Heterologous prime-boost-boost immunisation of Chinese cynomolgus macaques using DNA and recombinant poxvirus vectors expressing HIV-1 virus-like particles

Background: There is renewed interest in the development of poxvirus vector-based HIV vaccines due to the protective effect observed with repeated recombinant canarypox priming with gp120 boosting in the recent Thai placebo-controlled trial. This study sought to investigate whether a heterologous prime-boost-boost vaccine regimen in Chinese cynomolgus macaques with a DNA vaccine and recombinant poxviral vectors expressing HIV virus-like particles bearing envelopes derived from the most prevalent clades circulating in sub-Saharan Africa, focused the antibody response to shared neutralising epitopes. Methods: Three Chinese cynomolgus macaques were immunised via intramuscular injections using a regimen composed of a prime with two DNA vaccines expressing clade A Env/clade B Gag followed by boosting with recombinant fowlpox virus expressing HIV-1 clade D Gag, Env and cholera toxin B subunit followed by the final boost with recombinant modified vaccinia virus Ankara expressing HIV-1 clade C Env, Gag and human complement protein C3d. We measured the macaque serum antibody responses by ELISA, enumerated T cell responses by IFN-gamma ELISpot and assessed seroneutralisation of HIV-1 using the TZM-bl beta-galactosidase assay with primary isolates of HIV-1. Results: This study shows that large and complex synthetic DNA sequences can be successfully cloned in a single step into two poxvirus vectors: MVA and FPV and the recombinant poxviruses could be grown to high titres. The vaccine candidates showed appropriate expression of recombinant proteins with the formation of authentic HIV virus-like particles seen on transmission electron microscopy. In addition the b12 epitope was shown to be held in common by the vaccine candidates using confocal immunofluorescent microscopy. The vaccine candidates were safely administered to Chinese cynomolgus macaques which elicited modest T cell responses at the end of the study but only one out of the three macaques elicited an HIV-specific antibody response. However, the antibodies did not neutralise primary isolates of HIV-1 or the V3-sensitive isolate SF162 using the TZM-bl b-galactosidase assay. Conclusions: MVA and FP9 are ideal replication-deficient viral vectors for HIV-1 vaccines due to their excellent safety profile for use in humans. This study shows this novel prime-boost-boost regimen was poorly immunogenic in Chinese cynomolgus macaques

Spatial characterization of wildfire orientation patterns in California

Using 100 years of fire perimeter maps, we investigate the existence of geographical patterns in fire orientation across California. We computed fire perimeter orientation, at the watershed level, using principal component analysis. Circular statistics were used to test for the existence of preferential fire perimeter orientations. Where perimeters displayed preferential orientation, we searched for evidence of orographic channeling by comparing mean fire orientation with watershed orientation. Results show that in California, 49% of the burnt area is associated with watersheds, where fires displayed preferential orientation. From these, 25% of the burnt area is aligned along the NE/SW orientation and 18% in the E/W orientation. In 27 out of 86 watersheds with preferential fire alignment, there is also correspondence between mean fire orientation and watershed orientation. Topographic influence on fire spread and dominant wind patterns during the fire season can account for the consistency in fire perimeter orientation in these regions. Our findings highlight the historical pattern of fire perimeter orientation and identify watersheds with potential orographic channelingThis paper was supported by the Fundação para a Ciência e Tecnologia Ph.D. Grant SFRH/BD/40398/2007. JMCP participated in this research under the framework of research projects “Forest fire under climate, social and economic changes in Europe, the Mediterranean and other fire-affected areas of the world (FUME)”, EC FP7 Grant Agreement No. 243888

Human Ophthalmomyiasis Interna Caused by Hypoderma tarandi, Northern Canada

Human myiasis caused by bot flies of nonhuman animals is rare but may be increasing. The treatment of choice is laser photocoagulation or vitrectomy with larva removal and intraocular steroids. Ophthalmomyiasis caused by Hypoderma spp. should be recognized as a potentially reversible cause of vision loss

Does Board Independence Reduce the Cost of Debt?

Using the passage of the Sarbanes-Oxley Act and the associated change in listing standards as a natural experiment, we find that while board independence decreases the cost of debt when credit conditions are strong or leverage low, it increases the cost of debt when credit conditions are poor or leverage high. We also document that independent directors set corporate policies that increase firm risk. These results suggest that, acting in the interest of shareholders, independent directors are increasingly costly to bondholders with the intensification of the agency conflict between these two stakeholders

Greenspace & Us: Exploring co-design approaches to increase engagement with nature by girls and young women

Nature connection through engagement with greenspaces plays an important role in promoting well-being. In England, certain groups, such as girls and young women from disadvantaged backgrounds, have limited access to high-quality greenspaces and face other barriers to engaging with nature. In Oxfordshire, the County Council has committed to improving access to greenspace and nature for all. In 2022, a group consisting of twenty girls and young women (aged 10–16) from East Oxford not-for- profit organisations, academic institutions and public bodies came together to start an initiative called ‘Greenspace & Us’. The girls and young women participated in six three- hour workshops in February to March 2022. Using the COM-B (Capability, Opportunity, Motivation, Behaviour) approach, we explored the enablers and barriers to girls and young women in Oxford engaging more with nature, which included: increasing equity of access; introducing meaningful co-production; taking safety concerns seriously; making nature normal; promoting the right to play; and increasing the ability to connect with greenspaces.The outputs of this process were synthesised into the ‘Greenspace & Us Manifesto’, which was crafted collectively. Furthermore, these insights were used to design inclusive park furniture, which was later installed in a local park in East Oxford. In this practice-based article, we outline the methods, outcomes as well as the strengths and weaknesses of the engagement, co-design and co-production approaches we used in Greenspace & Us. We hope the insights from our project will support more inclusive and equitable design of greenspaces for all

Eliza Haywoods geschichte des fräuleins Elisabeth Thoughtless (1756): frühe selbsterkenntnis und ehekritik in der englischen ubersetzungsliteratur

Die Tradition, Frauenerleben aus weiblicher Perspektive zum Mittelpunkt eines Romans zu machen, beginnt in Deutschland nicht mit Sophie La Roches Geschichte des Fräuleins von Sternheim (1771), sondern mit den Werken englischer Schriftstellerinnen, die bereits bedeutend früher in deutschen Übersetzungen erschienen und bisher von der Germanistik nicht beachtet worden sind. An Eliza Haywoods Geschichte des Fräuleins Elisabeth Thoughtless (1756) soll hier exemplarisch gezeigt werden, wie in Deutschland Mitte des 18. Jahrhunderts bereits eine Form der Literatur von Frauen erscheint, die die Entwicklung eines weiblichen Charakters zum Mittelpunkt hat. Obwohl der Übersetzer die in diesem Roman enthaltene Kritik an der patriarchalisch geführten Ehe und der Idealisierung der Frau durch eine bewusst gewählte Übersetzungsstrategie abschwächt, um der Leserschaft den für deutsche Verhältnisse zu radikalen Text angenehmer zu machen, ist dieser, von Lessing als das Werk eines Genies bewertete Roman ein Meilenstein in der Literatur von Frauen

UK Parliament Environment, Food and Rural Affairs Select Committee Flooding Inquiry: Written Evidence from Dr Kate Smith et al. (FLO0043)

This submission presents the research conducted within the Energy and Environment Institute at the University of Hull. Our work demonstrates that hazards represented by flooding have multiple dimensions, and that solutions to them need to take these complex inter-relationships into account. The research described below covers both the physical and social impacts of flooding; the recommendations that follow from our work are based on our understanding that flood risk management needs to expand across land-water boundaries at the full range of spatial, temporal and societal scales. Responding to each of the terms of reference in turn, our data shows that the response to flooding needs to start changing now in order to ensure the resilience of our communities, businesses and infrastructure in the future

Research on HIV cure: Mapping the ethics landscape

According to current estimates, 36.7 million people are infected with HIV worldwide. Despite large-scale and growing programs to prevent and treat HIV infection, possible approaches to achieve a cure for HIV infection are of strong interest. In the development of candidate approaches to achieve an HIV cure, issues of future translation to human study participants, evidence-based practice, clinical care, diverse populations, and populations in low- and middle-income countries should all be considered. An HIV cure should be effective, safe, simple, affordable, and scalable. Acceptability research is a critical adjunct to ongoing biomedical HIV cure research efforts. Anticipating some of the ethical and implementation challenges related to HIV cure strategies is necessary before the availability of effective interventions. Ongoing engagement of stakeholders is needed to resolve ethical, logistical, social, cultural, policy, regulatory, and implementation challenges at all stages of the HIV cure research development process

HIV outbreaks among people who inject drugs in Europe, North America and Israel

During 2011–16, HIV outbreaks occurred among people who inject drugs (PWID) in Canada (southeastern Saskatchewan), Greece (Athens), Ireland (Dublin), Israel (Tel Aviv), Luxembourg, Romania (Bucharest), Scotland (Glasgow), and USA (Scott County, Indiana). Factors common to many of these outbreaks included community economic problems, homelessness, and changes in drug injection patterns. The outbreaks differed in size (from under 100 to over 1000 newly reported HIV cases among PWID) and in the extent to which combined prevention had been implemented before, during, and after the outbreaks. Countries need to ensure high coverage of HIV prevention services and coverage higher than the current UNAIDS recommendation might be needed in areas in which short acting drugs are injected. In addition, monitoring of PWID with special attention for changing drug use patterns, risk behaviours, and susceptible subgroups (eg, PWID experiencing homelessness) needs to be in place to prevent or rapidly detect and contain new HIV outbreaks