In Vivo Efficacy of a Cocktail of Human Monoclonal Antibodies (CL184) Against Diverse North American Bat Rabies Virus Variants

Following rabies virus (RABV) exposure, a combination of thorough wound washing, multiple-dose vaccine administration and the local infiltration of rabies immune globulin (RIG) are essential components of modern post-exposure prophylaxis (PEP). Although modern cell-culture-based rabies vaccines are increasingly used in many countries, RIG is much less available. The prohibitive cost of polyclonal serum RIG products has prompted a search for alternatives and design of anti-RABV monoclonal antibodies (MAbs) that can be manufactured on a large scale with a consistent potency and lower production costs. Robust in vitro neutralization activity has been demonstrated for the CL184 MAb cocktail, a 1:1 protein mixture of two human anti-RABV MAbs (CR57/CR4098), against a large panel of RABV isolates. In this study, we used a hamster model to evaluate the efficacy of experimental PEP against a lethal challenge. Various doses of CL184 and commercial rabies vaccine were assessed for the ability to protect against lethal infection with representatives of four distinct bat RABV lineages of public health relevance: silver-haired bat (Ln RABV); western canyon bat (Ph RABV); big brown bat (Ef-w1 RABV) and Mexican free-tailed bat RABV (Tb RABV). 42–100% of animals survived bat RABV infection when CL184 (in combination with the vaccine) was administered. A dose-response relationship was observed with decreasing doses of CL184 resulting in increasing mortality. Importantly, CL184 was highly effective in neutralizing and clearing Ph RABV in vivo, even though CR4098 does not neutralize this virus in vitro. By comparison, 19–95% survivorship was observed if human RIG (20 IU/kg) and vaccine were used following challenge with different bat viruses. Based on our results, CL184 represents an efficacious alternative for RIG. Both large-scale and lower cost production could ensure better availability and affordability of this critical life-saving biologic in rabies enzootic countries and as such, significantly contribute to the reduction of human rabies deaths globally

Deliberative multiattribute valuation of ecosystem services across a range of regional land-use, socioeconomic, and climate scenarios for the upper Merrimack River watershed, New Hampshire, USA

We evaluate the relative desirability of alternative futures for the upper Merrimack River watershed in New Hampshire, USA based on the value of ecosystem services at the end of the 21st century as gauged by its present-day inhabitants. This evaluation is accomplished by integrating land-use and socioeconomic scenarios, downscaled climate projections, biogeophysical simulation models, and the results of a citizen-stakeholder deliberative multicriteria evaluation. We find that although there are some trade-offs between alternative plausible futures, for the most part, it can be expected that future inhabitants of the watershed will be most satisfied if land-use planning in the intervening years prioritizes water supply and flood protection as well as maintenance of existing farmland and forest cover. With respect to climate change, it is expected that future watershed inhabitants will be more negatively affected by the projected loss of snow cover than the anticipated increase in hot summer days. More important than the specific results for the upper Merrimack River watershed, this integrative assessment demonstrates the complex yet ultimately informative potential to link stakeholder engagement with scenario generation, ecosystem models, and multiattribute evaluation for informing regional-scale planning and decision making

EPR analysis of multiple forms of [4Fe–4S] 3+ clusters in HiPIPs

The electron paramagnetic resonance (EPR) spectrum from the [4Fe–4S] 3+ cluster in several high-potential iron–sulfur proteins (HiPIPs) is complex: it is not the pattern of a single, isolated S =1/2 system. Multifrequency EPR from 9 to 130 GHz reveals that the apparent peak positions ( g values) are frequency-independent: the spectrum is dominated by the Zeeman interaction plus g -strain broadening. The spectra taken at frequencies above the X-band are increasingly sensitive to rapid-passage effects; therefore, the X-band data, which are slightly additionally broadened by dipolar interaction, were used for quantitative spectral analysis. For a single geometrical [4Fe–4S] 3+ structure the (Fe–Fe) 5+ mixed-valence dimer can be assigned in six different ways to a pair of iron ions, and this defines six valence isomers. Systematic multicomponent g -strain simulation shows that the [4Fe–4S] 3+ paramagnets in seven HiPIPs from different bacteria each consist of three to four discernible species, and these are assigned to valence isomers of the clusters. This interpretation builds on previous EPR analyzes of [4Fe–4S] 3+ model compounds, and it constitutes a high-resolution extension of the current literature model, proposed from paramagnetic NMR studies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47867/1/775_2005_Article_656.pd

Infection, colonization and shedding of Campylobacter and Salmonella in animals and their contribution to human disease: A review

Livestock meat and offal contribute significantly to human nutrition as sources of high‐quality protein and micronutrients. Livestock products are increasingly in demand, particularly in low‐ and middle‐income settings where economies are growing and meat is increasingly seen as an affordable and desirable food item. Demand is also driving intensification of livestock keeping and processing. An unintended consequence of intensification is increased exposure to zoonotic agents, and a contemporary emerging problem is infection with Campylobacter and Salmonella spp. from livestock (avian and mammalian), which can lead to disease, malabsorption and undernutrition through acute and chronic diarrhoea. This can occur at the farm, in households or through the food chain. Direct infection occurs when handling livestock and through bacteria shed into the environment, on food preparation surfaces or around the house and surroundings. This manuscript critically reviews Campylobacter and Salmonella infections in animals, examines the factors affecting colonization and faecal shedding of bacteria of these two genera as well as risk factors for human acquisition of the infection from infected animals or environment and analyses priority areas for preventive actions with a focus on resource‐poor settings

The regional and global significance of nitrogen removal in lakes and reservoirs

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Biogeochemistry 93 (2009): 143-157, doi:10.1007/s10533-008-9272-x.Human activities have greatly increased the transport of biologically available N through watersheds to potentially sensitive coastal ecosystems. Lentic water bodies (lakes and reservoirs) have the potential to act as important sinks for this reactive N as it is transported across the landscape because they offer ideal conditions for N burial in sediments or permanent loss via denitrification. However, the patterns and controls on lentic N removal have not been explored in great detail at large regional to global scales. In this paper we describe, evaluate, and apply a new, spatially explicit, annual-scale, global model of lentic N removal called NiRReLa (Nitrogen Retention in Reservoirs and Lakes). The NiRReLa model incorporates small lakes and reservoirs than have been included in previous global analyses, and also allows for separate treatment and analysis of reservoirs and natural lakes. Model runs for the mid-1990s indicate that lentic systems are indeed important sinks for N and are conservatively estimated to remove 19.7 Tg N yr-1 from watersheds globally. Small lakes (< 50 km2) were critical in the analysis, retaining almost half (9.3 Tg N yr-1) of the global total. In model runs, capacity of lakes and reservoirs to remove watershed N varied substantially (0-100%) both as a function of climate and the density of lentic systems. Although reservoirs occupy just 6% of the global lentic surface area, we estimate they retain approximately 33% of the total N removed by lentic systems, due to a combination of higher drainage ratios (catchment surface area : lake or reservoir surface area), higher apparent settling velocities for N, and greater N loading rates in reservoirs than in lakes. Finally, a sensitivity analysis of NiRReLa suggests that, on-average, N removal within lentic systems will respond more strongly to changes in land use and N loading than to changes in climate at the global scale.The NSF26 Research Coordination Network on denitrification for support for collaboration (award number DEB0443439 to S.P. Seitzinger and E.A. Davidson). This project was also supported by grants to J.A. Harrison from California Sea Grant (award number RSF8) and from the U.S. Geological Survey 104b program and R. Maranger (FQRNT Strategic Professor)

Are Foreign Firms Privileged By Their Host Governments? Evidence From The 2000 World Business Environment Survey

Using the data from World Business Environment Survey (WBES) on over 10,000 firms across eighty one countries, this paper finds preliminary evidence that foreign firms enjoy significant regulatory advantages - as perceived by the firms themselves - over domestic firms. The findings on regulatory advantages of foreign firms hold with a variety of alternative measures of regulations and with or without firm- and country-level attributes and industry and country controls. There is also evidence that foreign firms' regulatory advantages are especially substantial vis-a-vis the politically weak domestic firms. Furthermore, the regulatory advantages of foreign firms appear stronger in corrupt countries than in non-corrupt countries