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Sökning: WFRF:(Teichmann C.)

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  • Suzuki, H, et al. (författare)
  • The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line
  • 2009
  • Ingår i: Nature genetics. - 1546-1718. ; 41:5, s. 553-562
  • Tidskriftsartikel (refereegranskat)abstract
    • Using deep sequencing (deepCAGE), the FANTOM4 study measured the genome-wide dynamics of transcription-start-site usage in the human monocytic cell line THP-1 throughout a time course of growth arrest and differentiation. Modeling the expression dynamics in terms of predicted cis-regulatory sites, we identified the key transcription regulators, their time-dependent activities and target genes. Systematic siRNA knockdown of 52 transcription factors confirmed the roles of individual factors in the regulatory network. Our results indicate that cellular states are constrained by complex networks involving both positive and negative regulatory interactions among substantial numbers of transcription factors and that no single transcription factor is both necessary and sufficient to drive the differentiation process.
  • Clark, Andrew G., et al. (författare)
  • Evolution of genes and genomes on the Drosophila phylogeny.
  • 2007
  • Ingår i: Nature. - 0028-0836. ; 450:7167, s. 203-218
  • Tidskriftsartikel (refereegranskat)abstract
    • Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
  • Ravasi, T, et al. (författare)
  • An Atlas of Combinatorial Transcriptional Regulation in Mouse and Man
  • 2010
  • Ingår i: CELL. - 0092-8674. ; 140:5, s. 744-752
  • Tidskriftsartikel (refereegranskat)abstract
    • Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.
  • Bluth, T., et al. (författare)
  • Protective intraoperative ventilation with higher versus lower levels of positive end-expiratory pressure in obese patients (PROBESE) study protocol for a randomized controlled trial
  • 2017
  • Ingår i: Trials. - BIOMED CENTRAL LTD. - 1745-6215 .- 1745-6215. ; 18
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Postoperative pulmonary complications (PPCs) increase the morbidity and mortality of surgery in obese patients. High levels of positive end-expiratory pressure (PEEP) with lung recruitment maneuvers may improve intraoperative respiratory function, but they can also compromise hemodynamics, and the effects on PPCs are uncertain. We hypothesized that intraoperative mechanical ventilation using high PEEP with periodic recruitment maneuvers, as compared with low PEEP without recruitment maneuvers, prevents PPCs in obese patients.Methods/design: The PRotective Ventilation with Higher versus Lower PEEP during General Anesthesia for Surgery in OBESE Patients (PROBESE) study is a multicenter, two-arm, international randomized controlled trial. In total, 2013 obese patients with body mass index >= 35 kg/m(2) scheduled for at least 2 h of surgery under general anesthesia and at intermediate to high risk for PPCs will be included. Patients are ventilated intraoperatively with a low tidal volume of 7 ml/kg (predicted body weight) and randomly assigned to PEEP of 12 cmH(2)O with lung recruitment maneuvers (high PEEP) or PEEP of 4 cmH(2)O without recruitment maneuvers (low PEEP). The occurrence of PPCs will be recorded as collapsed composite of single adverse pulmonary events and represents the primary endpoint.Discussion: To our knowledge, the PROBESE trial is the first multicenter, international randomized controlled trial to compare the effects of two different levels of intraoperative PEEP during protective low tidal volume ventilation on PPCs in obese patients. The results of the PROBESE trial will support anesthesiologists in their decision to choose a certain PEEP level during general anesthesia for surgery in obese patients in an attempt to prevent PPCs.
  • Dubois, B, et al. (författare)
  • Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.
  • 2016
  • Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 12:3, s. 292-323
  • Tidskriftsartikel (refereegranskat)abstract
    • During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.
  • Emde, Claudia, et al. (författare)
  • A polarized discrete ordinate scattering model for simulations of limb and nadir long-wave measurements in 1-D/3-D spherical atmospheres
  • 2004
  • Ingår i: Journal of Geophysical Research - Atmospheres. - 0148-0227. ; 109:D24
  • Tidskriftsartikel (refereegranskat)abstract
    • This article describes one of the scattering algorithms of the three-dimensional polarized radiative transfer model ARTS (Atmospheric Radiative Transfer Simulator) which has been implemented to study for example the influence of cirrus clouds on microwave limb sounding. The model uses the DOIT (Discrete Ordinate Iterative) method to solve the vector radiative transfer equation. The implementation of a discrete ordinate method is challenging due to the spherical geometry of the model atmosphere which is required for the simulation of limb radiances. The involved numerical issues, which are grid optimization and interpolation methods, are discussed in this paper. Scattering simulations are presented for limb- and down-looking geometries, for one-dimensional and three-dimensional spherical atmospheres. They show the impact of cloud particle size, shape, and orientation on the brightness temperatures and on the polarization of microwave radiation in the atmosphere. The cloud effect is much larger for limb radiances than for nadir radiances. Particle size is a very important parameter in all simulations. The polarization signal is negligible for simulations with completely randomly oriented particles, whereas for horizontally aligned particles with random azimuthal orientation the polarization signal is significant. Moreover, the effect of particle shape is only relevant for oriented cloud particles. The simulations show that it is essential to use a three-dimensional scattering model for inhomogeneous cloud layers.
  • Kotlarski, S., et al. (författare)
  • Regional climate modeling on European scales: a joint standard evaluation of the EURO-CORDEX RCM ensemble
  • 2014
  • Ingår i: Geoscientific Model Development. - Copernicus Gesellschaft Mbh. - 1991-959X. ; 7:4, s. 1297-1333
  • Tidskriftsartikel (refereegranskat)abstract
    • EURO-CORDEX is an international climate downscaling initiative that aims to provide high-resolution climate scenarios for Europe. Here an evaluation of the ERA-Interim-driven EURO-CORDEX regional climate model (RCM) ensemble is presented. The study documents the performance of the individual models in representing the basic spatiotemporal patterns of the European climate for the period 1989-2008. Model evaluation focuses on near-surface air temperature and precipitation, and uses the E-OBS data set as observational reference. The ensemble consists of 17 simulations carried out by seven different models at grid resolutions of 12 km (nine experiments) and 50 km (eight experiments). Several performance metrics computed from monthly and seasonal mean values are used to assess model performance over eight subdomains of the European continent. Results are compared to those for the ERA40-driven ENSEMBLES simulations. The analysis confirms the ability of RCMs to capture the basic features of the European climate, including its variability in space and time. But it also identifies nonnegligible deficiencies of the simulations for selected metrics, regions and seasons. Seasonally and regionally averaged temperature biases are mostly smaller than 1.5 degrees C, while precipitation biases are typically located in the +/- 40% range. Some bias characteristics, such as a predominant cold and wet bias in most seasons and over most parts of Europe and a warm and dry summer bias over southern and southeastern Europe reflect common model biases. For seasonal mean quantities averaged over large European subdomains, no clear benefit of an increased spatial resolution (12 vs. 50 km) can be identified. The bias ranges of the EURO-CORDEX ensemble mostly correspond to those of the ENSEMBLES simulations, but some improvements in model performance can be identified (e. g., a less pronounced southern European warm summer bias). The temperature bias spread across different configurations of one individual model can be of a similar magnitude as the spread across different models, demonstrating a strong influence of the specific choices in physical parameterizations and experimental setup on model performance. Based on a number of simply reproducible metrics, the present study quantifies the currently achievable accuracy of RCMs used for regional climate simulations over Europe and provides a quality standard for future model developments.
  • Loos, Ruth J. F., et al. (författare)
  • Common variants near MC4R are associated with fat mass, weight and risk of obesity
  • 2008
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1546-1718. ; 40:6, s. 768-775
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
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