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  • 1
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    Discovery of AZD3147: A Potent, Selective Dual Inhibitor of mTORC1 and mTORC2 (2015)
    American Chemical Society (ACS)
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    Publication Date: 2015-02-20
    Description: Journal of Medicinal Chemistry DOI: 10.1021/jm501778s
    Topics: Chemistry and Pharmacology
    Published by American Chemical Society (ACS)
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  • 2
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    Comparison of GCM- and RCM-simulated precipitation following stochastic postprocessing (2014)
    Wiley
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    Publication Date: 2014-08-23
    Description: In order to assess to what extent regional climate models (RCMs) yield better representations of climatic states than general circulation models (GCMs) the output of each is usually directly compared with observations. RCM output is often bias-corrected and in some cases correction methods can also be applied to GCMs. This leads to the question of whether bias-corrected RCMs perform better than bias-corrected GCMs. Here, the first results from such a comparison are presented, followed by discussion of thevalue added by RCMs in this setup. Stochastic postprocessing, based on Model Output Statistics (MOS), is used to estimate daily precipitation at 465 stations across the United Kingdom between 1961–2000 using simulated precipitation from two RCMs (RACMO2and CCLM) and, for the first time, a GCM (ECHAM5) as predictors. The large-scale weather states in each simulation are forced toward observations. The MOS method uses logistic regression to model precipitation occurrence and a Gamma distribution for the wet-day distribution, and is cross-validated based on Brier and quantile skill scores. A major outcome of the study is that the corrected GCM-simulated precipitation yields consistently higher validation scores than the corrected RCM-simulated precipitation. This seems to suggest that, in a setup with postprocessing, there is no clear added value by RCMs with respect to downscaling individual weather states. However, due to the different ways of controlling the atmospheric circulation in the RCM and the GCM simulations, such a strong conclusion cannot be drawn. Yet, the study demonstrates how challenging it is to demonstrate the value added by RCMs in this setup.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 3
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    Loss of division potential in vitro: aging or differentiation? (1978)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 1978-12-15
    Description: We have examined the hypothesis that diploid cells grown in vitro age, and propose that only proliferative potential and not life-span is telescoped. We suggest that explanted or transplanted diploid cells are driven to divide by the process of subculturing in vitro or in vivo and, in response to this pressure, also complete their differentiation and become refractory to further mitotic stimulation. We conclude that differentiation rather than "mortality" distinguishes diploid from transformed cells and that the former may not age in vitro, but are lost because culture methods are selective for cycling cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bell, E -- Marek, L F -- Levinstone, D S -- Merrill, C -- Sher, S -- Young, I T -- Eden, M -- New York, N.Y. -- Science. 1978 Dec 15;202(4373):1158-63.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/725592" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle ; *Cell Differentiation ; *Cell Division ; *Cell Survival ; Cells, Cultured ; Fibroblasts
    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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    Loss of division potential in culture: aging or differentiation? (1980)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 1980-06-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bell, E -- Marek, L F -- Merrill, C -- Levinstone, D S -- Young, T -- Eden, M -- Sher, S -- New York, N.Y. -- Science. 1980 Jun 27;208(4451):1483.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17796697" target="_blank"〉PubMed〈/a〉
    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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  • 5
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    Multi-method attribution analysis of extreme precipitation in Boulder, Colorado (2016)
    Institute of Physics (IOP)
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    Publication Date: 2016-11-30
    Description: Understanding and attributing the characteristics of extreme events that lead to societal impacts is a key challenge in climate science. Detailed analysis of individual case studies is particularly important in assessing how anthropogenic climate change is changing the likelihood of extreme events and their associated risk at relevant spatial scales. Here, we conduct a comprehensive multi-method attribution analysis of the heavy precipitation that led to widespread flooding in Boulder, Colorado in September 2013. We provide clarification on the source regions of moisture associated with this event in order to highlight the difficulty of separating dynamic and thermodynamic contributions. Using extreme value analysis of, first of all, historical observations, we then assess the influence of anthropogenic climate change on the overall likelihood of one- and five-day precipitation events across the Boulder area. The same analysis is extended to the output of two general circulation...
    Print ISSN: 1748-9318
    Electronic ISSN: 1748-9326
    Topics: Biology , Energy, Environment Protection, Nuclear Power Engineering
    Published by Institute of Physics (IOP)
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  • 6
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    A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair (2014)
    Oxford University Press
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    Publication Date: 2014-05-20
    Description: DNA double-strand breaks (DSBs) are the most severe type of DNA damage. DSBs are repaired by non-homologous end-joining or homology directed repair (HDR). Identifying novel small molecules that affect HDR is of great importance both for research use and therapy. Molecules that elevate HDR may improve gene targeting whereas inhibiting molecules can be used for chemotherapy, since some of the cancers are more sensitive to repair impairment. Here, we performed a high-throughput chemical screen for FDA approved drugs, which affect HDR in cancer cells. We found that HDR frequencies are increased by retinoic acid and Idoxuridine and reduced by the antihypertensive drug Spironolactone. We further revealed that Spironolactone impairs Rad51 foci formation, sensitizes cancer cells to DNA damaging agents, to Poly (ADP-ribose) polymerase (PARP) inhibitors and cross-linking agents and inhibits tumor growth in xenografts, in mice. This study suggests Spironolactone as a new candidate for chemotherapy.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Pacific SST influence on spring precipitation in Addis Ababa, Ethiopia (2013)
    Wiley
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    Publication Date: 2013-06-25
    Description: ABSTRACT Recent periods of drought in Ethiopia and other parts of East Africa have highlighted the growing importance of producing reliable forecasts of seasonal precipitation. Key in deriving such forecasts is a good understanding of the atmospheric and oceanic drivers of different precipitation regimes. In Ethiopia and other parts of East Africa, interannual variability of precipitation depends on variations in sea surface temperature (SST) and atmospheric circulation on both regional and global scales. Links between summer precipitation in Ethiopia and large-scale modes of climate variability such as El Niño Southern Oscillation (ENSO) have previously been established but the influence of global SST on spring precipitation has not yet been fully explored. Here, we analyse the links between Pacific SST and precipitation in Addis Ababa, Ethiopia for a century-long period (1900–2004). A tripole correlation pattern between spring precipitation and SST in the Pacific basin is found. We develop regression-based models to estimate spring precipitation from Pacific SST with a lead time of two to three months. When subject to cross-validation, models based on principal component multiple linear regression (PC-MLR) calibrated on Pacific SST during December show substantial skill in reproducing observed temporal variability in Addis Ababa precipitation during February ( r  = 0.48) and March ( r  = 0.40), and the period spanning February to April ( r  = 0.44). Our findings suggest that the inclusion of Pacific SST in predictive models may benefit drought forecasting across Ethiopia.
    Print ISSN: 0899-8418
    Electronic ISSN: 1097-0088
    Topics: Geosciences , Physics
    Published by Wiley
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  • 8
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    An empirical prediction approach for seasonal fire risk in the boreal forests (2019)
    Wiley
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    Publication Date: 2019
    Description: Abstract The ability to predict forest fire risk at monthly, seasonal, and above‐annual time scales is critical to mitigate its impacts, including fire‐driven dynamics of ecosystem and socio‐economic services. Fire is the primary driving factor of the ecosystem dynamics in the boreal forest, directly affecting global carbon balance and atmospheric concentrations of the trace gases including carbon dioxide. Resilience of the ocean‐atmosphere system provides potential for advanced detection of upcoming fire season intensity. Here, we report on the development of a probabilistic empirical prediction system for forest fire risk on monthly‐to‐seasonal timescales across the circumboreal region. Quasi‐operational ensemble forecasts are generated for monthly drought code (MDC), an established indicator for seasonal fire activity in the Boreal biome based on monthly maximum temperature and precipitation values. Historical MDC forecasts are validated against observations, with good skill is found in across northern Eurasia and North America. In addition, we show that the MDC forecasts are an excellent indicator for satellite‐derived observations of burned area in large parts of the Boreal region. Our discussion considers the relative value of forecast information to a range of stakeholders when disseminated before and during the fire season. We also discuss the wider role of empirical predictions in benchmarking dynamical forecast systems and in conveying forecast information in a simple and digestible manner. This article is protected by copyright. All rights reserved.
    Print ISSN: 0899-8418
    Electronic ISSN: 1097-0088
    Topics: Geosciences , Physics
    Published by Wiley
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  • 9
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    Divergent Effects of Notch Signaling On Leukemia Stem Cells and Hematopoietic Stem Cells. (2009)
    American Society of Hematology
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    Publication Date: 2009-11-20
    Description: Abstract 395 The Leukemia Stem Cell (LSC) hypothesis proposes that a subset of the cells in the bulk tumor cell population is responsible for leukemia maintenance and propagation. We tested the LSC hypothesis in murine T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by retroviruses expressing strong gain-of-function Notch1 alleles. This model is relevant to human disease, as Notch1 is activated in ∼70% of human T-ALLs. By transferring sorted leukemia cells to syngeneic secondary recipients at limiting dilution, we found that LSC activity was enriched in the CD8+CD4-HSAhi (Immature Single Positive or “ISP”) T-cell subset. The LSC frequency was ∼1 in 1000 cells, two orders of magnitude higher than in the CD8+CD4+ (Double positive or “DP”) T-cell subset. We found similar results in a KrasG12D-driven T-ALL mouse model where activating Notch mutations occur spontaneously in ∼80% cases. Surprisingly, we were unable to isolate Notch-activated hematopoietic stem and progenitor cells (HSPCs) to test for LSC activity. Upon further analysis, we observed that activation of Notch in HSPCs caused loss of stem cell quiescence and progressive, complete loss of long-term hematopoietic stem cells (LT-HSCs) over several weeks. Notch signals had no significant effects on stem cell homing, apoptosis, or senescence. Similar results were obtained in both noncompetitive and competitive secondary transplants as well as in a mouse model in which Notch activation is conditionally induced in HSCs by Cre recombinase. We conclude that while Notch signaling promotes LSC activity, it extinguishes HSCs. These results provide a rationale for therapeutic targeting of the ISP-like T-cell subset in Notch-activated T-ALL while underscoring the potential difficulty of manipulating Notch signaling to expand normal, long-term stem cell populations for clinical applications. 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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  • 10
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    C-Myc, but Not Akt, Can Substitute for Notch in Lymphomagenesis. (2009)
    American Society of Hematology
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    Publication Date: 2009-11-20
    Description: Abstract 7 Notch signaling is activated in ∼70% of human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) samples and many human and mouse T-ALL cell lines require Notch signals for growth and survival. To gain insight into the role of Notch during induction of T-ALL, we used a fully penetrant, conditional, transgenic KrasG12D mouse model in which ∼80% of T-ALLs acquire activating Notch1 mutations in the endogenous locus. We crossed mice bearing this transgene with Rosa26-DNMAMLf/f mice, which conditionally express the pan-Notch inhibitor DNMAML. T-ALL developed in these mice despite the expression of DNMAML throughout T-cell development. ∼75% of T-ALL tumors acquired activating Notch1 mutations and suppressed expression of DNMAML, which is consistent with frequent “escape” of Notch from inhibition for efficient T-ALL development. We next compared T-ALL cells that lacked DNMAML expression with T-ALL cells that continued to express DNMAML. T-ALL cells lacking DNMAML expressed the direct Notch target c-Myc at higher levels, proliferated at a higher rate, and contained ∼10-fold higher levels of leukemia-initiating cells. Moreover, DNMAML-positive T-ALLs lost DNMAML after transfer into secondary recipients. These data underscore the strong selective pressure for Notch signals during generation and maintenance of T-ALL. We next sought a mechanistic answer for the strong selective pressure for Notch activation. c-Myc and Akt have both been posited to be critical targets of oncogenic Notch signals. To compare the relative contributions of c-Myc and Akt to lymphomagenesis, we overexpressed c-Myc and activated AKT in the KrasG12D-driven mouse model. T-ALLs induced by KrasG12D and Akt acquired activating Notch1 mutations in ∼70% of tumors, which were sensitive to Notch inhibitors (gamma-secretase inhibitors [GSI]). In contrast, T-ALLs induced by KrasG12D and c-Myc did not acquire Notch1 mutations and were resistant to GSI. We conclude that upregulation of c-Myc is sufficient to substitute for Notch in lymphomagenesis, whereas activation of Akt signaling is not. These data identify c-Myc not AKT as the driving force behind Notch-induced lymphomagenesis. These data emphasize the Notch/c-Myc axis as an attractive, rational, therapeutic target in T-ALL. 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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