Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention

Spatial and temporal facies evolution of a Lower Jurassic carbonate platform, NW Tethyan margin (Mallorca, Spain)

The variety of depositional facies of a Lower Jurassic carbonate platform has been investigated on the island of Mallorca along a transect comprising six stratigraphic profiles. Twenty-nine facies and sub-facies have been recognized, grouped into seven facies associations, ranging in depositional environment from supratidal/terrestrial and peritidal to outer platform. Spatial and temporal (2D) facies distribution along the transect reflects the evolution of the carbonate platform with time showing different facies associations, from a broad peritidal platform (stage 1) to a muddy open platform (stage 2), and finally to a peritidal to outer carbonate platform (stage 3). Stage 1 (early Sinemurian to earliest late Sinemurian) corresponds to a nearly-flat peritidal-shallow subtidal epicontinental platform with facies belts that shifted far and fast over the whole study area. The evolution from stage 1 to stage 2 (late Sinemurian) represents a rapid flooding of the epicontinental shallow platform, with more open-marine conditions, and the onset of differential subsidence. During stage 3 (latest Sinemurian), peritidal and shallow-platform environments preferentially developed to the northeast (Llevant Mountains domain) with a rapid transition to middle-outer platform environments toward the northwest (Tramuntana Range domain). Stages 1 and 3 present facies associations typical of Bahamian-type carbonates, whereas stage 2 represents the demise of the Bahamian-type carbonate factory and proliferation of muddy substrates with suspension-feeders. The described platform evolution responded to the interplay between the initial extensional tectonic phases related to Early Jurassic Tethyan rifting, contemporaneous environmental perturbations, and progressive platform flooding related to the Late Triassic–Early Jurassic worldwide marine transgression and associated accommodation changes

Deoxynivalenol in the liver and lymphoid organs of rats: effects of dose and duration on immunohistological changes

Deoxynivalenol (DON) is one of the most prevalent type B trichothecenes present in food inducing adverse effects, including intestinal changes and immunosuppression. The aim of the present study was to investigate the effects of DON on rats exposed for 7, 14 and 28 days to mycotoxin-contaminated diets, using histological and immunohistochemical analyses on liver and lymphoid organs. Fifty rats received a control diet, or a diet contaminated with 1.75 mg/kg of DON for 30 days, or a diet contaminated with 11.4 mg/kg of DON for 7, 14 or 30 days. Ingestion of contaminated feed induced a significant increase in the lesional score in the liver, spleen, and lymph nodes. The main histological findings observed in the liver were cytoplasmic vacuolisation and hepatocelular megalocytosis. A significant increase in hepatocyte proliferation was observed in rats that received 1.75 mg/kg of DON. Lymphoid depletion was the main histological alteration observed in lymphoid organs, resulting in a significant increase in the lesional score in all groups that received the contaminated diets. The histological changes and lymphocyte apoptosis were more severe in lymph nodes of rats fed 11.4 mg/kg of DON during 30 days. The results of the morphological and immunohistochemical analyses suggest that the ingestion of DON can induce functional hepatic impairment and immunosuppression in a dose- and time-dependent manner. </jats:p

Análisis magnético del tránsito Paleoceno/Eoceno en una secuencia sedimentaria continental (Formaciones Esplugafreda y Claret, cuenca Tremp-Graus, Pirineos)

Póster presentado en: XI Congreso Geológico de España (CGE24), Ávila, 2-6 julio 2024El máximo térmico del Paleoceno-Eoceno (PETM), corresponde a un episodio rápido (~ 170 ky) y global de aumento de temperatura que ocurrió hace aprox. 56 Ma y que quedó bien registrado en la llanura costera de la Cuenca Tremp-Graus en Pirineos, situada en el cinturón climático subtropical (paleolatitud ~35 °N). La secuencia muestreada en Esplugafreda (provincia de Lleida) abarca la Formación Esplugafreda (los 80 metros superiores) y la Formación Claret, que incluye cuatro intervalos distintivos: (i) el conglomerado Claret, (ii) los suelos amarillentos, (iii) la unidad rica en yesos, y (iv) las lutitas rojizas superiores. Según los datos de isótopos estables, los tres primeros intervalos de la Formación Claret corresponden a diferentes fases del PETM. En esta secuencia se ha realizado un estudio detallado de magnetismo de rocas y de variación de la mineralogía magnética. Los experimentos magnéticos han mostrado una muy buena correlación entre la estratigrafía y la variación de propiedades magnéticas. Se ha determinado tanto la contribución relativa, como el estado magnético de la magnetita/maghemita, goetita y hematites en toda la secuencia. La elevada concentración de maghemita estable en un nivel de la parte inferior de la Formación Esplugafreda podría relacionarse con un posible impacto térmico, como puede ser un paleoincendio.The Paleocene-Eocene thermal maximum (PETM) corresponds to a rapid (~ 170 ky) global warming episode that occurred about 56 Ma ago. It is well recorded in the coastal plain of the Tremp-Graus Basin in the Pyrenees, which was located in the subtropical climatic belt (paleolatitude ~35 °N). The succession sampled in Esplugafreda (Lleida province) comprises the Esplugafreda Formation (upper 80 m) and the Claret Formation, which includes four distinctive intervals: (i) the Claret conglomerate, (ii) the yellowish soils, (iii) the gypsum-rich unit, and (iv) the upper reddish mudstones. According to stable isotope data, the first three intervals of the Claret Formation correspond to different phases of the PETM. In this sequence, a detailed study of rock magnetism has been carried out to analyse the variation of the magnetic mineralogy along the sequence. The magnetic experiments have shown a very good correlation between the stratigraphy and the variation of magnetic properties. Both the relative contribution and the magnetic state of magnetite/maghemite, goethite and hematite throughout the sequence have been determined. The high concentration of stable maghemite in one level of the lower part of the Esplugafreda Formation could be related to a possible thermal impact, such as a paleo-fire.M.F.Bógalo, J.J. Villalaínand E. Vernet acknowledge Junta de Castilla y León and the European Regional Development Fund (project BU037P23). S. KéleandG.ÚjvarÍacknowledge National Research, Development and Innovation Office in Hungary, state agency (NKFI K-137767)

Bacteria-derived long chain fatty acid exhibits anti-inflammatory properties in colitis

ObjectiveData from clinical research suggest that certain probiotic bacterial strains have the potential to modulate colonic inflammation. Nonetheless, these data differ between studies due to the probiotic bacterial strains used and the poor knowledge of their mechanisms of action.DesignBy mass-spectrometry, we identified and quantified free long chain fatty acids (LCFAs) in probiotics and assessed the effect of one of them in mouse colitis.ResultsAmong all the LCFAs quantified by mass spectrometry in Escherichia coli Nissle 1917 (EcN), a probiotic used for the treatment of multiple intestinal disorders, the concentration of 3-hydroxyoctadecaenoic acid (C18-3OH) was increased in EcN compared with other E. coli strains tested. Oral administration of C18-3OH decreased colitis induced by dextran sulfate sodium in mice. To determine whether other bacteria composing the microbiota are able to produce C18-3OH, we targeted the gut microbiota of mice with prebiotic fructooligosaccharides (FOS). The anti-inflammatory properties of FOS were associated with an increase in colonic C18-3OH concentration. Microbiota analyses revealed that the concentration of C18-3OH was correlated with an increase in the abundance in Allobaculum, Holdemanella and Parabacteroides. In culture, Holdemanella biformis produced high concentration of C18-3OH. Finally, using TR-FRET binding assay and gene expression analysis, we demonstrated that the C18-3OH is an agonist of peroxisome proliferator activated receptor gamma.ConclusionThe production of C18-3OH by bacteria could be one of the mechanisms implicated in the anti-inflammatory properties of probiotics. The production of LCFA-3OH by bacteria could be implicated in the microbiota/host interactions.</jats:sec

The Genotoxin Colibactin Exacerbates Lymphopenia and Decreases Survival Rate in Mice Infected With Septicemic Escherichia coli

International audienceSepsis is a life-threatening infection. Escherichia coli is the first known cause of bacteremia leading to sepsis. Lymphopenia was shown to predict bacteremia better than conventional markers of infection. The pks genomic island, which is harbored by extraintestinal pathogenic E. coli (ExPEC) and encodes the genotoxin colibactin, is epidemiologically associated with bacteremia. To investigate a possible relationship between colibactin and lymphopenia, we examined the effects of transient infection of lymphocytes with bacteria that were and those that were not producing the genotoxin. A mouse model of sepsis was used to compare the virulence of a clinical ExPEC isolate with its isogenic mutant impaired for the production of colibactin. We observed that colibactin induced double-strand breaks in the DNA of infected lymphocytes, leading to cell cycle arrest and to cell death by apoptosis. E. coli producing colibactin induced a more profound lymphopenia in septicemic mice, compared with the isogenic mutant unable to produce colibactin. In a sepsis model in which the mice were treated by rehydration and antibiotics, the production of colibactin by the bacteria was associated with a significantly lower survival rate. In conclusion, we demonstrate that production of colibactin by E. coli exacerbates lymphopenia associated with septicemia and could impair the chances to survive sepsis

Bacteria-derived long chain fatty acid exhibits anti-inflammatory properties in colitis.

OBJECTIVE: Data from clinical research suggest that certain probiotic bacterial strains have the potential to modulate colonic inflammation. Nonetheless, these data differ between studies due to the probiotic bacterial strains used and the poor knowledge of their mechanisms of action. DESIGN: By mass-spectrometry, we identified and quantified free long chain fatty acids (LCFAs) in probiotics and assessed the effect of one of them in mouse colitis. RESULTS: Among all the LCFAs quantified by mass spectrometry in Escherichia coli Nissle 1917 (EcN), a probiotic used for the treatment of multiple intestinal disorders, the concentration of 3-hydroxyoctadecaenoic acid (C18-3OH) was increased in EcN compared with other E. coli strains tested. Oral administration of C18-3OH decreased colitis induced by dextran sulfate sodium in mice. To determine whether other bacteria composing the microbiota are able to produce C18-3OH, we targeted the gut microbiota of mice with prebiotic fructooligosaccharides (FOS). The anti-inflammatory properties of FOS were associated with an increase in colonic C18-3OH concentration. Microbiota analyses revealed that the concentration of C18-3OH was correlated with an increase in the abundance in Allobaculum, Holdemanella and Parabacteroides. In culture, Holdemanella biformis produced high concentration of C18-3OH. Finally, using TR-FRET binding assay and gene expression analysis, we demonstrated that the C18-3OH is an agonist of peroxisome proliferator activated receptor gamma. CONCLUSION: The production of C18-3OH by bacteria could be one of the mechanisms implicated in the anti-inflammatory properties of probiotics. The production of LCFA-3OH by bacteria could be implicated in the microbiota/host interactions

Fossil associations from the middle and upper eocene strata of the pamplona basin and surrounding areas (navarre, western pyrenees)

Se describen las asociaciones fósiles del Eoceno medio y superior (Bartoniense y Priaboniense) de la sucesión sedimentaria de la Cuenca de Pamplona. Esta sucesión se acumuló en la parte oeste de la Cuenca de antepaís periférica surpirenaica y comprende desde turbiditas marinas profundas (Formación Areniscas de Ezkaba) hasta depósitos deltaicos (Formaciones Margas de Pamplona, Areniscas de Ardanatz y Margas de Ilundain) y marinos marginales (Formación Gendulain). El contenido micropaleontológico es alto y está dominado por los foraminíferos. Los fósiles de ostrácodos y otros organismos son también abundantes. Las asociaciones de icnofósiles incluyen al menos 23 icnogéneros y 28 ichnoespecies, indicativas de las icnofacies de Nereites, Cruziana, y ?Scoyenia-Mermia. Se han identificado fósiles corporales de unos 80 taxones, correspondientes a macroforaminíferos, esponjas, corales, briozoos, braquiópodos, anélidos, moluscos, artrópodos, equinodermos y vertebrados. El número de icnotaxones y de especies (p. e. briozoos, moluscos gasterópodos, bivalvos y peces condríctios) puede ser considerablemente mayor. Las asociaciones de fósiles corporales son comparables a las del Eoceno del Área norpirenaica (Costa vasca) y de las partes central y este del Área surpirenaica (Aragón y Cataluña). A escala europea, la asociación de moluscos parece endémica del Área pirenaica, aunque contiene elementos del Tetis (Italia y Alpes) y de las cuencas del norte (Cuenca de París y Normandía). El contenido paleontológico de las unidades sedimentarias analizadas es coherente con el proceso de somerización que tiene lugar a lo largo del Eoceno medio y tardío, de acuerdo con lo que indican los datos sedimentológicos y estratigráficos.Fossil associations from the middle and upper Eocene (Bartonian and Priabonian) sedimentary succession of the Pamplona Basin are described. This succession was accumulated in the western part of the South Pyrenean peripheral foreland basin and extends from deep-marine turbiditic (Ezkaba Sandstone Formation) to deltaic (Pamplona Marl, Ardanatz Sandstone and Ilundain Marl formations) and marginal marine deposits (Gendulain Formation). The micropalaeontological content is high. It is dominated by foraminifera, and common ostracods and other microfossils are also present. The fossil ichnoasssemblages include at least 23 ichnogenera and 28 ichnospecies indicative of Nereites, Cruziana, and ?Scoyenia-Mermia ichnofacies. Body macrofossils of about 80 taxa corresponding to macroforaminifera, sponges, corals, bryozoans, brachiopods, annelids, molluscs, arthropods, echinoderms and vertebrates have been identified. Both the number of ichnotaxa and of species (e. g. bryozoans, molluscs and condrichthyans) may be considerably higher. Body fossil assemblages are comparable to those from the Eocene of the Nord Pyrenean area (Basque Coast), and also to those from the Eocene of the west-central and eastern part of South Pyrenean area (Aragon and Catalonia). At the European scale, the molluscs assemblages seem endemic from the Pyrenean area, although several Tethyan (Italy and Alps) and Northern elements (Paris Basin and Normandy) have been recorded. Palaeontological data of studied sedimentary units fit well with the shallowing process that throughout the middle and late Eocene occurs in the area, according to the sedimentological and stratigraphical data.Fil: Astibia, H.. Universidad del País Vasco; EspañaFil: Payros, A.. Universidad del País Vasco; EspañaFil: Ortiz, S.. Petrostrat Limited; Reino UnidoFil: Elorza, J.. Universidad del País Vasco; EspañaFil: Álvarez Pérez, G.. Universidad de Barcelona; EspañaFil: Badiola, A.. Universidad del País Vasco; EspañaFil: Bardet, N.. Muséum National Dhistoire Naturelle; FranciaFil: Berreteaga, A.. Universidad del País Vasco; EspañaFil: Bitner, M. A.. Polish Academy Of Science; PoloniaFil: Calzada, S.. Museu Geòlogic del Seminari de Barcelona; EspañaFil: Corral, J. C.. Museo de Ciencias Naturales de Álava; EspañaFil: Díaz Martínez, Ignacio. Universidad Nacional de Río Negro. Sede Alto Valle. Instituto de Investigaciones en Paleobiología y Geología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigación en Paleobiología y Geología; ArgentinaFil: Merle, D.. Muséum National Dhistoire Naturelle; FranciaFil: Pacaud, J. M.. Muséum National Dhistoire Naturelle; FranciaFil: Pereda Suberbiola, X.. Universidad del País Vasco; EspañaFil: Pisera, A.. Polish Academy Of Science; PoloniaFil: Rodríguez Tovar, F. J.. Universidad de Granada; EspañaFil: Tosquella, J.. Universidad de Huelva; Españ