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Nilsen G.,University of Oslo | Liestol K.,University of Oslo | Loo P.V.,Wellcome Trust Sanger Institute | Loo P.V.,and University of Leuven | And 10 more authors.
BMC Genomics | Year: 2012

Background: Cancer progression is associated with genomic instability and an accumulation of gains and losses of DNA. The growing variety of tools for measuring genomic copy numbers, including various types of array-CGH, SNP arrays and high-throughput sequencing, calls for a coherent framework offering unified and consistent handling of single- and multi-track segmentation problems. In addition, there is a demand for highly computationally efficient segmentation algorithms, due to the emergence of very high density scans of copy number.Results: A comprehensive Bioconductor package for copy number analysis is presented. The package offers a unified framework for single sample, multi-sample and multi-track segmentation and is based on statistically sound penalized least squares principles. Conditional on the number of breakpoints, the estimates are optimal in the least squares sense. A novel and computationally highly efficient algorithm is proposed that utilizes vector-based operations in R. Three case studies are presented.Conclusions: The R package copynumber is a software suite for segmentation of single- and multi-track copy number data using algorithms based on coherent least squares principles. © 2012 Nilsen et al.; licensee BioMed Central Ltd.


PubMed | QIMR Berghofer Medical Research Institute, Walter and Eliza Hall Institute of Medical Research, University of Adelaide, University of Regensburg and 2 more.
Type: | Journal: Nature communications | Year: 2015

IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFN-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(-)CCR2(+)) of GM-CSF/IFN-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFN/TNF/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFN-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFN-producing Th17 cells.


News Article | November 3, 2016
Site: www.eurekalert.org

If people continue using and changing the land over the next century in the same way they currently do, soils will have limited potential to counter the effect of climate change and will become a net source of atmospheric carbon dioxide, experts have warned. Experts have forecast that a quarter of the carbon found in soil in France could be lost to the atmosphere during the next 100 years. This could lead to soil becoming a net source of carbon dioxide to the atmosphere. At present soil is considered to absorb carbon dioxide and this partially counters the impact of man-made climate change. The pace and nature of predicted changes in climate over the next century will make the soil less able to store carbon, while business-as-usual land use change has limited capacity to counteract this trend, experts from the University of Exeter, INRA and CERFACS in France and University of Leuven in Belgium say in the journal Scientific Reports. If, as predicted, soils lose a significant amount of their carbon this will endanger their ability to produce food and store water and this could lead to increased soil erosion and flood damage. Researchers made these predictions for the 21st century by combining models of soil carbon and land use change with climate change predictions, using France as a case study. The study shows that land under almost all uses will be subject to dramatic losses of soil carbon by 2100. Only conversions of land into grass or forest result in limited additional storage of carbon in soils. Unfortunately these land changes are not likely to happen on a large scale because of the pressures on land resources imposed by urban expansion and food production. Lead author Dr Jeroen Meersmans, from the University of Exeter, said: "A reduction in anthropogenic CO2 levels is crucial to prevent further loss of carbon from our soils. However, promotion of land use changes and management that contribute to soil carbon sequestration remains essential in an integrated strategy to protect soil functions and mitigate climate change." Co-author Dr Dominique Arrouays of the French National Institute for Agricultural Research added, "Purposive, targeted land use and agricultural practice changes would be needed if climate change mitigation is to be maximized. Therefore, the efforts to enhance carbon sequestration in soils, as proposed by France during the COP21, should be promoted immediately." The research collaboration involved academics from the Geography Department at the College of Life and Environmental Sciences at the University of Exeter (UK), the InfoSol Unit at INRA in Orleans (France), CECI, CERFACS - CNRS in Toulouse (France), the Geography and Tourism Research Group at the Department of Earth and Environmental Sciences at the University of Leuven (Belgium). The research is funded by the European Commission through the Marie Curie Intra-European Fellowship for Career Development (IEF) project D3DC. Future C loss in mid-latitude mineral soils: climate change exceeds land use mitigation potential in France is published in the journal Scientific Reports.


News Article | November 4, 2016
Site: www.sciencedaily.com

If people continue using and changing the land over the next century in the same way they currently do, soils will have limited potential to counter the effect of climate change and will become a net source of atmospheric carbon dioxide, experts have warned. Experts have forecast that a quarter of the carbon found in soil in France could be lost to the atmosphere during the next 100 years. This could lead to soil becoming a net source of carbon dioxide to the atmosphere. At present soil is considered to absorb carbon dioxide and this partially counters the impact of human-made climate change. The pace and nature of predicted changes in climate over the next century will make the soil less able to store carbon, while business-as-usual land use change has limited capacity to counteract this trend, experts from the University of Exeter, INRA and CERFACS in France and University of Leuven in Belgium say in the journal Scientific Reports. If, as predicted, soils lose a significant amount of their carbon this will endanger their ability to produce food and store water and this could lead to increased soil erosion and flood damage. Researchers made these predictions for the 21st century by combining models of soil carbon and land use change with climate change predictions, using France as a case study. The study shows that land under almost all uses will be subject to dramatic losses of soil carbon by 2100. Only conversions of land into grass or forest result in limited additional storage of carbon in soils. Unfortunately these land changes are not likely to happen on a large scale because of the pressures on land resources imposed by urban expansion and food production. Lead author Dr Jeroen Meersmans, from the University of Exeter, said: "A reduction in anthropogenic CO levels is crucial to prevent further loss of carbon from our soils. However, promotion of land use changes and management that contribute to soil carbon sequestration remains essential in an integrated strategy to protect soil functions and mitigate climate change." Co-author Dr Dominique Arrouays of the French National Institute for Agricultural Research added, "Purposive, targeted land use and agricultural practice changes would be needed if climate change mitigation is to be maximized. Therefore, the efforts to enhance carbon sequestration in soils, as proposed by France during the COP21, should be promoted immediately." The research collaboration involved academics from the Geography Department at the College of Life and Environmental Sciences at the University of Exeter (UK), the InfoSol Unit at INRA in Orleans (France), CECI, CERFACS -- CNRS in Toulouse (France), the Geography and Tourism Research Group at the Department of Earth and Environmental Sciences at the University of Leuven (Belgium).


Papaemmanuil E.,Wellcome Trust Sanger Institute | Rapado I.,Hospital Universitario 12 Of Octubre | Li Y.,Wellcome Trust Sanger Institute | Potter N.E.,Institute for Cancer Research | And 36 more authors.
Nature Genetics | Year: 2014

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation. © 2014 Nature America, Inc.


Tian L.,and University of Leuven | De Hertogh G.,Catholic University of Leuven | Fedeli M.,San Raffaele Scientific Institute | Staats K.A.,and University of Leuven | And 9 more authors.
Journal of Autoimmunity | Year: 2012

With an increasing number of studies demonstrating alterations in T cell microRNA expression during autoimmune disease, modulation of the T cell microRNA network is considered a potential therapeutic strategy. Due to the complex and often opposing interactions of individual microRNA, prioritization of therapeutic targets first requires dissecting the dominant effects of the T cell microRNA network. Initial results utilizing a unidirectional screen suggested that the tolerogenic functions were dominant, with spontaneous colitis resulting from T cell-specific excision of Dicer. Here we performed a bidirectional screen for microRNA function by removing Dicer from the T cells of both wildtype mice and Transforming Growth Factor β (TGFβ) receptor-deficient mice. This allowed the impact of microRNA loss on T cell activation, effector T cell differentiation and autoimmune pathology to be systematically assessed. This bidirectional screen revealed a dominant immunogenic function for T cell microRNA, with potent suppression of T cell activation, IFNγ production and autoimmune pathology in all targeted organs except the colon, where Dicer-dependent microRNA demonstrated a dominant tolerogenic function. These results reverse the original conclusions of microRNA function in T cells by revealing a systemic pro-autoimmune function. © 2011 Elsevier Ltd.


Wilhelm K.,Max Planck Institute for Heart and Lung Research | Happel K.,Max Planck Institute for Heart and Lung Research | Eelen G.,Catholic University of Leuven | Eelen G.,Vesalius Research Center | And 23 more authors.
Nature | Year: 2016

Endothelial cells (ECs) are plastic cells that can switch between growth states with different bioenergetic and biosynthetic requirements. Although quiescent in most healthy tissues, ECs divide and migrate rapidly upon proangiogenic stimulation. Adjusting endothelial metabolism to the growth state is central to normal vessel growth and function, yet it is poorly understood at the molecular level. Here we report that the forkhead box O (FOXO) transcription factor FOXO1 is an essential regulator of vascular growth that couples metabolic and proliferative activities in ECs. Endothelial-restricted deletion of FOXO1 in mice induces a profound increase in EC proliferation that interferes with coordinated sprouting, thereby causing hyperplasia and vessel enlargement. Conversely, forced expression of FOXO1 restricts vascular expansion and leads to vessel thinning and hypobranching. We find that FOXO1 acts as a gatekeeper of endothelial quiescence, which decelerates metabolic activity by reducing glycolysis and mitochondrial respiration. Mechanistically, FOXO1 suppresses signalling by MYC (also known as c-MYC), a powerful driver of anabolic metabolism and growth. MYC ablation impairs glycolysis, mitochondrial function and proliferation of ECs while its EC-specific overexpression fuels these processes. Moreover, restoration of MYC signalling in FOXO1-overexpressing endothelium normalizes metabolic activity and branching behaviour. Our findings identify FOXO1 as a critical rheostat of vascular expansion and define the FOXO1-MYC transcriptional network as a novel metabolic checkpoint during endothelial growth and proliferation. © 2016 Macmillan Publishers Limited. All rights reserved.


PubMed | University Hospitals Leuven, Catholic University of Leuven and and University of Leuven
Type: Case Reports | Journal: Arthritis & rheumatology (Hoboken, N.J.) | Year: 2015

To identify the underlying genetic defect in a 16-year-old girl with severe early-onset and refractory systemic lupus erythematosus (SLE), IgA deficiency, and mild lower limb spasticity without neuroradiologic manifestations.Whole-exome sequencing and extensive immunologic analysis were performed on samples from the index patient.We identified a de novo p.R779H IFIH1 gain-of-function mutation in a patient with severe early-onset SLE, selective IgA deficiency, and mild lower limb spasticity. The same mutation in IFIH1 was recently identified in patients with Aicardi-Goutires syndrome, a rare neuroimmunologic disorder associated with elevated levels of type I interferon (IFN). IFN induced with helicase C domain 1 functions as an intracellular innate immune receptor that senses viral nucleic acids and leads to the induction of type I IFN and proinflammatory cytokines. Despite systemic immunosuppressive treatment, disease activity persisted in the patient and was associated with elevated serum levels of IFN and up-regulation of IFIH1 itself.This finding adds a new genetic causation for Mendelian lupus and greatly extends the disease spectrum associated with mutations in IFIH1 (ranging from inflammatory encephalopathy to prototypic systemic autoimmune disease). This marked phenotypic heterogeneity, despite an identical mutation, demonstrates the importance of modifying factors in type I IFN-dependent pathologies caused by mutations in IFIH1.


Liston A.,and University of Leuven | Piccirillo C.A.,McGill University
Advances in Immunology | Year: 2013

Murine and human CD4+ regulatory T (Treg) cells expressing the Forkhead box p3 (Foxp3) transcription factor represent a distinct, highly differentiated CD4+ T cell lineage that is programmed for dominant self-tolerance and control of immune responses against a variety of foreign antigens. Sustained Foxp3 expression in these cells drives the differentiation of a regulatory phenotype and ensures the stability of their suppressive functions under a variety of inflammatory settings. Some recent studies have challenged this premise and advanced the notion that Foxp3+ Treg cells manifest a high degree of functional plasticity that enables them to adapt and reprogram into effector-like T cells in response to various inflammatory stimuli. The concept of Treg cell plasticity remains highly contentious, with a high degree of variation in measured plasticity potential observed under different experimental conditions. In this chapter, we propose a unifying model of Treg cell plasticity, which hypothesizes that the stable fates of regulatory and effector T (Teff) cell lineages allow transient plasticity into the alternative lineage under a discrete set of microenvironmental influences associated with, respectively, the initiation and resolution phases of infection. This model utilizes a theoretical framework consistent with the requirements for effective immune regulation and accounts for both the extraordinary long-term stability of Treg cells and the observed fate plasticity. © 2013 Elsevier Inc.

Loading and University of Leuven collaborators
Loading and University of Leuven collaborators