The role of observation uncertainty in the calibration of hydrologic rainfall-runoff models

International audienceHydrologic rainfall-runoff models are usually calibrated with reference to a limited number of recorded flood events, for which rainfall and runoff measurements are available. In this framework, model's parameters consistency depends on the number of both events and hydrograph points used for calibration, and on measurements reliability. Recently, to make users aware of application limits, major attention has been devoted to the estimation of uncertainty in hydrologic modelling. Here a simple numerical experiment is proposed, that allows the analysis of uncertainty in hydrologic rainfall-runoff modelling associated to both quantity and quality of available data. A distributed rainfall-runoff model based on geomorphologic concepts has been used. The experiment involves the analysis of an ensemble of model runs, and its overall set up holds if the model is to be applied in different catchments and climates, or even if a different hydrologic model is used. With reference to a set of 100 synthetic rainfall events characterized by a given rainfall volume, the effect of uncertainty in parameters calibration is studied. An artificial truth ? perfect observation ? is created by using the model in a known configuration. An external source of uncertainty is introduced by assuming realistic, i.e. uncertain, discharge observations to calibrate the model. The range of parameters' values able to "reproduce" the observation is studied. Finally, the model uncertainty is evaluated and discussed. The experiment gives useful indications about the number of both events and data points needed for a careful and stable calibration of a specific model, applied in a given climate and catchment. Moreover, an insight on the expected and maximum error in flood peak discharge simulations is given: errors ranging up to 40% are to be expected if parameters are calibrated on insufficient data sets

Regional scale analysis of the altimetric stream network evolution

International audienceFloods result from the limited carrying capacity of stream channels when compared to the discharge peak value. The transit of flood waves - with the associated erosion and sedimentation processes - often modifies local stream geometry. In some cases this results in a reduction of the stream carrying capacity, and consequently in an enhancement of the flooding risk. A mathematical model for the prediction of potential altimetric stream network evolution due to erosion and sedimentation processes is here formalized. It works at the regional scale, identifying the tendency of river segments to sedimentation, stability, or erosion. The model builds on geomorphologic concepts, and derives its parameters from extensive surveys. As a case study, tendencies of rivers pertaining to the Valle d'Aosta region are analyzed. Some validation is provided both at regional and local scales of analysis. Local validation is performed both through a mathematical model able to simulate the temporal evolution of the stream profile, and through comparison of the prediction with ante and post-event river surveys, where available. Overall results are strongly encouraging. Possible use of the information derived from the model in the context of flood and landslide hazard mitigation is briefly discussed

Rational design and validation of a Tip60 histone acetyltransferase inhibitor

Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer

Intratumoral CRH modulates immuno-escape of ovarian cancer cells through FasL regulation

Although corticotropin-releasing hormone (CRH) and Fas ligand (FasL) have been documented in ovarian carcinoma, a clear association with tumour progression and immuno-escape has not been established. FasL plays an important role in promoting tumour cells' ability to counterattack immune cells. Here, we examined immunohistochemically the expression of CRH, CRHR1, CRHR2 and FasL in 47 human ovarian cancer cases. The ovarian cancer cell lines OvCa3 and A2780 were further used to test the hypothesis that CRH might contribute to the immune privilege of ovarian tumours, by modulating FasL expression on the cancer cells. We found that CRH, CRHR1, CRHR2 and FasL were expressed in 68.1, 70.2, 63.8 and 63.8% of the cases respectively. Positivity for CRH or FasL expression was associated with higher tumour stage. Finally, CRH increased the expression of FasL in OvCa3 and A2780 cells through CRHR1 thereby potentiated their ability to induce apoptosis of activated peripheral blood lymphocytes. Corticotropin-releasing hormone produced by human ovarian cancer might favour survival and progression of the tumour by promoting its immune privilege. These findings support the hypothesis that CRHR1 antagonists could potentially be used against ovarian cancer