Proteome survey reveals modularity of the yeast cell machinery

Protein complexes are key molecular entities that integrate multiple gene products to perform cellular functions. Here we report the first genome-wide screen for complexes in an organism, budding yeast, using affinity purification and mass spectrometry. Through systematic tagging of open reading frames (ORFs), the majority of complexes were purified several times, suggesting screen saturation. The richness of the data set enabled a de novo characterization of the composition and organization of the cellular machinery. The ensemble of cellular proteins partitions into 491 complexes, of which 257 are novel, that differentially combine with additional attachment proteins or protein modules to enable a diversification of potential functions. Support for this modular organization of the proteome comes from integration with available data on expression, localization, function, evolutionary conservation, protein structure and binary interactions. This study provides the largest collection of physically determined eukaryotic cellular machines so far and a platform for biological data integration and modelling.     

Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.     

Deep roots of the Messinian salinity crisis

The Messinian salinity crisis--the desiccation of the Mediterranean Sea between 5.96 and 5.33 million years (Myr) ago--was one of the most dramatic events on Earth during the Cenozoic era. It resulted from the closure of marine gateways between the Atlantic Ocean and the Mediterranean Sea, the causes of which remain enigmatic. Here we use the age and composition of volcanic rocks to reconstruct the geodynamic evolution of the westernmost Mediterranean from the Middle Miocene epoch to the Pleistocene epoch (about 12.1-0.65 Myr ago). Our data show that a marked shift in the geochemistry of mantle-derived volcanic rocks, reflecting a change from subduction-related to intraplate-type volcanism, occurred between 6.3 and 4.8 Myr ago, largely synchronous with the Messinian salinity crisis. Using a thermomechanical model, we show that westward roll back of subducted Tethys oceanic lithosphere and associated asthenospheric upwelling provides a plausible mechanism for producing the shift in magma chemistry and the necessary uplift (approximately 1 km) along the African and Iberian continental margins to close the Miocene marine gateways, thereby causing the Messinian salinity crisis.     

Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database

The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease (http://www.alzgene.org). We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.     

Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database

In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.     

Common variants at CD40 and other loci confer risk of rheumatoid arthritis

To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).     

User Driven Innovation in the Building Process

During the late years there has been an ever-increasing focus on the possibilities to change the building process to raise quality on the final building products as well as the activities of actors involved in the building process. One reason for this interest is the new opportunities evolving due to introduction of advanced information and communication technology (ICT). The paper focuses on creative changes of the building process powered by user driven innovation activities. An overview of existing user driven innovation methodologies is given as well experiences from the ongoing Virtual Innovation in Construction (VIC) project. One important driving force for change is the opportunity for users to develop and articulate real needs concerning for example different functionalities of a building and its parts, but also on artifacts supporting the actual needs capture and requirements formulation during building design. A general methodological framework and meta ontology for Virtual Innovation in Construction is presented as well as findings from implementation of the method.     

Energy input from quasars regulates the growth and activity of black holes and their host galaxies

In the early Universe, while galaxies were still forming, black holes as massive as a billion solar masses powered quasars. Supermassive black holes are found at the centres of most galaxies today, where their masses are related to the velocity dispersions of stars in their host galaxies and hence to the mass of the central bulge of the galaxy. This suggests a link between the growth of the black holes and their host galaxies, which has indeed been assumed for a number of years. But the origin of the observed relation between black hole mass and stellar velocity dispersion, and its connection with the evolution of galaxies, have remained unclear. Here we report simulations that simultaneously follow star formation and the growth of black holes during galaxy-galaxy collisions. We find that, in addition to generating a burst of star formation, a merger leads to strong inflows that feed gas to the supermassive black hole and thereby power the quasar. The energy released by the quasar expels enough gas to quench both star formation and further black hole growth. This determines the lifetime of the quasar phase (approaching 100 million years) and explains the relationship between the black hole mass and the stellar velocity dispersion.