SorCS2 Controls Functional Expression of Amino Acid Transporter EAAT3 and Protects Neurons from Oxidative Stress and Epilepsy-Induced Pathology

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Intracellular Calcium Deficits in Drosophila Cholinergic Neurons Expressing Wild Type or FAD-Mutant Presenilin

Much of our current understanding about neurodegenerative diseases can be attributed to the study of inherited forms of these disorders. For example, mutations in the presenilin 1 and 2 genes have been linked to early onset familial forms of Alzheimer''s disease (FAD). Using the Drosophila central nervous system as a model we have investigated the role of presenilin in one of the earliest cellular defects associated with Alzheimer''s disease, intracellular calcium deregulation. We show that expression of either wild type or FAD-mutant presenilin in Drosophila CNS neurons has no impact on resting calcium levels but does give rise to deficits in intracellular calcium stores. Furthermore, we show that a loss-of-function mutation in calmodulin, a key regulator of intracellular calcium, can suppress presenilin-induced deficits in calcium stores. Our data support a model whereby presenilin plays a role in regulating intracellular calcium stores and demonstrate that Drosophila can be used to study the link between presenilin and calcium deregulation.     

Salicylic acid accumulation as a result of Cu,Zn, Cd and Pb interactions in common reed (<Emphasis Type="Italic">Phragmites australis</Emphasis>) growing in natural ecosystems

Common reed (Phragmites australis (Cav.) Trin. ex Steud.) plants were harvested from four natural water ecosystems of the Bogdanka river catchment (Poznań, Poland) four times throughout the 2014 vegetative season. Over the year, average metal contents followed different decreasing trends according to the analyzed tissue: Zn > Cu ≈ Pb > Cd (rhizomes) and Zn > Pb > Cu > Cd (leaves), and mean translocation ratios (leaves/rhizomes) were found as follows: 0.93, 0.70, 0.65, 0.40 for Zn, Pb, Cd and Cu, respectively. Metal content increased gradually during the growing season, and in the case of Cu, Cd and Pb exceeded the upper limit of average concentration detected in plants from natural ecosystems. However, the content of salicylic acid did not follow the increase of metal accumulation. In rhizomes, the highest production of the metabolite was observed in May and reached 324 ng g^?1 fresh weight (FW) (mean value). Afterwards, a significant drop to 50 ng g^?1 FW was observed. Simultaneously, the highest values of total salicylic acid in P. australis leaves were observed in July and accompanied the intensive development of the aboveground biomass of the plant (11.3 µg g^?1 FW–mean value). Subsequently, its content in leaves showed a significant decrease down to 2.1 µg g^?1 FW in November. Multivariate regression analysis revealed significant interactions between analyzed metals influencing the plant response to metal-derived stress. Cu and Zn showed antagonistic properties considering their uptake and the induction of salicylic acid biosynthesis, whereas non-essential metals (Pb and Cd) acted similarly and stimulated the formation of salicylic acid glucoside.     

MDSCs Mediate Angiogenesis and Predispose Canine Mammary Tumor Cells for Metastasis via IL-28/IL-28RA (IFN-λ) Signaling

Background

Myeloid-derived suppressor cells (MDSCs) function in immunosuppression and tumor development by induction of angiogenesis in a STAT3-dependent manner. Knowledge of MDSC biology is mainly limited to mice studies, and more clinical investigations using spontaneous tumor models are required. Here we performed in vitro experiments and clinical data analysis obtained from canine patients.

Methods

Using microarrays we examined changes in gene expression in canine mammary cancer cells due to their co-culture with MDSCs. Further, using Real-time rt-PCR, Western blot, IHC, siRNA, angiogenesis assay and migration/invasion tests we examined a role of the most important signaling pathway.

Results

In dogs with mammary cancer, the number of circulating MDSCs increases with tumor clinical stage. Microarray analysis revealed that MDSCs had significantly altered molecular pathways in tumor cells in vitro. Particularly important was the detected increased activation of IL-28/IL-28RA (IFN-λ) signaling. The highest expression of IL-28 was observed in stage III/IV mammary tumor-bearing dogs. IL-28 secreted by MDSCs stimulates STAT3 in tumor cells, which results in increased expression of angiogenic factors and subsequent induction of angiogenesis by endothelial cells, epithelial-mesenchymal transition (EMT) and increased migration of tumor cells in vitro. Knockdown of IL-28RA decreased angiogenesis, tumor cell invasion and migration.

Conclusions

We showed for the first time that MDSCs secrete IL-28 (IFN-λ), which promotes angiogenesis, EMT, invasion and migration of tumor cells. Thus, IL-28 may constitute an interesting target for further therapies. Moreover, the similarity in circulating MDSC levels at various tumor clinical stages between canine and human patients indicates canines as a good model for clinical trials of drugs targeting MDSCs.     

Structure requirements for anaerobe processing of azo compounds: Implications for prodrug design

This Letter generalizes the metabolism of the azo class of compounds by Clostridium perfringens, an anaerobe found in the human colon. A recently reported 5-aminosalicylic acid-based prednisolone prodrug was shown to release the drug when incubated with the bacteria, while the para-aminobenzoic acid (PABA) based analogue did not. Instead, it showed a new HPLC peak with a relatively close retention time to the parent which was identified by LCMS as the partially reduced hydrazine product. This Letter investigates azoreduction across a panel of substrates with varying degrees of electronic and steric similarity to the PABA-based compound. Azo compounds with an electron donating group on the azo-containing aromatic ring showed immediate disproportionation to their parent amines without any detection of hydrazine intermediates by HPLC. Compounds containing only electron withdrawing groups are partially and reversibly reduced to produce a stable detectable hydrazine. They do not disproportionate to their parent amines, but regenerate the parent azo compound. This incomplete reduction is relevant to the design of azo-based prodrugs and the toxicology of azo-based dyes.     

Kinetic model of oxidation catalyzed by xanthine oxidase-the final enzyme in degradation of purine nucleosides and nucleotides

A new kinetic model is presented for analysis of experimental data of oxidation process catalyzed by milk xanthine oxidase. The kinetics for two substrates, xanthine and its analog 2-chloroadenine, in a broad pH range (5.8-9.0) are best described by an equation which is a rational function of degree 2:3 and 2:2, respectively.     

Female perception of a partner’s mate value discrepancy and controlling behaviour in romantic relationships

Mate value discrepancy (MVD) between heterosexual partners is an important factor influencing relationship satisfaction which, in turn, has an effect on the quality and the stability of the relationship. Therefore, partners’ involvement in mate retention behaviours, such as controlling behaviours, can be related to MVD and our study aims to determine whether such an association exists. In order to do so, we analysed female perception of MVD and their opinion regarding the intensity of controlling behaviours performed by themselves as well as their romantic partners. Female perception of the intensity of controlling behaviours performed by both partners was the highest in couples where a woman assesses her own mate value (MV) as higher than her partner’s MV and significantly different than in relationships where male MV exceeded those of the female. Our study also indicates that MVD should be taken into account when analysing sex differences in intensities of mate retention behaviours. Finally, we provide evidence supporting the significance of the relationship length for controlling behaviour intensity. Findings are discussed within an evolutionary perspective.