Male-pattern baldness susceptibility locus at 20p11

We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 x 10(-15)).     

The impact of cyclin-dependent kinase 5 depletion on poly(ADP-ribose) polymerase activity and responses to radiation

Cyclin-dependent kinase 5 (Cdk5) has been identified as a determinant of sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Here, the consequences of its depletion on cell survival, PARP activity, the recruitment of base excision repair (BER) proteins to DNA damage sites, and overall DNA single-strand break (SSB) repair were investigated using isogenic HeLa stably depleted (KD) and Control cell lines. Synthetic lethality achieved by disrupting PARP activity in Cdk5-deficient cells was confirmed, and the Cdk5^KD cells were also found to be sensitive to the killing effects of ionizing radiation (IR) but not methyl methanesulfonate or neocarzinostatin. The recruitment profiles of GFP-PARP-1 and XRCC1-YFP to sites of micro-irradiated Cdk5^KD cells were slower and reached lower maximum values, while the profile of GFP-PCNA recruitment was faster and attained higher maximum values compared to Control cells. Higher basal, IR, and hydrogen peroxide-induced polymer levels were observed in Cdk5^KD compared to Control cells. Recruitment of GFP-PARP-1 in which serines 782, 785, and 786, potential Cdk5 phosphorylation targets, were mutated to alanines in micro-irradiated Control cells was also reduced. We hypothesize that Cdk5-dependent PARP-1 phosphorylation on one or more of these serines results in an attenuation of its ribosylating activity facilitating persistence at DNA damage sites. Despite these deficiencies, Cdk5^KD cells are able to effectively repair SSBs probably via the long patch BER pathway, suggesting that the enhanced radiation sensitivity of Cdk5^KD cells is due to a role of Cdk5 in other pathways or the altered polymer levels.     

A mixed-model approach for genome-wide association studies of correlated traits in structured populations

Genome-wide association studies (GWAS) are a standard approach for studying the genetics of natural variation. A major concern in GWAS is the need to account for the complicated dependence structure of the data, both between loci as well as between individuals. Mixed models have emerged as a general and flexible approach for correcting for population structure in GWAS. Here, we extend this linear mixed-model approach to carry out GWAS of correlated phenotypes, deriving a fully parameterized multi-trait mixed model (MTMM) that considers both the within-trait and between-trait variance components simultaneously for multiple traits. We apply this to data from a human cohort for correlated blood lipid traits from the Northern Finland Birth Cohort 1966 and show greatly increased power to detect pleiotropic loci that affect more than one blood lipid trait. We also apply this approach to an Arabidopsis thaliana data set for flowering measurements in two different locations, identifying loci whose effect depends on the environment.     

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.     

An efficient multi-locus mixed-model approach for genome-wide association studies in structured populations

Population structure causes genome-wide linkage disequilibrium between unlinked loci, leading to statistical confounding in genome-wide association studies. Mixed models have been shown to handle the confounding effects of a diffuse background of large numbers of loci of small effect well, but they do not always account for loci of larger effect. Here we propose a multi-locus mixed model as a general method for mapping complex traits in structured populations. Simulations suggest that our method outperforms existing methods in terms of power as well as false discovery rate. We apply our method to human and Arabidopsis thaliana data, identifying new associations and evidence for allelic heterogeneity. We also show how a priori knowledge from an A. thaliana linkage mapping study can be integrated into our method using a Bayesian approach. Our implementation is computationally efficient, making the analysis of large data sets (n > 10,000) practicable.     

Breeding biology and flower visitors of the rare White River penstemon, Penstemon scariosus var. albifluvis (Scrophulariaceae)

We studied the breeding system and flower visitors of White River penstemon, a rare endemic from the Uintah Basin of eastern Utah and western Colorado. Bagging treatments and hand-pollination treatments showed that Penstemon scariosus var. albifluvis has a mixed mating system: while some seeds and fruits are produced through selfpollination (both autogamy and geitonogamy), significantly more are produced when flowers are cross-pollinated. The primary flower visitors, and likely pollinators, were several species of native twig- and ground-nesting bees in the families Apidae, Halictidae, and Megachilidae. We found no differences in fruit or seed production between open-pollinated controls and hand-outcrossed flowers, suggesting that pollinator visits were sufficient to maximize female reproductive success. Management plans to conserve White River penstemon must recognize that full reproductive success of this rare plant taxon relies on a suite of pollinating bees, and that the species richness and abundances of bee visitors should be maintained.     

因素空间与模糊决策

以汪培庄的因素空间理论为知识表示的框架，对其公理稍加补充之后提出后馈外延的概念；基于反馈外延，建立了一种面向目标的决策方法。     

Modèles écologiques et aménagement de l'espace

Summary With the increased impact of man's activities resulting from the industrial revolution, the fall-out of his actions widens in both space and time. It is impossible to proceed any further in the exploitation of Nature on the basis of economic concepts founded on the pursuit of sectorial short-term profit. We must on the contrary observe the rules governing the biosphere and the ecosystems.Economic development must not upset the energetic equilibrium of the biosphere. This is possible on condition that we use essentially balanced energy sources, instead of the energy released by potential sources.The whole organization of economy is based on a linear principle, resulting in the exhaustion of basic materials and overload by often polluting waste. The acceleration of the circuit is artificially induced by publicity factors which, pretexting fashion, regards as garbage still usable goods. The perenniality of ecosystems is ensured by the recycling of materials, an economy founded on the same principle can alone ensure the future of mankind.The sectorial development of economy and of professional training contributes to make it more difficult to organize the healthy management of natural resources.The obstacles to the achievement of a healthy policy of resource management are not technical, but pedagogic, economic and political.