High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans

Glycan structures attached to the C(H)2 domain of the Fc region of immunoglobulin G (IgG) are essential for specific effector functions but their role in modulating clearance is less clear. Clearance is of obvious importance for therapeutic monoclonal antibodies (Mabs) as it directly impacts efficacy. Here, we study the impact of Fc glycan structure on the clearance of four therapeutic human IgGs (one IgG1 and three IgG2s) in humans. The therapeutic IgGs were affinity purified from serum samples from human pharmacokinetic studies, and changes to the glycan profile over time were determined by peptide mapping employing high-resolution mass spectrometry. Relative levels of high-mannose 5 (M5) glycan decreased as a function of circulation time, whereas other glycans remained constant. These results demonstrate that therapeutic IgGs containing Fc high-mannose glycans are cleared more rapidly in humans than other glycan forms. The quantitative effect of this on pharmacokinetic area under the curve was calculated and shown to be relatively minor for three of the four molecules studied, but, depending on the dosing regimen and the relative level of the high-mannose glycan, this can also have significant impact. High-mannose content of therapeutic Mabs should be considered an important product quality attribute which may affect pharmacokinetic properties of therapeutic antibodies.     

Non-invasive microelectrode cadmium flux measurements reveal the spatial characteristics and real-time kinetics of cadmium transport in hyperaccumulator and nonhyperaccumulator ecotypes of Sedum alfredii

This study aims to determine the spatial characteristics and real-time kinetics of cadmium transport in hyperaccumulator (HE) and non hyperaccumulator (NHE) ecotypes of Sedum alfredii using a non-invasive Cd-selective microelectrode. Compared with the NHE S. alfredii, the HE S. alfredii showed a higher Cd influx in the root apical region and root hair cells, as well as a significantly higher Cd efflux in the leaf petiole after root pre-treatment with cadmium chloride (CdCl₂). Thus, HE S. alfredii has a higher capability for the translocation of absorbed Cd to the shoot. Moreover, the mesophyll tissues, isolated mesophyll protoplasts, and intact vacuoles from HE S. alfredii exhibited an instantaneous influx of Cd in response to CdCl₂ treatment with mean rates that are markedly higher than those from NHE S. alfredii. Therefore, the hyper-accumulating trait of HE S. alfredii is characterized by the rapid Cd uptake in specific root regions, including the apical region and root hair cells, as well as by the rapid root-to-shoot translocation and the highly efficient Cd-permeable transport system in the plasma membrane and mesophyll cell tonoplast. We suggest that the non-invasive Cd-selective microelectrode is an excellent method with a high degree of spatial resolution for the study of Cd transport at the tissue, cellular, and sub-cellular levels in plants.     

Interactive effects of selenium and antimony on the uptake of selenium, antimony and essential elements in paddy-rice

Aims

Selenium (Se) can be used to detoxify antimony (Sb); however, the associated mechanisms are not fully understood, in particular, the responses of essential elements to co-exposure to Se and Sb.

Methods

To resolve the above question, two nested hydroponic experiments based on a two-factor, five-level central composite design, were performed using a conventional indica rice (Fengmeizhan).

Results

The results showed that when the Se concentration was fixed at 0.8 mg L^-1, the addition of Sb, even at concentrations as low as 2.171 mg L^-1, could produce damages to this plant and significantly reduce both the aboveground and root biomasses, suggesting a high toxicity of Sb to this plant. However, when the Sb concentration was fixed at 5 mg L^-1, Se eliminated the negative effects of Sb on the aboveground growth of paddy-rice but did not noticeably affect the root biomass, suggesting a beneficial role of Se in conferring resistance to Sb toxicity in paddy-rice. Interestingly, when the Se concentration was fixed at 0.8 mg L^-1, the addition of Sb caused a consistent decrease in the Se concentration in the roots but a slight increase in the Se concentration in the aboveground, suggesting a dual effect of Sb on Se uptake. Furthermore, the addition of Sb could counterbalance the negative effects of 0.8 mg L^-1 Se on the uptake of most of the tested essential elements, significantly increased their concentrations in the different tissues of this plant.

Conclusions

The Se-mediated alleviation of Sb toxicity could be closely connected with (1) the direct inhibition of Sb uptake; and (2) the uptake regulation of some essential elements, such as calcium (Ca), magnesium (Mg) and potassium (K). This study contributes to the understanding of both the the interactions between Se and Sb and their effects on the uptake of essential elements in paddy-rice.     

Behavioral mechanisms of parasitic wasps for searching concealed insect hosts

Wood borers are important forest insect pests and difficult to be controlled owing to their concealed behavior. However, parasitic wasps can effectively ascertain and parasitize wood borers as well as other concealed pests by using special searching, finding and attacking mechanisms, which have been developed during the course of long-term coevolution with their hosts. The present paper summarizes the behavioral mechanisms of parasitic wasps involved in searching and locating their concealed hosts. Parasitic wasps can accurately find the location of their hidden hosts and then parasitize them, usually by using olfactory semiochemicals from hosts (lavare and adults), host frass and symbiotic microorganisms in host galleries; visual signals from color contrast of plant surface; contact stimuli from characters of host physical defense; substrate vibrations produced by host feeding and movement; infrared radiation from host activities and metabolizability. Some parasitic wasps may integrate the information of several stimuli from different sources to enhance the reliability and accuracy of host locations. In addition, the potentials for utilizing the host location signals of parasitoids in biological control are discussed.     

The TosMIC approach to 3-(oxazol-5-yl) indoles: application to the synthesis of indole-based IMPDH inhibitors

A modified approach to the synthesis of 3-(oxazolyl-5-yl) indoles is reported. This method was applied to the synthesis of series of novel indole based inhibitors of inosine monophosphate dehydrogenase (IMPDH). The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given.     

Multi-locus penetrance variance analysis method for association study in complex diseases

Common heritable diseases often result from the action of several different genes, each of which contributes to the total observed variability in the disease trait. Traditional single-locus association approaches rely heavily on the marginal effects of single-locus and tend to ignore the multigenic nature of complex diseases. The increasing request for localizing genes underlying traits in multi-gene diseases has led to the development of some statistical methods. In this study, we develop a multi-locus analysis method - multi-locus penetrance variance analysis (MPVA), and conduct systematical simulation studies to evaluate its performance. Our results show that compared with other multi-locus methods, MPVA has some advantage in detecting complicated interactions under different epistatic models, and its performance is stable and robust.     

How much expression divergence after yeast gene duplication could be explained by regulatory motif evolution?

We used the yeast genome sequences of gene families, microarray profiles and regulatory motif data to test the current wisdom that there is a strong correlation between regulatory motif structure and gene expression profile. Our results suggest that duplicate genes tend to be co-expressed but the correlation between motif content and expression similarity is generally poor, only approximately 2-3% of expression variation can be explained by the motif divergence. Our observations suggest that, in addition to the cis-regulatory motif structure in the upstream region of the gene, multiple trans-acting factors in the gene network can influence the pattern of gene expression significantly.     

Discovery and initial SAR of imidazoquinoxalines as inhibitors of the Src-family kinase p56(Lck)

We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.     

用榆树皮制无固相冲洗液和钻井液添加剂

将榆树皮干燥后磨制成粉。测得榆树皮粉内含29％木素,17％多糖等。未经提取,直接对榆树皮粉进行糊化、交联、磺甲基化等处理,分别研制出性能良好的无固相冲洗液(无粘土冲洗液)及钻井液添加剂SME-Fe。文章讨论了影响产品性能的因素。列举出两种产品的一些主要性能。