Ecological Factors Driving Avian Influenza Virus Dynamics in Spanish Wetland Ecosystems

Studies exploring the ecological interactions between avian influenza viruses (AIV), natural hosts and the environment are scarce. Most work has focused on viral survival and transmission under laboratory conditions and through mathematical modelling. However, more integrated studies performed under field conditions are required to validate these results. In this study, we combined information on bird community, environmental factors and viral epidemiology to assess the contribution of biotic and abiotic factors in the occurrence of low pathogenic AIV in Spanish wetlands. For that purpose, seven locations in five different wetlands were studied during two years (2007-2009), including seven sampling visits by location. In each survey, fresh faeces (n = 4578) of wild birds and water samples were collected for viral detection. Also, the vegetation structure, water physical properties of wetlands, climatic conditions and wild bird community composition were determined. An overall AIV prevalence of 1.7%±0.4 was detected in faecal samples with important fluctuations among seasons and locations. Twenty-six AIV were isolated from the 78 RRT-PCR positive samples and eight different haemagglutinines and five neuraminidases were identified, being the combination H3N8 the most frequent. Variation partitioning procedures identified the combination of space and time variables as the most important pure factor - independently to other factors - explaining the variation in AIV prevalence (36.8%), followed by meteorological factor (21.5%) and wild bird community composition/vegetation structure (21.1%). These results contribute to the understanding of AIV ecological drivers in Spanish ecosystems and provide useful guidelines for AIV risk assessment identifying potential hotspots of AIV activity

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.)

Scope for Credit Risk Diversification

This paper considers a simple model of credit risk and derives the limit distribution of losses under different assumptions regarding the structure of systematic risk and the nature of exposure or firm heterogeneity. We derive fat-tailed correlated loss distributions arising from Gaussian risk factors and explore the potential for risk diversification. Where possible the results are generalised to non-Gaussian distributions. The theoretical results indicate that if the firm parameters are heterogeneous but come from a common distribution, for sufficiently large portfolios there is no scope for further risk reduction through active portfolio management. However, if the firm parameters come from different distributions, then further risk reduction is possible by changing the portfolio weights. In either case, neglecting parameter heterogeneity can lead to underestimation of expected losses. But, once expected losses are controlled for, neglecting parameter heterogeneity can lead to overestimation of risk, whether measured by unexpected loss or value-at-risk

Vitamin D opposes multilineage cell differentiation induced by Notch inhibition and BMP4 pathway activation in human colon organoids

Understanding the mechanisms involved in colonic epithelial differentiation is key to unraveling the alterations causing inflammatory conditions and cancer. Organoid cultures provide an unique tool to address these questions but studies are scarce. We report a differentiation system toward enterocytes and goblet cells, the two major colonic epithelial cell lineages, using colon organoids generated from healthy tissue of colorectal cancer patients. Culture of these organoids in medium lacking stemness agents resulted in a modest ultrastructural differentiation phenotype with low-level expression of enterocyte (KLF4, KRT20, CA1, FABP2) and goblet cell (TFF2, TFF3, AGR2) lineage markers. BMP pathway activation through depletion of Noggin and addition of BMP4 resulted in enterocyte-biased differentiation. Contrarily, blockade of the Notch pathway using the γ-secretase inhibitor dibenzazepine (DBZ) favored goblet cell differentiation. Combination treatment with BMP4 and DBZ caused a balanced strong induction of both lineages. In contrast, colon tumor organoids responded poorly to BMP4 showing only weak signals of cell differentiation, and were unresponsive to DBZ. We also investigated the effects of 1α,25-dihydroxyvitamin D3 (calcitriol) on differentiation. Calcitriol attenuated the effects of BMP4 and DBZ on colon normal organoids, with reduced expression of differentiation genes and phenotype. Consistently, in normal organoids, calcitriol inhibited early signaling by BMP4 as assessed by reduction of the level of phospho-SMAD1/5/8. Our results show that BMP and Notch signaling play key roles in human colon stem cell differentiation to the enterocytic and goblet cell lineages and that calcitriol modulates these processes favoring stemness featuresThis work was supported by grant PID2019-104867RB-I00 funded by MCIN/AEI/10.13039/501100011033; grant PID2022-136729OB-I00 funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe”; grant S2022/BMD-7212 funded by Comunidad de Madrid; and grants ICI20/00057, CIBERONC/CB16/12/00273, CIBERONC/CB16/12/00453 and CIBERONC/CB16/12/00398 funded by the Instituto de Salud Carlos III - Fondo Europeo de Desarrollo Regional. PB-M and DA-R were supported by grants BES-2017-082483 and PRE2020-092713, respectively, funded by MCIN/AEI/10.13039/501100011033 and “ESF Investing in your future”. PBM, AB, DA-R, JR-C, JMG-S, MJL, AM and AF-B belong to the Spanish National Research Council (CSIC)‘s Cancer Hu

Sixty Years of Fractal Projections

Sixty years ago, John Marstrand published a paper which, among other things, relates the Hausdorff dimension of a plane set to the dimensions of its orthogonal projections onto lines. For many years, the paper attracted very little attention. However, over the past 30 years, Marstrand's projection theorems have become the prototype for many results in fractal geometry with numerous variants and applications and they continue to motivate leading research.Comment: Submitted to proceedings of Fractals and Stochastics

Vitamin D effects on human colon normal and tumour organoids

Trabajo presentado en FEBS Open Bio, celebrado en Lisboa (Portugal) del 09 al 14 de julio de 2022.Many studies indicate an association between vitamin D deficiency and increased colorectal cancer risk and, specially, mortality. Accordingly, the active vitamin D metabolite 1a,25-dihydroxyvitamin D3 (calcitriol) inhibits the proliferation and promotes the differentiation of colon carcinoma cells and of other tumour cell types, and also has antitumour effects in animal models of colon cancer. These results prompted us to analyse the effects of calcitriol on human colon normal and cancer stem cells. To this end, we established a living biobank of patient-derived colon organoids generated from the tumour mass and from the adjacent healthy tissue obtained from surgical biopsies. Organoids are a three-dimensional culture system of normal or cancer stem cells and their progeny with a self-organized multicellular structure. By immunohistochemistry and RNAscope in situ hybridization, we found that vitamin D receptor is expressed in LGR5+ colon stem cells in human tissue and in normal and tumour organoid cultures. RNA-sequencing assays showed that both organoid types respond differentially to calcitriol with profound and contrasting changes in their transcriptomic profiles. This was confirmed in an independent series of patient-derived organoids by RT-qPCR assays. In normal organoids, calcitriol upregulates stemness-related genes and inhibits cell proliferation. In contrast, in tumour organoids calcitriol has little effect on stemnessrelated genes, while it induces differentiation-associated genes, and variably reduces cell proliferation. Concordantly, electron microscopy analyses showed that calcitriol does not affect the blastic cell phenotype in normal organoids, but it induces a series of differentiated features in tumour organoids. These results indicate that calcitriol maintains the undifferentiated phenotype of human normal colon stem cells (homeostatic action), while it promotes the differentiation of colon cancer stem cells (anticancer action).

Neutrophils—the unexpected helpers of B‐cell activation

A specific subpopulation of neutrophils, termed N(BH), has been shown recently to provide help for the differentiation and function of B cells and plasma cells. These novel findings are put in the context of our current understanding of B-cell help

Detection of very high energy gamma-ray emission from the gravitationally-lensed blazar QSO B0218+357 with the MAGIC telescopes

Context. QSO B0218+357 is a gravitationally lensed blazar located at a redshift of 0.944. The gravitational lensing splits the emitted radiation into two components, spatially indistinguishable by gamma-ray instruments, but separated by a 10-12 day delay. In July 2014, QSO B0218+357 experienced a violent flare observed by the Fermi-LAT and followed by the MAGIC telescopes. Aims. The spectral energy distribution of QSO B0218+357 can give information on the energetics of z ~ 1 very high energy gamma- ray sources. Moreover the gamma-ray emission can also be used as a probe of the extragalactic background light at z ~ 1. Methods. MAGIC performed observations of QSO B0218+357 during the expected arrival time of the delayed component of the emission. The MAGIC and Fermi-LAT observations were accompanied by quasi-simultaneous optical data from the KVA telescope and X-ray observations by Swift-XRT. We construct a multiwavelength spectral energy distribution of QSO B0218+357 and use it to model the source. The GeV and sub-TeV data, obtained by Fermi-LAT and MAGIC, are used to set constraints on the extragalactic background light. Results. Very high energy gamma-ray emission was detected from the direction of QSO B0218+357 by the MAGIC telescopes during the expected time of arrival of the trailing component of the flare, making it the farthest very high energy gamma-ray sources detected to date. The observed emission spans the energy range from 65 to 175 GeV. The combined MAGIC and Fermi-LAT spectral energy distribution of QSO B0218+357 is consistent with current extragalactic background light models. The broad band emission can be modeled in the framework of a two zone external Compton scenario, where the GeV emission comes from an emission region in the jet, located outside the broad line region.Comment: 11 pages, 6 figures, accepted for publication in A&