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► A cDNA library of the sporozoite and oocyst stages of Cryptosporidium parvum was constructed and expressed on ribosome. ► The ribosome library were bound to IECs and enriched using ...a multi-step panning procedure. ► A new surface adherence protein of C. parvum was selected (Cp20). ► The Cp20 which was on the oocyst and apical region of sporozoite surface has been examined. ► The Cp20 gene could be served as candidate gene of a vaccine.
In this study, we described a novel display method to identify surface adhesion proteins of Cryptosporidium parvum. A cDNA library of the sporozoite and oocyst stages of C. parvum was expressed on ribosome and selectively and specifically screened with intestinal epithelial cells (IECs) from newborn Cryptosporidium-free Holstein calves. Proteins were then enriched using a multi-step panning procedure. A new surface adherence protein of C. parvum was selected, named Cp20. Sequence analyses showed that Cp20 has a N-terminal signal peptide and four transmembrane regions. Indirect immunofluorescence assay (IFA) using an antibody specific for rCp20 demonstrated that the antibody specifically bound to the surface of sporozoites and oocysts. The recombinant plasmid pVAX1-Cp20 was constructed to examine the potential of the Cp20 gene as a target for specific preventive and therapeutic measures for cryptosporidiosis. The in vivo efficacies of the DNA vaccine was tested in BALB/c mice. The results indicated that the DNA vaccine elicited significant antibody responses and specific cellular responses when compared to control mice that received vector only or PBS. The DNA vaccine induced strong protective immune response against C. parvum and lower level of the oocysts shedding after challenge infection. This study suggested that Cp20 could serve as an effective target for specific preventive and therapeutic measures for cryptosporidiosis.
For the last decade, there have been varying techniques for hardware prefetching to improve the system performance. However, untimely prefetching may pollution caches and resulting into significant ...performance degradation. In this work, we introduce an Adaptive Granularity and coordinated Prefetching (AGP) that consists of a coarse-grained and fine-grained prefetched mechanism to provide a better caching environment for parallel applications. AGP targets on the degree-adjusting and location-choosing and tries to minimize the influence caused by prefetcher for each core. AGP could produce more timely prefetched requests reducing the cache pollutions and contentions. Across a variety of PARSEC benchmarks, AGP can contribute 6.5% (up to 36%) of performance improvement on a 4-core multicore system compared to the non-prefetching.
The traditional LRU replacement policy is susceptible to memory-intensive workloads with large non-reused data like thrashing applications and scan applications. For such workloads, the majority of ...cache blocks don't get any cache hits during residing in the cache. Cache performance can be improved by reducing the interference from non-reused data. Therefore, the lifetime of other blocks is increased and it can contribute to cache hit. We propose a Lifetime-aware LRU Promotion Policy and show that changing the promotion policy can effective reduce cache miss in the last-level cache. Our promotion policy dynamically adjusts promotion strategy and increases the lifetime for useful cache blocks. The experimental results show that our proposal reduces the average MPKI by 6% and 9% over EAF and DIP, respectively. In multicore, we also improve the performance and reduce the MPKI.
For the last decade, there have been varying techniques for hardware prefetchers to improve the system performance. However, due to limited space and bandwidth in a multicore system, the prefetching ...data fetched by prefetcher may pollute L1 cache even though the data is useful, thus resulting into significant performance degradation. Most contemporary multicore systems simply disable prefetching to avoid unexpected contention. This paper proposes a cross-layer and dynamic Prefetch Allocation Management (PAM) to provide better caching strategies in a parallel environment. Our approach has two main mechanisms, targeting at the different prefetch degree and location choices to minimize the cache pollution and contention. Across a variety of SPLASH2 and PARSEC benchmark, our PAM approach can contribute up to 12% of performance improvement on a 4-core multicore system compared to the static prefetcher configuration and also saves 9.1% of the memory bandwidth consumption of memory system.
Aim： Aberrant c-Met activation plays a critical role in cancer formation, progression and dissemination, as well as in development of resistance to anticancer drugs. Therefore, c-Met has emerged as ...an attractive target for cancer therapy. The aim of this study was to develop new c-Met inhibitors and elaborate the structure-activity relationships of identified inhibitors. Methods： Based on the predicted binding modes of Compounds ,5 and 14 in docking studies, a new series of c-Met inhibitor-harboring 3-（（1H-pyrrolo3,2-cpyridin-1-yl）sulfonyl）imidazo1,2-apyridine scaffolds was discovered. Potent inhibitors were identified through extensive optimizations combined with enzymatic and cellular assays. A promising compound was further investigated in regard to its selectivity, its effects on c-Met signaling, cell proliferation and cell scattering in vitro. Results： The most potent Compound 31 inhibited c-Met kinase activity with an ICso value of 12.8 nmol/L, which was 〉78-fold higher than those of a panel of 16 different tyrosine kinases. Compound 31 （8, 40, 200 nmol/L） dose-dependently inhibited the phosphorylation of c-Met and its key downstream Akt and ERK signaling cascades in c-Met aberrant human EBC-1 cancer cells. In 12 human cancer cell lines harboring different background levels of c-Met expression/activation, Compound 31 potently inhibited c-Met- driven cell proliferation. Furthermore, Compound 31 dose-dependently impaired c-Met-mediated cell scattering of MDCK cells. Conclusion： This series of c-Met inhibitors is a promising lead for development of novel anticancer drugs.
Diclofenac sodium is a nonsteroidal anti-inflammatory drug with analgesic, antipyretic, and anti-inflammatory activity. When used in a topical application, diclofenac can diffuse through the skin and ...into the subcutaneous tissue to effect the anti-inflammatory action. In this study, in vitro evaluations of the percutaneous transport of diclofenac sodium in various bases containing fatty alcohols propylene glycol or fatty acid propylene glycol mixtures through the abdominal skin of the rabbit were investigated. Results show that the transdermal flux of diclofenac sodium in the fatty alcohol propylene glycol bases of the same ratio is affected by the chain length of the fatty alcohol, and its effect is in the order of C10> C12> C14> C18. However, the transdermal flux of diclofenac sodium in the fatty acid propylene glycol bases of the same ratio is also affected by the chain length of the fatty acid, but no absolute relationship was found. For the same chain length of fatty acid and fatty alcohol used in the formulation base that was otherwise the same, the transdermal flux of diclofenac sodium is higher in the formula containing fatty alcohol than that containing fatty acid.
Aim： To determine the active ingredient of Niuchangchih （Antrodia camphorata） responsible for its anti-inflammatory effects and the relevant molecular mechanisms. Methods： Five major antcins （A, B, ...C, H, and K） were isolated from fruiting bodies of Niuchangchih. Structural similarity between the antcins and 2 glucocorticoids （cortisone and dexamethasone） was compared. After incubation with each compound, the cytosolic glucocorticoid receptor （GR） was examined for its migration into the nucleus. Molecular docking was performed to model the tertiary structure of GR associated with antcins. Results： Incubation with cortisone, dexamethasone or antcin A （but not antcins B, C, H, and K） led to the migration of glucocorticoid receptor into the nucleus. The minimal concentration of antcin A, cortisone and dexamethasone to induce nuclear migration of glu- cocorticoid receptor was 10, 1, and 0.1 mol/L, respectively. The results are in agreement with the simulated binding affinity scores of these three ligands docking to the glucocorticoid receptor. Molecular modeling indicates that C-7 of antcin A or glucocorticoids is exposed to a hydrophobic region in the binding cavity of the glucocorticoid receptor, and the attachment of a hydrophilic group to C-7 of the other four antcins presumably results in their being expelled when docking to the cavity. Conclusion： The anti-inflammatory effect of Niuchangchih is, at least, partly attributed to antcin A that mimics glucocorticoids and triggers translocation of glucocorticoid receptor into nucleus to initiate the suppressing inflammation.
Abstract
The pharmacokinetics of ketoprofen was studied in rabbits following intravenous and intramuscular administrations of ketoprofen, both at a dose of 4.0 mg.Kg-1. Plasma levels of ketoprofen, ...as a function of time, were determined by a reversed-phase high performance liquid chromatography. The disposition of ketoprofen was described by a two-compartment open model with elimination from the central compartment. A model-independent method using the statistical moment theory was also applied. Pharmacokinetics of ketoprofen was characterized as a drug with terminal half-life of 3.15 hr, low apparent volumes of distribution (V = 0.031 L.Kg-1, Vdss = 0.070 L.Kg-1 and Vdβ = 0.130 L.Kgc-1). The mean residence time (MRT) was found to be 1.44 hr for i.v. injection and 2.86 hr for i.m. injection. The clearance (CL) and apparent volume of distribution at steady state (Vdss) after i.v. injection was determined to be 0.027 L.Kg-1.hr-1 and 0.03 9 L.Kg-1, respectively. The absorption rate constant from the limb muscle site into systemic circulation was calculated to be 2.19 hr-1 and peak plasma concentration after i.m. injection was observed to be at 0.31 ± 0.11 hr. The systemic availability of ketoprofen after intramuscular administration was determined to be 0.38, relative to the equal i.v dose.
Abstract
As a part of studies on the possible application of pluronic F-127 gels for drug delivery systems, an investigation was carried out to characterize cefazolin stability in aqueous pluronic ...F-127 gels. Pseudo-first-order rate constants for the cefazolin degradation were obtained from different concentrations of pluronic F-127 gels at temperatures of 35°, 45°, and 55°C. Rate measurements were also carried out in the gels composed of different pluronic F-127 concentrations (20%, 25%, and 30% w/v).
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