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  • 2010-2014  (13)
  • 2010  (13)
  • Linguistics  (13)
  • Biology  (13)
  • 1
    Online Resource
    Online Resource
    Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 30 ( 2010-07-27), p. 13432-13437
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 30 ( 2010-07-27), p. 13432-13437
    Abstract: Aberrant Hedgehog (Hh) pathway activation has been implicated in cancers of diverse tissues and organs, and the tumor growth-inhibiting effects of pathway antagonists in animal models have stimulated efforts to develop pathway antagonists for human therapeutic purposes. These efforts have focused largely on cyclopamine derivatives or other compounds that mimic cyclopamine action in binding to and antagonizing Smoothened, a membrane transductory component. We report here that arsenicals, in contrast, antagonize the Hh pathway by targeting Gli transcriptional effectors; in the short term, arsenic blocks Hh-induced ciliary accumulation of Gli2, the primary activator of Hh-dependent transcription, and with prolonged incubation arsenic reduces steady-state levels of Gli2. Arsenicals active in Hh pathway antagonism include arsenic trioxide (ATO), a curative agent in clinical use for acute promyelocytic leukemia (APL); in our studies, ATO inhibited growth of Hh pathway-driven medulloblastoma allografts derived from Ptch +/− p53 −/− mice within a range of serum levels comparable to those achieved in treatment of human APL. Arsenic thus could be tested rapidly as a therapeutic agent in malignant diseases associated with Hh pathway activation and could be particularly useful in such diseases that are inherently resistant or have acquired resistance to cyclopamine mimics.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1006822107
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 2
    Online Resource
    Online Resource
    A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 18 ( 2010-05-04), p. 8404-8409
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 18 ( 2010-05-04), p. 8404-8409
    Abstract: A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With 〉 1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0910878107
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 3
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    Sex-dependent association of common variants of microcephaly genes with brain structure
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 1 ( 2010-01-05), p. 384-388
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 1 ( 2010-01-05), p. 384-388
    Abstract: Loss-of-function mutations in the genes associated with primary microcephaly (MCPH) reduce human brain size by about two-thirds, without producing gross abnormalities in brain organization or physiology and leaving other organs largely unaffected [Woods CG, et al. (2005) Am J Hum Genet 76:717–728]. There is also evidence suggesting that MCPH genes have evolved rapidly in primates and humans and have been subjected to selection in recent human evolution [Vallender EJ, et al. (2008) Trends Neurosci 31:637–644]. Here, we show that common variants of MCPH genes account for some of the common variation in brain structure in humans, independently of disease status. We investigated the correlations of SNPs from four MCPH genes with brain morphometry phenotypes obtained with MRI. We found significant, sex-specific associations between common, nonexonic, SNPs of the genes CDK5RAP2 , MCPH1 , and ASPM , with brain volume or cortical surface area in an ethnically homogenous Norwegian discovery sample ( n = 287), including patients with mental illness. The most strongly associated SNP findings were replicated in an independent North American sample ( n = 656), which included patients with dementia. These results are consistent with the view that common variation in brain structure is associated with genetic variants located in nonexonic, presumably regulatory, regions.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0908454107
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 4
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    Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 22 ( 2010-06), p. 10256-10261
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 22 ( 2010-06), p. 10256-10261
    Abstract: The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer’s disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the ε4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has focused on whether there are domains of cognition and neuroanatomical regions more affected in noncarriers. Further, a major potential confound of prior in vivo studies is the possibility of different rates of clinical misdiagnosis for carriers vs. noncarriers. We compared phenotypic differences in cognition and topography of regional cortical atrophy of ε4 carriers ( n = 67) vs. noncarriers ( n = 24) with mild AD from the Alzheimer’s Disease Neuroimaging Initiative, restricted to those with a cerebrospinal fluid (CSF) molecular profile consistent with AD. Between-group comparisons were made for psychometric tests and morphometric measures of cortical thickness and hippocampal volume. Carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this cognitive dissociation, carriers exhibited greater MTL atrophy, whereas noncarriers had greater frontoparietal atrophy. Performance deficits in particular cognitive domains were associated with disproportionate regional brain atrophy within nodes of cortical networks thought to subserve these cognitive processes. These convergent cognitive and neuroanatomic findings in individuals with a CSF molecular profile consistent with AD support the hypothesis that APOE genotype modulates the clinical phenotype of AD through influence on specific large-scale brain networks.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1001412107
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 5
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    Online Resource
    Functional and Evolutionary Insights from the Genomes of Three Parasitoid Nasonia Species
    American Association for the Advancement of Science (AAAS) ; 2010
    In:  Science Vol. 327, No. 5963 ( 2010-01-15), p. 343-348
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 327, No. 5963 ( 2010-01-15), p. 343-348
    Abstract: We report here genome sequences and comparative analyses of three closely related parasitoid wasps: Nasonia vitripennis , N. giraulti , and N. longicornis . Parasitoids are important regulators of arthropod populations, including major agricultural pests and disease vectors, and Nasonia is an emerging genetic model, particularly for evolutionary and developmental genetics. Key findings include the identification of a functional DNA methylation tool kit; hymenopteran-specific genes including diverse venoms; lateral gene transfers among Pox viruses, Wolbachia , and Nasonia ; and the rapid evolution of genes involved in nuclear-mitochondrial interactions that are implicated in speciation. Newly developed genome resources advance Nasonia for genetic research, accelerate mapping and cloning of quantitative trait loci, and will ultimately provide tools and knowledge for further increasing the utility of parasitoids as pest insect-control agents.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1178028
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2010
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    detail.hit.zdb_id: 2060783-0
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  • 6
    Online Resource
    Online Resource
    Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 16 ( 2010-04-20), p. 7401-7406
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 16 ( 2010-04-20), p. 7401-7406
    Abstract: We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH ( P 〈 10 −75 ), ARMS2 ( P 〈 10 −59 ), C2/CFB ( P 〈 10 −20 ), C3 ( P 〈 10 −9 ), and CFI ( P 〈 10 −6 ). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10 −11 ), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci ( LIPC , P = 1.3 × 10 −7 ; CETP , P = 7.4 × 10 −7 ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL ( P = 3.0 × 10 −3 ) and ABCA1 ( P = 5.6 × 10 −4 ). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0912702107
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 7
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    Genome sequences of the human body louse and its primary endosymbiont provide insights into the permanent parasitic lifestyle
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 27 ( 2010-07-06), p. 12168-12173
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 27 ( 2010-07-06), p. 12168-12173
    Abstract: As an obligatory parasite of humans, the body louse ( Pediculus humanus humanus ) is an important vector for human diseases, including epidemic typhus, relapsing fever, and trench fever. Here, we present genome sequences of the body louse and its primary bacterial endosymbiont Candidatus Riesia pediculicola. The body louse has the smallest known insect genome, spanning 108 Mb. Despite its status as an obligate parasite, it retains a remarkably complete basal insect repertoire of 10,773 protein-coding genes and 57 microRNAs. Representing hemimetabolous insects, the genome of the body louse thus provides a reference for studies of holometabolous insects. Compared with other insect genomes, the body louse genome contains significantly fewer genes associated with environmental sensing and response, including odorant and gustatory receptors and detoxifying enzymes. The unique architecture of the 18 minicircular mitochondrial chromosomes of the body louse may be linked to the loss of the gene encoding the mitochondrial single-stranded DNA binding protein. The genome of the obligatory louse endosymbiont Candidatus Riesia pediculicola encodes less than 600 genes on a short, linear chromosome and a circular plasmid. The plasmid harbors a unique arrangement of genes required for the synthesis of pantothenate, an essential vitamin deficient in the louse diet. The human body louse, its primary endosymbiont, and the bacterial pathogens that it vectors all possess genomes reduced in size compared with their free-living close relatives. Thus, the body louse genome project offers unique information and tools to use in advancing understanding of coevolution among vectors, symbionts, and pathogens.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1003379107
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 8
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    Identification of Functional Elements and Regulatory Circuits by Drosophila modENCODE
    American Association for the Advancement of Science (AAAS) ; 2010
    In:  Science Vol. 330, No. 6012 ( 2010-12-24), p. 1787-1797
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 330, No. 6012 ( 2010-12-24), p. 1787-1797
    Abstract: To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1198374
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2010
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  • 9
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    RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 39 ( 2010-09-28), p. 16994-16998
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 39 ( 2010-09-28), p. 16994-16998
    Abstract: Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)–CA3–CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is area CA2, an intervening hippocampal region that is poorly understood. Schaffer collateral synapses on CA2 neurons are distinct from those on other hippocampal neurons in that they exhibit a perplexing lack of synaptic long-term potentiation (LTP). Here we demonstrate that the signaling protein RGS14 is highly enriched in CA2 pyramidal neurons and plays a role in suppression of both synaptic plasticity at these synapses and hippocampal-based learning and memory. RGS14 is a scaffolding protein that integrates G protein and H-Ras/ERK/MAP kinase signaling pathways, thereby making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, deletion of exons 2–7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) and now express robust LTP at glutamatergic synapses in CA2 neurons with no impact on synaptic plasticity in CA1 neurons. Treatment of RGS14-deficient CA2 neurons with a specific MEK inhibitor blocked this LTP, suggesting a role for ERK/MAP kinase signaling pathways in this process. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in spatial learning and in object recognition memory compared with their wild-type littermates, but showed no differences in their performance on tests of nonhippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory but distinct from the canonical DG–CA3–CA1 circuit.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1005362107
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
    detail.hit.zdb_id: 209104-5
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  • 10
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    Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 50 ( 2010-12-14), p. 21248-21255
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 50 ( 2010-12-14), p. 21248-21255
    Abstract: Priming of the organ-specific premetastatic sites is thought to be an important yet incompletely understood step during metastasis. In this study, we show that the metastatic tumors we examined overexpress granulocyte-colony stimulating factor (G-CSF), which expands and mobilizes Ly6G+Ly6C+ granulocytes and facilitates their subsequent homing at distant organs even before the arrival of tumor cells. Moreover, G-CSF–mobilized Ly6G+Ly6C+ cells produce the Bv8 protein, which has been implicated in angiogenesis and mobilization of myeloid cells. Anti–G-CSF or anti-Bv8 antibodies significantly reduced lung metastasis. Transplantation of Bv8 null fetal liver cells into lethally irradiated hosts also reduced metastasis. We identified an unexpected role for Bv8: the ability to stimulate tumor cell migration through activation of one of the Bv8 receptors, prokineticin receptor (PKR)-1. Finally, we show that administration of recombinant G-CSF is sufficient to increase the numbers of Ly6G+Ly6C+ cells in organ-specific metastatic sites and results in enhanced metastatic ability of several tumors.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1015855107
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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