一种快速分层递阶DSmT近似推理融合方法(C)

针对超幂集空间中部分不确定焦元或者混合焦元具有信度赋值的情形,将混合焦元转化为统一形式;根据纯不确定焦元平分原则进行平分信度赋值,并将新的或固有的冲突焦元的信度赋值分配到相应的单子焦元上;利用二叉树分组技术对单子焦元进行刚性分组,实现细粒度超向粗粒度超幂集空间的映射;运用DSmT组合规则和比例冲突分配规则对粗化超幂集空...     

矩形分流墩墩体壁压特性及其空化研究

通过系统的模型试验研究了中，低佛氏数下急流越过矩形分流墩，墩后通大气的情况下，墩体壁压及其空化可能性，得到了墩顶挑射流态下，墩上游和墩体壁压分布规律；分析了墩体阻力系数与相对墩高，收缩比及控制断面佛氏数的分布规律。试验结果证明，当墩后充分供气时，墩体产生空蚀的可能性极小。     

Physical performance and Darwinian fitness in lizards

Strong evidence for a genetic basis of variation in physical performance has accumulated. Considering one of the basic tenets of evolutionary physiology--that physical performance and darwinian fitness are tightly linked--one may expect phenotypes with exceptional physiological capacities to be promoted by natural selection. Why then does physical performance remain considerably variable in human and other animal populations? Our analysis of locomotor performance in the common lizard (Lacerta vivipara) demonstrates that initial endurance (running time to exhaustion measured at birth) is indeed highly heritable, but natural selection in favour of this trait can be unexpectedly weak. A manipulation of dietary conditions unravels a proximate mechanism explaining this pattern. Fully fed individuals experience a marked reversal of performance within only one month after birth: juveniles with low endurance catch up, whereas individuals with high endurance lose their advantage. In contrast, dietary restriction allows highly endurant neonates to retain their locomotor superiority as they age. Thus, the expression of a genetic predisposition to high physical performance strongly depends on the environment experienced early in life.     

A missense mutation in Tbce causes progressive motor neuronopathy in mice

Mice that are homozygous with respect to the progressive motor neuronopathy (pmn) mutation (chromosome 13) develop a progressive caudio-cranial degeneration of their motor axons from the age of two weeks and die four to six weeks after birth. The mutation is fully penetrant, and expressivity does not depend on the genetic background. Based on its pathological features, the pmn mutation has been considered an excellent model for the autosomal recessive proximal childhood form of spinal muscular atrophy (SMA). Previously, we demonstrated that the genes responsible for these disorders were not orthologous. Here, we identify the pmn mutation as resulting in a Trp524Gly substitution at the last residue of the tubulin-specific chaperone e (Tbce) protein that leads to decreased protein stability. Electron microscopy of the sciatic and phrenic nerves of affected mice showed a reduced number of microtubules, probably due to defective stabilization. Transgenic complementation with a wildtype Tbce cDNA restored a normal phenotype in mutant mice. Our observations indicate that Tbce is critical for the maintenance of microtubules in mouse motor axons, and suggest that altered function of tubulin cofactors might be implicated in human motor neuron diseases.     

An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.     

Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels

TRPV4 is a widely expressed cation channel of the 'transient receptor potential' (TRP) family that is related to the vanilloid receptor VR1 (TRPV1). It functions as a Ca2+ entry channel and displays remarkable gating promiscuity by responding to both physical stimuli (cell swelling, innoxious heat) and the synthetic ligand 4alphaPDD. An endogenous ligand for this channel has not yet been identified. Here we show that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome P450 epoxygenase-dependent formation of epoxyeicosatrienoic acids. Application of 5',6'-epoxyeicosatrienoic acid at submicromolar concentrations activates TRPV4 in a membrane-delimited manner and causes Ca2+ influx through TRPV4-like channels in vascular endothelial cells. Activation of TRPV4 in vascular endothelial cells might therefore contribute to the relaxant effects of endocannabinoids and their P450 epoxygenase-dependent metabolites on vascular tone.     

Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.     

Mathematical Arguments in Context

Except in very poor mathematical contexts, mathematical arguments do not stand in isolation of other mathematical arguments. Rather, they form trains of formal and informal arguments, adding up to interconnected theorems, theories and eventually entire fields. This paper critically comments on some common views on the relation between formal and informal mathematical arguments, most particularly applications of Toulmin’s argumentation model, and launches a number of alternative ideas of presentation inviting the contextualization of pieces of mathematical reasoning within encompassing bodies of explicit and implicit, formal and informal background knowledge.     

Le molybdène en biologie

Zusammenfassung Durch seine Beteiligung an der Reduktion der Nitrate und an der Aufnahme von Stickstoff, spielt das Molybdän eine erhebliche Rolle im Cyclus dieses Elements. Aus diesem Grunde ist es nützlich, diejenigen Stoffwechselprozesse zu kennen, an denen das Molybdän entscheidend beteiligt ist. Es ist das Ziel dieser Übersicht, einen zusammenfassenden Einblick in den Stand unserer Kenntnisse auf dem Gebiet dieses Oligoelements zu geben; eine chronologische Betrachtung erlaubt uns, zuerst diejenigen biochemischen Vorgänge zu betrachten, für die seine Einwirkung als gesichert gilt.Die Gesamtheit der Arbeiten über die Nitratreduktion lassen darauf schliessen, dass das Molybdän spezifisch zur Funktion der Nitratreduktase gehört. Indem es integraler Bestandteil der aus Mikroorganismen und höheren Pflanzen extrahierten Nitratreduktase ist, kommt ihm eine Rolle im Elektronentransport, welcher von den Nitraten zu den Nitriten führt, zu. Es handelt sich hier um die erste Stufe der Reaktionen, die zur Ammoniakbildung führen.Man weiss schon lange, dass Molybdän zur Bindung des Luftstickstoffs benötigt wird. Unsere Kenntnisse über eine spezifische Beteiligung des Elements an diesem Vorgang verdankt man jedoch neueren Arbeiten, vor allem jenen, welche die Bindung von Stickstoff in zellfreien Extrakten zum Gegenstand haben. Diese Ergebnisse werden im Lichte der neuern Theorien über den Mechanismus der Stickstoffbindung besprochen.Abschliessend werden einige andere Reaktionen des pflanzlichen und tierischen Stoffwechsels betrachtet, an denen das Molybdän Anteil hat.