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Yinyin Li Michael Monine Yu Huang Patrick Swann Ivan Nestorov Yelena Lyubarskaya 《MABS-AUSTIN》2016,8(6):1079-1087
A thorough understanding of drug metabolism and disposition can aid in the assessment of efficacy and safety. However, analytical methods used in pharmacokinetics (PK) studies of protein therapeutics are usually based on ELISA, and therefore can provide a limited perspective on the quality of the drug in concentration measurements. Individual post-translational modifications (PTMs) of protein therapeutics are rarely considered for PK analysis, partly because it is technically difficult to recover and quantify individual protein variants from biological fluids. Meanwhile, PTMs may be directly linked to variations in drug efficacy and safety, and therefore understanding of clearance and metabolism of biopharmaceutical protein variants during clinical studies is an important consideration. To address such challenges, we developed an affinity-purification procedure followed by peptide mapping with mass spectrometric detection, which can profile multiple quality attributes of therapeutic antibodies recovered from patient sera. The obtained data enable quantitative modeling, which allows for simulation of the PK of different individual PTMs or attribute levels in vivo and thus facilitate the assessment of quality attributes impact in vivo. Such information can contribute to the product quality attribute risk assessment during manufacturing process development and inform appropriate process control strategy. 相似文献
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Jeffrey T. Lell Michael D. Brown Theodore G. Schurr R. I. Sukernik Yelena B. Starikovskaya Antonio Torroni Lorna G. Moore Gary M. Troup D. C. Wallace 《Human genetics》1997,100(5-6):536-543
We have initiated a study of ancient male migrations from Siberia to the Americas using Y chromosome polymorphisms. The first
polymorphism examined, a C→T transition at nucleotide position 181 of the DYS199 locus, was previously reported only in Native
American populations. To investigate the origin of this DYS199 polymorphism, we screened Y chromosomes from a number of Siberian,
Asian, and Native American populations for this and other markers. This survey detected the T allele in all five Native American
populations studied at an average frequency of 61%, and in two of nine native Siberian populations, the Siberian Eskimo (21%)
and the Chukchi (17%). This finding suggested that the DYS199 T allele may have originated in Beringia and was then spread
throughout the New World by the founding populations of the major subgroups of modern Native Americans. We further characterized
Native American Y chromosome variation by analyzing two additional Y chromosome polymorphisms, the DYS287 Y Alu polymorphic (YAP) element insertion and a YAP-associated A→G transition at DYS271, both commonly found in Africans. We found
neither African allele associated with the DYS199 T allele in any of the Native American or native Siberian populations. However,
we did find DYS287 YAP+ individuals who harbored the DYS199 C allele in one Native American population, the Mixe, and in one
Asian group, the Tibetans. A correlation of these Y chromosome alleles in Native Americans with those of the DYS1 locus, as
detected by the p49a/p49f (p49a,f) probes on TaqI-digested genomic DNA, revealed a complete association of DYS1 alleles (p49a,f haplotypes) 13, 18, 66, 67 and 69 with the
DYS199 T allele, while DYS1 alleles 8 and 63 were associated with both the DYS199 C and T allele.
Received: 18 November 1996 / Accepted: 19 May 1997 相似文献
57.
V. I. Melnikova M. A. Afanasyeva A. M. Sapozhnikov L. A. Zakharova 《Russian Journal of Developmental Biology》2006,37(4):237-241
The levels of spontaneous apoptosis and proliferation of the rat thymic and spleen cells, as well as their regulation by the hypothalamo-hypophysial system were studied during perinatal development. The apoptotic and proliferating cells in the thymus and spleen were assayed using flow cytometry with the DNA-specific dye propidium iodide. The level of apoptosis in the thymus reached 25% on day 18 of embryogenesis (E18) and decreased to 5% thereafter. In the spleen, the level of apoptosis gradually increased from 15 to 37% during the period of E18 to day 30 of postnatal development (P30). The level of proliferating cells in the thymus was 20–25% at all developmental stages studied. In the spleen, it was at a maximum on E18 (32%) and decreased almost twice on E21 (17%). On P7, the amount of proliferating cells again increased to 22% and then gradually decreased to 7% by P30. The surgical ablation of hypothalamus in utero on E18 did not affect cell apoptosis or proliferation in the thymus and spleen. The surgical ablation of both hypothalamus and pituitary led a twofold decrease of the level of apoptosis in the spleen and insignificant increase of the level of proliferation in the thymus. Thus, the numbers of cells in the embryonic thymus is regulated not only by the thymus itself, but also by the hypothalamo-hypophysial system. The programmed cell death in the embryonic spleen appears to be regulated by the hypothalamo-hypophysial system as well. 相似文献
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Yelena Sterlin Oded Pri‐Tal Gil Zimran Sang‐Youl Park Julius Ben‐Ari Jiorgos Kourelis Inge Verstraeten Maayan Gal Sean R. Cutler Assaf Mosquna 《The Plant journal : for cell and molecular biology》2019,98(5):928-941
Abscisic acid (ABA) receptors belong to the START domain superfamily, which encompasses ligand‐binding proteins present in all kingdoms of life. START domain proteins contain a central binding pocket that, depending on the protein, can couple ligand binding to catalytic, transport or signaling functions. In Arabidopsis, the best characterized START domain proteins are the 14 PYR/PYL/RCAR ABA receptors, while the other members of the superfamily do not have assigned ligands. To address this, we used affinity purification of biotinylated proteins expressed transiently in Nicotiana benthamiana coupled to untargeted LC‐MS to identify candidate binding ligands. We optimized this method using ABA–PYL interactions and show that ABA co‐purifies with wild‐type PYL5 but not a binding site mutant. The Kd of PYL5 for ABA is 1.1 μm , which suggests that the method has sufficient sensitivity for many ligand–protein interactions. Using this method, we surveyed a set of 37 START domain‐related proteins, which resulted in the identification of ligands that co‐purified with MLBP1 (At4G01883) or MLP165 (At1G35260). Metabolite identification and the use of authentic standards revealed that MLBP1 binds to monolinolenin, which we confirmed using recombinant MLBP1. Monolinolenin also co‐purified with MLBP1 purified from transgenic Arabidopsis, demonstrating that the interaction occurs in a native context. Thus, deployment of this relatively simple method allowed us to define a protein–metabolite interaction and better understand protein–ligand interactions in plants. 相似文献
59.
A comparison of three techniques for quantitative analysis of galactosylation present on immunoglobulins is described. ESIMS, MALDI-TOF MS, and anion-exchange chromatography with fluorescence detection were evaluated in terms of repeatability, limit of quantitation, selectivity, and linearity. A recombinant monoclonal IgG was enzymatically modified in vitro to produce essentially completely galactosylated and degalactosylated forms of the immunoglobulin. Samples of known galactosylation levels were prepared by mixing the modified forms with the native form of the immunoglobulin. Good repeatability and linearity were demonstrated for all three assays (RSDs<1.0%, correlation coefficients>0.99). Differences in selectivity, sensitivity, and other performance aspects of the three techniques are also discussed in this paper. 相似文献
60.
Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production 总被引:2,自引:0,他引:2
Shmist YA Goncharov I Eichler M Shneyvays V Isaac A Vogel Z Shainberg A 《Molecular and cellular biochemistry》2006,283(1-2):75-83
Delta-9-tetrahydrocannabinol (THC), the major active component of marijuana, has a beneficial effect on the cardiovascular
system during stress conditions, but the defence mechanism is still unclear. The present study was designed to investigate
the central (CB1) and the peripheral (CB2) cannabinoid receptor expression in neonatal cardiomyoctes and possible function
in the cardioprotection of THC from hypoxia. Pre-treatment of cardiomyocytes that were grown in vitro with 0.1 – 10 μM THC for 24 h prevented hypoxia-induced lactate dehydrogenase (LDH) leakage and preserved the morphological
distribution of α-sarcomeric actin. The antagonist for the CB2 (10 μM), but not CB1 receptor antagonist (10 μM) abolished
the protective effect of THC. In agreement with these results using RT-PCR, it was shown that neonatal cardiac cells express
CB2, but not CB1 receptors. Involvement of NO in the signal transduction pathway activated by THC through CB2 was examined.
It was found that THC induces nitric oxide (NO) production by induction of NO synthase (iNOS) via CB2 receptors. L-NAME (NOS
inhibitor, 100 μM) prevented the cardioprotection provided by THC. Taken together, our findings suggest that THC protects
cardiac cells against hypoxia via CB2 receptor activation by induction of NO production. An NO mechanism occurs also in the
classical pre-conditioning process; therefore, THC probably pre-trains the cardiomyocytes to hypoxic conditions. 相似文献