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  • 1
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    Astrometry of mutual approximations between natural satellites. Application to the Galilean moons (2016)
    Oxford University Press
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    Publikationsdatum: 2016-06-26
    Beschreibung: Typically we can deliver astrometric positions of natural satellites with errors in the 50–150 mas range. Apparent distances from mutual phenomena, have much smaller errors, less than 10 mas. However, this method can only be applied during the equinox of the planets. We developed a method that can provide accurate astrometric data for natural satellites – the mutual approximations. The method can be applied when any two satellites pass close by each other in the apparent sky plane. The fundamental parameter is the central instant t 0 of the passage when the distances reach a minimum. We applied the method for the Galilean moons. All observations were made with a 0.6 m telescope with a narrow-band filter centred at 889 nm with width of 15 nm which attenuated Jupiter's scattered light. We obtained central instants for 14 mutual approximations observed in 2014–2015. We determined t 0 with an average precision of 3.42 mas (10.43 km). For comparison, we also applied the method for 5 occultations in the 2009 mutual phenomena campaign and for 22 occultations in the 2014–2015 campaign. The comparisons of t 0 determined by our method with the results from mutual phenomena show an agreement by less than 1 error in t 0 , typically less than 10 mas. This new method is particularly suitable for observations by small telescopes.
    Print ISSN: 0035-8711
    Digitale ISSN: 1365-2966
    Thema: Physik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
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    Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome (2015)
    Oxford University Press
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    Publikationsdatum: 2015-04-23
    Beschreibung: The Brugada syndrome (BrS) is a rare heritable cardiac arrhythmia disorder associated with ventricular fibrillation and sudden cardiac death. Mutations in the SCN5A gene have been causally related to BrS in 20–30% of cases. Twenty other genes have been described as involved in BrS, but their overall contribution to disease prevalence is still unclear. This study aims to estimate the burden of rare coding variation in arrhythmia-susceptibility genes among a large group of patients with BrS. We have developed a custom kit to capture and sequence the coding regions of 45 previously reported arrhythmia-susceptibility genes and applied this kit to 167 index cases presenting with a Brugada pattern on the electrocardiogram as well as 167 individuals aged over 65-year old and showing no history of cardiac arrhythmia. By applying burden tests, a significant enrichment in rare coding variation (with a minor allele frequency below 0.1%) was observed only for SCN5A , with rare coding variants carried by 20.4% of cases with BrS versus 2.4% of control individuals ( P = 1.4 x 10 –7 ). No significant enrichment was observed for any other arrhythmia-susceptibility gene, including SCN10A and CACNA1C . These results indicate that, except for SCN5A , rare coding variation in previously reported arrhythmia-susceptibility genes do not contribute significantly to the occurrence of BrS in a population with European ancestry. Extreme caution should thus be taken when interpreting genetic variation in molecular diagnostic setting, since rare coding variants were observed in a similar extent among cases versus controls, for most previously reported BrS-susceptibility genes.
    Print ISSN: 0964-6906
    Digitale ISSN: 1460-2083
    Thema: Biologie , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
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    Results of two multichord stellar occultations by dwarf planet (1) Ceres (2015)
    Oxford University Press
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    Publikationsdatum: 2015-06-15
    Beschreibung: We report the results of two multichord stellar occultations by the dwarf planet (1) Ceres that were observed from Brazil on 2010 August 17, and from the USA on 2013 October 25. Four positive detections were obtained for the 2010 occultation, and nine for the 2013 occultation. Elliptical models were adjusted to the observed chords to obtain Ceres’ size and shape. Two limb-fitting solutions were studied for each event. The first one is a nominal solution with an indeterminate polar aspect angle. The second one was constrained by the pole coordinates as given by Drummond et al. Assuming a Maclaurin spheroid, we determine an equatorial diameter of 972 ± 6 km and an apparent oblateness of 0.08 ± 0.03 as our best solution. These results are compared to all available size and shape determinations for Ceres made so far, and shall be confirmed by the NASA's Dawn space mission.
    Print ISSN: 0035-8711
    Digitale ISSN: 1365-2966
    Thema: Physik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
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    Neofiscalin A and fiscalin C are potential novel indole alkaloid alternatives for the treatment of multidrug-resistant Gram-positive bacterial infections (2016)
    Oxford University Press
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    Publikationsdatum: 2016-07-02
    Beschreibung: Ten indole alkaloids were obtained from the marine sponge-associated fungus Neosartorya siamensis KUFA 0017. We studied the antimicrobial properties of these and of three other compounds previously isolated from the soil fungus N. siamensis KUFC 6349. Only neofiscalin A showed antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE); with a minimum inhibitory concentration (MIC) of 8 μg mL –1 against both strains. Another compound, fiscalin C, presented synergistic activity against MRSA when combined with oxacillin, although alone showed no antibacterial effect. Moreover, neofiscalin A, when present at sub-MICs, hampered the ability of both MRSA and VRE strains to form a biofilm. Additionally, the biofilm inhibitory concentration values of neofiscalin A against the MRSA and VRE isolates were 96 and 80 μg mL –1 , respectively. At a concentration of 200 μg mL –1 , neofiscalin A was able to reduce the metabolic activity of the biofilms by ~50%. One important fact is that our results also showed that neofiscalin A had no cytotoxicity against a human brain capillary endothelial cell line.
    Schlagwort(e): Biotechnology & Synthetic Biology
    Print ISSN: 0378-1097
    Digitale ISSN: 1574-6968
    Thema: Biologie
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 5
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    Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cells (2015)
    Oxford University Press
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    Publikationsdatum: 2015-05-20
    Beschreibung: Abnormally expanded DNA repeats are associated with several neurodegenerative diseases. In Friedreich's ataxia (FRDA), expanded GAA repeats in intron 1 of the frataxin gene ( FXN ) reduce FXN mRNA levels in averaged cell samples through a poorly understood mechanism. By visualizing FXN expression and nuclear localization in single cells, we show that GAA-expanded repeats decrease the number of FXN mRNA molecules, slow transcription, and increase FXN localization at the nuclear lamina (NL). Restoring histone acetylation reverses NL positioning. Expanded GAA- FXN loci in FRDA patient cells show increased NL localization with increased silencing of alleles and reduced transcription from alleles positioned peripherally. We also demonstrate inefficiencies in transcription initiation and elongation from the expanded GAA- FXN locus at single-cell resolution. We suggest that repressive epigenetic modifications at the expanded GAA- FXN locus may lead to NL relocation, where further repression may occur.
    Print ISSN: 0964-6906
    Digitale ISSN: 1460-2083
    Thema: Biologie , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
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    Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of {gamma}-secretase activity (2015)
    Oxford University Press
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    Publikationsdatum: 2015-06-09
    Beschreibung: The PRESENILIN1 and PRESENILIN2 genes encode structurally related proteases essential for -secretase activity. Of nearly 200 PRESENILIN mutations causing early onset, familial Alzheimer's disease (FAD) only the K115Efx10 mutation of PSEN2 causes truncation of the open reading frame. If translated, the truncated product would resemble a naturally occurring isoform of PSEN2 named PS2V that is induced by hypoxia and found at elevated levels in late onset Alzheimer's disease (AD) brains. The function of PS2V is largely unexplored. We show that zebrafish possess a PS2V-like isoform, PS1IV, produced from the fish's PSEN1 rather than PSEN2 orthologous gene. The molecular mechanism controlling formation of PS2V/PS1IV was probably present in the ancient common ancestor of the PSEN1 and PSEN2 genes. Human PS2V and zebrafish PS1IV have highly divergent structures but conserved abilities to stimulate -secretase activity and to suppress the unfolded protein response (UPR) under hypoxia. The putative protein truncation caused by K115Efx10 resembles PS2V in its ability to increase -secretase activity and suppress the UPR. This supports increased Aβ levels as a common link between K115Efx10 early onset AD and sporadic, late onset AD. The ability of mutant variants of PS2V to stimulate -secretase activity partially correlates with their ability to suppress the UPR. The cytosolic, transmembrane and luminal domains of PS2V are all critical to its -secretase and UPR-suppression activities. Our data support a model in which chronic hypoxia in aged brains promotes excessive Notch signalling and accumulation of Aβ that contribute to AD pathogenesis.
    Print ISSN: 0964-6906
    Digitale ISSN: 1460-2083
    Thema: Biologie , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 7
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    Surface ozone at a coastal suburban site in 2009 and 2010: Relationships to chemical and meteorological processes (2012)
    Wiley
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    Publikationsdatum: 2012-03-07
    Beschreibung: Air quality and meteorological measurements were conducted at the Chemistry and Physics of the Atmospheric Boundary Layer Experiment (CAPABLE) site during the summers of 2009 and 2010 in Hampton, Virginia. Significant differences in surface ozone mixing ratios were observed between the two years and are correlated with meteorological parameters such as temperature, humidity, and cloud cover. The number of exceedance days for ozone set by the U.S. Environmental Protection Agency within this region has been decreasing for the past decade, especially in urban areas. There were no exceedance days with respect to ozone in 2009, and there were four exceedance days in 2010. The four highest ozone daily maxima and the two exceedance days observed during the 2010 measurement period were coincident with sea breeze phenomena. In one case, surface ozone increased at a rate of 14.6 ppb h−1 with the passage of a sea breeze front. A comprehensive multilinear regression model as well as an operational forecast was unable to resolve the high ozone observed during sea breeze events. As the number of exceedance days per year within this region continues to decrease, accurately forecasting sea breezes may become more important for the forecasting of pollution events.
    Print ISSN: 0148-0227
    Thema: Geologie und Paläontologie , Physik
    Publiziert von Wiley im Namen von American Geophysical Union (AGU).
    Standort Signatur Erwartet Verfügbarkeit
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  • 8
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    Differential, dominant activation and inhibition of Notch signalling and APP cleavage by truncations of PSEN1 in human disease (2014)
    Oxford University Press
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    Publikationsdatum: 2014-01-11
    Beschreibung: PRESENILIN1 ( PSEN1 ) is the major locus for mutations causing familial Alzheimer's disease (FAD) and is also mutated in Pick disease of brain, familial acne inversa and dilated cardiomyopathy. It is a critical facilitator of Notch signalling and many other signalling pathways and protein cleavage events including production of the Amyloidβ (Aβ) peptide from the AMYLOID BETA A4 PRECURSOR PROTEIN (APP). We previously reported that interference with splicing of transcripts of the zebrafish orthologue of PSEN1 creates dominant negative effects on Notch signalling. Here, we extend this work to show that various truncations of human PSEN1 (or zebrafish Psen1) protein have starkly differential effects on Notch signalling and cleavage of zebrafish Appa (a paralogue of human APP). Different truncations can suppress or stimulate Notch signalling but not Appa cleavage and vice versa. The G183V mutation possibly causing Pick disease causes production of aberrant transcripts truncating the open reading frame after exon 5 sequence. We show that the truncated protein potentially translated from these transcripts avidly incorporates into very stable Psen1-dependent higher molecular weight complexes and suppresses cleavage of Appa but not Notch signalling. In contrast, the truncated protein potentially produced by the P242LfsX11 acne inversa mutation has no effect on Appa cleavage but, unexpectedly, enhances Notch signalling. Our results suggest novel hypotheses for the pathological mechanisms underlying these diseases and illustrate the importance of investigating the function of dominant mutations at physiologically relevant expression levels and in the normally heterozygous state in which they cause human disease rather than in isolation from healthy alleles.
    Print ISSN: 0964-6906
    Digitale ISSN: 1460-2083
    Thema: Biologie , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 9
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    A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds (2013)
    Oxford University Press
    Details
    Publikationsdatum: 2013-11-28
    Beschreibung: Friedreich's ataxia (FRDA) is caused by large GAA expansions in intron 1 of the frataxin gene ( FXN ), which lead to reduced FXN expression through a mechanism not fully understood. Understanding such mechanism is essential for the identification of novel therapies for FRDA and this can be accelerated by the development of cell models which recapitulate the genomic context of the FXN locus and allow direct comparison of normal and expanded FXN loci with rapid detection of frataxin levels. Here we describe the development of the first GAA-expanded FXN genomic DNA reporter model of FRDA. We modified BAC vectors carrying the whole FXN genomic DNA locus by inserting the luciferase gene in exon 5a of the FXN gene (pBAC- FXN-Luc ) and replacing the six GAA repeats present in the vector with an ~310 GAA repeat expansion (pBAC- FXN-GAA-Luc ). We generated human clonal cell lines carrying the two vectors using site-specific integration to allow direct comparison of normal and expanded FXN loci. We demonstrate that the presence of expanded GAA repeats recapitulates the epigenetic modifications and repression of gene expression seen in FRDA. We applied the GAA-expanded reporter model to the screening of a library of novel small molecules and identified one molecule which up-regulates FXN expression in FRDA patient primary cells and restores normal histone acetylation around the GAA repeats. These results suggest the potential use of genomic reporter cell models for the study of FRDA and the identification of novel therapies, combining physiologically relevant expression with the advantages of quantitative reporter gene expression.
    Print ISSN: 0964-6906
    Digitale ISSN: 1460-2083
    Thema: Biologie , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 10
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    LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function (2016)
    Oxford University Press
    Details
    Publikationsdatum: 2016-02-16
    Beschreibung: Mutations in leucine-rich repeat kinase 2 ( LRRK2 ) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2 . To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions. Aged (18–21 months) G2019S and R1441C mutant transgenic rats exhibit L-DOPA-responsive motor dysfunction, impaired striatal dopamine release as determined by fast-scan cyclic voltammetry, and cognitive deficits. In addition, in vivo recordings of identified substantia nigra pars compacta dopamine neurons in R1441C LRRK2 transgenic rats reveal an age-dependent reduction in burst firing, which likely results in further reductions to striatal dopamine release. These alterations to dopamine circuit function occur in the absence of neurodegeneration or abnormal protein accumulation within the substantia nigra pars compacta, suggesting that nigrostriatal dopamine dysfunction precedes detectable protein aggregation and cell death in the development of Parkinson's disease. In conclusion, our longitudinal deep-phenotyping provides novel insights into how the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to dopamine circuit function and highlights a potential model for testing Parkinson's therapeutics.
    Print ISSN: 0964-6906
    Digitale ISSN: 1460-2083
    Thema: Biologie , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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