Intrinsic functional architecture in the anaesthetized monkey brain

The traditional approach to studying brain function is to measure physiological responses to controlled sensory, motor and cognitive paradigms. However, most of the brain's energy consumption is devoted to ongoing metabolic activity not clearly associated with any particular stimulus or behaviour. Functional magnetic resonance imaging studies in humans aimed at understanding this ongoing activity have shown that spontaneous fluctuations of the blood-oxygen-level-dependent signal occur continuously in the resting state. In humans, these fluctuations are temporally coherent within widely distributed cortical systems that recapitulate the functional architecture of responses evoked by experimentally administered tasks. Here, we show that the same phenomenon is present in anaesthetized monkeys even at anaesthetic levels known to induce profound loss of consciousness. We specifically demonstrate coherent spontaneous fluctuations within three well known systems (oculomotor, somatomotor and visual) and the 'default' system, a set of brain regions thought by some to support uniquely human capabilities. Our results indicate that coherent system fluctuations probably reflect an evolutionarily conserved aspect of brain functional organization that transcends levels of consciousness.     

Potentiation of neuroblastoma metastasis by loss of caspase-8

Neuroblastoma, the most common paediatric solid tumour, arises from defective neural crest cells. Genetic alterations occur frequently in the most aggressive neuroblastomas. In particular, deletion or suppression of the proapoptotic enzyme caspase-8 is common in malignant, disseminated disease, although the effect of this loss on disease progression is unclear. Here we show that suppression of caspase-8 expression occurs during the establishment of neuroblastoma metastases in vivo, and that reconstitution of caspase-8 expression in deficient neuroblastoma cells suppressed their metastases. Caspase-8 status was not a predictor of primary tumour growth; rather, caspase-8 selectively potentiated apoptosis in neuroblastoma cells invading the collagenous stroma at the tumour margin. Apoptosis was initiated by unligated integrins by means of a process known as integrin-mediated death. Loss of caspase-8 or integrin rendered these cells refractory to integrin-mediated death, allowed cellular survival in the stromal microenvironment, and promoted metastases. These findings define caspase-8 as a metastasis suppressor gene that, together with integrins, regulates the survival and invasive capacity of neuroblastoma cells.     

DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.     

Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia

Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.     

The mechanism of sodium and substrate release from the binding pocket of vSGLT

Membrane co-transport proteins that use a five-helix inverted repeat motif have recently emerged as one of the largest structural classes of secondary active transporters. However, despite many structural advances there is no clear evidence of how ion and substrate transport are coupled. Here we report a comprehensive study of the sodium/galactose transporter from Vibrio parahaemolyticus (vSGLT), consisting of molecular dynamics simulations, biochemical characterization and a new crystal structure of the inward-open conformation at a resolution of 2.7??. Our data show that sodium exit causes a reorientation of transmembrane helix 1 that opens an inner gate required for substrate exit, and also triggers minor rigid-body movements in two sets of transmembrane helical bundles. This cascade of events, initiated by sodium release, ensures proper timing of ion and substrate release. Once set in motion, these molecular changes weaken substrate binding to the transporter and allow galactose readily to enter the intracellular space. Additionally, we identify an allosteric pathway between the sodium-binding sites, the unwound portion of transmembrane helix 1 and the substrate-binding site that is essential in the coupling of co-transport.     

地下圆形衬砌洞室对SV及Rayleigh波的动应力集中(II):数值结果

为了解决在入射平面SV波和Rayleigh波作用下地下圆形衬砌洞室的动应力集中问题,利用文献[5]的级数解,分析了衬砌刚度、入射波长、入射角度诸因素对动应力集中系数(DSCF)的影响。数值结果表明:(1)衬砌刚度对DSCF有重要影响,柔性衬砌情况DSCF最小,刚性衬砌情况的最大;环向与轴向DSCF最大可分别达到32.31与16.12;(2)入射频率和入射角度对DSCF也有很大影响。     

High-amplitude fluctuations and alternative dynamical states of midges in Lake Myvatn

Complex dynamics are often shown by simple ecological models and have been clearly demonstrated in laboratory and natural systems. Yet many classes of theoretically possible dynamics are still poorly documented in nature. Here we study long-term time-series data of a midge, Tanytarsus gracilentus (Diptera: Chironomidae), in Lake Myvatn, Iceland. The midge undergoes density fluctuations of almost six orders of magnitude. Rather than regular cycles, however, these fluctuations have irregular periods of 4-7 years, indicating complex dynamics. We fit three consumer-resource models capable of qualitatively distinct dynamics to the data. Of these, the best-fitting model shows alternative dynamical states in the absence of environmental variability; depending on the initial midge densities, the model shows either fluctuations around a fixed point or high-amplitude cycles. This explains the observed complex population dynamics: high-amplitude but irregular fluctuations occur because stochastic variability causes the dynamics to switch between domains of attraction to the alternative states. In the model, the amplitude of fluctuations depends strongly on minute resource subsidies into the midge habitat. These resource subsidies may be sensitive to human-caused changes in the hydrology of the lake, with human impacts such as dredging leading to higher-amplitude fluctuations. Tanytarsus gracilentus is a key component of the Myvatn ecosystem, representing two-thirds of the secondary productivity of the lake and providing vital food resources to fish and to breeding bird populations. Therefore the high-amplitude, irregular fluctuations in midge densities generated by alternative dynamical states dominate much of the ecology of the lake.     

社鼠和针毛鼠线粒体DNA序列的歧异及其系统进化关系

社鼠和针毛鼠是有着广泛地理分布的山地鼠种,它们的一些形态特征及核型明显有别于同属的其它鼠类.社鼠的亚种--雷琼社鼠局限于分布在广东省西部地区和海南省,它的形态特征多似社鼠,但也有少数特征相似于针毛鼠.对于社鼠和针毛鼠的分类地位及社鼠亚种的分化一直有着各种讨论.本研究进行了社鼠和雷琼社鼠以及针毛鼠龙门种群和香港种群的细胞色素b (264个核苷酸位点)和12S rRNA (387个核苷酸位点)基因片段的测序.社鼠与雷琼社鼠线粒体的细胞色素b基因片段间包含有19个变异位点、12S rRNA 基因片段间包含11个变异位点和2个插入/缺失位点.针毛鼠的2个种群间的细胞色素b 和12S rRNA 基因片段分别包含了3个和11个变异位点.通过邻接法和最大简约法重建的系统进化关系表明:雷琼社鼠与社鼠有着紧密的亲缘关系,它的亚种地位得到了线粒体DNA序列证据的肯定.针毛鼠龙门种群和香港种群细胞色素b和12S rRNA 基因片段序列的歧异反映出两个种群由于长期的地理隔离及其所经历自然选择的结果.     

Genetic Tabu Search for the Multi-Objective Knapsack Problem

We introduce a hybrid algorithm for the 0 - 1 multidimensional multi-objective knapsack problem.This algorithm, called GTS^MOKP, combines a genetic procedure and a tabu search operator. The algorithm is evaluated on 9 well-known benchmark instances and shows highly competitive results compared with two state-of-the-art algorithms.