Cholesteryl ester transfer protein and hyperalphalipoproteinemia in Caucasians

It is unclear whether cholesteryl ester transfer protein (CETP) contributes to high density lipoprotein cholesterol (HDL-C) levels in hyperalphalipoproteinemia (HALP) in Caucasians. Moreover, even less is known about the effects of hereditary CETP deficiency in non-Japanese. We studied 95 unrelated Caucasian individuals with HALP. No correlations between CETP concentration or activity and HDL-C were identified. Screening for CETP gene defects led to the identification of heterozygosity for a novel splice site mutation in one individual. Twenty-five heterozygotes for this mutation showed reduced CETP concentration (-40%) and activity (-50%) and a 35% increase of HDL-C compared with family controls. The heterozygotes presented with an isolated high HDL-C, whereas the remaining subjects exhibited a typical high HDL-C/low-triglyceride phenotype. The increase of HDL-C in the CETP-deficient heterozygotes was primarily attributable to increased high density lipoprotein containing apolipoprotein A-I and A-II (LpAI:AII) levels, contrasting with an increase in both high density lipoprotein containing apolipoprotein A-I only and LpAI:AII in the other group. This study suggests the absence of a relationship between CETP and HDL-C levels in Caucasians with HALP. The data furthermore indicate that genetic CETP deficiency is rare among Caucasians and that this disorder presents with a phenotype that is different from that of subjects with HALP who have no mutation in the CETP gene.     

Parasitic hymenoptera fauna on agromyzidae (diptera) colonizing weeds in ecological compensation areas in northern Italian agroecosystems

Parasitoids (Hymenoptera) associated with agromyzid leafminers (Diptera: Agromyzidae) were studied in three rural farms located in northern Italy. The parasitoids were reared from mined foliage of weeds growing in field margins. We reared 998 Hymenoptera specimens, representing five families, 23 genera, and 53 species, from leafminers infesting weeds. Eulophidae was the most abundant family (67.64%), followed by Braconidae (28.86%), Eucoilinae (1.40%), Tetracampidae (1.40%), and Pteromalidae (0.7%). Braconids was the most species rich family, accounting for 28 species; eulophids were represented by 19 species, pteromalids by four species, and eucoilins and tetracampids by one species each. The dominant parasitoid was the eulophid Pediobius metallicus (Nees), representing 18.17% of the total, followed by Diglyphus isaea (Walker) (12.73%), and Neochrysocharis formosa (Westwood) (10.82%). The most abundant braconid parasitoid was Dacnusa maculipes Thomson (9.62%). More than 80% of parasitoids were recovered from 10 plant species: Cirsium arvense (L.) Scopoli, Plantago lanceolata L., Sonchus asper (L.) Hill, Papaver rhoeas L., Picris echioides L., Lactuca serriola L., Myagrum perfoliatum L., Ranunculus velutinus Tenore, Arctium lappa L., and Medicago sativa L. The retention and the management of wild plants within field margins can be crucial tools to enhance the populations of biological control agents of agromyzids and to conserve rare parasitic wasp species.     

The Spn4 gene from Drosophila melanogaster is a multipurpose defence tool directed against proteases from three different peptidase families

By alternative use of four RSL (reactive site loop) coding exon cassettes, the serpin (serine protease inhibitor) gene Spn4 from Drosophila melanogaster was proposed to enable the synthesis of multiple protease inhibitor isoforms, one of which has been shown to be a potent inhibitor of human furin. Here, we have investigated the inhibitory spectrum of all Spn4 RSL variants. The analyses indicate that the Spn4 gene encodes inhibitors that may inhibit serine proteases of the subtilase family (S8), the chymotrypsin family (S1), and the papain-like cysteine protease family (C1), most of them at high rates. Thus a cohort of different protease inhibitors is generated simply by grafting enzyme-adapted RSL sequences on to a single serpin scaffold, even though the target proteases contain different types and/or a varying order of catalytic residues and are descendents of different phylogenetic lineages. Since all of the Spn4 RSL isoforms are produced as intracellular residents and additionally as variants destined for export or associated with the secretory pathway, the Spn4 gene represents a versatile defence tool kit that may provide multiple antiproteolytic functions.     

In vivo and in vitro activity and mechanism of action of the multidrug cytarabine-L-glycerylyl-fluorodeoxyuridine

Multidrugs have the potential to bypass resistance. We investigated the in vitro activity and resistance circumvention of the multidrug cytarabine-L-fluorodeoxyuridine (AraC-L-5FdU), linked via a glycerophospholipid linkage. Cytotoxicity was determined using sensitive (A2780, FM3A/0) and resistant (AG6000, AraC resistant, deoxycytidine kinase deficient; FM3A/TK-, 5FdU resistant, thymidine kinase deficient) cell lines. Circumvention of nucleoside transporter and activating enzymes was determined using specific inhibitors, HPLC analysis and standard radioactivity assays. AraC-L-5FdU was active (IC50: 0.03 microM in both A2780 and FM3A/0), had some activity in AG6000 (IC50: 0.28 microM), but no activity in FM3A/TK(-) (IC50: 18.3 microM). AraC-nucleotides were not detected in AG6000. 5FdU-nucleotides were detected in all cell lines. AraC-L-5FdU did not inhibit TS in FM3A/TK(-) (5%). Since phosphatase/nucleotidase-inhibition reduced cytotoxicity 7-70-fold, cleavage seems to be outside the cell, presumably to nucleotides, and then to nucleosides. The multidrug was orally active in the HT-29 colon carcinoma xenografts which are resistant toward the single drugs.     

Application of a two‐pool model to soil carbon dynamics under elevated CO2

Elevated atmospheric CO₂ concentrations increase plant productivity and affect soil microbial communities, with possible consequences for the turnover rate of soil carbon (C) pools and feedbacks to the atmosphere. In a previous analysis (Van Groenigen et al., 2014), we used experimental data to inform a one‐pool model and showed that elevated CO₂ increases the decomposition rate of soil organic C, negating the storage potential of soil. However, a two‐pool soil model can potentially explain patterns of soil C dynamics without invoking effects of CO₂ on decomposition rates. To address this issue, we refit our data to a two‐pool soil C model. We found that CO₂ enrichment increases decomposition rates of both fast and slow C pools. In addition, elevated CO₂ decreased the carbon use efficiency of soil microbes (CUE), thereby further reducing soil C storage. These findings are consistent with numerous empirical studies and corroborate the results from our previous analysis. To facilitate understanding of C dynamics, we suggest that empirical and theoretical studies incorporate multiple soil C pools with potentially variable decomposition rates.     

Parasitoid diversity reduces the variability in pest control services across time on farms

Recent declines in biodiversity have increased interest in the link between biodiversity and the provision and sustainability of ecosystem services across space and time. We mapped the complex network of interactions between herbivores and parasitoids to examine the relationship between parasitoid species richness, functional group diversity and the provision of natural pest control services. Quantitative food webs were constructed for 10 organic and 10 conventional farms. Parasitoid species richness varied from 26 to 58 species and we found a significant positive relationship between parasitoid species richness and temporal stability in parasitism rates. Higher species richness was associated with lower variation in parasitism rate. A functional group analysis showed significantly greater parasitoid species complementarity on organic farms, with on average more species in each functional group. We simulated parasitoid removal to predict whether organic farms experienced greater robustness of parasitism in the face of local extinctions. This analysis showed no consistent differences between the organic and conventional farm pairs in terms of loss of pest control service. Finally, it was found that the different habitats that make up each farm do not contribute equally to parasitoid species diversity, and that hedgerows produced more parasitoid species, significantly more so on organic farms.     

Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man

Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.     

A polymorphism in the splice donor site of ZNF419 results in the novel renal cell carcinoma-associated minor histocompatibility antigen ZAPHIR

Nonmyeloablative allogeneic stem cell transplantation (SCT) can induce remission in patients with renal cell carcinoma (RCC), but this graft-versus-tumor (GVT) effect is often accompanied by graft-versus-host disease (GVHD). Here, we evaluated minor histocompatibility antigen (MiHA)-specific T cell responses in two patients with metastatic RCC who were treated with reduced-intensity conditioning SCT followed by donor lymphocyte infusion (DLI). One patient had stable disease and emergence of SMCY.A2-specific CD8+ T cells was observed after DLI with the potential of targeting SMCY-expressing RCC tumor cells. The second patient experienced partial regression of lung metastases from whom we isolated a MiHA-specific CTL clone with the capability of targeting RCC cell lines. Whole genome association scanning revealed that this CTL recognizes a novel HLA-B7-restricted MiHA, designated ZAPHIR, resulting from a polymorphism in the splice donor site of the ZNF419 gene. Tetramer analysis showed that emergence of ZAPHIR-specific CD8+ T cells in peripheral blood occurred in the absence of GVHD. Furthermore, the expression of ZAPHIR in solid tumor cell lines indicates the involvement of ZAPHIR-specific CD8+ T cell responses in selective GVT immunity. These findings illustrate that the ZNF419-encoded MiHA ZAPHIR is an attractive target for specific immunotherapy after allogeneic SCT.