Plasma Circulation Research Articles

Ex Vivo Heart Perfusion for 72 Hours Using Plasma Cross Circulation.

Preservation of a donor heart for transplantation is limited to 6-8 hours. Based on our demonstration of 12 hour perfusion with plasma cross circulation, this study aimed to evaluate ex vivo heart perfusion (EVHP) for up to 72 hours using cross plasma circulation (XC-plasma) from a live, awake paracorporeal sheep (PCS). Six ovine hearts were perfused for 72 hours using plasma cross circulation at a rate of 1 L/min with a live, awake PCS. Controls were seven perfused hearts without cross circulation. Experiments were electively ended at 72 hours, and epinephrine (0.1 mg) was delivered to demonstrate hormonal responsiveness. All controls failed at 6-10 hours. All six hearts perfused for 72 hours maintained normal heart function, metabolism, and responsiveness to epinephrine. Blood gases, electrolytes, and lactate levels were normal and stable throughout the study. All hearts appeared suitable for transplantation. We have demonstrated successful normothermic EVHP for 72 hours.

CSRP3 mediates polyphenols-induced cardioprotection in hypertension

Berries contain bioactive polyphenols, whose capacity to prevent cardiovascular diseases has been established recently in animal models as well in human clinical trials. However, cellular processes and molecular targets of berries polyphenols remain to be identified. The capacity of a polyphenol-enriched diet (i.e., blueberries, blackberries, raspberries, strawberry tree fruits and Portuguese crowberries berries mixture) to promote animal survival and protect cardiovascular function from salt-induced hypertension was evaluated in a chronic salt-sensitive Dahl rat model. The daily consumption of berries improved survival of Dahl/salt-sensitive rats submitted to high-salt diet and normalized their body weight, renal function and blood pressure. In addition, a prophylactic effect was observed at the level of cardiac hypertrophy and dysfunction, tissue cohesion and cardiomyocyte hypertrophy. Berries also protected the aorta from fibrosis and modulated the expression of aquaporin-1, a channel involved in endothelial water and nitric oxide permeability. Left ventricle proteomics analysis led to the identification of berries and salt metabolites targets, including cystein and glycin-rich protein 3 (CSRP3), a protein involved in myocyte cytoarchitecture. In neonatal rat ventricular cardiomyocytes, CSRP3 was validated as a target of a berries-derived polyphenol metabolite, 4-methylcatechol sulfate, at micromolar concentrations, mimicking physiological conditions of human plasma circulation. Accordingly, siRNA silencing of CSRP3 and 4-methylcatechol sulfate pretreatment reversed cardiomyocyte hypertrophy and CSRP3 overexpression induced by phenylephrine. Our systemic study clearly supports the modulation of CSRP3 by a polyphenol-rich berries diet as an efficient cardioprotective strategy in hypertension-induced heart failure.

Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery

The clinical utility of many peptide and protein drugs is limited by their short in-vivo half-life. To address this limitation, we report a new class of polypeptide-based materials that have a long plasma circulation time. The design of these polypeptides is motivated by the hypothesis that incorporating a zwitterionic sequence, within an intrinsically disordered polypeptide motif, would impart “stealth” behavior to the polypeptide and increase its plasma residence time, a behavior akin to that of synthetic stealth polymers. We designed these zwitterionic polypeptides (ZIPPs) with a repetitive (VPX1X2G)n motif, where X1 and X2 are cationic and anionic amino acids, respectively, and n is the number of repeats. To test this hypothesis, we synthesized a set of ZIPPs with different pairs of cationic and anionic residues with varied chain length. We show that a combination of lysine and glutamic acid in the ZIPP confer superior pharmacokinetics, for both intravenous and subcutaneous administration, compared to uncharged control polypeptides. Finally, to demonstrate their clinical utility, we fused the best performing ZIPP sequence to glucagon-like peptide-1 (GLP1), a peptide drug used for treatment of type-2 diabetes and show that the ZIPP-GLP1 fusion outperforms an uncharged polypeptide of the same molecular weight in a mouse model of type-2 diabetes.

Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent.

We describe a simple and effective bioconjugation strategy to extend the plasma circulation of a low molecular weight targeted phototheranostic agent, which achieves high tumor accumulation (9.74 ± 2.26%ID/g) and high tumor-to-background ratio (10:1). Long-circulating pyropheophorbide (LC-Pyro) was synthesized with three functional building blocks: (1) a porphyrin photosensitizer for positron-emission tomography (PET)/fluorescence imaging and photodynamic therapy (PDT), (2) a urea-based prostate-specific membrane antigen (PSMA) targeting ligand, and (3) a peptide linker to prolong the plasma circulation time. With porphyrin's copper-64 chelating and optical properties, LC-Pyro demonstrated its dual-modality (fluorescence/PET) imaging potential for selective and quantitative tumor detection in subcutaneous, orthotopic, and metastatic murine models. The peptide linker in LC-Pyro prolonged its plasma circulation time about 8.5 times compared to its truncated analog. High tumor accumulation of LC-Pyro enabled potent PDT, which resulted in significantly delayed tumor growth in a subcutaneous xenograft model. This approach can be applied to improve thepharmacokinetics of existing and future targeted PDT agents for enhanced tumor accumulation and treatmentefficacy.

Redox-sensitive micelles for targeted intracellular delivery and combination chemotherapy of paclitaxel and all-trans-retinoid acid

The application of paclitaxel (PTX) in clinic has been restricted due to its poor solubility. Several traditional nano-medicines have been developed to improve this defect, while they are still lack of tumor targeting ability and rapid drug release. In this work, an amphiphilic polymeric micelle of hyaluronic acid (HA) – all-trans-retinoid acid (ATRA) with a disulfide bond, was developed successfully for the co-delivery of PTX and ATRA. The combination chemotherapy of PTX and ATRA can strengthen the anti-tumor activity. Along with self-assembling to micelles in water, the delivery system displayed satisfying drug loading capacities for both PTX (32.62% ± 1.39%) and ATRA, due to directly using ATRA as the hydrophobic group. Rapid drug release properties of the PTX-loaded redox-sensitive micelles (HA-SS-ATRA) in vitro were confirmed under reducing condition containing GSH. Besides, HA-CD44 mediated endocytosis promoted the uptake of HA-SS-ATRA micelles by B16F10 cells. Due to these properties, cytotoxicity assay verified that PTX-loaded HA-SS-ATRA micelles showed concentration-dependent cytotoxicity and displayed obvious combination therapy of PTX and ATRA. Importantly, HA-SS-ATRA micelles could remarkably prolong plasma circulation time after intravenously administration. Therefore, redox-sensitive HA-SS-ATRA micelles could be utilized and explored as a promising drug delivery system for cancer combination chemotherapy.

Oral Delivery of Curcumin Using Silk Nano- and Microparticles.

The paper presents a study using silk nano- and microparticles as carriers to deliver curcumin (CUR), a multifunctional and efficient, yet water-insoluble, antioxidant, with the primary goal of enhancing bioavailability. CUR-loaded silk nanoparticles were prepared by emulsification, resulting in particle sizes ranging from 229 to 2286 nm in diameter, with loading efficiencies from 22 to 41%. The encapsulation mechanism involved hydrophobic interaction between the β-sheet structure fabricated from the silk and the phenol groups of curcumin. In vitro studies revealed that curcumin was released more slowly from the larger particles than the smaller particles. An HPLC-MS/MS method was developed to determine the content of curcumin in rat plasma. The particles were orally administered at a single dose in rats, and the pharmacokinetic parameters were evaluated and compared with those of plain curcumin crystals. After 24 h, the larger silk particles (CSN-800, CUR-silk nanoparticles with sizes ∼800 nm) showed longer plasma circulation time for CUR (Tmax was 1.76 ± 0.10 h) when compared with that of the smaller silk particles (CSN-200 with sizes ∼200 nm, Tmax was 1.17 ± 0.07 h). The Cmax of CSN-200 was 3-fold greater than that of CSN-800. By contrast to the groups of plain CUR (without silk particles), CSN-200 and CSN-800 increased CUR bioavailability 17- and 5- fold, respectively. When mixtures of CSN-200 and CSN-800 at different ratios were orally administered to rats, medium bioavailability (>13 times) and exposure time (T1/2 > 1.68 h) were obtained. These results elucidated the effect of CUR-silk particle sizes on bioavailability after oral delivery, as a basis for future applications.

Pharmacokinetic and Immunological Considerations for Expanding the Therapeutic Window of Next-Generation Antibody-Drug Conjugates.

Antibody-drug conjugate (ADC) development has evolved greatly over the last 3 decades, including the Food and Drug Administration (FDA) approval of several new drugs. However, translating ADCs from the design stage and preclinical promise to clinical success has been a major hurdle for the field, particularly for solid tumors. The challenge in clinical development can be attributed to the difficulty in connecting the design of these multifaceted agents with the impact on clinical efficacy, especially with the accelerated development of 'next-generation' ADCs containing a variety of innovative biophysical developments. Given their complex nature, there is an urgent need to integrate holistic ADC characterization approaches. This includes comprehensive invivo assessment of systemic, intratumoral and cellular pharmacokinetics, pharmacodynamics, toxicodynamics, and interactions with the immune system, with the aim of optimizing the ADC therapeutic window. Pharmacokinetic/pharmacodynamic factors influencing the ADC therapeutic window include (1) selecting optimal target and ADC components for prolonged and stable plasma circulation to increase tumoral uptake with minimal non-specific systemic toxicity, (2) balancing homogeneous intratumoral distribution with efficient cellular uptake, and (3) translating improved ADC potency to better clinical efficacy. Balancing beneficial immunological effects such as Fc-mediated and payload-mediated immune cell activation against harmful immunogenic/toxic effects is also an emerging concern for ADCs. Here, we review practical considerations for tracking ADC efficacy and toxicity, as aided by high-resolution biomolecular and immunological tools, quantitative pharmacology, and mathematical models, all of which can elucidate the relative contributions of the multitude of interactions governing the ADC therapeutic window.

Enhancement of the Jovian Magnetospheric Plasma Circulation Caused by the Change in Plasma Supply From the Satellite Io

AbstractThe innermost Galilean satellite, Io, supplies a large amount of volcanic gasses to the Jovian magnetosphere. The fast rotation of Jupiter and the outward transport of ionized gasses are responsible for forming a huge and rotationally dominant magnetosphere. The plasma supply from the satellite has a key role in the characterization of the Jovian magnetosphere. In fact, significant variations of the plasma population in the inner magnetosphere caused by the volcanic eruptions in Io were found in early 2015, using a continuous data set of the Io plasma torus obtained from an extreme ultraviolet spectroscope onboard the Hisaki satellite. The time evolution of the Io plasma torus radial distribution showed that the outward transport of plasma through 8 RJ from Jupiter was enhanced for approximately 2 months (from the end of January to the beginning of April 2015). Intense short‐lived auroral brightenings––which represent transient energy releases in the outer part of the magnetosphere—occurred frequently during this period. The short‐lived auroral brightenings accompanied well‐defined sporadic enhancements of the ion brightness in the plasma torus, indicating a rapid inward transport of energy from the outer part of the magnetosphere and the resultant enhancement of hot electron population in the inner magnetosphere. This evidently shows that the change in a plasma source in the inner magnetosphere affects a large‐scale radial circulation of mass and energy in a rotationally dominant magnetosphere.

Copper-CX-5461: A novel liposomal formulation for a small molecule rRNA synthesis inhibitor

CX-5461 is currently in Phase I/II clinical trials for advanced hematologic malignancies and triple negative or BRCA-deficient breast cancer. The compound is currently administered to patients intravenously (i.v.) at low pH (3.5) due to solubility challenges. Reliance of low pH to enhance solubility of CX-5461 can adversely impact pharmacokinetics, biodistribution and therapeutic potential. We have addressed this solubility issue through a formulation method that relies on the interactions between CX-5461 and copper. Copper binds CX-5461 through the nitrogens of the pyrazine ring. Here, we describe synthesizing this copper-complexed CX-5461 (Cu(CX-5461)) within liposomes. CX-5461 was added to copper-containing liposomes and incubated at 60 °C for 30 min. The pharmacokinetics of CX-5461 was assessed in mice following a single i.v. injection at 30 mg/kg. Efficacy studies were completed in multiple subcutaneous mouse xenografts as well as in a bone marrow engraftment model of acute myeloid leukemia (AML). The novel Cu(CX-5461) formulation was stable at pH 7.4 and exhibited increased plasma circulation longevity, increasing the total exposure to CX5461 by an order of magnitude. Cu(CX-5461) was more active than CX-5461 in AML models in vivo. In HCT116-B46 and Capan-1 solid tumour models that are BRCA-deficient, the Cu(CX-5461) formulation engendered activity that was comparable to that of the low pH CX-5461 formulation. We have generated the first Cu(CX-5461) formulation suitable for i.v. administration that is more efficacious than the existing low-pH formulation in pre-clinical models of AML. The Cu(CX-5461) formulation may serve as an alternative formulation for CX-5461 in BRCA-deficient cancers.

Dendritic PEG outer shells enhance serum stability of polymeric micelles

A higher surface density of poly(ethylene glycol) (PEG) on polymeric micelles enhances their stability in serum, leading to improved plasma circulation. To obtain fundamental, mechanistic understanding of the PEG effect associated with polymeric architecture/configuration, we have synthesized PEGylated dendron-based copolymers (PDCs) and linear block copolymers (LBCs) with similar molecular weights. These copolymers formed dendron (hyperbranched) and linear micelles, respectively, which were compared in terms of their stabilities in serum, micelle-serum protein interactions, and in vivo biodistributions. Overall, the dendron micelles exhibited a better serum stability (longer half-life) and thus a slower release profile than the linear micelles. Fluorescence quenching assays and molecular dynamics (MD) simulations revealed that the high serum stability of the dendron micelles can be attributed to reduced micelle-serum protein interactions, owing to their dendritic, dense PEG outer shell. These results provide an important design cue for various polymeric micelles and nanoparticles.

Anti-GD2 Immunoliposomes for Targeted Delivery of the Survivin Inhibitor Sepantronium Bromide (YM155) to Neuroblastoma Tumor Cells

PurposeSepantronium bromide (YM155) is a hydrophilic quaternary compound that cannot be administered orally due to its low oral bioavailability; it is furthermore rapidly eliminated via the kidneys. The current study aims at improving the pharmacokinetic profile of YM155 by its formulation in immunoliposomes that can achieve its enhanced delivery into tumor tissue and facilitate uptake in neuroblastoma cancer cells.MethodsPEGylated YM155 loaded liposomes composed of DPPC, cholesterol and DSPE-PEG2000 were prepared via passive film-hydration and extrusion method. Targeted (i.e. immuno-)liposomes were prepared by surface functionalization with SATA modified monoclonal anti-disialoganglioside (GD2) antibodies. Liposomes were characterized based on their size, charge, antibody coupling and YM155 encapsulation efficiency, and stability. Flow cytometry analysis and confocal microscopy were performed on IMR32 and KCNR neuroblastoma cell lines. The efficacy of developed formulations were assessed by in-vitro toxicity assays. A pilot pharmacokinetic analysis was performed to assess plasma circulation and tumor accumulation profiles of the developed liposomal formulations.ResultsYM155 loaded immunoliposomes had a size of 170 nm and zeta potential of −10 mV, with an antibody coupling efficiency of 60% andYM155 encapsulation efficiency of14%. Targeted and control liposomal formulations were found to have similar YM155 release rates in a release medium containing 50% serum. An in-vitro toxicity study on KCNR cells showed less toxicity for immunoliposomes as compared to free YM155. In-vivo pharmacokinetic evaluation of YM155 liposomes showed prolonged blood circulation and significantly increased half-lives of liposomal YM155 in tumor tissue, as compared to a bolus injection of free YM155.ConclusionsYM155 loaded immunoliposomes were successfully formulated and characterized, and initial in-vivo results show their potential for improving the circulation time and tumor accumulation of YM155.

Bioavailable Blueberry-Derived Phenolic Acids at Physiological Concentrations Enhance Nrf2-Regulated Antioxidant Responses in Human Vascular Endothelial Cells.

Blueberry consumption is believed to confer a cardiovascular health advantage, but the active compounds and effects require characterization. This study aims to identify the polyphenol metabolites in plasma after blueberry juice intake and determine their bioactivity on endothelial cells. Three healthy individuals are recruited to obtain profiles of bioavailable plasma polyphenol metabolites following intake of blueberry juice. Of 33 phenolic compounds screened, 12 aglycone phenolic acids are detected and their maximum plasma concentrations and circulation time determined. Using this information, the effect of three physiologically relevant mixtures of blueberry-derived phenolic acids is investigated for their ability to induce nuclear factor erythroid 2-related factor 2 (Nrf2)-nuclear translocation and downstream gene expression in human endothelial cells. Pretreatment with the phenolic acids for 18h results in a significant upregulation of the Nrf2-regulated antioxidant response proteins heme oxygenase 1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM), following 6h exposure to 2.5μm H2 O2 . Physiologically relevant concentrations of blueberry-derived aglycone phenolic acids can induce Nrf2-regulated antioxidant response proteins in vascular endothelial cells in response to lowμm concentrations of H2 O2 . Our results represent an advance over previous studies that have used single compounds or high concentrations in cell-based investigations.

High-density lipoprotein-mimicking nanodiscs carrying peptide for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia

Therapeutic strategies using endogenous stem cell mobilizer can provide effective cell-free therapy for addressing various ischemic diseases. In particular, substance P (SP) exhibited therapeutic regeneration by facilitating mobilization of endogenous stem cells from bone marrow to the injured sites. However, its therapeutic effect has been limited due to short half-life and rapid degradation of administered SP peptides in vivo. Here we sought to develop high-density lipoprotein (HDL)-mimicking nanodiscs conjugated with SP (HDL-SP) in order to increase the in vivo half-life, bone marrow targeting, and therapeutic efficacy of SP for the treatment of diabetic peripheral ischemia. Conjugation of SP onto HDL nanodisc led to remarkable ∼3215- and ∼1060-fold increase in the ex vivo and in vivo half-lives of SP, respectively. Accordingly, HDL-SP nanodiscs improved retention of SP in bone marrow after systemic administration, leading to efficient mobilization of stem cells from bone marrow into blood circulation and reduction of systemic inflammation. Consequently, nanodisc based SP peptide delivery promoted blood vessel formation, blood perfusion recovery and markedly improved limb salvage in diabetic hindlimb ischemia model relative to administration of free SP without nanodisc modification. Therefore, HDL-SP nanodisc can provide a novel strategy for the treatment of diabetic ischemia and HDL nanodisc modification could be potentially useful for the extension of plasma circulation of other labile peptides.

Intrinsic Fabry-Perot Sensors for Magnetic Field Detection

Within the context of ensuring stable nuclear fusion, it is important to monitor and control a number of parametersincluding the magnetic field associated with plasma circulation. Optical fibre sensing techniques have seen a surge in promulgation and research advances in recent years, due to their immunity to electromagnetic radiation and compact dimensions. Prior work has shown that fibre Bragg gratings are one method of recovering the induced magnetic field, with the main point of interest being their use as distributed point sensors. However, Bragg grating inscription leads to the creation of linear birefringence that increases detector noise and could obscure a given signal. We have hypothesised that by using an intrinsic Fabry-Perot cavity comprised of two identical Bragg gratings, we could obtain a more accurate detector with the removal of photo-induced birefringence in the detection region. We present a proof of concept optical fibre sensor based on an intrinsic Fabry-Perot cavity that shows spectrally visible amplitude modulation. Finally, we demonstrate faster data processing that allows real time monitoring of a given scenario.

Correlation between plasma microRNA and microglobulin and acute myocardial infarction

Objective To investigate the correlation in plasma microRNA, microglobulin and acute myocardial infarction. Methods A retrospective study was performed on 90 cases of patients with acute myocardial infarction who were admitted from May 2014 to May 2016.The 90 patients were divided into the observation group, another 90 volunteers were divided into the control group.The levels of microRNA and microglobulin in plasma circulation were detected by fluorescence quantitative PCR assay and the immune turbidimetry test in both groups. Results In the observation group of patients, plasma circulation related microRNA-208, microRNA-241, microRNA-423 and microRNA-499, the expression levels were significantly higher than those of the control group(P<0.05); α1-microglobulin and β2-microglobulin were significantly higher than those of the control group(P<0.05), and the differences were statistically significant(P<0.05). Conclusion The plasma circulation related microRNA in patients with acute myocardial infarction has significantly high expression, the expression level of the microglobulin also shows significant abnormal state; the expression level of plasma circulation related microRNA and microglobulin has significant correlation with the incidence of acute myocardial infarction. Key words: MicroRNA; Microglobulin; Acute myocardial infarction; Fluorescence quantitative PCR method; Immune turbidimetry

Recombinant Synthesis of Hybrid Lipid–Peptide Polymer Fusions that Self‐Assemble and Encapsulate Hydrophobic Drugs

AbstractInspired by biohybrid molecules that are synthesized in Nature through post‐translational modification (PTM), we have exploited a eukaryotic PTM to recombinantly synthesize lipid–polypeptide hybrid materials. By co‐expressing yeast N‐myristoyltransferase with an elastin‐like polypeptide (ELP) fused to a short recognition sequence in E. coli, we show robust and high‐yield modification of the ELP with myristic acid. The ELP's reversible phase behavior is retained upon myristoylation and can be tuned to span a 30–60 °C. Myristoylated ELPs provide a versatile platform for genetically pre‐programming self‐assembly into micelles of varied size and shape. Their lipid cores can be loaded with hydrophobic small molecules by passive diffusion. Encapsulated doxorubicin and paclitaxel exhibit cytotoxic effects on 4T1 and PC3‐luc cells, respectively, with potencies similar to chemically conjugated counterparts, and longer plasma circulation than free drug upon intravenous injection in mice.

Recombinant Synthesis of Hybrid Lipid-Peptide Polymer Fusions that Self-Assemble and Encapsulate Hydrophobic Drugs.

Inspired by biohybrid molecules that are synthesized in Nature through post-translational modification (PTM), we have exploited a eukaryotic PTM to recombinantly synthesize lipid-polypeptide hybrid materials. By co-expressing yeast N-myristoyltransferase with an elastin-like polypeptide (ELP) fused to a short recognition sequence in E. coli, we show robust and high-yield modification of the ELP with myristic acid. The ELP's reversible phase behavior is retained upon myristoylation and can be tuned to span a 30-60 °C. Myristoylated ELPs provide a versatile platform for genetically pre-programming self-assembly into micelles of varied size and shape. Their lipid cores can be loaded with hydrophobic small molecules by passive diffusion. Encapsulated doxorubicin and paclitaxel exhibit cytotoxic effects on 4T1 and PC3-luc cells, respectively, with potencies similar to chemically conjugated counterparts, and longer plasma circulation than free drug upon intravenous injection in mice.

An Evaluation of Optimal PEGylation Strategies for Maximizing the Lymphatic Exposure and Antiviral Activity of Interferon after Subcutaneous Administration.

Interferon α2 is an antiviral/antiproliferative protein that is currently used to treat hepatitis C infections and several forms of cancer. Two PEGylated variants of interferon α2 (containing 12 and 40 kDa PEGs) are currently marketed and display longer plasma circulation times than that of unmodified interferon. With increasing realization that the lymphatic system plays an important role in the extrahepatic replication of the hepatitis C virus and in the metastatic dissemination of cancers, this study sought to evaluate PEGylation strategies to optimally enhance the antiviral activity and plasma and lymphatic exposure of interferon after subcutaneous administration in rats. The results showed that conjugation with a linear 20 kDa PEG provided the most ideal balance between activity and plasma and lymph exposure. A linear 5 kDa PEG variant also exhibited excellent plasma and lymph exposure to interferon activity when compared to those of unmodified interferon and the clinically available linear 12 kDa PEGylated construct.

Granulocyte colony-stimulating factor (GCSF) fused with Fc Domain produced from E. coli is less effective than Polyethylene Glycol-conjugated GCSF

Human granulocyte colony-stimulating factor (GCSF) is a well-known cytokine for neutropenia treatment. However, daily injections are required due to the short circulating half-life of the protein. To overcome this bottleneck, we fused GCSF with the Fc domain of IgG1 at the C terminus (GCSF-Fc) and with the maltose binding protein (MBP) tag at the N-terminus and expressed it as a soluble protein in the cytoplasm of E. coli. We also conjugated PEG aldehyde to GCSF to make PEG-GCSF. The bioactivities of GCSF-Fc and PEG-GCSF were similar to native GCSF using the mouse M-NFS-60 myelogenous leukemia cell line. The EC50 dose-response curves for GCSF, GCSF-Fc and PEG-GCSF were 37 ± 12 pM, 75 ± 13.5 pM and 46 ± 5.5 pM, respectively. When the proteins were injected into neutropenic rats, the group injected with PEG-GCSF showed the highest and fastest recovery of neutrophils, followed by GCSF-Fc and GCSF. ELISA assay revealed the PEG-GCSF had the longest plasma circulation (>72 h), followed by GCSF-Fc (>48 h) and GCSF (~24 h), which is consistent with the in vivo activities of the proteins. In summary, the GCSF-Fc purified from E. coli was not as efficient as PEG-GCSF in treating neutropenic rats.

Aerodynamics of airfoil based on plasma circulation control

In order to study the aerodynamics of the airfoil based on plasma circulation control, the Reynolds average N-S equation and mathematics model of plasma excitation based on phenomenology method are used, and the change characteristics of lift affected by the trailing radius are simulated, the optimum radius is determined. Through the low speed wind, the experiment is conducted at the angle of attack of -4 to 12, and at the speed of 6 m/s, 10 m/s, 15 m/s. The pressure distribution and lift coefficient are obtained. The results of the simulation and experiment show: it is unfavorable for the formation of Coanda effect with too large trailing radius or too small trailing radius, and the optimum ratio of radius and wing chord is 0.048, with the efficiency-cost ratio up to 97.69. The laminar separation of long bubble and short bubble appears with the increase of the angle of attack at low Reynolds number. The influences of plasma jet not only include the tail flow field, but also include improving laminar separation based on the increased circulation, and increasing the lift.