Sequence Defined Disulfide-Linked Shuttle for Strongly Enhanced Intracellular Protein Delivery

Intracellular protein transduction technology is opening the door for a promising alternative to gene therapy. Techniques have to address all critical steps, like efficient cell uptake, endolysosomal escape, low toxicity, while maintaining full functional activity of the delivered protein. Here, we present the use of a chemically precise, structure defined three-arm cationic oligomer carrier molecule for protein delivery. This carrier of exact and low molecular weight combines good cellular uptake with efficient endosomal escape and low toxicity. The protein cargo is covalently attached by a bioreversible disulfide linkage. Murine 3T3 fibroblasts could be transduced very efficiently with cargo nlsEGFP, which was tagged with a nuclear localization signal. We could show subcellular delivery of the nlsEGFP to the nucleus, confirming cytosolic delivery and expected subsequent subcellular trafficking. Transfection efficiency was concentration-dependent in a directly linear mode and 20-fold higher in comparison with HIV-TAT-nlsEGFP containing a functional TAT transduction domain. Furthermore, β-galactosidase as a model enzyme cargo, modified with the carrier oligomer, was transduced into neuroblastoma cells in enzymatically active form

Genome-wide Association Study of Borderline Personality Disorder Reveals Genetic Overlap with Bipolar Disorder, Major Depression and Schizophrenia

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies

Browser selectivity alters post-fire competition between Erica arborea and E. trimera in the sub-alpine heathlands of Ethiopia

Mammalian herbivores have the potential to alter the competitive relations of woody species, if consumption is unevenly distributed between species. At elevations above 3500 m in the southern Ethiopian highlands, vegetation is dominated by Erica arborea and Erica trimera. Both species can potentially grow into short trees, but are burnt on a rotation of 6 to 10 years, and regenerate by re-sprouting from belowground lignotubers. The regenerating scrub is heavily browsed by cattle. We set up browsing exclosures at three burnt sites to quantify the impact of browsing over a three-year period. When protected from browsing, E. trimera had similar or better height growth than Erica arborea, but in browsed vegetation, Erica arborea instead grew taller. Browsing was more intense on E. trimera in the first years after fire, indicating a difference in palatability between the species. We checked if browse quality differed, by analysing shoot contents of acid detergent fibre, protein, phenolics and tannins. Contrary to expectations the preferred E. trimera contained more acid detergent fibre, less protein and had a higher tannin activity than E. arborea. Although the vegetative growth of E. arborea is favoured relative to E. trimera under high browsing pressure, rapid change in abundance would not be expected, since short-interval fire will repeatedly eradicate any gains in vegetative growth. However, within the typical fire return interval of less than 10 years, E. trimera barely reach a reproductive state, whereas E. arborea flower profusely. Under the current regime of fire and browsing this may in the long run be more important than differences in height growth, leading to a gradual increase in the proportion of E. arborea

Defining Insurance Models within Climate Change European Policies

The paper outlines the role of insurance as a political economic tool that can be used to face the issue of climate change. The magnitude of potential loss, the adverse social and economic consequences for millions of people and considerable fiscal strain imposed on the government budget by weather disasters indicate that governments can benefit significantly from the use of insurance instrument that would seamlessly not only cover damage but also incentivate risk reduction behaviours. Looking at the diversity of existing insurance systems in European countries, natural hazards insurance is examined in terms of private and public involvement, taking into account the EU climate change policies framework. The paper analyses the economic efficiency of different insurance models in relation to the informational imperfections, i.e. adverse selection, moral hazard, and market imperfection, i.e. charity hazard and transaction costs. Moreover, the different models are considered for the way they likely affect incentives to address climate change seeking mechanism to facilitate the mitigation of greenhouse gas emissions, the adaptation to the inevitable impacts of climate change, and the development of climate risk financial management. Conclusive remarks are presented about the possible future development of an European insurance system to find an economic efficient response to natural hazards caused by climate change