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  • 1
    Online Resource
    Online Resource
    Functional diversity of human intrinsically photosensitive retinal ganglion cells
    American Association for the Advancement of Science (AAAS) ; 2019
    In:  Science Vol. 366, No. 6470 ( 2019-12-06), p. 1251-1255
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 366, No. 6470 ( 2019-12-06), p. 1251-1255
    Abstract: Intrinsically photosensitive retinal ganglion cells (ipRGCs) are a subset of cells that participate in image-forming and non–image-forming visual responses. Although both functional and morphological subtypes of ipRGCs have been described in rodents, parallel functional subtypes have not been identified in primate or human retinas. In this study, we used a human organ donor preparation method to measure human ipRGCs’ photoresponses. We discovered three functional ipRGC subtypes with distinct sensitivities and responses to light. The response of one ipRGC subtype appeared to depend on exogenous chromophore supply, and this response is conserved in both human and mouse retinas. Rods and cones also provided input to ipRGCs; however, each subtype integrated outer retina light signals in a distinct fashion.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaz0898
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2019
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  • 2
    Online Resource
    Online Resource
    Functional motifs in the (6-4) photolyase crystal structure make a comparative framework for DNA repair photolyases and clock cryptochromes
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 17 ( 2009-04-28), p. 6962-6967
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 17 ( 2009-04-28), p. 6962-6967
    Abstract: Homologous flavoproteins from the photolyase (PHR)/cryptochrome (CRY) family use the FAD cofactor in PHRs to catalyze DNA repair and in CRYs to tune the circadian clock and control development. To help address how PHR/CRY members achieve these diverse functions, we determined the crystallographic structure of Arabidopsis thaliana (6-4) PHR (UVR3), which is strikingly ( 〉 65%) similar in sequence to human circadian clock CRYs. The structure reveals a substrate-binding cavity specific for the UV-induced DNA lesion, (6-4) photoproduct, and cofactor binding sites different from those of bacterial PHRs and consistent with distinct mechanisms for activities and regulation. Mutational analyses were combined with this prototypic structure for the (6-4) PHR/clock CRY cluster to identify structural and functional motifs: phosphate-binding and Pro-Lys-Leu protrusion motifs constricting access to the substrate-binding cavity above FAD, sulfur loop near the external end of the Trp electron-transfer pathway, and previously undefined C-terminal helix. Our results provide a detailed, unified framework for investigations of (6-4) PHRs and the mammalian CRYs. Conservation of key residues and motifs controlling FAD access and activities suggests that regulation of FAD redox properties and radical stability is essential not only for (6-4) photoproduct DNA repair, but also for circadian clock-regulating CRY functions. The structural and functional results reported here elucidate archetypal relationships within this flavoprotein family and suggest how PHRs and CRYs use local residue and cofactor tuning, rather than larger structural modifications, to achieve their diverse functions encompassing DNA repair, plant growth and development, and circadian clock regulation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0809180106
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
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  • 3
    Online Resource
    Online Resource
    Illumination of the Melanopsin Signaling Pathway
    American Association for the Advancement of Science (AAAS) ; 2005
    In:  Science Vol. 307, No. 5709 ( 2005-01-28), p. 600-604
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 307, No. 5709 ( 2005-01-28), p. 600-604
    Abstract: In mammals, a small population of intrinsically photosensitive retinal ganglion cells (ipRGCs) plays a key role in the regulation of nonvisual photic responses, such as behavioral responses to light, pineal melatonin synthesis, pupillary light reflex, and sleep latency. These ipRGCs also express melanopsin (Opn4), a putative opsin-family photopigment that has been shown to play a role in mediating these nonvisual photic responses. Melanopsin is required for the function of this inner retinal pathway, but its precise role in generating photic responses has not yet been determined. We found that expression of melanopsin in Xenopus oocytes results in light-dependent activation of membrane currents through the Gα q /Gα 11 G protein pathway, with an action spectrum closely matching that of melanopsin-expressing ipRGCs and of behavioral responses to light in mice lacking rods and cones. When coexpressed with arrestins, melanopsin could use all- trans -retinaldehyde as a chromophore, which suggests that it may function as a bireactive opsin. We also found that melanopsin could activate the cation channel TRPC3, a mammalian homolog of the Drosophila phototransduction channels TRP and TRPL. Melanopsin therefore signals more like an invertebrate opsin than like a classical vertebrate rod-and-cone opsin.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1105121
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2005
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  • 4
    Online Resource
    Online Resource
    Genome-Wide Expression Analysis in Drosophila Reveals Genes Controlling Circadian Behavior
    Society for Neuroscience ; 2002
    In:  The Journal of Neuroscience Vol. 22, No. 21 ( 2002-11-01), p. 9305-9319
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 22, No. 21 ( 2002-11-01), p. 9305-9319
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.22-21-09305.2002
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2002
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  • 5
    Online Resource
    Online Resource
    Diurnal transcriptome atlas of a primate across major neural and peripheral tissues
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 359, No. 6381 ( 2018-03-16)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 359, No. 6381 ( 2018-03-16)
    Abstract: Diurnal gene expression patterns underlie time-of-the-day–specific functional specialization of tissues. However, available circadian gene expression atlases of a few organs are largely from nocturnal vertebrates. We report the diurnal transcriptome of 64 tissues, including 22 brain regions, sampled every 2 hours over 24 hours, from the primate Papio anubis (baboon). Genomic transcription was highly rhythmic, with up to 81.7% of protein-coding genes showing daily rhythms in expression. In addition to tissue-specific gene expression, the rhythmic transcriptome imparts another layer of functional specialization. Most ubiquitously expressed genes that participate in essential cellular functions exhibit rhythmic expression in a tissue-specific manner. The peak phases of rhythmic gene expression clustered around dawn and dusk, with a “quiescent period” during early night. Our findings also unveil a different temporal organization of central and peripheral tissues between diurnal and nocturnal animals.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aao0318
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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  • 6
    Online Resource
    Online Resource
    Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 50 ( 2009-12-15), p. 21453-21458
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 50 ( 2009-12-15), p. 21453-21458
    Abstract: In mammals, the circadian oscillator generates approximately 24-h rhythms in feeding behavior, even under constant environmental conditions. Livers of mice held under constant darkness exhibit circadian rhythm in abundance in up to 15% of expressed transcripts. Therefore, oscillations in hepatic transcripts could be driven by rhythmic food intake or sustained by the hepatic circadian oscillator, or a combination of both. To address this question, we used distinct feeding and fasting paradigms on wild-type (WT) and circadian clock-deficient mice. We monitored temporal patterns of feeding and hepatic transcription. Both food availability and the temporal pattern of feeding determined the repertoire, phase, and amplitude of the circadian transcriptome in WT liver. In the absence of feeding, only a small subset of transcripts continued to express circadian patterns. Conversely, temporally restricted feeding restored rhythmic transcription of hundreds of genes in oscillator-deficient mouse liver. Our findings show that both temporal pattern of food intake and the circadian clock drive rhythmic transcription, thereby highlighting temporal regulation of hepatic transcription as an emergent property of the circadian system.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0909591106
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
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  • 7
    Online Resource
    Online Resource
    Reciprocity between phase shifts and amplitude changes in the mammalian circadian clock
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 51 ( 2007-12-18), p. 20356-20361
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 51 ( 2007-12-18), p. 20356-20361
    Abstract: Circadian rhythms help organisms adapt to predictable daily changes in their environment. Light resets the phase of the underlying oscillator to maintain the organism in sync with its surroundings. Light also affects the amplitude of overt rhythms. At a critical phase during the night, when phase shifts are maximal, light can reduce rhythm amplitude to nearly zero, whereas in the subjective day, when phase shifts are minimal, it can boost amplitude substantially. To explore the cellular basis for this reciprocal relationship between phase shift and amplitude change, we generated a photoentrainable, cell-based system in mammalian fibroblasts that shares several key features of suprachiasmatic nucleus light entrainment. Upon light stimulation, these cells exhibit calcium/cyclic AMP responsive element-binding (CREB) protein phosphorylation, leading to temporally gated acute induction of the Per2 gene, followed by phase-dependent changes in phase and/or amplitude of the PER2 circadian rhythm. At phases near the PER2 peak, photic stimulation causes little phase shift but enhanced rhythm amplitude. At phases near the PER2 nadir, on the other hand, the same stimuli cause large phase shifts but dampen rhythm amplitude. Real-time monitoring of PER2 oscillations in single cells reveals that changes in both synchrony and amplitude of individual oscillators underlie these phenomena.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0708877104
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
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  • 8
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    Online Resource
    Circadian physiology of metabolism
    American Association for the Advancement of Science (AAAS) ; 2016
    In:  Science Vol. 354, No. 6315 ( 2016-11-25), p. 1008-1015
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 354, No. 6315 ( 2016-11-25), p. 1008-1015
    Abstract: A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aah4967
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2016
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  • 9
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    Aligning mealtimes to live longer
    American Association for the Advancement of Science (AAAS) ; 2022
    In:  Science Vol. 376, No. 6598 ( 2022-06-10), p. 1159-1160
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 376, No. 6598 ( 2022-06-10), p. 1159-1160
    Abstract: Calorie restriction (CR) involves chronic reduction of energy intake by 20 to 40% without inducing malnutrition ( 1 ). CR extends life span in multiple animal models and reduces the risk of age-associated disorders, most of which arise from metabolic dysfunction and inflammation. However, extended daily fasting or aligning daily meal timing to the active period, even without reducing energy intake, can also improve health and increase life span in model organisms. On page 1192 of this issue, Acosta-Rodríguez et al. ( 2 ) reveal the specific contribution of fasting and timing of calorie-reduced meals to the efficacy of CR, as estimated by life-span extension in male mice.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.adc8824
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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  • 10
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    Histone Lysine Demethylase JARID1a Activates CLOCK-BMAL1 and Influences the Circadian Clock
    American Association for the Advancement of Science (AAAS) ; 2011
    In:  Science Vol. 333, No. 6051 ( 2011-09-30), p. 1881-1885
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 333, No. 6051 ( 2011-09-30), p. 1881-1885
    Abstract: In animals, circadian oscillators are based on a transcription-translation circuit that revolves around the transcription factors CLOCK and BMAL1. We found that the JumonjiC (JmjC) and ARID domain–containing histone lysine demethylase 1a (JARID1a) formed a complex with CLOCK-BMAL1, which was recruited to the Per2 promoter. JARID1a increased histone acetylation by inhibiting histone deacetylase 1 function and enhanced transcription by CLOCK-BMAL1 in a demethylase-independent manner. Depletion of JARID1a in mammalian cells reduced Per promoter histone acetylation, dampened expression of canonical circadian genes, and shortened the period of circadian rhythms. Drosophila lines with reduced expression of the Jarid1a homolog, lid , had lowered Per expression and similarly altered circadian rhythms. JARID1a thus has a nonredundant role in circadian oscillator function.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1206022
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2011
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