Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation.

Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages. We show that Nrbp1 interacts with key components of the ubiquitination machinery and that loss of Nrbp1 in the intestine results in the accumulation of Sall4, a key mediator of stem cell fate, and of Tsc22d2. We also reveal that somatic loss of Nrbp1 results in tumourigenesis, with haematological and intestinal tumours predominating, and that nuclear receptor binding protein 1 (NRBP1) is downregulated in a range of human tumours, where low expression correlates with a poor prognosis. Thus NRBP1 is a conserved regulator of cell fate, that plays an important role in tumour suppression

OMIP contribution to CMIP6: experimental and diagnostic protocol for the physical component of the Ocean Model Intercomparison Project

The Ocean Model Intercomparison Project (OMIP) is an endorsed project in the Coupled Model Intercomparison Project Phase 6 (CMIP6). OMIP addresses CMIP6 science questions, investigating the origins and consequences of systematic model biases. It does so by providing a framework for evaluating (including assessment of systematic biases), understanding, and improving ocean, sea-ice, tracer, and biogeochemical components of climate and earth system models contributing to CMIP6. Among the WCRP Grand Challenges in climate science (GCs), OMIP primarily contributes to the regional sea level change and near-term (climate/decadal) prediction GCs. OMIP provides (a) an experimental protocol for global ocean/sea-ice models run with a prescribed atmospheric forcing; and (b) a protocol for ocean diagnostics to be saved as part of CMIP6. We focus here on the physical component of OMIP, with a companion paper (Orr et al., 2016) detailing methods for the inert chemistry and interactive biogeochemistry. The physical portion of the OMIP experimental protocol follows the interannual Coordinated Ocean-ice Reference Experiments (CORE-II). Since 2009, CORE-I (Normal Year Forcing) and CORE-II (Interannual Forcing) have become the standard methods to evaluate global ocean/sea-ice simulations and to examine mechanisms for forced ocean climate variability. The OMIP diagnostic protocol is relevant for any ocean model component of CMIP6, including the DECK (Diagnostic, Evaluation and Characterization of Klima experiments), historical simulations, FAFMIP (Flux Anomaly Forced MIP), C4MIP (Coupled Carbon Cycle Climate MIP), DAMIP (Detection and Attribution MIP), DCPP (Decadal Climate Prediction Project), ScenarioMIP, HighResMIP (High Resolution MIP), as well as the ocean/sea-ice OMIP simulations

Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis

The evolution of colorectal cancer suggests the involvement of many genes. We performed insertional mutagenesis with the Sleeping Beauty (SB) transposon system in mice carrying germline or somatic Apc mutation. Analysis of common insertion sites (CISs) isolated from 446 tumors revealed many hundreds of candidate cancer drivers. Comparison to human datasets suggested that 234 CIS genes are also deregulated in human colorectal cancers. 183 CIS genes are candidate Wnt targets, and 20 are shown to be novel modifiers of canonical Wnt signaling. We also identified gene mutations associated with a subset of tumors containing an expanded number of Paneth cells, a hallmark of deregulated Wnt signaling, and genes associated with more severe dysplasia included members of the FGF signaling cascade. Some 70 genes showed pairwise co-occurrence clustering into 38 sub-networks that may regulate tumor development

The GFDL Global Ocean and Sea Ice Model OM4.0: Model Description and Simulation Features

We document the configuration and emergent simulation features from the Geophysical Fluid Dynamics Laboratory (GFDL) OM4.0 ocean/sea ice model. OM4 serves as the ocean/sea ice component for the GFDL climate and Earth system models. It is also used for climate science research and is contributing to the Coupled Model Intercomparison Project version 6 Ocean Model Intercomparison Project. The ocean component of OM4 uses version 6 of the Modular Ocean Model and the sea ice component uses version 2 of the Sea Ice Simulator, which have identical horizontal grid layouts (Arakawa C-grid). We follow the Coordinated Ocean-sea ice Reference Experiments protocol to assess simulation quality across a broad suite of climate-relevant features. We present results from two versions differing by horizontal grid spacing and physical parameterizations: OM4p5 has nominal 0.5 degrees spacing and includes mesoscale eddy parameterizations and OM4p25 has nominal 0.25 degrees spacing with no mesoscale eddy parameterization. Modular Ocean Model version 6 makes use of a vertical Lagrangian-remap algorithm that enables general vertical coordinates. We show that use of a hybrid depth-isopycnal coordinate reduces the middepth ocean warming drift commonly found in pure z* vertical coordinate ocean models. To test the need for the mesoscale eddy parameterization used in OM4p5, we examine the results from a simulation that removes the eddy parameterization. The water mass structure and model drift are physically degraded relative to OM4p5, thus supporting the key role for a mesoscale closure at this resolution.National Oceanic and Atmospheric Administration, U.S. Department of CommerceNational Oceanic Atmospheric Admin (NOAA) - USA [NA14OAR4320106]; Carbon Mitigation Initiative (CMI) project at Princeton University - BP; Natural Sciences and Engineering Research Council of Canada (NSERC)Natural Sciences and Engineering Research Council of Canada [RGPIN-2018-04985]; National Science FoundationNational Science Foundation (NSF) [1536350]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]