Role of innate signalling pathways in the immunogenicity of alphaviral replicon-based vaccines

<p>Abstract</p> <p>Background</p> <p>Alphaviral replicon-based vectors induce potent immune responses both when given as viral particles (VREP) or as DNA (DREP). It has been suggested that the strong immune stimulatory effect induced by these types of vectors is mediated by induction of danger signals and activation of innate signalling pathways due to the replicase activity. To investigate the innate signalling pathways involved, mice deficient in either toll-like receptors or downstream innate signalling molecules were immunized with DREP or VREP.</p> <p>Results</p> <p>We show that the induction of a CD8⁺T cell response did not require functional TLR3 or MyD88 signalling. However, IRF3, converging several innate signalling pathways and important for generation of pro-inflammatory cytokines and type I IFNs, was needed for obtaining a robust primary immune response. Interestingly, type I interferon (IFN), induced by most innate signalling pathways, had a suppressing effect on both the primary and memory T cell responses after DREP and VREP immunization.</p> <p>Conclusions</p> <p>We show that alphaviral replicon-based vectors activate multiple innate signalling pathways, which both activate and restrict the induced immune response. These results further show that there is a delicate balance in the strength of innate signalling and induction of adaptive immune responses that should be taken into consideration when innate signalling molecules, such as type I IFNs, are used as vaccine adjuvant.</p

Prinos suve mase lucerke u zavisnosti od sorte, faze razvića i otkosa

The main objective of this study was to assess dry matter productivity of different alfalfa cultivars depending on stage of maturity and cut, as well as the optimal time of harvest to achieve the maximum yield. Dry matter yield of alfalfa and red clover depended on all three factors and their interactions. The local variety of alfalfa, K 28, was more productive (from 6,8 to 2,3 t ha-1 from first to fourth cut, and from 3,4 to 5,5 t ha-1 from first to third stage of development) compared to US variety, G+13R+CZ (from 5,9 to 2,2 t ha-1 from first to fourth cut, and from 2,7 to 5,2 t ha-1 from first to third stage of development). The maximum yield of K 28 variety could be achieved by cutting alfalfa five times a year.Cilj ovih istraživanja je bio da se utvrdi produktivnost različitih sorti lucerke u zavisnosti od faze razvića i otkosa, kao i optimalno vreme košenja radi postizanja maksimalnog prinosa. Prinos suve materije lucerke zavisio je od sva tri ispitivana faktora i njihovih interakcija. Domaća sorta lucerke je produktivnija (6,8 do 2,3 t ha-1 od prvog do četvrtog otkosa, odnosno od 3,4 do 5,5 t ha-1 od prve do treće faze razvića) u odnosu na američku (5,9 do 2,2 t ha-1 od prvog do četvrtog otkosa, odnosno od 2,7 do 5,2 t ha-1 od prve do treće faze razvića). Maksimalan prinos sorte K-28 mogao bi se postići kosidbom pet puta godišnje

The need for an integrated multi‐OMICs approach in microbiome science in the food system

Microbiome science as an interdisciplinary research field has evolved rapidly over the past two decades, becoming a popular topic not only in the scientific community and among the general public, but also in the food industry due to the growing demand for microbiome-based technologies that provide added-value solutions. Microbiome research has expanded in the context of food systems, strongly driven by methodological advances in different -omics fields that leverage our understanding of microbial diversity and function. However, managing and integrating different complex -omics layers are still challenging. Within the Coordinated Support Action MicrobiomeSupport (https://www.microbiomesupport.eu/), a project supported by the European Commission, the workshop “Metagenomics, Metaproteomics and Metabolomics: the need for data integration in microbiome research” gathered 70 participants from different microbiome research fields relevant to food systems, to discuss challenges in microbiome research and to promote a switch from microbiome-based descriptive studies to functional studies, elucidating the biology and interactive roles ofmicrobiomes in food systems. A combination of technologies is proposed. This will reduce the biases resulting from each individual technology and result in a more comprehensive view of the biological system as a whole. Although combinations of different datasets are still rare, advanced bioinformatics tools and artificial intelligence approaches can contribute to understanding, prediction, and management of the microbiome, thereby providing the basis for the improvement of food quality and safety

Microbiome-based solutions to address new and existing threats to food security, nutrition, health and agrifood systems' sustainability

In addition to challenges like climate change and biodiversity loss, the sustainability and resilience of agrifood systems worldwide are currently challenged by new threats, such as the COVID-19 pandemic and the Ukraine war. Furthermore, the resilience and sustainability of our agrifood systems need to be enhanced in ways that simultaneously increase agricultural production, decrease post-harvest food losses and food waste, protect the climate, environment and health, and preserve biodiversity. The precarious situation of agrifood systems is also illustrated by the fact that overall, around 3 billion people worldwide still do not have regular access to a healthy diet. This results in various forms of malnutrition, as well as increasing number of people suffering from overweight and obesity, and diet-related, non-communicable diseases (NCDs) around the world. Findings from microbiome research have shown that the human gut microbiome plays a key role in nutrition and diet-related diseases and thus human health. Furthermore, the microbiome of soils, plants, and animals play an equally important role in environmental health and agricultural production. Upcoming, microbiome-based solutions hold great potential for more resilient, sustainable, and productive agrifood systems and open avenues toward preventive health management. Microbiome-based solutions will also be key to make better use of natural resources and increase the resilience of agrifood systems to future emerging and already-known crises. To realize the promises of microbiome science and innovation, there is a need to invest in enhancing the role of microbiomes in agrifood systems in a holistic One Health approach and to accelerate knowledge translation and implementation.YS, KD'H, LL, HS, LO, TK, EM, AM, IS, and AS received funding from the European Union's H2020 Research and Innovation Programme under Grant No. 818116 (Microbiome Support).Peer reviewe

Microbiome ethics, guiding principles for microbiome research, use and knowledge management

peer-reviewedThe overarching biological impact of microbiomes on their hosts, and more generally their environment, reflects the co-evolution of a mutualistic symbiosis, generating fitness for both. Knowledge of microbiomes, their systemic role, interactions, and impact grows exponentially. When a research field of importance for planetary health evolves so rapidly, it is essential to consider it from an ethical holistic perspective. However, to date, the topic of microbiome ethics has received relatively little attention considering its importance. Here, ethical analysis of microbiome research, innovation, use, and potential impact is structured around the four cornerstone principles of ethics: Do Good; Don’t Harm; Respect; Act Justly. This simple, but not simplistic approach allows ethical issues to be communicative and operational. The essence of the paper is captured in a set of eleven microbiome ethics recommendations, e.g., proposing gut microbiome status as common global heritage, similar to the internationally agreed status of major food crops

The Implementation of Managed Entry Agreements in Central and Eastern Europe : Findings and Implications

Funding Information: In Bosnia and Herzegovina, both The Federation of Bosnia and Herzegovina and the Republic of Srpska, also have special funds and budgets in place for the financing of expensive medicines, which are innovative and under patent. Similar earmarked funds are available in Scotland (the New Medicines Fund funded by the Pharmaceutical Price Regulation Scheme [PPRS] rebates) [35] and England (the Cancer Drugs Fund) [36]. However, support for such earmarked funds is mixed. While they facilitate access, critics raised issues about fairness towards other disease areas and patient groups that are not eligible for special funding [3, 39]. Further, the views of a Patient and Clinician Engagement meeting in Scotland [37] and the end-of-life criteria in England [38] offer opportunities for special considerations affecting medicines for end-of-life and very rare conditions to be taken into account in the health technology assessment process. Funding Information: The authors would like to acknowledge Dr. Jan Jones from the Scottish Medicines Consortium, Scotland, for contributing to the discussion with information on Scotland, Drs. Lyudmila Bezmelnitsyna and Anastasia Isaeva for contributing to data collection in Russia and Dr. Kate?ina Podrazilov? from SZP ?R for providing information on the Czech Republic. Alessandra Ferrario was a Research Officer at the LSE Health at the time this research was conducted. She is now a postdoctoral Research Fellow at the Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, USA. Email: [email protected] No sources of funding were used for this study. The authors declare they have no conflicts of interest. However, Di?na Ar?ja, Maria Dimitrova, Jurij F?rst, Ieva Grei?i?t?-Kuprijanov, Iris Hoxha, Arianit Jakupi, Erki Laidm?e, Vanda Markovic-Pekovic, Dmitry Meshkov, Guenka Petrova, Maciej Pomorski and Patricia Vella Bonanno work directly for national health authorities or are advisers to them. Alessandra Ferrario, Tomasz Bochenek, Ileana Mardare, Dominik Tomek, Luka Voncina, Alan Haycox, Panos Kanavos,?Olga L?blov?, and Brian Godman are academics and independent researchers also working with national and regional health authorities and others to improve the quality and efficiency of prescribing, and Tarik Catic, D?vid Dank?,and Tanja Novakovic are involved with pharmaceutical, pharmacoeconomics and outcomes research groups in their countries. Olga L?blov? has also carried out remunerated consultancy activities for A&R Partners, Baxter AG and Instytut Arcana and Ileana Mardare has signed a consulting contract with Ewopharma A.G. Romania. The content of the paper and the conclusions are those of each author and may not necessarily reflect those of any organisation that employs them. Publisher Copyright: © 2017, The Author(s).Background: Managed entry agreements (MEAs) are a set of instruments to facilitate access to new medicines. This study surveyed the implementation of MEAs in Central and Eastern Europe (CEE) where limited comparative information is currently available. Method: We conducted a survey on the implementation of MEAs in CEE between January and March 2017. Results: Sixteen countries participated in this study. Across five countries with available data on the number of different MEA instruments implemented, the most common MEAs implemented were confidential discounts (n = 495, 73%), followed by paybacks (n = 92, 14%), price-volume agreements (n = 37, 5%), free doses (n = 25, 4%), bundle and other agreements (n = 19, 3%), and payment by result (n = 10, >1%). Across seven countries with data on MEAs by therapeutic group, the highest number of brand names associated with one or more MEA instruments belonged to the Anatomical Therapeutic Chemical (ATC)-L group, antineoplastic and immunomodulating agents (n = 201, 31%). The second most frequent therapeutic group for MEA implementation was ATC-A, alimentary tract and metabolism (n = 87, 13%), followed by medicines for neurological conditions (n = 83, 13%). Conclusions: Experience in implementing MEAs varied substantially across the region and there is considerable scope for greater transparency, sharing experiences and mutual learning. European citizens, authorities and industry should ask themselves whether, within publicly funded health systems, confidential discounts can still be tolerated, particularly when it is not clear which country and party they are really benefiting. Furthermore, if MEAs are to improve access, countries should establish clear objectives for their implementation and a monitoring framework to measure their performance, as well as the burden of implementation.publishersversionPeer reviewe

The properties of chromium electrodeposited with programmed currents. Part II. Reversing current

The electrodeposition of chromium in programmed reversing current (RC), was investigated in the regime of high cathodic current density (77 A dm-2) and anodic current density (55 A dm-2). The ratio of the cathodic and anodic time (60 : 1) was used. Chromium was deposed on a steel substrate from a chromic-sulphuric acid solution, during one hour. Anode and cathode were suited in a system of parallel plates. Basic properties of deposits, like thickness, morphology, microhardness, brightness were examined. Surface distribution of the deposits was obtained from the measurements of the thicknesses of the deposits (between 32 and 67 µm). A ferromagnetic non-destructive method was used in the measurements. Based on the results, graphic models of deposit surface distribution were made. Two ranges of the thickness could be seen on the model (range 1 - average thickness 35.1 µm and range 2 - average thickness 57.81 µm). These results were statisticaly analysed by colums, rows and by the whole surface. For the whole specimens, the average thickness was 45.39 µm with a coefficient of variation of 0.2582. The basic properties of the deposits did not change with a variation of the thickness. Because of this, the coatings deposited with the reversing current could be much more considered reliable in wear and corrosion protection systems than ones deposited by direct current

Automated monitoring and control using new data integration paradigm

This paper introduces a new paradigm for data integration where the substation field data recorded by monitoring and protection Intelligent Electronic Devices (IEDs) is used to supplement Remote Terminal Unit (RTU) data for Supervisory Control and Data Acquisition (SCADA) system, which improves SCADA and other applications. This data integration paradigm allows very detailed monitoring of the power system and subsequently a more comprehensive decision making opportunities for the control applications. The data interfacing between the substation IEDs and EMS SCADA database to allow for such integration is elaborated on indicating various issues in using present IEC standards 61850 and 61970 to accomplish the required data interfacing. The paper ends with a discussion of the benefits of such an approach. 1

Indicators of agricultural and rural development in the east central and south-east European countries

© 2020, University of Montenegro. All rights reserved. Rural development is largely determined by the available resources and competitiveness of agriculture. The results achieved in agriculture are a significant factor that affects the improvement of the life quality in rural areas and the efficiency of the rural economy. Hence the indicators of agriculture and rural development are common and inseparable. The main purpose of the paper is systemic analysis of indicators of agriculture and rural development in the East Central and South-East European countries. The heterogeneous structure of the analysed group of countries enables their further division into the European Union (EU) Member States and non-EU countries and consideration of differences in the results achieved in these two subgroups. The methods applied in the paper are descriptive statistics, analysis of variance, cluster analysis and correlation analysis. The results of the research enable evaluation of the relative position of the countries according to the analysed indicators, identification of the countries with relatively better performance, but also the direction and intensity of the link between selected indicators of agricultural and rural development in the analysed group of countries