The Water Framework Directive’s “percentage of surface water bodies at good status”: unveiling the hidden side of a “hyperindicator”

The Water Framework Directive (WFD) has provided the means of standardizing the way surface water bodies are monitored throughout the European Union (EU), using a common evaluation measure, the percentage of surface water bodies at good status, based largely on the structure and functioning of aquatic ecosystems. However, the evaluation of good status is based on the way the WFD is implemented, which differs in each country. In this article, we analyze how the WFD is implemented in France, how the water agencies divide up the water bodies, the areas covered by their monitoring networks, and the modalities of obtaining data to provide the EU with the percentage of water bodies at good status. This analysis reveals that it is this hyperindicator itself that is at stake, obtained by successively aggregating values measured in time and space, from the monitoring station to the River Basin District (RBD), reducing vast amounts of information to a single measure per RBD, while long-term monitoring of the major European rivers and their sedimentary budgets, which show improvements in certain quality aspects, are largely overlooked by the WFD. When drawing up the indicator, the agencies identify certain biases but not others. This raises the question of its use and relevance for managers and politicians, at both national and European level.     

Binary Regression Analysis with Pooled Exposure Measurements: A Regression Calibration Approach

Summary It has become increasingly common in epidemiological studies to pool specimens across subjects to achieve accurate quantitation of biomarkers and certain environmental chemicals. In this article, we consider the problem of fitting a binary regression model when an important exposure is subject to pooling. We take a regression calibration approach and derive several methods, including plug‐in methods that use a pooled measurement and other covariate information to predict the exposure level of an individual subject, and normality‐based methods that make further adjustments by assuming normality of calibration errors. Within each class we propose two ways to perform the calibration (covariate augmentation and imputation). These methods are shown in simulation experiments to effectively reduce the bias associated with the naive method that simply substitutes a pooled measurement for all individual measurements in the pool. In particular, the normality‐based imputation method performs reasonably well in a variety of settings, even under skewed distributions of calibration errors. The methods are illustrated using data from the Collaborative Perinatal Project.     

Biomarker research with prospective study designs for the early detection of cancer

This article describes the principles of marker research with prospective studies along with examples for diagnostic tumor markers. A plethora of biomarkers have been claimed as useful for the early detection of cancer. However, disappointingly few biomarkers were approved for the detection of unrecognized disease, and even approved markers may lack a sound validation phase. Prospective studies aimed at the early detection of cancer are costly and long-lasting and therefore the bottleneck in marker research. They enroll a large number of clinically asymptomatic subjects and follow-up on incident cases. As invasive procedures cannot be applied to collect tissue samples from the target organ, biomarkers can only be determined in easily accessible body fluids. Marker levels increase during cancer development, with samples collected closer to the occurrence of symptoms or a clinical diagnosis being more informative than earlier samples. Only prospective designs allow the serial collection of pre-diagnostic samples. Their storage in a biobank upgrades cohort studies to serve for both, marker discovery and validation. Population-based cohort studies, which may collect a wealth of data, are commonly conducted with just one baseline investigation lacking serial samples. However, they can provide valuable information about factors that influence the marker level. Screening programs can be employed to archive serial samples but require significant efforts to collect samples and auxiliary data for marker research. Randomized controlled trials have the highest level of evidence in assessing a biomarker's benefit against usual care and present the most stringent design for the validation of promising markers as well as for the discovery of new markers. In summary, all kinds of prospective studies can benefit from a biobank as they can serve as a platform for biomarker research. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.     

A Graphical Weighted Power Improving Multiplicity Correction Approach for SNP Selections

Controlling for the multiplicity effect is an essential part of determining statistical significance in large-scale single-locus association genome scans on Single Nucleotide Polymorphisms (SNPs). Bonferroni adjustment is a commonly used approach due to its simplicity, but is conservative and has low power for large-scale tests. The permutation test, which is a powerful and popular tool, is computationally expensive and may mislead in the presence of family structure. We propose a computationally efficient and powerful multiple testing correction approach for Linkage Disequilibrium (LD) based Quantitative Trait Loci (QTL) mapping on the basis of graphical weighted-Bonferroni methods. The proposed multiplicity adjustment method synthesizes weighted Bonferroni-based closed testing procedures into a powerful and versatile graphical approach. By tailoring different priorities for the two hypothesis tests involved in LD based QTL mapping, we are able to increase power and maintain computational efficiency and conceptual simplicity. The proposed approach enables strong control of the familywise error rate (FWER). The performance of the proposed approach as compared to the standard Bonferroni correction is illustrated by simulation and real data. We observe a consistent and moderate increase in power under all simulated circumstances, among different sample sizes, heritabilities, and number of SNPs. We also applied the proposed method to a real outbred mouse HDL cholesterol QTL mapping project where we detected the significant QTLs that were highlighted in the literature, while still ensuring strong control of the FWER.     

Pollux: platform independent error correction of single and mixed genomes

Background

Second-generation sequencers generate millions of relatively short, but error-prone, reads. These errors make sequence assembly and other downstream projects more challenging. Correcting these errors improves the quality of assemblies and projects which benefit from error-free reads.

Results

We have developed a general-purpose error corrector that corrects errors introduced by Illumina, Ion Torrent, and Roche 454 sequencing technologies and can be applied to single- or mixed-genome data. In addition to correcting substitution errors, we locate and correct insertion, deletion, and homopolymer errors while remaining sensitive to low coverage areas of sequencing projects. Using published data sets, we correct 94% of Illumina MiSeq errors, 88% of Ion Torrent PGM errors, 85% of Roche 454 GS Junior errors. Introduced errors are 20 to 70 times more rare than successfully corrected errors. Furthermore, we show that the quality of assemblies improves when reads are corrected by our software.

Conclusions

Pollux is highly effective at correcting errors across platforms, and is consistently able to perform as well or better than currently available error correction software. Pollux provides general-purpose error correction and may be used in applications with or without assembly.     

G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor

The G protein-coupled ghrelin receptor GHSR1a is a potential pharmacological target for treating obesity and addiction because of the critical role ghrelin plays in energy homeostasis and dopamine-dependent reward. GHSR1a enhances growth hormone release, appetite, and dopamine signaling through G_q/11, G_i/o, and G_12/13 as well as β-arrestin-based scaffolds. However, the contribution of individual G protein and β-arrestin pathways to the diverse physiological responses mediated by ghrelin remains unknown. To characterize whether a signaling bias occurs for GHSR1a, we investigated ghrelin signaling in a number of cell-based assays, including Ca²⁺ mobilization, serum response factor response element, stress fiber formation, ERK1/2 phosphorylation, and β-arrestin translocation, utilizing intracellular second loop and C-tail mutants of GHSR1a. We observed that GHSR1a and β-arrestin rapidly form metastable plasma membrane complexes following exposure to an agonist, but replacement of the GHSR1a C-tail by the tail of the vasopressin 2 receptor greatly stabilizes them, producing complexes observable on the plasma membrane and also in endocytic vesicles. Mutations of the contiguous conserved amino acids Pro-148 and Leu-149 in the GHSR1a intracellular second loop generate receptors with a strong bias to G protein and β-arrestin, respectively, supporting a role for conformation-dependent signaling bias in the wild-type receptor. Our results demonstrate more balance in GHSR1a-mediated ERK signaling from G proteins and β-arrestin but uncover an important role for β-arrestin in RhoA activation and stress fiber formation. These findings suggest an avenue for modulating drug abuse-associated changes in synaptic plasticity via GHSR1a and indicate the development of GHSR1a-biased ligands as a promising strategy for selectively targeting downstream signaling events.     

RNA/DNA嵌合分子介导的高效基因修复

本文介绍了RNA/DNA嵌合分子介导的高效基因修复技术。这一技术是1996年开始发展起来的全新技术,它通过人工合成的双链开环RNA/DNA嵌合分子转染细胞而使特定基因靶位点产生单碱基改变,从而修复突变基因。这一技术高效（目前最高可达50％以上）、特异性强、安全、无随机插入致变的危险、无免疫反应、无明显毒性,能够用于定点突变、基因敲除、动植物功能基因组学、药物遗传学等很多方面的研究,在不久的将来能够应用于人类基因治疗,具有很高的应用价值和医学前景。 Abstract：We introduce a new technique?targeted gene correction directed by chimeric RNA/DNA oligonucleotides which began at 1996.It uses synthetic double?stranded non?circular RNA/DNA chimeric oligonucleotides to transfect cells and make a single?based change at the targeted site of the target gene.It is highly efficient (the highest efficiency is more than 50％),highly special,safe,without danger of mutation caused by random insertion,without immune response,and without obvious toxicity.It can be used to make point mutation,or gene knock?out plants and animals,and is very likely to be used in human gene therapy in the near future.It is also valuable in the study of functional genomics,pharmacogenetics,and medicine.     

时间序列修订对森林二氧化碳通量的影响

对长白山阔叶红松林2003年生长季的涡动相关实测时间序列进行了去倾修订与超声风速仪倾斜修订,并分析了不同修订方法对森林CO2通量计算值的影响．结果表明,基于未修订时间序列计算得到的森林CO2通量(Fcraw)被高估．线性与非线性去倾对Fcraw的修订量分别为1．6％、1．8％,两者差异很小．平面拟合坐标变换与流线坐标变换对Fcraw的修订量分别为3．7％、4．7％,两者差异较大．对线性去倾后的时间序列分别进行流线坐标变换与平面拟合坐标变换,二者对Fcraw的修订量分别为5．5％与4．6％．建议对时间序列进行线性去倾与平面拟合坐标变换综合修订．     

重庆市城市化与生态环境交互关系的协整分析

运用协整理论和误差修正模型考察了重庆市1978-2007年期间城市化与生态环境相互作用的关系,遴选出作用于生态环境的2项主要的城市化指标和影响城市化的4项主要的生态环境指标,它们能反映出交互作用的机制。结果发现:1978-2007年,重庆市城市化与生态环境之间存在长期均衡关系,城市化对生态环境的正向作用明显强于生态环境对城市化的反向影响,误差修正系数较长期协整方程中的系数要小。从长期来看,城市化水平对生态环境变化的解释能力正在逐步增强,这充分证明生态环境功能的弱化是城市化步伐推进的必然结果。就城市化对生态环境的响应效果而言,一方面城市化是影响重庆市生态环境的重要原因,另一方面生态环境对城市化也存在着反作用。生态环境对城市化进程产生外在压力,但这一反馈机制往往具有一定的滞后效应。城市化对解释生态环境预测方差分解起着重要作用,然而生态环境对城市化预测方差的贡献度较小。     

桂西北喀斯特区域植被变化趋势及其对气候和地形的响应

基于1999—2010年的SPOT NDVI数据,分析了河池市植被变化趋势及空间差异,并结合气象和地形数据分析了植被与气候、地形的关系。结果表明:(1)桂西北喀斯特地区植被变化总体上呈恢复趋势,年均气候因子对植被变化的作用不明显;(2)200—500m的海拔范围内植被恢复显著,但400—500m的海拔范围内有小面积植被退化现象,随着海拔增加,植被变化趋于稳定;(3)6—15°的坡度范围内植被恢复最显著,而2—6°及大于25°坡度范围存在植被退化的现象;(4)不同坡向上的植被恢复差异不明显,但随着坡向由阴坡转阳坡,植被总体恢复呈减小趋势。喀斯特地区人类生态建设取得一定成效,但由于人类活动的负面影响,在海拔400—500m、坡度大于25°的阳坡区域仍存在植被减少的现象。