Vaccine-associated respiratory pathology correlates with viral clearance and protective immunity after immunization with self-amplifying RNA expressing the spike (S) protein of SARS-CoV-2 in mouse models.

In this study, we evaluated the immunogenicity and protective immunity of in vitro transcribed Venezuelan equine encephalitis virus (VEEV TC-83 strain) self-amplifying RNA (saRNA) encoding the SARS-CoV-2 spike (S) protein in wild type (S-WT) and stabilized pre-fusion conformations (S-PP). Immunization with S-WT and S-PP saRNA induced specific neutralizing antibody responses in both K18-Tg hACE2 (K18) and BALB/c mice, as assessed using SARS-CoV-2 pseudotyped viruses. Protective immunity was assessed in challenge experiments. Two immunizations with S-WT and S-PP induced protective immunity, evidenced by lower mortality, lower weight loss and more than one log10 lower subgenomic virus RNA titers in the upper and lower respiratory tracts in both K18 and BALB/c mice. Histopathologic examination of lungs post-challenge showed that immunization with S-WT and S-PP resulted in a higher degree of immune cell infiltration and inflammatory changes, compared with control mice, characterized by high levels of T- and B-cell infiltration. No substantial differences were found in the presence and localization of eosinophils, macrophages, neutrophils, and natural killer cells. CD4 and CD8 T-cell depletion post immunization resulted in reduced lung inflammation post challenge but also prolonged virus clearance. These data indicate that immunization with saRNA encoding the SARS-CoV-2 S protein induces immune responses that are protective following challenge, that virus clearance is associated with pulmonary changes caused by T-cell and B-cell infiltration in the lungs, but that this T and B-cell infiltration plays an important role in viral clearance.

Risk-taking, loss aversion, and performance feedback in dynamic and heterogeneous tournaments.

Within the context of professional football, we examined the impact of the interim game state on risk-taking and performance during a dynamic tournament. This study used 9,256 segments from the top five European football leagues as samples. These segments were derived from 1,826 games played during the 2017-2018 season. Poisson regression was employed to analyze the distinct effects of game state and heterogeneity on performance under pressure. The results indicated that stronger teams tended to increase their attack intensity when facing weaker opponents. However, as their lead expanded, they tended to reduce their attack intensity, particularly in matches with heterogeneous characteristics. Moreover, teams trailing in scores tended to intensify their attacks but achieved little. However, leading teams consistently underperformed in terms of blocked shots and corner kicks. Additionally, tied teams systematically exhibited lower performance in shots on target and free kicks compared to leading teams, despite having a higher motivation to excel. These findings extend our understanding of how risk-taking and performance depend on disclosing information regarding relative performance.

Does success breed success? An investigation of momentum in elite recurve archery.

We investigate the existence of momentum or the "hot hand" phenomenon in recurve archery, in which archers have three shots per set. We collected the performance of archers along with the control variable (player difference) and game data (set score difference, shooting order and game type). We set out to compare the outcome (bullseye, 10 points, probability) and performance (scores of the third shot) in a range of cases with the previous two shots. The most obvious finding to emerge from this study is the powerful evidence for positive momentum in recurve archery. The key finding that hitting the bullseye creates momentum and momentum leads to better performance has been confirmed as the "success breeds success" mechanism. Furthermore, the performance of the third shot is influenced by competitive ability and match importance (Olympic Games or not).

Assessing the impact of hepatitis B immune globulin (HBIG) on responses to hepatitis B vaccine during co-administration.

INTRODUCTION: A hepatitis B vaccination (HepB) series with an initial dose of hepatitis B immune globulin (HBIG) is the recommended prophylaxis for infants born to mothers with chronic hepatitis B virus (HBV) infection and for HBV-exposed persons without known protection. The HepB and HBIG are administered at different sites (limbs). Instances of HepB and HBIG administered at the same site are documented but the impact on immune responses to HepB remains unanswered. METHODS: Newborn and adult BALB/c mice received one dose of HepB at time zero alone or with HBIG in the same or different sites, followed by 2 additional doses of HepB at 3 and 10 weeks (newborn mice) or 4 and 16 weeks (adult mice). To study memory responses mice were given a 4th, booster, dose of HepB at 26 weeks and B cells analyzed. RESULTS: Administration of HepB with HBIG resulted in reduced responses to HepB following the first 2 doses, regardless of site, compared to mice that received HepB only. Lower levels of antibody to HBV surface antigen (anti-HBs) were observed at the end of the 3-dose series (p < 0.0001) in all groups of newborn mice that received HepB and HBIG. In adult mice, this difference was only seen when HepB and HBIG were delivered at the same site. However, following a HepB booster at 26 weeks, HBsAg-specific B-cell expansion and memory phenotype were not impacted by initial HBIG administration CONCLUSION: Administration of HBIG with HepB can delay and reduce responses to HepB in mice. Our findings suggest that the initial circulating levels of HBIG could prevent infection despite an impaired response to vaccine and support the current recommendation of assessing seroprotection after series completion for infants born to HBV carrier mothers, including in cases where vaccine and HBIG are administered incorrectly at the same site.

Downtrends in Offside Offenses Among 'The Big Five' European Football Leagues.

This study examined the evolution of offside offenses and pass performance across a 10-season period in the top five European soccer leagues. Match performance observations (n = 18 259) were analysed for emergent trends. Two-way ANOVA analyses revealed significant league and seasonal differences among the five leagues (medium effect size). The total offside offenses committed during a match experienced a clear decline during the 10 seasons. In contrast, moderate increases were evident for all passing differential variables. Offside offenses per match were higher in the German Bundesliga and Spanish La Liga than in the English Premier League and France Ligue 1. However, the English Premier League had the greatest value in the touch differential, pass differential, successful pass differential, and key pass differential among all leagues. It is important to note that the number of offside offenses fell after the implementation of VAR.

Comparison of Goal Scoring Patterns in "The Big Five" European Football Leagues.

The objective of the study was to compare goal scoring patterns among the "Big Five" European football leagues during the 2009/2010-2018/2019 seasons. A total of 18 pattern dimensions related to the offense pattern, the shooting situation and the scoring time period were evaluated. Kruskal-Wallis analyses revealed significant pattern differences among the five leagues. The Spanish La Liga showed a greater proportion of goals from throw-ins. The English Premier League had a higher tendency to score from corner kicks. The German Bundesliga had the greatest number of goals from counterattacks and indirect free kicks, and the Italian Serie A had the greatest proportion of penalties. Ligue 1's scoring ability is weaker than that of the other leagues, especially Bundesliga. The Bundesliga had an overwhelming advantage in goals scored on big chances with assists, while the Premier League had an advantage in goals scored with assists that were not from big chances. However, the differences among the five leagues in the mean goals scored in the last 15 min and the goals from elaborate attacks and direct free kicks were not statistically significant. These results provide a valuable addition to the knowledge of different goal patterns of each league and allow us to better understand the differences among the leagues.

Differential Effects of Prior Influenza Exposures on H3N2 Cross-reactivity of Human Postvaccination Sera.

BACKGROUND: Effectiveness of seasonal influenza vaccines mainly depends upon how well vaccine strains represent circulating viruses; mismatched strains can lead to reduced protection. Humans have complex influenza exposure histories that increase with age, which may lead to different postvaccination responses to emerging influenza variants. Recent observational studies also suggest that prior vaccination may influence the performance of current seasonal vaccines. METHODS: To elucidate the effects of age and influenza preexposures on cross-reactivity of vaccination-induced human antibodies, we generated antigenic maps based on postvaccination hemagglutination inhibition titers against representative H3 variants circulating during the 2015-2016, 2014-2015, and 2012-2013 influenza seasons. RESULTS: Antigenic maps determined using sera from subjects 18-64 and ≥65 years of age correlated well with each other but poorly with those determined using sera from children. Antigenic maps derived from human postvaccination sera with H1 influenza preexposure also correlated poorly with those derived from sera with neither H1 nor type B influenza preexposure, and the correlation lessened considerably over time. In contrast, antigenic maps derived from human postvaccination sera with only type B influenza preexposure consistently showed good correlation with those derived from sera with neither H1 nor type B influenza preexposure. CONCLUSIONS: Our results suggest an age-specific difference in human postvaccination responses. Our findings also suggest that prior exposure to H1 or type B influenza may differentially affect cross-reactivity of vaccination-induced H3-specific hemagglutination inhibition antibody responses, and consequently might affect vaccine effectiveness. Our study highlights the need to study the impact of prior exposure on influenza vaccine performance.

H3N2 Mismatch of 2014-15 Northern Hemisphere Influenza Vaccines and Head-to-head Comparison between Human and Ferret Antisera derived Antigenic Maps.

The poor performance of 2014-15 Northern Hemisphere (NH) influenza vaccines was attributed to mismatched H3N2 component with circulating epidemic strains. Using human serum samples collected from 2009-10, 2010-11 and 2014-15 NH influenza vaccine trials, we assessed their cross-reactive hemagglutination inhibition (HAI) antibody responses against recent H3 epidemic isolates. All three populations (children, adults, and older adults) vaccinated with the 2014-15 NH egg- or cell-based vaccine, showed >50% reduction in HAI post-vaccination geometric mean titers against epidemic H3 isolates from those against egg-grown H3 vaccine strain A/Texas/50/2012 (TX/12e). The 2014-15 NH vaccines, regardless of production type, failed to further extend HAI cross-reactivity against H3 epidemic strains from previous seasonal vaccines. Head-to-head comparison between ferret and human antisera derived antigenic maps revealed different antigenic patterns among representative egg- and cell-grown H3 viruses characterized. Molecular modeling indicated that the mutations of epidemic H3 strains were mainly located in antibody-binding sites A and B as compared with TX/12e. To improve vaccine strain selection, human serologic testing on vaccination-induced cross-reactivity need be emphasized along with virus antigenic characterization by ferret model.

Zinc deficiency depresses p21 gene expression: inhibition of cell cycle progression is independent of the decrease in p21 protein level in HepG2 cells.

The influence of zinc status on p21 gene expression was examined in human hepatoblastoma (HepG2) cells. Cells were cultured for one passage in a basal medium depleted of zinc to induce severely zinc-deficient (ZD) cells or in basal medium supplemented with 0.4, 4.0, 16, or 32 microM zinc to represent mild zinc deficiency (ZD0.4), the amount of zinc in most normal media (ZN), the normal human plasma zinc level (zinc-adequate; ZA), or the high end of plasma zinc attainable by oral supplementation (ZS), respectively. In ZD and ZD0.4 cells, the nuclear p21 protein level, mRNA abundance, and promoter activity were reduced to 40, 70, and 65%, respectively, of ZN cells. However, p21 protein and mRNA levels, as well as p21 promoter activity, were not altered in ZA and ZS cells compared with ZN cells. Moreover, the amounts of acetylated histone-4 associated with the proximal and distal p21 promoter regions, as a measure of p21 promoter accessibility, were decreased in ZD (73 and 64%, respectively) and ZD0.4 (82 and 77%, respectively) cells compared with ZN cells (100 and 100%, respectively). Thus multiple lines of evidence indicate that the transcriptional process of p21 is downregulated by depressed zinc status in HepG2 cells. Furthermore, the transfection of 5 microg of plasmid cytomegalovirus-p21 plasmid, which constitutively expressed p21, was able to normalize the reduction in p21 protein level and cyclin D1-cdk4 complex activity but not the inhibition of cell growth and G1/S cell cycle progression in ZD cells.

The coexpression of the preS1 (1-42) and the core (1-144) antigen of HBV in E. coli.

OBJECTIVE: To study the therapeutic T cell vaccine for the treatment of chronic hepatitis B by improving the cellular immunization of HBsAg vaccine with the coexpression of the preS1 (1-42) and the Core (1-144) antigen of HBV in E. coli. METHODS: The genes of HBcAg (1-144) and preS1 (1-42) were amplified and fused by PCR. This fused gene was inserted in the prokaryotic expression vector pET-11d and expressed in E. coli. RESULTS: It was showed by SDS-PAGE that the protein molecular weight of the coexpression product was about 20 kD, 20% of all bacteria protein. The monoclonal antibodies against core and preS1 antibody could react with this fused protein by Western-blot technique respectively. The fused gene was verified by sequencing. Under the immune electron microscopy, this fused protein is typical particle of HBcAg but in an aggregated form. CONCLUSION: The results might aid for studying T cell immunotherapeutic vaccine for chronic hepatitis B.