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  • 1
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    An atlas of gene expression and gene co-regulation in the human retina (2016)
    Oxford University Press
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    Publication Date: 2016-07-09
    Description: The human retina is a specialized tissue involved in light stimulus transduction. Despite its unique biology, an accurate reference transcriptome is still missing. Here, we performed gene expression analysis (RNA-seq) of 50 retinal samples from non-visually impaired post-mortem donors. We identified novel transcripts with high confidence (Observed Transcriptome (ObsT)) and quantified the expression level of known transcripts (Reference Transcriptome (RefT)). The ObsT included 77 623 transcripts (23 960 genes) covering 137 Mb (35 Mb new transcribed genome). Most of the transcripts (92%) were multi-exonic: 81% with known isoforms, 16% with new isoforms and 3% belonging to new genes. The RefT included 13 792 genes across 94 521 known transcripts. Mitochondrial genes were among the most highly expressed, accounting for about 10% of the reads. Of all the protein-coding genes in Gencode, 65% are expressed in the retina. We exploited inter-individual variability in gene expression to infer a gene co-expression network and to identify genes specifically expressed in photoreceptor cells. We experimentally validated the photoreceptors localization of three genes in human retina that had not been previously reported. RNA-seq data and the gene co-expression network are available online ( http://retina.tigem.it ).
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    A systematic survey of the Cys2His2 zinc finger DNA-binding landscape (2015)
    Oxford University Press
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    Publication Date: 2015-02-18
    Description: Cys 2 His 2 zinc fingers (C2H2-ZFs) comprise the largest class of metazoan DNA-binding domains. Despite this domain's well-defined DNA-recognition interface, and its successful use in the design of chimeric proteins capable of targeting genomic regions of interest, much remains unknown about its DNA-binding landscape. To help bridge this gap in fundamental knowledge and to provide a resource for design-oriented applications, we screened large synthetic protein libraries to select binding C2H2-ZF domains for each possible three base pair target. The resulting data consist of 〉160 000 unique domain–DNA interactions and comprise the most comprehensive investigation of C2H2-ZF DNA-binding interactions to date. An integrated analysis of these independent screens yielded DNA-binding profiles for tens of thousands of domains and led to the successful design and prediction of C2H2-ZF DNA-binding specificities. Computational analyses uncovered important aspects of C2H2-ZF domain–DNA interactions, including the roles of within-finger context and domain position on base recognition. We observed the existence of numerous distinct binding strategies for each possible three base pair target and an apparent balance between affinity and specificity of binding. In sum, our comprehensive data help elucidate the complex binding landscape of C2H2-ZF domains and provide a foundation for efforts to determine, predict and engineer their DNA-binding specificities.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Proximity of H2A.Z containing nucleosome to the transcription start site influences gene expression levels in the mammalian liver and brain (2012)
    Oxford University Press
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    Publication Date: 2012-10-10
    Description: Nucleosome positioning maps of several organisms have shown that Transcription Start Sites (TSSs) are marked by nucleosome depleted regions flanked by strongly positioned nucleosomes. Using genome-wide nucleosome maps and histone variant occupancy in the mouse liver, we show that the majority of genes were associated with a single prominent H2A.Z containing nucleosome in their promoter region. We classified genes into clusters depending on the proximity of H2A.Z to the TSS. The genes with no detectable H2A.Z showed lowest expression level, whereas H2A.Z was positioned closer to the TSS of genes with higher expression levels. We confirmed this relation between the proximity of H2A.Z and expression level in the brain. The proximity of histone variant H2A.Z, but not H3.3 to the TSS, over seven consecutive nucleosomes, was correlated with expression. Further, a nucleosome was positioned over the TSS of silenced genes while it was displaced to expose the TSS in highly expressed genes. Our results suggest that gene expression levels in vivo are determined by accessibility of the TSS and proximity of H2A.Z.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Photometric and polarimetric observations of fast declining Type II supernovae 2013hj and 2014G (2015)
    Oxford University Press
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    Publication Date: 2015-11-27
    Description: We present broad-band photometric and polarimetric observations of two Type II supernovae (SNe) 2013hj and 2014G. SN 2014G is a spectroscopically classified Type IIL event, which we also confirm photometrically because its light curve shows characteristic features – a plateau slope of 2.55 mag (100 d) –1 in the V band and a duration of ~77 d – of a generic Type IIL SN. However, SN 2013hj also shows a high plateau decline rate of 1.5 mag (100 d) –1 in the V band, similar to SNe IIL, but marginally lower than SNe IIL template light curves. Our high cadence photometric observations of SNe 2013hj and 2014G enables us to cover all characteristic phases up to the radioactive tail of optical light curves. Broad-band polarimetric observations reveal some polarization in SN 2013hj with subtle enhancement as the SN evolves towards the plateau end. However, the polarization angle remains constant throughout the evolution. This characteristic is consistent with the idea that the evolving SN with recombining hydrogen envelope is slowly revealing a more asymmetric central region of explosion. Modelling of the bolometric light curve yields a progenitor mass of ~11 M with a radius of ~700 R for SN 2013hj, while for the SN 2014G model estimated progenitor mass is ~9 M with a radius of ~630 R , both having a typical energy budget of ~2 x 10 51  erg.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 5
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    CCAT: Combinatorial Code Analysis Tool for transcriptional regulation (2014)
    Oxford University Press
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    Publication Date: 2014-03-13
    Description: Combinatorial interplay among transcription factors (TFs) is an important mechanism by which transcriptional regulatory specificity is achieved. However, despite the increasing number of TFs for which either binding specificities or genome-wide occupancy data are known, knowledge about cooperativity between TFs remains limited. To address this, we developed a computational framework for predicting genome-wide co-binding between TFs (CCAT, C ombinatorial C ode A nalysis T ool), and applied it to Drosophila melanogaster to uncover cooperativity among TFs during embryo development. Using publicly available TF binding specificity data and DNaseI chromatin accessibility data, we first predicted genome-wide binding sites for 324 TFs across five stages of D. melanogaster embryo development. We then applied CCAT in each of these developmental stages, and identified from 19 to 58 pairs of TFs in each stage whose predicted binding sites are significantly co-localized. We found that nearby binding sites for pairs of TFs predicted to cooperate were enriched in regions bound in relevant ChIP experiments, and were more evolutionarily conserved than other pairs. Further, we found that TFs tend to be co-localized with other TFs in a dynamic manner across developmental stages. All generated data as well as source code for our front-to-end pipeline are available at http://cat.princeton.edu .
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Interaction-based discovery of functionally important genes in cancers (2014)
    Oxford University Press
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    Publication Date: 2014-02-11
    Description: A major challenge in cancer genomics is uncovering genes with an active role in tumorigenesis from a potentially large pool of mutated genes across patient samples. Here we focus on the interactions that proteins make with nucleic acids, small molecules, ions and peptides, and show that residues within proteins that are involved in these interactions are more frequently affected by mutations observed in large-scale cancer genomic data than are other residues. We leverage this observation to predict genes that play a functionally important role in cancers by introducing a computational pipeline ( http://canbind.princeton.edu ) for mapping large-scale cancer exome data across patients onto protein structures, and automatically extracting proteins with an enriched number of mutations affecting their nucleic acid, small molecule, ion or peptide binding sites. Using this computational approach, we show that many previously known genes implicated in cancers are enriched in mutations within the binding sites of their encoded proteins. By focusing on functionally relevant portions of proteins—specifically those known to be involved in molecular interactions—our approach is particularly well suited to detect infrequent mutations that may nonetheless be important in cancer, and should aid in expanding our functional understanding of the genomic landscape of cancer.
    Keywords: Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Deep sequencing of large library selections allows computational discovery of diverse sets of zinc fingers that bind common targets (2014)
    Oxford University Press
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    Publication Date: 2014-02-11
    Description: The Cys 2 His 2 zinc finger (ZF) is the most frequently found sequence-specific DNA-binding domain in eukaryotic proteins. The ZF’s modular protein–DNA interface has also served as a platform for genome engineering applications. Despite decades of intense study, a predictive understanding of the DNA-binding specificities of either natural or engineered ZF domains remains elusive. To help fill this gap, we developed an integrated experimental-computational approach to enrich and recover distinct groups of ZFs that bind common targets. To showcase the power of our approach, we built several large ZF libraries and demonstrated their excellent diversity. As proof of principle, we used one of these ZF libraries to select and recover thousands of ZFs that bind several 3-nt targets of interest. We were then able to computationally cluster these recovered ZFs to reveal several distinct classes of proteins, all recovered from a single selection, to bind the same target. Finally, for each target studied, we confirmed that one or more representative ZFs yield the desired specificity. In sum, the described approach enables comprehensive large-scale selection and characterization of ZF specificities and should be a great aid in furthering our understanding of the ZF domain.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Census 2: isobaric labeling data analysis (2014)
    Oxford University Press
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    Publication Date: 2014-07-19
    Description: Motivation: We introduce Census 2, an update of a mass spectrometry data analysis tool for peptide/protein quantification. New features for analysis of isobaric labeling, such as Tandem Mass Tag (TMT) or Isobaric Tags for Relative and Absolute Quantification (iTRAQ), have been added in this version, including a reporter ion impurity correction, a reporter ion intensity threshold filter and an option for weighted normalization to correct mixing errors. TMT/iTRAQ analysis can be performed on experiments using HCD (High Energy Collision Dissociation) only, CID (Collision Induced Dissociation)/HCD (High Energy Collision Dissociation) dual scans or HCD triple-stage mass spectrometry data. To improve measurement accuracy, we implemented weighted normalization, multiple tandem spectral approach, impurity correction and dynamic intensity threshold features. Availability and implementation: Census 2 supports multiple input file formats including MS1/MS2, DTASelect, mzXML and pepXML. It requires JAVA version 6 or later to run. Free download of Census 2 for academic users is available at http://fields.scripps.edu/census/index.php . Contact: jyates@scripps.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 9
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    High-z Type Ia supernova data: non-Gaussianity and direction dependence (2014)
    Oxford University Press
    Details
    Publication Date: 2014-04-19
    Description: We use the 2 statistic introduced in Gupta et al. and Gupta & Saini to study directional dependence, in the high- z supernovae data. This dependence could arise due to departures from the cosmological principle or from direction-dependent statistical systematics in the data. We apply our statistic to the gold data set from Riess et al. and Riess et al., and Union2 catalogue from Amanullah et al. Our results show that all the three data sets show a weak but consistent direction dependence. In 2007, data errors are Gaussian; however, other two data sets show non-Gaussian features.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 10
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    molBLOCKS: decomposing small molecule sets and uncovering enriched fragments (2014)
    Oxford University Press
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    Publication Date: 2014-07-04
    Description: : The chemical structures of biomolecules, whether naturally occurring or synthetic, are composed of functionally important building blocks. Given a set of small molecules—for example, those known to bind a particular protein—computationally decomposing them into chemically meaningful fragments can help elucidate their functional properties, and may be useful for designing novel compounds with similar properties. Here we introduce molBLOCKS , a suite of programs for breaking down sets of small molecules into fragments according to a predefined set of chemical rules, clustering the resulting fragments, and uncovering statistically enriched fragments. Among other applications, our software should be a great aid in large-scale chemical analysis of ligands binding specific targets of interest. Availability and implementation: molBLOCKS is available as GPL C++ source code at http://compbio.cs.princeton.edu/molblocks . Contact: mona@cs.princeton.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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