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  • Proceedings of the National Academy of Sciences  (15)
  • English  (15)
  • 1
    Online Resource
    Online Resource
    Mouse model implicates GNB3 duplication in a childhood obesity syndrome
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 37 ( 2013-09-10), p. 14990-14994
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 37 ( 2013-09-10), p. 14990-14994
    Abstract: Obesity is a highly heritable condition and a risk factor for other diseases, including type 2 diabetes, cardiovascular disease, hypertension, and cancer. Recently, genomic copy number variation (CNV) has been implicated in cases of early onset obesity that may be comorbid with intellectual disability. Here, we describe a recurrent CNV that causes a syndrome associated with intellectual disability, seizures, macrocephaly, and obesity. This unbalanced chromosome translocation leads to duplication of over 100 genes on chromosome 12, including the obesity candidate gene G protein β3 ( GNB3 ). We generated a transgenic mouse model that carries an extra copy of GNB3 , weighs significantly more than its wild-type littermates, and has excess intraabdominal fat accumulation. GNB3 is highly expressed in the brain, consistent with G-protein signaling involved in satiety and/or metabolism. These functional data connect GNB3 duplication and overexpression to elevated body mass index and provide evidence for a genetic syndrome caused by a recurrent CNV.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1305999110
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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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    Using evolutionary constraint to define novel candidate driver genes in medulloblastoma
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 33 ( 2023-08-15)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 33 ( 2023-08-15)
    Abstract: Current knowledge of cancer genomics remains biased against noncoding mutations. To systematically search for regulatory noncoding mutations, we assessed mutations in conserved positions in the genome under the assumption that these are more likely to be functional than mutations in positions with low conservation. To this end, we use whole-genome sequencing data from the International Cancer Genome Consortium and combined it with evolutionary constraint inferred from 240 mammals, to identify genes enriched in noncoding constraint mutations (NCCMs), mutations likely to be regulatory in nature. We compare medulloblastoma (MB), which is malignant, to pilocytic astrocytoma (PA), a primarily benign tumor, and find highly different NCCM frequencies between the two, in agreement with the fact that malignant cancers tend to have more mutations. In PA, a high NCCM frequency only affects the BRAF locus, which is the most commonly mutated gene in PA. In contrast, in MB, 〉 500 genes have high levels of NCCMs. Intriguingly, several loci with NCCMs in MB are associated with different ages of onset, such as the HOXB cluster in young MB patients. In adult patients, NCCMs occurred in, e.g., the WASF-2/AHDC1/FGR locus. One of these NCCMs led to increased expression of the SRC kinase FGR and augmented responsiveness of MB cells to dasatinib, a SRC kinase inhibitor. Our analysis thus points to different molecular pathways in different patient groups. These newly identified putative candidate driver mutations may aid in patient stratification in MB and could be valuable for future selection of personalized treatment options.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2300984120
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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    detail.hit.zdb_id: 1461794-8
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  • 3
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    Evolution of the ancestral mammalian karyotype and syntenic regions
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 40 ( 2022-10-04)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 40 ( 2022-10-04)
    Abstract: Decrypting the rearrangements that drive mammalian chromosome evolution is critical to understanding the molecular bases of speciation, adaptation, and disease susceptibility. Using 8 scaffolded and 26 chromosome-scale genome assemblies representing 23/26 mammal orders, we computationally reconstructed ancestral karyotypes and syntenic relationships at 16 nodes along the mammalian phylogeny. Three different reference genomes (human, sloth, and cattle) representing phylogenetically distinct mammalian superorders were used to assess reference bias in the reconstructed ancestral karyotypes and to expand the number of clades with reconstructed genomes. The mammalian ancestor likely had 19 pairs of autosomes, with nine of the smallest chromosomes shared with the common ancestor of all amniotes (three still conserved in extant mammals), demonstrating a striking conservation of synteny for ∼320 My of vertebrate evolution. The numbers and types of chromosome rearrangements were classified for transitions between the ancestral mammalian karyotype, descendent ancestors, and extant species. For example, 94 inversions, 16 fissions, and 14 fusions that occurred over 53 My differentiated the therian from the descendent eutherian ancestor. The highest breakpoint rate was observed between the mammalian and therian ancestors (3.9 breakpoints/My). Reconstructed mammalian ancestor chromosomes were found to have distinct evolutionary histories reflected in their rates and types of rearrangements. The distributions of genes, repetitive elements, topologically associating domains, and actively transcribed regions in multispecies homologous synteny blocks and evolutionary breakpoint regions indicate that purifying selection acted over millions of years of vertebrate evolution to maintain syntenic relationships of developmentally important genes and regulatory landscapes of gene-dense chromosomes.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2209139119
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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  • 4
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    Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis.
    Proceedings of the National Academy of Sciences ; 1994
    In:  Proceedings of the National Academy of Sciences Vol. 91, No. 25 ( 1994-12-06), p. 11811-11815
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 91, No. 25 ( 1994-12-06), p. 11811-11815
    Abstract: In vitro T-cell receptor-induced programmed cell death in both activated T cells from human immunodeficiency virus-seronegative (HIV-) donors and resting T cells from HIV+ donors was substantially influenced by cytokines. Addition of exogenous recombinant "type 1" lymphokines interferon gamma and interleukin 2 (IL-2), as well as the macrophage-produced IL-12, which favor cell-mediated T-cell responses, blocks both systems of T-lymphocyte programmed cell death. In contrast, the "type 2" lymphokines IL-4 and IL-10, which favor antibody responses, either had no effect or enhanced these systems of in vitro T-cell programmed cell death. A role for endogenously produced cytokines was suggested by the inhibition of T-cell receptor-mediated death by antibodies against IL-4 and IL-10 and its enhancement by anti-IL-12 in cultures containing monocytes. These results demonstrate that the functional properties of type 1 and type 2 cytokine classes may be further extended to include their effects on T-cell programmed cell death and their possible role in the pathogenesis of HIV infection.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.91.25.11811
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1994
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    detail.hit.zdb_id: 1461794-8
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  • 5
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    Isotopic evidence of early hominin diets
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 26 ( 2013-06-25), p. 10513-10518
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 26 ( 2013-06-25), p. 10513-10518
    Abstract: Carbon isotope studies of early hominins from southern Africa showed that their diets differed markedly from the diets of extant apes. Only recently, however, has a major influx of isotopic data from eastern Africa allowed for broad taxonomic, temporal, and regional comparisons among hominins. Before 4 Ma, hominins had diets that were dominated by C 3 resources and were, in that sense, similar to extant chimpanzees. By about 3.5 Ma, multiple hominin taxa began incorporating 13 C-enriched [C 4 or crassulacean acid metabolism (CAM)] foods in their diets and had highly variable carbon isotope compositions which are atypical for African mammals. By about 2.5 Ma, Paranthropus in eastern Africa diverged toward C 4 /CAM specialization and occupied an isotopic niche unknown in catarrhine primates, except in the fossil relations of grass-eating geladas ( Theropithecus gelada ). At the same time, other taxa (e.g., Australopithecus africanus ) continued to have highly mixed and varied C 3 /C 4 diets. Overall, there is a trend toward greater consumption of 13 C-enriched foods in early hominins over time, although this trend varies by region. Hominin carbon isotope ratios also increase with postcanine tooth area and mandibular cross-sectional area, which could indicate that these foods played a role in the evolution of australopith masticatory robusticity. The 13 C-enriched resources that hominins ate remain unknown and must await additional integration of existing paleodietary proxy data and new research on the distribution, abundance, nutrition, and mechanical properties of C 4 (and CAM) plants.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1222579110
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
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  • 6
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    Reply to Fontes-Villalba et al.: On a reluctance to conjecture about animal food consumption
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 43 ( 2013-10-22)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 43 ( 2013-10-22)
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1314368110
    RVK:
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    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
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  • 7
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    Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts.
    Proceedings of the National Academy of Sciences ; 1993
    In:  Proceedings of the National Academy of Sciences Vol. 90, No. 13 ( 1993-07), p. 6115-6119
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 90, No. 13 ( 1993-07), p. 6115-6119
    Abstract: Immunity against the intracellular protozoan Toxoplasma gondii is highly dependent on interferon gamma (IFN-gamma). We have previously shown that, in addition to T lymphocytes, natural killer (NK) cells can be stimulated by the parasite to produce this cytokine by a reaction requiring adherent accessory cells and tumor necrosis factor alpha. We now demonstrate that a recently characterized cytokine, interleukin 12 (IL-12), is also necessary for parasite-induced IFN-gamma synthesis by NK cells. Anti-IL-12 antibodies completely inhibited T. gondii or bacterial endotoxin-stimulated IFN-gamma production by NK-enriched spleen cells from severe combined immunodeficient mice. Moreover, potent NK cytokine responses were induced by the combination of IL-12 and tumor necrosis factor alpha. In addition, adherent spleen cells from scid/scid mice or thyoglycollate-elicited macrophages from BALB/c animals produced high levels of both IL-12 (p40) and tumor necrosis factor alpha mRNAs when exposed to either live tachyzoites, parasite extracts, or endotoxin, confirming that these cytokines are produced by accessory cells. Finally, in vivo studies showed that treatment with recombinant IL-12 results in prolonged survival of scid mice after infection with T. gondii by means of a response dependent on both IFN-gamma and NK cells. Together the data argue that IL-12 is required for the T-cell-independent triggering of NK cells by intracellular parasites and that the cytokine may be useful for inducing this protective pathway in immunodeficient hosts.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.90.13.6115
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1993
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 8
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    Endothelial cells are activated by cytokine treatment to kill an intravascular parasite, Schistosoma mansoni, through the production of nitric oxide.
    Proceedings of the National Academy of Sciences ; 1994
    In:  Proceedings of the National Academy of Sciences Vol. 91, No. 3 ( 1994-02), p. 999-1003
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 91, No. 3 ( 1994-02), p. 999-1003
    Abstract: Like many pathogens that undergo an intravascular stage of development, larvae of the helminth parasite Schistosoma mansoni migrate through the blood vessels, where they are in close contact with endothelial cells. In vitro exposure of murine endothelial cells to various cytokines (interferon gamma, tumor necrosis factor alpha, and interleukin 1 alpha or 1 beta) resulted in their activation to kill schistosomula through an arginine-dependent mechanism involving production of nitric oxide (NO). Cytokine-treated endothelial cells showed increased expression of mRNA for the inducible form of the NO synthase, and both NO production and larval killing were suppressed by treatment with competitive inhibitors. The effector function of cytokine-treated endothelial cells was similar to that of activated inflammatory tissue macrophages, although activation appeared to be differentially regulated in these two cell types. Activated endothelial cells killed older (18-day) forms of the parasite, such as those currently thought to be a primary target of immune elimination in the lungs of mice previously vaccinated with radiation-attenuated cercariae, as well as newly transformed larvae. In C57BL/6 mice, which become resistant to S. mansoni infection as a result of vaccination with irradiated cercariae, endothelial cell morphology characteristic of activation was observed in the lung by 1-2 weeks after challenge infection. Similar endothelial cell changes were absent in P-strain mice, which do not become resistant as a result of vaccination. Together, these observations indicate that endothelial cells, not traditionally considered to be part of the immune system, may play an important role in immunity to S. mansoni and, by means of NO-dependent killing, could serve as effectors of resistance to other intravascular pathogens.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.91.3.999
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1994
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 9
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    Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation.
    Proceedings of the National Academy of Sciences ; 1992
    In:  Proceedings of the National Academy of Sciences Vol. 89, No. 18 ( 1992-09-15), p. 8676-8680
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 89, No. 18 ( 1992-09-15), p. 8676-8680
    Abstract: Interleukin 10 (IL-10) inhibits interferon gamma-induced macrophage activation for cytotoxicity against larvae of the human parasite Schistosoma mansoni by suppressing production of the toxic effector molecule nitric oxide (NO). In this study, the mechanism of IL-10 action was identified as inhibition of endogenous tumor necrosis factor alpha (TNF-alpha) production by interferon gamma-activated macrophages. TNF-alpha appears to serve as a cofactor for interferon gamma-mediated activation, since both schistosomulum killing and NO production were inhibited by anti-TNF-alpha antibody, whereas TNF-alpha alone was unable to stimulate these macrophage functions. IL-10 blocked TNF-alpha production by interferon gamma-treated macrophages at the levels of both protein and mRNA synthesis. Addition of exogenous TNF-alpha reversed IL-10-mediated suppression of macrophage cytotoxic activity as well as NO production. Likewise, addition of a macrophage-triggering agent (bacterial lipopolysaccharide or muramyl dipeptide), which induced the production of TNF-alpha, also reversed the suppressive effect of IL-10 on cytotoxic function. In contrast to IL-10, two other cytokines, IL-4 and transforming growth factor beta, which also inhibit macrophage activation for schistosomulum killing and NO production, did not substantially suppress endogenous TNF-alpha production. These results, therefore, describe a separate pathway by which macrophage microbicidal function is inhibited by the down-regulatory cytokine IL-10.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.89.18.8676
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1992
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 10
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    IL-13 receptor α 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 2 ( 2004-01-13), p. 586-590
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 2 ( 2004-01-13), p. 586-590
    Abstract: An important feature of many chronic parasitic infections is the ability of the invading pathogen and host to establish a compromise, which ensures successful parasitism without killing the infected host. For many helminth infections, down-modulating the immune response is critical because persistent inflammation can become more damaging to the host than the invading pathogen itself. Such is the case with schistosomiasis mansoni, where chronic granulomatous inflammation in the liver causes portal hypertension, porto-pulmonary shunting, bleeding from collateral bypass vessels, and eventual death if not suppressed effectively. CD4 + T helper type 2 cells (Th2) (secreting IL-4, IL-5, and IL-13) characterize the host response after Schistosoma mansoni infection, and recent studies have identified IL-13 as the principal mediator of hepatic fibrosis. Here, we show that the IL-13 receptor α 2 (IL-13Rα2) is a critical mediator of immune down-modulation, identifying the receptor as a life-sustaining off signal for chronic and pernicious inflammation in schistosomiasis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0305064101
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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