Yersinia pestis, the causative agent of plague, is classified as a Tier I Select Agent of bioterrorism and is among a few pathogens of high concern as a potential cause of a future pandemic. Currently, there is no licensed vaccine against plague. Previously, we developed a live attenuated vaccine candidate, rLVS ΔcapB/Yp F1-V, that utilizes a highly attenuated capB mutant of Francisella tularensis Live Vaccine Strain as a vector to express a fusion protein of Y. pestis F1 and LcrV antigens. We showed that homologous prime-boost vaccination with this vaccine provided potent protection in mice against lethal respiratory challenge with virulent Y. pestis. Here, we report on the immunogenicity and efficacy of rLVS ΔcapB/Yp F1-V and additional LVS ΔcapB-vectored vaccine candidates in mice. We demonstrate that three homologous prime-boost immunizations with an optimized dose of rLVS ΔcapB/Yp F1-V provided complete protection against pneumonic plague in a stringent mouse model, outperforming other candidates and matching the survival efficacy of the toxic and unlicensed live attenuated Y. pestis EV76 strain vaccine; moreover, mice immunized with the rLVS ΔcapB/Yp F1-V vaccine had minimal weight loss post-challenge that was significantly less than mice immunized with the EV76 vaccine. Protection induced by rLVS ΔcapB/Yp F1-V correlates with F1 and LcrV-specific serum antibody levels. Our results highlight the potential of rLVS ΔcapB/Yp F1-V to address the unmet need for a plague vaccine.
Reproducibility of scientific data is a current concern throughout the neuroscience field. There are multiple on-going efforts to help resolve this problem. Within the preclinical neuroimaging field, the continued use of a region-of interest (ROI) type approaches combined with the well-known spatial heterogeneity of traumatic brain injury pathology is a barrier to the replicability and repeatability of data. Here we propose the conjoint use of an unbiased analysis of the whole brain after injury together with a population-based statistical analysis of sham-control brains as one approach that has been used in clinical research to help resolve this issue. The approach produces two volumes of pathology that are outside the normal range of sham brains, and can be interpreted as whole brain burden of injury. Using diffusion weighted imaging-derived scalars from a tensor analysis of data acquired from adult, male rats at 2, 9 days, 1 and 5 months after lateral fluid percussion injury (LFPI) and in shams (n = 73 and 12, respectively), we compared a data-driven, z-score mapping method to a whole brain and white matter-specific analysis, as well as an ROI-based analysis with brain regions preselected by virtue of their large group effect sizes. We show that the data-driven approach is statistically robust, providing the advantage of a large group effect size typical of a ROI analysis of mean scalar values derived from the tensor in regions of gross injury, but without the large multi-region statistical correction required for interrogating multiple brain areas, and without the potential bias inherent with using preselected ROIs. We show that the technique correctly captures the expected longitudinal time-course of the diffusion scalar volumes based on the spatial extent of the pathology and the known temporal changes in scalar values in the LFPI model.
The fossil record of mammals preserves evidence for dietary adaptations that allowed lineages to persist in dynamic ecosystems for tens of millions of years. We investigated ecological attributes of fossil mammals during the middle to late Miocene (17.5–8.5 Ma) in the western Mojave region of North America to evaluate the response of herbivorous ungulates to paleoenvironmental changes. Herbivores may utilize the same food resources across generations, relying on relationships with vegetation and habitats established over multiple generations. We employed stable isotopes of carbon and oxygen from ancient soils and herbivore tooth enamel to evaluate changes in vegetation and herbivore diets. We compiled isotopic data from published studies of three sequences from the warm Miocene Climatic Optimum and added new data from the Dove Spring Formation, which formed during the cooler Middle Miocene Climatic Transition. Herbivorous ungulates exhibited dietary fidelity for nearly nine million years, selectively consuming C3 plants even as C4 vegetation became more prevalent on the landscape. High oxygen stable isotope ratios in comparison to equids suggest that ancestral antilocaprids and camelids were likely facultative drinkers. These findings reveal enduring dietary preferences that enabled these herbivores to persist amid the profound environmental transitions of the Miocene.
Apolipoproteins are the defining functional component of lipoproteins and play critical roles in lipid transport and metabolism. High-density lipoprotein (HDL) and its primary functional constituent, apolipoprotein A-I, are of particular importance because of anti-inflammatory and antioxidant properties. Apolipoprotein mimetic peptides are short-chain amino acids designed to mimic the functions and alpha-helical structure of endogenous apolipoproteins and have demonstrated efficacy in ameliorating animal models of cardiovascular disease (CVD) and cancer. The mechanisms underlying the mimetics are yet to be fully elucidated, but a comprehensive review of the literature suggests that the peptides attack pathways shared in the pathophysiology of both diseases. This review also discusses the many pre-clinical studies on the mimetic peptides, highlighting possible mechanisms at work in each. Proposed mechanisms of protection against CVD and cancer include binding and removal of pro-inflammatory oxidized lipids, reduction in reactive oxygen species, and modulation of immune cell populations. Additionally, nanoparticles (NP) formulations incorporating apolipoprotein mimetic peptides or recombinant apolipoproteins have exhibited anti-atherogenic and anti-cancer activity. To date, clinical trials to assess the effect of reconstituted HDL NPs on CVD outcomes have not shown significant improvement. The large body of successful animal studies on apolipoproteins and apolipoprotein mimetic peptides presents a disconnect between pre-clinical and clinical efficacy, highlighting the need for a more complete understanding of the underlying pathways and mechanisms.
The non-marine Middle Miocene Monarch Mill Formation (Nevada, U.S.A.) outcrops in the Middlegate Basin and preserves fossil mammals that lived during the establishment of the present-day basin and range topography in central Nevada. The Monarch Mill Formation and its mammal fauna overlie the Middlegate Formation and its flora, and together the biota provides an informative window into ecosystem composition at the geographic crossroads between the Great Plains and the coastal regions of North America during the Middle Miocene. Here we report on previously undescribed and/or unfigured canids from the Monarch Mill Formation. To the previously known borophagine Tomarctus brevirostris and the fox-like canine Leptocyon we add two borophagine genera to the Eastgate Local Fauna of the Monarch Mill Formation. Specimens of the hypocarnivores Paracynarctus and Cynarctus are described and provide an enhanced understanding of the Middlegate Basin canid assemblage, now comprising at least four genera. Together with floral evidence, this canid assemblage is indicative of mesocarnivore-sustaining vegetation and locally limited open environments, with no hypercarnivorous canid occurrences. Rapid regional subsidence was an overarching factor in the shift towards present-day hyper- and meso-carnivore dominated canid assemblages in the Basin and Range Province, and the appearance of hypercarnivores in post-Barstovian times may reflect contemporaneous regional topographic shifts in the Great Basin at large.
Techno-economic analysis of distributed wellhead water treatment and desalination (DWTD) systems was carried out based on a three-year field study in three small, disadvantaged communities (DACs) to evaluate the reliability and affordability of upgrading their impaired well water. The local water supplies of the three study DACs, located in Salinas Valley, California, were contaminated with nitrate at levels (∼ 12-87 mg/L NO3--N) above the California maximum contaminant level (MCL) of 10 mg/L NO3--N, and had elevated water salinity (∼600-1,600 mg/L total dissolved solids(TDS)) above its secondary MCL (SMCL) of 500 mg/L TDS. Well water nitrate removal and salinity reduction were accomplished via reverse osmosis (RO) based DWTD systems that operated autonomously, supported by remote monitoring and supervisory cyberinfrastructure. Reliable DWTD operation provided treated water quality, with respect to nitrate and salinity, in the range of 0.5-6.3 mg/L NO3--N and 57-161 mg/L TDS, respectively, which were well below the respective MCL and SMCL. The levelized cost of water treatment was in the range of ∼$2/m3- $2.9/m3 which aligns with typical residential water costs in California and in the study region, and monthly residential water costs ($39-$74/residential unit/month) were also within the range in California. The study showcased the DWTD approach as a viable and potentially scalable solution for upgrading impaired local potable water supply of communities lacking centralized water delivery infrastructure. However, streamlined permitting processes and standardized regulatory frameworks are critical to promoting wider adoption and maximizing the socio-economic benefits of the DWT approach. Moreover, DACs are likely to require government subsidies in order to cover the CapEx of DWTD systems in addition to upgrade of site infrastructure.
