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  • 1
    Online Resource
    Online Resource
    Substrate recognition by the cell surface palmitoyl transferase DHHC5
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 49 ( 2014-12-09), p. 17534-17539
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 49 ( 2014-12-09), p. 17534-17539
    Abstract: The cardiac phosphoprotein phospholemman (PLM) regulates the cardiac sodium pump, activating the pump when phosphorylated and inhibiting it when palmitoylated. Protein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol, is catalyzed by the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases. The cell surface palmitoyl acyltransferase DHHC5 regulates a growing number of cellular processes, but relatively few DHHC5 substrates have been identified to date. We examined the expression of DHHC isoforms in ventricular muscle and report that DHHC5 is among the most abundantly expressed DHHCs in the heart and localizes to caveolin-enriched cell surface microdomains. DHHC5 coimmunoprecipitates with PLM in ventricular myocytes and transiently transfected cells. Overexpression and silencing experiments indicate that DHHC5 palmitoylates PLM at two juxtamembrane cysteines, C40 and C42, although C40 is the principal palmitoylation site. PLM interaction with and palmitoylation by DHHC5 is independent of the DHHC5 PSD-95/Discs-large/ZO-1 homology (PDZ) binding motif, but requires a ∼120 amino acid region of the DHHC5 intracellular C-tail immediately after the fourth transmembrane domain. PLM C42A but not PLM C40A inhibits the Na pump, indicating PLM palmitoylation at C40 but not C42 is required for PLM-mediated inhibition of pump activity. In conclusion, we demonstrate an enzyme–substrate relationship for DHHC5 and PLM and describe a means of substrate recruitment not hitherto described for this acyltransferase. We propose that PLM palmitoylation by DHHC5 promotes phospholipid interactions that inhibit the Na pump.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1413627111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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  • 2
    Online Resource
    Online Resource
    Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 37 ( 2013-09-10), p. 15001-15006
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 37 ( 2013-09-10), p. 15001-15006
    Abstract: Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti–PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti–PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1312772110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 36 ( 2014-09-09), p. 13193-13198
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 36 ( 2014-09-09), p. 13193-13198
    Abstract: Activation of melanocortin-4 receptors (MC4Rs) restrains feeding and prevents obesity; however, the identity, location, and axonal projections of the neurons bearing MC4Rs that control feeding remain unknown. Reexpression of MC4Rs on single-minded 1 (SIM1) + neurons in mice otherwise lacking MC4Rs is sufficient to abolish hyperphagia. Thus, MC4Rs on SIM1 + neurons, possibly in the paraventricular hypothalamus (PVH) and/or amygdala, regulate food intake. It is unknown, however, whether they are also necessary, a distinction required for excluding redundant sites of action. Hence, the location and nature of obesity-preventing MC4R-expressing neurons are unknown. Here, by deleting and reexpressing MC4Rs from cre-expressing neurons, establishing both necessity and sufficiency, we demonstrate that the MC4R-expressing neurons regulating feeding are SIM1 + , located in the PVH, glutamatergic and not GABAergic, and do not express oxytocin, corticotropin-releasing hormone, vasopressin, or prodynorphin. Importantly, these excitatory MC4R-expressing PVH neurons are synaptically connected to neurons in the parabrachial nucleus, which relays visceral information to the forebrain. This suggests a basis for the feeding-regulating effects of MC4Rs.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1407843111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Storytelling and story testing in domestication
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 17 ( 2014-04-29), p. 6159-6164
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 17 ( 2014-04-29), p. 6159-6164
    Abstract: The domestication of plants and animals marks one of the most significant transitions in human, and indeed global, history. Traditionally, study of the domestication process was the exclusive domain of archaeologists and agricultural scientists; today it is an increasingly multidisciplinary enterprise that has come to involve the skills of evolutionary biologists and geneticists. Although the application of new information sources and methodologies has dramatically transformed our ability to study and understand domestication, it has also generated increasingly large and complex datasets, the interpretation of which is not straightforward. In particular, challenges of equifinality, evolutionary variance, and emergence of unexpected or counter-intuitive patterns all face researchers attempting to infer past processes directly from patterns in data. We argue that explicit modeling approaches, drawing upon emerging methodologies in statistics and population genetics, provide a powerful means of addressing these limitations. Modeling also offers an approach to analyzing datasets that avoids conclusions steered by implicit biases, and makes possible the formal integration of different data types. Here we outline some of the modeling approaches most relevant to current problems in domestication research, and demonstrate the ways in which simulation modeling is beginning to reshape our understanding of the domestication process.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1400425111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    Current perspectives and the future of domestication studies
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 17 ( 2014-04-29), p. 6139-6146
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 17 ( 2014-04-29), p. 6139-6146
    Abstract: It is difficult to overstate the cultural and biological impacts that the domestication of plants and animals has had on our species. Fundamental questions regarding where, when, and how many times domestication took place have been of primary interest within a wide range of academic disciplines. Within the last two decades, the advent of new archaeological and genetic techniques has revolutionized our understanding of the pattern and process of domestication and agricultural origins that led to our modern way of life. In the spring of 2011, 25 scholars with a central interest in domestication representing the fields of genetics, archaeobotany, zooarchaeology, geoarchaeology, and archaeology met at the National Evolutionary Synthesis Center to discuss recent domestication research progress and identify challenges for the future. In this introduction to the resulting Special Feature, we present the state of the art in the field by discussing what is known about the spatial and temporal patterns of domestication, and controversies surrounding the speed, intentionality, and evolutionary aspects of the domestication process. We then highlight three key challenges for future research. We conclude by arguing that although recent progress has been impressive, the next decade will yield even more substantial insights not only into how domestication took place, but also when and where it did, and where and why it did not.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1323964111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 6
    Online Resource
    Online Resource
    Convergent evolution and parallelism in plant domestication revealed by an expanding archaeological record
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 17 ( 2014-04-29), p. 6147-6152
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 17 ( 2014-04-29), p. 6147-6152
    Abstract: Recent increases in archaeobotanical evidence offer insights into the processes of plant domestication and agricultural origins, which evolved in parallel in several world regions. Many different crop species underwent convergent evolution and acquired domestication syndrome traits. For a growing number of seed crop species, these traits can be quantified by proxy from archaeological evidence, providing measures of the rates of change during domestication. Among domestication traits, nonshattering cereal ears evolved more quickly in general than seed size. Nevertheless, most domestication traits show similarly slow rates of phenotypic change over several centuries to millennia, and these rates were similar across different regions of origin. Crops reproduced vegetatively, including tubers and many fruit trees, are less easily documented in terms of morphological domestication, but multiple lines of evidence outline some patterns in the development of vegecultural systems across the New World and Old World tropics. Pathways to plant domestication can also be compared in terms of the cultural and economic factors occurring at the start of the process. Whereas agricultural societies have tended to converge on higher population densities and sedentism, in some instances cultivation began among sedentary hunter–gatherers whereas more often it was initiated by mobile societies of hunter–gatherers or herder–gatherers.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1308937110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
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