Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4.

Chromatin remodeling accompanies differentiation, however, its role in self-renewal is less well understood. We report that in Drosophila, the chromatin remodeler Kismet/CHD7/CHD8 limits intestinal stem cell (ISC) number and proliferation without affecting differentiation. Stem-cell-specific whole-genome profiling of Kismet revealed its enrichment at transcriptionally active regions bound by RNA polymerase II and Brahma, its recruitment to the transcription start site of activated genes and developmental enhancers and its depletion from regions bound by Polycomb, Histone H1, and heterochromatin Protein 1. We demonstrate that the Trithorax-related/MLL3/4 chromatin modifier regulates ISC proliferation, colocalizes extensively with Kismet throughout the ISC genome, and co-regulates genes in ISCs, including Cbl, a negative regulator of Epidermal Growth Factor Receptor (EGFR). Loss of kismet or trr leads to elevated levels of EGFR protein and signaling, thereby promoting ISC self-renewal. We propose that Kismet with Trr establishes a chromatin state that limits EGFR proliferative signaling, preventing tumor-like stem cell overgrowths

Validated imaging biomarkers as decision-making tools in clinical trials and routine practice: current status and recommendations from the EIBALL* subcommittee of the European Society of Radiology (ESR)

Abstract: Observer-driven pattern recognition is the standard for interpretation of medical images. To achieve global parity in interpretation, semi-quantitative scoring systems have been developed based on observer assessments; these are widely used in scoring coronary artery disease, the arthritides and neurological conditions and for indicating the likelihood of malignancy. However, in an era of machine learning and artificial intelligence, it is increasingly desirable that we extract quantitative biomarkers from medical images that inform on disease detection, characterisation, monitoring and assessment of response to treatment. Quantitation has the potential to provide objective decision-support tools in the management pathway of patients. Despite this, the quantitative potential of imaging remains under-exploited because of variability of the measurement, lack of harmonised systems for data acquisition and analysis, and crucially, a paucity of evidence on how such quantitation potentially affects clinical decision-making and patient outcome. This article reviews the current evidence for the use of semi-quantitative and quantitative biomarkers in clinical settings at various stages of the disease pathway including diagnosis, staging and prognosis, as well as predicting and detecting treatment response. It critically appraises current practice and sets out recommendations for using imaging objectively to drive patient management decisions

Effects of maternal lifestyle interventions on child neurobehavioral development : Follow-up of randomized controlled trials

Obesity is a major public health problem. Children of women who were obese before or during pregnancy are at increased risk for neurobehavioral developmental problems. Whether a maternal lifestyle intervention conducted before and during pregnancy in obese women affects child neurobehavioral development is unknown. This study reports on the follow-up of a subsample of two randomized controlled trials, the Finnish RADIEL (n = 216) and Dutch LIFEstyle (n = 305) trial. Women with a pre-pregnancy BMI >= 29 kg/m(2) wishing to conceive or who were already pregnant (Peer reviewe

The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update

Galaxy (homepage: https://galaxyproject.org, main public server: https://usegalaxy.org) is a web-based scientific analysis platform used by tens of thousands of scientists across the world to analyze large biomedical datasets such as those found in genomics, proteomics, metabolomics and imaging. Started in 2005, Galaxy continues to focus on three key challenges of data-driven biomedical science: making analyses accessible to all researchers, ensuring analyses are completely reproducible, and making it simple to communicate analyses so that they can be reused and extended. During the last two years, the Galaxy team and the open-source community around Galaxy have made substantial improvements to Galaxy's core framework, user interface, tools, and training materials. Framework and user interface improvements now enable Galaxy to be used for analyzing tens of thousands of datasets, and >5500 tools are now available from the Galaxy ToolShed. The Galaxy community has led an effort to create numerous high-quality tutorials focused on common types of genomic analyses. The Galaxy developer and user communities continue to grow and be integral to Galaxy's development. The number of Galaxy public servers, developers contributing to the Galaxy framework and its tools, and users of the main Galaxy server have all increased substantially

L'effet synergique de la répression transcriptionelle par piwi et post-transcriptionelle par Dicer-2 contrôle l'expression de transposon dans les têtes de Drosophila Melanogaster

Transposable elements are major components of eukaryotic genomes and have been proposed as important drivers of gene network evolution, as they can move or “transpose” in their host genome, creating gene duplications, gene inactivations or altogether altering gene function. Nevertheless, uncontrolled high-rate transposition leads to DNA damage and genomic instabilities, and therefore needs to be kept at a low level. In the fruitfly Drosophila melanogaster, transposition is counteracted by multiple mechanisms, amongst which the generation of small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs). siRNAs and piRNAs belong to the category of small RNAs, and these are involved in negative regulation of complementary target RNAs abundance, but siRNAs and piRNAs have distinct mechanisms of biogenesis, target recognition and mechanisms of target regulation. Notably, piRNAs are only abundant in gonads and are transmitted to the embryo. By sequencing small RNAs and normal transcripts in adult heads, I conclude that, while piRNAs are likely absent in adult heads, they induce a repressive state on TEs. If this repressive state is lost, the siRNA pathway can compensate and limit Transposable element levels. If siRNAs are lost, the repressive state induced by piRNAs suffices to limit Transposable element levels. If both piRNAs and siRNAs are lost, the expression level of Transposable elements increases, and flies have a shorter life span. The requirement to analyse large-scale sequencing data led to the development of multiple tools for the reproducible research platform Galaxy.Les éléments transposables (ET) sont des constituants majeurs des génomes eucaryotes. Leur mobilisation joue un rôle important dans l'évolution et l'adaptation des organismes. Cependant, la transposition des ET peut conduire à des dommages irréversibles du génome et elle doit donc être étroitement contrôlé. Chez Drosophila melanogaster, la transposition des ET est contrôlée par les siRNA (small interfering RNAs) et les piRNA (Piwi-interacting RNAs) qui agissent en réprimant des cibles ARN de séquences complémentaires. Les siRNA et piRNA ont des modes distincts de biogenèse, de reconnaissance de cibles et d'activité repressive. Les piRNAs sont seulement présents en abondance dans les gonades, et transmis maternellement aux embryons. Par une approche de séquençage à haut débit, j'ai pu montrer que bien qu'ils induisent une répression transcriptionnelle des ET à ce stade du développement, ils sont pratiquement absents des têtes de drosophiles adultes. Cet état est cependant hérité et il est suffisant pour limiter l'expression des ET dans l'adulte, même en l'absence de siRNA. A l'inverse, si la répression transcriptionnelle précoce n'est pas établie, les siRNA agissent comme un système de sauvegarde en limitant l'expression des ET. En cas de perte conjointe des piRNA et siRNA, l'expression des ET augmente significativement et la durée de vie des mouches adultes se trouve réduite. Les analyses de sequences à grande échelle m'ont par ailleurs conduit à développer des outils logiciels intégrés dans Galaxy et à m'impliquer significativement dans la communauté qui développe ce système au niveau international

Isolation of small interfering RNAs using viral suppressors of RNA interference

International audienceThe tombusvirus P19 VSR (viral suppressor of RNA interference) binds siRNAs with high affinity, whereas the Flockhouse Virus (FHV) B2 VSR binds both long double-stranded RNA (dsRNA) and small interfering RNAs (siRNAs). Both VSRs are small proteins and function in plant and animal cells. Fusing a Nuclear Localization Signal (NLS) to the N-terminus shifts the localization of the VSR from cytoplasmic to nuclear, allowing researchers to specifically probe the subcellular distribution of siRNAs, and to investigate the function of nuclear and cytoplasmic siRNAs. This chapter provides a detailed protocol for the immunoprecipitation of siRNAs bound to epitope-tagged VSR and subsequent analysis by 3'-end-labeling using cytidine-3',5'-bis phosphate ([5'-(32)P]pCp) and northern blotting