Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs.

2.5 weeks) resumption of SSZ resistance and ABCG2 expression as in the original CEM/SSZ cells. CEM/SSZ cells displayed diminished sensitivity to the DMARDs leflunomide (5.1-fold) and methotrexate (1.8-fold), were moderately more sensitive (1.6-2.0 fold) to cyclosporin A and chloroquine, and markedly more sensitive (13-fold) to the glucocorticoid dexamethasone as compared with parental CEM cells. CONCLUSION: The drug efflux pump ABCG2 has a major role in conferring resistance to SSZ. The collateral sensitivity of SSZ resistant cells for some other (non-related) DMARDs may provide a further rationale for sequential mono- or combination therapies with distinct DMARDs upon decreased efficacy of SSZ

Spatio-Temporal Characteristics of Global Warming in the Tibetan Plateau during the Last 50 Years Based on a Generalised Temperature Zone - Elevation Model

Temperature is one of the primary factors influencing the climate and ecosystem, and examining its change and fluctuation could elucidate the formation of novel climate patterns and trends. In this study, we constructed a generalised temperature zone elevation model (GTEM) to assess the trends of climate change and temporal-spatial differences in the Tibetan Plateau (TP) using the annual and monthly mean temperatures from 1961-2010 at 144 meteorological stations in and near the TP. The results showed the following: (1) The TP has undergone robust warming over the study period, and the warming rate was 0.318°C/decade. The warming has accelerated during recent decades, especially in the last 20 years, and the warming has been most significant in the winter months, followed by the spring, autumn and summer seasons. (2) Spatially, the zones that became significantly smaller were the temperature zones of -6°C and -4°C, and these have decreased 499.44 and 454.26 thousand sq km from 1961 to 2010 at average rates of 25.1% and 11.7%, respectively, over every 5-year interval. These quickly shrinking zones were located in the northwestern and central TP. (3) The elevation dependency of climate warming existed in the TP during 1961-2010, but this tendency has gradually been weakening due to more rapid warming at lower elevations than in the middle and upper elevations of the TP during 1991-2010. The higher regions and some low altitude valleys of the TP were the most significantly warming regions under the same categorizing criteria. Experimental evidence shows that the GTEM is an effective method to analyse climate changes in high altitude mountainous regions

Evolution of 21st Century Sea Level Rise Projections

The modern era of scientific global‐mean sea level rise (SLR) projections began in the early 1980s. In subsequent decades, understanding of driving processes has improved, and new methodologies have been developed. Nonetheless, despite more than 70 studies, future SLR remains deeply uncertain. To facilitate understanding of the historical development of SLR projections and contextualize current projections, we have compiled a comprehensive database of 21st century global SLR projections. Although central estimates of 21st century global‐mean SLR have been relatively consistent, the range of projected SLR has varied greatly over time. Among studies providing multiple estimates, the range of upper projections shrank from 1.3–1.8 m during the 1980s to 0.6–0.9 m in 2007, before expanding again to 0.5–2.5 m since 2013. Upper projections of SLR from individual studies are generally higher than upper projections from the Intergovernmental Panel on Climate Change, potentially due to differing percentile bounds or a predisposition of consensus‐based approaches toward relatively conservative outcomes.Plain Language SummaryIn spite of more than 35 years of research, and over 70 individual studies, the upper bound of future global‐mean sea level rise (SLR) remains deeply uncertain. In an effort to improve understanding of the history of the science behind projected SLR, we present and analyze the first comprehensive database of 21st century global‐mean SLR projections. Results show a reduction in the range of SLR projections from the first studies through the mid‐2000s that has since reversed. In addition, results from this work indicate a tendency for Intergovernmental Panel on Climate Change reports to err on the side of least drama—a conservative bias that could potentially impede risk management.Key PointsWe present the first comprehensive database of 21st century global sea level rise projectionsUpper estimates of sea level rise in 2100 are often higher than upper bounds found in Intergovernmental Panel on Climate Change reportsA comparison of recent global sea level rise projections reveals far greater agreement among studies in 2050 compared to 2100Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147167/1/eft2484_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147167/2/eft2484.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147167/3/eft2_84-sup-0001-2018EF000991-Figs01.pd

Factors Affecting European Farmers’Participation in Biodiversity Policies

This article reports the major findings from an interdisciplinary research project that synthesises key insights into farmers’ willingness and ability to co-operate with biodiversity policies. The results of the study are based on an assessment of about 160 publications and research reports from six EU member states and from international comparative research.We developed a conceptual framework to systematically review the existent literature relevant for our purposes. This framework provides a common structure for analysing farmers’ perspectives regarding the introduction into farming practices of measures relevant to biodiversity. The analysis is coupled and contrasted with a survey of experts. The results presented above suggest that it is important to view support for practices oriented towards biodiversity protection not in a static sense – as a situation determined by one or several influencing factors – but rather as a process marked by interaction. Financial compensation and incentives function as a necessary, though clearly not sufficient condition in this process

Stakeholder influence on teaming and absorptive capacity in innovation networks

Through technological developments, innovation increasingly occurs within a network of organizations such as Industry 4.0 fieldlabs. As a result, collaboration between different companies and institutions with different interests needs to take place. Three Dutch smart industry fieldlabs were analysed to study how these collaborative relationships are being established and what their impact is on the absorptive capacity of the network in question. Contrary to what was expected, we found that stakeholders hardly exercised power. Also, a high level of psychological safety was found in the network, which positively affects collaboration. Furthermore, collaborative elements—such as open conversation, collaborating, experimenting and reflecting—are important factors affecting the absorptive capacity in the fieldlabs examined. The article concludes with several practical implications on how to stimulate innovation capability

Potential climatic transitions with profound impact on Europe

We discuss potential transitions of six climatic subsystems with large-scale impact on Europe, sometimes denoted as tipping elements. These are the ice sheets on Greenland and West Antarctica, the Atlantic thermohaline circulation, Arctic sea ice, Alpine glaciers and northern hemisphere stratospheric ozone. Each system is represented by co-authors actively publishing in the corresponding field. For each subsystem we summarize the mechanism of a potential transition in a warmer climate along with its impact on Europe and assess the likelihood for such a transition based on published scientific literature. As a summary, the ‘tipping’ potential for each system is provided as a function of global mean temperature increase which required some subjective interpretation of scientific facts by the authors and should be considered as a snapshot of our current understanding. <br/

Trust in governance networks: Its impacts on outcomes

__Abstract__ Governance networks are characterized by complex interaction and decision making, and much uncertainty. Surprisingly, there is very little research on the impact of trust in achieving results in governance networks. This article asks two questions: (a) Does trust influence the outcomes of environmental projects? and (b) Does active network management improve the level of trust in networks? The study is based on a Web-based survey of respondents involved in environmental projects. The results indicate that trust does matter for perceived outcomes and that network management strategies enhance the level of trust

Molecular Mechanisms of Bortezomib Resistant Adenocarcinoma Cells

Bortezomib (Velcade™) is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM). Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ∼30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response

The future sea-level rise contribution of Greenland’s glaciers and ice caps

We calculate the future sea-level rise contribution from the surface mass balance of all of Greenland's glaciers and ice caps (GICs, ~90 000 km2) using a simplified energy balance model which is driven by three future climate scenarios from the regional climate models HIRHAM5, RACMO2 and MAR. Glacier extent and surface elevation are modified during the mass balance model runs according to a glacier retreat parameterization. Mass balance and glacier surface change are both calculated on a 250 m resolution digital elevation model yielding a high level of detail and ensuring that important feedback mechanisms are considered. The mass loss of all GICs by 2098 is calculated to be 2016 ± 129 Gt (HIRHAM5 forcing), 2584 ± 109 Gt (RACMO2) and 3907 ± 108 Gt (MAR). This corresponds to a total contribution to sea-level rise of 5.8 ± 0.4, 7.4 ± 0.3 and 11.2 ± 0.3 mm, respectively. Sensitivity experiments suggest that mass loss could be higher by 20–30% if a strong lowering of the surface albedo were to take place in the future. It is shown that the sea-level rise contribution from the north-easterly regions of Greenland is reduced by increasing precipitation while mass loss in the southern half of Greenland is dominated by steadily decreasing summer mass balances. In addition we observe glaciers in the north-eastern part of Greenland changing their characteristics towards greater activity and mass turnover

Active Wnt signaling in response to cardiac injury

Although the contribution of Wnt signaling in infarct healing is suggested, its exact role after myocardial infarction (MI) still needs to be unraveled. We evaluated the cardiac presence of active Wnt signaling in vivo following MI, and investigated in which cell types active Wnt signaling was present by determining Axin2 promoter-driven LacZ expression. C57BL/6 Axin2-LacZ reporter mice were sacrificed at days 0, 1, 3, 7, 14, and 21 after LAD ligation. Hearts were snap-frozen for immunohistochemistry (IHC) or enzymatically digested to obtain a single cell suspension for flow cytometric analysis. For both FACS and IHC, samples were stained for β-galactosidase and antibodies against Sca-1, CD31, ckit, and CD45. Active Wnt signaling increased markedly in the myocardium, from 7 days post-MI onwards. Using Sca-1 and CD31, to identify progenitor and endothelial cells, a significant increase in LacZ+ cells was found at 7 and 14 days post-MI. LacZ+ cells also increased in the ckit+ and CD45+ cell population. IHC revealed LacZ+ cells co-expressing Sca, CD31, CD45, vWF, and αSMA in the border zone and the infarcted area. Wnt signaling increased significantly after MI in Sca+- and CD31+-expressing cells, suggesting involvement of Wnt signaling in resident Sca+ progenitor cells, as well as endothelial cells. Moreover, active Wnt signaling was present in ckit+ cells, leukocytes, and fibroblast. Given its broad role during the healing phase after cardiac injury, additional research seems warranted before a therapeutic approach on Wnt to enhance cardiac regeneration can be carried out safely