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  • Proceedings of the National Academy of Sciences  (7)
  • 2005-2009  (7)
  • 1
    Online Resource
    Online Resource
    High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 7 ( 2008-02-19), p. 2634-2639
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 7 ( 2008-02-19), p. 2634-2639
    Abstract: Cerebral malaria (CM) in children is associated with a high mortality and long-term neurocognitive sequelae. Both erythropoietin (Epo) and vascular endothelial growth factor (VEGF) have been shown to be neuroprotective. We hypothesized that high plasma and cerebrospinal fluid (CSF) levels of these cytokines would prevent neurological sequelae in children with CM. We measured Epo, VEGF, and tumor necrosis factor in paired samples of plasma and CSF of Kenyan children admitted with CM. Logistic regression models were used to identify risk and protective factors associated with the development of neurological sequelae. Children with CM ( n = 124) were categorized into three groups: 76 without sequelae, 32 with sequelae, and 16 who died. Conditional logistic regression analysis matching the 32 patients with CM and neurological sequelae to 64 patients with CM without sequelae stratified for hemoglobin level estimated that plasma Epo ( 〉 200 units/liter) was associated with 〉 80% reduction in the risk of developing neurological sequelae [adjusted odds ratio (OR) 0.18; 95% C.I. 0.05–0.93; P = 0.041]. Admission with profound coma (adjusted OR 5.47; 95% C.I. 1.45–20.67; P = 0.012) and convulsions after admission (adjusted OR 16.35; 95% C.I. 2.94–90.79; P = 0.001) were also independently associated with neurological sequelae. High levels of Epo were associated with reduced risk of neurological sequelae in children with CM. The age-dependent Epo response to anemia and the age-dependent protective effect may influence the clinical epidemiology of CM. These data support further study of Epo as an adjuvant therapy in CM.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0709715105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 25 ( 2007-06-19), p. 10619-10624
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 25 ( 2007-06-19), p. 10619-10624
    Abstract: Bone is accrued and maintained primarily through the coupled actions of bone-forming osteoblasts and bone-resorbing osteoclasts. Cumulative in vitro studies indicated that proline-rich tyrosine kinase 2 (PYK2) is a positive mediator of osteoclast function and activity. However, our investigation of PYK2−/− mice did not reveal evidence supporting an essential function for PYK2 in osteoclasts either in vivo or in culture. We find that PYK2−/− mice have high bone mass resulting from an unexpected increase in bone formation. Consistent with the in vivo findings, mouse bone marrow cultures show that PYK2 deficiency enhances differentiation and activity of osteoprogenitor cells, as does expressing a PYK2-specific short hairpin RNA or dominantly interfering proteins in human mesenchymal stem cells. Furthermore, the daily administration of a small-molecule PYK2 inhibitor increases bone formation and protects against bone loss in ovariectomized rats, an established preclinical model of postmenopausal osteoporosis. In summary, we find that PYK2 regulates the differentiation of early osteoprogenitor cells across species and that inhibitors of the PYK2 have potential as a bone anabolic approach for the treatment of osteoporosis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0701421104
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
    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
    The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 13 ( 2007-03-27), p. 5336-5341
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 13 ( 2007-03-27), p. 5336-5341
    Abstract: Glycosylation of macrolide antibiotics confers host cell immunity from endogenous and exogenous agents. The Streptomyces antibioticus glycosyltransferases, OleI and OleD, glycosylate and inactivate oleandomycin and diverse macrolides including erythromycin, respectively. The structure of these enzyme–ligand complexes, in tandem with kinetic analysis of site-directed variants, provide insight into the interaction of macrolides with their synthetic apparatus. Erythromycin binds to OleD and the 23S RNA of its target ribosome in the same conformation and, although the antibiotic contains a large number of polar groups, its interaction with these macromolecules is primarily through hydrophobic contacts. Erythromycin and oleandomycin, when bound to OleD and OleI, respectively, adopt different conformations, reflecting a subtle effect on sugar positioning by virtue of a single change in the macrolide backbone. The data reported here provide structural insight into the mechanism of resistance to both endogenous and exogenous antibiotics, and will provide a platform for the future redesign of these catalysts for antibiotic remodelling.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0607897104
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
    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
  • 4
    Online Resource
    Online Resource
    Central amygdala glucocorticoid receptor action promotes fear-associated CRH activation and conditioning
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 33 ( 2008-08-19), p. 12004-12009
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 33 ( 2008-08-19), p. 12004-12009
    Abstract: The amygdala is a key limbic area involved in fear responses and pavlovian conditioning with the potential to directly respond to endocrine signals associated with fear or stress. To gain insights into the molecular mechanisms and subregional specificity of fear conditioning, we disrupted type II glucocorticoid receptors (GRs) in the central nucleus of the amygdala (CeA) by delivering lentiviral vectors containing Cre-recombinase into floxed-GR mice. GR deletion in the CeA (CeAGRKO mice) prevented conditioned fear behavior. In contrast, forebrain disruption of GRs excluding the CeA did not. The conditioned fear deficit in CeAGRKO mice was associated with decreases in cFos and corticotropin-releasing hormone (CRH) expression. Moreover, intracerebroventricular delivery of CRH rescued the conditioned fear deficit in CeAGRKO mice. We conclude that fear conditioning involves a neuroendocrine circuit by using GR activation in the CeA for acute CRH induction and long-lasting behavioral modulation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0803216105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    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
    ESAT-6-specific CD4 T cell responses to aerosol Mycobacterium tuberculosis infection are initiated in the mediastinal lymph nodes
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 31 ( 2008-08-05), p. 10961-10966
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 31 ( 2008-08-05), p. 10961-10966
    Abstract: CD4 + T cell responses to aerosol Mycobacterium tuberculosis (Mtb) infection are characterized by the relatively delayed appearance of effector T cells in the lungs. This delay in the adaptive response is likely critical in allowing the bacteria to establish persistent infection. Because of limitations associated with the detection of low frequencies of naïve T cells, it had not been possible to precisely determine when and where naïve antigen-specific T cells are first activated. We have addressed this problem by using early secreted antigenic target 6 (ESAT-6)-specific transgenic CD4 T cells to monitor early T cell activation in vivo . By using an adoptive transfer approach, we directly show that T cell priming to ESAT-6 occurs only after 10 days of infection, is initially restricted to the mediastinal lymph nodes, and does not involve other lymph nodes or the lungs. Primed CD4 T cells rapidly differentiated into proliferating effector cells and ultimately acquired the ability to produce IFN-γ and TNF-α ex vivo . Initiation of T cell priming was enhanced by two full days depending on the magnitude of the challenge inoculum, which suggests that antigen availability is a factor limiting the early CD4 T cell response. These data define a key period in the adaptive immune response to Mtb infection.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0801496105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    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
    In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 46 ( 2008-11-18), p. 17961-17966
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 46 ( 2008-11-18), p. 17961-17966
    Abstract: Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of diffuse large cell lymphomas. Myc-driven tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2 protein family. Given the need to identify new therapies for such lymphomas, we have evaluated the efficacy of ABT-737, a small molecule that mimics the action of the BH3-only proteins, natural antagonists of the prosurvival Bcl-2 proteins. ABT-737 selectively targets certain prosurvival proteins (Bcl-2, Bcl-x L , and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with lymphomas derived either from Eμ- myc transgenic mice or Eμ- myc mice that also expressed an Eμ- bcl -2 transgene. As a single agent, ABT-737 significantly prolonged the survival of mice transplanted with the myc / bcl -2 lymphomas but was ineffective for the myc lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose cyclophosphamide, ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc / bcl -2 lymphomas tested. The combination therapy was also more effective against some myc lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional therapy for the treatment of Myc-driven lymphomas that over-express this prosurvival molecule.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0809957105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    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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  • 7
    Online Resource
    Online Resource
    Bim and Bad mediate imatinib-induced killing of Bcr/Abl + leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic
    Proceedings of the National Academy of Sciences ; 2006
    In:  Proceedings of the National Academy of Sciences Vol. 103, No. 40 ( 2006-10-03), p. 14907-14912
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 40 ( 2006-10-03), p. 14907-14912
    Abstract: Cell killing is a critical pharmacological activity of imatinib to eradicate Bcr/Abl + leukemias. We found that imatinib kills Bcr/Abl + leukemic cells by triggering the Bcl-2-regulated apoptotic pathway. Imatinib activated several proapoptotic BH3-only proteins: bim and bmf transcription was increased, and both Bim and Bad were activated posttranslationally. Studies using RNAi and cells from gene-targeted mice revealed that Bim plays a major role in imatinib-induced apoptosis of Bcr/Abl + leukemic cells and that the combined loss of Bim and Bad abrogates this killing. Loss of Bmf or Puma had no effect. Resistance to imatinib caused by Bcl-2 overexpression or loss of Bim (plus Bad) could be overcome by cotreatment with the BH3 mimetic ABT-737. These results demonstrate that Bim and Bad account for most, perhaps all, imatinib-induced killing of Bcr/Abl + leukemic cells and suggest previously undescribed drug combination strategies for cancer therapy.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0606176103
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2006
    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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