T-cell epitopes with broad population coverage may form the basis for a new generation of SARS-CoV-2 vaccines. However, published studies on immunoprevalence are limited by small test cohorts, low frequencies of antigen-specific cells and lack of data correlating eluted HLA ligands with T-cell responsiveness. As the protective role of pre-existing cross-reactivity to homologous peptides is unclear, we aimed to identify SARS-CoV-2-specific minimal epitopes recognized by CD8 T-cells among 48 peptides eluted from prevalent HLA alleles, and an additional 84 predicted binders, in a large cohort of convalescents (n=83) and pre-pandemic control samples (n=19). We identified nine conserved SARS-CoV-2-specific epitopes restricted by four of the most prevalent HLA class I alleles in the Norwegian study cohort, to which responding CD8 T cells were detected in 70-100% of convalescents expressing the relevant HLA allele. Only two of these were derived from the Spike protein, included in current vaccines. We found a strong correlation between immunoprevalence and immunodominance. Thus, the CD8 T-cell response to SARS-CoV-2 is more focused than previously believed. Using a new algorithm, we predict that a vaccine including these epitopes could induce a T-cell response in 83% of Caucasians.

Low-rise residential and public masonry structures constitute a large portion of the building patrimony, yet they were erected during the massive reconstruction of Southeast Europe after World War II before any design rules existed in the engineering praxis. Unreinforced unconfined masonry buildings (URM) were proven rather vulnerable during stronger earthquake motions in the recent past. To determine lateral strength, stiffness, and capacity of energy dissipation of the URM walls, in-plane tests were performed at the University of Sarajevo. Two full-scale plain walls (233 × 241 × 25 cm) built with solid clay brick and lime-cement mortar and two walls strengthened with RC jacketing on both sides were subjected to cyclic lateral loading under constant vertical precompression. Plain walls failed in shear with a typical cross-diagonal crack pattern. Jacketed walls exhibited rocking with characteristic S-shaped hysteretic curves and significantly larger ductility compared with plain walls. Wallets were tested for modulus of elasticity and compressive strength of masonry and the results showed considerable variations.

The effects of graded sodium chloride (NaCl) concentrations (0-, 50-, 100-, 150-, and 200-mM) on photosynthetic pigment contents in in vitro grown shoots of important medicinal plant species (Centaurium erythraea Rafn) were investigated. Non-transformed, one AtCKX1 and two AtCKX2 transgenic centaury lines, with altered cytokinin profiles, were used in this study. The chlorophyll (Chl) and carotenoid contents differed in the non-transformed and transgenic lines. In general, salinity significantly reduced the Chl a and Chl b contents in comparison to the NaCl-free medium. The lowest Chl content was observed in AtCKX2 transgenic shoots grown on all the culture media. The total carotenoid content was increased in shoots of non-transformed and both AtCKX2 transgenic lines grown in 50-mM NaCl. On the other hand, in concentrations >50-mM NaCl, the total carotenoid content was decreased in all analysed centaury shoots. The Chl a/Chl b ratio in all the shoots increased progressively in the graded NaCl concentrations. Contrarily, the addition of NaCl in the culture medium reduced the Chl/carotenoid ratio in centaury shoots. Taken together, the results of this study partly explained the mode of centaury plant adaptations to salt stress in vitro. Thus, the results on centaury shoots confirmed that the determination of the photosynthetic pigment contents can be a very useful non-destructive screening method in order to discriminate susceptible and resistant plant species/lines to salt stress conditions.

. The limited availability of large image datasets, mainly due to data privacy and differences in acquisition protocols or hardware, is a significant issue in the development of accurate and generalizable machine learning methods in medicine. This is especially the case for Magnetic Resonance (MR) images, where different MR scanners introduce a bias that limits the performance of a machine learning model. We present a novel method that learns to ignore the scanner-related features present in MR images, by introducing specific additional constraints on the latent space. We focus on a real-world classification scenario, where only a small dataset provides images of all classes. Our method Learn to Ignore (L2I) outperforms state-of-the-art domain adaptation methods on a multi-site MR dataset for a classification task between multiple sclerosis patients and healthy controls.

Background Microvascular dysfunction might be a major determinant of clinical deterioration and outcome in patients with hypertrophic cardiomyopathy (HCM). However, long‐term prognostic value of transthoracic Doppler echocardiography (TDE) coronary flow velocity reserve (CFVR) on clinical outcome is uncertain in HCM patients. Therefore, the aim of our study was to assess long‐term prognostic value of CFVR on clinical outcome in HCM population. Methods and Results We prospectively included 150 HCM patients (82 women; mean age 48±15 years). Patients’ clinical characteristics, echocardiographic and CFVR findings (both for left anterior descending [LAD] and posterior descending artery [PD]), were assessed in all patients. The primary outcome was a composite of: HCM related death, heart failure requiring hospitalization, sustained ventricular tachycardia and ischemic stroke. Patients were stratified into 2 subgroups depending on CFVR LAD value: Group 1 (CFVR LAD>2, [n=87]) and Group 2 (CFVR LAD≤2, [n=63]). During a median follow‐up of 88 months, 41/150 (27.3%) patients had adverse cardiac events. In Group 1, there were 8/87 (9.2%), whereas in Group 2 there were 33/63 (52.4%, P<0.001 vs. Group 1) adverse cardiac events. By Kaplan‐Meier analysis, patients with preserved CFVR LAD had significantly higher cumulative event‐free survival rate compared to patients with impaired CFVR LAD (96.4% and 90.9% versus 66.9% and 40.0%, at 5 and 8 years, respectively: log‐rank 37.2, P<0.001). Multivariable analysis identified only CFVR LAD≤2 as an independent predictor for adverse cardiac outcome (HR 6.54; 95% CI 2.83–16.30, P<0.001), while CFVR PD was not significantly associated with outcome. Conclusions In patients with HCM, impaired CFVR LAD (≤2) is a strong, independent predictor of adverse cardiac outcome. When the aim of testing is HCM risk stratification and CFVR LAD data are available, the evaluation of CFVR PD is redundant.

The Seismic Experiment for Interior Structure (SEIS) of the InSight mission to Mars, has been providing direct information on Martian interior structure and dynamics of that planet since it landed. Compared to seismic recordings on Earth, ground motion measurements acquired by SEIS on Mars are made under dramatically different ambient noise conditions, but include idiosyncratic signals that arise from coupling between different InSight sensors and spacecraft components. This work is to synthesize what is known about these signal types, illustrate how they can manifest in waveforms and noise correlations, and present pitfalls in structural interpretations based on standard seismic analysis methods. We show that glitches, a type of prominent transient signal, can produce artifacts in ambient noise correlations. Sustained signals that vary in frequency, such as lander modes which are affected by variations in temperature and wind conditions over the course of the Martian Sol, can also contaminate ambient noise results. Therefore, both types of signals have the potential to bias interpretation in terms of subsurface layering. We illustrate that signal processing in the presence of identified nonseismic signals must be informed by an understanding of the underlying physical processes in order for high fidelity waveforms of ground motion to be extracted. While the origins of most idiosyncratic signals are well understood, the 2.4 Hz resonance remains debated and the literature does not contain an explanation of its fine spectral structure. Even though the selection of idiosyncratic signal types discussed in this paper may not be exhaustive, we provide guidance on best practices for enhancing the robustness of structural interpretations.

Abstract To provide the most comprehensive picture of species phylogeny and phylogeography of European roe deer (Capreolus capreolus), we analyzed mtDNA control region (610 bp) of 1469 samples of roe deer from Central and Eastern Europe and included into the analyses additional 1541 mtDNA sequences from GenBank from other regions of the continent. We detected two mtDNA lineages of the species: European and Siberian (an introgression of C. pygargus mtDNA into C. capreolus). The Siberian lineage was most frequent in the eastern part of the continent and declined toward Central Europe. The European lineage contained three clades (Central, Eastern, and Western) composed of several haplogroups, many of which were separated in space. The Western clade appeared to have a discontinuous range from Portugal to Russia. Most of the haplogroups in the Central and the Eastern clades were under expansion during the Weichselian glacial period before the Last Glacial Maximum (LGM), while the expansion time of the Western clade overlapped with the Eemian interglacial. The high genetic diversity of extant roe deer is the result of their survival during the LGM probably in a large, contiguous range spanning from the Iberian Peninsula to the Caucasus Mts and in two northern refugia.

The antioxidants present in natural food products show a higher antioxidant activity than synthetic one [1]. Polyphenolic compounds are the most important antioxidants in bee honey. Bee honey is the most popular bee product by human [2]. In addition to the polyphenols there are non-phenolic compounds with antioxidant potential, such as proteins, gluconic acid, L-ascorbic acid, hydrogen peroxide, hydroxyl methyl furfural (HMF), Maillard reaction products, etc. The antioxidant activity of honey largely depends on the content of micro biogenic elements. The aims of this paper are to present the complex role of micro biogenic elements in the human. It is especially important to point out micro biogenic elements that can act both as antioxidants and as pro-oxidants, such as Cu. Cu acts as antioxidant because it is an integral part of some enzymes involved in the antioxidant activity of the organism. Cu in honey also acts as a pro-oxidant through Haber-weis reaction with L-ascorbic acid also present in honey. In addition to being an essential micro-nutrient Cu is potentially very hazardous because of the capacity change in oxidation state leading to the initiation of the reaction in which free radicals are formed. Therefore, the balanced intake of copper and other trace elements in the human body is very important. Therefore, changes in the antioxidant activity of food are the result of chemical changes in antioxidant active compounds present in the food product.

This study investigates how global manufacturers offer advanced services, such as outcome-based contracts, to global customers. Offering advanced services requires companies to engage in and manage win–win collaborations with a diverse set of service network partners. However, there is currently a lack of insights into the value co-creation challenges faced by manufacturers’ R&D units and their service network partners. Equally, there is a pressing need for roles to be properly aligned when offering advanced services in global markets. Based on 34 exploratory interviews with respondents from two manufacturers and their six globally dispersed front-end service network partners, this study identifies diverse co-creation challenges related to the provision of advanced services in global markets. The results show that complex collaborations of this nature often do not lead to win–win relationships but rather to less understood win–lose or lose–win scenarios. Our proposed framework unpacks how to manage value co-creation challenges and establish win–win relationships through role alignment. This study’s findings show that the successful provision of advanced services requires manufacturers to play the role of global service orchestrators and service network partners to act as global service integrators. Thus, role alignment provides greater latitude to establish a joint sphere of value co-creation for back-end and front-end actors. We conclude by discussing this paper’s theoretical and practical contributions to the emerging literature on servitization in global markets and global service networks.

Background Diabetes mellitus rates and associated costs continue to rise across Europe enhancing health authority focus on its management. The risk of complications is enhanced by poor glycaemic control, with long-acting insulin analogues developed to reduce hypoglycaemia and improve patient convenience. There are concerns though with their considerably higher costs, but moderated by reductions in complications and associated costs. Biosimilars can help further reduce costs. However, to date, price reductions for biosimilar insulin glargine appear limited. In addition, the originator company has switched promotional efforts to more concentrated patented formulations to reduce the impact of biosimilars. There are also concerns with different devices between the manufacturers. As a result, there is a need to assess current utilisation rates for insulins, especially long-acting insulin analogues and biosimilars, and the rationale for patterns seen, among multiple European countries to provide future direction. Methodology. Health authority databases are examined to assess utilisation and expenditure patterns for insulins, including biosimilar insulin glargine. Explanations for patterns seen were provided by senior-level personnel. Results Typically increasing use of long-acting insulin analogues across Europe including both Western and Central and Eastern European countries reflects perceived patient benefits despite higher prices. However, activities by the originator company to switch patients to more concentrated insulin glargine coupled with lowering prices towards biosimilars have limited biosimilar uptake, with biosimilars not currently launched in a minority of European countries. A number of activities were identified to address this. Enhancing the attractiveness of the biosimilar insulin market is essential to encourage other biosimilar manufacturers to enter the market as more long-acting insulin analogues lose their patents to benefit all key stakeholder groups. Conclusions There are concerns with the availability and use of insulin glargine biosimilars among European countries despite lower costs. This can be addressed.

ABSTRACT Introduction Disease-specific treatments are available only for a minority of patients with genetic epilepsies, while the rest are treated with anticonvulsants, which are ineffective in almost one-third of patients. Areas covered Recently approved and the most effective emerging therapeutics under development for the treatment of genetic epilepsies are overviewed after systematic search and analysis of relevant literature. Expert opinion New and emerging drugs for genetic epilepsies exploit one of the two approaches: inhibiting hyperactive brain foci through blocking excitatory or augmenting inhibitory neurotransmission, or correcting the underlying genetic defect. The first is limited by insufficient selectivity of available compounds, and the second by imperfection of currently used vectors of genetic material, unselective and transient transgene expression. Besides, the treatment may come too late, after structural abnormalities and epilepsy deterioration takes place. However, with recent improvements, we can expect to see soon gradual decline in the number of patients with therapy-resistant genetic epilepsies.

It is well-known that, in the past decades, the burning of fossil fuels was identified as the major cause of climate change. Climate change mitigation is becoming a central concern of global society. Limiting global warming to below 2 °C above the temperature of the pre-industrial period is the key to preserving global ecosystems and providing a secure basis for human activities, as well as reducing excessive environmental change. The ambitions increased at an accelerated pace with a dramatic expansion of net zero-emission targets. Increasing pressure from citizens and society has forced countries to intensify their climate plans, while the private sector has bought a record amount of renewable energy. An energy system based on fossil fuels must be replaced by renewable energy with low carbon emissions with improved energy efficiency. That applies to all consumers of fossil energy: cities, villages, building sectors, industry, transport, agriculture, and forestry. The paper explores and presents the strategy of energy development of renewable energy sources in the world. The application of new technologies that have led to developing renewable energy sources is presented in detail: wind energy, solar energy, small hydropower plants, biomass, and their increase in the total share of energy production, i.e., reduced fossil fuel use in energy production. Investments in new technologies used in renewable energy sources have led to increases in employment worldwide. Analysis of the trend of increased energy production from RES (Renewable Energy Sources) with investment plans, the employment rate for each energy source, and the development of renewable energy sources in the coming period are provided.

Rad govori o važnosti književnih pravaca, književnih vrsta i psihoterapije. Ovdje je prikazano kako jedna biblioterapijska tehnika može pomoći osobama koje imaju problem tj. prikazano je ciljano čitanje bajki kroz knjževnoteorijske pravce, a koje znatno doprinose rješenju problema kao i pomoć u samootkrivanju. Također, prikazan je način na koji se pomaže osobama da svoje nevolje prevaziđu koristeći likove ili situacije u bajkama. Namjera poređenja knjževnoteorijskih pravaca i psihoterapije jste staviti akcenat na važnost saradnje različitih disciplina u pristupu temi – analizi i korisnosti bajki na osnovu različitih književnoteorijskih pristupa, pri čemu su posebno naglašeni terapijski učinci postignuti ovakvim čitanjem. Art terapija je vid rada sa djecom i maloljetnicima koji su u sukobu sa zakonnom. Art terapija kao prevencija, kao intervencija u toku primjene ili izvršenja neke alternativne mjere, alternativne sankcije ili krivične sankcije institucionalnog karaktera. Nošena idejom primjene programa restorativne pravde veliki je broj terapijskih programa koji su na mala ili velika vrata ušli u rad sa djecom i maloljetnicima koji su na određeni način u sukobu sa zakonom. Jedna od njih je i biblioterapija čije „vrijeme tek dolazi“ jer se njena promocija i primjena očekuje. Savremene metode koje koriste bajku u terapijske svrhe otvaraju nove aspekte terapijskog učinka čitanja/slušanja. U tim aspektima bitno je razumjeti znanja iz teorije i prakse psihoterapije kao i književnih teorija i pogledati šta se dešava u psihoterapijskom procesu između klijenata i sadržaja koji nudi bajka, odnosno slušalaca i teksta u procesu čitanja/slušanja. Isto kao što su književne vrste u terapijskoj praksi zanemarene od domaće stručne populacije, susret između prakse čitanja/slušanja i prakse psihoterapije zanemaren je unutar nacionalnih aspekata društvenih i humanističkih znanosti. I upravo taj prostor nedovoljno prepoznatog i neistraženog spoja, ovome radu otvara recepcijske i interpretacijske mogućnosti za moguće i stvarne plodonosne učinke njihovog susreta.