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991.
Summary Fibroblasts from a heterozygous carrier for the Martin-Bell syndrome, who manifests the fragile site Xq27, were cloned to separate the population carrying the primary defect on the active X chromosome from the population with this defect on the inactive X. Clones with this defect on the active X manifest the fra(X)(q27) whereas clones from the other population are fra(X)-negative (Steinbach et al. 1983b). In this project, the replication status of the X chromosome manifesting the fra(X)(q27) was studied in seven clones with this defect on the active X.The results obtained on the clones were very similar to the results obtained from uncloned fibroblasts and lymphocytes. In the clones the fragile site was found manifested on the early replicating X in 73 cells and on the late replicating X in four cells.Since the defect is located on the active X chromosome of these cells the manifestation of the fragile site on the late replicating X suggests that the defect and the fragile site cannot be identical. It is concluded that there is no obligate synteny of this defect and the manifested fragile site. 相似文献
992.
Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma 总被引:1,自引:0,他引:1
Daniel J. Merk Jasmin Ohli Natalie D. Merk Venu Thatikonda Sorana Morrissy Melanie Schoof Susanne N. Schmid Luke Harrison Severin Filser Julia Ahlfeld Serap Erkek Kaamini Raithatha Thomas Andreska Marc Weißhaar Michael Launspach Julia E. Neumann Mehdi Shakarami Dennis Plenker Ulrich Schüller 《Developmental cell》2018,44(6):709-724.e6
993.
994.
Margarete Poppelreuther Simone Sander Fadil Minden Marina S. Dietz Tarik Exner Chen Du Ingrid Zhang Friedrich Ehehalt Laura Knüppel Susanne Domschke Anna Badenhop Sarah Staudacher Robert Ehehalt Wolfgang Stremmel Christoph Thiele Mike Heilemann Joachim Füllekrug 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2018,1863(6):614-624
ACSL3 is the only long chain fatty acyl-CoA synthetase consistently found on growing and mature lipid droplets (LDs), suggesting that this specific localization has biological relevance. Current models for LD growth propose that triglycerides are synthesized by enzymes at the LD surface, with activated fatty acids provided by LD localized ACSL3, thus allowing growth independent of the ER. Here, we tested this hypothesis by quantifying ACSL3 on LDs from human A431 cells.RNAi of ACSL3 reduced the oleoyl-CoA synthetase activity by 83%, suggesting that ACSL3 is by far the dominant enzyme of A431 cells. Molar quantification revealed that there are 1.4 million ACSL3 molecules within a single cell. Metabolic labeling indicated that each ACSL3 molecule contributed a net gain of 3.1 oleoyl-CoA/s. 3D reconstruction of confocal images demonstrated that 530 individual lipid droplets were present in an average oleate fed A431 cell. A representative single lipid droplet with a diameter of 0.66?μm contained 680 ACSL3 molecules on the surface. Subcellular fractionation showed that at least 68% of ACSL3 remain at the ER even during extensive fatty acid supplementation. High resolution single molecule microscopy confirmed the abundance of cytoplasmic ACSL3 outside of LDs. Model calculations for triglyceride synthesis using only LD localized ACSL3 gave significant slower growth of LDs as observed experimentally.In conclusion, although ACSL3 is an abundant enzyme on A431 LDs, the metabolic capacity is not sufficient to account for LD growth solely by the local synthesis of triglycerides. 相似文献
995.
Joana M. Murad Susanne H. Baumeister Lillian Werner Heather Daley Hélène Trébéden-Negre Jake Reder Charles L. Sentman David Gilham Frederic Lehmann Sarah Snykers Marie-Louise Sentman Terri Wade Adam Schmucker Michael W. Fanger Glenn Dranoff Jerome Ritz Sarah Nikiforow 《Cytotherapy》2018,20(7):952-963
Background aims
Adoptive cell therapy employing natural killer group 2D (NKG2D) chimeric antigen receptor (CAR)-modified T cells has demonstrated preclinical efficacy in several model systems, including hematological and solid tumors. We present comprehensive data on manufacturing development and clinical production of autologous NKG2D CAR T cells for treatment of acute myeloid leukemia and multiple myeloma (ClinicalTrials.gov Identifier: NCT02203825). An NKG2D CAR was generated by fusing native full-length human NKG2D to the human CD3ζ cytoplasmic signaling domain. NKG2D naturally associates with native costimulatory molecule DAP10, effectively generating a second-generation CAR against multiple ligands upregulated during malignant transformation including MIC-A, MIC-B and the UL-16 binding proteins.Methods
CAR T cells were infused fresh after a 9-day process wherein OKT3-activated T cells were genetically modified with replication-defective gamma-retroviral vector and expanded ex vivo for 5 days with recombinant human interleukin-2.Results
Despite sizable interpatient variation in originally collected cells, release criteria, including T-cell expansion and purity (median 98%), T-cell transduction (median 66% CD8+ T cells), and functional activity against NKG2D ligand-positive cells, were met for 100% of healthy donors and patients enrolled and collected. There was minimal carryover of non–T cells, particularly malignant cells; both effector memory and central memory cells were generated, and inflammatory cytokines such as granulocyte colony-stimulating factor, RANTES, interferon-γ and tumor necrosis factor-α were selectively up-regulated.Conclusions
The process resulted in production of required cell doses for the first-in-human phase I NKG2D CAR T clinical trial and provides a robust, flexible base for further optimization of NKG2D CAR T-cell manufacturing. 相似文献996.
Assessing uncertainties in crop and pasture ensemble model simulations of productivity and N2O emissions 下载免费PDF全文
Fiona Ehrhardt Jean‐François Soussana Gianni Bellocchi Peter Grace Russel McAuliffe Sylvie Recous Renáta Sándor Pete Smith Val Snow Massimiliano de Antoni Migliorati Bruno Basso Arti Bhatia Lorenzo Brilli Jordi Doltra Christopher D. Dorich Luca Doro Nuala Fitton Sandro J. Giacomini Brian Grant Matthew T. Harrison Stephanie K. Jones Miko U. F. Kirschbaum Katja Klumpp Patricia Laville Joël Léonard Mark Liebig Mark Lieffering Raphaël Martin Raia S. Massad Elizabeth Meier Lutz Merbold Andrew D. Moore Vasileios Myrgiotis Paul Newton Elizabeth Pattey Susanne Rolinski Joanna Sharp Ward N. Smith Lianhai Wu Qing Zhang 《Global Change Biology》2018,24(2):e603-e616
Simulation models are extensively used to predict agricultural productivity and greenhouse gas emissions. However, the uncertainties of (reduced) model ensemble simulations have not been assessed systematically for variables affecting food security and climate change mitigation, within multi‐species agricultural contexts. We report an international model comparison and benchmarking exercise, showing the potential of multi‐model ensembles to predict productivity and nitrous oxide (N2O) emissions for wheat, maize, rice and temperate grasslands. Using a multi‐stage modelling protocol, from blind simulations (stage 1) to partial (stages 2–4) and full calibration (stage 5), 24 process‐based biogeochemical models were assessed individually or as an ensemble against long‐term experimental data from four temperate grassland and five arable crop rotation sites spanning four continents. Comparisons were performed by reference to the experimental uncertainties of observed yields and N2O emissions. Results showed that across sites and crop/grassland types, 23%–40% of the uncalibrated individual models were within two standard deviations (SD) of observed yields, while 42 (rice) to 96% (grasslands) of the models were within 1 SD of observed N2O emissions. At stage 1, ensembles formed by the three lowest prediction model errors predicted both yields and N2O emissions within experimental uncertainties for 44% and 33% of the crop and grassland growth cycles, respectively. Partial model calibration (stages 2–4) markedly reduced prediction errors of the full model ensemble E‐median for crop grain yields (from 36% at stage 1 down to 4% on average) and grassland productivity (from 44% to 27%) and to a lesser and more variable extent for N2O emissions. Yield‐scaled N2O emissions (N2O emissions divided by crop yields) were ranked accurately by three‐model ensembles across crop species and field sites. The potential of using process‐based model ensembles to predict jointly productivity and N2O emissions at field scale is discussed. 相似文献
997.
Saskia Lehr Juliane Vier Georg Häcker Susanne Kirschnek 《Microbes and infection / Institut Pasteur》2018,20(5):284-292
The obligate intracellular bacterium Chlamydia trachomatis is the most common bacterial agent of sexually transmitted disease world-wide. Chlamydia trachomatis primarily infects epithelial cells of the genital tract but the infection may be associated with ascending infection. Infection-associated inflammation can cause tissue damage resulting in female infertility and ectopic pregnancy. The precise mechanism of inflammatory tissue damage is unclear but earlier studies implicate the chlamydial cryptic plasmid as well as responding neutrophils. We here rebuilt the interaction of Chlamydia trachomatis-infected epithelial cells and neutrophils in-vitro. During infection of human (HeLa) or mouse (oviduct) epithelial cells with Chlamydia trachomatis, a soluble factor was produced that attracted neutrophils and prolonged neutrophil survival, independently of Toll-like receptor signaling but dependent on the chlamydial plasmid. A number of cytokines, but most strongly GM-CSF, were secreted at higher amounts from cells infected with plasmid-bearing, compared to plasmid-deficient, bacteria. Blocking GM-CSF removed the secreted pro-survival activity towards neutrophils. A second, neutrophil TNF-stimulatory activity was detected in supernatants, requiring MyD88 or TRIF independently of the plasmid. The results identify two pro-inflammatory activities generated during chlamydial infection of epithelial cells and suggest that the epithelial cell, partly through the chlamydial plasmid, can initiate a myeloid immune response and inflammation. 相似文献
998.
A review and meta‐analysis of the effects of climate change on Holarctic mountain and upland bird populations 下载免费PDF全文
Davide Scridel Mattia Brambilla Kathy Martin Aleksi Lehikoinen Aaron Iemma Anderle Matteo Susanne Jähnig Enrico Caprio Giuseppe Bogliani Paolo Pedrini Antonio Rolando Raphaël Arlettaz Dan Chamberlain 《Ibis》2018,160(3):489-515
Mountain regions are globally important areas for biodiversity but are subject to multiple human‐induced threats, including climate change, which has been more severe at higher elevations. We reviewed evidence for impacts of climate change on Holarctic mountain bird populations in terms of physiology, phenology, trophic interactions, demography and observed and projected distribution shifts, including effects of other factors that interact with climate change. We developed an objective classification of high‐elevation, mountain specialist and generalist species, based on the proportion of their breeding range occurring in mountain regions. Our review found evidence of responses of mountain bird populations to climate (extreme weather events, temperature, rainfall and snow) and environmental (i.e. land use) change, but we know little about either the underlying mechanisms or the synergistic effects of climate and land use. Long‐term studies assessing reproductive success or survival of mountain birds in relation to climate change were rare. Few studies have considered shifts in elevational distribution over time and a meta‐analysis did not find a consistent direction in elevation change. A meta‐analysis carried out on future projections of distribution shifts suggested that birds whose breeding distributions are largely restricted to mountains are likely to be more negatively impacted than other species. Adaptation responses to climate change rely mostly on managing and extending current protected areas for both species already present, and for expected colonizing species that are losing habitat and climate space at lower elevation. However, developing effective management actions requires an improvement in the current knowledge of mountain species ecology, in the quality of climate data and in understanding the role of interacting factors. Furthermore, the evidence was mostly based on widespread species rather than mountain specialists. Scientists should provide valuable tools to assess the status of mountain birds, for example through the development of a mountain bird population index, and policy‐makers should influence legislation to develop efficient agri‐environment schemes and forestry practices for mountain birds, as well as to regulate leisure activities at higher elevations. 相似文献
999.
1000.
Susanne Sjöberg Nolwenn Callac Bert Allard Rienk H. Smittenberg Christophe Dupraz 《Geomicrobiology journal》2018,35(8):657-674
The dominant initial phase formed during microbially mediated manganese oxidation is a poorly crystalline birnessite-type phyllomanganate. The occurrence of manganese deposits containing this mineral is of interest for increased understanding of microbial involvement in the manganese cycle. A culture independent molecular approach is used as a first step to investigate the role of microorganisms in forming rare earth element enriched birnessite-type manganese oxides, associated with water bearing rock fractures in a tunnel of the Ytterby mine, Sweden. 16S rRNA gene results show that the chemotrophic bacterial communities are diverse and include a high percentage of uncultured unclassified bacteria while archaeal diversity is low with Thaumarchaeota almost exclusively dominating the population. Ytterby clones are frequently most similar to clones isolated from subsurface environments, low temperature milieus and/or settings rich in metals. Overall, bacteria are dominant compared to archaea. Both bacterial and archaeal abundances are up to four orders of magnitude higher in manganese samples than in fracture water. Potential players in the manganese cycling are mainly found within the ferromanganese genera Hyphomicrobium and Pedomicrobium, and a group of Bacteroidetes sequences that cluster within an uncultured novel genus most closely related to the Terrimonas. This study strongly suggest that the production of the YBS deposit is microbially mediated. 相似文献