An integrated semiconductor device enabling non-optical genome sequencing

The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.     

Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation

We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder.     

Regulatory networks define phenotypic classes of human stem cell lines

Stem cells are defined as self-renewing cell populations that can differentiate into multiple distinct cell types. However, hundreds of different human cell lines from embryonic, fetal and adult sources have been called stem cells, even though they range from pluripotent cells-typified by embryonic stem cells, which are capable of virtually unlimited proliferation and differentiation-to adult stem cell lines, which can generate a far more limited repertoire of differentiated cell types. The rapid increase in reports of new sources of stem cells and their anticipated value to regenerative medicine has highlighted the need for a general, reproducible method for classification of these cells. We report here the creation and analysis of a database of global gene expression profiles (which we call the 'stem cell matrix') that enables the classification of cultured human stem cells in the context of a wide variety of pluripotent, multipotent and differentiated cell types. Using an unsupervised clustering method to categorize a collection of approximately 150 cell samples, we discovered that pluripotent stem cell lines group together, whereas other cell types, including brain-derived neural stem cell lines, are very diverse. Using further bioinformatic analysis we uncovered a protein-protein network (PluriNet) that is shared by the pluripotent cells (embryonic stem cells, embryonal carcinomas and induced pluripotent cells). Analysis of published data showed that the PluriNet seems to be a common characteristic of pluripotent cells, including mouse embryonic stem and induced pluripotent cells and human oocytes. Our results offer a new strategy for classifying stem cells and support the idea that pluripotency and self-renewal are under tight control by specific molecular networks.     

A Model for Design of Human Activity Systems

A background is given to the common failures of management information systems and the authors' view of the causes behind these failures. There seems to be a lack of effective methods for analyzing information requirements. Different scientific methods are discussed as to their propensity for analyzing the information requirements. The importance of the systems design approach instead of the system improvement approach is emphasized. The concept of Human Activity Systems is discussed and an analysis of the interdependence of the soft and hard parts of these systems indicates that an integrated view is necessary. A methodology based on a systemic and systematic analysis of the information requirements in an organization is proposed. This methodology focuses the settings of the decisions on all levels in organizations and also indicates organizational discrepancies and information imbalances. The methodology can be regarded as a dynamic, learning system.     

A Design View on Research in Social Sciences

Research in social sciences has not had the same impact as research in natural sciences and several authors are critical of social science research methods. In order to elucidate this problem, the author analyzes the purpose of research in general and in social sciences in particular. The author makes reference to various research methods that are suggested and used in social sciences. Social science research differs from research in natural sciences. It differs not only in being dependent on actions of human individuals but also because systems in social sciences are a complex mixture of Hard and Soft systems. The paper argues that research in Human Activity Systems should focus on design. This view changes the research perspective and the demands on the research methods to be used. The author suggests a method based on focusing decision settings combined with Action Research.     

Ecology: living in synchrony on Greenland coasts?

Theory indicates that correlated weather may synchronize populations, but the extent to which this holds for non-identical, nonlinear systems is uncertain. Post and Forchhammer claim to have shown climate-induced synchrony for musk oxen and caribou that are separated by the Greenland ice sheet. However, logical and mathematical errors undermine their finding. Whether or not large-scale weather can be a major synchronizing factor across species remains an open question.     

Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10?1? and P = 4.1 × 10??, respectively).