Two independent alleles at 6q23 associated with risk of rheumatoid arthritis

To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, approximately 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10(-3), GWA scan; P < 10(-6), replication; P = 10(-9), combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 x 10(-6) in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.     

Ultrathin compound semiconductor on insulator layers for high-performance nanoscale transistors

Over the past several years, the inherent scaling limitations of silicon (Si) electron devices have fuelled the exploration of alternative semiconductors, with high carrier mobility, to further enhance device performance. In particular, compound semiconductors heterogeneously integrated on Si substrates have been actively studied: such devices combine the high mobility of III-V semiconductors and the well established, low-cost processing of Si technology. This integration, however, presents significant challenges. Conventionally, heteroepitaxial growth of complex multilayers on Si has been explored-but besides complexity, high defect densities and junction leakage currents present limitations in this approach. Motivated by this challenge, here we use an epitaxial transfer method for the integration of ultrathin layers of single-crystal InAs on Si/SiO(2) substrates. As a parallel with silicon-on-insulator (SOI) technology, we use 'XOI' to represent our compound semiconductor-on-insulator platform. Through experiments and simulation, the electrical properties of InAs XOI transistors are explored, elucidating the critical role of quantum confinement in the transport properties of ultrathin XOI layers. Importantly, a high-quality InAs/dielectric interface is obtained by the use of a novel thermally grown interfacial InAsO(x) layer (~1?nm thick). The fabricated field-effect transistors exhibit a peak transconductance of ~1.6?mS?μm(-1) at a drain-source voltage of 0.5?V, with an on/off current ratio of greater than 10,000.     

Earthquake prediction,biological clocks,and the cold war psy-ops: Using animals as seismic sensors in the 1970s California

A familiar story of seismology is that of a small field originally focused on local studies of earthquakes through diverse disciplinary perspectives being transformed, in the second half of the twentieth century, into a highly specialized field focused on global studies of the earth's deep interior via sophisticated instruments and transnational networks of seismological stations. Against this backdrop, this essay offers a complementing account, highlighting the significance of local circumstances and disciplinary agendas that were contingent not only on transformations in the geophysical sciences but also on the concurrently changing biological sciences during the Cold War. Using examples of the studies of unusual animal behavior prior to earthquakes conducted under the auspices of the US Geological Survey on the West Coast of the United States in the 1970s, this essay examines a variety of motivations behind the attempts to bridge geophysics and biology. These examples illustrate the ways in which earthquake prediction became entangled with concerns over the use of seismological data, pioneering research on biological rhythms, and the troubled field of Cold War-driven military brain studies.     

Composition,characteristics and long-term variability of the freshwater microcrustacean fauna of the Faroe Islands

ABSTRACT

Despite the accessibility of the Faroe Islands, faunistic research on their numerous lakes and ponds is quite rare. The biota of Faroese freshwaters is still underexplored, and its specific traits raise many questions. In the present survey, 32 microcrustacean species were observed, 8 of which were new to the Faroese fauna. The obtained species list shows that Cladocera species prevail over Copepoda here, which is not typical of northern territories. This fact is due to (1) the extraordinarily warm climate of the Faroe Islands compared to other areas at similar latitudes because of the heating effect of the surrounding North Atlantic Current and (2) the lack of calanoid species, which have never been found in the freshwaters of the Faroe Islands. The diachronic analysis of the species diversity and composition over the centuries of research on the archipelago showed no evidence of the impact of global climate change on the fauna.     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.     

Deep Geothermal:The‘Moon Landing’ Mission in the Unconventional Energy and Minerals Space

Deep geothermal from the hot crystalline basement has remained an unsolved frontier for the geothermal industry for the past 30 years. This poses the challenge for developing a new un-conventional geom...     

8-oxo-guanine bypass by human DNA polymerases in the presence of auxiliary proteins

Specialized DNA polymerases (DNA pols) are required for lesion bypass in human cells. Auxiliary factors have an important, but so far poorly understood, role. Here we analyse the effects of human proliferating cell nuclear antigen (PCNA) and replication protein A (RP-A) on six different human DNA pols--belonging to the B, Y and X classes--during in vitro bypass of different lesions. The mutagenic lesion 8-oxo-guanine (8-oxo-G) has high miscoding potential. A major and specific effect was found for 8-oxo-G bypass with DNA pols lambda and eta. PCNA and RP-A allowed correct incorporation of dCTP opposite a 8-oxo-G template 1,200-fold more efficiently than the incorrect dATP by DNA pol lambda, and 68-fold by DNA pol eta, respectively. Experiments with DNA-pol-lambda-null cell extracts suggested an important role for DNA pol lambda. On the other hand, DNA pol iota, together with DNA pols alpha, delta and beta, showed a much lower correct bypass efficiency. Our findings show the existence of an accurate mechanism to reduce the deleterious consequences of oxidative damage and, in addition, point to an important role for PCNA and RP-A in determining a functional hierarchy among different DNA pols in lesion bypass.     

R-spondin1 is essential in sex determination, skin differentiation and malignancy

R-spondins are a recently characterized small family of growth factors. Here we show that human R-spondin1 (RSPO1) is the gene disrupted in a recessive syndrome characterized by XX sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. Our data show, for the first time, that disruption of a single gene can lead to complete female-to-male sex reversal in the absence of the testis-determining gene, SRY.