A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M

Fanconi anemia is a genetic disease characterized by genomic instability and cancer predisposition. Nine genes involved in Fanconi anemia have been identified; their products participate in a DNA damage-response network involving BRCA1 and BRCA2 (refs. 2,3). We previously purified a Fanconi anemia core complex containing the FANCL ubiquitin ligase and six other Fanconi anemia-associated proteins. Each protein in this complex is essential for monoubiquitination of FANCD2, a key reaction in the Fanconi anemia DNA damage-response pathway. Here we show that another component of this complex, FAAP250, is mutant in individuals with Fanconi anemia of a new complementation group (FA-M). FAAP250 or FANCM has sequence similarity to known DNA-repair proteins, including archaeal Hef, yeast MPH1 and human ERCC4 or XPF. FANCM can dissociate DNA triplex, possibly owing to its ability to translocate on duplex DNA. FANCM is essential for monoubiquitination of FANCD2 and becomes hyperphosphorylated in response to DNA damage. Our data suggest an evolutionary link between Fanconi anemia-associated proteins and DNA repair; FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA.     

一种适合宽范围电容负载的三级运放

结合精确度和稳定性的要求提出了一种适合宽范围电容负载的CMOS运放.在多径嵌套式密勒补偿结构中加入一个抑制电容,得到适合各种电容负载的稳定性.为了证实稳定性的提高,对该结构进行了理论分析并计算得出数学表达式.基于这种新的频率补偿结构,利用CMOS 0.7μm工艺模型设计了样品芯片.测试结果表明该运放可以驱动从100 pF到100μF负载电容,直流增益为90dB,最小相位裕度为26°.该运放在100 pF负载情况下单位增益带宽为1 MHz,抑制电容仅为18 pF.     

A Bayesian nonlinear support vector machine error correction model

The use of linear error correction models based on stationarity and cointegration analysis, typically estimated with least squares regression, is a common technique for financial time series prediction. In this paper, the same formulation is extended to a nonlinear error correction model using the idea of a kernel‐based implicit nonlinear mapping to a high‐dimensional feature space in which linear model formulations are specified. Practical expressions for the nonlinear regression are obtained in terms of the positive definite kernel function by solving a linear system. The nonlinear least squares support vector machine model is designed within the Bayesian evidence framework that allows us to find appropriate trade‐offs between model complexity and in‐sample model accuracy. From straightforward primal–dual reasoning, the Bayesian framework allows us to derive error bars on the prediction in a similar way as for linear models and to perform hyperparameter and input selection. Starting from the results of the linear modelling analysis, the Bayesian kernel‐based prediction is successfully applied to out‐of‐sample prediction of an aggregated equity price index for the European chemical sector. Copyright © 2006 John Wiley & Sons, Ltd.     

The European dimension for the mouse genome mutagenesis program

The European Mouse Mutagenesis Consortium is the European initiative contributing to the international effort on functional annotation of the mouse genome. Its objectives are to establish and integrate mutagenesis platforms, gene expression resources, phenotyping units, storage and distribution centers and bioinformatics resources. The combined efforts will accelerate our understanding of gene function and of human health and disease.     

Summing up the noise in gene networks

Random fluctuations in genetic networks are inevitable as chemical reactions are probabilistic and many genes, RNAs and proteins are present in low numbers per cell. Such 'noise' affects all life processes and has recently been measured using green fluorescent protein (GFP). Two studies show that negative feedback suppresses noise, and three others identify the sources of noise in gene expression. Here I critically analyse these studies and present a simple equation that unifies and extends both the mathematical and biological perspectives.     

How Not to Attack Intelligent Design Creationism: Philosophical Misconceptions About Methodological Naturalism

In recent controversies about Intelligent Design Creationism (IDC), the principle of methodological naturalism (MN) has played an important role. In this paper, an often neglected distinction is made between two different conceptions of MN, each with its respective rationale and with a different view on the proper role of MN in science. According to one popular conception, MN is a self-imposed or intrinsic limitation of science, which means that science is simply not equipped to deal with claims of the supernatural (Intrinsic MN or IMN). Alternatively, we will defend MN as a provisory and empirically grounded attitude of scientists, which is justified in virtue of the consistent success of naturalistic explanations and the lack of success of supernatural explanations in the history of science (Provisory MN or PMN). Science does have a bearing on supernatural hypotheses, and its verdict is uniformly negative. We will discuss five arguments that have been proposed in support of IMN: the argument from the definition of science, the argument from lawful regularity, the science stopper argument, the argument from procedural necessity, and the testability argument. We conclude that IMN, because of its philosophical flaws, proves to be an ill-advised strategy to counter the claims of IDC. Evolutionary scientists are on firmer ground if they discard supernatural explanations on purely evidential grounds, instead of ruling them out by philosophical fiat.     

SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype

DNA interstrand crosslink repair requires several classes of proteins, including structure-specific endonucleases and Fanconi anemia proteins. SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair. Here we report the first human individuals found to have biallelic mutations in SLX4. These individuals, who were previously diagnosed as having Fanconi anemia, add SLX4 as an essential component to the FA-BRCA genome maintenance pathway.     

Common variants at 12q15 and 12q24 are associated with infant head circumference

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.     

Ligand-dependent localization and function of ORP–VAP complexes at membrane contact sites

Oxysterol-binding protein/OSBP-related proteins (ORPs) constitute a conserved family of sterol/phospholipid-binding proteins with lipid transporter or sensor functions. We investigated the spatial occurrence and regulation of the interactions of human OSBP/ORPs or the S. cerevisiae orthologs, the Osh (OSBP homolog) proteins, with their endoplasmic reticulum (ER) anchors, the VAMP-associated proteins (VAPs), by employing bimolecular fluorescence complementation and pull-down set-ups. The ORP–VAP interactions localize frequently at distinct subcellular sites, shown in several cases to represent membrane contact sites (MCSs). Using established ORP ligand-binding domain mutants and pull-down assays with recombinant proteins, we show that ORP liganding regulates the ORP–VAP association, alters the subcellular targeting of ORP–VAP complexes, or modifies organelle morphology. There is distinct protein specificity in the effects of the mutants on subcellular targeting of ORP–VAP complexes. We provide evidence that complexes of human ORP2 and VAPs at ER–lipid droplet interfaces regulate the hydrolysis of triglycerides and lipid droplet turnover. The data suggest evolutionarily conserved, complex ligand-dependent functions of ORP–VAP complexes at MCSs, with implications for cellular lipid homeostasis and signaling.