SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150

SPROUTY-2 (SPRY2) is a modulator of tyrosine kinase receptor signaling with receptor- and cell type-dependent inhibitory or enhancing effects. Studies on the action of SPRY2 in major cancers are conflicting and its role remains unclear. Here we have dissected SPRY2 action in human colon cancer. Global transcriptomic analyses show that SPRY2 downregulates genes encoding tight junction proteins such as claudin-7 and occludin and other cell-to-cell and cell-to-matrix adhesion molecules in human SW480- ADH colon carcinoma cells. Moreover, SPRY2 represses LLGLL2/HUGL2, PATJ1/INADL and ST14, main regulators of the polarized epithelial phenotype, and ESRP1, an epithelial-to-mesenchymal transition (EMT) inhibitor. A key action of SPRY2 is the upregulation of the major EMT inducer ZEB1, as these effects are reversed by ZEB1 knock-down by means of RNA interference. Consistently, we found an inverse correlation between the expression level of claudin-7 and those of SPRY2 and ZEB1 in human colon tumors. Mechanistically, ZEB1 upregulation by SPRY2 results from the combined induction of ETS1 transcription factor and the repression of microRNAs (miR-200 family, miR-150) that target ZEB1 RNA. Moreover, SPRY2 increased AKT activation by epidermal growth factor (EGF) whereas AKT and also Src inhibition reduced the induction of ZEB1. Altogether, these data suggest that AKT and Src are implicated in SPRY2 action. Collectively, these results show a tumorigenic role of SPRY2 in colon cancer that is based on the dysregulation of tight junction and epithelial polarity master genes via upregulation of ZEB1. The dissection of the mechanism of action of SPRY2 in colon cancer cells is important to understand the upregulation of this gene in a subset of patients with this neoplasia that have poor prognosis.This study was supported by the Ministerio de Economía y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER) (grant SAF2013-43468-R to A.M., SAF2011-29530 to F.X.R.); FEDERInstituto de Salud Carlos III (RD12/0036/0021 to A.M. and J.M.R., RD12/0036/0034 to F.X.R., RD12/0036/0016 to M.S., RD12/0036/0012 to H.G.P., RD06/0020/0003, PS09/00562 and PI13/00703 to J.M.R.); Comunidad de Madrid (S2010/BMD-2344 Colomics2 to A.M.); Fundación Científica de la Asociación Española contra el Cáncer (to J.M.R.); U.S. Department of Defense (CA093471 and CA110602 to E.H.); National Institutes of Health/National Cancer Institute (1R01CA155234-01 to E.H.); National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R21AR062239-01 to E.H.); and the Melanoma Research Alliance (to E. H.)

Coupling ecological concepts with an ocean-colour model: Phytoplankton size structure

This is the final version. Available on open access from Elsevier via the DOI in this recordData availability: Data will be made available on request.Phytoplankton play a central role in the planetary cycling of important elements and compounds. Understanding how phytoplankton are responding to climate change is consequently a major question in Earth Sciences. Monitoring phytoplankton is key to answering this question. Satellite remote sensing of ocean colour is our only means of monitoring phytoplankton in the entire surface ocean at high temporal and large spatial scales, and the continuous ocean-colour data record is now approaching a length suitable for addressing questions around climate change, at least in some regions. Yet, developing ocean-colour algorithms for climate change studies requires addressing issues of ambiguity in the ocean-colour signal. For example, for the same chlorophyll-a concentration (Chl-a) of phytoplankton, the colour of the ocean can be different depending on the type of phytoplankton present. One route to tackle the issue of ambiguity is by enriching the ocean-colour data with information on sea surface temperature (SST), a good proxy of changes in three phytoplankton size classes (PSCs) independent of changes in total Chl-a, a measure of phytoplankton biomass. Using a global surface in-situ dataset of HPLC (high performance liquid chromatography) pigments, size-fractionated filtration data, and concurrent satellite SST spanning from 1991 to 2021, we re-tuned, validated and advanced an SST-dependent three-component model that quantifies the relationship between total Chl-a and Chl-a associated with the three PSCs (pico-, nano- and microplankton). Similar to previous studies, striking dependencies between model parameters and SST were captured, which were found to improve model performance significantly. These relationships were applied to 40 years of monthly composites of satellite SST, and significant trends in model parameters were observed globally, in response to climate warming. Changes in these parameters highlight issues in estimating long-term trends in phytoplankton biomass (Chl-a) from ocean colour using standard empirical algorithms, which implicitly assume a fixed relationship between total Chl-a and Chl-a of the three size classes. The proposed ecological model will be at the centre of a new ocean-colour modelling framework, designed for investigating the response of phytoplankton to climate change, described in subsequent parts of this series of papers

TIGER : The gene expression regulatory variation landscape of human pancreatic islets

Genome-wide association studies (GWASs) identified hundreds of signals associated with type 2 diabetes (T2D). To gain insight into their underlying molecular mechanisms, we have created the translational human pancreatic islet genotype tissue-expression resource (TIGER), aggregating >500 human islet genomic datasets from five cohorts in the Horizon 2020 consortium T2DSystems. We impute genotypes using four reference panels and meta-analyze cohorts to improve the coverage of expression quantitative trait loci (eQTL) and develop a method to combine allele-specific expression across samples (cASE). We identify >1 million islet eQTLs, 53 of which colocalize with T2D signals. Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identify eight cASE colocalizations, among which we found a T2D-associated SLC30A8 variant. We make all data available through the TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translates into therapeutic insight and precision medicine for T2D.Peer reviewe

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Membrane anchoring stabilizes and favors secretion of New Delhi metallo-β-lactamase

Carbapenems, 'last-resort' β-lactam antibiotics, are inactivated by zinc-dependent metallo-β-lactamases (MBLs). The host innate immune response withholds nutrient metal ions from microbial pathogens by releasing metal-chelating proteins such as calprotectin. We show that metal sequestration is detrimental for the accumulation of MBLs in the bacterial periplasm, because those enzymes are readily degraded in their nonmetallated form. However, the New Delhi metallo-β-lactamase (NDM-1) can persist under conditions of metal depletion. NDM-1 is a lipidated protein that anchors to the outer membrane of Gram-negative bacteria. Membrane anchoring contributes to the unusual stability of NDM-1 and favors secretion of this enzyme in outer-membrane vesicles (OMVs). OMVs containing NDM-1 can protect nearby populations of bacteria from otherwise lethal antibiotic levels, and OMVs from clinical pathogens expressing NDM-1 can carry this MBL and the bla[subscript NDM] gene. We show that protein export into OMVs can be targeted, providing possibilities of new antibacterial therapeutic strategies.Kinship Foundation. Searle Scholars ProgramMassachusetts Institute of Technology. Department of Chemistr

Observation of Azimuth-Dependent Suppression of Hadron Pairs in Electron Scattering Off Nuclei

We present the first measurement of dihadron angular correlations in electron-nucleus scattering. The data were taken with the CLAS detector and a 5.0 GeV electron beam incident on deuterium, carbon, iron, and lead targets. Relative to deuterium, the nuclear yields of charged-pion pairs show a strong suppression for azimuthally opposite pairs, no suppression for azimuthally nearby pairs, and an enhancement of pairs with large invariant mass. These effects grow with increased nuclear size. The data are qualitatively described by the gibuu model, which suggests that hadrons form near the nuclear surface and undergo multiple scattering in nuclei. These results show that angular correlation studies can open a new way to elucidate how hadrons form and interact inside nuclei

Gene Circuit Analysis of the Terminal Gap Gene huckebein

The early embryo of Drosophila melanogaster provides a powerful model system to study the role of genes in pattern formation. The gap gene network constitutes the first zygotic regulatory tier in the hierarchy of the segmentation genes involved in specifying the position of body segments. Here, we use an integrative, systems-level approach to investigate the regulatory effect of the terminal gap gene huckebein (hkb) on gap gene expression. We present quantitative expression data for the Hkb protein, which enable us to include hkb in gap gene circuit models. Gap gene circuits are mathematical models of gene networks used as computational tools to extract regulatory information from spatial expression data. This is achieved by fitting the model to gap gene expression patterns, in order to obtain estimates for regulatory parameters which predict a specific network topology. We show how considering variability in the data combined with analysis of parameter determinability significantly improves the biological relevance and consistency of the approach. Our models are in agreement with earlier results, which they extend in two important respects: First, we show that Hkb is involved in the regulation of the posterior hunchback (hb) domain, but does not have any other essential function. Specifically, Hkb is required for the anterior shift in the posterior border of this domain, which is now reproduced correctly in our models. Second, gap gene circuits presented here are able to reproduce mutants of terminal gap genes, while previously published models were unable to reproduce any null mutants correctly. As a consequence, our models now capture the expression dynamics of all posterior gap genes and some variational properties of the system correctly. This is an important step towards a better, quantitative understanding of the developmental and evolutionary dynamics of the gap gene network