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  • 1
    Online Resource
    Online Resource
    IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 48 ( 2013-11-26)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 48 ( 2013-11-26)
    Abstract: Replication of lentiviruses generates different DNA forms, including RNA:DNA hybrids, ssDNA, and dsDNA. Nucleic acids stimulate innate immune responses, and pattern recognition receptors detecting dsDNA have been identified. However, sensors for ssDNA have not been reported, and the ability of RNA:DNA hybrids to stimulate innate immune responses is controversial. Using ssDNAs derived from HIV-1 proviral DNA, we report that this DNA form potently induces the expression of IFNs in primary human macrophages. This response was stimulated by stem regions in the DNA structure and was dependent on IFN-inducible protein 16 (IFI16), which bound immunostimulatory DNA directly and activated the stimulator of IFN genes –TANK-binding kinase 1 - IFN regulatory factors 3/7 (STING–TBK1–IRF3/7) pathway. Importantly, IFI16 colocalized and associated with lentiviral DNA in the cytoplasm in macrophages, and IFI16 knockdown in this cell type augmented lentiviral transduction and also HIV-1 replication. Thus, IFI16 is a sensor for DNA forms produced during the lentiviral replication cycle and regulates HIV-1 replication in macrophages.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1311669110
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 2
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    Online Resource
    Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 29 ( 2011-07-19), p. 12137-12142
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 29 ( 2011-07-19), p. 12137-12142
    Abstract: Inhibitors of the serotonin transporter (SERT) and norepinephrine transporter (NET) are widely used in the treatment of major depressive disorder. Although SERT/NET selectivity is a key determinant for the therapeutic properties of these drugs, the molecular determinants defining SERT/NET selectivity are poorly understood. In this study, the structural basis for selectivity of the SERT selective inhibitor citalopram and the structurally closely related NET selective inhibitor talopram is delineated. A systematic structure-activity relationship study allowed identification of the substituents that control activity and selectivity toward SERT and NET and revealed a common pattern showing that SERT and NET have opposite preference for the stereochemical configuration of these inhibitors. Mutational analysis of nonconserved SERT/NET residues within the central substrate binding site was performed to determine the molecular basis for inhibitor selectivity. Changing only five residues in NET to the complementary residues in SERT transferred a SERT-like affinity profile for R - and S -citalopram into NET, showing that the selectivity of these compounds is determined by amino acid differences in the central binding site of the transporters. In contrast, the activity of R - and S -talopram was largely unaffected by any mutations within the central substrate binding site of SERT and NET and in the outer vestibule of NET, suggesting that citalopram and talopram bind to distinct sites on SERT and NET. Together, these findings provide important insight into the molecular basis for SERT/NET selectivity of antidepressants, which can be used to guide rational development of unique transporter inhibitors with fine-tuned transporter selectivity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1103060108
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
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  • 3
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    Online Resource
    RNA Exosome Depletion Reveals Transcription Upstream of Active Human Promoters
    American Association for the Advancement of Science (AAAS) ; 2008
    In:  Science Vol. 322, No. 5909 ( 2008-12-19), p. 1851-1854
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 322, No. 5909 ( 2008-12-19), p. 1851-1854
    Abstract: Studies have shown that the bulk of eukaryotic genomes is transcribed. Transcriptome maps are frequently updated, but low-abundant transcripts have probably gone unnoticed. To eliminate RNA degradation, we depleted the exonucleolytic RNA exosome from human cells and then subjected the RNA to tiling microarray analysis. This revealed a class of short, polyadenylated and highly unstable RNAs. These promoter upstream transcripts (PROMPTs) are produced ∼0.5 to 2.5 kilobases upstream of active transcription start sites. PROMPT transcription occurs in both sense and antisense directions with respect to the downstream gene. In addition, it requires the presence of the gene promoter and is positively correlated with gene activity. We propose that PROMPT transcription is a common characteristic of RNA polymerase II (RNAPII) transcribed genes with a possible regulatory potential.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1164096
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2008
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
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  • 4
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    Online Resource
    Bottom-Up Biases in Feature-Selective Attention
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 47 ( 2012-11-21), p. 16953-16958
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 47 ( 2012-11-21), p. 16953-16958
    Abstract: Previous studies of feature-selective attention have focused on situations in which attention is directed to one of two spatially superimposed stimuli of equal salience. While such overlapping stimuli should maximize stimulus interactions, it is still unknown how bottom-up biases favoring one or the other stimulus influence the efficiency of feature-selective attention. We examined the integration of bottom-up contrast and top-down feature-selection biases on stimulus processing. Two fully overlapping random dot kinematograms (RDKs) of light and dark dots were presented on a gray background of intermediate luminance. On each trial, human participants attended one RDK to detect brief coherent motion targets, while ignoring any events in the unattended RDK. Concurrently, through changes in background luminance, stimulus contrast could be set to five different levels: the stimuli could either be equal, or one of the two stimuli could have twice or four times the contrast of the other stimulus. This manipulation introduced a bottom-up bias toward the stimulus with the higher contrast while keeping the difference between the stimuli constant. Stimulus processing was measured by means of steady-state visual evoked potentials (SSVEPs). SSVEP amplitudes generally increased with higher contrast of the driving stimulus. At earlier levels of processing, attention increased the slope of this linear relation, i.e., attention multiplicatively enhanced SSVEP amplitudes. However, at later levels of processing, attention had an additive effect. These effects of attention can be attributed to the differential integration of gain enhancement and inhibitory stimulus competition at different levels of the visual processing hierarchy.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1767-12.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
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  • 5
    Online Resource
    Online Resource
    Emotional Processing in a Salient Motion Context: Integration of Motion and Emotion in Both V5/hMT+ and the Amygdala
    Society for Neuroscience ; 2010
    In:  The Journal of Neuroscience Vol. 30, No. 15 ( 2010-04-14), p. 5204-5210
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 15 ( 2010-04-14), p. 5204-5210
    Abstract: Recent studies have suggested that the extent to which primary task demands draw on attentional resources determines whether or not task-irrelevant emotional stimuli are processed. Another important factor that can bias task-relevant and task-irrelevant stimulus competition is the bottom-up factor of stimulus salience. Here, we investigated the effect of stimulus salience associated with a primary motion task on the processing of emotional face distractors. Faces of different emotional valences were presented within a context of randomly moving dots. Subjects had to detect short intervals of coherent motion while ignoring the background faces. Task salience was manipulated by the level of motion coherence of the dots with high motion coherence being associated with high salience. Using functional magnetic resonance imaging, we show that emotional faces, compared with neutral faces, more strongly interfered with the primary task, as reflected in significant signal decreases in task-related motion area V5/hMT+. In addition, these faces elicited significant signal increases in the left amygdala. Most importantly, task salience was found to further increase amygdala's activity when presented together with an emotional face. Our data support a more general role of the amygdala as a behavioral relevance detector, which flexibly integrates behavioral relevant, salient context information to decode the emotional content of a visual scene.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5029-09.2010
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2010
    detail.hit.zdb_id: 1475274-8
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  • 6
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    Online Resource
    Sustained Multifocal Attentional Enhancement of Stimulus Processing in Early Visual Areas Predicts Tracking Performance
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 12 ( 2013-03-20), p. 5346-5351
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 12 ( 2013-03-20), p. 5346-5351
    Abstract: Keeping track of multiple moving objects is an essential ability of visual perception. However, the mechanisms underlying this ability are not well understood. We instructed human observers to track five or seven independent randomly moving target objects amid identical nontargets and recorded steady-state visual evoked potentials (SSVEPs) elicited by these stimuli. Visual processing of moving targets, as assessed by SSVEP amplitudes, was continuously facilitated relative to the processing of identical but irrelevant nontargets. The cortical sources of this enhancement were located to areas including early visual cortex V1–V3 and motion-sensitive area MT, suggesting that the sustained multifocal attentional enhancement during multiple object tracking already operates at hierarchically early stages of visual processing. Consistent with this interpretation, the magnitude of attentional facilitation during tracking in a single trial predicted the speed of target identification at the end of the trial. Together, these findings demonstrate that attention can flexibly and dynamically facilitate the processing of multiple independent object locations in early visual areas and thereby allow for tracking of these objects.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.4015-12.2013
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
    detail.hit.zdb_id: 1475274-8
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  • 7
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    Online Resource
    Global Facilitation of Attended Features Is Obligatory and Restricts Divided Attention
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 46 ( 2013-11-13), p. 18200-18207
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 46 ( 2013-11-13), p. 18200-18207
    Abstract: In many common situations such as driving an automobile it is advantageous to attend concurrently to events at different locations (e.g., the car in front, the pedestrian to the side). While spatial attention can be divided effectively between separate locations, studies investigating attention to nonspatial features have often reported a “global effect”, whereby items having the attended feature may be preferentially processed throughout the entire visual field. These findings suggest that spatial and feature-based attention may at times act in direct opposition: spatially divided foci of attention cannot be truly independent if feature attention is spatially global and thereby affects all foci equally. In two experiments, human observers attended concurrently to one of two overlapping fields of dots of different colors presented in both the left and right visual fields. When the same color or two different colors were attended on the two sides, deviant targets were detected accurately, and visual-cortical potentials elicited by attended dots were enhanced. However, when the attended color on one side matched the ignored color on the opposite side, attentional modulation of cortical potentials was abolished. This loss of feature selectivity could be attributed to enhanced processing of unattended items that shared the color of the attended items in the opposite field. Thus, while it is possible to attend to two different colors at the same time, this ability is fundamentally constrained by spatially global feature enhancement in early visual-cortical areas, which is obligatory and persists even when it explicitly conflicts with task demands.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1913-13.2013
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
    detail.hit.zdb_id: 1475274-8
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  • 8
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    Online Resource
    Congestive heart failure in rats is associated with increased expression and targeting of aquaporin-2 water channel in collecting duct
    Proceedings of the National Academy of Sciences ; 1997
    In:  Proceedings of the National Academy of Sciences Vol. 94, No. 10 ( 1997-05-13), p. 5450-5455
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 10 ( 1997-05-13), p. 5450-5455
    Abstract: We tested whether severe congestive heart failure (CHF), a condition associated with excess free-water retention, is accompanied by altered regulation of the vasopressin-regulated water channel, aquaporin-2 (AQP2), in the renal collecting duct. CHF was induced by left coronary artery ligation. Compared with sham-operated animals, rats with CHF had severe heart failure with elevated left ventricular end-diastolic pressures (LVEDP): 26.9 ± 3.4 vs. 4.1 ± 0.3 mmHg, and reduced plasma sodium concentrations (142.2 ± 1.6 vs. 149.1 ± 1.1 mEq/liter). Quantitative immunoblotting of total kidney membrane fractions revealed a significant increase in AQP2 expression in animals with CHF (267 ± 53%, n = 12) relative to sham-operated controls (100 ± 13%, n = 14). In contrast, immunoblotting demonstrated a lack of an increase in expression of AQP1 and AQP3 water channel expression, indicating that the effect on AQP2 was selective. Furthermore, postinfarction animals without LVEDP elevation or plasma Na reduction showed no increase in AQP2 expression (121 ± 28% of sham levels, n = 6). Immunocytochemistry and immunoelectron microscopy demonstrated very abundant labeling of the apical plasma membrane and relatively little labeling of intracellular vesicles in collecting duct cells from rats with severe CHF, consistent with enhanced trafficking of AQP2 to the apical plasma membrane. The selective increase in AQP2 expression and enhanced plasma membrane targeting provide an explanation for the development of water retention and hyponatremia in severe CHF.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.94.10.5450
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1997
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  • 9
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    A Lotus japonicus cytoplasmic kinase connects Nod factor perception by the NFR5 LysM receptor to nodulation
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 28 ( 2019-07-09), p. 14339-14348
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 28 ( 2019-07-09), p. 14339-14348
    Abstract: The establishment of nitrogen-fixing root nodules in legume–rhizobia symbiosis requires an intricate communication between the host plant and its symbiont. We are, however, limited in our understanding of the symbiosis signaling process. In particular, how membrane-localized receptors of legumes activate signal transduction following perception of rhizobial signaling molecules has mostly remained elusive. To address this, we performed a coimmunoprecipitation-based proteomics screen to identify proteins associated with Nod factor receptor 5 (NFR5) in Lotus japonicus. Out of 51 NFR5-associated proteins, we focused on a receptor-like cytoplasmic kinase (RLCK), which we named NFR5-interacting cytoplasmic kinase 4 (NiCK4). NiCK4 associates with heterologously expressed NFR5 in Nicotiana benthamiana , and directly binds and phosphorylates the cytoplasmic domains of NFR5 and NFR1 in vitro. At the cellular level, Nick4 is coexpressed with Nfr5 in root hairs and nodule cells, and the NiCK4 protein relocates to the nucleus in an NFR5/NFR1-dependent manner upon Nod factor treatment. Phenotyping of retrotransposon insertion mutants revealed that NiCK4 promotes nodule organogenesis. Together, these results suggest that the identified RLCK, NiCK4, acts as a component of the Nod factor signaling pathway downstream of NFR5.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1815425116
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
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  • 10
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    Long-term social dynamics drive loss of function in pathogenic bacteria
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 34 ( 2015-08-25), p. 10756-10761
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 34 ( 2015-08-25), p. 10756-10761
    Abstract: Laboratory experiments show that social interactions between bacterial cells can drive evolutionary change at the population level, but significant challenges limit attempts to assess the relevance of these findings to natural populations, where selection pressures are unknown. We have increasingly sophisticated methods for monitoring phenotypic and genotypic dynamics in bacteria causing infectious disease, but in contrast, we lack evidence-based adaptive explanations for those changes. Evolutionary change during infection is often interpreted as host adaptation, but this assumption neglects to consider social dynamics shown to drive evolutionary change in vitro. We provide evidence to show that long-term behavioral dynamics observed in a pathogen are driven by selection to outcompete neighboring conspecific cells through social interactions. We find that Pseudomonas aeruginosa bacteria, causing lung infections in patients with cystic fibrosis, lose cooperative iron acquisition by siderophore production during infection. This loss could be caused by changes in iron availability in the lung, but surprisingly, we find that cells retain the ability to take up siderophores produced by conspecifics, even after they have lost the ability to synthesize siderophores. Only when cooperative producers are lost from the population is the receptor for uptake lost. This finding highlights the potential pitfalls of interpreting loss of function in pathogenic bacterial populations as evidence for trait redundancy in the host environment. More generally, we provide an example of how sequence analysis can be used to generate testable hypotheses about selection driving long-term phenotypic changes of pathogenic bacteria in situ.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1508324112
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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