Sinemurian–Pliensbachian calcareous nannofossil biostratigraphy and organic carbon isotope stratigraphy in the Paris Basin: Calibration to the ammonite biozonation of NW Europe

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Available online 12 December 2016The biostratigraphy of Sinemurian to lower Toarcian calcareous nannofossils has been investigated in the Sancerre-Couy core (Paris Basin), which contains a mixed assemblage of species with affinities to the northern and southern areas of the peri-tethyan realm, thus allowing for the use and calibration of the Mediterranean Province (Italy/S France) and NW Europe (UK) biozonation schemes. This study is based on semi-quantitative analyses of the calcareous nannofossil assemblage performed on 145 samples and the recorded bioevents are calibrated to the NW European Ammonite Zonation and to a new organic carbon isotope curve based on 385 data points. The main bioevents, i.e. the first occurrences of Parhabdolithus liasicus, Crepidolithus pliensbachensis, Crepidolithus crassus, Mitrolithus lenticularis, Similiscutum cruciulus sensu lato, Lotharingius hauffii, Crepidolithus cavus and Lotharingius sigillatus as well as the last occurrence of Parhabdolithus robustus, have been identified. However, we show that a large number of standard biostratigraphic markers show inconsistent occurrences at the base and top of their range, possibly accounting for some of the significant discrepancies observed between the different domains. In addition to the nine main bioevents used for the biozonation of the core, we document an additional 50 distinct bioevents, evaluate their reliability and discuss their potential significance by comparison to previous studies. A total of five significant negative organic carbon isotope excursions are identified and defined in the Paris Basin including the well-documented Sinemurian–Pliensbachian boundary event. One positive excursion is further defined in the Pliensbachian interval. Our calibration of high-resolution calcareous nannofossil biostratigraphy to ammonite biostratigraphy and organic carbon isotopes represents a new stratigraphic reference for the Lower Jurassic series

Stratigraphic and environmental control on marine benthic community change through the early Toarcian extinction event (Iberian Range, Spain)

In the Early Jurassic (~183 Ma ago) global warming and associated environmental changes coincided with an extinction event in the marine realm (early Toarcian extinction event). Anoxia was previously considered to have been the main cause of extinction, but extinctions also occur at localities that remained oxygenated throughout the event, suggesting that other factors, such as temperature, may have played a major role. To test this hypothesis, we integrated quantitative analyses of benthic macro-invertebrates with high-resolution geochemical proxies on the bulk rock (TOC, δ13C, δ18O) and on belemnites and brachiopod shells (δ13C, δ18O) from two sections from the Iberian Range, Spain, with no black shale deposition. The sections are orientated SE-NW along an onshore-offshore gradient deepening to the north. The dominant benthic groups, bivalves and brachiopods, show a different response to the extinction: brachiopods go through a complete species-level turnover, while many bivalve species range through the event. In the shallower section, changes in richness and evenness correlate with TOC (Total Organic Carbon), suggesting that variations in nutrient input from runoff, and the possible local onset of low-redox conditions (TOC > 4 wt%), controlled faunal diversity. In contrast, at the deeper section, community change correlates with changes in δ18O, indicating that temperature variations might have influenced faunal change. Different stratigraphic patterns of extinction occur between the two localities, with last-occurrences clustering at the maximum flooding surface in the shallower section, and at the transgressive surface in the deeper one. The observed differences between the two localities highlight the important role of local sedimentary and stratigraphic processes in controlling the shape of the geochemical and fossil record, and the need for studying multiple sections along onshore-offshore gradients in order to extrapolate regional and global patterns

Sedimentology and carbon isotope stratigraphy of the Rhaetian Hochalm section (Late Triassic, Austria)

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordThe Rhaetian (201–209 Ma, the latest stage of the Triassic) is an important time-interval for the study of environmental changes preceding the End-Triassic Mass extinction. A detailed sedimentological and chemostratigraphic study was conducted in the lower Kössen Formation at Hochalm (Austria), the type-section of the Hochalm Member (Mb). This section exposes mid-Rhaetian sediments deposited in an intraplatform shallow marine basin on the north-western margin of the Tethys. The study highlights eight apparent shallowing-upward sequences from the middle of Unit 2 to Unit 4 of the Hochalm Mb stacked within the long-term transgression that characterizes the Kössen Formation. Both the bulk carbonate and the bulk organic matter δ13C records indicate the presence of a distinct increase in carbon isotope values in the lower part of the lower Hochalm Mb. This excursion might represent a new chemostratigraphic marker that could be used for refining the Rhaetian stratigraphy and represents another important Late Triassic carbon-cycle perturbation prior to the major disturbance associated with the End Triassic biotic crisis

The Impact of Global Warming and Anoxia on Marine Benthic Community Dynamics: an Example from the Toarcian (Early Jurassic)

The Pliensbachian-Toarcian (Early Jurassic) fossil record is an archive of natural data of benthic community response to global warming and marine long-term hypoxia and anoxia. In the early Toarcian mean temperatures increased by the same order of magnitude as that predicted for the near future; laminated, organic-rich, black shales were deposited in many shallow water epicontinental basins; and a biotic crisis occurred in the marine realm, with the extinction of approximately 5% of families and 26% of genera. High-resolution quantitative abundance data of benthic invertebrates were collected from the Cleveland Basin (North Yorkshire, UK), and analysed with multivariate statistical methods to detect how the fauna responded to environmental changes during the early Toarcian. Twelve biofacies were identified. Their changes through time closely resemble the pattern of faunal degradation and recovery observed in modern habitats affected by anoxia. All four successional stages of community structure recorded in modern studies are recognised in the fossil data (i.e. Stage III: climax; II: transitional; I: pioneer; 0: highly disturbed). Two main faunal turnover events occurred: (i) at the onset of anoxia, with the extinction of most benthic species and the survival of a few adapted to thrive in low-oxygen conditions (Stages I to 0) and (ii) in the recovery, when newly evolved species colonized the re-oxygenated soft sediments and the path of recovery did not retrace of pattern of ecological degradation (Stages I to II). The ordination of samples coupled with sedimentological and palaeotemperature proxy data indicate that the onset of anoxia and the extinction horizon coincide with both a rise in temperature and sea level. Our study of how faunal associations co-vary with long and short term sea level and temperature changes has implications for predicting the long-term effects of “dead zones” in modern oceans

Meneco, a Topology-Based Gap-Filling Tool Applicable to Degraded Genome-Wide Metabolic Networks

International audienceIncreasing amounts of sequence data are becoming available for a wide range of non-model organisms. Investigating and modelling the metabolic behaviour of those organisms is highly relevant to understand their biology and ecology. As sequences are often incomplete and poorly annotated, draft networks of their metabolism largely suffer from incompleteness. Appropriate gap-filling methods to identify and add missing reactions are therefore required to address this issue. However, current tools rely on phenotypic or taxonomic information, or are very sensitive to the stoichiometric balance of metabolic reactions, especially concerning the co-factors. This type of information is often not available or at least prone to errors for newly-explored organisms. Here we introduce Meneco, a tool dedicated to the topological gap-filling of genome-scale draft metabolic networks. Meneco reformulates gap-filling as a qualitative combinatorial optimization problem, omitting constraints raised by the stoichiometry of a metabolic network considered in other methods, and solves this problem using Answer Set Programming. Run on several artificial test sets gathering 10,800 degraded Escherichia coli networks Meneco was able to efficiently identify essential reactions missing in networks at high degradation rates, outperforming the stoichiometry-based tools in scalability. To demonstrate the utility of Meneco we applied it to two case studies. Its application to recent metabolic networks reconstructed for the brown algal model Ectocarpus siliculosus and an associated bacterium Candidatus Phaeomarinobacter ectocarpi revealed several candidate metabolic pathways for algal-bacterial interactions. Then Meneco was used to reconstruct, from transcriptomic and metabolomic data, the first metabolic network for the microalga Euglena mutabilis. These two case studies show that Meneco is a versatile tool to complete draft genome-scale metabolic networks produced from heterogeneous data, and to suggest relevant reactions that explain the metabolic capacity of a biological system

IRGM Is a Common Target of RNA Viruses that Subvert the Autophagy Network

Autophagy is a conserved degradative pathway used as a host defense mechanism against intracellular pathogens. However, several viruses can evade or subvert autophagy to insure their own replication. Nevertheless, the molecular details of viral interaction with autophagy remain largely unknown. We have determined the ability of 83 proteins of several families of RNA viruses (Paramyxoviridae, Flaviviridae, Orthomyxoviridae, Retroviridae and Togaviridae), to interact with 44 human autophagy-associated proteins using yeast two-hybrid and bioinformatic analysis. We found that the autophagy network is highly targeted by RNA viruses. Although central to autophagy, targeted proteins have also a high number of connections with proteins of other cellular functions. Interestingly, immunity-associated GTPase family M (IRGM), the most targeted protein, was found to interact with the autophagy-associated proteins ATG5, ATG10, MAP1CL3C and SH3GLB1. Strikingly, reduction of IRGM expression using small interfering RNA impairs both Measles virus (MeV), Hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1)-induced autophagy and viral particle production. Moreover we found that the expression of IRGM-interacting MeV-C, HCV-NS3 or HIV-NEF proteins per se is sufficient to induce autophagy, through an IRGM dependent pathway. Our work reveals an unexpected role of IRGM in virus-induced autophagy and suggests that several different families of RNA viruses may use common strategies to manipulate autophagy to improve viral infectivity

Stopping renin-angiotensin system blockers after acute kidney injury and risk of adverse outcomes: parallel population-based cohort studies in English and Swedish routine care.

BACKGROUND: The safety of restarting angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) after acute kidney injury (AKI) is unclear. There is concern that previous users do not restart ACEI/ARB despite ongoing indications. We sought to determine the risk of adverse events after an episode of AKI, comparing prior ACEI/ARB users who stop treatment to those who continue. METHODS: We conducted two parallel cohort studies in English and Swedish primary and secondary care, 2006-2016. We used multivariable Cox regression to estimate hazard ratios (HR) for hospital admission with heart failure (primary analysis), AKI, stroke, or death within 2 years after hospital discharge following a first AKI episode. We compared risks of admission between people who stopped ACEI/ARB treatment to those who were prescribed ACEI/ARB within 30 days of AKI discharge. We undertook sensitivity analyses, including propensity score-matched samples, to explore the robustness of our results. RESULTS: In England, we included 7303 people with AKI hospitalisation following recent ACEI/ARB therapy for the primary analysis. Four thousand three (55%) were classified as stopping ACEI/ARB based on no prescription within 30 days of discharge. In Sweden, we included 1790 people, of whom 1235 (69%) stopped treatment. In England, no differences were seen in subsequent risk of heart failure (HR 1.10; 95% confidence intervals (CI) 0.93-1.30), AKI (HR 0.90; 95% CI 0.77-1.05), or stroke (HR 0.99; 95% CI 0.71-1.38), but there was an increased risk of death (HR 1.27; 95% CI 1.15-1.41) in those who stopped ACEI/ARB compared to those who continued. Results were similar in Sweden: no differences were seen in risk of heart failure (HR 0.91; 95% CI 0.73-1.13) or AKI (HR 0.81; 95% CI 0.54-1.21). However, no increased risk of death was seen (HR 0.94; 95% CI 0.78-1.13) and stroke was less common in people who stopped ACEI/ARB (HR 0.56; 95% CI 0.34-0.93). Results were similar across all sensitivity analyses. CONCLUSIONS: Previous ACEI/ARB users who continued treatment after an episode of AKI did not have an increased risk of heart failure or subsequent AKI compared to those who stopped the drugs

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient's circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails

EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation