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991.
992.
Harald Rouha Adriana Badarau Zehra C Visram Michael B Battles Bianka Prinz Zoltán Magyarics Gábor Nagy Irina Mirkina Lukas Stulik Manuel Zerbs Michaela J?gerhofer Barbara Maierhofer Astrid Teubenbacher Ivana Dolezilkova Karin Gross Srijib Banerjee Gerhild Zauner Stefan Malafa Jakub Zmajkovic Sabine Maier Robert Mabry Eric Krauland K Dane Wittrup Tillman U Gerngross Eszter Nagy 《MABS-AUSTIN》2015,7(1):243-254
Staphylococcus aureus is a major human pathogen associated with high mortality. The emergence of antibiotic resistance and the inability of antibiotics to counteract bacterial cytotoxins involved in the pathogenesis of S. aureus call for novel therapeutic approaches, such as passive immunization with monoclonal antibodies (mAbs). The complexity of staphylococcal pathogenesis and past failures with single mAb products represent considerable barriers for antibody-based therapeutics. Over the past few years, efforts have focused on neutralizing α-hemolysin. Recent findings suggest that the concerted actions of several cytotoxins, including the bi-component leukocidins play important roles in staphylococcal pathogenesis. Therefore, we aimed to isolate mAbs that bind to multiple cytolysins by employing high diversity human IgG1 libraries presented on the surface of yeast cells. Here we describe cross-reactive antibodies with picomolar affinity for α-hemolysin and 4 different bi-component leukocidins that share only ∼26% overall amino acid sequence identity. The molecular basis of cross-reactivity is the recognition of a conformational epitope shared by α-hemolysin and F-components of gamma-hemolysin (HlgAB and HlgCB), LukED and LukSF (Panton-Valentine Leukocidin). The amino acids predicted to form the epitope are conserved and known to be important for cytotoxic activity. We found that a single cross-reactive antibody prevented lysis of human phagocytes, epithelial and red blood cells induced by α-hemolysin and leukocidins in vitro, and therefore had superior effectiveness compared to α-hemolysin specific antibodies to protect from the combined cytolytic effect of secreted S. aureus toxins. Such mAb afforded high levels of protection in murine models of pneumonia and sepsis. 相似文献
993.
Cluster analysis plays vital role in pattern recognition in several fields of science. Silhouette width is a widely used index for assessing the fit of individual objects in the classification, as well as the quality of clusters and the entire classification. Silhouette combines two clustering criteria, compactness and separation, which imply that spherical cluster shapes are preferred over others—a property that can be seen as a disadvantage in the presence of complex, nonspherical clusters, which is common in real situations. We suggest a generalization of the silhouette width using the generalized mean. By changing the p parameter of the generalized mean between ?∞ and +∞, several specific summary statistics, including the minimum, maximum, the arithmetic, harmonic, and geometric means, can be reproduced. Implementing the generalized mean in the calculation of silhouette width allows for changing the sensitivity of the index to compactness versus connectedness. With higher sensitivity to connectedness, the preference of silhouette width toward spherical clusters should reduce. We test the performance of the generalized silhouette width on artificial data sets and on the Iris data set. We examine how classifications with different numbers of clusters prepared by different algorithms are evaluated, if p is set to different values. When p was negative, well‐separated clusters achieved high silhouette widths despite their elongated or circular shapes. Positive values of p increased the importance of compactness; hence, the preference toward spherical clusters became even more detectable. With low p, single linkage clustering was deemed the most efficient clustering method, while with higher parameter values the performance of group average, complete linkage, and beta flexible with beta = ?0.25 seemed better. The generalized silhouette allows for adjusting the contribution of compactness and connectedness criteria, thus avoiding underestimation of clustering efficiency in the presence of clusters with high internal heterogeneity. 相似文献
994.
Lawrence T. Wong Arthur R. Beaubien Attila P. Pakuts 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1982,231(1):145-154
Pre-column derivatization of amikacin with 1-fluoro-2,4-dinitrobenzene in 25 μl of guinea pig plasma or human serum produced a stable chromophore which was measured by UV detection after rapid separation on normal-phase or reversed-phase high-performance liquid chromatography systems. The reversed-phase system, selected for routine analysis due to instability of the normal-phase column, consisted of an Ultrasphere-ODS C18 column preceded by a guard column, and used acetonitrile—water (68:32) as the mobile phase. A high degree of linearity was found in the range of 2—64 μg/ml with a coefficient of variation averaging less than 5%. 相似文献
995.
996.
Cells cope with the threat of xenobiotic stress by activating a complex molecular network that recognizes and eliminates chemically diverse toxic compounds. This “chemoimmune system” consists of cellular Phase I and Phase II metabolic enzymes, Phase 0 and Phase III ATP Binding Cassette (ABC) membrane transporters, and nuclear receptors regulating these components. In order to provide a systems biology characterization of the chemoimmune network, we designed a reaction kinetic model based on differential equations describing Phase 0–III participants and regulatory elements, and characterized cellular fitness to evaluate toxicity. In spite of the simplifications, the model recapitulates changes associated with acquired drug resistance and allows toxicity predictions under variable protein expression and xenobiotic exposure conditions. Our simulations suggest that multidrug ABC transporters at Phase 0 significantly facilitate the defense function of successive network members by lowering intracellular drug concentrations. The model was extended with a novel toxicity framework which opened the possibility of performing in silico cytotoxicity assays. The alterations of the in silico cytotoxicity curves show good agreement with in vitro cell killing experiments. The behavior of the simplified kinetic model suggests that it can serve as a basis for more complex models to efficiently predict xenobiotic and drug metabolism for human medical applications. 相似文献
997.
998.
999.
Andrea Szigeti Erika Tátrai Boglárka Enik? Varga Anna Szamosi Delia Cabrera DeBuc Zoltán Zsolt Nagy János Németh Gábor Márk Somfai 《PloS one》2015,10(11)
Purpose
The aim of this study was to evaluate the effect of axial length (AL) on the thickness of intraretinal layers in the macula using optical coherence tomography (OCT) image analysis.Methods
Fifty three randomly selected eyes of 53 healthy subjects were recruited for this study. The median age of the participants was 29 years (range: 6 to 67 years). AL was measured for each eye using a Lenstar LS 900 device. OCT imaging of the macula was also performed by Stratus OCT. OCTRIMA software was used to process the raw OCT scans and to determine the weighted mean thickness of 6 intraretinal layers and the total retina. Partial correlation test was performed to assess the correlation between the AL and the thickness values.Results
Total retinal thickness showed moderate negative correlation with AL (r = -0.378, p = 0.0007), while no correlation was observed between the thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCC), retinal pigment epithelium (RPE) and AL. Moderate negative correlation was observed also between the thickness of the ganglion cell layer and inner plexiform layer complex (GCL+IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL) and AL which were more pronounced in the peripheral ring (r = -0.402, p = 0.004; r = -0.429, p = 0.002; r = -0.360, p = 0.01; r = -0.448, p = 0.001).Conclusions
Our results have shown that the thickness of the nuclear layers and the total retina is correlated with AL. The reason underlying this could be the lateral stretching capability of these layers; however, further research is warranted to prove this theory. Our results suggest that the effect of AL on retinal layers should be taken into account in future studies. 相似文献1000.
Mária Kovács Attila Kiss Márton G?nczi Gottfried Miskolczi Gy?rgy Seprényi József Kaszaki Mark J. Kohr Elizabeth Murphy ágnes Végh 《PloS one》2015,10(4)