The development of recombinant Adenoviral vaccines to target pneumovirus infection

Respiratory Syncytial Virus (RSV) is a member of the pneumovirus genus (family Paramyxoviridae, subfamily Pneumovirinae). RSV is an important respiratory virus of both infants and the elderly, representing an underappreciated burden on health care systems. In addition, re-infections can occur despite the presence of pre-existing immunity, suggesting that immunological memory to RSV is incomplete. To date, treatment of RSV infection is limited to the provision of supportive care and no effective vaccine is available. Although several are currently under investigation, these candidates focus upon the delivery of the F and G antigens of RSV to stimulate the immune system, rather than the internal antigens, which may provide cross protection between different subtypes of RSV. Vaccine development has been greatly hindered by the lack of an appropriate animal model in which to study vaccine efficacy and pneumovirus pathogenesis. Pneumonia virus of mice (PVM) is also a member of the Pneumovirus genus and, like RSV infection of humans, causes a bronchiolitis and fatal pneumonia in its natural host, the mouse. PVM has been proposed as an appropriate model system in which to both study pneumovirus pathogenesis and vaccine efficacy. The PVM model system was adapted to investigate a potential vaccination strategy to address the lack of an available RSV vaccine. Replication deficient recombinant adenovirus serotype 5 (rAd5) vectors were constructed which expressed the F, M and N genes of PVM J3666, in addition to a control construct, which expressed the LacZ gene of E. coli. The constructs were administered via the intranasal route to BALB/c mice and were able to elicit complete protection against a lethal dose of pathogenic PVM J3666, in both short-term experiments and in a long-term experiment, up to 20 weeks post immunisation. The protection effect elicited by the constructs was observed when administered in a single dose, and in alternative mouse strains, C3H/He-mg and C57BL/6, which had differing immunity haplotypes. The rAd5 vectors generated a PVM specific IgG humoral response to PVM and Ad5 antigen which did not correlate as the primary mediator of protection. The rAd5 candidate expressing the N gene of PVM was shown to induce IFNγ secreting T-cells. The use of a peptide library of PVM N protein determined that a specific response could be identified towards the amino acids N41-90, N81-130, N161-210 and N281-330. Thus, the PVM infection model of BALB/c mice provides an immunological platform to facilitate the study of RSV and PVM pathogenesis, immunology and vaccine development.EThOS - Electronic Theses Online ServiceMedical Research Council (Great Britain) (MRC)GBUnited Kingdo

Shock vaporization/devolatilization of evaporitic minerals, halite and gypsum, in an open system investigated by a two-stage light gas gun

Dry lakebeds might constitute large volatile reservoirs on Mars. Hypervelocity impacts onto ancient dry lakebeds would have affected the volatile distribution on Mars. We developed a new experimental method to investigate the response of evaporitic minerals (halite and gypsum) to impact shocks in an open system. This technique does not result in chemical contamination from the operation of the gas gun. The technique is termed the two-valve method and the gun system is located in the Planetary Exploration Research Center, Chiba Institute of Technology, Japan. We detected the vaporization of halite at 31 GPa and devolatilization from gypsum at 11 GPa, suggesting that impact-induced volatile release from dry lakebeds has periodically occurred throughout Martian history. The vaporization of halite deposits might have enhanced the production of perchlorates, which are found globally on Mars. The water loss from gypsum possibly explains the coexisting types of Ca-sulfates found in Gale Crater.Comment: 17 pages, 4 figures, 1 supporting information, accepted for publication in Geophysical Research Letter

Suzaku observations of the Hydra A cluster out to the virial radius

We report Suzaku observations of the northern half of the Hydra A cluster out to ~1.4 Mpc, reaching the virial radius. This is the first Suzaku observations of a medium-size (kT ~3 keV) cluster out to the virial radius. Two observations were conducted, north-west and north-east offsets, which continue in a filament direction and a void direction of the large-scale structure of the Universe, respectively. The X-ray emission and distribution of galaxies elongate in the filament direction. The temperature profiles in the two directions are mostly consistent with each other within the error bars and drop to 1.5 keV at 1.5 r_500. As observed by Suzaku in hot clusters, the entropy profile becomes flatter beyond r_500, in disagreement with the r^1.1 relationship that is expected from accretion shock heating models. When scaled with the average intracluster medium (ICM) temperature, the entropy profiles of clusters observed with Suzaku are universal and do not depend on system mass. The hydrostatic mass values in the void and filament directions are in good agreement, and the Navarro, Frenk, and White universal mass profile represents the hydrostatic mass distribution up to ~ 2 r_500. Beyond r_500, the ratio of gas mass to hydrostatic mass exceeds the result of the Wilkinson microwave anisotropy probe, and at r_100, these ratios in the filament and void directions reach 0.4 and 0.3, respectively. We discuss possible deviations from hydrostatic equilibrium at cluster outskirts. We derived radial profiles of the gasmass- to-light ratio and iron-mass-to-light ratio out to the virial radius. Within r_500, the iron-mass-to-light ratio of the Hydra A cluster was compared with those in other clusters observed with Suzaku.Comment: 16 pages, 15 figures; Accepted for publication in PAS

Phospholane-phosphite ligands for Rh catalyzed enantioselective conjugate addition : unusually reactive catalysts for challenging couplings

We would like to thank the University of St Andrews, and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT) for financial support [Ph.D. studentship to SG; Grant code: EP/L016419/1], and the EPSRC for funding of JAF (EP/M003868/1).The use of Rh catalysts derived from a phospholane-phosphite ligand were found to be more productive than the classic rhodium/BINAP system in enantioselective conjugate additions. These catalysts enable the use of lower amounts of aryl boronic acid in an asymmetric arylation reaction that required an impractical excess of nucleophile. This catalyst was also found to enable the coupling of a poorly reactive Michael acceptor, N-CBz-2-3-dehydro-4-piperidone, or the coupling of poorly reactive 2-furyl boronic acids at ambient or near temperatures.Publisher PDFPeer reviewe

Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis

Background: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS. Methods: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence. Results: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin. Conclusions: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence

Incorporation of Mg2+ in surface Ca2+ sites of aragonite: an ab initio study

First-principles calculations of Mg2+-containing aragonite surfaces are important because Mg2+ can affect the growth of calcium carbonate polymorphs. New calculations that incorporate Mg2+ substitution for Ca2+ in the aragonite {001} and {110} surfaces clarify the stability of Mg2+ near the aragonite surface and the structure of the Mg2+-containing aragonite surface. The results suggest that the Mg2+ substitution energy for Ca2+ at surface sites is lower than that in the bulk structure and that Mg2+ can be easily incorporated into the surface sites; however, when Mg2+ is substituted for Ca2+ in sites deeper than the second Ca2+ layer, the substitution energy approaches the value of the bulk structure. Furthermore, Mg2+ at the aragonite surface has a significant effect on the surface structure. In particular, CO3 groups rotate to achieve six-coordinate geometry when Mg2+ is substituted for Ca2+ in the top layer of the {001} surface or even in the deeper layers of the {110} surface. The rotation may relax the atomic structure around Mg2+ and reduces the substitution energy. The structural rearrangements observed in this study of the aragonite surface induced by Mg2+ likely change the stability of aragonite and affect the polymorph selection of CaCO3

Complex motivations of Japanese medical students to an online medical English course during the COVID-19 pandemic [version 2; peer review: 2 approved]

Background: In response to globalism, many East-Asian countries now include a Medical English course in their undergraduate medical education syllabus. Traditional didactic educational culture is a potential barrier for teaching and learning medical English in East-Asian countries. Online technology-based learning has been recognized as an effective instructional strategy for teaching medical English in the East. The purpose of this study was to explore the relationship between the related attribute factors of students' motivation to learn medical English through an online modality. Methods: Of 134 eligible fourth-year medical students who participated in an online medical English course at a Japanese medical school, 105 were enrolled in this single cohort study. The participants completed pre- and post-course surveys regarding their motivation during the course, including perceived academic control and task value, and their assignment scores. A structural equation model was used to examine the hypothesized relationship of constructs, based on control-value theory. Results: The model showed a good fit for the data (χ 2[df=7] = 1.821, p=0.969, CFI = 1.000, RMSEA < 0.001, SRMR < 0.05, GFI = 0.993, AGFI = 0.980). The latent variables of the perceived course achievement related to the observed variables of academic control and task value scale scores, and negatively predicted willingness for self-study after course completion. In addition, the preference of English as the course language negatively predicted willingness for self-study of medical English. Conclusion: Choice of English as the language of instruction and perceived high course achievement negatively predicted students’ motivation for further English self-study after the class. The importance of incorporating the perspective of lifelong learning into the teaching of medical English was recognized