Can abenomics succeed? Botman, Dennis; Danninger, Stephan; Schiff, Jerald
2015., 2015-03-04, 2015
eBook, Book
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Japan's revitalization plan, dubbed the "three arrows of Abenomics," devises a three-pronged strategy-combining fiscal, monetary, and structural policies-to overcome that country's apparent inability ...to sustain economic recovery. This book is the first comprehensive assessment of Abenomics and the reforms needed to make it a success, including aggressive monetary easing, growth-friendly fiscal consolidation, and structural and financial sector reforms.
Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1(R132H), a structural alteration that leads to catalysis of α-ketoglutarate to the oncometabolite ...D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1(R132H) that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1(R132H) mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1(R132H) inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1(R132H) inhibitors in these patients may limit irradiation efficacy in this setting.
The cAMP-PKA signalling cascade in budding yeast regulates adaptation to changing environments. We developed yEPAC, a FRET-based biosensor for cAMP measurements in yeast. We used this sensor with ...flow cytometry for high-throughput single cell-level quantification during dynamic changes in response to sudden nutrient transitions. We found that the characteristic cAMP peak differentiates between different carbon source transitions, and is rather homogenous among single-cells, especially for transitions to glucose. The peaks are mediated by a combination of extracellular sensing and intracellular metabolism. Moreover, the cAMP peak follows the Weber-Fechner law; its height scales with the relative, and not the absolute, change in glucose. Lastly, our results suggest that the cAMP peak height conveys information about prospective growth rates. In conclusion, our yEPAC-sensor makes possible new avenues for understanding yeast physiology, signalling and metabolic adaptation. Media: see text.
For the design of next-generation tuberculosis chemotherapy, insight into bacterial defence against drugs is required. Currently, targeting respiration has attracted strong attention for combatting ...drug-resistant mycobacteria. Q203 (telacebec), an inhibitor of the cytochrome bcc complex in the mycobacterial respiratory chain, is currently evaluated in phase-2 clinical trials. Q203 has bacteriostatic activity against M. tuberculosis, which can be converted to bactericidal activity by concurrently inhibiting an alternative branch of the mycobacterial respiratory chain, cytochrome bd. In contrast, non-tuberculous mycobacteria, such as Mycobacterium smegmatis, show only very little sensitivity to Q203. In this report, we investigated factors that M. smegmatis employs to adapt to Q203 in the presence or absence of a functional cytochrome bd, especially regarding its terminal oxidases. In the presence of a functional cytochrome bd, M. smegmatis responds to Q203 by increasing the expression of cytochrome bcc as well as of cytochrome bd, whereas a M. smegmatisbd-KO strain adapted to Q203 by increasing the expression of cytochrome bcc. Interestingly, single-cell studies revealed cell-to-cell variability in drug adaptation. We also investigated the role of a putative second cytochrome bd isoform postulated for M. smegmatis. Although this putative isoform showed differential expression in response to Q203 in the M. smegmatisbd-KO strain, it did not display functional features similar to the characterised cytochrome bd variant.
Portfolio rebalancing is a key transmission channel of quantitative easing in Japan. We construct a realistic rebalancing scenario, which suggests that the BoJ may need to taper its JGB purchases in ...2017 or 2018, given collateral needs of banks, asset-liability management constraints of insurers, and announced asset allocation targets of major pension funds. Nonetheless, the BoJ could deliver continued monetary stimulus by extending the maturity of its JGB purchases or by scaling up private asset purchases. We quantify the impact of rebalancing on capital outflows and discuss JGB market signals that can be indicative of limits being within reach.
Abstract
Budding yeast uses the TORC1-Sch9p and cAMP-PKA signalling pathways to regulate adaptations to changing nutrient environments. Dynamic and single-cell measurements of the activity of these ...cascades will improve our understanding of the cellular adaptation of yeast. Here, we employed the AKAR3-EV biosensor developed for mammalian cells to measure the cellular phosphorylation status determined by Sch9p and PKA activity in budding yeast. Using various mutant strains and inhibitors, we show that AKAR3-EV measures the Sch9p- and PKA-dependent phosphorylation status in intact yeast cells. At the single-cell level, we found that the phosphorylation responses are homogenous for glucose, sucrose, and fructose, but heterogeneous for mannose. Cells that start to grow after a transition to mannose correspond to higher normalized Förster resonance energy transfer (FRET) levels, in line with the involvement of Sch9p and PKA pathways to stimulate growth-related processes. The Sch9p and PKA pathways have a relatively high affinity for glucose (K0.5 of 0.24 mM) under glucose-derepressed conditions. Lastly, steady-state FRET levels of AKAR3-EV seem to be independent of growth rates, suggesting that Sch9p- and PKA-dependent phosphorylation activities are transient responses to nutrient transitions. We believe that the AKAR3-EV sensor is an excellent addition to the biosensor arsenal for illuminating cellular adaptation in single yeast cells.
The AKAR3-EV biosensor measures the signalling activity of two major kinases -PKA and Sch9- in single living budding yeast cells.
Fluorescent proteins (FPs) are widely used in many organisms, but are commonly characterised in vitro. However, the in vitro properties may poorly reflect in vivo performance. Therefore, we ...characterised 27 FPs in vivo using Saccharomyces cerevisiae as model organism. We linked the FPs via a T2A peptide to a control FP, producing equimolar expression of the 2 FPs from 1 plasmid. Using this strategy, we characterised the FPs for brightness, photostability, photochromicity and pH-sensitivity, achieving a comprehensive in vivo characterisation. Many FPs showed different in vivo properties compared to existing in vitro data. Additionally, various FPs were photochromic, which affects readouts due to complex bleaching kinetics. Finally, we codon optimized the best performing FPs for optimal expression in yeast, and found that codon-optimization alters FP characteristics. These FPs improve experimental signal readout, opening new experimental possibilities. Our results may guide future studies in yeast that employ fluorescent proteins.
This paper compares the general tax provisions and investment incentives in the Philippines to six other East Asian economies - Malaysia, Indonesia, Lao, Vietnam, Cambodia and Thailand. It finds that ...general effective tax rates are relatively high in the Philippines, while investment incentives are comparable to those in neighboring countries. Tax holidays are most attractive for very profitable firms, creating redundancy, and for investment in short-lived assets. Two recently proposed tax reforms would replace tax holidays by a reduced corporate income tax rate or a low tax on gross receipts. The results suggest that this would result in stronger incentives to invest, while government revenue would increase. Alternatively, replacing tax holidays with a general reduction in the corporate tax rate and accelerated depreciation would either not provide the same incentives or be very costly.
cAMP in budding yeast: Also a messenger for sucrose metabolism? Botman, Dennis; Kanagasabapathi, Sineka; Rep, Mila I. ...
Biochimica et biophysica acta. Molecular cell research,
April 2024, 2024-Apr, 2024-04-00, 20240401, Letnik:
1871, Številka:
4
Journal Article
Recenzirano
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S. cerevisiae (or budding yeast) is an important micro-organism for sucrose-based fermentation in biotechnology. Yet, it is largely unknown how budding yeast adapts to sucrose transitions. Sucrose ...can only be metabolized when the invertase or the maltose machinery are expressed and we propose that the Gpr1p receptor signals extracellular sucrose availability via the cAMP peak to adapt cells accordingly. A transition to sucrose or glucose gave a transient cAMP peak which was maximally induced for sucrose. When transitioned to sucrose, cAMP signalling mutants showed an impaired cAMP peak together with a lower growth rate, a longer lag phase and a higher final OD600 compared to a glucose transition. These effects were not caused by altered activity or expression of enzymes involved in sucrose metabolism and imply a more general metabolic adaptation defect. Basal cAMP levels were comparable among the mutant strains, suggesting that the transient cAMP peak is required to adapt cells correctly to sucrose. We propose that the short-term dynamics of the cAMP signalling cascade detects long-term extracellular sucrose availability and speculate that its function is to maintain a fermentative phenotype at continuously low glucose and fructose concentrations.
•The adaptation of budding yeast to sucrose is still enigmatic.•cAMP signalling mutants show a deteriorated cAMP response for sucrose.•These mutants have growth defects on specifically sucrose.•Basal cAMP levels are not affected in these mutants.•The short-term dynamics of cAMP ensure proper sucrose adaption for yeast.
Coordination of speculation Botman, Dennis P.J.; Jager, Henk
Journal of international economics,
10/2002, Letnik:
58, Številka:
1
Journal Article
Recenzirano
We extend the models of Krugman Journal of Money, Credit and Banking, 11 (1979) 311 and Flood and Garber Journal of International Economics, 17 (1984) 1 on balance of payments crises to a ...multi-country setting such that coordination among speculators is important for a focal point to emerge. The moment of successful coordination when the currency is devalued is shown to depend on initial beliefs, the degree of imperfect communication, the rate of domestic credit creation, and the number of countries that have overvalued currencies. Contagion arises naturally in our framework. Subsequent speculative attacks occur faster and faster and communication among speculators results in fluctuating stocks of reserves prior to the attack.
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