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Shin, Sung-Young,Rath, Oliver,Choo, Sang-Mok,Fee, Frances,McFerran, Brian,Kolch, Walter,Cho, Kwang-Hyun Cambridge University Press 2009 Journal of cell science Vol.122 No.3
<P>The Ras-Raf-MEK-ERK pathway (or ERK pathway) is an important signal transduction system involved in the control of cell proliferation, survival and differentiation. However, the dynamic regulation of the pathway by positive- and negative-feedback mechanisms, in particular the functional role of Raf kinase inhibitor protein (RKIP) are still incompletely understood. RKIP is a physiological endogenous inhibitor of MEK phosphorylation by Raf kinases, but also participates in a positive-feedback loop in which ERK can inactivate RKIP. The aim of this study was to elucidate the hidden dynamics of these feedback mechanisms and to identify the functional role of RKIP through combined efforts of biochemical experiments and in silico simulations based on an experimentally validated mathematical model. We show that the negative-feedback loop from ERK to SOS plays a crucial role in generating an oscillatory behavior of ERK activity. The positive-feedback loop in which ERK functionally inactivates RKIP also enhances the oscillatory activation pattern of ERK. However, RKIP itself has an important role in inducing a switch-like behavior of MEK activity. When overexpressed, RKIP also causes delayed and reduced responses of ERK. Thus, positive- and negative-feedback loops and RKIP work together to shape the response pattern and dynamical characteristics of the ERK pathway.</P>
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Maag, Roman,Northrop, Brian H.,Butterfield, Anna,Linden, Anthony,Zerbe, Oliver,Lee, Young Min,Chi, Ki-Whan,Stang, Peter J.,Siegel, Jay S. Royal Society of Chemistry 2009 Organic & biomolecular chemistry Vol.7 No.23
<P>The synthesis and characterization of two direct platinum (1 and 6a/b) and three ethynyl-platinum corannulene derivatives (2, 8 and 9), bearing 2, 4, or 5 square planar platinum centers, are presented. The structure of the bowl bearing substituents remains comparable to corannulene and the dynamic behavior of the bowl inversion as assessed by VT NMR supports a persistent bowl structure in solution. These platinum-corannulenes are well-structured tectons for the future assembly of coordination Platonic polyhedra.</P> <P>Graphic Abstract</P><P>Direct platination of chloro and TMSethynyl corannulenes leads to new supramolecular tectons. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=b916020e'> </P>
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Liu Ying,Zhang Xin,Zhang Li,Oliver Brian G,Wang Hong Guang,Liu Zhi Peng,Chen Zhi Hong,Wood Lisa,Hsu Alan Chen-Yu,Xie Min,McDonald Vanessa,Wan Hua Jing,Luo Feng Ming,Liu Dan,Li Wei Min,Wang Gang 대한천식알레르기학회 2022 Allergy, Asthma & Immunology Research Vol.14 No.4
Purpose: The molecular links between metabolism and inflammation that drive different inflammatory phenotypes in asthma are poorly understood. We aimed to identify the metabolic signatures and underlying molecular pathways of different inflammatory asthma phenotypes. Methods: In the discovery set (n = 119), untargeted ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was applied to characterize the induced sputum metabolic profiles of asthmatic patients with different inflammatory phenotypes using orthogonal partial least-squares discriminant analysis (OPLS-DA), and pathway topology enrichment analysis. In the validation set (n = 114), differential metabolites were selected to perform targeted quantification. Correlations between targeted metabolites and clinical indices in asthmatic patients were analyzed. Logistic and negative binomial regression models were established to assess the association between metabolites and severe asthma exacerbations. Results: Seventy-seven differential metabolites were identified in the discovery set. Pathway topology analysis uncovered that histidine metabolism, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism, linoleic acid metabolism as well as phenylalanine, tyrosine and tryptophan biosynthesis were involved in the pathogenesis of different asthma phenotypes. In the validation set, 24 targeted quantification metabolites were significantly expressed between asthma inflammatory phenotypes. Finally, adenosine 5′-monophosphate (adjusted relative risk [adj RR] = 1.000; 95% confidence interval [CI] = 1.000–1.000; P = 0.050), allantoin (adj RR = 1.000; 95% CI = 1.000–1.000; P = 0.043) and nicotinamide (adj RR = 1.001; 95% CI = 1.000–1.002; P = 0.021) were demonstrated to predict severe asthma exacerbation rates. Conclusions: Different inflammatory asthma phenotypes have specific metabolic profiles in induced sputum. The potential metabolic signatures may identify therapeutic targets in different inflammatory asthma phenotypes.
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Adam M. Greenbaum,Damian J. Green,Leona A. Holmberg,Ted Gooley,Brian G. Till,Lihua E. Budde,Heather Rasmussen,Oliver W. Press,Ajay K. Gopal 대한혈액학회 2018 Blood Research Vol.53 No.3
Background Bendamustine is a chemotherapeutic agent that has shown broad activity in patients with lymphoid malignancies. It contains both alkylating and nucleoside analog moieties, and thus, is not commonly used for stem cell mobilization due to concerns that it may ad-versely affect stem cell collection. Here we describe the lymphoma subset of a pro-spective, non-randomized phase II study of bendamustine, etoposide, and dex-amethasone (BED) as a mobilization agent for lymphoid malignancies. Methods This subset analysis includes diffuse large B-cell lymphoma (N=3), follicular lymphoma (N=1), primary mediastinal B-cell lymphoma (N=1), and NK/T-cell lymphoma (N=1). Patients received bendamustine (120 mg/m2 IV d 1, 2), etoposide (200 mg/m2 IV d 1‒3), and dexamethasone (40 mg PO d 1‒4) followed by filgrastim (10 mcg/kg/d sc. through collection). Results We successfully collected stem cells from all patients, with a median of 7.9×106/kg of body weight (range, 4.4 to 17.3×106/kg) over a median of 1.5 days (range, 1 to 3) of apheresis. All patients who received transplants were engrafted using kinetics that were comparable to those of other mobilization regimens. Three non-hematologic significant adverse events were observed in one patient, and included bacterial sepsis (grade 3), tumor lysis syndrome (grade 3), and disease progression (grade 5). Conclusion For non-Hodgkin lymphoma, mobilization with bendamustine is safe and effective.
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Riahi, Keywan,van Vuuren, Detlef P.,Kriegler, Elmar,Edmonds, Jae,O’Neill, Brian C.,Fujimori, Shinichiro,Bauer, Nico,Calvin, Katherine,Dellink, Rob,Fricko, Oliver,Lutz, Wolfgang,Popp, Alexander,Cuaresm Elsevier 2017 Global environmental change Vol.42 No.-
<P><B>Abstract</B></P> <P>This paper presents the overview of the Shared Socioeconomic Pathways (SSPs) and their energy, land use, and emissions implications. The SSPs are part of a new scenario framework, established by the climate change research community in order to facilitate the integrated analysis of future climate impacts, vulnerabilities, adaptation, and mitigation. The pathways were developed over the last years as a joint community effort and describe plausible major global developments that together would lead in the future to different challenges for mitigation and adaptation to climate change. The SSPs are based on five narratives describing alternative socio-economic developments, including sustainable development, regional rivalry, inequality, fossil-fueled development, and middle-of-the-road development. The long-term demographic and economic projections of the SSPs depict a wide uncertainty range consistent with the scenario literature. A multi-model approach was used for the elaboration of the energy, land-use and the emissions trajectories of SSP-based scenarios. The baseline scenarios lead to global energy consumption of 400–1200 EJ in 2100, and feature vastly different land-use dynamics, ranging from a possible reduction in cropland area up to a massive expansion by more than 700 million hectares by 2100. The associated annual CO<SUB>2</SUB> emissions of the baseline scenarios range from about 25 GtCO<SUB>2</SUB> to more than 120 GtCO<SUB>2</SUB> per year by 2100. With respect to mitigation, we find that associated costs strongly depend on three factors: (1) the policy assumptions, (2) the socio-economic narrative, and (3) the stringency of the target. The carbon price for reaching the target of 2.6W/m<SUP>2</SUP> that is consistent with a temperature change limit of 2°C, differs in our analysis thus by about a factor of three across the SSP marker scenarios. Moreover, many models could not reach this target from the SSPs with high mitigation challenges. While the SSPs were designed to represent different mitigation and adaptation challenges, the resulting narratives and quantifications span a wide range of different futures broadly representative of the current literature. This allows their subsequent use and development in new assessments and research projects. Critical next steps for the community scenario process will, among others, involve regional and sectoral extensions, further elaboration of the adaptation and impacts dimension, as well as employing the SSP scenarios with the new generation of earth system models as part of the 6th climate model intercomparison project (CMIP6).</P> <P><B>Highlights</B></P> <P> <UL> <LI> We present an overview of the Shared Socioeconomic Pathways (SSPs), which were developed as a community effort over the last years. </LI> <LI> The SSPs comprise five narratives and a set of driving forces. </LI> <LI> Our SSP scenarios quantify energy and land-use developments and associated uncertainties for greenhouse gas and air pollutant emissions. </LI> <LI> We conduct an SSP mitigation analysis, and estimate mitigation costs. We find that very low climate targets might be out of reach in SSPs featuring high challenges. </LI> <LI> The SSPs are now ready for use by the climate change research community. </LI> </UL> </P>
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Adam M. Greenbaum,Damian J. Green,Leona A. Holmberg,Ted Gooley,Brian G. Till,Lihua E. Budde,Heather Rasmussen,Oliver W. Press,Ajay K. Gopal 대한혈액학회 2018 Blood Research Vol.53 No.3
Background Bendamustine is a chemotherapeutic agent that has shown broad activity in patients with lymphoid malignancies. It contains both alkylating and nucleoside analog moieties, and thus, is not commonly used for stem cell mobilization due to concerns that it may ad-versely affect stem cell collection. Here we describe the lymphoma subset of a pro-spective, non-randomized phase II study of bendamustine, etoposide, and dex-amethasone (BED) as a mobilization agent for lymphoid malignancies. Methods This subset analysis includes diffuse large B-cell lymphoma (N=3), follicular lymphoma (N=1), primary mediastinal B-cell lymphoma (N=1), and NK/T-cell lymphoma (N=1). Patients received bendamustine (120 mg/m2 IV d 1, 2), etoposide (200 mg/m2 IV d 1‒3), and dexamethasone (40 mg PO d 1‒4) followed by filgrastim (10 mcg/kg/d sc. through collection). Results We successfully collected stem cells from all patients, with a median of 7.9×106/kg of body weight (range, 4.4 to 17.3×106/kg) over a median of 1.5 days (range, 1 to 3) of apheresis. All patients who received transplants were engrafted using kinetics that were comparable to those of other mobilization regimens. Three non-hematologic significant adverse events were observed in one patient, and included bacterial sepsis (grade 3), tumor lysis syndrome (grade 3), and disease progression (grade 5). Conclusion For non-Hodgkin lymphoma, mobilization with bendamustine is safe and effective.
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Bulitta, Jü,rgen B.,Ly, Neang S.,Landersdorfer, Cornelia B.,Wanigaratne, Nicholin A.,Velkov, Tony,Yadav, Rajbharan,Oliver, Antonio,Martin, Lisandra,Shin, Beom Soo,Forrest, Alan,Tsuji, Brian T. American Society for Microbiology 2015 Antimicrobial Agents and Chemotherapy Vol.59 No.4
<P>Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-negative bacteria remains poorly characterized. Here, we developed a novel quantitative model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against three <I>Pseudomonas aeruginosa</I> strains. At low-intermediate tobramycin concentrations (<4 mg/liter), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concentrations (≥8 mg/liter). The extent of killing was comparable across all inocula; however, the rate of bacterial killing and growth was substantially lower at the 10<SUP>8.9</SUP> CFU/ml inoculum than that at the lower inocula. At 1 to 4 mg/liter tobramycin for strain PAO1-RH, there was a 0.5- to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be critical to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quantitative model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens.</P>
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