Influenza A virus (IAV) encodes a polymerase composed of three subunits: PA, with endonuclease activity, PB1 with polymerase activity and PB2 with host RNA five-prime cap binding site. Their ...cooperation and stepwise activation include a process called cap-snatching, which is a crucial step in the IAV life cycle. Reproduction of IAV can be blocked by disrupting the interaction between the PB2 domain and the five-prime cap. An inhibitor of this interaction called pimodivir (VX-787) recently entered the third phase of clinical trial; however, several mutations in PB2 that cause resistance to pimodivir were observed. First major mutation, F404Y, causing resistance was identified during preclinical testing, next the mutation M431I was identified in patients during the second phase of clinical trials. The mutation H357N was identified during testing of IAV strains at Centers for Disease Control and Prevention. We set out to provide a structural and thermodynamic analysis of the interactions between cap-binding domain of PB2 wild-type and PB2 variants bearing these mutations and pimodivir. Here we present four crystal structures of PB2-WT, PB2-F404Y, PB2-M431I and PB2-H357N in complex with pimodivir. We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors.
The interest rate pass‐through describes how changes in a reference rate (the monetary policy, money market or T‐bill rate) transmit to bank lending rates. We review the empirical literature on the ...interest rate pass‐through and systematize it by means of meta‐analysis and meta‐regressions. Using the pass‐through to corporate lending rates as the baseline, we find systematically lower estimated pass‐through coefficients in studies that focus on the pass‐through to consumer lending rates and rates on long‐term loans. Also studies estimating the pass‐through by averaging all lending rates into one category report a lower pass‐through. Importantly, the interest rate pass‐through is significantly influenced by the country's macro‐financial environment. In economies with deepening stock markets, the estimated pass‐through strengthens significantly. Interestingly, after the global financial crisis, the pass‐through weakened across the board, including because of growing trade openness and supply chain financing, rising volatility and stock market turnovers, as well as declining central bank independence. Inflation targeting frameworks, if in place, helped diminish this pass‐through weakening.
This paper assesses how changes in the monetary policy rate affect the lending rates for the small and medium enterprise (SME), consumer, mortgage, and corporate loans in the Czech Republic—a ...high-income, OECD country. It further examines whether such interest rate pass-through is stable or could vary at different levels of bank competition, leverage, non-performing loans, and foreign exchange (FX) interventions. Using the co-integration approach, we find a significant and complete pass-through for SME lending rates. For consumer lending rates, we estimate the pass-through as unreliable. For both the mortgage and corporate rates, the pass-through shows significant structural shifts that can be entirely and largely explained by bank deleveraging. The markup for all lending rates, except for the corporate rates, increases with a growing spread between the government bond and monetary policy rates. FX interventions mostly affect the markups for corporate and SME rates.
•We assess how the monetary policy rate affects retail and corporate lending rates in the Czech Republic.•We allow the pass-through to possibly vary with the changing macro-financial environment (determinants).•We find a complete pass-through for SME lending rates, and an unreliable pass-through for consumer lending rates.•We identify significant structural shifts in the pass-through for mortgage and corporate lending rates.•These structural shifts can be entirely and largely explained by bank deleveraging (level of capitalization).
This paper provides research on the theme of the political budget cycles. The goal is to find out whether or not the government tries to manipulate the state budget and its components for the purpose ...of re-election across the countries of the European Union. In order to verify this theory a dynamic panel data model was used. The results were significant, but only if predetermined elections were not counted into the estimations. In that case, the theory of the political budget cycles could be accepted as valid for the EU countries. The main driving force of the political budget cycles across the countries of the European Union is fluctuation of the government expenditures. During the election year, the government expenditures are higher, and a year after the election, government expenditures are lower. This is reflected into the state budget balance.
Waste management has still been a developing and progressing field, which demands continual improvements in waste transportation as well as proper selection of locations and technical operation of ...new treatment facilities. Most of research papers on waste management planning have been dealing with optimisation of network flows, thus minimising the cost and improving economic criteria. The shortest paths to treatment facilities are considered together with detailed analysis of their operation including heat and electricity demands in their vicinity. The tasks sometimes include social and global environmental criterions, however, the direct local consequences also play an important role and should be examined. A decision-making strategy in waste management updated with the local emission impact on the population is proposed in this paper. The paper focuses on the first move in analysing the production, dispersion, and impact of pollutants, originating in transport, with regards to the population living close to routes. The calculation of emission produced during the transport of waste takes into consideration the altitude profiles of routes, container loads, and specific types of vehicles. The consecutive estimated impact on the population reckons with the distances between routes and municipalities as well as their sizes in terms of the numbers of inhabitants, where the transportation routes are divided into smaller segments and dispersion is limited with threshold value. The proposed approach describing the emission effect has been tested using real-life operating data corresponding to the specific, 81 km long route along which approximately 25 t of waste is transported 800 times a year. The impact of pollutants on the population was evaluated and discussed. Results of the analysis were quantified for this route to create an edge characterisation needed for further calculations. This approach applied to the whole network then yields input data needed for future research of novel strategies in facility location problems. Other possible extensions of the presented approach include more accurate dispersion function or detailed calculation of the impact of pollutants with respect to specific locations of residential houses.
•Local environmental impacts should be considered when siting waste treatment facilities using reverse logistic models.•A local-based method for impact of emission produced from transport and facility is proposed with regards to the population.•The new procedure is tested through a small case study using real data with edge impact results.
The authors present their contribution to the improvement of methods suitable for the detection of the freezing and thawing damage of cells of cryopreserved venous grafts used for lower limb ...revascularization procedures. They studied the post-thaw viability of cells of the wall of cryopreserved venous grafts (CVG) immediately after thawing and after 24 and 48 h culture at +37 °C in two groups of six CVG selected randomly for slow thawing in the refrigerator and rapid thawing in a water bath at +37 °C. The grafts were collected from multi-organ and tissue brain-dead donors, cryopreserved, and stored in a liquid nitrogen vapor phase for five years. The viability was assessed from tissue slices obtained by perpendicular and longitudinal cuts of the thawed graft samples using in situ staining with fluorescence vital dyes. The mean and median immediate post-thaw viability values above 70% were found in using both thawing protocols and both types of cutting. The statistically significant decline in viability after the 48-h culture was observed only when using the slow thawing protocol and perpendicular cutting. The possible explanation might be the “solution effect damage” during slow thawing, which caused a gentle reduction in the graft cellularity. The possible influence of this phenomenon on the immunogenicity of CVG should be the subject of further investigations.
Discovering Mathematics presents how advanced mathematical software can aid all stages of reasoning while the mathematical content remains in foreground. The text explores the ways software can ...contribute to deeper understanding, widening the scope of teaching for students and teachers alike.
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