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  • 1
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    Selective expression of Parkinson's disease-related Leucine-rich repeat kinase 2 G2019S missense mutation in midbrain dopaminergic neurons impairs dopamine release and dopaminergic gene expression (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-27
    Description: Preferential dysfunction/degeneration of midbrain substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons contributes to the main movement symptoms manifested in Parkinson's disease (PD). Although the Leucine-rich repeat kinase 2 ( LRRK2 ) G2019S missense mutation ( LRRK2 G2019S) is the most common causative genetic factor linked to PD, the effects of LRRK2 G2019S on the function and survival of SNpc DA neurons are poorly understood. Using a binary gene expression system, we generated transgenic mice expressing either wild-type human LRRK2 (WT mice) or the LRRK2 G2019S mutation (G2019S mice) selectively in the midbrain DA neurons. Here we show that overexpression of LRRK2 G2019S did not induce overt motor abnormalities or substantial SNpc DA neuron loss. However, the LRRK2 G2019S mutation impaired dopamine homeostasis and release in aged mice. This reduction in dopamine content/release coincided with the degeneration of DA axon terminals and decreased expression of DA neuron-enriched genes tyrosine hydroxylase (TH), vesicular monoamine transporter 2, dopamine transporter and aldehyde dehydrogenase 1. These factors are responsible for dopamine synthesis, transport and degradation, and their expression is regulated by transcription factor paired-like homeodomain 3 (PITX3). Levels of Pitx3 mRNA and protein were similarly decreased in the SNpc DA neurons of aged G2019S mice. Together, these findings suggest that PITX3-dependent transcription regulation could be one of the many potential mechanisms by which LRRK2 G2019S acts in SNpc DA neurons, resulting in downregulation of its downstream target genes critical for dopamine homeostasis and release.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    Spherulites as in-situ recorders of thermal history in lava flows (2015)
    Geological Society of America (GSA)
    In: Geology
    Details
    Publication Date: 2015-06-23
    Description: Spherulites in rhyolitic obsidian provide a record of the thermal history of their host lava during the interval of spherulite growth. We use trace element concentration profiles across spherulites and into the obsidian host from Yellowstone National Park (USA) to reconstruct the conditions that existed during spherulite formation. The measured transects reveal three behaviors: expulsion of the most diffusively mobile elements from spherulites with no concentration gradients in the surrounding glass (type 1); enrichment of slower-diffusing elements around spherulites, with concentration gradients extending outward into the glass (type 2); and complete entrapment of the slowest-diffusing elements by the spherulite (type 3). We compare the concentration profiles, measured by laser ablation–inductively coupled plasma–mass spectrometry and Fourier transform infrared spectroscopy, to the output of a spherulite growth model that incorporates known diffusion parameters, the temperature interval of spherulite growth, the cooling rate of the lava, and data on the temporal evolution of spherulite radius. Our results constrain spherulite nucleation to the temperature interval 700–550 °C and spherulite growth to 700–400 °C in a portion of lava that cooled at 10 –5.2 ± 0.3 °C s –1 , which matches an independent experimental estimate of 10 –5.3 °C s –1 measured using differential scanning calorimetry. Maximum spherulite growth rates at nucleation are on the order of 1 μm hr –1 and are inferred to decrease exponentially with time. Hence, spherulites may serve as valuable in-situ recorders of the thermal history of lava flows.
    Print ISSN: 0091-7613
    Electronic ISSN: 1943-2682
    Topics: Geosciences
    Published by Geological Society of America (GSA)
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  • 3
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    TEMPORAL DYNAMICS OF SHALLOW SEAGRASS-ASSOCIATED MOLLUSCAN ASSEMBLAGES IN ST. CROIX, U.S. VIRGIN ISLANDS: TOWARD THE CALIBRATION OF TAPHONOMIC INERTIA (2014)
    Society for Sedimentary Geology (SEPM)
    In: PALAIOS
    Details
    Publication Date: 2014-09-20
    Description: By comparing censuses of living, shallow marine molluscan communities with their associated time-averaged dead remains, we gain an understanding of compositional changes that have taken place through time. Our ability to diagnose anthropogenic or natural environmental changes based on dissimilarities between life and death assemblages, however, is contingent on the existence of a time lag between changes in the life assemblage and their manifestations in the time-averaged death assemblage (taphonomic inertia). Here, we utilized a unique set of multiyear census records of live and dead marine mollusks from Smuggler's Cove, St. Croix, U.S. Virgin Islands to determine the magnitude of taphonomic inertia in this setting. We found that over a more than three-decade interval from 1980 to 2012, both the life and death assemblage composition varied significantly. Most of this variation was driven by shifting rank orders of several key species, including: Cerithium litteratum , Modulus modulus , and lucinid bivalves. Decadal-scale variations in the life assemblage for the most abundant species, C. litteratum , are mirrored in death assemblages collected throughout the entire study interval, suggesting that the upper limit of taphonomic inertia is a decade or less. On the other hand, notable differences in composition between life assemblages, but not death assemblages, among samples collected 1.5 years apart suggest a minimum degree of inertia that is greater than seasonal. Precipitation and temperature, investigated as possible environmental drivers of change, vary significantly over the period in question, and likely play some role in regulating the abundances of these key species, although this remains speculative.
    Print ISSN: 0883-1351
    Electronic ISSN: 0883-1351
    Topics: Geosciences
    Published by Society for Sedimentary Geology (SEPM)
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  • 4
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    Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-12-18
    Description: DNA double-strand breaks (DSBs) are highly cytotoxic lesions that are generated by ionizing radiation and various DNA-damaging chemicals. Following DSB formation, cells activate the DNA-damage response (DDR) protein kinases ATM, ATR and DNA-PK (also known as PRKDC). These then trigger histone H2AX (also known as H2AFX) phosphorylation and the accumulation of proteins such as MDC1, 53BP1 (also known as TP53BP1), BRCA1, CtIP (also known as RBBP8), RNF8 and RNF168/RIDDLIN into ionizing radiation-induced foci (IRIF) that amplify DSB signalling and promote DSB repair. Attachment of small ubiquitin-related modifier (SUMO) to target proteins controls diverse cellular functions. Here, we show that SUMO1, SUMO2 and SUMO3 accumulate at DSB sites in mammalian cells, with SUMO1 and SUMO2/3 accrual requiring the E3 ligase enzymes PIAS4 and PIAS1. We also establish that PIAS1 and PIAS4 are recruited to damage sites via mechanisms requiring their SAP domains, and are needed for the productive association of 53BP1, BRCA1 and RNF168 with such regions. Furthermore, we show that PIAS1 and PIAS4 promote DSB repair and confer ionizing radiation resistance. Finally, we establish that PIAS1 and PIAS4 are required for effective ubiquitin-adduct formation mediated by RNF8, RNF168 and BRCA1 at sites of DNA damage. These findings thus identify PIAS1 and PIAS4 as components of the DDR and reveal how protein recruitment to DSB sites is controlled by coordinated SUMOylation and ubiquitylation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904806/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904806/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Galanty, Yaron -- Belotserkovskaya, Rimma -- Coates, Julia -- Polo, Sophie -- Miller, Kyle M -- Jackson, Stephen P -- 086861/Wellcome Trust/United Kingdom -- 11224/Cancer Research UK/United Kingdom -- A5290/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Dec 17;462(7275):935-9. doi: 10.1038/nature08657.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust and Cancer Research UK Gurdon Institute, and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20016603" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; BRCA1 Protein/metabolism ; Cell Line ; Cell Line, Tumor ; *DNA Breaks, Double-Stranded ; *DNA Repair ; DNA-Binding Proteins/genetics/metabolism ; Fluorescence Recovery After Photobleaching ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Models, Biological ; Phosphorylation ; Protein Inhibitors of Activated STAT/chemistry/genetics/*metabolism ; Protein Structure, Tertiary ; Replication Protein A/metabolism ; Small Ubiquitin-Related Modifier Proteins/genetics/*metabolism ; Ubiquitin-Conjugating Enzymes/genetics/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 5
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    HAATI survivors replace canonical telomeres with blocks of generic heterochromatin (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-09-11
    Description: The notion that telomeres are essential for chromosome linearity stems from the existence of two chief dangers: inappropriate DNA damage response (DDR) reactions that mistake natural chromosome ends for double-strand DNA breaks (DSBs), and the progressive loss of DNA from chromosomal termini due to the end replication problem. Telomeres avert the former peril by binding sequence-specific end-protection factors that control the access of DDR activities. The latter threat is tackled by recruiting telomerase, a reverse transcriptase that uses an integral RNA subunit to template the addition of telomere repeats to chromosome ends. Here we describe an alternative mode of linear chromosome maintenance in which canonical telomeres are superseded by blocks of heterochromatin. We show that in the absence of telomerase, Schizosaccharomyces pombe cells can survive telomere sequence loss by continually amplifying and rearranging heterochromatic sequences. Because the heterochromatin assembly machinery is required for this survival mode, we have termed it 'HAATI' (heterochromatin amplification-mediated and telomerase-independent). HAATI uses the canonical end-protection protein Pot1 (ref. 4) and its interacting partner Ccq1 (ref. 5) to preserve chromosome linearity. The data suggest a model in which Ccq1 is recruited by the amplified heterochromatin and provides an anchor for Pot1, which accomplishes its end-protection function in the absence of its cognate DNA-binding sequence. HAATI resembles the chromosome end-maintenance strategy found in Drosophila melanogaster, which lacks specific telomere sequences but nonetheless assembles terminal heterochromatin structures that recruit end-protection factors. These findings reveal a previously unrecognized mode by which cancer cells might escape the requirement for telomerase activation, and offer a tool for studying genomes that sustain unusually high levels of heterochromatinization.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jain, Devanshi -- Hebden, Anna K -- Nakamura, Toru M -- Miller, Kyle M -- Cooper, Julia Promisel -- Cancer Research UK/United Kingdom -- England -- Nature. 2010 Sep 9;467(7312):223-7. doi: 10.1038/nature09374.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20829796" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Cycle Proteins/metabolism ; Chromosomes, Fungal/*metabolism ; Drosophila melanogaster/metabolism ; *Heterochromatin ; Humans ; Methyltransferases/metabolism ; Rad51 Recombinase/metabolism ; Schizosaccharomyces/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Telomerase/metabolism ; Telomere/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 6
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    Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-02-03
    Description: The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions. Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Poltheta; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Poltheta has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718306/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718306/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mateos-Gomez, Pedro A -- Gong, Fade -- Nair, Nidhi -- Miller, Kyle M -- Lazzerini-Denchi, Eros -- Sfeir, Agnel -- AG038677/AG/NIA NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- R01 AG038677/AG/NIA NIH HHS/ -- England -- Nature. 2015 Feb 12;518(7538):254-7. doi: 10.1038/nature14157. Epub 2015 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU School of Medicine, New York, New York 10016, USA. ; Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin. 2506 Speedway Stop A5000, Austin, Texas 78712, USA. ; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25642960" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Death/genetics ; Cell Line ; Chromosome Aberrations ; Chromosomes, Mammalian/genetics/*metabolism ; *DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; DNA-Directed DNA Polymerase/deficiency/*metabolism ; Genes, BRCA1 ; Genes, BRCA2 ; HeLa Cells ; Humans ; Mice ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Rad51 Recombinase/metabolism ; *Recombination, Genetic/genetics ; Recombinational DNA Repair/genetics ; Telomere/*genetics/*metabolism ; Translocation, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 7
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    Genomic signatures predict migration and spawning failure in wild Canadian salmon (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-01-15
    Description: Long-term population viability of Fraser River sockeye salmon (Oncorhynchus nerka) is threatened by unusually high levels of mortality as they swim to their spawning areas before they spawn. Functional genomic studies on biopsied gill tissue from tagged wild adults that were tracked through ocean and river environments revealed physiological profiles predictive of successful migration and spawning. We identified a common genomic profile that was correlated with survival in each study. In ocean-tagged fish, a mortality-related genomic signature was associated with a 13.5-fold greater chance of dying en route. In river-tagged fish, the same genomic signature was associated with a 50% increase in mortality before reaching the spawning grounds in one of three stocks tested. At the spawning grounds, the same signature was associated with 3.7-fold greater odds of dying without spawning. Functional analysis raises the possibility that the mortality-related signature reflects a viral infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, Kristina M -- Li, Shaorong -- Kaukinen, Karia H -- Ginther, Norma -- Hammill, Edd -- Curtis, Janelle M R -- Patterson, David A -- Sierocinski, Thomas -- Donnison, Louise -- Pavlidis, Paul -- Hinch, Scott G -- Hruska, Kimberly A -- Cooke, Steven J -- English, Karl K -- Farrell, Anthony P -- New York, N.Y. -- Science. 2011 Jan 14;331(6014):214-7. doi: 10.1126/science.1196901.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Genetics Section, Pacific Biological Station, 3190 Hammond Bay Road, Fisheries and Oceans Canada, Nanaimo, BC V9T 6N7, Canada. kristi.miller@dfo-mpo.gc.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21233388" target="_blank"〉PubMed〈/a〉
    Keywords: *Animal Migration ; Animals ; Canada ; Female ; Fish Diseases/genetics/immunology/mortality ; *Gene Expression ; *Gene Expression Profiling ; Genome ; Gills ; Male ; Mortality ; Oligonucleotide Array Sequence Analysis ; Pacific Ocean ; Population Dynamics ; Principal Component Analysis ; Remote Sensing Technology ; *Reproduction ; Rivers ; Salmon/*genetics/*physiology ; Stress, Physiological ; Survival Analysis ; Virus Diseases/genetics/immunology/mortality/veterinary
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 8
    Electronic Resource
    Electronic Resource
    A gas scintillation proportional counter using a photomultiplier tube array
    Amsterdam : Elsevier
    Nuclear Instruments and Methods 163 (1979), S. 583-586 
    Details
    ISSN: 0029-554X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Physics
    Type of Medium: Electronic Resource
    URL: http://linkinghub.elsevier.com/retrieve/pii/0029-554X(79)90153-8
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  • 9
    Electronic Resource
    Electronic Resource
    Minisatellite DNA variation and stock identification of coho salmon (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of fish biology 49 (1996), S. 0 
    Details
    ISSN: 1095-8649
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology
    Notes: Geographic variation in minisatellite DNA variation was examined in 18 stocks of coho salmon Oncorhynchus kisutch from British Columbia and three stocks from Kamchatka or Western Alaska. Genomic DNA was restricted with Mbo I or Hae III and hybridized with two minisatellite probes (pSsa-A34, Ots PBS-1). Allele frequencies and DNA band counts derived from the two probes were combined with band counts from the probe Ssa to show a regional stock structure. In British Columbia, stocks from the Fraser River were distinct from those on Vancouver Island, and all were differentiated from those on the mainland of British Columbia. Average heterozygosity at the Ssa-A34 locus was 71%. Compared with a previous study of British Columbia coho salmon population structure in which variation at 26 allozyme loci was examined, greater population differentiation and higher heterozygosity were observed at minisatellite loci. Estimated stock compositions of simulated mixtures of fishery samples from British Columbia stocks were accurate and precise, with the potential of identifying stocks within the drainage basin of a major river, the Fraser River. Minisatellite DNA variation may provide accurate and precise estimates of stock composition in actual fishery applications, and has the potential of identifying individual fish to region or stock of origin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1095-8649.1996.tb00038.x
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  • 10
    Electronic Resource
    Electronic Resource
    Structure of (benzenethiolato)(2,3,7,8,12,13,17,18-octaethylporphinato)iron(III), [Fe(C36H44N4)(C6H5S)] (1984)
    Oxford [u.a.] : International Union of Crystallography (IUCr)
    Acta crystallographica 40 (1984), S. 1324-1327 
    Details
    ISSN: 1600-5759
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1107/S0108270184007836
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