the UK. The racetrack market is chosen for investigation because it offers a clear and well‐defined set of costs and returns. As such, it provides a useful perspective from which to consider the efficiency of professional forecasting performance. Five services are selected based on their reported success in a period prior to the sample selection. The results of this study indicate that all the services showed evidence of net pre‐tax profits, notably for more strongly recommended tips, but this would have required quite high stakes to cover the costs of accessing the information. Statistical tests of significance were unable, however, to confirm the evidence of profitability at conventional levels of acceptance. Taking into account the transactions costs of using these services, it is even more difficult to confirm the existence of abnormal returns. Copyright © 2000 John Wiley & Sons, Ltd.     

考虑解答者公平关切的众包竞赛知识共享激励

研究了解答者之间的横向公平关切特征对众包竞赛发包方知识共享激励的影响。在构建公平关切下解答者效用函数的基础上,建立并求解了无知识共享激励模型(NKS)和知识共享激励模型(KS),用理论分析和数值仿真方法研究了公平关切敏感度对发包方最优知识共享激励程度、解答者最优私有解答努力程度及知识共享努力程度、众包项目绩效以及双方期望经济收益的影响,并与无知识共享激励进行了对比。研究表明：解答者公平关切心理能降低实施共享知识激励机制的门槛,并提升发包方最优知识共享激励程度;解答方知识共享努力与公平关切正相关,但私有解答努力与之负相关;众包项目绩效、发包方绝对经济收益与公平关切的关系取决于解答努力绩效转化率和知识共享努力绩效转化率之间的比值;知识共享激励机制能实现发包方和解答者双方经济利益的共赢,且其经济价值随公平关切敏感度增大而提高,并受到参赛人数的调节作用。     

A copy number variation morbidity map of developmental delay

To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ～14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.     

Carbon isotope discrimination and water relations of oak hybrid populations in southwestern Utah

The evergreen oak Quercus turbinella and the deciduous Q. gambelii form natural hybrids in southwestern Utah and northern Arizona. Hybrid individuals also are found in northern Utah in a region where only Q. gambelii currently exists, indicating that Q. turbinella has recently retreated southward. Our objectives were to (1) examine the ecophysiology of parental taxa and hybrids under natural conditions in southeastern Utah, and (2) investigate the level of integration between leaf carbon isotope discrimination (a synthetic gas exchange trait) and structural and chemical traits of leaves in morphologically variable hybrid populations. Leaf length, width, mass-to-area ratio (LMA, g m -2 ), and nitrogen concentration (N, g g -1 ) within 2 hybrid populations near New Harmony, Utah, were highly intercorrelated. Variation within the hybrid populations spanned mean values for these traits observed in parental taxa from adjacent ""pure"" populations of each species. Carbon isotope discrimination (Δ), an integrated measure of the ratio of intercellular to ambient CO 2 concentration, ranged from 16.1‰ to 19.6‰ within the 2 hybrid populations and was positively correlated with leaf nitrogen concentration and negatively correlated with LMA; individuals in hybrid populations with leaves resembling Q. gambelii had the highest leaf Δ and N concentrations and lowest LMA compared with leaves from plants that resembled Q. turbinella . CO 2 uptake is limited by stomatal conductance and possibly by mesophyll resistance to a greater extent in Q. turbinella phenotypes than in intermediate or Q. gambelii phenotypes. δD of stem xylem water (an indication of active rooting depth) and predawn water potential during the peak monsoon period in August were not correlated to leaf Δ values within the hybrid populations. Several individuals that were morphologically similar to Q. turbinella in the hybrid populations maintained high predawn water potentials and derived moisture from winter recharge that presumably was taken from deep soil layers. Apparently, a few adult individuals of the Q. turbinella phenotype in hybrid populations accessed water from deep in the soil profile, which enabled them to avoid summer drought. Reduced monsoonal activity may have been an important, but not the single, determinant of Q. turbinella s retreat from northern Utah during the recent Holocene.