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Abolhasani, Milad, Nicholas C. Bruno, and Klavs F. Jensen. "Oscillatory three-phase flow reactor for studies of bi-phasic catalytic reactions." Chemical Communications 51, no. 43 (2015): 8916–19. http://dx.doi.org/10.1039/c5cc02051d.
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Oscillatory flow reactor strategy removes the mixing, mass transfer and residence time limitations associated with continuous multi-phase flow approaches for studies of bi-phasic C–C and C–N catalytic reactions.
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Moran, Paul R. "4654591 NMR flow imaging using bi-phasic excitation field gradients." Magnetic Resonance Imaging 5, no. 5 (January 1987): II. http://dx.doi.org/10.1016/0730-725x(87)90139-1.
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Gasmi, S., and F. Z. Nouri. "A study of a bi-phasic flow problem in porous media." Applied Mathematical Sciences 7 (2013): 2055–64. http://dx.doi.org/10.12988/ams.2013.13185.
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Sharma, Prerna, P. Aswathi, Anit Sane, Shankar Ghosh, and S. Bhattacharya. "Three-dimensional real-time imaging of bi-phasic flow through porous media." Review of Scientific Instruments 82, no. 11 (November 2011): 113704. http://dx.doi.org/10.1063/1.3658822.
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Elangovan, T., D. Mangalaraj, K. Prabakar, P. Kuppusami, Shabana Khan, and E. Mohandas. "Microstructure Analysis of TaN/Cu Nanocomposite Coatings Deposited by Pulsed DC Magnetron Sputtering." Advanced Materials Research 123-125 (August 2010): 427–30. http://dx.doi.org/10.4028/www.scientific.net/amr.123-125.427.
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TaN-Cu nanocomposite thin films used as materials for thin-film resistors (TFR) were prepared by magnetron pulsed dc reactive sputtering. Structural and morphological properties of films deposited on (100) Si as a function of nitrogen flow rate and substrate temperature is investigated. With the introduction of N2 gas flow indicated with different phases of nanocrystalline h-Ta, Ta2N, TaN, Ta4N5 and Cu. XRD analysis of the films deposited with increasing substrate temperature at constant flow rate of nitrogen 10 sccm indicated that the nanocrystalline with bi-phasic (fcc-TaN and fcc-Cu). The microstructure of the films was investigated by scanning electron microscopy and high-resolution transmission electron microscopy.
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Yang, H., D. C. Florence, E. L. McCoy, W. A. Dick, and P. S. Grewal. "Design and hydraulic characteristics of a field-scale bi-phasic bioretention rain garden system for storm water management." Water Science and Technology 59, no. 9 (May 1, 2009): 1863–72. http://dx.doi.org/10.2166/wst.2009.186.
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A field-scale bioretention rain garden system was constructed using a novel bi-phasic (i.e. sequence of anaerobic to aerobic) concept for improving retention and removal of storm water runoff pollutants. Hydraulic tests with bromide tracer and simulated runoff pollutants (nitrate-N, phosphate-P, Cu, Pb, and Zn) were performed in the system under a simulated continuous rainfall. The objectives of the tests were (1) to determine hydraulic characteristics of the system, and (2) to evaluate the movement of runoff pollutants through the system. For the 180 mm/24 h rainfall, the bi-phasic bioretention system effectively reduced both peak flow (∼70%) and runoff volume (∼42%). The breakthrough curves (BTCs) of bromide tracer suggest that the transport pattern of the system is similar to dispersed plug flow under this large runoff event. The BTCs of bromide showed mean 10% and 90% breakthrough times of 5.7 h and 12.5 h, respectively. Under the continuous rainfall, a significantly different transport pattern was found between each runoff pollutant. Nitrate-N was easily transported through the system with potential leaching risk from the initial soil medium, whereas phosphate-P and metals were significantly retained indicating sorption-mediated transport. These findings support the importance of hydraulics, in combination with the soil medium, when creating bioretention systems for bioremediation that are effective for various rainfall sizes and intervals.
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Barranco, David, Leslie N. Sutton, Sandra Florin, Joel Greenberg, Teresa Sinnwell, Laszlo Ligeti, and Alan C. McLaughlin. "Use of 19F NMR Spectroscopy for Measurement of Cerebral Blood Flow: A Comparative Study Using Microspheres." Journal of Cerebral Blood Flow & Metabolism 9, no. 6 (December 1989): 886–91. http://dx.doi.org/10.1038/jcbfm.1989.122.
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19F NMR was used to determine washout curves of an inert, diffusible gas (CHF3) from the cat brain. The cerebral blood flow was estimated from a bi- or tri-phasic fit to the deconvoluted wash-out curve, using the Kety-Schmidt approach. Cerebral blood flow values determined by 19F NMR show the expected responsiveness to alterations in Paco2, but are approximately 28% lower than cerebral blood flow values determined simultaneously by radioactive microsphere techniques. High concentrations of CHF3 have little effect on intracranial pressure, mean arterial blood pressure or Paco2, but cause small changes in the blood flow to certain regions of the brain. We conclude that 19F NMR techniques utilizing low concentrations of CHF3 have potential for the noninvasive measurement of cerebral blood flow.
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Jian, Ranran, Zhonghe Shi, Haichao Liu, Weimin Yang, and Mohini Sain. "Enhancing Mixing and Thermal Management of Recycled Carbon Composite Systems by Torsion-Induced Phase-to-Phase Thermal and Molecular Mobility." Polymers 12, no. 4 (April 1, 2020): 771. http://dx.doi.org/10.3390/polym12040771.
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A novel torsion screw has been proposed to resolve the inadequate control of mass transfer and the thermal management of two component polymer blends and their carbon fiber composites. The novel torsional screw distinctly introduced radial flow in the torsion screw channel, which is a significant improvement over the flow pattern developed by the conventional screw. The heat transfer and mixing behavior of melt mixtures are enhanced by adapting screws with torsion elements compared with the traditional screw elements. Heat transfer efficacy in the polypropylene–polystyrene bi-phasic extrusion process improved with the increase in torsion element numbers. An increased number of newly designed torsional elements also improved the dispersion of minor phase in bi-phase polypropylene–polystyrene composition and their carbon fiber composites. The unique flow pattern induced by the torsion elements shows a synergistic effect on the melt-phase mass flow and the thermal flow field facilitating phase-to-phase thermal and molecular mobility and enhanced fiber orientation, crystallinity and mechanical properties of composite made from recycled carbon fiber/polypropylene. Microtomographs of recycled carbon fiber demonstrated the extraordinary ability of a torsion screw element to orient carbon fiber in both axial and radial directions.
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Nicolas Receveur, Dmitry Nechipurenko, Yannick Knapp, Aleksandra Yakusheva, Eric Maurer, Cécile V. Denis, François Lanza, Mikhail Panteleev, Christian Gachet, and Pierre H. Mangin. "Shear rate gradients promote a bi-phasic thrombus formation on weak adhesive proteins, such as fibrinogen in a VWF-dependent manner." Haematologica 105, no. 10 (November 14, 2019): 2471–83. http://dx.doi.org/10.3324/haematol.2019.235754.
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Blood flow profoundly varies throughout the vascular tree due to its pulsatile nature and to the complex vessel geometry. While thrombus formation has been extensively studied in vitro under steady flow, and in vivo under normal blood flow conditions, the impact of complex hemodynamics such as flow acceleration found in stenosed arteries has gained increased appreciation. We investigated the effect of flow acceleration, characterized by shear rate gradients, on the function of platelets adhering to fibrinogen, a plasma protein which plays a key role in hemostais and thrombosis. While we confirmed that under steady flow, fibrinogen only supports single platelet adhesion, we observed that under shear rate gradients, this surface becomes highly thrombogenic, supporting efficient platelet aggregation leading to occlusive thrombus formation. This shear rate gradient-driven thrombosis is biphasic with an initial step of slow platelet recruitment supported by direct plasma VWF adsorption to immobilized fibrinogen and followed by a second phase of explosive thrombosis initiated by VWF fiber formation on platelet monolayers. In vivo experiments confirmed that shear rate gradients accelerate thrombosis in a VWF-dependent manner. Together, this study characterizes a process of plasma VWF-dependent accelerated thrombosis on immobilized fibrinogen in the presence of shear rate gradients.
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Gonawan, Fadzil Noor, and Azlina Harun Kamaruddin. "Conceptual Study of Transesterification of Vegetable Oils in the Continuous-Stirred-Tank Reactor at Unsteady-State and Isothermal Conditions." Malaysian Journal of Fundamental and Applied Sciences 17, no. 2 (April 29, 2021): 181–94. http://dx.doi.org/10.11113/mjfas.v17n2.2006.
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The continuous-stirred-tank reactor (CSTR) is favorable for bi-phasic enzymatic reaction due to ease of operation, cost-effective and low downtime. Lack of study on the enzymatic reaction in the CSTR has disfavor this type of reactor compared to batch and packed bed. Presently, a simulation was carried out to simulate the behavior of the lipase-catalyzed production of biodiesel by using CSTR at isothermal conditions. The mathematical model incorporated the effect of the kinetic, thermal, and operating parameters. The parameters such as Michaelis constant (Km), inhibition constant (Ki), Gibbs inactivation energy (DelG) and mol flow rate are among determining factors of the course of the reaction. It is suggested that the enzyme with lower , higher , and higher should be chosen for the reaction. In continuous operation in the CSTR, the volumetric flow rate of the substrates and the initial concentration of the feed could be used to control reaction performance as these parameters will determine the total mol or ratio of the substrates in the reactor. Most, importantly, the longer residence time is preferred to achieve higher conversion, however, the volumetric flow rate must not be too low to prevent underperformance of reaction.
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Lungu, Adrian. "A DES-SST Based Assessment of Hydrodynamic Performances of the Wetted and Cavitating PPTC Propeller." Journal of Marine Science and Engineering 8, no. 4 (April 23, 2020): 297. http://dx.doi.org/10.3390/jmse8040297.
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The paper describes an investigation of the hydrodynamic performances of a five-bladed controllable pitch propeller, whose geometry was provided by Schiffbau-Versuchsanstalt (SVA) Potsdam GmbH Model Basin. Both cavitating and non-cavitating regimes are numerically simulated for different advance ratio coefficients. The numerical approach is based on a finite volume approach in which closure to the turbulence is achieved through detached eddy simulation (DES). Propeller open water (POW) characteristics are computed, and the numerical solutions are validated through extensive comparisons with experimental data. In addition, the bi-phasic flow for the cavitating regime is simulated, for which comparisons with the cavitation sketches are performed to check the ability of the solver to estimate the cavitation extent. Grid convergence tests are performed for both working regimes together with validation and verification checks, not only to size the level of the numerical errors, but also to prove the robustness of the chosen numerical approach. Finally, a set of final remarks will conclude the present research.
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Pillarella, M. R., and A. L. Zydney. "Theoretical Analysis of the Effect of Convective Flow on Solute Transport and Insulin Release in a Hollow Fiber Bioartificial Pancreas." Journal of Biomechanical Engineering 112, no. 2 (May 1, 1990): 220–28. http://dx.doi.org/10.1115/1.2891175.
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The bioartificial pancreas, in which transplanted pancreatic tissue or isolated cells are cultured on a hollow fiber membrane, is an attractive approach to restore physiologic insulin delivery in the treatment of diabetes. Insulin response in prototype devices has been unacceptable due to the large mass transport limitations associated with the membrane and the surrounding shell region. Although available theoretical analyses provide some insight into the combined effects of transport and reaction in the bioartificial pancreas, they cannot quantitatively account for the effects of convective recirculation flow, complex intrinsic insulin secretory kinetics, and nonuniform distribution of pancreatic cells. We have developed a detailed model for glucose and insulin transport and insulin secretion in the hollow fiber bioartificial pancreas based on the solution of the mass and momentum conservation equations describing flow and transport in the lumen, matrix, and shell. Model predictions are in good agreement with literature data obtained in a hollow fiber device with minimal radial convective flow. Although no quantitative data are available for a device with significant radial convection, model simulations demonstrate that convective recirculation flow can dramatically improve insulin response, allowing the device to accurately capture the bi-phasic insulin secretion characteristic of the normal physiologic response. Results provide fundamental insights into the coupling between kinetics and transport in the hollow fiber system and a rational basis for the design of clinical devices.
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Messina-Graham, Steven, and Hal E. Broxmeyer. "SDF-1/CXCL12 Modulates Mitochondrial Respiration of Hematopoietic Stem and Progenitor Cells in a Bi-Phasic Manner." Blood 126, no. 23 (December 3, 2015): 2389. http://dx.doi.org/10.1182/blood.v126.23.2389.2389.
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Abstract SDF-1, also known as CXCL12, is a potent and well-characterized chemokine required for the homing and engraftment of hematopoietic stem and progenitor cells (HSPCs) during hematopoietic stem cell transplantation (Sharma et al., 2011, Stem Cells Dev., 6:933) as well as HSC maintenance in the bone marrow (Greenbaum et al., 2013, Nature, 495:227). Data from our group has shown that in an SDF-1/CXCL12 transgenic mouse model, Lineage- Sca-1+ c-Kit+ (LSK) bone marrow cells have reduced mitochondrial membrane potential versus wild-type (Mantel et al., 2010, Cell Cycle, 9:2008). These results suggest that SDF-1/CXCL12 potentially functions to keep mitochondrial respiration low in HSPCs in the bone marrow. Low mitochondrial metabolism helps to maintain low levels of reactive oxygen species (ROS), which can promote differentiation and be detrimental to HSCs in the bone marrow (Mantel, et. al., 2015, Cell 161:1553). To test whether SDF-1/CXCL12 regulates mitochondrial metabolism, we first employed the human leukemia cell line HL-60 as a model of hematopoietic progenitor cells in vitro. HL-60 cells are known to express high levels of the SDF-1/CXCL12 receptor, CXCR4. First, HL-60 cells were treated with 50ng/ml SDF-1/CXCL12 for 2 and 24 hours, respectively. After 2 and 24 hours, the oxygen consumption rates (OCR), a measure of mitochondrial respiration, were analyzed by the Seahorse Bioscience XF96 Extracellular Flux Analyzer. The OCR of HL-60 cells treated for 2 hours was significantly reduced as compared to untreated control. Conversely, cells treated with SDF-1/CXCL12 for 24 hours had significantly increased OCR versus untreated control. Also, HL-60 cells treated for 2 hours with SDF-1/CXCL12 had significantly reduced mitochondrial membrane potential, while cells treated for 24 hours had significantly increased mitochondrial membrane potential. These results suggest a novel function of SDF-1/CXCL12 in regulating mitochondrial respiration. Furthermore, after two hour of SDF-1/CXCL12 treatment, OCR associated mitochondrial ATP production is decreased versus untreated control. On the other hand 24 hours of treatment produces an increase in OCR associated mitochondrial ATP production. These results begin to establish a role for SDF-1/CXCL12 in regulating mitochondrial oxidative phosphorylation (OXPHOS) and in an SDF-1/CXCL12-CXCR4 mediated process. To begin understanding the mechanism by which SDF-1/CXCL12 regulates mitochondrial respiration, HL-60 cells were again treated for 2 and 24 hours, respectively, with 50ng/ml of SDF-1/CXCL12 and mitochondrial mass was assayed using the mitochondrial specific fluorescent dye MitoTracker Green as measured by flow cytometry. Mitochondrial mass was significantly reduced in cells treated for 2 hours while cells treated for 24 hours had significantly increased levels of mitochondrial mass, suggesting that changes in mitochondrial respiration could be accounted for by changes in mitochondrial content. Furthermore, lineage- primary mouse bone marrow cells were treated with 50ng/ml of SDF-1/CXCL12 for 2 and 24 hours, respectively, ex vivo. The OCR of treated lineage- cells was assayed for using the Seahorse Bioscience XF96 Extracellular Flux Analyzer. Much like the HL-60 cells, lineage- bone marrow cells treated for 2 hours had significantly reduced OCR, while lineage- cells treated for 24 hours had significantly increased OCR. Taken together our results suggest that SDF-1/CXCL12 functions to regulate mitochondrial respiration by regulating mitochondrial oxidative phosphorylation, ATP production and mitochondrial content in a bi-phasic manner. The in vitro data obtained from experiments with HL-60 cells and ex vivo studies with lineage- primary bone marrow cells are first examples of a role for SDF-1/CXCL12 as a regulator of mitochondrial respiration in immature hematopoietic cells. Disclosures No relevant conflicts of interest to declare.
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Sajjan, Kiran, N. Ameer Ahammad, C. S. K. Raju, M. Karuna Prasad, Nehad Ali Shah, and Thongchai Botmart. "Study of nonlinear thermal convection of ternary nanofluid within Darcy-Brinkman porous structure with time dependent heat source/sink." AIMS Mathematics 8, no. 2 (2023): 4237–60. http://dx.doi.org/10.3934/math.2023211.
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<abstract> <p>The dynamical behaviour and thermal transportation feature of mixed convective Casson bi-phasic flows of water-based ternary Hybrid nanofluids with different shapes are examined numerically in a Darcy- Brinkman medium bounded by a vertical elongating slender concave-shaped surface. The mathematical framework of the present flow model is developed properly by adopting the single-phase approach, whose solid phase is selected to be metallic or metallic oxide nanoparticles. Besides, the influence of thermal radiation is taken into consideration in the presence of an internal variable heat generation. A set of feasible similarity transformations are applied for the conversion of the governing PDEs into a nonlinear differential structure of coupled ODEs. An advanced differential quadrature algorithm is employed herein to acquire accurate numerical solutions for momentum and energy equations. Results of the conducted parametric study are explained and revealed in graphs using bvp5c in MATLAB to solve the governing system. The solution with three mixture compositions is provided (Type-I and Type-II). Al<sub>2</sub>O<sub>3</sub> (Platelet), GNT (Cylindrical), and CNTs (Spherical), Type-II mixture of copper (Cylindrical), silver (Platelet), and copper oxide (Spherical). In comparison to Type-I ternary combination Type-II ternary mixtures is lesser in terms of the temperature distribution. The skin friction coefficient is more in Type-1 compared to Type-2.</p> </abstract>
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Laille, E., R. Ward, A. Nasser, M. Stoltz, C. Cogle, S. Gore, B. S. Skikne, and G. Garcia-Manero. "The pharmacokinetics of azacitidine following subcutaneous treatment in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 7087. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.7087.
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7087 Background: 5-azacitidine (AZA), through its effects on DNA metabolism, gene expression, and cell differentiation, has proven beneficial in treatment of MDS and AML and AZA therapy significantly increases survival in higher-risk MDS and AML compared to conventional care. Few studies have evaluated the pharmacokinetics (PK) of AZA and the renal elimination of AZA has not been previously published to our knowledge. Plasma PK of AZA are herein reported in patients receiving SC doses of 75 mg/m2. This study was designed to also assess the contribution of renal elimination to the overall clearance of AZA. Methods: Adult patients with MDS or AML and ECOG status 0–2 were treated with 7 consecutive daily SC doses of 75 mg/m2 AZA during their first treatment cycle. PK parameters of AZA were derived from drug concentrations in plasma and urine collected after the first and last dose (day 7) of AZA. Safety was evaluated by adverse event reporting (NCI-CTC). Results: Currently, 18 patients have been treated with SC AZA. AZA was rapidly absorbed and reached peak plasma concentrations (concs) within 0.5 hr post dosing. The AUCinf after SC doses was 1170 hr*ng/mL. The AZA concs declined in a pseudo bi-phasic manner with an elimination half-life of 1.25 hours. The plasma PK profiles after the first and last dose were superimposable. The apparent total clearance (CL/F) and volume of distribution (Vd/F) were 143 L/hr and 318 L, respectively. AZA recovery in urine was very small relative to dose (<2%). AZA was well tolerated and no unexpected toxicities were observed. Conclusions: The AZA AUCinf after SC doses is similar to the published AUC value (1044 hr*ng/mL) after 75 mg/m2 IV doses indicating approximating 100% systemic bioavailability. After SC dosing, CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism. Vd/F was 4–5 fold greater than total body water suggesting extensive AZA tissue distribution. Renal elimination appears to play a minor role in the overall clearance of AZA. [Table: see text]
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Nodland, Sonja E., Anna A. Bajer, and Tucker W. LeBien. "Charting the Early Stages of Human B Lymphopoiesis Using the IL-7 Receptor as a Navigational Marker." Blood 114, no. 22 (November 20, 2009): 95. http://dx.doi.org/10.1182/blood.v114.22.95.95.
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Abstract Abstract 95 The identity and developmental potential of human lymphoid progenitors (LP) restricted to differentiate into T, B and/or NK cells at the exclusion of myeloid/erythroid lineages is not completely understood. Although LP from cord blood and marrow been described, there is no consensus as to the phenotype of LP committed to the B-lineage from either tissue source, or the identity of the cytokine signals that regulate lineage commitment of these progenitors. Resolution of this question has implications for identifying potential leukemic stem cells in acute lymphoblastic leukemia, as well as for lymphocyte reconstitution in the setting of cord blood and marrow transplantation. One of the challenges in conducting a comprehensive cellular and molecular characterization of LP is their low frequency in normal marrow and cord blood. The xenogeneic human hematopoietic stem cell/murine stromal cell (MS-5) model of lymphohematopoiesis has been shown to support the development of all human lymphoid lineages from human CD34+ hematopoietic progenitor cells (HPC). Therefore, the goal of the current study was to use the MS-5 model as a cellular resource to identify and characterize candidate LP subsets, and to evaluate the expression and function of the IL-7 receptor in B-lineage cell development. We initially determined whether expression of CD127 (the IL-7 receptor alpha chain) and CD34 were sufficient to define CD19- LP with enhanced B lymphopoietic potential. Xenogeneic cultures were initiated by plating cord blood CD34+ HPC onto MS-5, and CD19- lymphohematopoietic cells were characterized by polychromatic flow cytometry. Gating on CD19-/CD14-/CD15- cells revealed four populations: CD19-/CD34+/CD127-, CD19-/CD34+/CD127+, CD19-/CD34-/CD127+, and CD19-/CD34-/CD127-. CD19-/CD34+/CD127- cells were the predominant population during the first week of culture but sharply declined thereafter. A low frequency CD19-/CD34+/CD127+ population was first detected at 5-7 days and largely disappeared by 2 wks. The CD19-/CD34-/CD127+ population was initially detected at 1 wk, and underwent a bi-phasic increase and decrease over the following 3 wks. Evaluation of sorted fractions by quantitative PCR showed that the onset of expression of RAG1, RAG2, TDT, CD79A, VPREB, IGλ LIKE, and EBF-1 were coincident with onset of CD127 expression. Differentiation of CD34+/CD127+ to CD34-/CD127+ LP was accompanied by an ∼ 50-fold increase in expression of PAX5 and CD19, suggesting that the latter population was the immediate precursor of CD19+ B-lineage cells. When the three populations were FACS-purified on day 14 and re-plated on MS-5, a progression from CD34+/CD127- > CD34+/CD127+ > CD34-/CD127+ was suggested by the kinetics of CD19+ cell development. We have previously shown that neutralization of MS-5 produced murine IL-7 reduces the development of CD19+ cells from cord blood CD34+ HPC by ∼ 80%. When fetal liver, pediatric marrow or adult marrow CD34+ cells were used to initiate xenogeneic cultures, we observed a similar dependency on IL-7 for CD19+ cell development. However, neutralization of murine IL-7 had no effect on the development of CD34-/CD127+/CD19- LP. Surprisingly, independent of the source of CD34+ HPC used to initiate xenogeneic cultures, B-lineage cells expressing cell surface IgM developed in the absence of the canonical CD34+/CD19+ pro-B cell population present in human marrow. The absence of CD19+/CD34+ pro-B cells was not due to MS-5 xenogeneic culture conditions being non-permissive, since CD19+/CD34+ pro-B cells FACS-purified from fresh pediatric marrow and plated on MS-5 survived and differentiated over 3-4 wks of culture into surface IgM+/IgD+ naive B cells. Additionally, CD34 was stably expressed on CD19- cells in xenogeneic cultures for ∼ 2 wks. We conclude that expression of CD127 on CD19- LP and CD19+ B-lineage cells may define an early continuum in human B cell development, which at least partially encompasses a pathway that either bypasses or is distinct from development of canonical CD34+/CD19+ pro-B cells. Disclosures: No relevant conflicts of interest to declare.
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MacBeth, Kyle J., Eric Laille, Yuhong Ning, Christopher R. Cogle, Barry Skikne, Steven D. Gore, Guillermo Garcia-Manero, and M. Renee Ward. "A Comparative Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of Azacitidine Following Subcutaneous (SC) and Oral Administration in Subjects with Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML), Results From a Phase 1 Study." Blood 114, no. 22 (November 20, 2009): 1772. http://dx.doi.org/10.1182/blood.v114.22.1772.1772.
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Abstract Abstract 1772 Poster Board I-798 Background Parenteral azacitidine significantly improves overall survival in patients with higher-risk MDS and WHO AML (20-30% blasts) compared to conventional care (Fenaux, Lancet Oncol 2009;10:223). An oral azacitidine formulation is in development. A Phase 1, “3+3”, dose-escalation study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, PK and PD profiles of SC and increasing doses of orally-administered azacitidine in subjects with MDS or AML (not candidates for other therapies) by WHO criteria. In this study, each subject served as their own control and received SC azacitidine in Cycle 1 followed by oral azacitidine in subsequent cycles (Cycle 2+). PK and PD were evaluated in blood, following SC and oral administration. DNA methylation patterns in blood pre- and post-treatment (SC and oral) were explored to build an understanding of how DNA methylation may relate to azacitidine PK parameters. Methods Azacitidine was administered SC (75 mg/m2/day x 7 days) in Cycle 1, then orally in Cycle 2 starting at a dose of 120 mg/day x 7 days of every 28-day cycle. PK parameters were derived from azacitidine concentrations in plasma and urine collected after the first and last dose. Samples collected in Cycles 1 and 2 were assayed for DNA methylation using Illumina's Infinium Human Methylation27 BeadArrays, which provide methylation levels for >27,000 CpG loci. A linear models for microarray analysis (LIMMA) was performed to identify loci that were differentially methylated from baseline versus (vs.) each post-treatment timepoint across subjects. To identify loci whose methylation levels were modulated in relation to azacitidine PK parameters, Spearman's correlation coefficients were computed for azacitidine exposure (AUCinf) or peak plasma concentration (Cmax) vs. the fold change in methylation at Day 15 for each locus across subjects. Results To date, PK data have been generated for 31 of 45 enrolled subjects. Oral doses evaluated were 120, 180, 240, 300, 360, 480 and 600 mg. Following SC and oral administrations, azacitidine was rapidly absorbed and reached Cmax within 0.5 hr (0.2, 1.1) and 1.0 hr (0.5, 2.5) post-dose (median [min, max]), respectively. The concentration vs. time profiles declined in a pseudo bi-phasic manner, with a mean elimination half-life of 1.8 ± 1.1 hr and 0.74 ± 0.28 hr for SC and oral, respectively. For SC azacitidine, mean AUCinf = 1090 ± 470 hr*ng/mL, mean apparent total clearance (CL/F) = 170 ± 130 L/hr, and mean apparent volume of distribution (Vd/F) = 445 ± 450 L. Following either SC or oral treatments, azacitidine recovery in urine was very small relative to dose (<2%). The median (min, max) relative oral bioavailability was 13% (5%, 35%) and the median (min, max) exposure (AUCinf) of oral azacitidine compared to SC was 31% (14%, 74%) (except for 1 subject whose oral exposure was 167% SC). CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism; Vd/F was 9- to 11-fold greater than total body water suggesting extensive tissue distribution. To date, PD data have been generated for 8 and 3 subjects during SC and oral treatment, respectively. The numbers of significantly (p<0.010) hypomethylated loci peaked at Day 15 of Cycle 1 (SC) with over 4000 loci hypomethylated and at Day 15 of Cycle 2 (oral) with less than 300 loci hypomethylated vs. either baseline or Day 1 of Cycle 2. Approximately 260 hypomethylated loci are common to both groups. Spearman correlation analyses showed that DNA hypomethylation for 252 and 98 loci were correlated (r>0.8) with Day 1 SC and oral azacitidine AUCinf and Cmax, respectively. Conclusion Following oral administration, azacitidine demonstrated increased exposure with increasing dose. At dose levels tested to date, oral exposures are lower than SC. Non-renal clearance (hepatic and extra-hepatic) is the major elimination pathway with renal elimination playing a minor role. Changes in DNA methylation were observed in the blood of MDS/AML subjects following SC and oral azacitidine treatment, and a set of CpG loci was identified for which these changes were associated with AUCinf and/or Cmax. PK/PD correlations identified in these initial subjects will be further explored. The lower exposures and PD effects observed with oral vs. SC azacitidine on a 7-day schedule provide rationale for testing extended schedules and BID dosing in future trials. Disclosures MacBeth: Celgene Corporation: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Ning:Celgene: Employment, Equity Ownership. Cogle:Celgene: Research Funding, Speakers Bureau; Eisai: Speakers Bureau. Skikne:Celgene: Employment. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Ward:Celgene: Employment, Equity Ownership.
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Pinho, Bruno, Lindsay M. Williams, Julien Mahin, Yunhu Gao, and Laura Torrente-Murciano. "Enhancing mixing efficiency in curved channels: A 3D study of bi-phasic Dean-Taylor flow with high spatial and temporal resolution." Chemical Engineering Journal, June 2023, 144342. http://dx.doi.org/10.1016/j.cej.2023.144342.
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O’Neill, Brian, Timothy P. Quinn, Victor Frenkel, and King C. P. Li. "A Multi-Phasic, Continuum Damage Mechanics Model of Mechanically Induced Increased Permeability in Tissues." MRS Proceedings 898 (2005). http://dx.doi.org/10.1557/proc-0898-l02-05.
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AbstractRecently, we have reported enhanced permeability of tissues due to in vivo treatment with pulsed high intensity focused ultrasound (pHIFU). This new therapy has shown promise as a way of increasing the penetration of large drug molecules, both out of the vasculature and through the tissue. To date, no clear physical model of tissue exists that can account for these effects.A new model is proposed that clearly establishes the link between tissue structure and fluid flow properties on one hand, and the history of applied mechanical forces on the other. The model draws inspiration from two different theoretical fields of materials science, multi-phase theory and continuum damage mechanics. The theory differs from the traditional bi-phasic solid-fluid model of tissues in that the fluid part here is broken into trapped (moving with the solid) and free (moving through the solid) parts. A damage-like variable links the effective elasticity of the tissue to the ratio of the trapped to free fluids. As the damage increases, the tissue becomes, in effect, less stiff and more permeable. Release of elastic energy drives the process. A distribution of energy barriers opposes the process and governs how the fluid is released as damage increases.
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Cuypers, Fabian, Alexander Schäfer, Sebastian B. Skorka, Surabhi Surabhi, Lea A. Tölken, Antje D. Paulikat, Thomas P. Kohler, et al. "Innate immune responses at the asymptomatic stage of influenza A viral infections of Streptococcus pneumoniae colonized and non-colonized mice." Scientific Reports 11, no. 1 (October 18, 2021). http://dx.doi.org/10.1038/s41598-021-00211-y.
Full textAbstract:
AbstractSeasonal Influenza A virus (IAV) infections can promote dissemination of upper respiratory tract commensals such as Streptococcus pneumoniae to the lower respiratory tract resulting in severe life-threatening pneumonia. Here, we aimed to compare innate immune responses in the lungs of healthy colonized and non-colonized mice after IAV challenge at the initial asymptomatic stage of infection. Responses during a severe bacterial pneumonia were profiled for comparison. Cytokine and innate immune cell imprints of the lungs were analyzed. Irrespective of the colonization status, mild H1N1 IAV infection was characterized by a bi-phasic disease progression resulting in full recovery of the animals. Already at the asymptomatic stage of viral infection, the pro-inflammatory cytokine response was as high as in pneumococcal pneumonia. Flow cytometry analyses revealed an early influx of inflammatory monocytes into the lungs. Neutrophil influx was mostly limited to bacterial infections. The majority of cells, except monocytes, displayed an activated phenotype characterized by elevated CCR2 and MHCII expression. In conclusion, we show that IAV challenge of colonized healthy mice does not automatically result in severe co-infection. However, a general local inflammatory response was noted at the asymptomatic stage of infection irrespective of the infection type.
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Kick, Andrew R., Amanda F. Amaral, Alba Frias-De-Diego, Lizette M. Cortes, Jonathan E. Fogle, Elisa Crisci, Glen W. Almond, and Tobias Käser. "The Local and Systemic Humoral Immune Response Against Homologous and Heterologous Strains of the Type 2 Porcine Reproductive and Respiratory Syndrome Virus." Frontiers in Immunology 12 (March 9, 2021). http://dx.doi.org/10.3389/fimmu.2021.637613.
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The humoral immune response plays a crucial role in the combat and protection against many pathogens including the economically most important, highly prevalent, and diverse pig pathogen PRRSV – the Porcine Reproductive and Respiratory Syndrome Virus. In addition to viremia and viral shedding analyses, this study followed the local and systemic humoral immune response of pigs for 63 days upon inoculation with one of three types of Type-2 PRRSV (PRRSV-2) strains – one modified live virus (MLV) vaccine strain, and two lineage 1 PRRSV-2 strains, NC134 and NC174. The local response was analyzed by quantifying immunoglobulin (Ig)A in nasal swabs. The systemic response was studied by the quantification of IgG with ELISA and homo- and heterologous neutralizing antibodies (NAs) utilizing a novel method of flow cytometry. In all PRRSV-2 inoculated groups, viral nasal shedding started at 3 dpi, peaked between 3 and 7 days post inoculation, and was cleared at 28–35 dpi with sporadic rebounds thereafter. The local IgA response started 4–7 days after viral shedding occurred and showed a bi-phasic course with peaks at 14 dpi and at 28–35 dpi. Of note, the NC134 and NC174 strains induced a much stronger local IgA response. As reported earlier, main viremia lasted from 7 dpi to 28 dpi (NC174), 42 dpi (NC134) or until the end of the study (MLV). Similar to the local IgA response, the systemic IgG response started 4–7 days after viremia; but in contrast to viremia, serum IgG levels stayed high for all PRRSV-2 inoculated groups until the end of the study. A significant finding was that while the serum NA response in the MLV group was delayed by 28 days, serum NAs in pigs infected with our two NC134 and NC174 strains could be detected as early as 7 dpi (NC134) and 14 dpi (NC174). Compared to homologous NA responses, the NA responses against heterologous strains was strong but slightly delayed between our lineage 1 one strains or non-existent between the MLV and lineage 1 strains. This study improves our understanding of the relationship between local and systemic infections and the humoral immune response induced by PRRSV-2 infection or MLV vaccination. Our data also provide novel insights into the timeline of the development of homologous and heterologous NA levels – by both MLV vaccination or infection with two strains from the currently prevalent PRRSV-2 lineage 1.
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Lyle, Alicia N., Ebony W. Remus, Aaron E. Fan, and W. Robert Taylor. "Abstract 202: Hydrogen Peroxide Increases Osteopontin Expression Through Activation of Transcriptional and Translational Pathways." Arteriosclerosis, Thrombosis, and Vascular Biology 32, suppl_1 (May 2012). http://dx.doi.org/10.1161/atvb.32.suppl_1.a202.
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The occlusion of blood vessels in the setting of cardiovascular disease leads to ischemia, initiating processes that promote neovascularization to restore blood flow and preserve tissue function. Our in vivo studies show that Osteopontin (OPN) is a critical mediator of post-ischemic neovascularization and that ischemia-induced increases in OPN expression are H 2 O 2 -dependent. However, the mechanisms by which H 2 O 2 increases OPN expression are poorly defined. To determine if H 2 O 2 mediates transcriptional, post-transcriptional, and/or translational regulation of OPN expression in vitro, we used rat aortic smooth muscle cells as an in vitro system and stimulated with H 2 O 2 . Dose response studies showed OPN expression increased with 50 μM H 2 O 2 (51.9%±2.2, p<0.05). Using 50 μM H 2 O 2 , we performed time courses and measured OPN mRNA by qRT-PCR and protein by Western blot. OPN mRNA levels significantly increased in response to H 2 O 2 at 8 (70.4%±5.7, p<0.05) and 18 hours (120.2%±5.2, p<0.005). Interestingly, the increases in OPN protein expression in response to H 2 O 2 occurred in an unusual bi-phasic pattern, with significant increases at 6 (96.9%±1.5, p<0.001) and 18 hours (234.0%±3.6, p<0.001), with a return to baseline in between. An increase in OPN mRNA preceded the increase in OPN protein at 18 hours, suggesting transcriptional regulation; however, the acute increase in OPN at 6 hours was not preceded by increased mRNA, suggesting multiple mechanisms of OPN regulation by H 2 O 2 . To determine if the increase in OPN at 6 hours is due to increased mRNA stability or translation, we performed an RNA stability assay. H 2 O 2 stimulation did not alter OPN stability or the rate of OPN RNA degradation, leading us to conclude the increase in OPN expression at 6 hours is due to increased translation. Further studies reveal H 2 O 2 -mediated increases in phosphorylation of 4E-BP1 at the redox-sensitive Ser65 site (89.4%±6.1, p<0.05), allowing for the subsequent release of eukaryotic initiation factor eIF4E and increased phosphorylation at Ser209 (139.2%±3.9, p<0.05), resulting in increased OPN translation. In conclusion, H 2 O 2 enhances OPN expression through acute increases in translation, while long-term increases in OPN occur through increased transcriptional regulation.