Estimation récursive des cumulants d'Ordre quatre avec application à l'identification

Les Statistiques d'Ordre Élevé (SOE) sont de plus en plus utilisées dans les applications de traitement du signal. Toutefois, des formules générales d'estimation récursive des cumulants d'ordre supérieur à trois font jusqu'à aujourd'hui défaut. Cet article comble en partie cette lacune en présentant une formule récursive pour l'estimation des cumulants d'ordre quatre. Cette formule est ensuite utilisée dans le cadre de l'identification de modèles paramétriques de type Réponse Impulsionnelle Finie (RIF). Une version moindres carrés de l'algorithme C(Q,k), basée sur cette formule, est proposée. Des résultats de simulation illustrant le comportement de cette méthode d'identification sont présentés

Mof-associated complexes have overlapping and unique roles in regulating pluripotency in embryonic stem cells and during differentiation

The histone acetyltransferase (HAT) Mof is essential for mouse embryonic stem cell (mESC) pluripotency and early development. Mof is the enzymatic subunit of two different HAT complexes, MSL and NSL. The individual contribution of MSL and NSL to transcription regulation in mESCs is not well understood. Our genome-wide analysis show that i) MSL and NSL bind to specific and common sets of expressed genes, ii) NSL binds exclusively at promoters, iii) while MSL binds in gene bodies. Nsl1 regulates proliferation and cellular homeostasis of mESCs. MSL is the main HAT acetylating H4K16 in mESCs, is enriched at many mESC-specific and bivalent genes. MSL is important to keep a subset of bivalent genes silent in mESCs, while developmental genes require MSL for expression during differentiation. Thus, NSL and MSL HAT complexes differentially regulate specific sets of expressed genes in mESCs and during differentiation

Circulating Human Eosinophils Share a Similar Transcriptional Profile in Asthma and Other Hypereosinophilic Disorders

Eosinophils are leukocytes that are released into the peripheral blood in a phenotypically mature state and are capable of being recruited into tissues in response to appropriate stimuli. Eosinophils, traditionally considered cytotoxic effector cells, are leukocytes recruited into the airways of asthma patients where they are believed to contribute to the development of many features of the disease. This perception, however, has been challenged by recent findings suggesting that eosinophils have also immunomodulatory functions and may be involved in tissue homeostasis and wound healing. Here we describe a transcriptome-based approach-in a limited number of patients and controls-to investigate the activation state of circulating human eosinophils isolated by flow cytometry. We provide an overview of the global expression pattern in eosinophils in various relevant conditions, e.g., eosinophilic asthma, hypereosinophilic dermatological diseases, parasitosis and pulmonary aspergillosis. Compared to healthy subjects, circulating eosinophils isolated from asthma patients differed in their gene expression profile which is marked by downregulation of transcripts involved in antigen presentation, pathogen recognition and mucosal innate immunity, whereas up-regulated genes were involved in response to non-specific stimulation, wounding and maintenance of homeostasis. Eosinophils from other hypereosinophilic disorders displayed a very similar transcriptional profile. Taken together, these observations seem to indicate that eosinophils exhibit non-specific immunomodulatory functions important for tissue repair and homeostasis and suggest new roles for these cells in asthma immunobiology

Hemidesmosome integrity protects the colon against colitis and colorectal cancer

OBJECTIVE: Epidemiological and clinical data indicate that patients suffering from IBD with long-standing colitis display a higher risk to develop colorectal high-grade dysplasia. Whereas carcinoma invasion and metastasis rely on basement membrane (BM) disruption, experimental evidence is lacking regarding the potential contribution of epithelial cell/BM anchorage on inflammation onset and subsequent neoplastic transformation of inflammatory lesions. Herein, we analyse the role of the alpha6beta4 integrin receptor found in hemidesmosomes that attach intestinal epithelial cells (IECs) to the laminin-containing BM. DESIGN: We developed new mouse models inducing IEC-specific ablation of alpha6 integrin either during development (alpha6DeltaIEC) or in adults (alpha6DeltaIEC-TAM). RESULTS: Strikingly, all alpha6DeltaIEC mutant mice spontaneously developed long-standing colitis, which degenerated overtime into infiltrating adenocarcinoma. The sequence of events leading to disease onset entails hemidesmosome disruption, BM detachment, IL-18 overproduction by IECs, hyperplasia and enhanced intestinal permeability. Likewise, IEC-specific ablation of alpha6 integrin induced in adult mice (alpha6DeltaIEC-TAM) resulted in fully penetrant colitis and tumour progression. Whereas broad-spectrum antibiotic treatment lowered tissue pathology and IL-1beta secretion from infiltrating myeloid cells, it failed to reduce Th1 and Th17 response. Interestingly, while the initial intestinal inflammation occurred independently of the adaptive immune system, tumourigenesis required B and T lymphocyte activation. CONCLUSIONS: We provide for the first time evidence that loss of IECs/BM interactions triggered by hemidesmosome disruption initiates the development of inflammatory lesions that progress into high-grade dysplasia and carcinoma. Colorectal neoplasia in our mouse models resemble that seen in patients with IBD, making them highly attractive for discovering more efficient therapies.PMC559510

The App-Runx1 Region Is Critical for Birth Defects and Electrocardiographic Dysfunctions Observed in a Down Syndrome Mouse Model

Down syndrome (DS) leads to complex phenotypes and is the main genetic cause of birth defects and heart diseases. The Ts65Dn DS mouse model is trisomic for the distal part of mouse chromosome 16 and displays similar features with post-natal lethality and cardiovascular defects. In order to better understand these defects, we defined electrocardiogram (ECG) with a precordial set-up, and we found conduction defects and modifications in wave shape, amplitudes, and durations in Ts65Dn mice. By using a genetic approach consisting of crossing Ts65Dn mice with Ms5Yah mice monosomic for the App-Runx1 genetic interval, we showed that the Ts65Dn viability and ECG were improved by this reduction of gene copy number. Whole-genome expression studies confirmed gene dosage effect in Ts65Dn, Ms5Yah, and Ts65Dn/Ms5Yah hearts and showed an overall perturbation of pathways connected to post-natal lethality (Coq7, Dyrk1a, F5, Gabpa, Hmgn1, Pde10a, Morc3, Slc5a3, and Vwf) and heart function (Tfb1m, Adam19, Slc8a1/Ncx1, and Rcan1). In addition cardiac connexins (Cx40, Cx43) and sodium channel sub-units (Scn5a, Scn1b, Scn10a) were found down-regulated in Ts65Dn atria with additional down-regulation of Cx40 in Ts65Dn ventricles and were likely contributing to conduction defects. All these data pinpoint new cardiac phenotypes in the Ts65Dn, mimicking aspects of human DS features and pathways altered in the mouse model. In addition they highlight the role of the App-Runx1 interval, including Sod1 and Tiam1, in the induction of post-natal lethality and of the cardiac conduction defects in Ts65Dn. These results might lead to new therapeutic strategies to improve the care of DS people

Comments on: fold change rank ordering statistics: a new method for detecting differentially expressed genes

We published a new method (BMC Bioinformatics 2014, 15:14) for searching for differentially expressed genes from two biological conditions datasets. The presentation of theorem 1 in this paper was incomplete. We received an anonymous comment about our publication that motivates the present work. Here, we present a complementary result which is necessary from the theoretical point of view to demonstrate our theorem. We also show that this result has no negative impact on our conclusions obtained with synthetic and experimental microarrays datasets

Comments on: fold change rank ordering statistics: a new method for detecting differentially expressed genes

We published a new method (BMC Bioinformatics 2014, 15:14) for searching for differentially expressed genes from two biological conditions datasets. The presentation of theorem 1 in this paper was incomplete. We received an anonymous comment about our publication that motivates the present work. Here, we present a complementary result which is necessary from the theoretical point of view to demonstrate our theorem. We also show that this result has no negative impact on our conclusions obtained with synthetic and experimental microarrays datasets

Comments on: fold change rank ordering statistics: a new method for detecting differentially expressed genes

We published a new method (BMC Bioinformatics 2014, 15:14) for searching for differentially expressed genes from two biological conditions datasets. The presentation of theorem 1 in this paper was incomplete. We received an anonymous comment about our publication that motivates the present work. Here, we present a complementary result which is necessary from the theoretical point of view to demonstrate our theorem. We also show that this result has no negative impact on our conclusions obtained with synthetic and experimental microarrays datasets

Density of points clustering, application to transcriptomic data analysis

With the increasing amount of data produced by high-throughput technologies in many fields of science, clustering has become an integral step in exploratory data analysis in order to group similar elements into classes. However, many clustering algorithms can only work properly if aided by human expertise. For example, one parameter which is crucial and often manually set is the number of clusters present in the analyzed set. We present a novel stopping rule to find the optimal number of clusters based on the comparison of the density of points inside the clusters and between them. The method is evaluated on synthetic as well as on real transcriptomic data and compared with two current methods. Finally, we illustrate its usefulness in the analysis of the expression profiles of promyelocytic cells before and after treatment with all-trans retinoic acid. Simultaneous clustering for gene regulation and absolute initial expression levels allowed the identification of numerous genes associated with signal transduction revealing the complexity of retinoic acid signaling

Systematic gene expression mapping clusters nuclear receptors according to their function in the brain

Nuclear receptors (NRs) compose a large family of transcription factors that operate at the interface between genes and environment, acting as sensors and effectors that translate endocrine and metabolic cues into well-defined gene expression programs. We report here on a systematic quantitative and anatomical expression atlas of the 49 NR genes in 104 regions of the adult mouse brain, organized in the interactive MousePat database. MousePat defines NR expression patterns to cellular resolution, a requirement for functional genomic strategies to understand the function of a highly heterogeneous and complex organ such as the brain. Using MousePat data, NR expression patterns can be clustered into anatomical and regulatory networks that delineate the role of NRs in brain functions, like the control of feeding and learning/memory. Mining the MousePat resource will improve the understanding of NR function in the brain and elucidate hierarchical networks that control behavior and whole body homeostasis