Independent and complementary bio-functional effects of CuO and Ga2O3 incorporated as therapeutic agents in silica- and phosphate-based bioactive glasses

The incorporation of therapeutic-capable ions into bioactive glasses (BGs), either based on silica (SBGs) or phosphate (PBGs), is currently envisaged as a proficient path for facilitating bone regeneration. In conjunction with this view, the single and complementary structural and bio-functional roles of CuO and Ga2O3 (in the 2–5 mol% range) were assessed, by deriving a series of SBG and PBG formulations starting from the parent glass systems, FastOs®BG – 38.5SiO2—36.1CaO—5.6P2O5—19.2MgO—0.6CaF2, and 50.0P2O5—35.0CaO—10.0Na2O—5.0 Fe2O3 (mol%), respectively, using the process of melt-quenching. The inter-linked physico-chemistry – biological response of BGs was assessed in search of bio-functional triggers. Further light was shed on the structural role – as network former or modifier – of Cu and Ga, immersed in SBG and PBG matrices. The preliminary biological performance was surveyed in vitro by quantification of Cu and Ga ion release under homeostatic conditions, cytocompatibility assays (in fibroblast cell cultures) and antibacterial tests (against Staphylococcus aureus). The similar (Cu) and dissimilar (Ga) structural roles in the SBG and PBG vitreous networks governed their release. Namely, Cu ions were leached in similar concentrations (ranging from 10–35 ppm and 50–110 ppm at BG doses of 5 and 50 mg/mL, respectively) for both type of BGs, while the release of Ga ions was 1–2 orders of magnitude lower in the case of SBGs (i.e., 0.2–6 ppm) compared to PBGs (i.e., 9–135 ppm). This was attributed to the network modifier role of Cu in both types of BGs, and conversely, to the network former (SBGs) and network modifier (PBGs) roles of Ga. All glasses were cytocompatible at a dose of 5 mg/mL, while at the same concentration the antimicrobial efficiency was found to be accentuated by the coupled release of Cu and Ga ions from SBG. By collective assessment, the most prominent candidate material for the further development of implant coatings and bone graft substitutes was delineated as the 38.5SiO2—34.1CaO—5.6P2O5—16.2MgO—0.6CaF2—2.0CuO—3.0Ga2O3 (mol%) SBG system, which yielded moderate Cu and Ga ion release, excellent cytocompatibility and marked antibacterial efficacy.publishe

Financial stability, wealth effects and optimal macroeconomic policy combination in the United Kingdom: A New-Keynesian Dynamic Stochastic General Equilibrium Framework

This study derives an optimal macroeconomic policy combination for financial sector stability in the United Kingdom by employing a New Keynesian Dynamic Stochastic General Equilibrium (NK-DSGE) framework. The empirical results obtained show that disciplined fiscal and accommodative monetary policies stance is optimal for financial sector stability. Furthermore, fiscal indiscipline countered by contractionary monetary stance adversely affects financial sector stability. Financial markets, e.g. stocks and Gilts show a short-term asymmetric response to macroeconomic policy interaction and to each other. The asymmetry is a reflection of portfolio adjustment. However in the long-run, the responses to suggested optimal policy combination had homogenous effects and there was evidence of co-movement in the stock and Gilt markets

Maintaining natural and traditional cultural green infrastructures across Europe: learning from historic and current landscape transformations

CONTEXT: Maintaining functional green infrastructures (GIs) require evidence-based knowledge about historic and current states and trends of representative land cover types. OBJECTIVES: We address: (1) the long-term loss and transformation of potential natural forest vegetation; (2) the effects of site productivity on permanent forest loss and emergence of traditional cultural landscapes; (3) the current management intensity; and (4) the social-ecological contexts conducive to GI maintenance. METHODS: We selected 16 case study regions, each with a local hotspot landscape, ranging from intact forest landscapes, via contiguous and fragmented forest covers, to severe forest loss. Quantitative open access data were used to estimate (i) the historic change and (ii) transformation of land covers, and (iii) compare the forest canopy loss from 2000 to 2018. Qualitative narratives about each hotspot landscape were analysed for similarities (iv). RESULTS: While the potential natural forest vegetation cover in the 16 case study regions had a mean of 86%, historically it has been reduced to 34%. Higher site productivity coincided with transformation to non-forest land covers. The mean annual forest canopy loss for 2000–2018 ranged from 0.01 to 1.08%. The 16 case studies represented five distinct social-ecological contexts (1) radical transformation of landscapes, (2) abuse of protected area concepts, (3) ancient cultural landscapes (4) multi-functional forests, and (5) intensive even-aged forest management, of which 1 and 4 was most common. CONCLUSIONS: GIs encompass both forest naturalness and traditional cultural landscapes. Our review of Pan-European regions and landscapes revealed similarities in seemingly different contexts, which can support knowledge production and learning about how to sustain GIs

Nanoparticle display of neuraminidase elicits enhanced antibody responses and protection against influenza A virus challenge

Current Influenza virus vaccines primarily induce antibody responses against variable epitopes in hemagglutinin (HA), necessitating frequent updates. However, antibodies against neuraminidase (NA) can also confer protection against influenza, making NA an attractive target for the development of novel vaccines. In this study, we aimed to enhance the immunogenicity of recombinant NA antigens by presenting them multivalently on a nanoparticle carrier. Soluble tetrameric NA antigens of the N1 and N2 subtypes, confirmed to be correctly folded by cryo-electron microscopy structural analysis, were conjugated to Mi3 self-assembling protein nanoparticles using the SpyTag-SpyCatcher system. Immunization of mice with NA-Mi3 nanoparticles induced higher titers of NA-binding and -inhibiting antibodies and improved protection against a lethal challenge compared to unconjugated NA. Additionally, we explored the co-presentation of N1 and N2 antigens on the same Mi3 particles to create a mosaic vaccine candidate. These mosaic nanoparticles elicited antibody titers that were similar or superior to the homotypic nanoparticles and effectively protected against H1N1 and H3N2 challenge viruses. The NA-Mi3 nanoparticles represent a promising vaccine candidate that could complement HA-directed approaches for enhanced potency and broadened protection against influenza A virus

Measuring Financial Stress and Economic Sensitivity in CEE Countries

This report presents the methodology for the construction of the Financial Stress Index (FSI) and the Economic Sensitivity Index (ESI) and investigates the economic situation in twelve Central and East European Countries (CEECs) between 2001 and 2012. The objective of this paper is to capture key features of financial and economic vulnerability and examine the co-movement of economic turmoil and financial disturbances that strongly affected the CEECs in the last decade. Our main finding is that the FSI can be used as a leading indicator and can be used to recognize changing trends in the index. A shift in the value of the index proves that EU accession has a positive, but minor influence on financial stability in the CEECs. On the other hand, the impact of the introduction of the euro in Estonia, Slovakia and Slovenia is ambiguous. For most of the countries in our sample, in 2007, the FSI started to grow rapidly, reaching its peak around the third quarter of 2008. Consequently, financial stress remained high for a few quarters and started to fall gradually. For a number of countries, we observe higher financial stress in the latest period of our analysis, i.e. 2010-2012. However, the value of the FSI was significantly lower than three years earlier. The results show that indices might be helpful in predicting future recessions. However, forecasting properties seem to be limited at this stage of our work

Macroeconomic policy interaction: State dependency and implications for financial stability in UK: A systemic review

The association between economic and financial stabilities and influence of macroeconomic policies on the financial sector creates scope of active policy role in financial stability. As a contribution to the existing body of knowledge, this study has analysed the implications of macroeconomic policy interaction/coordination for financial stability, proxied by financial assets, i.e. equity and bonds price oscillation. The critical review and analysis of the existing literature on the subject suggests that there is also ample evidence of interdependence between monetary and fiscal policies and this interrelation necessitates coordination between them for the sake of financial stability. There is also a case for analysing the symmetry of financial markets responses to macroeconomic policy interaction. On methodological and empirical grounds, it is vital to test the robustness of policy recommendations to overcome the limitation of a single empirical approach (Jeffrey–Lindley’s paradox). Hence, the Frequentist and Bayesian approaches should be used in commentary manner. The policy interaction and optimal policy combination should also be analysed in the context of institutional design and major financial events to gain insight into the implications of policy interaction in the periods of stable economic and financial environments as well as period of financial and economic distress

Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals

Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan solenodon (Solenodon paradoxus). We constructed a genome to underpin proteomic identifications of solenodon venom toxins, before undertaking evolutionary analyses of those constituents, and functional assessments of the secreted venom. Our findings show that solenodon venom consists of multiple paralogous kallikrein 1 (KLK1) serine proteases, which cause hypotensive effects in vivo, and seem likely to have evolved to facilitate vertebrate prey capture. Comparative analyses provide convincing evidence that the oral venom systems of solenodons and shrews have evolved convergently, with the 4 independent origins of venom in eulipotyphlans outnumbering all other venom origins in mammals. We find that KLK1s have been independently coopted into the venom of shrews and solenodons following their divergence during the late Cretaceous, suggesting that evolutionary constraints may be acting on these genes. Consequently, our findings represent a striking example of convergent molecular evolution and demonstrate that distinct structural backgrounds can yield equivalent functions

A diarylamine derived from anthranilic acid inhibits ZIKV replication

Zika virus (ZIKV) is a mosquito-transmitted Flavivirus, originally identified in Uganda in 1947 and recently associated with a large outbreak in South America. Despite extensive efforts there are currently no approved antiviral compounds for treatment of ZIKV infection. Here we describe the antiviral activity of diarylamines derived from anthranilic acid (FAMs) against ZIKV. A synthetic FAM (E3) demonstrated anti-ZIKV potential by reducing viral replication up to 86%. We analyzed the possible mechanisms of action of FAM E3 by evaluating the intercalation of this compound into the viral dsRNA and its interaction with the RNA polymerase of bacteriophage SP6. However, FAM E3 did not act by these mechanisms. In silico results predicted that FAM E3 might bind to the ZIKV NS3 helicase suggesting that this protein could be one possible target of this compound. To test this, the thermal stability and the ATPase activity of the ZIKV NS3 helicase domain (NS3Hel) were investigated in vitro and we demonstrated that FAM E3 could indeed bind to and stabilize NS3Hel