Efficient synthesis of DNA duplexes containing reduced acetaldehyde interstrand cross-links

DNA interstrand cross-links (ICLs) prevent DNA replication and transcription and can lead to potentially lethal events, such as cancer or bone marrow failure. ICLs are typically repaired by proteins within the Fanconi Anemia (FA) pathway, although the details of the pathway are not fully established. Methods to generate DNA containing ICLs are key to furthering the understanding of DNA cross-link repair. A major route to ICL formation in vivo involves reaction of DNA with acetaldehyde, derived from ethanol metabolism. This reaction forms a three-carbon bridged ICL involving the amino groups of adjacent guanines in opposite strands of a duplex resulting in amino and imino functionalities. A stable reduced form of the ICL has applications in understanding the recognition and repair of these types of adducts. Previous routes to creating DNA duplexes containing these adducts have involved lengthy post-DNA synthesis chemistry followed by reduction of the imine. Here, an efficient and high-yielding approach to the reduced ICL using a novel N2-((R)-4-trifluoroacetamidobutan-2-yl)-2′-deoxyguanosine phosphoramidite is described. Following standard automated DNA synthesis and deprotection, the ICL is formed overnight in over 90% yield upon incubation at room temperature with a complementary oligodeoxyribonucleotide containing 2-fluoro-2′-deoxyinosine. The cross-linked duplex displayed a melting transition 25 °C higher than control sequences. Importantly, we show using the Xenopus egg extract system that an ICL synthesized by this method is repaired by the FA pathway. The simplicity and efficiency of this methodology for preparing reduced acetaldehyde ICLs will facilitate access to these DNA architectures for future studies on cross-link repair

Explosive volcanic activity on Venus: The roles of volatile contribution, degassing, and external environment

We investigate the conditions that will promote explosive volcanic activity on Venus. Conduit processes were simulated using a steady-state, isothermal, homogeneous flow model in tandem with a degassing model. The response of exit pressure, exit velocity, and degree of volatile exsolution was explored over a range of volatile concentrations (H2O and CO2), magma temperatures, vent altitudes, and conduit geometries relevant to the Venusian environment. We find that the addition of CO2 to an H2O-driven eruption increases the final pressure, velocity, and volume fraction gas. Increasing vent elevation leads to a greater degree of magma fragmentation, due to the decrease in the final pressure at the vent, resulting in a greater likelihood of explosive activity. Increasing the magmatic temperature generates higher final pressures, greater velocities, and lower final volume fraction gas values with a correspondingly lower chance of explosive volcanism. Cross-sectionally smaller, and/or deeper, conduits were more conducive to explosive activity. Model runs show that for an explosive eruption to occur at Scathach Fluctus, at Venus’ mean planetary radius (MPR), 4.5% H2O or 3% H2O with 3% CO2 (from a 25 m radius conduit) would be required to initiate fragmentation; at Ma’at Mons (~9 km above MPR) only ~2% H2O is required. A buoyant plume model was used to investigate plume behaviour. It was found that it was not possible to achieve a buoyant column from a 25 m radius conduit at Scathach Fluctus, but a buoyant column reaching up to ~20 km above the vent could be generated at Ma’at Mons with an H2O concentration of 4.7% (at 1300 K) or a mixed volatile concentration of 3% H2O with 3% CO2 (at 1200 K). We also estimate the flux of volcanic gases to the lower atmosphere of Venus, should explosive volcanism occur. Model results suggest explosive activity at Scathach Fluctus would result in an H2O flux of ~107 kg s-1. Were Scathach Fluctus emplaced in a single event, our model suggests that it may have been emplaced in a period of ~15 days, supplying 1-2 x 104 Mt H2O to the atmosphere locally. An eruption of this scale might increase local atmospheric H2O abundance by several ppm over an area large enough to be detectable by near-infrared nightside sounding using the 1.18 µm spectral window such as that carried out by the Venus Express/VIRTIS spectrometer. Further interrogation of the VIRTIS dataset is recommended to search for ongoing volcanism on Venus

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Limit on Bs0B^0_s oscillation using a jet charge method

A lower limit is set on the B_{s}^{0} meson oscillation parameter \Delta m_{s} using data collected from 1991 to 1994 by the ALEPH detector. Events with a high transverse momentum lepton and a reconstructed secondary vertex are used. The high transverse momentum leptons are produced mainly by b hadron decays, and the sign of the lepton indicates the particle/antiparticle final state in decays of neutral B mesons. The initial state is determined by a jet charge technique using both sides of the event. A maximum likelihood method is used to set a lower limit of \, \Delta m_{s}. The 95\% confidence level lower limit on \Delta m_s ranges between 5.2 and 6.5(\hbar/c^{2})~ps^{-1} when the fraction of b quarks from Z^0 decays that form B_{s}^{0} mesons is varied from 8\% to 16\%. Assuming that the B_{s}^{0} fraction is 12\%, the lower limit would be \Delta m_{s} 6.1(\hbar/c^{2})~ps^{-1} at 95\% confidence level. For x_s = \Delta m_s \, \tau_{B_s}, this limit also gives x_s 8.8 using the B_{s}^{0} lifetime of \tau_{B_s} = 1.55 \pm 0.11~ps and shifting the central value of \tau_{B_s} down by 1\sigma

Measurement of the Bs0^0_s lifetime and production rate with Ds−l+^-_s l^+ combinations in Z decays

The lifetime of the \bs meson is measured in approximately 3 million hadronic Z decays accumulated using the ALEPH detector at LEP from 1991 to 1994. Seven different \ds decay modes were reconstructed and combined with an opposite sign lepton as evidence of semileptonic \bs decays. Two hundred and eight \dsl candidates satisfy selection criteria designed to ensure precise proper time reconstruction and yield a measured \bs lifetime of \mbox{\result .} Using a larger, less constrained sample of events, the product branching ratio is measured to be \mbox{\pbrresult