Journal articles on the topic 'Limiting factors for fuel cell'
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FRENI, S., S. CAVALLARO, M. AQUINO, D. RAVIDA, and N. GIORDANO. "Lifetime-limiting factors for a molten carbonate fuel cell." International Journal of Hydrogen Energy 19, no. 4 (April 1994): 337–41. http://dx.doi.org/10.1016/0360-3199(94)90065-5.
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Fry, M. R., H. Watson, and J. C. Hatchman. "Design of a prototype fuel cell/composite cycle power station." Proceedings of the Institution of Mechanical Engineers, Part A: Journal of Power and Energy 211, no. 2 (March 1, 1997): 171–80. http://dx.doi.org/10.1243/0957650971537088.
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The aspiration for fuel cells, in a public utility context, is that they are envisaged in the developed world as a means of significantly increasing the overall efficiency of power plants and of utilizing poor-quality fuel supplies. The thermodynamic and practical aspects in the design of a prototype power station consisting of a composite cycle of fuel cells, a gas turbine expander and a steam plant, or a steam plant only, are reported. The design was based on tubular fuel cell development. Overall efficiencies are estimated and limiting factors in the design are identified. Performance and emission characteristics are compared with existing plant.
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Papurello, Davide, Andrea Lanzini, Davide Drago, Pierluigi Leone, and Massimo Santarelli. "Limiting factors for planar solid oxide fuel cells under different trace compound concentrations." Energy 95 (January 2016): 67–78. http://dx.doi.org/10.1016/j.energy.2015.11.070.
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Yurova, Polina A., Viktoria R. Malakhova, Ekaterina V. Gerasimova, Irina A. Stenina, and Andrey B. Yaroslavtsev. "Nafion/Surface Modified Ceria Hybrid Membranes for Fuel Cell Application." Polymers 13, no. 15 (July 30, 2021): 2513. http://dx.doi.org/10.3390/polym13152513.
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Low chemical durability of proton exchange membranes is one the main factors limiting their lifetime in fuel cells. Ceria nanoparticles are the most common free radical scavengers. In this work, hybrid membranes based on Nafion-117 membrane and sulfonic or phosphoric acid functionalized ceria synthesized from various precursors were prepared by the in situ method for the first time. Ceria introduction led to a slight decrease in conductivity of hybrid membranes in contact with water. At the same time, conductivity of membranes containing sulfonic acid modified ceria exceeded that of the pristine Nafion-117 membrane at 30% relative humidity (RH). Hydrogen permeability decreased for composite membranes with ceria synthesized from cerium (III) nitrate, which correlates with their water uptake. In hydrogen-air fuel cells, membrane electrode assembly fabricated with the hybrid membrane containing ceria synthesized from cerium (IV) sulfate exhibited a peak power density of 433 mW/cm2 at a current density of 1080 mA/cm2, while operating at 60 °C and 70% RH. It was 1.5 times higher than for the pristine Nafion-117 membrane (287 mW/cm2 at a current density of 714 mA/cm2).
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Yim, Chae-Ho, and Yaser Abu-Lebdeh. "Understanding Key Limiting Factors of Electrode and Cell Designs in Solid-State Lithium Batteries." ECS Meeting Abstracts MA2022-01, no. 2 (July 7, 2022): 213. http://dx.doi.org/10.1149/ma2022-012213mtgabs.
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Solid-state batteries (SSBs) use solid electrolytes (SE) to replace flammable liquid electrolytes that result in safer batteries with increased energy density enabled by lithium metal as an anode. Even though there have been recent major breakthroughs at the material level and some at the cell level, there are still many more challenges to overcome that are mostly related to the solid-solid interfaces besides the grand challenge of manufacturing these type of batteries with or without existing manufacturing processes with the promised energy density ( > 400Wh/Kg) at targeted low costs (< 100$/KWh). For this to happen, it is important to look into all the changes that need to be made at the material, electrode and cell levels compared to what is currently used in Li-ion cells and critically evaluate their impact on the cell energy density. In this work, we have first used an equation that we have previously modified and used to calculate the impact of Si content in Si-graphite composite on the full-cell energy density (2) to evaluate the impact of the following parameters (type of anode-or no anode- and cathode materials. N/P ratio, thickness of SE and most importantly the composite cathode formulation on the full-cell energy density. In the latter, we have evaluated the thickness of two electrodes, amount and volume of cathode active material, and amount of catholyte). We will present the impact of each of the above-mentioned factors on the cell energy density supported by data from half and full cells using composite cathodes coupled with and without lithium metal as an anode. References: (1) Mauro Pasta et al 2020 J. Phys. Energy 2 032008. (2) Chae-Ho Yim, Svetlana Niketic, Nuha Salem, Olga Naboka and Yaser Abu-Lebdeh, 2017, J. Electrochem. Soc. 164 A6294.
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Jahan, Sarowar, Md Tarikul Islam, and Suman Chowdhury. "Investigation of Power Performance of a PEM Fuel Cell Using MATLAB Simulation." Malaysian Journal of Applied Sciences 5, no. 1 (April 30, 2020): 83–94. http://dx.doi.org/10.37231/myjas.2020.5.1.230.
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Fuel cell based power generation systems have gained remarkable interest in this modern age, due to its high conversion efficiency and reliability. Among the different types of fuel cells, PEM fuel cells are achieving more significance due to its fast start up time and low operating temperature. This paper studies the mathematical model of proton exchange membrane of fuel cell (PEMFC) using Matlab/SIMULINK software. The paper consists of the calculation of cell voltage, stack current, ohmic loss, activation loss. This model is used to research the fuel cell behavior and the characteristic of output values at different parameters. The model consists of the cathode gas channel, gas diffuser, catalyst layer, and the membrane. In order to composite shape of the gas diffuser and for its gradient in liquid water content, the gas diffuser is modeled as a series of parallel layers with different porosity. It represents in terms of the physical and thermodynamic parameters of the fuel cell. The curve of polarization is expressed parametrically as a function of the surface over potential. This paper expresses for cathode internal as well as overall effectiveness factors, active fraction of the catalyst layer resistance, catalyst layer, limiting current density, and the slope of the polarization curve.
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Chick, Larry A., Kerry D. Meinhardt, Steve P. Simner, Brent W. Kirby, Mike R. Powell, and Nathan L. Canfield. "Factors affecting limiting current in solid oxide fuel cells or debunking the myth of anode diffusion polarization." Journal of Power Sources 196, no. 10 (May 2011): 4475–82. http://dx.doi.org/10.1016/j.jpowsour.2011.01.035.
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Stöver, Detlev, Hans Peter Buchkremer, Andreas Mai, Norbert H. Menzler, and Mohsine Zahid. "Processing and Properties of Advanced Solid Oxide Fuel Cells." Materials Science Forum 539-543 (March 2007): 1367–72. http://dx.doi.org/10.4028/www.scientific.net/msf.539-543.1367.
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Up to now, Solid Oxide Fuel Cell (SOFC) materials and processing does not meet the cost goals for commercialization. This resulted in a worldwide increase in R&D activities dealing with advanced materials and effective manufacturing methods. The present paper describes efforts to process novel SOFC materials as well as optimization of well known ones. The R&D trends are explained for key components such as anode, electrolyte, cathode, contact- and protective layers. Typical SOFC manufacturing methods include tape casting, extrusion, calendaring and axial pressing. Each of these techniques has advantages and limitations. Examples for the highly efficient use of these methods are given for electrolyte supported cells as well as anode and cathode supported designs. An evaluation in reference to automation, process complexity and costs is given under the present limiting factors. Exemplary the processing by tape casting and the micro structural fine tuning of an advanced anode-supported system is discussed in detail. To produce the layered components of an SOFC, techniques like screen printing, wet powder spraying, PVD and CVD are under development. While the layer properties are excellent, PVD and CVD are nowadays too expensive in some cases, due to the low deposition rates. If thin layers are required, these techniques become interesting under cost considerations. The effectiveness of a PVD interlayer between electrolyte and high power density cathodes is shown in comparison to a sintered layer. In thin electrolyte concepts, the cathode becomes the power limiting component at operating temperatures below around 750°C. Thus new cathode materials and adjusted processing parameters are under development. The possibilities to manufacture advanced cathode layers by screen printing, wet powder spraying and other wet chemical methods are discussed. As an example screen printing of LSCF is described which results in a high power density cathode layer for low temperature SOFC operation. Finally, future needs to achieve the technical and economic goals are summarized.
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Vlachopoulos, Nick, and Anders Hagfeldt. "Photoelectrochemical Cells Based on Dye Sensitization for Electricity and Fuel Production." CHIMIA International Journal for Chemistry 73, no. 11 (November 1, 2019): 894–905. http://dx.doi.org/10.2533/chimia.2019.894.
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Dye-sensitized semiconductor oxide photoelectrodes in which light is absorbed by a monomolecular layer of dye chemisorbed on a porous oxide substrate have attracted considerable interest in the last 35 years, mainly for the conversion of sunlight to electricity, in dye-sensitized solar cells (DSSCs) with maximal efficiencies in the range 10–15%, and, most recently, as dye-sensitized photoelectrochemical cells (DSPECs) for the generation of solar fuels. In the latter direction, considerable progress has been achieved but the efficiency is notably lower than for electricity generation. In the present review, the basic physicochemical principles of the DSSC and DSPEC operation are described, several keynote results reported, and the factors limiting the performance and necessitating further research highlighted.
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Cai, Wenfang, and Yunhai Wang. "Investigation of a two-dimensional model on Cu2+ recovery in bioemectrochemical system." IOP Conference Series: Earth and Environmental Science 1135, no. 1 (January 1, 2023): 012013. http://dx.doi.org/10.1088/1755-1315/1135/1/012013.
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Abstract A novel microbial fuel cell (MFC) was designed to recover Cu2+ from simulated electroplating wastewater. The BES has two chambers separated by a bipolar membrane and two cathodes. To explore the rate controlling step affecting Cu2+ deposition rate, spatial mass distribution and its deposition process during Cu2+ deposition on MFC cathode. A two-dimensional, transient model was built to study the factors that limiting Cu2+ deposition in MFC. We found that the formation of ion scarcity zone would decrease Cu2+ deposition rate, which leading to mass transfer limiting Cu2+ reduction on cathode surface (x=0 m). While near the cathode tip (x=0.02 m), the highest deposition rate and thickness was obtained. Furthermore, diffusion and electro-migration of Cu2+ were synergistic to improve Cu2+ reduction efficiency, and electro-migration of Cu2+ had a great impact on Cu2+ transferring from electrolyte domain to electrode surface. This research provided a new studying direction for heavy metal wastewater treatment and metal separation and recovery in the electroplating industry to improve metal ions deposition rate.
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Ikyo, B. A., D. Sunday, M. S. Lyam, and A. Itodo. "Performance Efficiency of a Silicon Based Photovoltaic Cell Operating under Ambient Conditions in Benue State, Nigeria." NIGERIAN ANNALS OF PURE AND APPLIED SCIENCES 1 (March 8, 2019): 301–7. http://dx.doi.org/10.46912/napas.53.
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The use of photovoltaic cells (solar cells) for generation of electricity is no longer uncommon in Nigeria; this is because solar energy is undoubtedly part of the solution to the problem of dwindling fossil-fuel reserves. Various technologies of photovoltaic systems are imported from different countries and are being used locally with little or no information of their appraisal and field performance. In this work the performance efficiency of a silicon based solar panel operating under ambient conditions has been determined in an experiment using an off the shelf PV module. Measurements were taken while varying the direction of the panel, the tilt angle and illuminance during the day. Results show that PV installations within Benue State and most areas within the north-Central geopolitical region will perform optimally when installed at 15⁰ in the direction of the south. Apart from outlining the efficiency limiting factors, this work also provides an efficiency chart with data that can be used for solar installation.
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Venkatramanan, V., Shachi Shah, and Ram Prasad. "A Critical Review on Microbial Fuel Cells Technology: Perspectives on Wastewater Treatment." Open Biotechnology Journal 15, no. 1 (July 8, 2021): 131–41. http://dx.doi.org/10.2174/1874070702115010131.
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Increasing demand for renewable energy in the backdrop of global change calls for waste valorization and circular economy strategies. Public health concerns and demand for clean energy provide impetus to the development of wastewater based MFC. Wastewater treatment and simultaneous generation of bioelectricity offer a myriad of environmental benefits. Nevertheless, it is pertinent to know the challenges with the microbial fuel cell (MFC) technology to upscale the wastewater based MFC. This paper attempts to critically analyse the processes, application, challenges and opportunities of wastewater based MFCs. A literature survey was conducted to find out the advances in the field of wastewater based MFCs and the focus was to decipher the challenges to the implementation of wastewater based MFCs. Recent developments in MFC technology have improved the power output and studies show that a diverse group of organic-rich wastewater can be treated with MFCs. The developments include improvements in MFC configuration, development of biocatalysts and biocathode, anodic biofilm formation, microbial community interactions, and progress in the organic and pollutant removal. Nevertheless, the MFC technology is replete with challenges about the organic removal rate, power density, electrode performance limiting factors, economic viability, high initial and maintenance cost and difficulty to maintain the exoelectrogens activity in a complex wastewater environment. Opportunities exist in scaling up of MFCs, integration with other wastewater treatment methods and measures to minimise the operating costs. MFCs have the potential to increase the resilience capacity of the sustainable wastewater treatment plant.
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Rossi, Ruggero, Derek M. Hall, Xu Wang, John M. Regan, and Bruce E. Logan. "Quantifying the factors limiting performance and rates in microbial fuel cells using the electrode potential slope analysis combined with electrical impedance spectroscopy." Electrochimica Acta 348 (July 2020): 136330. http://dx.doi.org/10.1016/j.electacta.2020.136330.
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Froitzheim, J., and J. E. Svensson. "Nanocoatings for SOFC Interconnects - Mitigating Chromium Volatilization and Improving Corrosion Properties." Materials Science Forum 696 (September 2011): 412–16. http://dx.doi.org/10.4028/www.scientific.net/msf.696.412.
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Two important degradation mechanisms in Solid Oxide Fuel Cells (SOFC) are directly related to the metallic interconnects. The formation of volatile chromium oxides from metallic interconnects commonly causes fast degradation in cell performance due to poisoning the cathode. Secondly is the ability of the metallic interconnect to form a thin protective oxide one of the most important lifetime limiting factors for SOFC. Chromium volatilization of various uncoated steels is studied as a function of temperature by a recently developed denuder technique which allows time resolved quantification of volatile chromium species. The inhibition of Cr evaporation by Co thin film coatings (800nm) is investigated; it will be shown that these coatings are more effective than much thicker ceramic coatings that are commonly used for this purpose. In order to increase the lifetime of the metallic components in SOFC nano-coatings of reactive elements (RE) have been investigated as well. The application of such coatings can reduce the corrosion rates substantially and thus increase the lifetime of the fuel cell stack. It will be shown that it is possible to combine the positive effects of RE with the beneficial effects of a Co coating and thus to obtain an interconnect material with low Cr evaporation and increased oxidation resistance.
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Varize, Camila S., Augusto Bücker, Lucas D. Lopes, Renata M. Christofoleti-Furlan, Mariane S. Raposo, Luiz C. Basso, and Boris U. Stambuk. "Increasing Ethanol Tolerance and Ethanol Production in an Industrial Fuel Ethanol Saccharomyces cerevisiae Strain." Fermentation 8, no. 10 (September 20, 2022): 470. http://dx.doi.org/10.3390/fermentation8100470.
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The stress imposed by ethanol to Saccharomyces cerevisiae cells are one of the most challenging limiting factors in industrial fuel ethanol production. Consequently, the toxicity and tolerance to high ethanol concentrations has been the subject of extensive research, allowing the identification of several genes important for increasing the tolerance to this stress factor. However, most studies were performed with well-characterized laboratory strains, and how the results obtained with these strains work in industrial strains remains unknown. In the present work, we have tested three different strategies known to increase ethanol tolerance by laboratory strains in an industrial fuel–ethanol producing strain: the overexpression of the TRP1 or MSN2 genes, or the overexpression of a truncated version of the MSN2 gene. Our results show that the industrial CAT-1 strain tolerates up to 14% ethanol, and indeed the three strategies increased its tolerance to ethanol. When these strains were subjected to fermentations with high sugar content and cell recycle, simulating the industrial conditions used in Brazilian distilleries, only the strain with overexpression of the truncated MSN2 gene showed improved fermentation performance, allowing the production of 16% ethanol from 33% of total reducing sugars present in sugarcane molasses. Our results highlight the importance of testing genetic modifications in industrial yeast strains under industrial conditions in order to improve the production of industrial fuel ethanol by S. cerevisiae.
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Kregar, Ambroz, Andraž Kravos, and Tomaž Katrašnik. "Mathematical Model of Hydrogen Peroxide Production in Anode, Cathode, and Membrane of LT-PEMFC." ECS Meeting Abstracts MA2022-01, no. 35 (July 7, 2022): 1524. http://dx.doi.org/10.1149/ma2022-01351524mtgabs.
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Degradation of proton exchange membrane in low-temperature fuel cells represents one of the main limiting factors for wider adoption of this clean, carbon emission free energy device. In combination with mechanical degradation caused by membrane swelling and shrinkage during water content change, chemical degradation of the membrane is considered to be the main mechanism leading to loss of membrane conductivity, membrane thinning and eventual pinhole formation. Chemical degradation is caused by the attack of reactive radical species on the perfluorinated polymer chains of the membrane, which are formed in Fenton reaction between hydrogen peroxide and ions of transition metals, which are inevitably present in the membrane in small traces. Since the metal ions are recycled in Fenton reactions, the rate of chemical degradation is mainly determined by the production of hydrogen peroxide, formed as a side product to water in reaction between oxygen and protons in the fuel cell. [1] The source of hydrogen peroxide production in low-temperature fuel cells have long been debated in scientific literature. On one hand, the abundance of oxygen in the cathode suggest that the production takes place there, but high local electric potential strongly promotes 4-electron reaction, forming water, over 2-electron reaction required for production of hydrogen peroxide [2]. The conditions in the anode are reversed, low electric potential is well suited for peroxide production, but the concentration of oxygen, present in the anode due to diffusion through the membrane, is in general expected to be quite low, making it a rate limiting factor for the peroxide production in the anode. The last possible source of hydrogen peroxide is closely related to the degradation of platinum (Pt) catalyst in the cathode. When Pt catalyst nanoparticles dissolve due to high local electric potential on the cathode, part of the dissolved ions diffuses into the membrane, where it is reduced by counter-diffusing hydrogen from the anode. These Pt particles in the membrane, the so-called Pt band, serve as a catalyst for the reaction between diffusing oxygen from cathode and hydrogen in anode. Since these particles are not electrically connected to either anode or cathode, their electric potential is determined by the rates of oxygen reduction and hydrogen oxidation on their surface, which result in production of water and potentially also hydrogen peroxide. The complex interplay between the processes determining the peroxide production, explained above, suggest that different sources of peroxide might be relevant in different fuel cell operation conditions and at different states of health of the fuel cell. To explore this question quantitatively, we propose a mathematical model of peroxide production which describes physical and electrochemical processes for hydrogen peroxide production in fuel cell catalysts and the membrane, relevant for hydrogen peroxide production: oxygen and hydrogen diffusion in the membrane, electrochemical oxygen reduction in the cathode, anode and on Pt band inside membrane, hydrogen oxidation on Pt band and electric charging of Pt particles in the band due to electrochemical reactions on their surface. To provide realistic internal states of the fuel cell during operation, the model is coupled with advanced spatially and temporally resolved model of the fuel cell operation. [3] Preliminary results of the model indicate that main source of peroxide production depends on the fuel cell operating conditions. In fresh fuel cell, where Pt band in membrane is not yet formed, low current densities and high fuel cell voltages promote the peroxide formation mainly on the anode from the diffused oxygen, while at high current densities the electric potential on the cathode is low enough to allow for significant peroxide production there, outweighing the production on the anode. The formation of the Pt band shifts the production of peroxide from anode to the Pt particles in the band, since large amount of the oxygen is consumed there and therefore its diffusion to the anode is reduced. The results indicate that the question of where the peroxide is formed cannot be resolved by a single answer and that the use of sufficiently complex models, coupling physical and electrochemical processes in different fuel cell components, are required to properly manage fuel cell operation in order to avoid or at least mitigate its detrimental effects of chemical membrane degradation. [1] Frühwirt, P., Kregar, A., Törring, J. T., Katrašnik, T., Gescheidt, G. (2020). Physical Chemistry Chemical Physics, 22(10), 5647–5666. [2] Sethuraman, V. A., Weidner, J. W., Haug, A. T., Motupally, S., Protsailo, L. V. (2008). Journal of The Electrochemical Society, 155(1), B50. [3] Kregar, A., Tavčar, G., Kravos, A., Katrašnik, T. (2020). Applied Energy, 263(March), 114547.
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Yang, Jing, Mark A. McCormick, Jiashun Zheng, Zhengwei Xie, Mitsuhiro Tsuchiya, Scott Tsuchiyama, Hana El-Samad, et al. "Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry." Proceedings of the National Academy of Sciences 112, no. 38 (September 8, 2015): 11977–82. http://dx.doi.org/10.1073/pnas.1506054112.
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Budding yeast divides asymmetrically, giving rise to a mother cell that progressively ages and a daughter cell with full lifespan. It is generally assumed that mother cells retain damaged, lifespan limiting materials (“aging factors”) through asymmetric division. However, the identity of these aging factors and the mechanisms through which they limit lifespan remain poorly understood. Using a flow cytometry-based, high-throughput approach, we quantified the asymmetric partitioning of the yeast proteome between mother and daughter cells during cell division, discovering 74 mother-enriched and 60 daughter-enriched proteins. While daughter-enriched proteins are biased toward those needed for bud construction and genome maintenance, mother-enriched proteins are biased towards those localized in the plasma membrane and vacuole. Deletion of 23 of the 74 mother-enriched proteins leads to lifespan extension, a fraction that is about six times that of the genes picked randomly from the genome. Among these lifespan-extending genes, three are involved in endosomal sorting/endosome to vacuole transport, and three are nitrogen source transporters. Tracking the dynamic expression of specific mother-enriched proteins revealed that their concentration steadily increases in the mother cells as they age, but is kept relatively low in the daughter cells via asymmetric distribution. Our results suggest that some mother-enriched proteins may increase to a concentration that becomes deleterious and lifespan-limiting in aged cells, possibly by upsetting homeostasis or leading to aberrant signaling. Our study provides a comprehensive resource for analyzing asymmetric cell division and aging in yeast, which should also be valuable for understanding similar phenomena in other organisms.
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Smyrnioti, Maria, and Theophilos Ioannides. "Dimethyl Ether Hydrolysis over WO3/γ-Al2O3 Supported Catalysts." Catalysts 12, no. 4 (April 1, 2022): 396. http://dx.doi.org/10.3390/catal12040396.
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Dimethyl ether (DME) is considered an alternative hydrogen carrier with potential use in fuel cells and automotive and domestic applications. Dimethyl ether hydrolysis to methanol is a thermodynamically limited reaction catalyzed by solid-acid catalysts, mainly Al2O3 and zeolites. Moreover, it is the rate-limiting step of the DME steam reforming reaction, which is employed for the production of hydrogen fuel for fuel cell feeding. In the present study, the performance of WO3/Al2O3 catalysts (0–44% wt. WO3) was tested in DME hydrolysis reaction. The catalysts were characterized by means of N2-physisorption, XRD, Raman spectroscopy, XPS, NH3-TPD and 2,6-di-tert-butylpyridine adsorption experiments. The reaction rate of DME hydrolysis exhibited a volcanic trend as a function of tungsten surface density, while the best-performing catalyst was 37WO3/Al2O3, with a tungsten surface density of 7.4 W/nm2, noting that the theoretical monolayer coverage for the specific system is 4–5 W/nm2. Brønsted acidity was directly associated with the catalytic activity, following the same volcanic trend as a function of tungsten surface density. Blocking of Brønsted acid sites with 2,6-di-tert-butylpyridine led to a dramatic decrease in hydrolysis rates by 40 times, proving that Brønsted acid sites are primarily responsible for the catalytic activity. Thus, the type and strength rather than the concentration of acid sites are the key factors influencing the catalytic activity.
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Tan, Thomas C. J., John Knight, Thomas Sbarrato, Kate Dudek, Anne E. Willis, and Rose Zamoyska. "Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells." Proceedings of the National Academy of Sciences 114, no. 30 (July 10, 2017): E6117—E6126. http://dx.doi.org/10.1073/pnas.1700939114.
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Global transcriptomic and proteomic analyses of T cells have been rich sources of unbiased data for understanding T-cell activation. Lack of full concordance of these datasets has illustrated that important facets of T-cell activation are controlled at the level of translation. We undertook translatome analysis of CD8 T-cell activation, combining polysome profiling and microarray analysis. We revealed that altering T-cell receptor stimulation influenced recruitment of mRNAs to heavy polysomes and translation of subsets of genes. A major pathway that was compromised, when TCR signaling was suboptimal, was linked to ribosome biogenesis, a rate-limiting factor in both cell growth and proliferation. Defective TCR signaling affected transcription and processing of ribosomal RNA precursors, as well as the translation of specific ribosomal proteins and translation factors. Mechanistically, IL-2 production was compromised in weakly stimulated T cells, affecting the abundance of Myc protein, a known regulator of ribosome biogenesis. Consequently, weakly activated T cells showed impaired production of ribosomes and a failure to maintain proliferative capacity after stimulation. We demonstrate that primary T cells respond to various environmental cues by regulating ribosome biogenesis and mRNA translation at multiple levels to sustain proliferation and differentiation.
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Sharma, Preetam, Douglas Aaron, Lei Cheng, Jonathan Braaten, Nathan Craig, Christina Johnston, and Matthew M. Mench. "Localized Electrochemical Performance Degradation in Polymer Electrolyte Fuel Cells (PEFCs)." ECS Meeting Abstracts MA2022-02, no. 42 (October 9, 2022): 1571. http://dx.doi.org/10.1149/ma2022-02421571mtgabs.
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Pt electrocatalyst durability in polymer electrolyte fuel cells (PEFCs) is generally evaluated through an accelerated stress test (AST); for example, one AST features repeated square-wave cycling with H2/N2 between 0.6 V to 0.95 V vs. reversible hydrogen electrode (RHE) [1]. A separate triangular-wave AST with a higher potential range (1 – 1.5 V vs. RHE) assesses the durability of carbon-based supports [2]. Recent studies [3]–[5] have revealed the heterogeneous nature of cathode catalyst layer degradation. In general, Pt particle size growth mimics the flow field geometry with greater particle size growth under lands compared to channels. Additionally, growth is typically shown to be greater near the air outlet than the inlet and is assumed to be correlated to local performance decay. The impact of such localized degradation on distributed cell performance is investigated in this work. In the present study, a segmented cell is used to quantify functional dependence of local current distributions in aged samples to heterogeneous catalyst layer degradation (Pt particle size growth and carbon support corrosion). The outcome of this enhanced understanding is to identify limiting factors in cell performance at end-of-life (EOL). Single cell studies with 25-cm2 active area are performed using catalyst-coated Nafion® XL membranes (Ion Power Inc.) and SGL-22 BB gas diffusion layers (GDLs) as membrane electrode assembly (MEA) materials and 7-channel serpentine flow field. An S++® current scan shunt (CSS) sensor plate (25-cm2) with 100 current and 25 temperature measurement segments is utilized for current and temperature mapping, respectively. The MEAs are subjected to DOE’s square-wave cycling (0.6 to 0.95 V vs. RHE), triangular-wave cycling (1 to 1.5 V vs. RHE), and a sequence of square-wave cycling followed by triangular-wave cycling. Complete in-situ electrochemical characterization and post-mortem ex-situ diagnostics such as micro-X-ray diffraction (micro-XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) are used to obtain particle size distribution and spatial degradation profiles. Results indicate a strong dependence of current distributions on localized catalyst layer degradation. For example, MEA with relatively uniform current distributions at the beginning-of-life (BOL) in Figure 1 exhibits severe mass transport limitations (significantly higher current at the air inlet than the outlet) at EOL when subjected to triangular-wave carbon corrosion AST. Furthermore, an increase of ~1.5x in Tafel slope is observed for the aged sample at EOL, highlighting increased transport losses. These mass transport losses are believed to originate from loss of catalyst layer porosity and subsequent compaction due to carbon support corrosion [2]. This work seeks to achieve a greater understanding of the functional dependence between catalyst growth and carbon corrosion and observed local performance. References: [1] S. Stariha et al., “Recent Advances in Catalyst Accelerated Stress Tests for Polymer Electrolyte Membrane Fuel Cells,” J. Electrochem. Soc., vol. 165, no. 7, pp. F492–F501, 2018, doi: 10.1149/2.0881807jes. [2] N. Macauley et al., “Carbon Corrosion in PEM Fuel Cells and the Development of Accelerated Stress Tests,” J. Electrochem. Soc., vol. 165, no. 6, pp. F3148–F3160, 2018, doi: 10.1149/2.0061806jes. [3] L. Cheng et al., “Mapping of Heterogeneous Catalyst Degradation in Polymer Electrolyte Fuel Cells,” Adv. Energy Mater., vol. 2000623, pp. 1–7, 2020, doi: 10.1002/aenm.202000623. [4] P. Sharma et al., “Influence of Flow Rate on Catalyst Layer Degradation in Polymer Electrolyte Fuel Cells,” {ECS} Meet. Abstr., vol. {MA}2020-0, no. 36, p. 2345, Nov. 2020, doi: 10.1149/ma2020-02362345mtgabs. [5] K. Khedekar et al., “Probing Heterogeneous Degradation of Catalyst in PEM Fuel Cells under Realistic Automotive Conditions with Multi-Modal Techniques,” Adv. Energy Mater., 2021, doi: 10.1002/aenm.202101794. Figure 1
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Blair, Megan C., Michael D. Neinast, and Zoltan Arany. "Whole-body metabolic fate of branched-chain amino acids." Biochemical Journal 478, no. 4 (February 24, 2021): 765–76. http://dx.doi.org/10.1042/bcj20200686.
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Oxidation of branched-chain amino acids (BCAAs) is tightly regulated in mammals. We review here the distribution and regulation of whole-body BCAA oxidation. Phosphorylation and dephosphorylation of the rate-limiting enzyme, branched-chain α-ketoacid dehydrogenase complex directly regulates BCAA oxidation, and various other indirect mechanisms of regulation also exist. Most tissues throughout the body are capable of BCAA oxidation, and the flux of oxidative BCAA disposal in each tissue is influenced by three key factors: 1. tissue-specific preference for BCAA oxidation relative to other fuels, 2. the overall oxidative activity of mitochondria within a tissue, and 3. total tissue mass. Perturbations in BCAA oxidation have been implicated in many disease contexts, underscoring the importance of BCAA homeostasis in overall health.
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Dosset, Magalie, Elodie Lauret-Marie Joseph, Thaiz Rivera Vargas, and Lionel Apetoh. "Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors." Cells 9, no. 7 (July 19, 2020): 1727. http://dx.doi.org/10.3390/cells9071727.
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Immune checkpoint inhibitors (ICPi) have shown their superiority over conventional therapies to treat some cancers. ICPi are effective against immunogenic tumors. However, patients with tumors poorly infiltrated with immune cells do not respond to ICPi. Combining ICPi with other anticancer therapies such as chemotherapy, radiation, or vaccines, which can stimulate the immune system and recruit antitumor T cells into the tumor bed, may be a relevant strategy to increase the proportion of responding patients. Such an approach still raises the following questions: What are the immunological features modulated by immunogenic therapies that can be critical to ensure not only immediate but also long-lasting tumor protection? How must the combined treatments be administered to the patients to harness their full potential while limiting adverse immunological events? Here, we address these points by reviewing how immunogenic anticancer therapies can provide novel therapeutic opportunities upon combination with ICPi. We discuss their ability to create a permissive tumor microenvironment through the generation of inflamed tumors and stimulation of memory T cells such as resident (TRM) and stem-cell like (TSCM) cells. We eventually underscore the importance of sequence, dose, and duration of the combined anticancer therapies to design optimal and successful cancer immunotherapy strategies.
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Selokar, N. L., A. George, A. P. Saha, R. Sharma, M. Muzaffar, P. Palta, M. S. Chauhan, R. S. Manik, and S. K. Singla. "59 SYNCHRONIZATION OF CELL CYCLE STAGE OF BUFFALO (BUBALUS BUBALIS) FETAL FIBROBLAST CELLS BY DIFFERENT TREATMENTS." Reproduction, Fertility and Development 23, no. 1 (2011): 135. http://dx.doi.org/10.1071/rdv23n1ab59.
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Cell cycle stage of donor cells significantly influences the cloning efficiency during SCNT. Donor cells in G1/G0 stage have better capability to undergo nuclear reprogramming following transfer to an unfertilized oocyte. The lack of availability of cells synchronized at G1/G0 stage is one of the major factors limiting cloning efficiency in buffalo. The aim of this study was to compare the efficacy of various methods for cell cycle synchronization of buffalo fetal fibroblast cells for SCNT. Cells isolated from fetus, 2 to 3 months old, were cultured in DMEM + 10% FBS. The primary culture was sub-cultured 8 to 10 times. For cell cycle synchronization, the cells were cultured to 1) 60 to 70% confluence (controls), 2) 60 to 70% confluence followed by serum starvation (DMEM + 0.5% FBS) for 24 h (serum starved), 3), full confluence followed by culture for additional 3 to 5 days (full confluent), 4) full confluence followed by serum starvation (DMEM + 0.5% FBS) for 24 h (full confluent+serum starved) and 5) 60 to 70% confluence followed by treatment with roscovitine (10, 20, or 30 μM) for 24 h. The synchronization efficiency was examined by propidium iodide staining followed by analysis of DNA content using flow cytometry and the data were analysed by 1-way ANOVA followed by Fisher’s l.s.d. test after arcsine transformation. The percentage of cells in G0/G1 phase of cell cycle was significantly higher (P < 0.05) in the full confluent+serum starved and roscovitine treated (20 or 30 μM) groups than that in the full confluent group and that treated with 10 μM roscovitine which, in turn, was higher (P < 0.05) than that in the serum starved and control groups. These results suggest that buffalo fetal fibroblast cells can be synchronized by roscovitine treatment or by serum starvation of fully confluent cell cultures to obtain a high proportion of cells in G0/G1 stage for SCNT. Table 1.Buffalo skin fibroblast cells at various stages following different treatments for cell cycle synchronization Supported by grant No. 1(5)/2007-NAIP from ICAR, India.
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Sheng, Zhi, Yanping Liang, Chih-Yin Lin, Lucio Comai, and William J. Chirico. "Direct Regulation of rRNA Transcription by Fibroblast Growth Factor 2." Molecular and Cellular Biology 25, no. 21 (November 1, 2005): 9419–26. http://dx.doi.org/10.1128/mcb.25.21.9419-9426.2005.
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ABSTRACT Fibroblast growth factor 2 (FGF-2), which is highly expressed in developing tissues and malignant cells, regulates cell growth, differentiation, and migration. Five isoforms (18 to ∼34 kDa) of FGF-2 are derived from alternative initiation codons of a single mRNA. The 18-kDa FGF-2 isoform is released from cells by a nonclassical secretory pathway and regulates gene expression by binding to cell surface receptors. This isoform also localizes to the nucleolus, raising the possibility that it may directly regulate ribosome biogenesis, a rate-limiting process in cell growth. Although several growth factors have been shown to accumulate in the nucleolus, their function and mechanism of action remain unclear. Here we show that 18-kDa FGF-2 interacts with upstream binding factor (UBF), an architectural transcription factor essential for rRNA transcription. The maximal activation of rRNA transcription in vitro by 18-kDa FGF-2 requires UBF. The 18-kDa FGF-2 localizes to rRNA genes and is necessary for the full activation of pre-rRNA synthesis in vivo. Our results demonstrate that 18-kDa FGF-2 directly regulates rRNA transcription.
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Ludlow, Andrew T., Aaron L. Slusher, and Mohammed E. Sayed. "Insights into Telomerase/hTERT Alternative Splicing Regulation Using Bioinformatics and Network Analysis in Cancer." Cancers 11, no. 5 (May 14, 2019): 666. http://dx.doi.org/10.3390/cancers11050666.
Full textAbstract:
The reactivation of telomerase in cancer cells remains incompletely understood. The catalytic component of telomerase, hTERT, is thought to be the limiting component in cancer cells for the formation of active enzymes. hTERT gene expression is regulated at several levels including chromatin, DNA methylation, transcription factors, and RNA processing events. Of these regulatory events, RNA processing has received little attention until recently. RNA processing and alternative splicing regulation have been explored to understand how hTERT is regulated in cancer cells. The cis- and trans-acting factors that regulate the alternative splicing choice of hTERT in the reverse transcriptase domain have been investigated. Further, it was discovered that the splicing factors that promote the production of full-length hTERT were also involved in cancer cell growth and survival. The goals are to review telomerase regulation via alternative splicing and the function of hTERT splicing variants and to point out how bioinformatics approaches are leading the way in elucidating the networks that regulate hTERT splicing choice and ultimately cancer growth.
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Moraes, Carlos T., Lesley Kenyon, and Huiling Hao. "Mechanisms of Human Mitochondrial DNA Maintenance: The Determining Role of Primary Sequence and Length over Function." Molecular Biology of the Cell 10, no. 10 (October 1999): 3345–56. http://dx.doi.org/10.1091/mbc.10.10.3345.
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Although the regulation of mitochondrial DNA (mtDNA) copy number is performed by nuclear-coded factors, very little is known about the mechanisms controlling this process. We attempted to introduce nonhuman ape mtDNA into human cells harboring either no mtDNA or mutated mtDNAs (partial deletion and tRNA gene point mutation). Unexpectedly, only cells containing no mtDNA could be repopulated with nonhuman ape mtDNA. Cells containing a defective human mtDNA did not incorporate or maintain ape mtDNA and therefore died under selection for oxidative phosphorylation function. On the other hand, foreign human mtDNA was readily incorporated and maintained in these cells. The suicidal preference for self-mtDNA showed that functional parameters associated with oxidative phosphorylation are less relevant to mtDNA maintenance and copy number control than recognition of mtDNA self-determinants. Non–self-mtDNA could not be maintained into cells with mtDNA even if no selection for oxidative phosphorylation was applied. The repopulation kinetics of several mtDNA forms after severe depletion by ethidium bromide treatment showed that replication and maintenance of mtDNA in human cells are highly dependent on molecular features, because partially deleted mtDNA molecules repopulated cells significantly faster than full-length mtDNA. Taken together, our results suggest that mtDNA copy number may be controlled by competition for limiting levels of trans-acting factors that recognize primarily mtDNA molecular features. In agreement with this hypothesis, marked variations in mtDNA levels did not affect the transcription of nuclear-coded factors involved in mtDNA replication.
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Pan, Lili, Chao Hong, Lai N. Chan, Gang Xiao, Parmanand Malvi, Mark E. Robinson, Huimin Geng, et al. "PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis." Proceedings of the National Academy of Sciences 118, no. 7 (February 2, 2021): e2016553118. http://dx.doi.org/10.1073/pnas.2016553118.
Full textAbstract:
Unlike other cell types, developing B cells undergo multiple rounds of somatic recombination and hypermutation to evolve high-affinity antibodies. Reflecting the high frequency of DNA double-strand breaks, adaptive immune protection by B cells comes with an increased risk of malignant transformation. B lymphoid transcription factors (e.g., IKZF1 and PAX5) serve as metabolic gatekeepers by limiting glucose to levels insufficient to fuel transformation. We here identified aberrant expression of the lactonase PON2 in B cell acute lymphoblastic leukemia (B-ALL) as a mechanism to bypass metabolic gatekeeper functions. Compared to normal pre-B cells, PON2 expression was elevated in patient-derived B-ALL samples and correlated with poor clinical outcomes in pediatric and adult cohorts. Genetic deletion of Pon2 had no measurable impact on normal B cell development. However, in mouse models for BCR-ABL1 and NRASG12D-driven B-ALL, deletion of Pon2 compromised proliferation, colony formation, and leukemia initiation in transplant recipient mice. Compromised leukemogenesis resulted from defective glucose uptake and adenosine triphosphate (ATP) production in PON2-deficient murine and human B-ALL cells. Mechanistically, PON2 enabled glucose uptake by releasing the glucose-transporter GLUT1 from its inhibitor stomatin (STOM) and genetic deletion of STOM largely rescued PON2 deficiency. While not required for glucose transport, the PON2 lactonase moiety hydrolyzes the lactone-prodrug 3OC12 to form a cytotoxic intermediate. Mirroring PON2 expression levels in B-ALL, 3OC12 selectively killed patient-derived B-ALL cells but was well tolerated in transplant recipient mice. Hence, while B-ALL cells critically depend on aberrant PON2 expression to evade metabolic gatekeeper functions, PON2 lactonase activity can be leveraged as synthetic lethality to overcome drug resistance in refractory B-ALL.
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Wei, Fei, Aslan Kosakian, Jiafei Liu, and Marc Secanell. "Water Transport Characterization of Anion and Proton Exchange Membranes." ECS Meeting Abstracts MA2022-02, no. 50 (October 9, 2022): 2620. http://dx.doi.org/10.1149/ma2022-02502620mtgabs.
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Proton exchange membrane (PEM) and anion exchange membrane (AEM) fuel cells (FCs) are the two types of fuel cell devices that electrochemically convert the chemical energy of hydrogen into electricity and heat with water as the only by-product. Due to no requirement of precious and non-renewable platinum as the catalyst material, AEMFCs have attracted great attention in recent years [1,2]. However, water balance between anode and cathode in AEMFCs is more crucial than in PEMFCs, as water not only is produced in the anode, hindering hydrogen transport to the anode catalyst layer, but also functions as reactant in the cathode. Water transport properties of AEMs is one of the key factors affecting water balance between anode and cathode [1]. Accurate measurement of AEM water transport properties is paramount for AEM design and manufacturing to improve AEMFC water management and, in turn, performance and durability. AEMFCs with recently developed PiperION AEMs have been shown to achieve good AEMFC performance [3,4]; however, there is no available study in the literature measuring its water transport properties. To the best of the authors' knowledge, there are only a few studies reporting the measurement of AEMs water diffusivity, such as Fumapem FAA-3 [5,6], Aemion [5], Tokuyama A201 [7,8] and SnowPure Excellion I-200 [9]. Even in those limited studies, interfacial transport rates were either not considered in the data analysis [6,8,9] or not given as a function of water activity [5,7,8]. In this work, the interfacial desorption rate of AEMs is determined from a liquid-vapor permeation setup by measuring the water flux through the membrane at different relative humidity (RH). To quantify the interfacial exchange rate and determine which mode of transport is dominant (bulk or interfacial), a novel approach involving three different mathematical models was used: a diffusion-dominant model, a desorption-dominant model, and a combined diffusion-desorption model. By analyzing the sensitivity of the modeling results to the individual transport process, the dominant mode was identified. The model correctly identified the limiting transport mode in Nafion membranes, and suggested that interfacial transport was also limiting in AEMs of Aemion AH1-HNN8-50-X, Fumapem FAA-3-30/50 and PiperION-A40. With the developed model, semi-empirical relationships for the water desorption rate from AEMs and Nafion membranes as functions of the water content and temperature were obtained. These relationships can be readily used in AEMFCs and PEMFCs models. References [1] K. Yassin, et al., Quantifying the critical effect of water diffusivity in anion exchange membranes for fuel cell applications, Journal of Membrane Science 608 (2020) 118206. [2] X. Luo, et al., Structure-transport relationships of poly (aryl piperidinium) anion-exchange membranes: Eeffect of anions and hydration, Journal of Membrane Science 598 (2020) 117680. [3] J. Wang, et al., Poly (aryl piperidinium) membranes and ionomers for hydroxide exchange membrane fuel cells, Nature Energy 4(5) (2019) 392-398. [4] T. Wang, et al., High-performance hydroxide exchange membrane fuel cells through optimization of relative humidity, backpressure and catalyst selection, Journal of The Electrochemical Society 166(7) (2019) F3305. [5] X. Luo, et al., Water permeation through anion exchange membranes, Journal of Power Sources 375 (2018) 442-451. [6] M. Marino, et al., Hydroxide, halide and water transport in a model anion exchange membrane, Journal of Membrane Science 464 (2014) 61-71. [7] Y. Li, et al., Measurements of water uptake and transport properties in anion-exchange membranes, International Journal of Hydrogen Energy 35 (11) (2010) 5656-5665. [8] B. Eriksson, et al., Quantifying water transport in anion exchange membrane fuel cells, International Journal of Hydrogen Energy 44 (10) (2019) 4930–4939. [9] T.D. Myles, et al., Calculation of water diffusion coefficients in an anion exchange membrane using a water permeation technique, Journal of the Electrochemical Society 158(7) (2011) B790.
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Vecchi, Valeria, Simone Barera, Roberto Bassi, and Luca Dall’Osto. "Potential and Challenges of Improving Photosynthesis in Algae." Plants 9, no. 1 (January 3, 2020): 67. http://dx.doi.org/10.3390/plants9010067.
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Sunlight energy largely exceeds the energy required by anthropic activities, and therefore its exploitation represents a major target in the field of renewable energies. The interest in the mass cultivation of green microalgae has grown in the last decades, as algal biomass could be employed to cover a significant portion of global energy demand. Advantages of microalgal vs. plant biomass production include higher light-use efficiency, efficient carbon capture and the valorization of marginal lands and wastewaters. Realization of this potential requires a decrease of the current production costs, which can be obtained by increasing the productivity of the most common industrial strains, by the identification of factors limiting biomass yield, and by removing bottlenecks, namely through domestication strategies aimed to fill the gap between the theoretical and real productivity of algal cultures. In particular, the light-to-biomass conversion efficiency represents one of the major constraints for achieving a significant improvement of algal cell lines. This review outlines the molecular events of photosynthesis, which regulate the conversion of light into biomass, and discusses how these can be targeted to enhance productivity through mutagenesis, strain selection or genetic engineering. This review highlights the most recent results in the manipulation of the fundamental mechanisms of algal photosynthesis, which revealed that a significant yield enhancement is feasible. Moreover, metabolic engineering of microalgae, focused upon the development of renewable fuel biorefineries, has also drawn attention and resulted in efforts for enhancing productivity of oil or isoprenoids.
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Holling, G. Aaron, Anand Sharda, Mackenzie M. Honikel, Guanxi Qiao, Elizabeth A. Repasky, Kelvin P. Lee, and Scott H. Olejniczak. "CD28 regulates T cell metabolic reprogramming through ARS2-dependent effects on alternative splicing." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 78.12. http://dx.doi.org/10.4049/jimmunol.204.supp.78.12.
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Abstract An adaptive immune response requires activation of naïve T cells via T cell receptor (TCR) ligation and engagement of costimulatory molecules such as CD28, which enables cell growth, rapid proliferation, and effector differentiation. To accomplish such bioenergetically demanding processes, T cells must dynamically regulate their metabolism upon activation. After initial TCR triggering of aerobic glycolysis, CD28 co-stimulation maintains uptake and catabolism of glucose required for CD8+ T cells to attain full effector status. Despite evidence that CD28 signaling through the PI3-kinase pathway induces glucose uptake via increased GLUT1 surface expression, knockin T cells expressing PI3-kinase signaling-deficient CD28 are functional in vivo and displayed only transient defects in glycolysis. In contrast, knockin T cells expressing Grb2/Vav signaling-deficient CD28 lacked in vivo function and displayed sustained defects in glycolysis. Here we identify a novel link between CD28-Grb2/Vav signaling and T cell glycolytic reprogramming through the RNA binding protein ARS2, a protein central to co-transcriptional processing of nascent RNA polymerase II transcripts. Data show that ARS2 is a critical downstream mediator of CD28-Grb2/Vav signaling that supports alternative splicing (AS) of the rate-limiting glycolytic enzyme pyruvate kinase M from the M1 to M2 isoform. Mechanistically, ARS2 binds known Pkm splicing factors and promotes their interaction with Pkm mRNA. Consistent with this, ARS2 knockout T cells displayed reduced Pkm2 AS, defective glycolytic reprogramming and lacked the ability to control in vivo tumor growth, suggesting a novel mechanism by which co-stimulation drives T cell metabolic reprogramming.
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Deng, Y., J. W. Yewdell, L. C. Eisenlohr, and J. R. Bennink. "MHC affinity, peptide liberation, T cell repertoire, and immunodominance all contribute to the paucity of MHC class I-restricted peptides recognized by antiviral CTL." Journal of Immunology 158, no. 4 (February 15, 1997): 1507–15. http://dx.doi.org/10.4049/jimmunol.158.4.1507.
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Abstract MHC class I-restricted T cell responses to viral proteins focus on a limited set of peptides. To better understand this phenomenon, we examined all of the 26 nonameric peptides encoded by the influenza virus A/Puerto Rico/8/34 (PR8) conforming to the canonical Kd binding motif. Ten peptides bound strongly to Kd as assessed by a cell surface stabilization assay. Five of these 10 induced in vitro secondary CD8+ T cell responses from splenocytes derived from PR8-immunized mice. The strongest responses were induced by the two previously defined antigenic peptides, which ranked only second and fifth in relative binding affinity. To examine the limiting factors in the immunogenicity of Kd-binding peptides, we produced recombinant vaccinia viruses (rVVs) expressing cytosolic or endoplasmic reticulum (ER)-targeted peptides. rVVs expressing ER-targeted versions of the 7 peptides with the highest relative affinities for Kd rescued Kd cell surface expression in T2 cells, while those expressing the 3 lowest affinity peptides did not. The immunogenicity of several, but not all, of the highest affinity peptides was greatly enhanced when expressed as VV-encoded cytosolic or ER-targeted peptides as compared with full length proteins. We conclude that limitations in the immunogenicity of class I binding peptides reflects, in order of decreasing importance, peptide liberation by cellular proteases, T cell repertoire, and TAP-mediated peptide transport. We also observed an additional important contributing factor: suppression of T cell responses to nondominant peptides by an immunodominant peptide located in the same protein.
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Ibanez, Jorge, Haley Houke, Abdul Elayan, Jennifer Ocasio-Adorno, Nikhil Hebbar, Paulina Velasquez, Suzanne Baker, and Giedre Krenciute. "EXTH-40. DIPGS SUPPRESS THE EFFICACY OF T CELL THERAPIES THROUGH DYSFUNCTIONAL IMMUNE SYNAPSE FORMATION." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii218. http://dx.doi.org/10.1093/neuonc/noac209.838.
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Abstract Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal pediatric brain tumors. Thus, there is an urgent need for novel therapeutics. While chimeric antigen receptor (CAR) T-cell therapy has the potential to meet this need and early phase clinical studies with CAR T cells have shown safety and some efficacy, additional studies are needed to understand the lack of efficacy of CAR T cells against DIPGs. The goal of this study was to identify CAR T cell efficacy limiting factors in DIPG setting. To study that, we focused on targeting GRP78, an endoplasmic reticulum chaperone protein that is broadly expressed on the cell surface of DIPGs. We generated GRP78-specific CAR T cells and compared their effector function against U87 glioma and the patient-derived DIPG007 cell line. Despite that GRP78-CAR T cells recognize and kill U87 and DIPG007 tumor cells in vitro, they were only effective against U87 in vivo. In addition, in vitro cytokine production and T cell proliferation were heavily diminished in DIPG007, compared to U87. For full activation, T cells require a cell-to-cell interaction and the formation of a highly organized structure called immune synapse (IS). Experiments using confocal microscopy showed that the IS quality, measured as lytic granule accumulation and cytoskeleton organization at the IS, was impaired in DIPG007 when compared to U87. This dysfunctional IS correlated with poor T cell activation (calcium flux) as determined by live cell imaging. We observed the same dysfunctional IS formation regardless of CAR T cell specificity and targeted antigen expression level, indicating that the suppressive effect is DIPG tumor mediated. In summary, we demonstrate that DIPGs suppress CAR T cell effector function through dysfunctional IS formation. We are now testing genetic engineering approaches directed at improving IS formation to overcome the suppressive effects of DIPGs.
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Thiel, Eckhard, Igor W. Blau, Martin Neumann, Carola Tietze-Buerger, Armin Gerbitz, and Lutz Uharek. "Treatment of Leukemic Meningeosis by CD 14 Depleted Adoptive Intrathecal Cell Therapy." Blood 112, no. 11 (November 16, 2008): 3261. http://dx.doi.org/10.1182/blood.v112.11.3261.3261.
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Abstract Background: Leukemic relapse within the central nervous system (CNS) is generally difficult to treat and results in poor outcome. Limiting factors for effective treatment are mainly extended neurotoxicity and availability of only few agents that will effectively act across the blood brain barrier (BBB). Although graft versus leukemia effects after allogeneic stem cell transplantation are well documented, its application is not recommended in patients with CNS disease. Since the CNS represents an immunologically privileged organ, conventional donor lymphocyte infusion (DLI) has not proven to be effective in CNS relapse situation after stem cell transplantation. Here we present results from three patients suffering from isolated CNS relapse of CML or AML after allogeneic stem cell transplantation receiving for the first time intrathecal cell therapy using CD14 depleted peripheral blood mononuclear cells from their allogeneic donor. Besides leukemic blast cell counts of the CSF molecular genetic analyses for chimerism as well as for translocations were applied for monitoring in addition to MRI and to neuroclinical symptoms. Results: Up to eight consecutive CD14 depleted intrathecal infusions were applied in escalating doses starting at 1x106 CD3+ cells. In all cases we did not observe any immediate or delayed side effects post application. In the case of the CML patient we observed disappearance of the leukemic blasts and of bcr-abl translocations and reversal to full donor chimerism of the CSF. In one AML patient we observed a transient disappearance of leukemic blasts, followed by a delayed increase. No clear and sustained response was recorded in the other AML patient. All patients are still under observation (9–14 months) and remained full chimeras in peripheral blood and bone marrow; however, the AML patients meanwhile developed chloroma lesions. Conclusion: Intrathecal DLI for CNS relapse of leukemia after allogeneic stem cell transplantation is a new still experimental approach. The first applications indicate no side effects e.g. cerebral or meningeal GVHD and a possible efficacy in CNS relapse of CML. This new approach merits further investigation in the setting of a clinical trial.
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Karschnia, Philipp, Jens Blobner, Nico Teske, Florian Schöberl, Esther Fitzinger, Martin Dreyling, Joerg-Christian Tonn, Niklas Thon, Marion Subklewe, and Louisa von Baumgarten. "CAR T-Cells for CNS Lymphoma: Driving into New Terrain?" Cancers 13, no. 10 (May 20, 2021): 2503. http://dx.doi.org/10.3390/cancers13102503.
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Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma.
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Goodman, M. G. "Mechanism of synergy between T cell signals and C8-substituted guanine nucleosides in humoral immunity: B lymphotropic cytokines induce responsiveness to 8-mercaptoguanosine." Journal of Immunology 136, no. 9 (May 1, 1986): 3335–40. http://dx.doi.org/10.4049/jimmunol.136.9.3335.
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Abstract B lymphocytes require a source of T cell-like help to produce antibody to T cell-dependent antigens. T cell-derived lymphokines and C8-substituted guanine ribonucleosides (such as 8-mercaptoguanosine; 8MGuo) are effective sources of such T cell-like help. Addition of T cell-derived lymphokines to antigen-activated B cells together with 8MGuo results in synergistic B cell differentiation, amplifying the sum of the individual responses twofold to four-fold. Lymphokine activity is required at initiation of culture for optimal synergy with 8MGuo, whereas the nucleoside can be added up to 48 hr after the lymphokines with full synergy. 8MGuo provides a perceived T cell-like differentiation signal to B cells from immunodeficient xid mice, thereby distinguishing a subset of Lyb-5- nucleoside-responsive B cells from those activated by soluble anti-mu followed by B cell stimulatory factor-1, interleukin 1, and B cell differentiation factors, which are Lyb-5+. Moreover, at least a subset of the B cells recruited by the synergistic interaction of lymphokines and nucleoside is distinct from that responsive to 8MGuo + antigen, insofar as Sephadex G-10 nonadherent xid B cells fail to respond to either 8MGuo or lymphokines alone, but do respond to the combination. A distinct subpopulation can also be demonstrated among normal B cells by limiting dilution analysis in which the precursor frequency of antigen-reactive B cells in the presence of lymphokines or nucleoside alone increases substantially when both agents are present together. In concert with the kinetic data, these observations suggest that synergy derives at least in part from the ability of lymphokines to induce one or more elements the absence of which limits the capacity of a distinct B cell subpopulation to respond to 8MGuo.
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Helm, Maria, Juliane Loui, Jan C. Simon, and Ruben A. Ferrer. "Cell Population Dynamics in Wound-Induced Hair Follicle Neogenesis Model." Life 12, no. 7 (July 15, 2022): 1058. http://dx.doi.org/10.3390/life12071058.
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Hair follicle (HF) regeneration can be achieved in the center of large full-thickness wounds on mouse backs (wound-induced HF neogenesis model, WIHN). Investigations with this model have allowed for the identification of some of the factors limiting the extent of fibrosis, which creates a permissive environment for the reposition of HF. For WIHN, specific subpopulations of cells rather than cell types are permissive to this process. Detailed information on the cellular composition in WIHN is not available. Here, we provide a description of changes in cell numbers of fibroblasts, HF dermal papilla, endothelial cells, keratinocytes (interfollicular epidermis, HF-infundibulum, HF-isthmus, HF-bulge (basal and suprabasal), HF-hair germ) and immune cells (macrophages, monocytes, dendritic cells, T cells (CD4+, CD8+, CD4+/CD8+, regulatory T cells) and neutrophils) based on flow cytometric analysis. We compared unwounded skin with large wounds (1.5 × 1.5 cm) at different time points after wounding. We found that non-immune dermal cells have the largest share in the skin at all time points studied, and that the number of epidermal cells started increasing nine days after wounding, which precede isthmus cells and bulge cells, mirroring the development of hair follicles. Monocytes and neutrophils represent most myeloid cells in wounds and remain in wounds even beyond the inflammatory phase of wound healing. Macrophages can be identified as inflammatory and alternative cells and are also found in wounds even in the late remodeling phase of wound healing. Lastly, we provide information about T cells in large wounds. Most T cells in the wounds were CD8+ at all time points and expressed γδTCR, which was previously thought to be expressed mainly on CD4+. We also report the existence of double positive CD4/CD8. Our study provides a guide in terms of time points suitable for the further study of cell subpopulations aiming to dissect the cellular heterogeneity in WIHN. Our results might set the base for the comparison of WIHN between control mice and animals manipulated to influence HF neogenesis and the full understanding of the responsible actors allowing for HF regeneration.
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Audrito, Valentina, Vincenzo Gianluca Messana, Enrico Moiso, Nicoletta Vitale, Francesca Arruga, Lorenzo Brandimarte, Federica Gaudino, et al. "NAMPT Over-Expression Recapitulates the BRAF Inhibitor Resistant Phenotype Plasticity in Melanoma." Cancers 12, no. 12 (December 20, 2020): 3855. http://dx.doi.org/10.3390/cancers12123855.
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Serine–threonine protein kinase B-RAF (BRAF)-mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a driving factor in BRAFi resistance development. Using stable and inducible NAMPT over-expression systems, we showed that forced NAMPT expression in MM BRAF-mutated cell lines led to increased energy production, MAPK activation, colony-formation capacity, and enhance tumorigenicity in vivo. Moreover, NAMPT over-expressing cells switched toward an invasive/mesenchymal phenotype, up-regulating expression of ZEB1 and TWIST, two transcription factors driving the epithelial to mesenchymal transition (EMT) process. Consistently, within the NAMPT-overexpressing cell line variants, we observed an increased percentage of a rare, drug-effluxing stem cell-like side population (SP) of cells, paralleled by up-regulation of ABCC1/MRP1 expression and CD133-positive cells. The direct correlation between NAMPT expression and gene set enrichments involving metastasis, invasiveness and mesenchymal/stemness properties were verified also in melanoma patients by analyzing The Cancer Genome Atlas (TCGA) datasets. On the other hand, CRISPR/Cas9 full knock-out NAMPT BRAFi-resistant MM cells are not viable, while inducible partial silencing drastically reduces tumor growth and aggressiveness. Overall, this work revealed that NAMPT over-expression is both necessary and sufficient to recapitulate the BRAFi-resistant phenotype plasticity.
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Lozano, Marcos Iglesias, Maria Chicco, W. P. Andrew Lee, Gerald Brandacher, and Giorgio Raimondi. "The enigmatic impact of donor T cell subsets on the therapeutic efficacy of tolerogenic protocols for transplant rejection." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 55.31. http://dx.doi.org/10.4049/jimmunol.200.supp.55.31.
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Abstract Costimulation blockade (CoB) regimens are a promising immunomodulatory strategy to prevent transplant rejection. However, we are learning that their efficacy is affected by multiple factors. Recent reports have started highlighting the unexpected capacity of passenger donor lymphocytes to enhance the recipient’s anti-graft response. New studies are necessary to understand this novel phenomenon and how it can affect the induction of transplant tolerance. In this study we assessed if T lymphocytes contained in the donor specific transfusion (DST) inoculum, used in combination with anti-CD154 (MR1) as CoB regimen, impact the regulation of mouse skin transplant rejection. When T cells were depleted from the DST, transplant survival was almost doubled. T cell subset-depletion studies indicated, unexpectedly, that donor CD8 T cells were responsible for limiting the efficacy of the tolerogenic regimen. Even more surprisingly, the presence of CD4 T cells in DST induced a remarkable improvement in transplant survival, beyond that observed with full T cell depletion. Ongoing experiments are determining the correlation between donor T lymphocytes and variations in humoral and cellular anti-donor responses. Overall, these data reveal the existence of a novel and unexpected opposing role of donor passenger lymphocytes that significantly modifies the therapeutic efficacy of DST+MR1 based regimens: a deleterious role for donor CD8, and a beneficial one for CD4 T cells. Identification of the specific mechanisms through which these divergent modulations of the anti-donor alloresponse are exerted could suggest significant changes in how we should approach immunoregulation, both experimentally as well as clinically.
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Roebuck, K. A., R. J. Walker, and W. E. Stumph. "Multiple functional motifs in the chicken U1 RNA gene enhancer." Molecular and Cellular Biology 7, no. 12 (December 1987): 4185–93. http://dx.doi.org/10.1128/mcb.7.12.4185-4193.1987.
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The DNA sequence requirements of chicken U1 RNA gene expression have been examined in an oocyte transcription system. An enhancer region, which was required for efficient U1 RNA gene expression, is contained within a region of conserved DNA sequences spanning nucleotide positions -230 to -183, upstream of the transcriptional initiation site. These DNA sequences can be divided into at least two distinct subregions or domains that acted synergistically to provide a greater than 20-fold stimulation of U1 RNA synthesis. The first domain contains the octamer sequence ATGCAAAT and was recognized by a DNA-binding factor present in HeLa cell extracts. The second domain (the SPH domain) consists of conserved sequences immediately downstream of the octamer and is an essential component of the enhancer. In the oocyte, the DNA sequences of the SPH domain were able to enhance gene expression at least 10-fold in the absence of the octamer domain. In contrast, the octamer domain, although required for full U1 RNA gene activity, was unable to stimulate expression in the absence of the adjacent downstream DNA sequences. These findings imply that sequences 3' of the octamer play a major role in the function of the chicken U1 RNA gene enhancer. This concept was supported by transcriptional competition studies in which a cloned chicken U4B RNA gene was used to compete for limiting transcription factors in oocytes. Multiple sequence motifs that can function in a variety of cis-linked configurations may be a general feature of vertebrate small nuclear RNA gene enhancers.
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Egle, Alexander, Michael Steurer, Franz Gassner, Roland Geisberger, Thomas Melchardt, Lukas Weiss, Michael A. Fridrik, Josef Thaler, Alois Lang, and Richard Greil. "A Combination of Fludarabine/Rituximab with Escalating Doses of Lenalidomide in Previously Untreated Chronic Lymphocytic Leukemia (CLL): The REVLIRIT CLL5 AGMT Phase I/II Study, Clinical and Exploratory Analyses of Induction Results." Blood 118, no. 21 (November 18, 2011): 292. http://dx.doi.org/10.1182/blood.v118.21.292.292.
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Abstract Abstract 292 Introduction: CLL cells derive essential cues from their microenvironment, that may be targets for therapy. To this end the immunomodulatory drug Lenalidomide has shown remarkable clinical activity in monotherapy trials in CLL. However, tumor lysis and tumor flare have been major obstacles in development and marked and unexplained differences in the individual tolerance of the substance remains an unsolved problem. Furthermore, the potential for interaction with standard treatment for CLL is unknown. We employed the combination of Fludarabine and Rituximab for early reduction of tumorload and used it as a backbone to establish a tolerable Lenalidomide dose in combination. Study design: In the induction phase a maximal tolerated dose (MTD) of Lenalidomide in combination with FR was to be determined during 6 cycles of Fludarabine (40mg/m2 po d1-3 q28d) and Rituximab (375mg/m2 iv d4 cycle 1; 500mg/m2 iv d1 cycles 2–6, q28d). In cycle 1 Lenalidomide was added day 7–21 at 2,5 mg. Toxicity permitting, Lenalidomide dose was escalated to 5, 10, 15, 20 and 25mg d1-21 over cycles 2–6. Data from this phase are presented in this planned analysis. Data from a 6 month Lenalidomide/Rituximab maintenance phase will be presented later. Results: The median age of the 45 recruited patients was 66 years (range 43–79). Half of the patients were in stages Rai III/IV and the median β2-MG was 4.4 mg/l. At least one high risk feature from CD38, FISH analysis and mutation status was present in 64% of patients. Five patients stopped treatment during induction (Two due to rashes, two as patient's choice and one due to early Richter's transformation). No systematic toxicity determining an MTD, the primary study endpoint, was found. In striking contrast to a small previous report, 34% of our patients proceeded through dose escalation steps as planned to receive a dose of 25mg of Lenalidomide with their last cycle of FR. The individual MTD was equal or higher than 10mg in 73% of ITT patients and 71% in this group were dose-limited due to individual differences in myelotoxicity. In ITT analysis 27% of patients had an MTD of less than 10mg. Grade 3 and 4 neutropenia was expected in this combination and observed in 88% of patients in any cycle. While it was not used as a dose limiting toxicity per se, 42% of patients were dose-limited due to myelotoxicity at some level. Infectious episodes of grade 3 severity were observed in 5 patients (11%), resulting in a relatively mild rate given the observed myelotoxicity and the phase I/II design. Surprisingly, 1/3 of the patients experienced greater than G2 skin toxicity and this was deemed dose-limiting in nine patients. No tumor lysis or greater than G2 flare reactions were observed. Full response assessment for induction treatment is available for 39 patients. Complete responses were observed in 49% and partial responses in 38% of the ITT population. In 35 patients flow MRD is available and 10 patients have reached MRD negativity. Response quality was not associated with risk factors, age or with lenalidomide dose in those receiving 6 cycles of treatment. Remarkably, one of three patients with deletion 17 achieved an MRD negative CR. Since we could not define a clinical predictor for the patients' tolerance of lenalidomide, we performed extensive immunophenotyping of T cells in pretreatment samples, using markers for functional T cells subsets, their Th polarity and for suppressive or exhausted T cell subsets. Employing a combined endpoint including non-hematological dose-limiting events or MTD < 10mg as a comparator, we identified a fraction of non-exhausted memory CD4 cells as highly significant predictor of dose-limiting non-hematologic events (p<0,005). Using a cut-off the T cell fraction has an 85% NPV for such events, possibly allowing for future identification of patients that will have difficulty with higher lenalidomide doses. Conclusions: A combination of Lenalidomide with FR seems clinically feasible. While no clear dose dependent limiting toxicity has uniformly emerged in this combination, more than a third of patients had to be dose-limited due to not clearly dose-dependent non-hematologic toxicities (mostly skin-related). Novel biomarkers may be efficient in identifying those patients. In addition, the regimen shows encouraging clinical efficacy with limited clinical complication, particularly in the patients tolerating doses above 5mg. A follow-up study with higher starting dose is planned. Disclosures: Egle: Celgene: Consultancy, Research Funding, Speakers Bureau; Roche: Speakers Bureau. Off Label Use: Use of Lenalidomide in CLL. Steurer:Roche: Speakers Bureau. Fridrik:Roche: Speakers Bureau. Thaler:Roche: Speakers Bureau. Lang:Roche: Speakers Bureau. Greil:Roche: Speakers Bureau.
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Casamayor, Antonio, Raquel Serrano, María Platara, Carlos Casado, Amparo Ruiz, and Joaquín Ariño. "The role of the Snf1 kinase in the adaptive response of Saccharomyces cerevisiae to alkaline pH stress." Biochemical Journal 444, no. 1 (April 26, 2012): 39–49. http://dx.doi.org/10.1042/bj20112099.
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Alkaline pH stress invokes a potent and fast transcriptional response in Saccharomyces cerevisiae that includes many genes repressed by glucose. Certain mutants in the glucose-sensing and -response pathways, such as those lacking the Snf1 kinase, are sensitive to alkalinization. In the present study we show that the addition of glucose to the medium improves the growth of wild-type cells at high pH, fully abolishes the snf1 alkali-sensitive phenotype and attenuates high pH-induced Snf1 phosphorylation at Thr210. Lack of Elm1, one of the three upstream Snf1 kinases (Tos3, Elm1 and Sak1), markedly increases alkali sensitivity, whereas the phenotype of the triple mutant tos3 elm1 sak1 is even more pronounced than that of snf1 cells and is poorly rescued by glucose supplementation. DNA microarray analysis reveals that about 75% of the genes induced in the short term by high pH are also induced by glucose scarcity. Snf1 mediates, in full or in part, the activation of a significant subset (38%) of short-term alkali-induced genes, including those encoding high-affinity hexose transporters and phosphorylating enzymes. The induction of genes encoding enzymes involved in glycogen, but not trehalose, metabolism is largely dependent of the presence of Snf1. Therefore the function of Snf1 in adaptation to glucose scarcity appears crucial for alkaline pH tolerance. Incorporation of micromolar amounts of iron and copper to a glucose-supplemented medium resulted in an additive effect and allows near-normal growth at high pH, thus indicating that these three nutrients are key limiting factors for growth in an alkaline environment.
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Prasad, Joni M., Xinli Du, Eric S. Mullins, Senad Divanovic, Kathryn E. Talmage, Keith W. Kombrinck, Alice G. Cheng, Olaf Schneewind, Matthew J. Flick, and Jay L. Degen. "Host Fibrinogen and the S. Aureus-Encoded Procoagulant Vwbp Are Context-Dependent Determinants of Bacterial Virulence." Blood 116, no. 21 (November 19, 2010): 1152. http://dx.doi.org/10.1182/blood.v116.21.1152.1152.
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Abstract Abstract 1152 Microbial pathogens frequently express bacterial products that are specifically designed to engage hemostatic system components in their vertebrate hosts. Staphylococcus aureus has evolved a particularly impressive repertoire of factors to control fibrin deposition, dissolution, and binding, including two bacterial products that form proteolytically active procoagulant complexes with prothrombin, staphylocoagulase (Coa) and von Willebrand factor binding protein (vWbp). These findings support the working hypothesis that hemostatic factors, in general, and fibrinogen, in particular, are likely to be important determinants of S. aureus virulence/host defense. To directly explore the role of fibrin(ogen) in host inflammatory/antimicrobial processes, a comparative analysis of bacterial clearance was done in control and fibrinogen-deficient mice in the context of S. aureus peritonitis. Control mice challenged with 109 CFU of S. aureus were found to efficiently clear S. aureus within the peritoneal cavity and eliminated ∼99.5% of bacterial CFUs within 20 minutes, whereas fibrin(ogen)-deficient mice exhibited little capacity to clear the microbe, even after several hours. Consistent with these findings, fibrinogen-deficient mice challenged with S. aureus peritonitis also exhibited a poor survival profile relative to control animals. More detailed studies to define the mechanism(s) underlying the rapid, fibrin(ogen)-dependent clearance of S. aureus have thus far excluded a critical contribution of host T cells, B cells, neutrophils, immunglobulins, complement, toll-like receptor signaling pathways, and the bacterial fibrinogen receptor clumping factor A (ClfA). However, mice carrying low levels of circulating prothrombin or expressing a mutant form of fibrinogen that cannot be converted to fibrin, exhibited a profound defect in S. aureus clearance following i.p. infection, suggesting a central role for fibrin polymer in the implementation of an effective antimicrobial program. Although fibrin formation is necessary, it is not sufficient for efficient bacterial clearance; Fibγ390-396A mice retaining full clotting function, but lacking the leukocyte integrin Mac-1 binding motif, also exhibit an impediment in bacterial clearance relative to wild-type mice. Complementary studies of S. aureus mutants deficient in bacterial procoagulants indicate that vWbp, but not Coa, is a fundamental determinant of bacterial clearance in this peritonitis model. Remarkably, bacterial procoagulant vWbp is distinctly counter-productive to the microbe in the context of peritonitis and supports the rapid, fibrin(ogen)-dependent clearance of intraperitoneal S. aureus. Based on findings indicating that host fibrinogen and bacterial factors that engage fibrin(ogen) support S. aureus virulence in other infection settings, the present findings suggest that host hemostatic factors and the bacterial procoagulant vWbp are likely to be context-dependent determinants of bacterial virulence. A better understanding of the interactions between bacterial proteins and host hemostatic factors, as well as interactions between the host hemostatic and inflammatory/immune systems, may well reveal novel therapeutic approaches for limiting microbial infections and sepsis. Disclosures: No relevant conflicts of interest to declare.
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Six, Emmanuelle, Delphine Bonhomme, Kheira Beldjord, Monika Jurkowska, Liliane Dal Cortivo, Marta Monteiro, Alexandrine Garrigue, Alain Fischer, Marina Cavazzana-Calvo, and Isabelle Andre-Schmutz. "Characterization of Post Natal Human Lymphoid Progenitors." Blood 108, no. 11 (November 16, 2006): 1659. http://dx.doi.org/10.1182/blood.v108.11.1659.1659.
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Abstract In humans, little is known about post-natal lymphoid progenitors, especially those able to circulate, colonize the thymus and generate T lymphocytes. On the basis of a previous work published by Anne Galy in 1995, we have detected in the human post-natal bone marrow up to 60 yrs of age a population of progenitors characterized by their CD34+Lin-CD10+ phenotype. Their differentiation potential analysed by culture in methylcellulose medium indicated that in contrast with their CD10− counterparts, CD10+ progenitors have lost erythroid and myeloid potential. On the other hand, CD10+ progenitors cultured on MS5 or OP9/hDL1 stroma demonstrated an enriched capacity to generate B, T and NK lymphocytes as compared to CD10− precursors. In limiting dilution assays, the high lymhoid potential of CD10+ population was confirmed, since 1 out 15 of them gave rise to T cells, 1 out 23 to B cells and 1 out 90 to NK cells. Gene expression profile shows that CD10+ cells express both B and T restricted factors, such as RAG, Gata3, Pax 5 and TdT. In addition, recombination at the IgH locus is already going on, with multiple DJ, but also VDJ recombination products detected. More importantly, CD10+ precursors circulate in the peripheral blood and are detected in the thymus where they are part of the most immature thymocytes CD34+CD1a-CD38-. Altogether, our results demonstrate for the first time the existence of a post-natal lymphoid progenitor population with a broad lymphoid potential and the ability to reach the thymus and generate efficiently T cells. On the long term, their full characterization will pave the way for their enrichment and usage in therapy of primary lymphoid immunodeficiencies.
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Ramirez, Samuel A., Michael Pablo, Sean Burk, Daniel J. Lew, and Timothy C. Elston. "A novel stochastic simulation approach enables exploration of mechanisms for regulating polarity site movement." PLOS Computational Biology 17, no. 7 (July 15, 2021): e1008525. http://dx.doi.org/10.1371/journal.pcbi.1008525.
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Cells polarize their movement or growth toward external directional cues in many different contexts. For example, budding yeast cells grow toward potential mating partners in response to pheromone gradients. Directed growth is controlled by polarity factors that assemble into clusters at the cell membrane. The clusters assemble, disassemble, and move between different regions of the membrane before eventually forming a stable polarity site directed toward the pheromone source. Pathways that regulate clustering have been identified but the molecular mechanisms that regulate cluster mobility are not well understood. To gain insight into the contribution of chemical noise to cluster behavior we simulated clustering using the reaction-diffusion master equation (RDME) framework to account for molecular-level fluctuations. RDME simulations are a computationally efficient approximation, but their results can diverge from the underlying microscopic dynamics. We implemented novel concentration-dependent rate constants that improved the accuracy of RDME-based simulations, allowing us to efficiently investigate how cluster dynamics might be regulated. Molecular noise was effective in relocating clusters when the clusters contained low numbers of limiting polarity factors, and when Cdc42, the central polarity regulator, exhibited short dwell times at the polarity site. Cluster stabilization occurred when abundances or binding rates were altered to either lengthen dwell times or increase the number of polarity molecules in the cluster. We validated key results using full 3D particle-based simulations. Understanding the mechanisms cells use to regulate the dynamics of polarity clusters should provide insights into how cells dynamically track external directional cues.
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Parnell, Emily J., Timothy J. Parnell, Chao Yan, Lu Bai, and David J. Stillman. "Ash1 and Tup1 dependent repression of the Saccharomyces cerevisiae HO promoter requires activator-dependent nucleosome eviction." PLOS Genetics 16, no. 12 (December 31, 2020): e1009133. http://dx.doi.org/10.1371/journal.pgen.1009133.
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Transcriptional regulation of the Saccharomyces cerevisiae HO gene is highly complex, requiring a balance of multiple activating and repressing factors to ensure that only a few transcripts are produced in mother cells within a narrow window of the cell cycle. Here, we show that the Ash1 repressor associates with two DNA sequences that are usually concealed within nucleosomes in the HO promoter and recruits the Tup1 corepressor and the Rpd3 histone deacetylase, both of which are required for full repression in daughters. Genome-wide ChIP identified greater than 200 additional sites of co-localization of these factors, primarily within large, intergenic regions from which they could regulate adjacent genes. Most Ash1 binding sites are in nucleosome depleted regions (NDRs), while a small number overlap nucleosomes, similar to HO. We demonstrate that Ash1 binding to the HO promoter does not occur in the absence of the Swi5 transcription factor, which recruits coactivators that evict nucleosomes, including the nucleosomes obscuring the Ash1 binding sites. In the absence of Swi5, artificial nucleosome depletion allowed Ash1 to bind, demonstrating that nucleosomes are inhibitory to Ash1 binding. The location of binding sites within nucleosomes may therefore be a mechanism for limiting repressive activity to periods of nucleosome eviction that are otherwise associated with activation of the promoter. Our results illustrate that activation and repression can be intricately connected, and events set in motion by an activator may also ensure the appropriate level of repression and reset the promoter for the next activation cycle.
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Muslimani, Ala'a, Donald C. Moore, Tanner Ringley, and Myra M. Robinson. "Impact of Body Mass Index (BMI) on the Incidence of Bortezomib -Induced Peripheral Neuropathy (BIPN) in Patients with Newly Diagnosed Multiple Myeloma (MM)." Blood 132, Supplement 1 (November 29, 2018): 2002. http://dx.doi.org/10.1182/blood-2018-99-110255.
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Abstract Background Peripheral neuropathy (PN) is one of the most common dose-limiting toxicities associated with bortezomib (B); it can lead to dose reductions or therapy discontinuation. Diabetes mellitus, prior thalidomide treatment, and advanced age have been identified as being risk factors for the developing bortezomib-induced peripheral neuropathy (BIPN). Obesity has been identified as being a risk factor for the development of PN with other neurotoxic anticancer agents.We aimed to evaluate the impact of BMI on the incidence and severity of BIPN. Methods This is a retrospective, single-center study of patients treated at Levine Cancer Institute with subcutaneous B between January 1, 2012 and June 1, 2017. Eligible patients received at least one full cycle of subcutaneous B and had previously untreated, newly diagnosed MM. Patients who received intravenous B or concomitant thalidomide were excluded. Patients were divided into three groups based on their BMI: normal/underweight (BMI <25), overweight (BMI 25-29.9), and obese (BMI ≥ 30). Patient and disease characteristics were summarized with frequencies and proportions for categorical factors and descriptive statistics for continuous factors. The individual impact of BMI on PN incidence was evaluated with univariable logistic regression. Multivariable logistic regression evaluated additional factors that might be confounders: gender, race, age, MM type and stage, smoking status, comorbidities, concomitant antimyeloma therapy, and B dose and schedule. We used the Common Toxicity Criteria for Adverse Events (CTCAE v4.03) to grade the intensity of the neurologic symptoms. Association of grade of PN with BMI was evaluated with Fisher's exact test. Results A total of 143 patients fit the inclusion criteria were identified (59% were male, and 41% were female, median age was 66 years (range 25-85). Patients across the three groups received B at similar doses and schedules (weekly vs. biweekly). Obese patients had an increased incidence in developing BIPN (56.4%) compared to normal/underweight (17.3%) and overweight patients (26.9%). On multivariable analysis adjusting for B dose and schedule, obesity was associated with increased odds in developing BIPN compared to normal/underweight patients (OR 7.24, 95% CI 2.37-22.13; p=0.002). Further analysis showed that compared to normal/underweight and overweight patients, obesity was not found to associated with an increased risk of grade 3-4 BIPN (p=0.451). Obese patients receiving B required dose adjustments (31%) and started medications (36%) for BIPN more frequently than normal/underweight patients (12% and 10%, respectively); both groups had similar discontinuation rates for BIPN (obese 13%, normal/underweight 8%). Conclusion Obese patients were found to be at higher risk for the development of BIPN compared to non-obese patients. Future studies should answer the question if lifestyle modifications including exercise and weight management during B treatment may influence the incidence of BIPN. Disclosures Muslimani: Daiichi-Sankyo: Speakers Bureau. Ringley:Pfizer Oncology: Speakers Bureau.
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Karol, Seth E., Wenjian Yang, Leonard A. Mattano, Kelly W. Maloney, Colton Smith, Chengcheng Liu, Laura B. Ramsey, et al. "Genetic Risk Factors for the Development of Osteonecrosis in Children Under Age 10 Treated for Acute Lymphoblastic Leukemia." Blood 126, no. 23 (December 3, 2015): 250. http://dx.doi.org/10.1182/blood.v126.23.250.250.
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Abstract Background: Therapy induced osteonecrosis has become a limiting toxicity in the intensification of treatment for pediatric acute lymphoblastic leukemia (ALL), particularly among patients 10 to 20 years of age. Prior studies on the genetic determinants of osteonecrosis have focused primarily on patients older than 10 years, leaving the genetic risk factors for the larger group of children with ALL less than 10 years old incompletely understood. It is hypothesized that genetic risk factors may account for a greater proportion of risk of osteonecrosis or involve differing mechanisms in younger than in older patients. Methods: We performed the first evaluation of genetic risk factors for osteonecrosis in children less than 10 years old using a discovery cohort of 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) protocol AALL0331 (NCI standard risk ALL) and tested for replication in 817 children less than 10 treated on COG protocol AALL0232 (high risk ALL). Genotyping was performed using the Affymetrix Gene Chip Human Mapping Array 6.0 and the Illumina Human Exome BeadChip v1.1. A subset of 15 cases in the discovery cohort had coding variant calls verified by whole exome sequencing. Both discovery and replication genome-wide association studies (GWAS) adjusted for demographic and therapy variables known to modify the risk of osteonecrosis. Enhancer enrichment analysis using HaploReg identified tissues affected by the identified single nucleotide polymorphisms (SNPs). Genes associated with the identified SNPs were evaluated using Ingenuity Pathway Analysis for enrichment in biologically relevant pathways. Results: Within the discovery cohort, top ranked variants were rs76599360 and rs77556622 which were in full linkage disequilibrium [P=1.13x10-9, odds ratio (OR) 22.0, 95% confidence interval (95%CI) 8.15-59.6] located near bone morphogenic protein 7 (BMP7). The top replicated SNPs were located near BMP7 [rs75161997, P=5.34x10-8 (OR 15.0; 95%CI 5.64-39.7) and P =0.0498 (OR 8.44; 95%CI 1.002-71.1) in the discovery and replication cohorts, respectively] and PROX1-antisense RNA1 [PROX1-AS1:rs1891059, P=2.28x10-7 (OR 6.48; 95%CI 3.19-13.1) and P=0.0077 (OR 3.78; 95%CI 1.42-10.1) for the discovery and replication cohorts, respectively]. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene [GRID2, P=8.65x10-6 (OR 3.46; 95%CI 2.00-5.98) and 0.0136 (OR 10.8; 95%CI 1.63-71.4) in the discovery and replication cohorts, respectively], and the genotyping of this variant was verified in the whole exome sequencing data. In a meta-analysis of both cohorts, the replicated BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) and a variant in NCRNA00251 (rs141059755) met the genome-wide significance threshold of <5x10-8 (Figure 1). In a meta-analysis of both cohorts, replicated SNPs with meta-analysis P<1 x10-5 showed enrichment in enhancers active in mesenchymal stem cells. Pathway analysis of genes linked to top SNPs (meta-analysis P <0.001) demonstrated enrichment in glutamate receptor signaling and adipogenesis pathways. Conclusions: Variants in genes important to bone and fat differentiation from mesenchymal stem cells were associated with osteonecrosis in children less than 10 years old. The importance of variants in glutamate receptor signaling in children less than 10 also confirms the findings of a recently completed GWAS of osteonecrosis in AALL0232 (Blood 2014 124:367; 2014) including patients of all ages and in which osteonecrosis occurred primarily in older children. These data provide new insights into osteonecrosis with implications for patients of all ages. Figure 1. Manhattan plot of meta-analysis for osteonecrosis risk in children <10 years old Figure 1. Manhattan plot of meta-analysis for osteonecrosis risk in children <10 years old Disclosures Hunger: Sigma Tau: Consultancy; Jazz Pharmaceuticals: Consultancy; Merck: Equity Ownership; Spectrum Pharmaceuticals: Consultancy.
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Somtrakoon, Khanitta, Aphidech Sangdee, Areeya Phumsa-ard, Nichaboon Thanarit, Pattamawan Namchumchung, Yossawadee Khunthong, and Waraporn Chouychai. "Suitable Materials for Paenibacillus sp. BSR1-1 Immobilization and Crop Growth Stimulation under Low Water Condition." Pertanika Journal of Tropical Agricultural Science 45, no. 2 (April 11, 2022): 433–49. http://dx.doi.org/10.47836/pjtas.45.2.06.
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Agricultural challenges due to a water shortage are factors limiting plant growth and productivity worldwide. One way to improve plant growth under unsuitable conditions is to use plant growth-promoting bacteria (PGPB). The objective of this study was to investigate the ability of PGPB to increase peanut, rice, and sweet corn growth under low water conditions. Suitable agricultural materials were selected first to be used in Paenibacillus sp. BSR1-1 immobilization. The materials were water hyacinth, reed, and coconut husk. Water hyacinth maintained the bacterial cell number when kept at either -4, 4, or 27-30 °C for both storage times, and water hyacinth soaked with a bacterial cell suspension prepared in 0.5 % ammonium sulfate ((NH4)2SO4) + 1 % glucose was the most suitable method to immobilize the bacterial cells. Paenibacillus sp. BSR1-1 with indole-3-acetic acid (IAA) and exopolysaccharide-producing abilities significantly increased root growth of peanuts under the low water condition. Root length and dry weight of inoculated peanut grown under low water conditions were 138.91 % and 156.51 % higher than uninoculated peanut, respectively. This bacterial isolate significantly increased rice shoot dry weight and root length under low and full water conditions. However, it only increased shoot length and root dry weight under the full water condition. Paenibacillus sp. BSR1-1 increased the dry weight of sweet corn under both conditions but only increased the root length of sweet corn under the full water condition. The shoot dry weight of inoculated sweet corn under the low water condition was 170.59 % higher than that of the un-inoculated sweet corn. When rice received Paenibacillus sp. BSR1-1 under the full water condition, and when peanuts received these bacteria under both conditions, they could produce more tillers and pods than the un-inoculated plants. Thus, Paenibacillus sp. BSR1-1 was an appropriate strain to use as a biofertilizer for agricultural proposes in water-limited areas.
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Yokokawa, Harumi, Hengyong Tu, Boris Iwanschitz, and Andreas Mai. "Fundamental mechanisms limiting solid oxide fuel cell durability." Journal of Power Sources 182, no. 2 (August 2008): 400–412. http://dx.doi.org/10.1016/j.jpowsour.2008.02.016.
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Cheung, Alice M. S., Stefan Wohrer, Paul H. Miller, Suzan Imren, Shabnam Rostamirad, Kiran Dhillon, David Knapp, Robert A. J. Oostendorp, R. Keith Humphries, and Connie J. Eaves. "In Vitro Expansion of Human Hematopoietic Cells with Delayed but Sustained Multi-Lineage Repopulating Activity." Blood 118, no. 21 (November 18, 2011): 1270. http://dx.doi.org/10.1182/blood.v118.21.1270.1270.
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Abstract Abstract 1270 In vivo expansion of hematopoietic stem cells (HSCs) involves local interactions with stimuli generated from non-hematopoietic niche environments, but the full spectrum of molecular mechanisms responsible have remained elusive. Initial experiments in mice showed that highly purified HSCs from adult mouse bone marrow are consistently expanded 3–5-fold with full maintenance of their long term (≥6 months), serially transplantable, multi-lineage repopulating ability when cultured for 7 days in serum-free UG26 stromal-cell conditioned medium (CM) supplemented with 100 ng/ml mouse Steel Factor (SF) and 20 ng/ml mouse IL-11. To explore the potential effects of this CM on HSCs in human cord blood, we conducted an initial experiment in which CD34+CD38− cells were cultured for 7 days in UG26 CM supplemented with 100 ng/ml human Flt3-ligand, 100 ng/ml human SF, and 20 ng/ml each of human IL-3, IL-6 and G-CSF. The results of limiting dilution transplants of the cultured cells in intravenously injected NSG mice showed retention of input numbers of cells with equivalent robust 6-month lympho-myeloid repopulating activity. To characterize the initial target cells and determine whether their proliferative responses might be predictive of their self-renewal behavior, we set up single cell cultures with the CD49f+ subset of CD34+CD38−CD45RA−CD90+Rho−cells with the 5 growth factors in the presence or absence of CM. Under both conditions, 7/13 and 4/13 input cells, respectively, died within the first 72 hours in culture. The subsequent rate of proliferation of the survivors was similar with all completing a first division after 96 hours and a second division 24–48 hours later. By day 8, clones of variable sizes were noted (6–1100 and 4–200 cells/clone, respectively). Clones generated under the same conditions were pooled and injected intravenously into 2 NSG mice each. We then looked for the presence of human cells in the mice by analysis of serial bone marrow aspirates starting 3 weeks post-transplant. Human cells were detected in only one of each of the 2 pairs of mice and, interestingly, in both cases, no evidence of human cells was detectable until 3 months post-transplant. In the positive mouse injected with cells generated in the absence of CM, this repopulation was transient, peaking at ∼0.1% of the mouse bone marrow compartment at 4 months post-transplant and undetectable a month later. In contrast, in the positive recipient of cells from the cultures that contained CM, both lymphoid and myeloid human cells reached much higher levels (together making up ∼20% of the mouse bone marrow compartment) which were maintained for another 3 months when the mouse was sacrificed. Transplants of cells obtained at this time from the marrow gave positive repopulation of secondary mice. In a subsequent experiment, in which similar cultures were initiated with CD34+ cord blood cells, evidence of a late continuing effect of the CM was obtained with a net absolute expansion of CD34+CD45RA−CD90+ cell numbers during the interval between 12 and 21 days in vitro. These findings highlight the important potential of as yet unidentified secreted stromal cell factors to stabilize the stem cell state in HSCs stimulated to proliferate in vitro by growth factors that favor their self-renewal. Disclosures: No relevant conflicts of interest to declare.