Modulation of immunogenicity of poly(sarcosine) displayed on various nanoparticle surfaces due to different physical properties

Poly(sarcosine) displayed on polymeric micelle is reported to trigger a T cell‐independent type2 reaction with B1a cells in the mice to produce IgM and IgG3 antibodies. In addition to polymeric micelle, three kinds of vesicles displaying poly(sarcosine) on surface were prepared here to evaluate the amounts and avidities of IgM and IgG3, which were produced in mice, to correlate them with physical properties of the molecular assemblies. The largest amount of IgM was produced after twice administrations of a polymeric micelle of 35 nm diameter ( G1 ). On the other hand, the production amount of IgG3 became the largest after twice administrations of G3 (vesicle of 229 nm diameter) or G4 (vesicle of 85 nm diameter). The augmented avidity of IgG3 after the twice administrations compared with that at the single administration was the highest with G3 . These differences in immune responses are discussed in terms of surface density of poly(sarcosine) chains, nanoparticle size, hydrophobic component of poly(L‐lactic acid) or (Leu‐ or Val‐Aib)_n, and membrane elasticity of the nanoparticles. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.     

2-C-Methyl-d-erythritol. Produced in plants,forms aerosols in the atmosphere. An alternative pathway in isoprenoid biosynthesis

2-C-Methyltetritols, or 2-methyl-1,2,3,4-butanetetraols, which exist as four stereoisomers, are found to be present in the atmosphere above the Amazonian rainforest. 2-C-methyl-d-erythritol was originally isolated from Convolvulus glomeratus and later synthesized enantiomerically pure. It has been claimed that these compounds are produced from isoprene by radical oxidation in the atmosphere. More recently, detailed analysis has shown that the mixture of stereoisomers from forests in both Brazil and Sweden contains unequal amounts of enantiomers. This shows that the oxidation must be due to enzymatic activity in plants. A review of the history of these compounds, synthesis and the significance of stereochemistry is given. Moreover, the significance of 2-C-methyl-d-erythritol for the non-mevalonate route to isoprenoids is briefly discussed.     

Small molecule sensitization to TRAIL is mediated via nuclear localization,phosphorylation and inhibition of chaperone activity of Hsp27

The small chaperone protein Hsp27 confers resistance to apoptosis, and therefore is an attractive anticancer drug target. We report here a novel mechanism underlying the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitizing activity of the small molecule {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511, an inactive analog of the phosphoinositide 3-kinase inhibitor inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, in HeLa cells that are refractory to TRAIL-induced apoptosis. On the basis of the fact that {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511 is derived from {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, itself derived from quercetin, and earlier findings indicating that quercetin and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 affected Hsp27 expression, we investigated whether {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511 sensitized cancer cells to TRAIL via a conserved inhibitory effect on Hsp27. We provide evidence that upon treatment with {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511, Hsp27 is progressively sequestered in the nucleus, thus reducing its protective effect in the cytosol during the apoptotic process. {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511-induced nuclear translocation of Hsp27 is linked to its sustained phosphorylation via activation of p38 kinase and MAPKAP kinase 2 and the inhibition of PP2A. Furthermore, Hsp27 phosphorylation leads to the subsequent dissociation of its large oligomers and a decrease in its chaperone activity, thereby further compromising the death inhibitory activity of Hsp27. Furthermore, genetic manipulation of Hsp27 expression significantly affected the TRAIL sensitizing activity of {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511, which corroborated the Hsp27 targeting activity of {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511. Taken together, these data indicate a novel mechanism of small molecule sensitization to TRAIL through targeting of Hsp27 functions, rather than its overall expression, leading to decreased cellular protection, which could have therapeutic implications for overcoming chemotherapy resistance in tumor cells.     

Three new species of Hagnagora Druce, 1885 (Lepidoptera,Geometridae, Larentiinae) from Ecuador and Costa Rica and a concise revision of the genus

Three new Hagnagora Druce species (Geometridae, Larentiinae) are described: Hagnagora richardi Brehm, sp. n. from Ecuador, Hagnagora hedwigae Brehm, sp. n. from Ecuador, and Hagnagora mirandahenrichae Brehm, sp. n. from Costa Rica. A checklist of taxa assigned to Hagnagora is provided. Hagnagora is provisionally divided into six clades: the anicata clade (6 species), the buckleyi clade (3 species), the croceitincta clade (3 species), the ephestris clade (3 species), the mortipax clade (4 species) and Hagnagora subrosea (1 species). Two taxa are revived from synonymy: Hagnagora catagrammina Druce, stat. rev. and Hagnagora luteoradiata Thierry-Mieg, stat. rev. Two taxa are reinstated from subspecies to species level: Hagnagora acothysta Schaus, stat. rev. and Hagnagora jamaicensis Schaus, stat. rev. Four taxa are provisionally removed from Hagnagora: “Hagnagora” ignipennis, “Hagnagora” mesenata, “Hagnagora” vittata, and “Hagnagora” ceraria. After these changes, the genus Hagnagora now comprises 20 valid species.     

Robust regression for clustered data with application to binary responses

Generalized estimating equations (GEE) can be highly influenced by the presence of unusual data points. A generalization of the GEE procedure, which yields parameter estimates and fitted values that are resistant to influential data, is introduced. Resistant generalized estimating equations (REGEE) include weights in the estimating equations to downweight influential observations or clusters. Influential observations are downweighted according to their leverage or residual in an example of correlated binary regression applied to 137 urinary incontinent elderly patients from 38 medical practices.     

Improving aquaporin Z expression in <Emphasis Type="Italic">Escherichia coli</Emphasis> by fusion partners and subsequent condition optimization

Aquaporin Z (AqpZ), a typical orthodox aquaporin with six transmembrane domains, was expressed as a fusion protein with TrxA in E. coli in our previous work. In the present study, three fusion partners (DsbA, GST and MBP) were employed to improve the expression level of this channel protein in E. coli. The result showed that, compared with the expression level of TrxA-AqpZ, five- to 40-fold increase in the productivity of AqpZ with fusion proteins was achieved by employing these different fusion partners, and MBP was the most efficient fusion partner to increase the expression level. By using E. coli C43 (DE3)/pMAL-AqpZ, the effects of different expression conditions were investigated systematically to improve the expression level of MBP-AqpZ in E. coli. The high productivity of MBP-AqpZ (200 mg/l) was achieved under optimized conditions. The present work provides a novel approach to improve the expression level of membrane proteins in E. coli.     

MHC gene configuration variation in geographically disparate populations of California sea lions (Zalophus californianus)

Major histocompatibility complex (MHC) class II DRB genotypes were examined in two geographically isolated populations of California sea lions (Zalophus californianus) (Gulf of California and California coastal Pacific Ocean). Genomic DNA from 227 California sea lions was examined using eight sequence-specific primer (SSP) pairs flanking the putative peptide-binding site. A total of 40 different Zaca-DRB genotype configurations were identified among the 227 individuals. Using SSP-PCR, significant differences were found between coastal California and Gulf of California Zalophus populations in numbers of DRB sequences per individual and configuration of sequences within individuals. Additionally, unique local patterns of MHC diversity were identified among the Midriff Island animals. These population differences are consistent with either ecologically distinct patterns of selection pressures and/or geographical isolation. The consequences of these partitioned MHC configurations at the population level are as yet unknown; however, the worldwide increase in emerging marine diseases lends urgency to their examination.     

Topoisomerase I‐Mediated Antiproliferative Activity of 10‐Substituted and 12‐Substituted Homocamptothecins

Homocamptothecin (hCPT) is an E‐ring modified camptothecin (CPT) analogue, which showed pronounced inhibitory activity of topoisomerase I. In search of novel hCPT‐type anticancer agents, two series of hCPT derivatives were synthesized and evaluated in vitro against three human tumor cell lines. The results indicated that the 10‐substituted hCPT derivatives had a considerably higher cytotoxic activity than the 12‐substituted ones. Among the 10‐substituted compounds, 8a, 8b, 9b , and 9i showed an equivalent or even more potent activity than the positive control drug topotecan against the lung cancer cell line A‐549. Moreover, the hCPT analogues 8a and 8b exhibited a higher topoisomerase I inhibitory activity than CPT at a concentration of 100 μM .