Though therapeutics based on messenger RNA (mRNA) have broad potential in applications such as protein replacement therapy, cancer immunotherapy, and genomic engineering, their effective ...intracellular delivery remains a challenge. A chemically diverse suite of delivery materials with origins as materials for cellular transfection of DNA and small interfering RNAs (siRNAs) has recently been reported to have promise as non-viral delivery agents for mRNA. These materials include covalent conjugates, protamine complexes, nanoparticles based on lipids or polymers, and hybrid formulations. This review will highlight the use of delivery materials for mRNA, with a specific focus on their mechanisms of action, routes of administration, and dosages. Additionally, strategies in which these materials can be adapted and optimized to address challenges specific to mRNA delivery are also discussed. The technologies included have shown varying promise for therapeutic use, specifically having been used to deliver mRNA in vivo or exhibiting characteristics that could make in vivo use a possibility. In so doing, it is the intention of this review to provide a comprehensive look at the progress and possibilities in applying nucleic acid delivery technology specifically toward the emerging area of mRNA therapeutics.
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Ungulate migrations are assumed to stem from learning and cultural transmission of information regarding seasonal distribution of forage, but this hypothesis has not been tested empirically. We ...compared the migratory propensities of bighorn sheep and moose translocated into novel habitats with those of historical populations that had persisted for hundreds of years. Whereas individuals from historical populations were largely migratory, translocated individuals initially were not. After multiple decades, however, translocated populations gained knowledge about surfing green waves of forage (tracking plant phenology) and increased their propensity to migrate. Our findings indicate that learning and cultural transmission are the primary mechanisms by which ungulate migrations evolve. Loss of migration will therefore expunge generations of knowledge about the locations of high-quality forage and likely suppress population abundance.
Time can be a limiting constraint for consumers, particularly when resource phenology mediates foraging opportunity. Though a large body of research has explored how resource phenology influences ...trophic interactions, this work has focused on the topics of trophic mismatch or predator swamping, which typically occur over short periods, at small spatial extents or coarse resolutions. In contrast many consumers integrate across landscape heterogeneity in resource phenology, moving to track ephemeral food sources that propagate across space as resource waves. Here we provide a conceptual framework to advance the study of phenological diversity and resource waves. We define resource waves, review evidence of their importance in recent case studies, and demonstrate their broader ecological significance with a simulation model. We found that consumers ranging from fig wasps (Chalcidoidea) to grizzly bears (Ursus arctos) exploit resource waves, integrating across phenological diversity to make resource aggregates available for much longer than their component parts. In model simulations, phenological diversity was often more important to consumer energy gain than resource abundance per se. Current ecosystem‐based management assumes that species abundance mediates the strength of trophic interactions. Our results challenge this assumption and highlight new opportunities for conservation and management. Resource waves are an emergent property of consumer–resource interactions and are broadly significant in ecology and conservation.
Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors for safe and effective delivery. Synthetic nanoparticle vectors composed of poly(β‐amino esters) (PBAEs) ...and nucleic acids have previously demonstrated potential utility for local delivery applications. To expand this potential utility to include systemic delivery of mRNA, hybrid polymer–lipid nanoformulations for systemic delivery to the lungs were developed. Through coformulation of PBAEs with lipid–polyethylene glycol (PEG), mRNA formulations were developed with increased serum stability and increased in vitro potency. The formulations were capable of functional delivery of mRNA to the lungs after intravenous administration in mice. To our knowledge, this is the first report of the systemic administration of mRNA for delivery to the lungs using degradable polymer–lipid nanoparticles.
mRNA‐loaded nanoparticles were synthesized using degradable poly(β‐amino ester) terpolymers formulated with a PEG‐lipid. The PEG‐lipid imparted serum stability to the nanoparticles, which resulted in successful mRNA delivery to the lungs after systemic nanoparticle administration in mice.
Chronic wasting disease (CWD) is an invariably fatal transmissible spongiform encephalopathy of white-tailed deer, mule deer, elk, and moose. Despite a 100% fatality rate, areas of high prevalence, ...and increasingly expanding geographic endemic areas, little is known about the population-level effects of CWD in deer. To investigate these effects, we tested the null hypothesis that high prevalence CWD did not negatively impact white-tailed deer population sustainability. The specific objectives of the study were to monitor CWD-positive and CWD-negative white-tailed deer in a high-prevalence CWD area longitudinally via radio-telemetry and global positioning system (GPS) collars. For the two populations, we determined the following: a) demographic and disease indices, b) annual survival, and c) finite rate of population growth (λ). The CWD prevalence was higher in females (42%) than males (28.8%) and hunter harvest and clinical CWD were the most frequent causes of mortality, with CWD-positive deer over-represented in harvest and total mortalities. Survival was significantly lower for CWD-positive deer and separately by sex; CWD-positive deer were 4.5 times more likely to die annually than CWD-negative deer while bucks were 1.7 times more likely to die than does. Population λ was 0.896 (0.859-0.980), which indicated a 10.4% annual decline. We show that a chronic disease that becomes endemic in wildlife populations has the potential to be population-limiting and the strong population-level effects of CWD suggest affected populations are not sustainable at high disease prevalence under current harvest levels.
Chronic wasting disease (CWD) is a fatal transmissible spongiform encephalopathy affecting white-tailed deer (Odocoileus virginianus), mule deer (Odocoileus hemionus), Rocky Mountain elk (Cervus ...elaphus nelsoni), and moose (Alces alces shirasi) in North America. In southeastern Wyoming average annual CWD prevalence in mule deer exceeds 20% and appears to contribute to regional population declines. We determined the effect of CWD on mule deer demography using age-specific, female-only, CWD transition matrix models to estimate the population growth rate (λ). Mule deer were captured from 2010-2014 in southern Converse County Wyoming, USA. Captured adult (≥ 1.5 years old) deer were tested ante-mortem for CWD using tonsil biopsies and monitored using radio telemetry. Mean annual survival rates of CWD-negative and CWD-positive deer were 0.76 and 0.32, respectively. Pregnancy and fawn recruitment were not observed to be influenced by CWD. We estimated λ = 0.79, indicating an annual population decline of 21% under current CWD prevalence levels. A model derived from the demography of only CWD-negative individuals yielded; λ = 1.00, indicating a stable population if CWD were absent. These findings support CWD as a significant contributor to mule deer population decline. Chronic wasting disease is difficult or impossible to eradicate with current tools, given significant environmental contamination, and at present our best recommendation for control of this disease is to minimize spread to new areas and naïve cervid populations.
Large herbivores surf waves of green-up during spring Merkle, Jerod A.; Monteith, Kevin L.; Aikens, Ellen O. ...
Proceedings - Royal Society. Biological sciences/Proceedings - Royal Society. Biological Sciences,
06/2016, Volume:
283, Issue:
1833
Journal Article
Peer reviewed
Open access
The green wave hypothesis (GWH) states that migrating animals should track or ‘surf’ high-quality forage at the leading edge of spring green-up. To index such high-quality forage, recent work ...proposed the instantaneous rate of green-up (IRG), i.e. rate of change in the normalized difference vegetation index over time. Despite this important advancement, no study has tested the assumption that herbivores select habitat patches at peak IRG. We evaluated this assumption using step selection functions parametrized with movement data during the green-up period from two populations each of bighorn sheep, mule deer, elk, moose and bison, totalling 463 individuals monitored 1–3 years from 2004 to 2014. Accounting for variables that typically influence habitat selection for each species, we found seven of 10 populations selected patches exhibiting high IRG—supporting the GWH. Nonetheless, large herbivores selected for the leading edge, trailing edge and crest of the IRG wave, indicating that other mechanisms (e.g. ruminant physiology) or measurement error inherent with satellite data affect selection for IRG. Our evaluation indicates that IRG is a useful tool for linking herbivore movement with plant phenology, paving the way for significant advancements in understanding how animals track resource quality that varies both spatially and temporally.
1. Birds that migrate long distances use stopover sites to optimize fuel loads and complete migration as quickly as possible. Stopover use has been predicted to facilitate a time-minimization ...strategy in land migrants as well, but empirical tests have been lacking, and alternative migration strategies have not been considered. 2. We used fine-scale movement data to evaluate the ecological role of stopovers in migratory mule deer Odocoileus hemionus — a land migrant whose fitness is strongly influenced by energy intake rather than migration speed. 3. Although deer could easily complete migrations (range 18—144 km) in several days, they took an average of 3 weeks and spent 95% of that time in a series of stopover sites that had higher forage quality than movement corridors. Forage quality of stopovers increased with elevation and distance from winter range. Mule deer use of stopovers corresponded with a narrow phenological range, such that deer occupied stopovers 44 days prior to peak green-up, when forage quality was presumed to be highest. Mule deer used one stopover for every 5·3 and 6·7 km travelled during spring and autumn migrations, respectively, and used the same stopovers in consecutive years. 4. Study findings indicate that stopovers play a key role in the migration strategy of mule deer by allowing individuals to migrate in concert with plant phenology and maximize energy intake rather than speed. Our results suggest that stopover use may be more common among non-avian taxa than previously thought and, although the underlying migration strategies of temperate ungulates and birds are quite different, stopover use is important to both. 5. Exploring the role of stopovers in land migrants broadens the scope of stopover ecology and recognizes that the applied and theoretical benefits of stopover ecology need not be limited to avian taxa.
The Green Wave Hypothesis posits that herbivore migration manifests in response to waves of spring green‐up (i.e. green‐wave surfing). Nonetheless, empirical support for the Green Wave Hypothesis is ...mixed, and a framework for understanding variation in surfing is lacking. In a population of migratory mule deer (Odocoileus hemionus), 31% surfed plant phenology in spring as well as a theoretically perfect surfer, and 98% surfed better than random. Green‐wave surfing varied among individuals and was unrelated to age or energetic state. Instead, the greenscape, which we define as the order, rate and duration of green‐up along migratory routes, was the primary factor influencing surfing. Our results indicate that migratory routes are more than a link between seasonal ranges, and they provide an important, but often overlooked, foraging habitat. In addition, the spatiotemporal configuration of forage resources that propagate along migratory routes shape animal movement and presumably, energy gains during migration.
Migrating bison engineer the green wave Geremia, Chris; Merkle, Jerod A.; Eacker, Daniel R. ...
Proceedings of the National Academy of Sciences - PNAS,
12/2019, Volume:
116, Issue:
51
Journal Article
Peer reviewed
Open access
Newly emerging plants provide the best forage for herbivores. To exploit this fleeting resource, migrating herbivores align their movements to surf the wave of spring green-up. With new technology to ...track migrating animals, the Green Wave Hypothesis has steadily gained empirical support across a diversity of migratory taxa. This hypothesis assumes the green wave is controlled by variation in climate, weather, and topography, and its progression dictates the timing, pace, and extent of migrations. However, aggregate grazers that are also capable of engineering grassland ecosystems make some of the world’s most impressive migrations, and it is unclear how the green wave determines their movements. Here we show that Yellowstone’s bison (Bison bison) do not choreograph their migratory movements to the wave of spring green-up. Instead, bison modify the green wave as they migrate and graze. While most bison surfed during early spring, they eventually slowed and let the green wave pass them by. However, small-scale experiments indicated that feedback from grazing sustained forage quality. Most importantly, a 6-fold decadal shift in bison density revealed that intense grazing caused grasslands to green up faster, more intensely, and for a longer duration. Our finding broadens our understanding of the ways in which animal movements underpin the foraging benefit of migration. The widely accepted Green Wave Hypothesis needs to be revised to include large aggregate grazers that not only move to find forage, but also engineer plant phenology through grazing, thereby shaping their own migratory movements.
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