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  • 1
    Language: English
    In: Trends in Biochemical Sciences, 1996, Vol.21(9), pp.342-345
    Description: The human general co-factors werediscovered during biochemical fractionation of mammalian nuclear extracts in functional assays. They appear to act in concert with other coactivators that bind tightly to the TATA-binding protein and RNA polymerase II. Several co-factors have been shown to interact with general transcription factors, leading either to activation or repression of transcription. At least one subgroup of co-factors that enhance the effects of activators on transcription are DNA-binding proteins located in the chromatin. In fact, one co-factor, the repressor NC2, is structurally related to histones. The understanding of the molecular interplay of such components of the initiation complex in the chromatin—including general co-factors, other co-factors, general factors and activators—will be a major challenge in the future.
    Keywords: Biology
    ISSN: 0968-0004
    E-ISSN: 1362-4326
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  • 2
    Language: English
    In: PLOS ONE, 2014, Vol.9(8), pp.urn:issn:1932-6203
    Description: Cognitive bias, the altered information processing resulting from the background emotional state of an individual, has been suggested as a promising new indicator of animal emotion. Comparable to anxious or depressed humans, animals in a putatively negative emotional state are more likely to judge an ambiguous stimulus as if it predicts a negative event, than those in positive states. The present study aimed to establish a cognitive bias test for mice based on a spatial judgment task and to apply it in a pilot study to serotonin transporter (5-HTT) knockout mice, a well-established mouse model for the study of anxiety- and depression-related behavior. In a first step, we validated that our setup can assess different expectations about the outcome of an ambiguous stimulus: mice having learned to expect something positive within a maze differed significantly in their behavior towards an unfamiliar location than animals having learned to expect something negative. In a second step, the use of spatial location as a discriminatory stimulus was confirmed by showing that mice interpret an ambiguous stimulus depending on its spatial location, with a position exactly midway between a positive and a negative reference point provoking the highest level of ambiguity. Finally, the anxiety- and depression-like phenotype of the 5-HTT knockout mouse model manifested - comparable to human conditions - in a trend for a negatively distorted interpretation of ambiguous information, albeit this effect was not statistically significant. The results suggest that the present cognitive bias test provides a useful basis to study the emotional state in mice, which may not only increase the translational value of animal models in the study of human affective disorders, but which is also a central objective of animal welfare research.
    Keywords: Research Article ; Biology And Life Sciences ; Research And Analysis Methods;
    ISSN: 1932-6203
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  • 3
    Language: English
    In: Cell, 1994, Vol.78(3), pp.525-534
    Description: Our investigations of mammalian class II gene transcription resulted in identification, purification, and cloning of the corresponding cDNA of a cellular factor (p15) that mediates the effects of several distinct activators on transcription in vitro. Functional deletion analyses revealed a bipartite structure of p15 comprising an amino-terminal regulatory domain and a carboxy-terminal cryptic DNA-binding domain. We provide evidence that activity of p15 is controlled by protein kinases that target the regulatory domain. Structural and functional similarities, including sequence homology to domains essential for cofactor function, cofactor activity, promiscuity with respect to transcriptional activators, and interactions with components of the basal transcription machinery, relate this novel cellular cofactor to viral immediate-early transcriptional regulators.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 4
    Language: English
    In: Chemosphere, 1999, Vol.38(14), pp.3237-3245
    Description: The use of probabilistic neural networks (PNN) to model the acute toxicity (96 h LC50) to the fathead minnow (Pimephales promelas), based on 865 chemical data sets, is described. The octanol/water partition co-efficient was not used as an input parameter and the information fed into the PNN was solely based on simple molecular descriptors that could be derived from the chemical structure. An extensive list of functional group descriptors is provided and the development of a model and cross validation procedures is explained. Predictions resulted from procedures involved in 5 subsets, each containing 20 per cent of the data, and compared to measured (expected) output data. High values of the correlations between the measured and predicted values strongly suggested the use of linear correlation to improve the model. The excellent statistics obtained with the PNN model indicate its applicability to a great variety of compounds.
    Keywords: Fathead Minnow ; Acute Toxicity ; Neural Network ; Model ; Prediction ; Chemistry ; Ecology
    ISSN: 0045-6535
    E-ISSN: 1879-1298
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  • 5
    In: Nature Biotechnology, 1998, Vol.16(11), p.1077
    Description: Almost all biological substances of value are produced from materials of animal or human origin, such as cultured cells, organs, medium components, or blood. Thus, the danger exists that manufactured biopharmaceutical products bear a risk of viral contamination. This has been shown...
    Keywords: General Topics and Reviews ; Miscellaneous, Reviews;
    ISSN: 1087-0156
    E-ISSN: 15461696
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  • 6
    Language: English
    In: PLoS ONE, 2011, Vol.6(9), p.e25485
    Description: The ATP-dependent molecular chaperone Hsp90 is required for the activation of a variety of client proteins involved in various cellular processes. Despite the abundance of known client proteins, functions of Hsp90 in the organismal context are not fully explored. In Caenorhabditis elegans , Hsp90 (DAF-21) has been implicated in the regulation of the stress-resistant dauer state, in chemosensing and in gonad formation. In a C. elegans strain carrying a DAF-21 mutation with a lower ATP turnover, we observed motility defects. Similarly, a reduction of DAF-21 levels in wild type nematodes leads to reduced motility and induction of the muscular stress response. Furthermore, aggregates of the myosin MYO-3 are visible in muscle cells, if DAF-21 is depleted, implying a role of Hsp90 in the maintenance of muscle cell functionality. Similar defects can also be observed upon knockdown of the Hsp90-cochaperone UNC-45. In life nematodes YFP-DAF-21 localizes to the I-band and the M-line of the muscular ultrastructure, but the protein is not stably attached there. The Hsp90-cofactor UNC-45-CFP contrarily can be found in all bands of the nematode muscle ultrastructure and stably associates with the UNC-54 containing A-band. Thus, despite the physical interaction between DAF-21 and UNC-45, apparently the two proteins are not always localized to the same muscular structures. While UNC-45 can stably bind to myofilaments in the muscular ultrastructure, Hsp90 (DAF-21) appears to participate in the maintenance of muscle structures as a transiently associated diffusible factor.
    Keywords: Research Article ; Biology ; Cell Biology ; Biochemistry
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, January 2019, Vol.33(1), pp.1482-1495
    Description: Dysfunctional HDL is associated with coronary artery disease (CAD), but its effect on inflammation in vascular smooth muscle cells (VSMCs) in atherosclerosis is unknown. We investigated the effect of healthy human HDL and CAD-HDL on TNF-α-driven inflammation in VSMCs and examined whether HDL-associated sphingosine-1-phosphate (HDL-S1P) could modulate inflammation with the aim of designing novel HDL-based anti-inflammatory strategies. Healthy human HDL, human CAD-HDL, and mouse HDL were isolated by ultracentrifugation, S1P was measured by liquid chromatography-tandem mass spectrometry, and TNF-α-induced inflammation was characterized by gene expression and analysis of NF-κB-dependent signaling. Mechanisms of S1P interference with TNF-α were assessed by S1P receptor antagonists, mouse knockouts, and short interfering RNA. We observed that healthy HDL potently inhibited the induction of TNF-α-stimulated inflammatory genes, such as iNOS (inducible NO synthase) and MMP9 (matrix metalloproteinase 9), a process that was entirely dependent on HDL-S1P, as evidenced by loss-of-function using S1P-less HDL and mimicked by genuine S1P. Inhibition was based on suppression of TNF-α-activated Akt signaling resulting in reduced IkBαSer32 and p65Ser534 NF-κB phosphorylation based on a persistent phosphatase and tensin homolog activation by S1P through the S1P receptor 2. Intriguingly, S1P suppressed inflammation even hours after initial TNF-α stimulation. The anti-inflammatory effect of healthy HDL correlated with HDL-S1P content and was superior to that of CAD-HDL featuring lower HDL-S1P. Nevertheless, therapeutic loading of HDL with S1P completely restored the anti-inflammatory capacity of CAD-HDL and greatly boosted that of both healthy and CAD-HDL. Suppression of inflammation by HDL-S1P defines a novel pathophysiologic characteristic that distinguishes functional from dysfunctional HDL. The anti-inflammatory HDL function can be boosted by S1P-loading and exploited by S1P receptor-targeting to prevent and even turn off ongoing inflammation.-Keul, P., Polzin, A., Kaiser, K., Gräler, M., Dannenberg, L., Daum, G., Heusch, G., Levkau, B. Potent anti-inflammatory properties of HDL in vascular smooth muscle cells mediated by HDL-S1P and their impairment in coronary artery disease due to lower HDL-S1P: a new aspect of HDL dysfunction and its therapy.
    Keywords: Cad ; S1p ; Tnf-Α ; Vsmc ; Inflammation ; Coronary Artery Disease -- Metabolism ; Inflammation -- Prevention & Control ; Lipoproteins, HDL -- Metabolism ; Lysophospholipids -- Metabolism ; Muscle, Smooth, Vascular -- Metabolism ; Sphingosine -- Analogs & Derivatives
    ISSN: 08926638
    E-ISSN: 1530-6860
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  • 8
    Language: English
    In: Environmental Toxicology and Chemistry, February 2001, Vol.20(2), pp.420-431
    Description: A methodology based on probabilistic neural networks (PNNs) is applied to model the acute toxicity (48‐h LC50) of a set of 700 highly diverse chemicals to . First, cross‐validation experiments confirming the potential use of the PNN as modeling tool for the problem at hand were performed. Next, various approaches to construct‐improved models are presented. The resulting four models are then validated using an external test set of 76 additional compounds. Input to the PNNs is derived solely from simple molecular descriptors and structural fragments and excludes bulk property parameters, such as the water solubility or the octanol/water partition coefficient.
    Keywords: Daphnia Magna ; Toxicity Modeling ; Probabilistic Neural Network ; Neural Network Validation ; Median Lethal Concentration
    ISSN: 0730-7268
    E-ISSN: 1552-8618
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  • 9
    Language: English
    In: Behavioural Brain Research, 2011, Vol.219(2), pp.291-301
    Description: ► Aggression towards a docile opponent depended on 5-HTT genotype and venue of a contest. ► Homozygous 5-HTT KO mice reacted to the venue and the opponent's behaviour. ► Heterozygous 5-HTT KO mice were only influenced by the venue of the contest. ► Wildtypes behaved always the same, irrespective of venue and opponent. ► Varying inborn levels of anxiety and perception of environmental adversity are seen as causal factors. Aggression can be modulated by both genetic and environmental factors. Here, we analyse how the serotonin transporter (5-HTT) genotype and the environmental situation in which a contest takes place shape the display of offensive aggression. Therefore, male wildtype, heterozygous, and homozygous 5-HTT knockout mice, which are known to differ in inborn levels of anxiety, were confronted three times with a docile opponent in one of three environmental situations: own territory, opponent's territory or neutral area. The main findings were: The frequency of the contestant in order to gather information about him depended significantly on the venue but not on the genotype with lowest frequencies in the opponent's territory. The the opponent was significantly influenced by the 5-HTT genotype but not by the venue: Homozygous 5-HTT knockout mice showed longest latencies. The was significantly influenced by the 5-HTT genotype, the environmental situation, and a genotype by environment interaction. It is likely that, due to their varying genetic predisposition for anxiety, mice of the three genotypes were differentially affected by the aversiveness of the respective venue and the opponent's behaviour, which influenced their decision to display offensive aggression. As a consequence, the amount of aggression shown by homozygous 5-HTT knockout mice was influenced by the venue and the opponent's behaviour, whereas heterozygotes reacted only to the venue. Strikingly, wildtypes behaved always the same way, irrespective of venue and opponent.
    Keywords: 5-Htt ; Genotype ; Anxiety ; Gene × Environment Interaction ; Risk Profile ; Cost/Benefit Ratio ; Anatomy & Physiology
    ISSN: 0166-4328
    E-ISSN: 0166-4328
    E-ISSN: 18727549
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  • 10
    Language: English
    In: Science of the Total Environment, 1987, Vol.67(1), pp.41-51
    Description: The relative importance of migrating eels (Anguilla rostrata ) and suspended particulate material (biotic and abiotic) as transporters of mirex from Lake Ontario to the St. Lawrence River Estuary is evaluated in the context of a possible adverse impact on the St. Lawrence beluga (Delphinapterus leucas ) population. Estimates suggest that transport of mirex out of Lake Ontario by eels (2270 g annually) is almost twice that due to suspended particulate flux (1370 g annually). Mass balance calculations for mirex in Lake Ontario indicate that transport by migrating eels and particulate matter, combined with coverage of surficial sediments by continuing deposition of new material, could effectively "cleanse" Lake Ontario of mirex inputs in 100 years or less. Using mirex as a prototype to simulate the fate of hydrophobic organic chemicals in Lake Ontario led to a revised sediment budget for this final lake in the Great Lakes-St. Lawrence system. According to this budget, 94% of the suspended particulate material entering Lake Ontario is retained in the depositional basins and, by inference, most hydrophobic organic contaminants and metal forms having a dominant association with the particulate phase, would be expected to behave in a similar fashion.
    Keywords: Environmental Sciences ; Biology ; Public Health
    ISSN: 0048-9697
    E-ISSN: 1879-1026
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