Inhibition of the Intrinsic but Not the Extrinsic Apoptosis Pathway Accelerates and Drives Myc-Driven Tumorigenesis Towards Acute Myeloid Leukemia

Myc plays an important role in tumor development, including acute myeloid leukemia (AML). However, MYC is also a powerful inducer of apoptosis, which is one of the major failsafe programs to prevent cancer development. To clarify the relative importance of the extrinsic (death receptor-mediated) versus the intrinsic (mitochondrial) pathway of apoptosis in MYC-driven AML, we coexpressed MYC together with anti-apoptotic proteins of relevance for AML; BCL-XL/BCL-2 (inhibiting the intrinsic pathway) or FLIPL (inhibiting the extrinsic pathway), in hematopoietic stems cells (HSCs). Transplantation of HSCs expressing MYC into syngeneic recipient mice resulted in development of AML and T-cell lymphomas within 7–9 weeks as expected. Importantly, coexpression of MYC together with BCL-XL/BCL-2 resulted in strongly accelerated kinetics and favored tumor development towards aggressive AML. In contrast, coexpression of MYC and FLIPL did neither accelerate tumorigenesis nor change the ratio of AML versus T-cell lymphoma. However, a change in distribution of immature CD4+CD8+ versus mature CD4+ T-cell lymphoma was observed in MYC/FLIPL mice, possibly as a result of increased survival of the CD4+ population, but this did not significantly affect the outcome of the disease. In conclusion, our findings provide direct evidence that BCL-XL and BCL-2 but not FLIPL acts in synergy with MYC to drive AML development

Reducing emissions from agriculture to meet the 2 °C target

More than 100 countries pledged to reduce agricultural greenhouse gas (GHG) emissions in the 2015 Paris Agreement of the United Nations Framework Convention on Climate Change. Yet technical information about how much mitigation is needed in the sector vs. how much is feasible remains poor. We identify a preliminary global target for reducing emissions from agriculture of ~1 GtCO2e yr−1 by 2030 to limit warming in 2100 to 2 °C above pre-industrial levels. Yet plausible agricultural development pathways with mitigation cobenefits deliver only 21–40% of needed mitigation. The target indicates that more transformative technical and policy options will be needed, such as methane inhibitors and finance for new practices. A more comprehensive target for the 2 °C limit should be developed to include soil carbon and agriculture-related mitigation options. Excluding agricultural emissions from mitigation targets and plans will increase the cost of mitigation in other sectors or reduce the feasibility of meeting the 2 °C limit

Luminosity determination in pp collisions at root s=7 TeV using the ATLAS detector at the LHC

Measurements of luminosity obtained using the ATLAS detector during early running of the Large Hadron Collider (LHC) at root s = 7 TeV are presented. The luminosity is independently determined using several detectors and multiple algorithms, each having different acceptances, systematic uncertainties and sensitivity to background. The ratios of the luminosities obtained from these methods are monitored as a function of time and of mu, the average number of inelastic interactions per bunch crossing. Residual time- and mu-dependence between the methods is less than 2% for 0 < mu < 2.5. Absolute luminosity calibrations, performed using beam separation scans, have a common systematic uncertainty of +/- 11%, dominated by the measurement of the LHC beam currents. After calibration, the luminosities obtained from the different methods differ by at most +/- 2%. The visible cross sections measured using the beam scans are compared to predictions obtained with the PYTHIA and PHOJET event generators and the ATLAS detector simulation

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of root s = 7 TeV corresponding to an integrated luminosity of 38 pb(-1). Jets are reconstructed with the anti-k(t) algorithm with distance parameters R = 0.4 or R = 0.6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT >= 20 GeV and pseudorapidities vertical bar eta vertical bar < 4.5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2.5 % in the central calorimeter region (vertical bar eta vertical bar < 0.8) for jets with 60 <= p(T) < 800 GeV, and is maximally 14 % for p(T) < 30 GeV in the most forward region 3.2 <= vertical bar eta vertical bar < 4.5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon p(T), the sum of the transverse momenta of tracks associated to the jet, or a system of low-p(T) jets recoiling against a high-p(T) jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-p(T) jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined