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Berlin Brandenburg

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  • 1
    Language: English
    In: Science (New York, N.Y.), 11 June 2010, Vol.328(5984), pp.1394-8
    Description: Gamma-interferon-inducible lysosomal thiolreductase (GILT) promotes major histocompatibility complex (MHC) class II-restricted presentation of exogenous antigens containing disulfide bonds. Here, we show that GILT also facilitates MHC class I-restricted recognition of such antigens by CD8+ T cells, or cross-presentation. GILT is essential for cross-presentation of a CD8+ T cell epitope of glycoprotein B (gB) from herpes simplex virus 1 (HSV-1) but not for its presentation by infected cells. Initiation of the gB-specific CD8+ T cell response during HSV-1 infection, or cross-priming, is highly GILT-dependent, as is initiation of the response to the envelope glycoproteins of influenza A virus. Efficient cross-presentation of disulfide-rich antigens requires a complex pathway involving GILT-mediated reduction, unfolding, and partial proteolysis, followed by translocation into the cytosol for proteasomal processing.
    Keywords: Cross-Priming ; Antigens, Viral -- Immunology ; Herpes Simplex -- Immunology ; Herpesvirus 1, Human -- Immunology ; Oxidoreductases -- Metabolism ; Viral Envelope Proteins -- Immunology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 14 July 2015, Vol.112(28), pp.8579-83
    Description: The variable domains of Ig and T-cell receptor genes in vertebrates are assembled from gene fragments by the V(D)J recombination process. The RAG1-RAG2 recombinase (RAG1/2) initiates this recombination by cutting DNA at the borders of recombination signal sequences (RSS) and their neighboring gene segments. The RAG1 protein is also known to contain a ubiquitin E3 ligase activity, located in an N-terminal region that is not strictly required for the basic recombination reaction but helps to regulate recombination. The isolated E3 ligase domain was earlier shown to ubiquitinate one site in a neighboring RAG1 sequence. Here we show that autoubiquitination of full-length RAG1 at this specific residue (K233) results in a large increase of DNA cleavage by RAG1/2. A mutational block of the ubiquitination site abolishes this effect and inhibits recombination of a test substrate in mouse cells. Thus, ubiquitination of RAG1, which can be promoted by RAG1's own ubiquitin ligase activity, plays a significant role in governing the level of V(D)J recombination activity.
    Keywords: Diversification ; Immunoglobulin ; Ubiquitin ; Ubiquitination ; V(D)J Recombination ; Homeodomain Proteins -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Science (New York, N.Y.), 25 January 2013, Vol.339(6118), pp.446-8
    Description: The human genome contains ~50 genes that were derived from transposable elements or transposons, and many are now integral components of cellular gene expression programs. The human THAP9 gene is related to the Drosophila P-element transposase. Here, we show that human THAP9 can mobilize Drosophila P-elements in both Drosophila and human cells. Chimeric proteins formed between the Drosophila P-element transposase N-terminal THAP DNA binding domain and the C-terminal regions of human THAP9 can also mobilize Drosophila P elements. Our results indicate that human THAP9 is an active DNA transposase that, although "domesticated," still retains the catalytic activity to mobilize P transposable elements across species.
    Keywords: DNA Transposable Elements ; Transposases -- Genetics
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 4
    Language: English
    In: NeuroImage, 15 August 2012, Vol.62(2), pp.1121-1130
    Description: Over the last 20 years, BOLD-FMRI has proved itself to be a powerful and versatile tool for the study of the neural substrate underpinning many of our cognitive and perceptual functions. However, exactly how it is coupled to the underlying neurophysiology, and how this coupling varies across the brain, across tasks and across individuals is still unclear. The story is further complicated by the fact that within the same cortical region, multiple evoked and induced oscillatory effects may be modulated during task execution, supporting different cognitive roles, and any or all of these may have metabolic demands that then drive the BOLD response. In this paper I shall concentrate on one experimental approach to shedding light on this problem i.e. the execution of the same experimental tasks using MEG and fMRI in order to reveal which electrophysiological responses best match the BOLD response spatially, temporally and functionally. The results demonstrate a rich and complex story that does not fit with a simplistic view of BOLD reflecting “neural activity” and suggests that we could consider the coupling between BOLD and the various parameters of neural function as an ill-posed inverse problem. Finally, I describe recent work linking individual variability in both cortical oscillations and the BOLD-fMRI response to variability in endogenous GABA concentration.
    Keywords: Fmri ; Bold ; Meg ; Behaviour ; Oscillations ; Vision ; Gaba ; Variability ; Medicine
    ISSN: 1053-8119
    E-ISSN: 1095-9572
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 18 August 2015, Vol.112(33), pp.10431-6
    Description: Infertility is a prevalent health issue, affecting ∼15% of couples of childbearing age. Nearly one-half of idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. Traditional methods for studying inheritance, such as genome-wide association studies and linkage analyses, have been confounded by the genetic and phenotypic complexity of reproductive processes. Here we describe an association- and linkage-free approach to identify segregating infertility alleles, in which CRISPR/Cas9 genome editing is used to model putatively deleterious nonsynonymous SNPs (nsSNPs) in the mouse orthologs of fertility genes. Mice bearing "humanized" alleles of four essential meiosis genes, each predicted to be deleterious by most of the commonly used algorithms for analyzing functional SNP consequences, were examined for fertility and reproductive defects. Only a Cdk2 allele mimicking SNP rs3087335, which alters an inhibitory WEE1 protein kinase phosphorylation site, caused infertility and revealed a novel function in regulating spermatogonial stem cell maintenance. Our data indicate that segregating infertility alleles exist in human populations. Furthermore, whereas computational prediction of SNP effects is useful for identifying candidate causal mutations for diverse diseases, this study underscores the need for in vivo functional evaluation of physiological consequences. This approach can revolutionize personalized reproductive genetics by establishing a permanent reference of benign vs. infertile alleles.
    Keywords: Crispr/Cas9 ; Cyclin ; Genome Editing ; Meiosis ; Spermatogenesis ; Mutation ; Polymorphism, Single Nucleotide ; Infertility, Female -- Genetics ; Infertility, Male -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 6
    Language: English
    In: Biological Conservation, 2011, Vol.144(5), pp.1753-1757
    Description: Carnivores in Asia and throughout the world face high risk of extinction due to factors such as continued habitat loss and hunting. However, the Asiatic lion of Gir forest, India presents a conservation success story whose history may help to guide the recovery and conservation of other imperiled predators. Protection of core and satellite habitats and the relocation of pastoral communities and their livestock triggered forest recovery and coincident increases in native prey populations. Wild ungulate populations increased by 10-fold between 1970 and 2010, supporting an increase in the lion population from 180 animals in 1974 to 411 animals in 2010. Coincident with this increase, lions shifted their predation preferences from a diet composed of 75% livestock to one composed of just 25% livestock. This example demonstrates the value of native prey populations to sustain imperiled carnivore species, and the use of protected areas and livestock exclusion to maintain healthy prey populations.
    Keywords: Carnivores ; Endangered Species Management ; Livestock Depredation ; Predator–Prey Dynamics ; Protected Areas ; Tropical Forests ; Agriculture ; Biology ; Ecology
    ISSN: 0006-3207
    E-ISSN: 18732917
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  • 7
    Language: English
    In: Biochemical and Biophysical Research Communications, 09 March 2012, Vol.419(2), pp.321-325
    Description: ► Sphingomyelin headgroup is necessary for ligand binding to serotonin receptors. ► Removal of sphingomyelin headgroup does not alter hippocampal membrane order. ► Our results show the importance of sphingomyelin in receptor function. Sphingolipids are essential components of eukaryotic cell membranes and are thought to be involved in a variety of cellular functions. Sphingomyelin is the most abundant sphingolipid in the nervous system. In this work, we explored the ligand binding function of the hippocampal serotonin receptor upon hydrolyzing sphingomyelin to ceramide and phosphocholine using sphingomyelinase. The serotonin receptor is an important neurotransmitter receptor and belongs to the superfamily of G-protein coupled receptors. It is involved in the generation and modulation of various cognitive, behavioral and developmental functions. We show here that specific agonist binding to serotonin receptors in native hippocampal membranes is considerably reduced upon sphingomyelinase treatment. Interestingly, the overall membrane order does not exhibit any appreciable change under these conditions. Our results show the importance of sphingomyelin (specifically, the sphingomyelin headgroup) for the function of serotonin receptors. These novel results constitute the first report on the effect of enzymatic hydrolysis of sphingomyelin on the ligand binding function of this important neurotransmitter receptor in native hippocampal membranes. Our results assume greater relevance in the broader perspective of the influence of the membrane lipid environment on the function of the serotonin receptor in particular, and other G-protein coupled receptors in general.
    Keywords: Serotonin1a Receptor ; Sphingomyelinase ; Sphingolipid ; Ligand Binding ; Fluorescence Anisotropy ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 28 May 2013, Vol.110(22), pp.8960-5
    Description: Establishment and maintenance of apico-basolateral trafficking pathways are critical to epithelial homeostasis. Loss of polarity and trafficking fidelity are thought to occur as a consequence of transformation; however, here we report that selective mistrafficking of the epidermal growth factor receptor (EGFR) ligand epiregulin (EREG) from the basolateral to the apical cell surface drives transformation. Normally, EREG is preferentially delivered to the basolateral surface of polarized Madin-Darby canine kidney cells. EREG basolateral trafficking is regulated by a conserved tyrosine-based basolateral sorting motif in its cytoplasmic domain (YXXΦ: Y(156)ERV). Both Y156 and V159 are required for basolateral sorting of EREG, because Y156A and V159G substitutions redirect EREG to the apical cell surface. We also show that basolateral sorting of EREG is adaptor protein 1B-independent. Apical mistrafficking of EREG has a distinctive phenotype. In contrast to transient EGFR tyrosine phosphorylation after basolateral EREG stimulation, apical EREG leads to prolonged EGFR tyrosine phosphorylation, which may be related, at least in part, to a lack of negative regulatory Y1045 phosphorylation and subsequent ubiquitylation. Notably, Madin-Darby canine kidney cells stably expressing apically mistrafficked EREG form significantly larger, hyperproliferative, poorly differentiated, and locally invasive tumors in nude mice compared with WT EREG-expressing cells.
    Keywords: Epithelial Transformation ; Growth Factor Trafficking ; Protein Sorting ; Receptor Tyrosine Kinase ; Cell Polarity -- Physiology ; Cell Transformation, Neoplastic -- Metabolism ; Epidermal Growth Factor -- Metabolism ; Epithelial Cells -- Physiology ; Signal Transduction -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    Language: English
    In: Nature, 07 May 2015, Vol.521(7550), pp.112
    Description: In July last year, neurobiologist Björn Brembs published a paper about how fruit flies walk. Nine months on, his paper looks different: another group has fed its data into the article, altering one of the figures.
    Keywords: Drosophila Melanogaster ; Publishing -- Trends
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 14 February 2012, Vol.109(7), pp.2184-5
    Description: Author contributions: H.S.M. wrote the paper.
    Keywords: Endogenous Retroviruses -- Genetics ; Gene Products, Env -- Physiology ; Placentation -- Physiology ; Pregnancy Proteins -- Physiology ; Viral Envelope Proteins -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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