Fast learning rates in statistical inference through aggregation

We develop minimax optimal risk bounds for the general learning task consisting in predicting as well as the best function in a reference set $\mathcal{G}$ up to the smallest possible additive term, called the convergence rate. When the reference set is finite and when $n$ denotes the size of the training data, we provide minimax convergence rates of the form $C(\frac{\log|\mathcal{G}|}{n})^v$ with tight evaluation of the positive constant $C$ and with exact $0<v\le1$, the latter value depending on the convexity of the loss function and on the level of noise in the output distribution. The risk upper bounds are based on a sequential randomized algorithm, which at each step concentrates on functions having both low risk and low variance with respect to the previous step prediction function. Our analysis puts forward the links between the probabilistic and worst-case viewpoints, and allows to obtain risk bounds unachievable with the standard statistical learning approach. One of the key ideas of this work is to use probabilistic inequalities with respect to appropriate (Gibbs) distributions on the prediction function space instead of using them with respect to the distribution generating the data. The risk lower bounds are based on refinements of the Assouad lemma taking particularly into account the properties of the loss function. Our key example to illustrate the upper and lower bounds is to consider the $L_q$-regression setting for which an exhaustive analysis of the convergence rates is given while $q$ ranges in $[1;+\infty[$.Comment: Published in at http://dx.doi.org/10.1214/08-AOS623 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

DNA-encoded nucleosome occupancy is associated with transcription levels in the human malaria parasite Plasmodium falciparum.

BackgroundIn eukaryotic organisms, packaging of DNA into nucleosomes controls gene expression by regulating access of the promoter to transcription factors. The human malaria parasite Plasmodium falciparum encodes relatively few transcription factors, while extensive nucleosome remodeling occurs during its replicative cycle in red blood cells. These observations point towards an important role of the nucleosome landscape in regulating gene expression. However, the relation between nucleosome positioning and transcriptional activity has thus far not been explored in detail in the parasite.ResultsHere, we analyzed nucleosome positioning in the asexual and sexual stages of the parasite's erythrocytic cycle using chromatin immunoprecipitation of MNase-digested chromatin, followed by next-generation sequencing. We observed a relatively open chromatin structure at the trophozoite and gametocyte stages, consistent with high levels of transcriptional activity in these stages. Nucleosome occupancy of genes and promoter regions were subsequently compared to steady-state mRNA expression levels. Transcript abundance showed a strong inverse correlation with nucleosome occupancy levels in promoter regions. In addition, AT-repeat sequences were strongly unfavorable for nucleosome binding in P. falciparum, and were overrepresented in promoters of highly expressed genes.ConclusionsThe connection between chromatin structure and gene expression in P. falciparum shares similarities with other eukaryotes. However, the remarkable nucleosome dynamics during the erythrocytic stages and the absence of a large variety of transcription factors may indicate that nucleosome binding and remodeling are critical regulators of transcript levels. Moreover, the strong dependency between chromatin structure and DNA sequence suggests that the P. falciparum genome may have been shaped by nucleosome binding preferences. Nucleosome remodeling mechanisms in this deadly parasite could thus provide potent novel anti-malarial targets

NOrMAL: accurate nucleosome positioning using a modified Gaussian mixture model

Motivation: Nucleosomes are the basic elements of chromatin structure. They control the packaging of DNA and play a critical role in gene regulation by allowing physical access to transcription factors. The advent of second-generation sequencing has enabled landmark genome-wide studies of nucleosome positions for several model organisms. Current methods to determine nucleosome positioning first compute an occupancy coverage profile by mapping nucleosome-enriched sequenced reads to a reference genome; then, nucleosomes are placed according to the peaks of the coverage profile. These methods are quite accurate on placing isolated nucleosomes, but they do not properly handle more complex configurations. Also, they can only provide the positions of nucleosomes and their occupancy level, whereas it is very beneficial to supply molecular biologists additional information about nucleosomes like the probability of placement, the size of DNA fragments enriched for nucleosomes and/or whether nucleosomes are well positioned or ‘fuzzy’ in the sequenced cell sample

Influence de stress oxydatifs sur la biosynthèse de mycotoxines de Fusarium spp. Contaminantes de l'épi de Maïs.

Fusarium est un champignon responsable de la fusariose, maladie nécrosante observée chez de nombreuses céréales et le maïs. Certaines espèces fusariennes sont également productrices de mycotoxines, métabolites secondaires extrêmement stables dont les toxicités pour l'homme et les animaux sont largement décrites. Ces biosynthèses interviennent avant la récolte et entraînent la contamination des grains de céréales. A l'heure actuelle, il n'existe pas de procédé permettant d'éliminer les mycotoxines ni même de réduire leurs toxicités. Ainsi, limiter l'occurrence des mycotoxines sur les grains de céréales implique de limiter leurs productions au champ. Parmi les facteurs susceptibles de moduler les productions de toxines par Fusarium, la nature du substrat, dans notre cas les composés du grain de maïs, pourrait être déterminante. De façon plus précise, les molécules pro ou anti-oxydantes impliquées dans les mécanismes de défense de la plante en réponse à l'attaque par un pathogène sont-elles susceptibles d'influencer la biosynthèse de mycotoxines ? Le rôle central et ubiquitaire de H2O2 lors de la mise en place des mécanismes de défense de la plante nous a conduit à détailler les effets potentiels in vitro de H2O2 sur la production de toxines de la famille des trichothécènes de type B (TCTB) par Fusarium graminearum et Fusarium culmorum. Les effets d'autres composés pro- ou anti-oxydants impliqués ou non dans les mécanismes de défense de la plante ont également été testés. Après une phase de mise au point méthodologique, l'ensemble de nos résultats a permis de mettre en évidence l'existence d'un lien important entre la biosynthèse de TCTB et le métabolisme oxydatif fongique. De plus, il semblerait que la nature de ce lien dépende du type de TCTB considéré. Une approche transcriptomique locale sur des gènes Tri a permis de conclure à l'implication de régulations transcriptionnelles dans les modulations de la production de TCTB en conditions de stress oxydatifs. Une approche transcriptomique globale devrait, à terme, permettre d'identifier des voies métaboliques liées à celle de la production de toxines.Fusarium is a fungus that causes tissue necrosis on many cereals and corn. Several species can also produce mycotoxins, very stable secondary metabolites which toxicities for human beings and animals are widely illustrated. These biosynthesis take place before harvest and lead to kernel contamination. Nowadays, no process exists that could allow neither to remove the toxins nor to reduce their toxicities. Therefore, limiting toxins occurrences in kernels implies limiting their production in the field, before harvest. Among the factors liable to modulate toxins productions by Fusarium, the substrate composition, in our case corn kernel composition, could be decisive. More precisely, are pro- or anti-oxidant molecules involved in plant defence mechanisms against a pathogen attack likely to influence the biosynthesis of mycotoxins? The central and ubiquitous role of H2O2 when plant defence mechanisms are triggered leaded us to look in detail at possible effects of H2O2 on the production of toxins that belong to the type B trichothecenes family (TCTB) by Fusarium graminearum and Fusarium culmorum. Effects of other pro- or anti-oxidant compounds, involved or not in plant defence mechanisms, were tested as well. After a period of methods adjustments, our results allowed us to observe a link between TCTB biosynthesis and the oxidative metabolism of the fungus. Furthermore, this link seems to be different depending on the type of TCTB that is considered. A local transcriptomic approach on Tri genes allowed us to conclude to transcriptional regulations occurring when situations of oxidative stress occur. Forward, a total transcriptomic approach should let us identify other metabolic pathways linked to toxins biosynthesis

The multifunctional autophagy pathway in the human malaria parasite, Plasmodium falciparum.

Autophagy is a catabolic pathway typically induced by nutrient starvation to recycle amino acids, but can also function in removing damaged organelles. In addition, this pathway plays a key role in eukaryotic development. To date, not much is known about the role of autophagy in apicomplexan parasites and more specifically in the human malaria parasite Plasmodium falciparum. Comparative genomic analysis has uncovered some, but not all, orthologs of autophagy-related (ATG) genes in the malaria parasite genome. Here, using a genome-wide in silico analysis, we confirmed that ATG genes whose products are required for vesicle expansion and completion are present, while genes involved in induction of autophagy and cargo packaging are mostly absent. We subsequently focused on the molecular and cellular function of P. falciparum ATG8 (PfATG8), an autophagosome membrane marker and key component of the autophagy pathway, throughout the parasite asexual and sexual erythrocytic stages. In this context, we showed that PfATG8 has a distinct and atypical role in parasite development. PfATG8 localized in the apicoplast and in vesicles throughout the cytosol during parasite development. Immunofluorescence assays of PfATG8 in apicoplast-minus parasites suggest that PfATG8 is involved in apicoplast biogenesis. Furthermore, treatment of parasite cultures with bafilomycin A 1 and chloroquine, both lysosomotropic agents that inhibit autophagosome and lysosome fusion, resulted in dramatic morphological changes of the apicoplast, and parasite death. Furthermore, deep proteomic analysis of components associated with PfATG8 indicated that it may possibly be involved in ribophagy and piecemeal microautophagy of the nucleus. Collectively, our data revealed the importance and specificity of the autophagy pathway in the malaria parasite and offer potential novel therapeutic strategies

Effect of oxidant stressors and phenolic antioxidants on the ochratoxigenic fungus Aspergillus carbonarius

28 pages, 4 figures.--Article first published online: 27 FEB 2015BACKGROUND:There are few studies dealing with the relationship between oxidative stress and ochratoxin A (OTA) biosynthesis. In this work, we analyzed the effect of the oxidant stressor menadione and the antioxidants 3,5-di-tert-butyl-4-hydroxytoluene (BHT), catechin, resveratrol and a polyphenolic extract on growth, generation of reactive oxygen species (ROS), OTA production and gene expression of antioxidant enzymes of Aspergillus carbonarius. RESULTS:Exposure to menadione concentrations higher than 20 µmol L−1 led to increases in ROS and OTA levels and a decrease in growth rate. Exposure to 2.5–10 mmol L−1 BHT also led to higher ROS and OTA levels, although growth rate was only affected above 5 mmol L−1. Naturally occurring concentrations of catechin, resveratrol and polyphenolic extract barely affected growth rate, but they produced widely different effects on OTA production level depending on the antioxidant concentration used. In general, gene expression of antioxidant enzymes superoxide dismutase (SOD) and peroxiredoxin (PRX) was downregulated after exposure to oxidant and antioxidant concentrations that enhanced OTA production level. CONCLUSION:Aspergillus carbonarius responds to oxidative stress, increasing OTA production. Nevertheless, the use of naturally occurring concentrations of antioxidant phenolic compounds to reduce oxidative stress is not a valid approach by itself for OTA contamination control in grapes.A Crespo-Sempere is the recipient of an FPI fellowship from the Spanish Government. This research was supported by grants AGL2005-00707 and AGL2008-04828-C03-02 from the Spanish Government.Peer reviewe