Relative impact of model quality and ensemble deficiencies on the performance of ensemble based probabilistic forecasts evaluated through the Brier score

International audienceThe relative impact of model quality and ensemble deficiencies, on the performance of ensemble based probabilistic forecasts, is investigated from a set of idealized experiments. Data are generated according to a statistical model, the validation of which is achieved by comparing generated data to ECMWF ensemble forecasts and analyses. The performance of probabilistic forecasts is evaluated through the reliability and resolution terms of the Brier score. Results are as follows. (i) Resolution appears essentially attributable to the average level of forecast skill. (ii) The lack of reliability comes primarily from forecast bias, and to a lower extent from the ensemble being systematically under-dispersive (or over-dispersive). (iii) Forecast skill contributes very little to reliability in the absence of forecast bias, and this impact is entirely due to the finiteness of the ensemble population. (iv) In the presence of forecast bias, reducing forecast skill leads to improve the reliability. This unexpected feature comes from the fact that lower forecast skill leads to a larger ensemble spread, that compensates for the strong proportion of outliers consequent to forecast bias. (v) The lack of ensemble skill, i.e. non systematic errors affecting both ensemble mean and ensemble spread, contributes little, but significantly, to the lack of reliability and resolution

Verification of intense precipitation forecasts from single models and ensemble prediction systems

International audienceThe performance of single models and ensemble prediction systems has been investigated with respect to quantitative precipitation forecasts. Evaluation is based on the potential economic value of + 72 h/ + 96 h forecasts. The verification procedure consists of taking into account all precipitation amounts that are predicted in the vicinity of an observation in order to compute spatial, multi-event contingency tables. A probabilistic forecast from an ensemble can thus be compared to a probabilistic forecast from a single model run. The main results are the following: (1) The performance of the forecasts increases with the precipitation threshold. High levels of potential value reflect high hit rates that are obtained at the expense of a high frequency of false alarms. (2) The ECMWF ensemble performs better than a single forecast based on the same model, even when the resolution of the ensemble is lower. This is true for the NCEP ensemble as well, but only for morning precipitations. (3) The ECMWF ensemble performs better than the 5-member NCEP ensemble running at 12:00 UTC, even when the population of the former is reduced to 5 members. (4) The impact of reducing the population of the ECMWF ensemble is rather small. Differences between 51 members and 21 members are hardly significant. (5) A 2-member poorman ensemble consisting of the control forecasts of the ECMWF and the NCEP ensembles performs as well as the ECMWF ensemble for afternoon precipitations

Regulation of Mammalian Physiology by Interconnected Circadian and Feeding Rhythms.

Circadian clocks are endogenous timekeeping systems that adapt in an anticipatory fashion the physiology and behavior of most living organisms. In mammals, the master pacemaker resides in the suprachiasmatic nucleus and entrains peripheral clocks using a wide range of signals that differentially schedule physiology and gene expression in a tissue-specific manner. The peripheral clocks, such as those found in the liver, are particularly sensitive to rhythmic external cues like feeding behavior, which modulate the phase and amplitude of rhythmic gene expression. Consequently, the liver clock temporally tunes the expression of many genes involved in metabolism and physiology. However, the circadian modulation of cellular functions also relies on multiple layers of posttranscriptional and posttranslational regulation. Strikingly, these additional regulatory events may happen independently of any transcriptional oscillations, showing that complex regulatory networks ultimately drive circadian output functions. These rhythmic events also integrate feeding-related cues and adapt various metabolic processes to food availability schedules. The importance of such temporal regulation of metabolism is illustrated by metabolic dysfunctions and diseases resulting from circadian clock disruption or inappropriate feeding patterns. Therefore, the study of circadian clocks and rhythmic feeding behavior should be of interest to further advance our understanding of the prevention and therapy of metabolic diseases

Mise en oeuvre d'un outil d'alerte et de cartographie temps réel des aléas naturels liés aux précipitations dans les régions montagneuses et méditerranéennes du Sud-Est de la France

International audienceDue to its mountainous topography and its Mediterranean climate, the Provence-Alpes-Côte d'Azur (PACA) region in Southeastern France is particularly prone to flash floods, debris flows and mass movements (landslides and rockfall). A mapping system for these rainfall induced hazards has been tested by local and regional authorities and Government agencies since 2011 as part of the RHYTMME project. This system allows, thank to radar rainfall estimation and rainfall-runoff modelling, the real-time warning and monitoring of flash floods wherever they may occur in the PACA territory. It is also intended to enable, during intense rainfall events, the localisation of the streams susceptible to generate debris flows and of the slopes the more likely to trigger landslides and/or rockfalls

Nuclear Proteomics Uncovers Diurnal Regulatory Landscapes in Mouse Liver.

Diurnal oscillations of gene expression controlled by the circadian clock and its connected feeding rhythm enable organisms to coordinate their physiologies with daily environmental cycles. While available techniques yielded crucial insights into regulation at the transcriptional level, much less is known about temporally controlled functions within the nucleus and their regulation at the protein level. Here, we quantified the temporal nuclear accumulation of proteins and phosphoproteins from mouse liver by SILAC proteomics. We identified around 5,000 nuclear proteins, over 500 of which showed a diurnal accumulation. Parallel analysis of the nuclear phosphoproteome enabled the inference of the temporal activity of kinases accounting for rhythmic phosphorylation. Many identified rhythmic proteins were parts of nuclear complexes involved in transcriptional regulation, ribosome biogenesis, DNA repair, and the cell cycle and its potentially associated diurnal rhythm of hepatocyte polyploidy. Taken together, these findings provide unprecedented insights into the diurnal regulatory landscape of the mouse liver nucleus

Circadian and Feeding Rhythms Orchestrate the Diurnal Liver Acetylome.

Lysine acetylation is involved in various biological processes and is considered a key reversible post-translational modification in the regulation of gene expression, enzyme activity, and subcellular localization. This post-translational modification is therefore highly relevant in the context of circadian biology, but its characterization on the proteome-wide scale and its circadian clock dependence are still poorly described. Here, we provide a comprehensive and rhythmic acetylome map of the mouse liver. Rhythmic acetylated proteins showed subcellular localization-specific phases that correlated with the related metabolites in the regulated pathways. Mitochondrial proteins were over-represented among the rhythmically acetylated proteins and were highly correlated with SIRT3-dependent deacetylation. SIRT3 activity being nicotinamide adenine dinucleotide (NAD) <sup>+</sup> level-dependent, we show that NAD <sup>+</sup> is orchestrated by both feeding rhythms and the circadian clock through the NAD <sup>+</sup> salvage pathway but also via the nicotinamide riboside pathway. Hence, the diurnal acetylome relies on a functional circadian clock and affects important diurnal metabolic pathways in the mouse liver

Calibrating ensemble reliability whilst preserving spatial structure

Ensemble forecasts aim to improve decision-making by predicting a set of possible outcomes. Ideally, these would provide probabilities which are both sharp and reliable. In practice, the models, data assimilation and ensemble perturbation systems are all imperfect, leading to deficiencies in the predicted probabilities. This paper presents an ensemble post-processing scheme which directly targets local reliability, calibrating both climatology and ensemble dispersion in one coherent operation. It makes minimal assumptions about the underlying statistical distributions, aiming to extract as much information as possible from the original dynamic forecasts and support statistically awkward variables such as precipitation. The output is a set of ensemble members preserving the spatial, temporal and inter-variable structure from the raw forecasts, which should be beneficial to downstream applications such as hydrological models. The calibration is tested on three leading 15-d ensemble systems, and their aggregation into a simple multimodel ensemble. Results are presented for 12 h, 1° scale over Europe for a range of surface variables, including precipitation. The scheme is very effective at removing unreliability from the raw forecasts, whilst generally preserving or improving statistical resolution. In most cases, these benefits extend to the rarest events at each location within the 2-yr verification period. The reliability and resolution are generally equivalent or superior to those achieved using a Local Quantile-Quantile Transform, an established calibration method which generalises bias correction. The value of preserving spatial structure is demonstrated by the fact that 3×3 averages derived from grid-scale precipitation calibration perform almost as well as direct calibration at 3×3 scale, and much better than a similar test neglecting the spatial relationships. Some remaining issues are discussed regarding the finite size of the output ensemble, variables such as sea-level pressure which are very reliable to start with, and the best way to handle derived variables such as dewpoint depression

Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease Progression

BACKGROUND:Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs). While current treatment therapies are limited, a few drugs tested in Npc1(-/-) mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) and allopregnanolone, we noted increased lifespan for Npc1(-/-) mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD), the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit. METHODOLOGY/PRINCIPAL FINDINGS:Administration of CD to Npc1(-/-) mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/-) mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage. CONCLUSIONS/SIGNIFICANCE:Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/-) and Npc2(-/-) mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis

Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids.

Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism