| 1. |
- Saunois, M., et al.
(författare)
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The global methane budget 2000–2012
- 2016
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Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3508 .- 1866-3516. ; 8:2, s. 697-751
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Tidskriftsartikel (refereegranskat)abstract
- The global methane (CH4) budget is becoming an increasingly important component for managing realistic pathways to mitigate climate change. This relevance, due to a shorter atmospheric lifetime and a stronger warming potential than carbon dioxide, is challenged by the still unexplained changes of atmospheric CH4 over the past decade. Emissions and concentrations of CH4 are continuing to increase, making CH4 the second most important human-induced greenhouse gas after carbon dioxide. Two major difficulties in reducing uncertainties come from the large variety of diffusive CH4 sources that overlap geographically, and from the destruction of CH4 by the very short-lived hydroxyl radical (OH). To address these difficulties, we have established a consortium of multi-disciplinary scientists under the umbrella of the Global Carbon Project to synthesize and stimulate research on the methane cycle, and producing regular (∼ biennial) updates of the global methane budget. This consortium includes atmospheric physicists and chemists, biogeochemists of surface and marine emissions, and socio-economists who study anthropogenic emissions. Following Kirschke et al. (2013), we propose here the first version of a living review paper that integrates results of top-down studies (exploiting atmospheric observations within an atmospheric inverse-modelling framework) and bottom-up models, inventories and data-driven approaches (including process-based models for estimating land surface emissions and atmospheric chemistry, and inventories for anthropogenic emissions, data-driven extrapolations). For the 2003–2012 decade, global methane emissions are estimated by top-down inversions at 558 Tg CH4 yr−1, range 540–568. About 60 % of global emissions are anthropogenic (range 50–65 %). Since 2010, the bottom-up global emission inventories have been closer to methane emissions in the most carbon-intensive Representative Concentrations Pathway (RCP8.5) and higher than all other RCP scenarios. Bottom-up approaches suggest larger global emissions (736 Tg CH4 yr−1, range 596–884) mostly because of larger natural emissions from individual sources such as inland waters, natural wetlands and geological sources. Considering the atmospheric constraints on the top-down budget, it is likely that some of the individual emissions reported by the bottom-up approaches are overestimated, leading to too large global emissions. Latitudinal data from top-down emissions indicate a predominance of tropical emissions (∼ 64 % of the global budget, < 30° N) as compared to mid (∼ 32 %, 30–60° N) and high northern latitudes (∼ 4 %, 60–90° N). Top-down inversions consistently infer lower emissions in China (∼ 58 Tg CH4 yr−1, range 51–72, −14 %) and higher emissions in Africa (86 Tg CH4 yr−1, range 73–108, +19 %) than bottom-up values used as prior estimates. Overall, uncertainties for anthropogenic emissions appear smaller than those from natural sources, and the uncertainties on source categories appear larger for top-down inversions than for bottom-up inventories and models. The most important source of uncertainty on the methane budget is attributable to emissions from wetland and other inland waters. We show that the wetland extent could contribute 30–40 % on the estimated range for wetland emissions. Other priorities for improving the methane budget include the following: (i) the development of process-based models for inland-water emissions, (ii) the intensification of methane observations at local scale (flux measurements) to constrain bottom-up land surface models, and at regional scale (surface networks and satellites) to constrain top-down inversions, (iii) improvements in the estimation of atmospheric loss by OH, and (iv) improvements of the transport models integrated in top-down inversions. The data presented here can be downloaded from the Carbon Dioxide Information Analysis Center (http://doi.org/10.3334/CDIAC/GLOBAL_METHANE_BUDGET_2016_V1.1) and the Global Carbon Project.
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| 2. |
- Kontro, M, et al.
(författare)
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HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia
- 2017
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 31:2, s. 301-309
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.Leukemia advance online publication, 2 September 2016; doi:10.1038/leu.2016.222.
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| 3. |
- Saunois, M., et al.
(författare)
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Variability and quasi-decadal changes in the methane budget over the period 2000–2012
- 2017
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 17:18, s. 11135-11161
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Tidskriftsartikel (refereegranskat)abstract
- Following the recent Global Carbon Project (GCP) synthesis of the decadal methane (CH4) budget over 2000–2012 (Saunois et al., 2016), we analyse here the same dataset with a focus on quasi-decadal and inter-annual variability in CH4 emissions. The GCP dataset integrates results from top-down studies (exploiting atmospheric observations within an atmospheric inverse-modelling framework) and bottom-up models (including process-based models for estimating land surface emissions and atmospheric chemistry), inventories of anthropogenic emissions, and data-driven approaches. The annual global methane emissions from top-down studies, which by construction match the observed methane growth rate within their uncertainties, all show an increase in total methane emissions over the period 2000–2012, but this increase is not linear over the 13 years. Despite differences between individual studies, the mean emission anomaly of the top-down ensemble shows no significant trend in total methane emissions over the period 2000–2006, during the plateau of atmospheric methane mole fractions, and also over the period 2008–2012, during the renewed atmospheric methane increase. However, the top-down ensemble mean produces an emission shift between 2006 and 2008, leading to 22 [16–32] Tg CH4 yr−1 higher methane emissions over the period 2008–2012 compared to 2002–2006. This emission increase mostly originated from the tropics, with a smaller contribution from mid-latitudes and no significant change from boreal regions. The regional contributions remain uncertain in top-down studies. Tropical South America and South and East Asia seem to contribute the most to the emission increase in the tropics. However, these two regions have only limited atmospheric measurements and remain therefore poorly constrained. The sectorial partitioning of this emission increase between the periods 2002–2006 and 2008–2012 differs from one atmospheric inversion study to another. However, all top-down studies suggest smaller changes in fossil fuel emissions (from oil, gas, and coal industries) compared to the mean of the bottom-up inventories included in this study. This difference is partly driven by a smaller emission change in China from the top-down studies compared to the estimate in the Emission Database for Global Atmospheric Research (EDGARv4.2) inventory, which should be revised to smaller values in a near future. We apply isotopic signatures to the emission changes estimated for individual studies based on five emission sectors and find that for six individual top-down studies (out of eight) the average isotopic signature of the emission changes is not consistent with the observed change in atmospheric 13CH4. However, the partitioning in emission change derived from the ensemble mean is consistent with this isotopic constraint. At the global scale, the top-down ensemble mean suggests that the dominant contribution to the resumed atmospheric CH4 growth after 2006 comes from microbial sources (more from agriculture and waste sectors than from natural wetlands), with an uncertain but smaller contribution from fossil CH4 emissions. In addition, a decrease in biomass burning emissions (in agreement with the biomass burning emission databases) makes the balance of sources consistent with atmospheric 13CH4 observations. In most of the top-down studies included here, OH concentrations are considered constant over the years (seasonal variations but without any inter-annual variability). As a result, the methane loss (in particular through OH oxidation) varies mainly through the change in methane concentrations and not its oxidants. For these reasons, changes in the methane loss could not be properly investigated in this study, although it may play a significant role in the recent atmospheric methane changes as briefly discussed at the end of the paper.
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| 4. |
- Anastasopoulos, M., et al.
(författare)
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Multi-Grid detector for neutron spectroscopy : Results obtained on time-of-flight spectrometer CNCS
- 2017
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Ingår i: Journal of Instrumentation. - : IOP PUBLISHING LTD. - 1748-0221 .- 1748-0221. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- The Multi-Grid detector technology has evolved from the proof-of-principle and characterisation stages. Here we report on the performance of the Multi-Grid detector, the MG.CNCS prototype, which has been installed and tested at the Cold Neutron Chopper Spectrometer, CNCS at SNS. This has allowed a side-by-side comparison to the performance of 3He detectors on an operational instrument. The demonstrator has an active area of 0.2 m2. It is specifically tailored to the specifications of CNCS. The detector was installed in June 2016 and has operated since then, collecting neutron scattering data in parallel to the He-3 detectors of CNCS. In this paper, we present a comprehensive analysis of this data, in particular on instrument energy resolution, rate capability, background and relative efficiency. Stability, gamma-ray and fast neutron sensitivity have also been investigated. The effect of scattering in the detector components has been measured and provides input to comparison for Monte Carlo simulations. All data is presented in comparison to that measured by the 3He detectors simultaneously, showing that all features recorded by one detector are also recorded by the other. The energy resolution matches closely. We find that the Multi-Grid is able to match the data collected by 3He, and see an indication of a considerable advantage in the count rate capability. Based on these results, we are confident that the Multi-Grid detector will be capable of producing high quality scientific data on chopper spectrometers utilising the unprecedented neutron flux of the ESS.
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| 5. |
- Hjorth-Hansen, H., et al.
(författare)
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Safety and efficacy of the combination of pegylated interferon-alpha 2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients
- 2016
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 30:9, s. 1853-1860
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Tidskriftsartikel (refereegranskat)abstract
- Dasatinib (DAS) and interferon-a have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-alpha 2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 mu g/week and it increased to 25 mu g/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR4 was achieved by 46% and MR4.5 by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS +/- PegIFN is warranted.
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| 6. |
- Leuzy, A., et al.
(författare)
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Longitudinal tau and metabolic PET imaging in relation to novel CSF tau measures in Alzheimer's disease
- 2019
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 46:5, s. 1152-1163
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Studies comparing CSF and PET tau biomarkers have included only commercial CSF assays examining specific phosphorylation sites (e.g. threonine 181, P-tau(181p)) and mid-domain tau (i.e. total tau, T-tau). Moreover, these studies did not examine CSF tau levels in relation to cerebral glucose metabolism. We thus aimed to examine CSF tau measures, using both commercial and novel assays, in relation to [F-18]THK5317 (tau) and [F-18]FDG PET (glucose metabolism). Methods Fourteen Alzheimer's disease (AD) patients (seven prodromal, seven dementia) underwent [F-18]THK5317 and [F-18]FDG PET studies, with follow-up performed in ten subjects (six prodromal, four dementia) after 17 months. In addition to commercial assays, novel measures capturing N-terminus+mid-domain (tau N-Mid) and C-terminally truncated (tau-368) fragments were included. Results While the levels of all forms of CSF tau were found to be inversely associated with baseline [F-18]FDG uptake, associations with baseline [F-18]THK5317 uptake varied in relation to the degree of isocortical hypometabolism ([F-18]FDG SUVR). Changes in the levels of the novel CSF markers tracked longitudinal changes in tracer uptake better than changes in P-tau(181p) and T-tau levels, and improved concordance with dichotomized regional [F-18]THK5317 measures. Conclusion Our findings suggest that neurodegeneration may modulate the relationship between CSF and PET tau biomarkers, and that, by comparison to P-tau(181p) and T-tau, tau-368 and tau N-Mid may better capturetau pathology and synaptic impairment.
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| 7. |
- Onatsu, J., et al.
(författare)
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Serum Neurofilament Light Chain Concentration Correlates with Infarct Volume but Not Prognosis in Acute Ischemic Stroke
- 2019
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Ingår i: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057. ; 28:8, s. 2242-2249
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: We studied serum neurofilaments diagnostic value in patients with acute ischemic stroke (AIS) or TIA and evaluated any correlation with symptom severity, cerebral infarction volume, aetiology, and clinical outcome. Methods: One hundred and thirty-six patients (101 with AIS, and 35 with TIA) were included. Acute-phase serum neurofilament light chain (sNfL) was analyzed with a novel ultrasensitive single molecule array (Simoa). Cerebral infarction volume was measured from brain computed tomography in the subacute phase (> 2 days). Stroke aetiology was defined by trial of ORG 10172 in acute stroke treatment classification, severity by National Institute of Health stroke scale (NIHSS) and the degree of disability by the Modified Rankin Scale (mRS) after 90 days. Results: sNfL was markedly higher in patients with AIS (89.5 pg/mL [IQR: 44.7-195.3]) than with TIA (25.2 pg/mL [IQR: 14.6-48.0]), P = <. 001), also after adjusting for age, NIHSS, and stroke volume (P=.003). In receiver operating characteristic analysis, sNfL concentration greater than or equal to 49 pg/mL proved to be the best cut-off value to differentiate between patients with stroke and those with TIA (sensitivity of 73% and specificity of 80%). sNfL concentration significantly correlated with cerebral infarction volume (r = .413, P = < .001), this association remained significant after adjusting for established predictors (P=.019). Patients with AIS due to cardioembolism or large artery atherosclerosis had the highest sNfL concentrations. NIHSS on admission (r = .343, P =< .001) and mRS scores after 3 months (r = .306, P = .004) correlated with sNfL concentration, however functional outcome 3 months after stroke was not associated with sNfL after adjusting for potential confounders. Conclusions: Cases with stroke were distinguishable from those with TIA following the determination of sNfL in the blood samples. The presence and amount of axonal damage estimated by sNfL correlated with the final cerebral infarction volume but was not predictive of degree of disability.
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| 8. |
- Shafer, Aaron B. A., et al.
(författare)
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Genomics and the challenging translation into conservation practice
- 2015
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Ingår i: Trends in Ecology & Evolution. - : Elsevier. - 0169-5347 .- 1872-8383. ; 30:2, s. 78-87
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Tidskriftsartikel (refereegranskat)abstract
- The global loss of biodiversity continues at an alarming rate. Genomic approaches have been suggested as a promising tool for conservation practice as scaling up to genome-wide data can improve traditional conservation genetic inferences and provide qualitatively novel insights. However, the generation of genomic data and subsequent analyses and interpretations remain challenging and largely confined to academic research in ecology and evolution. This generates a gap between basic research and applicable solutions for conservation managers faced with multifaceted problems. Before the real-world conservation potential of genomic research can be realized, we suggest that current infrastructures need to be modified, methods must mature, analytical pipelines need to be developed, and successful case studies must be disseminated to practitioners.
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| 9. |
- Bogstedt, A., et al.
(författare)
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Development of Immunoassays for the Quantitative Assessment of Amyloid-β in the Presence of Therapeutic Antibody: Application to Pre-Clinical Studies
- 2015
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 46:4, s. 1091-1101
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Tidskriftsartikel (refereegranskat)abstract
- Utilizing decision making biomarkers in drug development requires thorough assay validation. Special considerations need to be taken into account when monitoring biomarkers using immunoassays in the presence of therapeutic antibodies. We have developed robust and sensitive assays to assess target engagement and proof of mechanism to support the clinical progression of a human monoclonal antibody against the neurotoxic amyloid-β (Aβ)42 peptide. Here we present the introduction of novel pre-treatment steps to ensure drug-tolerant immunoassays and describe the validation of the complete experimental procedures to measure total Aβ42 concentration (bound and unbound) in cerebrospinal fluid (CSF) and plasma, free Aβ42 concentration (unbound) in CSF, and Aβ40 concentration in CSF. The difference in composition of the matrices (CSF and plasma) and antigen levels therein, in combination with the hydrophobic properties of Aβ protein, adds to the complexity of validation. Monitoring pharmacodynamics of an Aβ42 specific monoclonal antibody in a non-human primate toxicology study using these assays, we demonstrated a 1500-fold and a 3000-fold increase in total Aβ42 in plasma, a 4-fold and 8-fold increase in total Aβ42 in CSF together with a 95% and 96% reduction of free Aβ42 in CSF following weekly intravenous injections of 10 mg/kg and 100 mg/kg, respectively. Levels of Aβ40 were unchanged. The accuracy of these data is supported by previous pre-clinical studies as well as predictive pharmacokinetic/pharmacodynamics modeling. In contrast, when analyzing the same non-human primate samples excluding the pre-treatment steps, we were not able to distinguish between free and total Aβ42. Our data clearly demonstrate the importance of thorough evaluation of antibody interference and appropriate validation to monitor different types of biomarkers in the presence of a therapeutic antibody. © 2015-IOS Press and the authors. All rights reserved.
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| 10. |
- Christensen, Torben Røjle, et al.
(författare)
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Tracing the climate signal : mitigation of anthropogenic methane emissions can outweigh a large Arctic natural emission increase
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Natural methane emissions are noticeably influenced by warming of cold arctic ecosystems and permafrost. An evaluation specifically of Arctic natural methane emissions in relation to our ability to mitigate anthropogenic methane emissions is needed. Here we use empirical scenarios of increases in natural emissions together with maximum technically feasible reductions in anthropogenic emissions to evaluate their potential influence on future atmospheric methane concentrations and associated radiative forcing (RF). The largest amplification of natural emissions yields up to 42% higher atmospheric methane concentrations by the year 2100 compared with no change in natural emissions. The most likely scenarios are lower than this, while anthropogenic emission reductions may have a much greater yielding effect, with the potential of halving atmospheric methane concentrations by 2100 compared to when anthropogenic emissions continue to increase as in a business-as-usual case. In a broader perspective, it is shown that man-made emissions can be reduced sufficiently to limit methane-caused climate warming by 2100 even in the case of an uncontrolled natural Arctic methane emission feedback, but this requires a committed, global effort towards maximum feasible reductions.
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