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  • American Association for the Advancement of Science (AAAS)  (5)
  • American Society of Hematology  (3)
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  • 1
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    The oceanic sink for anthropogenic CO2 from 1994 to 2007 (2019)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2019
    Description: 〈p〉We quantify the oceanic sink for anthropogenic carbon dioxide (CO〈sub〉2〈/sub〉) over the period 1994 to 2007 by using observations from the global repeat hydrography program and contrasting them to observations from the 1990s. Using a linear regression–based method, we find a global increase in the anthropogenic CO〈sub〉2〈/sub〉 inventory of 34 ± 4 petagrams of carbon (Pg C) between 1994 and 2007. This is equivalent to an average uptake rate of 2.6 ± 0.3 Pg C year〈sup〉–1〈/sup〉 and represents 31 ± 4% of the global anthropogenic CO〈sub〉2〈/sub〉 emissions over this period. Although this global ocean sink estimate is consistent with the expectation of the ocean uptake having increased in proportion to the rise in atmospheric CO〈sub〉2〈/sub〉, substantial regional differences in storage rate are found, likely owing to climate variability–driven changes in ocean circulation.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-06-08
    Description: Heterologous prime/boost regimens have the potential for raising high levels of immune responses. Here we report that DNA priming followed by a recombinant modified vaccinia Ankara (rMVA) booster controlled a highly pathogenic immunodeficiency virus challenge in a rhesus macaque model. Both the DNA and rMVA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at 0 and 8 weeks and a single rMVA booster at 24 weeks effectively controlled an intrarectal challenge administered 7 months after the booster. These findings provide hope that a relatively simple multiprotein DNA/MVA vaccine can help to control the acquired immune deficiency syndrome epidemic.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Amara, R R -- Villinger, F -- Altman, J D -- Lydy, S L -- O'Neil, S P -- Staprans, S I -- Montefiori, D C -- Xu, Y -- Herndon, J G -- Wyatt, L S -- Candido, M A -- Kozyr, N L -- Earl, P L -- Smith, J M -- Ma, H L -- Grimm, B D -- Hulsey, M L -- Miller, J -- McClure, H M -- McNicholl, J M -- Moss, B -- Robinson, H L -- P01 AI 43045/AI/NIAID NIH HHS/ -- P30 DA 12121/DA/NIDA NIH HHS/ -- P51 RR000165/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2001 Apr 6;292(5514):69-74.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center and Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30329, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11393868" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/administration & dosage/*immunology ; Acquired Immunodeficiency Syndrome/immunology/*prevention & control/virology ; Animals ; Antibodies, Viral/blood/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Germinal Center/immunology ; HIV Antibodies/blood/immunology ; HIV-1/genetics/immunology/physiology ; Immunity, Mucosal ; Immunization, Secondary ; Immunologic Memory ; Interferon-gamma/biosynthesis ; Lymph Nodes/immunology ; Macaca mulatta ; SAIDS Vaccines/administration & dosage/immunology ; Simian Acquired Immunodeficiency Syndrome/immunology/prevention & ; control/virology ; Simian Immunodeficiency Virus/genetics/immunology/physiology ; T-Lymphocytes/immunology ; Vaccines, DNA/administration & dosage/*immunology ; Vaccines, Synthetic/administration & dosage/immunology ; Vaccinia virus/immunology ; Viral Load
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    The oceanic sink for anthropogenic CO2 (2004)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2004-07-17
    Description: Using inorganic carbon measurements from an international survey effort in the 1990s and a tracer-based separation technique, we estimate a global oceanic anthropogenic carbon dioxide (CO2) sink for the period from 1800 to 1994 of 118 +/- 19 petagrams of carbon. The oceanic sink accounts for approximately 48% of the total fossil-fuel and cement-manufacturing emissions, implying that the terrestrial biosphere was a net source of CO2 to the atmosphere of about 39 +/- 28 petagrams of carbon for this period. The current fraction of total anthropogenic CO2 emissions stored in the ocean appears to be about one-third of the long-term potential.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sabine, Christopher L -- Feely, Richard A -- Gruber, Nicolas -- Key, Robert M -- Lee, Kitack -- Bullister, John L -- Wanninkhof, Rik -- Wong, C S -- Wallace, Douglas W R -- Tilbrook, Bronte -- Millero, Frank J -- Peng, Tsung-Hung -- Kozyr, Alexander -- Ono, Tsueno -- Rios, Aida F -- New York, N.Y. -- Science. 2004 Jul 16;305(5682):367-71.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Oceanic and Atmospheric Administration (NOAA) Pacific Marine Environmental Laboratory, 7600 Sand Point Way NE, Seattle, WA 98115, USA. chris.sabine@noaa.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15256665" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Atmosphere ; Calcification, Physiologic ; Calcium Carbonate/analysis ; Carbon/analysis/metabolism ; Carbon Dioxide/*analysis ; Fossil Fuels ; Hydrogen-Ion Concentration ; *Industry ; Oceans and Seas ; Seawater/*chemistry ; Temperature
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Synergistic Control of Acute GvHD: Effectively Down-Regulating T Cell Proliferation and Cytotoxicity with Combined mTOR Inhibition and CD28:CD80/86 Costimulation Blockade. (2012)
    American Society of Hematology
    Details
    Publication Date: 2012-11-16
    Description: Abstract 2998 Introduction: GvHD remains the most deadly complication of HSCT despite current prevention strategies. To address the unmet need for better GvHD control, we have created a non-human primate (NHP) model with which to rigorously test mechanism and efficacy of novel therapeutics. In this study, we determined whether a novel combination of mTOR inhibition (with sirolimus) and CD28:CD80/86 costimulation blockade (with belatacept) could control GvHD. Here we show for the first time that these two agents combine synergistically to prevent both the clinical and immunologic manifestations of primate aGvHD. Methods: Rhesus macaque recipients were irradiated (9.6 Gy in 2 fractions at 7cGy/min), and then transplanted with G-CSF-mobilized PBSC from a haplo-identical donor (1–5×108 TNC/kg). Recipients were treated with either sirolimus alone (n = 4, troughs targeted at 5–10 ng/mL), belatacept alone (receiving weekly doses of 20 mg/kg), or combination therapy. Clinical GvHD was monitored using our previously described NHP grading scale (Miller et al., Blood 2010), and multiparameter flow cytometric analysis was performed. Results: Untreated controls (n = 5) developed rapid, severe histopathologically-proven aGvHD and succumbed rapidly (MST = 7 days). Recipients treated with either sirolimus or belatacept alone were partially protected from the clinical manifestations of GvHD. Sirolimus-treated recipients (n = 6) developed predominantly GI disease (with diarrhea but no elevation of bilirubin) and had an MST of 14 days (Figure 1). Recipients treated with belatacept alone (n = 3) developed primarily liver aGvHD (bilirubin rapidly rising to 6–30 × normal with histologically-confirmed lymphocytic infiltration) and an MST of 11 days. In striking contrast, recipients treated with combined sirolimus + belatacept (n = 5) demonstrated neither uncontrolled diarrhea nor hyperbilirubinemia at the timed terminal analysis (1 month post-transplant). We employed multiparameter flow cytometry to determine the immunologic consequences of sirolimus and belatacept on T cell proliferation (using Ki-67 expression) and cytotoxity (using granzyme B expression). We found that the clinical synergy observed with combined therapy was recapitulated immunologically. Thus, while untreated aGvHD was associated with rampant CD8+ proliferation (with 83 +/− 14% Ki-67+ CD8+ vs 4.7 +/− 0.6% pre-transplant), sirolimus or belatacept as monotherapy both partially controlled proliferation (35 +/− 3% and 65 +/− 23% Ki-67+ CD8+ with sirolimus or belatacept, respectively). Combined sirolimus + belatacept dramatically reduced proliferation (to 8 +/− 3%, favorably comparing with 13% Ki-67+ CD8+ T cells using standard Calcineurin Inhibitor/Methotrexate (CNI/MTX) prophylaxis). Sirolimus and belatacept both also partially controlled GvHD-related T cell cytotoxicity. Thus, while untreated aGvHD was associated with excessive granzyme B expression in CD8+ T cells (82 +/− 2% granzyme Bvery high CD8+ cells vs 0.3 +/− 0.2% pre-transplant) sirolimus or belatacept monotherapy also partially controlled cytotoxicity (8 +/− 1% and 35 +/− 1% granzyme Bvery high with sirolimus or belatacept, respectively). Combination therapy dramatically reduced the proportion of these cells, to 1.5 +/− 0.8 % granzyme Bvery high, favorably comparing with 4% granzyme Bvery high using CNI/MTX. The ability of sirolimus, belatacept, or the combination to control Ki-67 and Granzyme B expression closely correlated with survival (Figure 2A, B) supporting a pathogenic role for these highly proliferative and cytotoxic cells in aGvHD pathology. Moreover, significant co-expression of granzyme B in the Ki-67+ cells was observed (Figure 2C) suggesting that dual-positive Ki-67/Granzyme B cells may mark a pathogenic population, amenable to tracking in the peripheral blood. Implications: These results reveal a previously undiscovered synergy between sirolimus and belatacept in the control of primate aGvHD, and provide support for future clinical investigation of this novel prevention strategy. They also identify CD8+/Ki-67+/Granzyme Bvery high dual-positive T cells as a potentially sensitive biomarker of GvHD pathogenesis, amenable to monitoring in either the blood or in GvHD target organs. Disclosures: No relevant conflicts of interest to declare.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 5
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    Sirolimus Inhibits Proliferation but Enhances Suppressive Activity of Rhesus Macaque Natural CD4 Regulatory T Cells (2011)
    American Society of Hematology
    Details
    Publication Date: 2011-11-18
    Description: Abstract 1008 Regulatory T cells (Tregs) have been shown to be potent inhibitors of autoimmunity, and to be capable of suppressing alloimmune responses that occur during both allograft rejection and graft-versus host disease. However, they have yet to gain widespread use clinically, due in part to the fact that it remains extremely costly and difficult to produce them in sufficient numbers and with sufficient suppressive capacity to significantly impact the alloimmune response. Here we have used our established non-human primate model to demonstrate that significant Treg expansion (up to 600-fold in 21 days) can be maintained, and suppressive capacity enhanced by exposing Treg cultures to a short burst of sirolimus at the end of the culture period. Using a highly sensitive and specific in vitro CFSE-MLR assay we show that Tregs significantly inhibit allo-proliferation of multiple T cell subpopulations including both CD4+ and CD8+ T cells (3.2 and 2.7-fold inhibition of proliferation, respectively), as well as their CD28+CD95+ and CD28-CD95+ subpopulations (2.2 and 2.1 and 1.9 and 2.7-fold inhibition of CD4+ and CD8+ subpopulation proliferation, respectively). Tregs were able to combine in vitro with the newly FDA-approved CTLA4-Ig analog belatacept to enhance the inhibition of alloproliferation that occurred with either agent alone (4.8-fold inhibition of CD8 T cell proliferation with Tregs + belatacept, compared to 3.0-fold or 1.9-fold inhibition of CD8 T cell proliferation with Tregs or belatacept alone, respectively). Importantly, we have found that the suppressive activity of ex-vivo expanded Tregs could be further enhanced by pulsing with sirolimus. Thus, while long-term culture of Tregs in the presence of sirolimus (1–1000 nM) profoundly inhibited Treg expansion (50–800 fold inhibition of expansion when cultured in the presence of 1–1000 nM sirolimus), a 48 hour pulse of sirolimus (100 nM) on days 20–21 of culture completely preserved Treg yields while doubling their suppressive function against CD8 proliferation when compared to unpulsed Tregs, p
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 6
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    Defining the Primate GvHD Transcriptome: Network Analysis Identifies the Key Pathways Responsible for GvHD Pathogenesis and the Mechanisms of Partial GvHD Control with Sirolimus (2012)
    American Society of Hematology
    Details
    Publication Date: 2012-11-16
    Description: Abstract 1888 Introduction: There is a critical unmet need to devise effective strategies to prevent GvHD. However, the best combinatorial therapies remain undetermined, and the identification of new targeted approaches to GvHD prevention remains a challenge. To address this, we have developed a genome-wide approach to studying GvHD, using whole-transcriptome analysis of pathogenic T cells in a clinically-relevant non-human primate (NHP) model. Using computational approaches, we have identified, for the first time, the transcriptional networks that drive primate GvHD, and that lead to its partial control with sirolimus. Methods: CD3+/CD20- T cells were purified flow cytometrically from 4 cohorts: (1) Healthy Controls (“HC” n = 15); (2) Recipients of an autologous HSCT (“Auto” n = 3); (3) Haplo-identical allogeneic HSCT recipients without GvHD prophylaxis, who developed histopathologically confirmed severe aGvHD (“GvHD” n = 4); and (4) Allo-HSCT recipients who received sirolimus alone, and were partially protected from aGvHD (“Sirolimus” n = 4). Purification of T cells after allo-HSCT occurred 1–2 weeks post-transplant. RNA was purified (Qiagen), and rhesus macaque-specific Affymetrix Gene Arrays were performed. Computation: Gene array signals were processed and normalized using the Robust Multichip Averaging Method and ComBat. Principal Component Analysis (PCA) was applied to summarize modes of gene array variance. Importantly, PCA revealed that variation was primarily determined by the experimental cohort (Figure 1). This result was critical, and confirmed that transcriptomics could be applied to identify genes and pathways controlling GvHD. Differentially expressed genes (“DE”, fold change 〉 2) were defined between cohorts, yielding unique and overlapping gene signatures. We found that 775 annotated genes were DE between GvHD and HC and 286 were DE between Sirolimus and HC (Figure 2A, B). Importantly, a subset of the GvHD and Sirolimus DE gene sets were overlapping, indicating incomplete control of T cell activation with sirolimus (Figure 2B), and identifying pathways that could be targeted in combination with sirolimus for improved GvHD control. To further define genes by their individual expression profiles using an unbiased approach, we applied Class Neighbor Analysis (GenePattern, Figure 3A). Finally, using Ingenuity Pathway Analysis (IPA) we characterized gene signatures according to molecular pathways (using right-tailed Fisher's Exact test and FDR correction, Figure 3B). Results: T cells from animals with severe aGvHD demonstrated transcriptional signs of rampant proliferation and cytotoxicity as well as potentially counter-regulatory cell death pathways. IPA identified highly statistically significant upregulation of Cell Cycle and Cellular Movement networks (Figure 3B, p〈 0.001) as well as Cell Trafficking and Inflammatory Response Networks (Figure 3B, p 〈 0.001). These networks contained some expected genes and some surprises. Thus, as previously documented, GvHD was associated with upregulation of JAK and IFN signaling (p 〈 0.001). Unexpectedly, GvHD was also associated with upregulation of the Sonic Hedgehog and Aurora Kinase A Pathways (p 〈 0.01). Both of these represent targetable pathways for which novel therapeutics are currently available. Sirolimus resulted in significantly different gene expression patterns compared to uncontrolled GvHD. This included partial downregulation of the proliferation marker Ki-67 and the cytotoxicity gene, Granzyme B. However, there were many genes, pathways and networks that were shared between the Sirolimus and GvHD cohorts. These prominently included upregulation of the FOXM1 and IRF8 transcription factors, involved in cell cycle progression (p
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 7
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    The Oceanic Sink for Anthropogenic CO〈sub〉2〈/sub〉 (2004)
    American Association for the Advancement of Science (AAAS)
    In:  Science, 305 . pp. 367-371.
    Details
    Publication Date: 2016-09-09
    Description: Using inorganic carbon measurements from an international survey effort in the 1990s and a tracer-based separation technique, we estimate a global oceanic anthropogenic carbon dioxide (CO2) sink for the period from 1800 to 1994 of 118 ± 19 petagrams of carbon. The oceanic sink accounts for ∼48% of the total fossil-fuel and cement-manufacturing emissions, implying that the terrestrial biosphere was a net source of CO2 to the atmosphere of about 39 ± 28 petagrams of carbon for this period. The current fraction of total anthropogenic CO2 emissions stored in the ocean appears to be about one-third of the long-term potential.
    Type: Article , PeerReviewed
    Format: text
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  • 8
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    The oceanic sink for anthropogenic CO2 from 1994 to 2007 (2019)
    American Association for the Advancement of Science (AAAS)
    In:  Science, 363 (6432). pp. 1193-1199.
    Details
    Publication Date: 2022-01-31
    Description: We quantify the oceanic sink for anthropogenic carbon dioxide (CO 2 ) over the period 1994 to 2007 by using observations from the global repeat hydrography program and contrasting them to observations from the 1990s. Using a linear regression–based method, we find a global increase in the anthropogenic CO 2 inventory of 34 ± 4 petagrams of carbon (Pg C) between 1994 and 2007. This is equivalent to an average uptake rate of 2.6 ± 0.3 Pg C year −1 and represents 31 ± 4% of the global anthropogenic CO 2 emissions over this period. Although this global ocean sink estimate is consistent with the expectation of the ocean uptake having increased in proportion to the rise in atmospheric CO 2 , substantial regional differences in storage rate are found, likely owing to climate variability–driven changes in ocean circulation.
    Type: Article , PeerReviewed , info:eu-repo/semantics/article
    Format: text
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