Global gene expression profiling in human lung cells exposed to cobalt.

International audienceBACKGROUND: It has been estimated that more than 1 million workers in the United States are exposed to cobalt. Occupational exposure to 59 Co occurs mainly via inhalation and leads to various lung diseases. Cobalt is classified by the IARC as a possible human carcinogen (group 2B). Although there is evidence for in vivo and in vitro toxicity, the mechanisms of cobalt-induced lung toxicity are not fully known. The purpose of this work was to identify potential signatures of acute cobalt exposure using a toxicogenomic approach. Data analysis focused on some cellular processes and protein targets that are thought to be relevant for carcinogenesis, transport and biomarker research. RESULTS: A time course transcriptome analysis was performed on A549 human pulmonary cells, leading to the identification of 85 genes which are repressed or induced in response to soluble 59 Co. A group of 29 of these genes, representing the main biological functions, was assessed by quantitative RT-PCR. The expression profiles of six of them were then tested by quantitative RT-PCR in a time-dependent manner and three modulations were confirmed by Western blotting. The 85 modulated genes include potential cobalt carriers (FBXL2, ZNT1, SLC12A5), tumor suppressors or transcription factors (MAZ, DLG1, MYC, AXL) and genes linked to the stress response (UBC, HSPCB, BNIP3L). We also identified nine genes coding for secreted proteins as candidates for biomarker research. Of those, TIMP2 was found to be down-regulated and this modulation was confirmed, in a dose-dependent manner, at protein level in the supernatant of exposed cells. CONCLUSION: Most of these genes have never been described as related to cobalt stress and provide original hypotheses for further study of the effects of this metal ion on human lung epithelial cells. A putative biomarker of cobalt toxicity was identified

Searches for point-like sources of cosmic neutrinos with 13 years of ANTARES data

The main goal of the ANTARES neutrino telescope is the identification of neutrinos from astrophysical sources. Thanks to its location in the Northern hemisphere, ANTARES can rely on an advantageous view of the Southern Sky, in particular for neutrino energies below 100 TeV. This feature, combined with a very good angular resolution for high-quality selected events, makes the telescope an excellent tool to test for the presence of point-like sources, especially of Galactic origin. In ANTARES, track-like events are reconstructed with a median angular resolution of 0.4º while for shower-like events a median angular resolution of 3º is achieved. The ANTARES Collaboration published the result of the search for cosmic point-like neutrino sources using track-like and shower-like events collected during nine years of data taking [Phys. Rev. D 96 (2017) 082001]. In this contribution, the update to this analysis using a total of 13 years of data recorded between early 2007 and early 2020 (3845 days of livetime) is presented. Moreover, the results of the dedicated searches for neutrino candidates from the tidal disruption events AT2019dsg and AT2019fdr, recently indicated as the most likely counterparts of two high-energy IceCube neutrinos, IC191001A and IC200530A, are reported.Article signat per 142 autors/es: A. Albert, S. Alves, M. André, M. Anghinolfi, G. Anton, M. Ardid, S. Ardid, J.-J. Aubert, J. Aublin, B. Baret, S. Basa,B. Belhorma, B. Belhorma, M. Bendahman, V. Bertin, S. Biagi, M. Bissinger, J. Boumaaza, M. Bouta, M.C. Bouwhuis, H. Brânzas, R. Bruijn, J. Brunner, J. Busto, B. Caiffi, A. Capone, L. Caramete, J. Carr, V. Carretero, S. Celli, M. Chabab,T. N. Chau, R. Cherkaoui El Moursli, T. Chiarusi, M. Circella, A. Coleiro, M. Colomer-Molla, R. Coniglione, P. Coyle, A. Creusot, A. F. Díaz, G. de Wasseige, A. Deschamps, C. Distefano, I. Di Palma, A. Domi, C. Donzaud, D. Dornic, D. Drouhin, T. Eberl, T. van Eeden, D. van Eijk, N. El Khayati, A. Enzenhöfer, P. Fermani, G. Ferrara, F. Filippini, L.A. Fusco, Y. Gatelet, P. Gay, H. Glotin, R. Gozzini, R. Gracia Ruiz, K. Graf, C. Guidi, S. Hallmann, H. van Haren, A.J. Heijboer, Y. Hello, J.J. Hernández-Rey, J. Hößl, J. Hofestädt, F. Huang, G. Illuminati, C.W James, B. Jisse-Jung, M. de Jong, P. de Jong, M. Kadler, O. Kalekin, U. Katz, N.R. Khan Chowdhury, A. Kouchner, I. Kreykenbohm, V. Kulikovskiy, R. Lahmann, R. Le Breton, D. Lefèvre, E. Leonora, G. Levi, M. Lincetto, D. Lopez-Coto, S. Loucatos, L. Maderer, J. Manczak, M. Marcelin, A. Margiotta, A. Marinelli, J.A. Martínez-Mora, K. Melis, P. Migliozzi, A. Moussa, R. Muller, L.Nauta, S.Navas, E.Nezri, B. O’Fearraigh, A. Paun, G.E. Pavalas, C. Pellegrino, M. Perrin-Terrin,V. Pestel, P. Piattelli, C. Pieterse, C. Poirè,V. Popa, T. Pradier,N. Randazzo, S.Reck, G. Riccobene, A. Romanov, A. Sánchez-Losa, F. Salesa Greus, D. F. E. Samtleben, M. Sanguineti, P. Sapienza, J. Schnabel, J. Schumann, F. Schüssler, M. Spurio, Th. Stolarczyk, M. Taiuti, Y. Tayalati, S.J. Tingay, B. Vallage, V. Van Elewyck, F. Versari, S. Viola, D. Vivolo, J. Wilms, S. Zavatarelli5, A. Zegarelli, J.D. Zornoza, and J. ZúñigaPostprint (published version

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Intestinal toxicity evaluation of TiO2 degraded surface-treated nanoparticles: a combined physico-chemical and toxicogenomics approach in caco-2 cells

International audienceBackground: Titanium dioxide (TiO2) nanoparticles (NPs) are widely used due to their specific properties, like UV filters in sunscreen. In that particular case TiO2 NPs are surface modified to avoid photocatalytic effects. These surface-treated nanoparticles (STNPs) spread in the environment and might release NPs as degradation residues. Indeed, degradation by the environment (exposure to UV, water and air contact ... ) will occur and could profoundly alter the physicochemical properties of STNPs such as chemistry, size, shape, surface structure and dispersion that are important parameters for toxicity. Although the toxicity of surface unmodified TiO2 NPs has been documented, nothing was done about degraded TiO2 STNPs which are the most likely to be encountered in environment. The superoxide production by aged STNPs suspensions was tested and compared to surface unmodified TiO2 NPs. We investigated the possible toxicity of commercialized STNPs, degraded by environmental conditions, on human intestinal epithelial cells. STNPs sizes and shape were characterized and viability tests were performed on Caco-2 cells exposed to STNPs. The exposed cells were imaged with SEM and STNPs internalization was researched by TEM. Gene expression microarray analyses were performed to look for potential changes in cellular functions. Results: The production of reactive oxygen species was detected with surface unmodified TiO2 NPs but not with STNPs or their residues. Through three different toxicity assays, the STNPs tested, which have a strong tendency to aggregate in complex media, showed no toxic effect in Caco-2 cells after exposures to STNPs up to 100 mu g/mL over 4 h, 24 h and 72 h. The cell morphology remained intact, attested by SEM, and internalization of STNPs was not seen by TEM. Moreover gene expression analysis using pangenomic oligomicroarrays (4x 44000 genes) did not show any change versus unexposed cells after exposure to 10 mu g/mL, which is much higher than potential environmental concentrations. Conclusions: TiO2 STNPs, degraded or not, are not harmful to Caco-2 cells and are unlikely to penetrate the body via oral route. It is likely that the strong persistence of the aluminium hydroxide layer surrounding these nanoparticles protects the cells from a direct contact with the potentially phototoxic TiO2 core

Reply to comment on Fisichella et al. (2012), ``Intestinal toxicity evaluation of TiO2 degraded surface-treated nanoparticles: a combined physico-chemical and toxicogenomics approach in Caco-2 cells'' by Faust et al.

International audienceIn this response, we discuss the major differences that clearly distinguish our results from those mentioned by Faust et al.. In particular, the experiments have been conducted on nanoparticles of different nature, what mainly explains the observed discrepancies. This is a reply to http://www.particleandfibretoxicology.com/content/pdf/1743-8977-9-39.pdf

Intestinal toxicity evaluation of TiO₂ degraded surface-treated nanoparticles: a combined physico-chemical and toxicogenomics approach in caco-2 cells

Abstract Background Titanium dioxide (TiO2) nanoparticles (NPs) are widely used due to their specific properties, like UV filters in sunscreen. In that particular case TiO2 NPs are surface modified to avoid photocatalytic effects. These surface-treated nanoparticles (STNPs) spread in the environment and might release NPs as degradation residues. Indeed, degradation by the environment (exposure to UV, water and air contact …) will occur and could profoundly alter the physicochemical properties of STNPs such as chemistry, size, shape, surface structure and dispersion that are important parameters for toxicity. Although the toxicity of surface unmodified TiO2 NPs has been documented, nothing was done about degraded TiO2 STNPs which are the most likely to be encountered in environment. The superoxide production by aged STNPs suspensions was tested and compared to surface unmodified TiO2 NPs. We investigated the possible toxicity of commercialized STNPs, degraded by environmental conditions, on human intestinal epithelial cells. STNPs sizes and shape were characterized and viability tests were performed on Caco-2 cells exposed to STNPs. The exposed cells were imaged with SEM and STNPs internalization was researched by TEM. Gene expression microarray analyses were performed to look for potential changes in cellular functions. Results The production of reactive oxygen species was detected with surface unmodified TiO2 NPs but not with STNPs or their residues. Through three different toxicity assays, the STNPs tested, which have a strong tendency to aggregate in complex media, showed no toxic effect in Caco-2 cells after exposures to STNPs up to 100 μg/mL over 4 h, 24 h and 72 h. The cell morphology remained intact, attested by SEM, and internalization of STNPs was not seen by TEM. Moreover gene expression analysis using pangenomic oligomicroarrays (4x 44000 genes) did not show any change versus unexposed cells after exposure to 10 μg/ mL, which is much higher than potential environmental concentrations. Conclusions TiO2 STNPs, degraded or not, are not harmful to Caco-2 cells and are unlikely to penetrate the body via oral route. It is likely that the strong persistence of the aluminium hydroxide layer surrounding these nanoparticles protects the cells from a direct contact with the potentially phototoxic TiO2 core.</p

Toxicity evaluation of manufactured CeO2 nanoparticles before and after alteration: combined physicochemical and whole-genome expression analysis in Caco-2 cells

International audienceBackground: Engineered nanomaterials may release nanosized residues, by degradation, throughout their life cycle. These residues may be a threat for living organisms. They may be ingested by humans through food and water. Although the toxicity of pristine CeO2 nanoparticles (NPs) has been documented, there is a lack of studies on manufactured nanoparticles, which are often surface modified. Here, we investigated the potential adverse effects of CeO2 Nanobyk 3810 (TM) NPs, used in wood care, and their residues, altered by light or acid. Results: Human intestinal Caco-2 cells were exposed to residues degraded by daylight or in a medium simulating gastric acidity. Size and zeta potential were determined by dynamic light scattering. The surface structure and redox state of cerium were analyzed by transmission electronic microscopy (TEM) and X-ray absorption spectroscopy, respectively. Viability tests were performed in Caco-2 cells exposed to NPs. Cell morphology was imaged with scanning electronic microscopy. Gene expression profiles obtained from cells exposed to NPs before and after their alteration were compared, to highlight differences in cellular functions. No change in the cerium redox state was observed for altered NPs. All CeO2 NPs suspended in the culture medium became microsized. Cytotoxicity tests showed no toxicity after Caco-2 cell exposure to these various NPs up to 170 mu g/mL (24 h and 72 h). Nevertheless, a more-sensitive whole-gene-expression study, based on a pathway-driven analysis, highlighted a modification of metabolic activity, especially mitochondrial function, by altered Nanobyk 3810 (TM). The down-regulation of key genes of this pathway was validated by qRT-PCR. Conversely, Nanobyk 3810 (TM) coated with ammonium citrate did not display any adverse effect at the same concentration. Conclusion: The degraded nanoparticles were more toxic than their coated counterparts. Desorption of the outside layer was the most likely cause of this discrepancy in toxicity. It can be assumed that the safe design of engineered nanoparticles could include robust protective layers conferring on them greater resistance to alteration during their life cycle