Genetic studies of diseases

Genomic alterations lead to cancer complexity and form a major hurdle for comprehensive understanding of the molecular mechanisms underlying oncogenesis. In this review, we describe recent advances in studying cancer-associated genes from a systems biology point of view. The integration of known cancer genes onto protein and signaling networks reveals the characteristics of cancer genes within networks. This approach shows that cancer genes often function as network hub proteins which are involved in many cellular processes and form focal nodes in information exchange between many signaling pathways. Literature mining allows constructing gene-gene networks, in which new cancer genes can be identified. The gene expression profiles of cancer cells are used for reconstructing gene regulatory networks. By doing so, genes which are involved in the regulation of cancer progression can be picked up from these networks, after which their functions can be further confirmed in the laboratory.     

Computational protein function prediction: Are we making progress?

The computational prediction of gene and protein function is rapidly gaining ground as a central undertaking in computational biology. Making sense of the flood of genomic data requires fast and reliable annotation. Many ingenious algorithms have been devised to infer a protein's function from its amino acid sequence, 3D structure and chromosomal location of the encoding genes. However, there are significant challenges in assessing how well these programs perform. In this article we explore those challenges and review our own attempt at assessing the performance of those programs. We conclude that the task is far from complete and that a critical assessment of the performance of function prediction programs is necessary to make true progress in computational function prediction.     

Cellular internalization of proinsulin C-peptide

Proinsulin C-peptide is known to bind specifically to cell membranes and to exert intracellular effects, but whether it is internalized in target cells is unknown. In this study, using confocal microscopy and immunostained or rhodamine-labeled peptide, we show that C-peptide is internalized and localized to the cytosol of Swiss 3T3 and HEK-293 cells. In addition, transport into nuclei was found using the labeled peptide. The internalization was followed at 37°C for up to 1 h, and was reduced at 4°C and after preincubation with pertussis toxin. Hence, it is concluded to occur via an energy-dependent, pertussis toxin-sensitive mechanism and without detectable degradation within the experimental time course. Surface plasmon resonance measurements demonstrated binding of HEK-293 cell extract components to C-peptide, and subsequent elution of bound material revealed the components to be intracellular proteins. The identification of C-peptide cellular internalization, intracellular binding proteins, absence of rapid subsequent C-peptide degradation and apparent nuclear internalization support a maintained activity similar to that of an intracrine peptide hormone. Hence, the data suggest the possibility of one further C-peptide site of action. Received 31 October 2006; received after revision 27 December 2006; accepted 30 December 2006     

量子全加法器的修改和算法研究

通过与经典全加器的基本模型进行比较后,讨论了一个改进后的量子平面加法器的基本构型.对其原理、组件和算法进行了研究,比较了本加法器两个主要组件与一般量子加法器的不同.作为应用的例,设计了一个n比特量子全加法器的模型,对其具体运算过程和基本功能进行了说明.     

Pensions for 'cultivators of science'

The occasional (and belated) concern of the British Government with science in the nineteenth century is a matter of potential interest to historians of science, yet many previous studies have tended to range over a variety of different aspects of the question. There have been too many vague allusions to financial support as 'money for science' in general. It is time that particular parts of the problem were unpacked. For example, the award of money (from the 1820s) to pay a few people of independent means for apparatus was quite distinct from the provision (from the 1830s) of an occasional pension. Even then, to speak of 'pensions' uncovers unfortunate ambiguities. For too long science in Britain was regarded as no more than a private hobby for the well-to-do. As late as 1856 an official government statement seemed to make this attitude official. The English attitude to pensions differed remarkably from the French, who established a precedent in the reward of savants, sometimes quoted enviously by British men of science. In 1837 Robert Peel virtually admitted that, in awarding pensions to 'cultivators of science', he was following the French practice. It may also be useful to emphasise the contrast between the English (often led by Cambridge professors) and the Scots, mostly from Edinburgh, mainly represented here by Whewell and Brewster, respectively. Babbage had a different role in this story from that usually told. A large part in supporting men of science of modest means could have been played by the British Association for the Advancement of Science but it consistently refused to do so, although it supported an elite among its own members.     

THEMIS星座对2008年2月26日磁层亚暴的观测--磁尾重联触发的亚暴分析研究

本文利用THEMIS卫星结合地面极光和地磁的观测,研究了2008年2月26日04：05和04：55UT的两次亚暴事件.Angelopoulos已经对发生在04：55UT的第二个亚暴事件做了分析.本文对两次亚暴的相关活动进行了详细研究,特别对第一次做了深入讨论,并着重分析了磁重联与亚暴活动的关系.在两次亚暴的初始阶段,第一次极光增亮发生在中磁尾磁重联后2～3min,但是持续时间较短,极向膨胀缓慢,与伪暴的特征相似,标志了亚暴的初突发（initial onset）.两次亚暴都存在第二次极光增亮和极光的极向膨胀,且时间与近地磁尾观测的地向流和磁场偶极化同时发生,并与亚暴膨胀相的其他活动的发生同步,标志了亚暴的主突发（major onset）.在两次亚暴的增长相期间,极盖区开放磁通量持续增加;在亚暴膨胀相和恢复相中,极盖区磁通量迅速减少.表明两次亚暴膨胀相的演化分别与两次尾瓣开放磁力线重联过程相联系的.从亚暴活动的参数分析,这两次亚暴都属于小亚暴范围;从重联率分析,两次磁重联都属于弱重联.本文的观测结果表明,中磁尾磁尾重联首先触发伪暴;高速流将磁通量和能量传输到近地磁尾;高速流减速最终导致亚暴...更多电流楔（substorm current wedge,简称SCW）的形成和电流中断,产生近地偶极化和极光膨胀,引起亚暴膨胀相突发.本文的观测结果是对近地中性线模型（near earth neutral line,简称NENL）和重联-电流中断协同模型（synthesis scenario of MR and CD,简称RCS）模型及亚暴膨胀相两步突发观点的有力支持.     

Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency

An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.     

Yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity

Plague is a pandemic human invasive disease caused by the bacterial agent Yersinia pestis. We here report a comparison of 17 whole genomes of Y. pestis isolates from global sources. We also screened a global collection of 286 Y. pestis isolates for 933 SNPs using Sequenom MassArray SNP typing. We conducted phylogenetic analyses on this sequence variation dataset, assigned isolates to populations based on maximum parsimony and, from these results, made inferences regarding historical transmission routes. Our phylogenetic analysis suggests that Y. pestis evolved in or near China and spread through multiple radiations to Europe, South America, Africa and Southeast Asia, leading to country-specific lineages that can be traced by lineage-specific SNPs. All 626 current isolates from the United States reflect one radiation, and 82 isolates from Madagascar represent a second radiation. Subsequent local microevolution of Y. pestis is marked by sequential, geographically specific SNPs.