Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.     

Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis

Following up on recent genome-wide association studies (GWAS) of Crohn's disease, we investigated 50 previously reported susceptibility loci in a German sample of individuals with Crohn's disease (n = 1,850) or ulcerative colitis (n = 1,103) and healthy controls (n = 1,817). Among these loci, we identified variants in 3p21.31, NKX2-3 and CCNY as susceptibility factors for both diseases, whereas variants in PTPN2, HERC2 and STAT3 were associated only with ulcerative colitis in our sample collection.     

Insects breathe discontinuously to avoid oxygen toxicity

The respiratory organs of terrestrial insects consist of tracheal tubes with external spiracular valves that control gas exchange. Despite their relatively high metabolic rate, many insects have highly discontinuous patterns of gas exchange, including long periods when the spiracles are fully closed. Two explanations have previously been put forward to explain this behaviour: first, that this pattern serves to reduce respiratory water loss, and second, that the pattern may have initially evolved in underground insects as a way of dealing with hypoxic or hypercapnic conditions. Here we propose a third possible explanation based on the idea that oxygen is necessary for oxidative metabolism but also acts as a toxic chemical that can cause oxidative damage of tissues even at relatively low concentrations. At physiologically normal partial pressures of CO2, the rate of CO2 diffusion out of the insect respiratory system is slower than the rate of O2 entry; this leads to a build-up of intratracheal CO2. The spiracles must therefore be opened at intervals to rid the insect of accumulated CO2, a process that exposes the tissues to dangerously high levels of O2. We suggest that the cyclical pattern of open and closed spiracles observed in resting insects is a necessary consequence of the need to rid the respiratory system of accumulated CO2, followed by the need to reduce oxygen toxicity.     

High-velocity streams of dust originating from Saturn

High-velocity submicrometre-sized dust particles expelled from the jovian system have been identified by dust detectors on board several spacecraft. On the basis of periodicities in the dust impact rate, Jupiter's moon Io was found to be the dominant source of the streams. The grains become positively charged within the plasma environment of Jupiter's magnetosphere, and gain energy from its co-rotational electric field. Outside the magnetosphere, the dynamics of the grains are governed by the interaction with the interplanetary magnetic field that eventually forms the streams. A similar process was suggested for Saturn. Here we report the discovery by the Cassini spacecraft of bursts of high-velocity dust particles (> or = 100 km s(-1)) within approximately 70 million kilometres of Saturn. Most of the particles detected at large distances appear to originate from the outskirts of Saturn's outermost main ring. All bursts of dust impacts detected within 150 Saturn radii are characterized by impact directions markedly different from those measured between the bursts, and they clearly coincide with the spacecraft's traversals through streams of compressed solar wind.     

Possible solar origin of the 1,470-year glacial climate cycle demonstrated in a coupled model

Many palaeoclimate records from the North Atlantic region show a pattern of rapid climate oscillations, the so-called Dansgaard-Oeschger events, with a quasi-periodicity of approximately 1,470 years for the late glacial period. Various hypotheses have been suggested to explain these rapid temperature shifts, including internal oscillations in the climate system and external forcing, possibly from the Sun. But whereas pronounced solar cycles of approximately 87 and approximately 210 years are well known, a approximately 1,470-year solar cycle has not been detected. Here we show that an intermediate-complexity climate model with glacial climate conditions simulates rapid climate shifts similar to the Dansgaard-Oeschger events with a spacing of 1,470 years when forced by periodic freshwater input into the North Atlantic Ocean in cycles of approximately 87 and approximately 210 years. We attribute the robust 1,470-year response time to the superposition of the two shorter cycles, together with strongly nonlinear dynamics and the long characteristic timescale of the thermohaline circulation. For Holocene conditions, similar events do not occur. We conclude that the glacial 1,470-year climate cycles could have been triggered by solar forcing despite the absence of a 1,470-year solar cycle.     

Earthquake rupture dynamics frozen in exhumed ancient faults

Most of our knowledge about co-seismic rupture propagation is derived from inversion and interpretation of strong-ground-motion seismograms, laboratory experiments on rock and rock-analogue material, or inferred from theoretical and numerical elastodynamic models. However, additional information on dynamic rupture processes can be provided by direct observation of faults exhumed at the Earth's surface. Pseudotachylytes (solidified friction-induced melts) are the most certain fault-rock indicator of seismicity on ancient faults. Here we show how the asymmetry in distribution and the orientation of pseudotachylyte-filled secondary fractures around an exhumed fault can be used to reconstruct the earthquake rupture directivity, rupture velocity and fracture energy, by comparison with the theoretical dynamic stress field computed around propagating fractures. In particular, the studied natural network of pseudotachylytes is consistent with a dominant propagation direction during repeated seismic events and subsonic rupture propagation close to the Rayleigh wave velocity.     

Current issues in mouse genome engineering

The mouse is the foremost vertebrate experimental model because its genome can be precisely and variously engineered. Now that the mouse genome has been sequenced and annotated, the task of mutating each gene is feasible, and an international cooperation is providing mutated embryonic stem cells and mice as readily available resources. Because these resources will change biomedical research, decisions about their nature will have far-reaching effects. It is therefore timely to consider topical issues for mouse genome engineering, such as the background genotype; homologous, site-specific and transpositional recombination; conditional mutagenesis; RNA-mediated interference; and functional genomics with embryonic stem cells.     

Hydrogen effect on the mechanical behaviour and microstructural features of a Fe-Mn-C twinning induced plasticity steel

The influences of hydrogen on the mechanical properties and the fracture behaviour of Fe-22Mn-0.6C twinning induced plasticity steel have been investigated by slow strain rate tests and fractographic analysis.The steel showed high susceptibility to hydrogen embrittlement,which led to 62.9%and 74.2%reduction in engineering strain with 3.1 and 14.4 ppm diffusive hydrogen,respectively.The fracture surfaces revealed a transition from ductile to brittle dominated fracture modes with the rising hydrogen contents.The underlying deformation and fracture mechanisms were further exploited by examining the hydrogen effects on the dislocation substructure,stacking fault probability,and twinning behaviour in pre-strained slow strain rate test specimens and notched tensile specimens using coupled electron channelling contrast imaging and electron backscatter diffraction techniques.The results reveal that the addition of hydrogen promotes planar dislocation structures,earlier nucleation of stacking faults,and deformation twinning within those grains which have tensile axis orientations close to<111>//rolling direction and<112>//rolling direction.The developed twin lamellae result in strain localization and micro-voids at grain boundaries and eventually lead to grain boundary decohesion.     

Low-energy control of electrical turbulence in the heart

Controlling the complex spatio-temporal dynamics underlying life-threatening cardiac arrhythmias such as fibrillation is extremely difficult, because of the nonlinear interaction of excitation waves in a heterogeneous anatomical substrate. In the absence of a better strategy, strong, globally resetting electrical shocks remain the only reliable treatment for cardiac fibrillation. Here we establish the relationship between the response of the tissue to an electric field and the spatial distribution of heterogeneities in the scale-free coronary vascular structure. We show that in response to a pulsed electric field, E, these heterogeneities serve as nucleation sites for the generation of intramural electrical waves with a source density ρ(E) and a characteristic time, τ, for tissue depolarization that obeys the power law τ?∝?E(α). These intramural wave sources permit targeting of electrical turbulence near the cores of the vortices of electrical activity that drive complex fibrillatory dynamics. We show in vitro that simultaneous and direct access to multiple vortex cores results in rapid synchronization of cardiac tissue and therefore, efficient termination of fibrillation. Using this control strategy, we demonstrate low-energy termination of fibrillation in vivo. Our results give new insights into the mechanisms and dynamics underlying the control of spatio-temporal chaos in heterogeneous excitable media and provide new research perspectives towards alternative, life-saving low-energy defibrillation techniques.