p53 requires the stress sensor USF1 to direct appropriate cell fate decision

Genomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway

Climat et biocontamination. Études de cas d’archives

Following problems of microbiological contamination of documents in archives, we were repeatedly appointed to evaluate the biocontamination levels and propose recommendations and solutions. It is from the study of both climate and biocontamination that we were able, in most of the cases, to relate the observed fungal situations to their likely causes. We present in this article two cases which seemed to us interesting and complementary: the consequences of dysfunctions of an air handling system and the instability of climates produced by a Mechanical Extract Ventilation system. Even if the fungal situations seem identical, causes of fungal growth can vary greatly. Thus, it is essential to go back up to the origins of the dysfunctions and climate instabilities. The microbiological study states levels of viable species on documents, in environment and in the ambient air. It localizes the areas of strong concentration that it connects directly to the microclimate data collected in the storerooms. Thus while leaning on the study of the microclimates, on the analysis of climate-related events in archives and environmental weather conditions one can hope to determine the factors of contamination

Demographic stochasticity drives epidemiological patterns in wildlife with implications for diseases and population management

Abstract Infectious diseases raise many concerns for wildlife and new insights must be gained to manage infected populations. Wild ungulates provide opportunities to gain such insights as they host many pathogens. Using modelling and data collected from an intensively monitored population of Pyrenean chamois, we investigated the role of stochastic processes in governing epidemiological patterns of pestivirus spread in both protected and hunted populations. We showed that demographic stochasticity led to three epidemiological outcomes: early infection fade-out, epidemic outbreaks with population collapse, either followed by virus extinction or by endemic situations. Without re-introduction, the virus faded out in >50% of replications within 4 years and did not persist >20 years. Test-and-cull of infected animals and vaccination had limited effects relative to the efforts devoted, especially in hunted populations in which only quota reduction somewhat improve population recovery. Success of these strategies also relied on the maintenance of a high level of surveillance of hunter-harvested animals. Our findings suggested that, while surveillance and maintenance of population levels at intermediate densities to avoid large epidemics are useful at any time, a ‘do nothing’ approach during epidemics could be the ‘least bad’ management strategy in populations of ungulates species facing pestivirus infection

Human TYRP1: two functions for a single gene?

International audienceIn the animal kingdom, skin pigmentation is highly variable between species, and it contributes to phenotypes. In humans, skin pigmentation plays a part in sun protection. Skin pigmentation depends on the ratio of the two pigments pheomelanin and eumelanin, both synthesized by a specialized cell population, the melanocytes. In this review, we explore one important factor in pigmentation: the tyrosinase-related protein 1 (TYRP1) gene which is involved in eumelanin synthesis via the TYRP1 protein. Counterintuitively, high TYRP1 mRNA expression is associated with a poor clinical outcome for patients with metastatic melanomas. Recently, we were able to explain this unexpected TYRP1 function by demonstrating that TYRP1 mRNA sequesters microRNA-16, a tumor suppressor miRNA. Here, we focus on actors influencing TYRP1 mRNA abundance, particularly transcription factors, single nucleotide polymorphisms (SNPs), and miRNAs, as they all dictate the indirect oncogenic activity of TYRP1

Combining seroprevalence and capture-mark-recapture data to estimate the force of infection of brucellosis in a managed population of Alpine ibex

International audienceIn wildlife, epidemiological data are often collected using cross-sectional surveys and antibody tests, and seroprevalence is the most common measure used to monitor the transmission dynamics of infectious diseases. On the contrary, the force of infection, a measure of transmission intensity that can help understand epidemiological dynamics and monitor management interventions, remains rarely used. The force of infection can be derived from age-stratified cross-sectional serological data, or from longitudinal data (although less frequently available in wildlife populations). Here, we combined seroprevalence and capture-mark-recapture data to estimate the force of infection of brucellosis in an Alpine ibex (Capra ibex) population monitored from 2012 to 2018. Because the seroprevalence of brucellosis was 38% in this population in 2012, managers conducted two culling operations in 2013 and 2015, as well as captures every year since 2012, where seronegative individuals were marked and released, and seropositive individuals were removed. We obtained two estimates of the force of infection and its changes across time, by fitting (i) a catalytic model to age-seroprevalence data obtained from unmarked animals (cross-sectional), and (ii) a survival model to event time data obtained from recaptures of marked animals (longitudinal). Using both types of data allowed us to make robust inference about the temporal dynamics of the force of infection: indeed, there was evidence for a decrease in the force of infection between mid-2014 and late 2015 in both datasets. The force of infection was estimated to be reduced from 0.115 year-1 [0.074-0.160] to 0.016 year-1 [0.001-0.057]. These results confirm that transmission intensity decreased during the study period, probably due to management interventions and natural changes in infection dynamics. Estimating the force of infection could therefore be a valuable complement to classical seroprevalence analyses to monitor the dynamics of wildlife diseases, especially in the context of ongoing disease management interventions

Estimating disease prevalence and temporal dynamics using biased capture serological data in a wildlife reservoir: The example of brucellosis in Alpine ibex (Capra ibex)

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Targeted strategies for the management of wildlife diseases: the case of brucellosis in Alpine ibex

International audienceThe management of infectious diseases in wildlife reservoirs is challenging and faces several limitations. However, detailed knowledge of host-pathogen systems often reveal heterogeneity among the hosts' contribution to transmission. Management strategies targeting specific classes of individuals and/or areas, having a particular role in transmission, could be more effective and more acceptable than population-wide interventions. In the wild population of Alpine ibex (Capra ibex-a protected species) of the Bargy massif (French Alps), females transmit brucellosis (Brucella melitensis) infection in ~90% of cases, and most transmissions occur in the central spatial units ("core area"). Therefore, we expanded an individual-based model, developed in a previous study, to test whether strategies targeting females or the core area, or both, would be more effective. We simulated the relative efficacy of realistic strategies for the studied population, combining test-and-remove (euthanasia of captured animals with seropositive test results) and partial culling of unmarked animals. Targeting females or the core area was more effective than untargeted management options, and strategies targeting both were even more effective. Interestingly, the number of ibex euthanized and culled in targeted strategies were lower than in untargeted ones, thus decreasing the conservation costs while increasing the sanitary benefits. Although there was no silver bullet for the management of brucellosis in the studied population, targeted strategies offered a wide range of promising refinements to classical sanitary measures. We therefore encourage to look for heterogeneity in other wildlife diseases and to evaluate potential strategies for improving management in terms of efficacy but also acceptability

Self-clearance of Pestivirus in a Pyrenean Chamois ( Rupicapra pyrenaica

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Self-clearance of Pestivirus in a Pyrenean Chamois ( Rupicapra pyrenaica ) Population

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Environmental determinants of spatial and temporal variations in the transmission of Toxoplasma gondii in its definitive hosts.

International audienceToxoplasmosis is a major zoonosis, and its prevention requires multiple approaches due to the complex life-cycle of its causative agent, Toxoplasma gondii. Environmental contamination by oocysts is a key factor in the transmission of T. gondii to both humans and meat-producing animals; however, its spatial and temporal variations are poorly understood. We analysed the distribution of T. gondii seropositivity in a sample of 210 cats, including the European wildcat (Felis silvestris silvestris), the domestic cat (Felis silvestris catus) and their hybrids that were collected in Central and Eastern France between 1996 and 2006. We searched for spatial variability among communes and temporal variations among years to relate this variability to landscape and meteorological conditions, which can affect the population dynamics of rodent hosts and the survival of oocysts. The overall seroprevalence was 65.2% (95% CI: 58.6-71.4). As expected, adults were more often infected than young individuals, while the occurrence of infection was not related to cat genotypes. Seroprevalence correlated significantly with farm density and the North-Atlantic Oscillation index, which describes temporal variations of meteorological conditions at the continental scale. The highest seroprevalence values were obtained in areas with high farm densities and during years with cool and moist winters. These results suggest that both farming areas and years with cool and wet winters are associated with increased T. gondii seroprevalence in cats. As cat infection determines the environmental contamination by oocysts, climate and landscape characteristics should be taken into account to improve the risk analysis and prevention of T. gondii