Teleconnections of the Quasi‐Biennial Oscillation in a multi‐model ensemble of QBO‐resolving models

The Quasi-biennial Oscillation (QBO) dominates the interannual variability of the tropical stratosphere and influences other regions of the atmosphere. The high predictability of the QBO implies that its teleconnections could lead to increased skill of seasonal and decadal forecasts provided the relevant mechanisms are accurately represented in models. Here modelling and sampling uncertainties of QBO teleconnections are examined using a multi-model ensemble of QBO-resolving atmospheric general circulation models that have carried out a set of coordinated experiments as part of the Stratosphere-troposphere Processes And their Role in Climate (SPARC) QBO initiative (QBOi). During Northern Hemisphere winter, the stratospheric polar vortex in most of these models strengthens when the QBO near 50 hPa is westerly and weakens when it is easterly, consistent with, but weaker than, the observed response. These weak responses are likely due to model errors, such as systematically weak QBO amplitudes near 50 hPa, affecting the teleconnection. The teleconnection to the North Atlantic Oscillation is less well captured overall, but of similar strength to the observed signal in the few models that do show it. The models do not show clear evidence of a QBO teleconnection to the Northern Hemisphere Pacific-sector subtropical jet

Genome-Wide Discovery of Somatic Regulatory Variants in Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3′ UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.&nbsp

mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer

The mammalian gene function resource: The International Knockout Mouse Consortium

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed highthroughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research

Overview of experiment design and comparison of models participating in phase 1 of the SPARC Quasi-Biennial Oscillation initiative (QBOi)

The Stratosphere–troposphere Processes And their Role in Climate (SPARC) Quasi-Biennial Oscillation initiative (QBOi) aims to improve the fidelity of tropical stratospheric variability in general circulation and Earth system models by conducting coordinated numerical experiments and analysis. In the equatorial stratosphere, the QBO is the most conspicuous mode of variability. Five coordinated experiments have therefore been designed to (i) evaluate and compare the verisimilitude of modelled QBOs under present-day conditions, (ii) identify robustness (or alternatively the spread and uncertainty) in the simulated QBO response to commonly imposed changes in model climate forcings (e.g. a doubling of CO2 amounts), and (iii) examine model dependence of QBO predictability. This paper documents these experiments and the recommended output diagnostics. The rationale behind the experimental design and choice of diagnostics is presented. To facilitate scientific interpretation of the results in other planned QBOi studies, consistent descriptions of the models performing each experiment set are given, with those aspects particularly relevant for simulating the QBO tabulated for easy comparison.The design of the experiments described here grew out of community discussions at the first QBOi workshop in March 2015 in Victoria, Canada. Funding for the workshop from the UK Natural Environment Research Council (NE/M005828/1), the World Climate Research Programme (WCRP), Stratosphere– troposphere Processes And their Role in Climate (SPARC) activity, and the Canadian Centre for Climate Modelling and Analysis is gratefully acknowledged. We further acknowledge the scientific guidance of the WCRP for helping motivate this work, coordinated under the framework of the SPARC QBO initiative (QBOi) led by James Anstey, Neal Butchart, Kevin Hamilton, and Scott Osprey. The Centre for Environmental Data Analysis (CEDA) have very kindly offered to host the QBOi data archive. Neal Butchart and Adam Scaife were supported by the Joint UK BEIS/Defra Met Office Hadley Centre Climate Programme (GA01101). Scott Osprey and Lesley Gray were supported by NERC projects NE/M005828/1 and NE/P006779/1. Shingo Watanabe and Yoshio Kawatani used the Earth simulator for QBOi simulations and were supported by the SOUSEI programme, MEXT Japan, and the Japan Science and Technology Agency (JST) as part of the Belmont Forum. Yoshio Kawatani was supported by Grant-in-Aid for Scientific Research B (26287117), joint international research (15KK0178) from the Japan Society for the Promotion of Science, and the Environment Research and Technology Development Fund (2-1503) of the Ministry of the Environment, Japan. Francois Lott and Scott Osprey were supported by the ANR/JPI-Climate/Belmont Forum project GOTHAM (ANR-15-JCLI-0004-01). Federico Serva was supported by the European Commission under grant StratoClim-603557-FP7-ENV.2013.6.1-2, with computing resources for the ECHAM5sh simulations provided by an ECMWF special project. Young-Ha Kim was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1C1A1A02036449). Holger Pohlmann was supported by the German Federal Ministry for Education and Research (BMBF) project MiKlip (FKZ 01LP1519A) and thanks Elisa Manzini for providing additional information on the MPI model. BSC contribution is supported by the Spanish MINECO-funded DANAE project (CGL2015-68342-R) and Red Española de Supercomputación (RES project AECT-2017-3-0015).Peer Reviewe

A simple method to cure established tumors by inflammatory killing of normal cells.

We describe a simple technology used to cure an established metastatic disease. Intradermal injection of plasmid DNA encoding a transcriptionally targeted cytotoxic gene, along with hsp70, not only promoted tissue-specific, inflammatory killing of normal melanocytes, but also induced a CD8(+) T-cell-dependent, antigen-specific response in mice that eradicated systemically established B16 tumors. This CD8(+) T cell response was subsequently suppressed in vivo within a few days. The data demonstrate that deliberate destruction of normal tissue can be exploited to generate immunity against a malignant disease originating from that tissue. This approach obviates the need to identify tumor antigens and does not require complex isolation of tumor cells or their derivatives. In addition, it provides a model system for studying the mechanisms underlying the etiology and control of autoimmune diseases. Finally, despite targeting normal tissue, therapy could be separated from development of overt autoimmune symptoms, suggesting that the strategy may be valuable against tumors derived from both non-essential and essential tissue types