Qualification sanitaire des troupeaux, représentations du risque selon les acteurs et les disciplines

La qualification sanitaire vise à établir de manière objective et fiable le statut sanitaire d'un animal ou d'un ensemble d'animaux au regard d'une maladie infectieuse. Concevoir une qualification sanitaire repose sur des connaissances biologiques concernant l'agent pathogène, ses voies de transmission et les moyens de détection de la maladie. Les modèles mathématiques et les outils statistiques et probabilistes permettent d'intégrer ces connaissances tout en prenant en compte l'incertitude et la variabilité des données biologiques. Les sciences humaines apportent un éclairage sur les enjeux, les perceptions et les logiques des individus et des collectifs, afin d'étudier la demande et l'acceptabilité de la qualification sanitaire. Chaque discipline apporte ainsi son point de vue sur la notion de risque sous-jacente à la démarche de qualification. Cette approche interdisciplinaire nécessite une coconstruction de la recherche, qui doit dépasser les différences culturelles et épistémologiques entre disciplines. Elle n'obéit pas à un seul type de rationalité, scientifique ou juridico-administrative ; elle mobilise nécessairement des connaissances savantes et des savoirs empiriques et dépend de nombreuses décisions pouvant engendrer convergences ou contradictions. (Résumé d'auteur

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Lmx1a is a Novel Regulator of Drosophila Ovarian Stem Cell Niche Establishment and Ovary Morphogenesis

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2018.The Drosophila ovary has served as a model for pioneering studies of the interaction between stem cells and their niches, with defined cell types and signaling pathways contributing to the regulation and maintenance of both germline and somatic stem cells in individual ovarioles. The most crucial component of the Drosophila ovarian niche is the terminal filament-cap structure (TF-cap), which is a stack of cells central not only for adult stem cell regulation, but also the coordinated morphogenesis of the ovary. While the function of these ovarian niches has been extensively studied, the genetics underlying their development remains largely unknown. Here we show that a highlyconserved LIM-homeobox transcription factor, Lmx1a, is required specifically for Drosophila ovary morphogenesis. We found that Lmx1a is expressed in early ovarian somatic lineages and that its expression is progressively restricted to terminal filaments and cap cells. Without Lmx1a, the cells comprising TF-cap structures are not fully specified and fail to form proper stacks. This results in the failure of the muscle sheaths to develop, an almost complete absence of ovaries, and sterility by adulthood. We further show that Lmx1a is required specifically in terminal filaments at the time of their formation, is controlled by key transcription factors necessary for ovarian morphogenesis and regulates several conserved signaling pathways essential to stem cell niche development and function. Strikingly, we found that expression of chicken Lmx1b, an ortholog of Drosophila Lmx1a, is sufficient to rescue the null Lmx1a phenotype, indicating functional conservation across the animal kingdom. In mammals, Lmx1a and Lmx1b are known to be essential to several developing and adult tissues, with involvement in several human diseases, including Parkinson’s Disease, Nail-Patella syndrome and multiple forms of cancer, including ovarian carcinoma. Consistent with such pleiotropic requirements, we provide evidence that Drosophila Lmx1a and Lmx1b also play roles in multiple other tissues, including the nervous system and the gut. These results will expand our understanding not only of how stem cell niche units are established, but also of the mechanisms through which LIM-HD factors serve as core mediators of tissue morphogenesis and contribute to patholog

Misregulation of an Adaptive Metabolic Response Contributes to the Age-Related Disruption of Lipid Homeostasis in Drosophila

Loss of metabolic homeostasis is a hallmark of aging and is commonly characterized by the deregulation of adaptive signaling interactions that coordinate energy metabolism with dietary changes. The mechanisms driving age-related changes in these adaptive responses remain unclear. Here, we characterize the deregulation of an adaptive metabolic response and the development of metabolic dysfunction in the aging intestine of Drosophila. We find that activation of the insulin-responsive transcription factor Foxo in intestinal enterocytes is required to inhibit the expression of evolutionarily conserved lipases as part of a metabolic response to dietary changes. This adaptive mechanism becomes chronically activated in the aging intestine, mediated by changes in Jun-N-terminal kinase (JNK) signaling. Age-related chronic JNK/Foxo activation in enterocytes is deleterious, leading to sustained repression of intestinal lipase expression and the disruption of lipid homeostasis. Changes in the regulation of Foxo-mediated adaptive responses thus contribute to the age-associated breakdown of metabolic homeostasis

Role of Tis11 in Drosophila Intestinal Stem Cell Function

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2016.Many tissues contain a population of adult stem cells whose function is precisely regulated to promote tissue homeostasis. Tissues whose stem cells fail to respond to regenerative cues atrophy, while stem cells that are continuously proliferating can promote hyperproliferative diseases. Therefore, an understanding of the precise regulation of adult stem cell function will lead to insights on how these adult stem cells function to maintain healthy tissues. Many adult stem cells exhibit a proliferative plasticity where their proliferation rates dynamically increase in response to damage to their resident tissue. For these adult stem cells, a critical part of maintaining tissue homeostasis is the reacquisition of basal proliferation rates after the tissue has been repaired. Currently, little is known about the molecular mechanisms that promote the restoration of basal proliferation rates. Here I show that Tis11, an Adenine-uridine Rich Element (ARE) binding protein that promotes mRNA degradation, is required to re-establish basal proliferation rates in the Drosophila intestinal epithelium after regenerative episodes. Through lineage tracing techniques and detailed kinetic studies of the ISC regenerative response, I find Tis11 functions cell autonomously to limit ISC proliferation. I also find that Tis11 is dynamically regulated, as its expression and activity is increased in ISCs during tissue repair. Furthermore, promoting defects in mRNA stability independent of Tis11 activity also limits ISC proliferation rates. This observation along with the finding that clone size of Tis11 gain-of-function ISCs can be rescued by simultaneously making them deficient in RNA degradation support that Tis11 is functioning in ISCs by promoting mRNA decay. Based on transcriptome and RNA immunoprecipitation data, I propose that Tis11 activation represents an integral part of a negative feedback mechanism that limits the expression of several components of pro-mitotic signaling pathways. Our results identify Tis11 mediated mRNA decay as a new, evolutionarily conserved mechanism of re-establishing the basal proliferation rates of stem cells in regenerating tissues

ERF Nuclear Shuttling, a Continuous Monitor of Erk Activity That Links It to Cell Cycle Progression

The ets domain transcriptional repressor ERF is an effector of the receptor tyrosine kinase/Ras/Erk pathway, which, it has been suggested, is regulated by subcellular localization as a result of Erk-dependent phosphorylation and is capable of suppressing cell proliferation and ras-induced tumorigenicity. Here, we analyze the effect of ERF phosphorylation on nuclear import and export, the timing of its phosphorylation and dephosphorylation in relation to its subcellular location, Erk activity, and the requirements for ERF-induced cell cycle arrest. Our findings indicate that ERF continuously shuttles between the nucleus and the cytoplasm and that both phosphorylation and dephosphorylation of ERF occur within the nucleus. While nuclear import is not affected by phosphorylation, ERF nuclear export and cytoplasmic release require multisite phosphorylation and dephosphorylation. ERF export is CRM1 dependent, although ERF does not have a detectable nuclear export signal. ERF phosphorylation and export correlate with the levels of nuclear Erk activity. The cell cycle arrest induced by nonphosphorylated ERF requires the wild-type retinoblastoma protein and can be suppressed by overexpression of cyclin. These data suggest that ERF may be a very sensitive and constant sensor of Erk activity that can affect cell cycle progression through G(1), providing another link between the Ras/Erk pathway and cellular proliferation

Notch-Mediated Suppression of TSC2 Expression Regulates Cell Differentiation in the <em>Drosophila</em> Intestinal Stem Cell Lineage

<div><p>Epithelial homeostasis in the posterior midgut of <em>Drosophila</em> is maintained by multipotent intestinal stem cells (ISCs). ISCs self-renew and produce enteroblasts (EBs) that differentiate into either enterocytes (ECs) or enteroendocrine cells (EEs) in response to differential Notch (N) activation. Various environmental and growth signals dynamically regulate ISC activity, but their integration with differentiation cues in the ISC lineage remains unclear. Here we identify Notch-mediated repression of Tuberous Sclerosis Complex 2 (TSC2) in EBs as a required step in the commitment of EBs into the EC fate. The TSC1/2 complex inhibits TOR signaling, acting as a tumor suppressor in vertebrates and regulating cell growth. We find that TSC2 is expressed highly in ISCs, where it maintains stem cell identity, and that N-mediated repression of TSC2 in EBs is required and sufficient to promote EC differentiation. Regulation of TSC/TOR activity by N signaling thus emerges as critical for maintenance and differentiation in somatic stem cell lineages.</p> </div

Assessing Carnivorous Plants for the Production of Recombinant Proteins

The recovery of recombinant proteins from plant tissues is an expensive and time-consuming process involving plant harvesting, tissue extraction, and subsequent protein purification. The downstream process costs can represent up to 80% of the total cost of production. Secretion-based systems of carnivorous plants might help circumvent this problem. Drosera and Nepenthes can produce and excrete out of their tissues a digestive fluid containing up to 200 mg. L-1 of natural proteins. Based on the properties of these natural bioreactors, we have evaluated the possibility to use carnivorous plants for the production of recombinant proteins. In this context, we have set up original protocols of stable and transient genetic transformation for both Drosera and Nepenthes sp. The two major drawbacks concerning the proteases naturally present in the secretions and a polysaccharidic network composing the Drosera glue were overcome by modulating the pH of the plant secretions. At alkaline pH, digestive enzymes are inactive and the interactions between the polysaccharidic network and proteins in the case of Drosera are subdued allowing the release of the recombinant proteins. For D. capensis, a concentration of 25 μg of GFP/ml of secretion (2% of the total soluble proteins from the glue) was obtained for stable transformants. For N. alata, a concentration of 0.5 ng of GFP/ml secretions (0.5% of total soluble proteins from secretions) was reached, corresponding to 12 ng in one pitcher after 14 days for transiently transformed plants. This plant-based expression system shows the potentiality of biomimetic approaches leading to an original production of recombinant proteins, although the yields obtained here were low and did not allow to qualify these plants for an industrial platform project