Computational methods for studying epigenomic regulation

In the nucleus, DNA is tightly wrapped around proteins in a structure called chromatin in order to protect it from degradation. Chromatin is composed of nucleosomes which are a structure of eight histones around which the DNA is wrapped. Nucleosomes can be modified by enzymes on amino acids located on their N-terminal tails. These modifications allow the chromatin to open and close in targeted regions, providing control over gene expression. At present, chromatin immuno-precipitation (ChIP) and assay of transposase-accessible chromatin (ATAC) combined with high-throughput sequencing (ChIP-seq and ATAC-seq) are the major high-throughput methods allowing the study of histone modifications and genome-wide chromatin openness, respectively. Typically, ChIP-seq targets one histone at a time by enriching the histone-bound regions of the genome using immuno-precipitation, while ATAC-seq uses a transposase enzyme to cut the open chromatin into fragments of DNA. The DNA fragments obtained from both techniques can be sequenced and aligned against a reference genome. Once the location of the fragments is determined, the genome is scanned for significant enrichment in a process called peak calling. Differential analysis is then used to compare local enrichment-level variations between different biological conditions. Combining ChIP-seq and ATAC-seq data with other information, such as RNA-seq–derived transcriptomics data, can further help to build a comprehensive picture of the complex underlying biology. This work therefore focuses on the development of computational tools to help with the analysis of epigenomics research data. In this thesis, a robust workflow for the differential analysis of ChIP-seq and ATAC-seq data is developed and evaluated against existing tools using one synthetic dataset, two biological ChIP-seq datasets and two biological ATAC-seq datasets. RNA-seq data is then further correlated with the detected peaks. An efficient replicate-driven visualisation tool is also proposed to visualise coverage of DNA fragments on the genome, which is compared to two existing tools, highlighting its efficiency. Lastly, two studies are presented showcasing the usefulness of the differential analysis approaches in extracting knowledge in a real-life biological setting

Le portrait des agricultrices wallonnes en 2014. Comprendre les besoins des agricultrices afin de leur apporter un soutien adapté

L'objectif de la présente étude était de comprendre les préoccupations actuelles des agricultrices afin de leur apporter un soutien adapté. Cet objectif a été décliné en cinq sous-objectifs qui sont : déterminer le portrait des agricultrices, caractériser leur métier, caractériser l'exploitation sur laquelle elles travaillent, déterminer leurs besoins en lien avec leur métier, et déterminer leur niveau d'information

Correspondence

Presents letters to the editor to comment on articles in previous issues. Robert Wright's article "Faux Pas," in the October 11, 1993 issue which castigates Economic Policy Institute President Jeff Faux for his criticism of the North American Free Trade Agreement (NAFTA); Robert Wright's reply; Simon Seba Montefiore's article "Mother Dolores" in the October 4, 1993 issue; Michael Kinsley's "Trading Places" in the October 4 issue in which he criticizes the Republicans who may desert the NAFTA cause; Praise for Jacob Weisberg for finding the unpublished "Blythe Spirit," by William Faulkner, in Weisberg's September 6, 1993 article

Dynamic simulation and optimization of artificial insect-sized flapping wings for a bioinspired kinematics using a two resonant vibration modes combination

This paper addresses the design of the elastic structure of artificial wings to optimize their dynamical behaviour to reproduce insect wings kinematics. Our bioinspired kinematics is based on the original concept of using the resonant properties of the wing structure in order to combine the motion of two vibration modes, a flapping and a twisting mode, in a quadrature phase shift. Oneway of achieving this particular combination is to optimize the geometry and elastic characteristics of the flexible structure such that the two modes are successive in the eigenspectrum and close in frequency. This paper first proposes a semi-analytical model, based on assembled Euler-Bernoulli beams, to understand, compute and optimize the artificial wing dynamic vibrations. Then, using this model, it is shown that it is possible to obtain several artificial wing structures with a flapping and a twisting mode close in frequency. Finally, experimental validations are performed on micromachined insect-sized prototypes to validate the model and the concept

Two modes resonant combined motion for insect wings kinematics reproduction and lift generation

This paper presents an original concept using a two resonant vibration modes combined motion to reproduce insect wings kinematics and generate lift. The key issue is to design the geometry and the elastic characteristics of artificial wings such that a combination of flapping and twisting motions in a quadrature phase shift could be obtained. This qualitatively implies to bring the frequencies of the two resonant modes closer. For this purpose, a polymeric prototype was micromachined with a wingspan of 3 cm, flexible wings and a single actuator. An optimal wings configuration was determined with a modeling and validated through experimental modal analyses to verify the proximity of the two modes frequencies. A dedicated lift force measurement bench was developed and used to demonstrate a lift force equivalent to the prototype weight. Finally, at the maximum lift frequency, high-speed camera measurements confirmed a kinematics of the flexible wings with flapping and twisting motions in phase quadrature as expected.ANR-ASTRID CLEARFlight (ANR-13-ASTR-0012), RENATECH program, Direction Generale de l’Armement et Haut-de-France Regio

ROTS: An R package for reproducibility-optimized statistical testing

Differential expression analysis is one of the most common types of analyses performed on various biological data (e.g. RNA-seq or mass spectrometry proteomics). It is the process that detects features, such as genes or proteins, showing statistically significant differences between the sample groups under comparison. A major challenge in the analysis is the choice of an appropriate test statistic, as different statistics have been shown to perform well in different datasets. To this end, the reproducibility-optimized test statistic (ROTS) adjusts a modified t-statistic according to the inherent properties of the data and provides a ranking of the features based on their statistical evidence for differential expression between two groups. ROTS has already been successfully applied in a range of different studies from transcriptomics to proteomics, showing competitive performance against other state-of-the-art methods. To promote its widespread use, we introduce here a Bioconductor R package for performing ROTS analysis conveniently on different types of omics data. To illustrate the benefits of ROTS in various applications, we present three case studies, involving proteomics and RNA-seq data from public repositories, including both bulk and single cell data. The package is freely available from Bioconductor (https://www.bioconductor.org/packages/ROTS)

Differential ATAC-seq and ChIP-seq peak detection using ROTS

Changes in cellular chromatin states fine-tune transcriptional output and ultimately lead to phenotypic changes. Here we propose a novel application of our reproducibility-optimized test statistics (ROTS) to detect differential chromatin states (ATAC-seq) or differential chromatin modification states (ChIP-seq) between conditions. We compare the performance of ROTS to existing and widely used methods for ATAC-seq and ChIP-seq data using both synthetic and real datasets. Our results show that ROTS outperformed other commonly used methods when analyzing ATAC-seq data. ROTS also displayed the most accurate detection of small differences when modeling with synthetic data. We observed that two-step methods that require the use of a separate peak caller often more accurately called enrichment borders, whereas one-step methods without a separate peak calling step were more versatile in calling sub-peaks. The top ranked differential regions detected by the methods had marked correlation with transcriptional differences of the closest genes. Overall, our study provides evidence that ROTS is a useful addition to the available differential peak detection methods to study chromatin and performs especially well when applied to study differential chromatin states in ATAC-seq data. </p

Powell-Sabin B-splines and unstructured standard T-splines for the solution of the Kirchhoff-Love plate theory exploiting Bézier extraction

The equations that govern Kirchhoff–Love plate theory are solved using quadratic Powell–Sabin B-splines and unstructured standard T-splines. Bézier extraction is exploited to make the formulation computationally efficient. Because quadratic Powell–Sabin B-splines result in inline image-continuous shape functions, they are of sufficiently high continuity to capture Kirchhoff–Love plate theory when cast in a weak form. Unlike non-uniform rational B-splines (NURBS), which are commonly used in isogeometric analysis, Powell–Sabin B-splines do not necessarily capture the geometry exactly. However, the fact that they are defined on triangles instead of on quadrilaterals increases their flexibility in meshing and can make them competitive with respect to NURBS, as no bending strip method for joined NURBS patches is needed. This paper further illustrates how unstructured T-splines can be modified such that they are inline image-continuous around extraordinary points, and that the blending functions fulfil the partition of unity property. The performance of quadratic NURBS, unstructured T-splines, Powell–Sabin B-splines and NURBS-to-NURPS (non-uniform rational Powell–Sabin B-splines, which are obtained by a transformation from a NURBS patch) is compared in a study of a circular plat

Histone H3K4me3 breadth in hypoxia reveals endometrial core functions and stress adaptation linked to endometriosis

Trimethylation of histone H3 at lysine 4 (H3K4me3) is a marker of active promoters. Broad H3K4me3 promoter domains have been associated with cell type identity, but H3K4me3 dynamics upon cellular stress have not been well characterized. We assessed this by exposing endometrial stromal cells to hypoxia, which is a major cellular stress condition. We observed that hypoxia modifies the existing H3K4me3 marks and that promoter H3K4me3 breadth rather than height correlates with transcription. Broad H3K4me3 domains mark genes for endometrial core functions and are maintained or selectively extended upon hypoxia. Hypoxic extension of H3K4me3 breadth associates with stress adaptation genes relevant for the survival of endometrial cells including transcription factor KLF4, for which we found increased protein expression in the stroma of endometriosis lesions. These results substantiate the view on broad H3K4me3 as a marker of cell identity genes and reveal participation of H3K4me3 extension in cellular stress adaptation

Different genes interact with particulate matter and tobacco smoke exposure in affecting lung function decline in the general population

BACKGROUND: Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes. OBJECTIVES: We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures. METHODS: For 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV(1)), FEV(1) over forced vital capacity (FEV(1)/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF(25-75)) was regressed on interval exposure to particulate matter >10 microm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (p(interaction)>0.05). Replication was attempted for SNPs with MAF<10% in 3320 SAPALDIA participants without GWAS. RESULTS: On the SNP-level, rs2035268 in gene SNCA accelerated FEV(1)/FVC decline by 3.8% (p(interaction) = 2.5x10(-6)), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml p(interaction) = 9.7x10(-8)) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (p(interaction) = 3.0x10(-4)) on FEV(1)/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful. CONCLUSIONS: Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobac smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challengin