To be effective, RNA vaccines require both in situ translation and the induction of an immune response to recruit cells to the site of immunization. These factors can pull in opposite directions with ...the inflammation reducing expression of the vaccine antigen. We investigated how formulation affects the acute systemic cytokine response to a self-amplifying RNA (saRNA) vaccine. We compared a cationic polymer (pABOL), a lipid emulsion (nanostructured lipid carrier, NLC), and three lipid nanoparticles (LNP). After immunization, we measured serum cytokines and compared the response to induced antibodies against influenza virus. Formulations that induced a greater cytokine response induced a greater antibody response, with a significant correlation between IP-10, MCP-1, KC, and antigen-specific antibody titers. We then investigated how innate immune sensing and signaling impacted the adaptive immune response to vaccination with LNP-formulated saRNA. Mice that lacked MAVS and are unable to signal through RIG-I-like receptors had an altered cytokine response to saRNA vaccination and had significantly greater antibody responses than wild-type mice. This indicates that the inflammation induced by formulated saRNA vaccines is not solely deleterious in the induction of antibody responses and that targeting specific aspects of RNA vaccine sensing might improve the quality of the response.
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RNA vaccines were a vital part of the pandemic response. But further research is required to broaden their usage. In the current study, we investigated the interplay of RNA vaccine-induced inflammation and the downstream adaptive response. We show that acute inflammation after immunization is required for protective antibody responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the southern Beaufort Sea of the United States and Canada, prior investigations have linked declines in summer sea ice to reduced physical condition, growth, and survival of polar bears (
Ursus ...maritimus
). Combined with projections of population decline due to continued climate warming and the ensuing loss of sea ice habitat, those findings contributed to the 2008 decision to list the species as threatened under the U.S. Endangered Species Act. Here, we used mark-recapture models to investigate the population dynamics of polar bears in the southern Beaufort Sea from 2001 to 2010, years during which the spatial and temporal extent of summer sea ice generally declined. Low survival from 2004 through 2006 led to a 25-50% decline in abundance. We hypothesize that low survival during this period resulted from (1) unfavorable ice conditions that limited access to prey during multiple seasons; and possibly, (2) low prey abundance. For reasons that are not clear, survival of adults and cubs began to improve in 2007 and abundance was comparatively stable from 2008 to 2010, with ~900 bears in 2010 (90% CI 606-1212). However, survival of subadult bears declined throughout the entire period. Reduced spatial and temporal availability of sea ice is expected to increasingly force population dynamics of polar bears as the climate continues to warm. However, in the short term, our findings suggest that factors other than sea ice can influence survival. A refined understanding of the ecological mechanisms underlying polar bear population dynamics is necessary to improve projections of their future status and facilitate development of management strategies.
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BFBNIB, FZAB, GIS, IJS, INZLJ, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
Projections of polar bear (Ursus maritimus) sea ice habitat distribution in the polar basin during the 21st century were developed to understand the consequences of anticipated sea ice reductions on ...polar bear populations. We used location data from satellite-collared polar bears and environmental data (e.g., bathymetry, distance to coastlines, and sea ice) collected from 1985 to 1995 to build resource selection functions (RSFs). RSFs described habitats that polar bears preferred in summer, autumn, winter, and spring. When applied to independent data from 1996 to 2006, the RSFs consistently identified habitats most frequently used by polar bears. We applied the RSFs to monthly maps of 21st-century sea ice concentration projected by 10 general circulation models (GCMs) used in the Intergovernmental Panel of Climate Change Fourth Assessment Report, under the A1B greenhouse gas forcing scenario. Despite variation in their projections, all GCMs indicated habitat losses in the polar basin during the 21st century. Losses in the highest-valued RSF habitat (optimal habitat) were greatest in the southern seas of the polar basin, especially the Chukchi and Barents seas, and least along the Arctic Ocean shores of Banks Island to northern Greenland. Mean loss of optimal polar bear habitat was greatest during summer; from an observed 1.0 million km2 in 1985—1995 (baseline) to a projected multi-model mean of 0.32 million km2 in 2090—2099 (-68% change). Projected winter losses of polar bear habitat were less: from 1.7 million km2 in 1985—1995 to 1.4 million km2 in 2090—2099 (-17% change). Habitat losses based on GCM multi-model means may be conservative; simulated rates of habitat loss during 1985—2006 from many GCMs were less than the actual observed rates of loss. Although a reduction in the total amount of optimal habitat will likely reduce polar bear populations, exact relationships between habitat losses and population demographics remain unknown. Density and energetic effects may become important as polar bears make long-distance annual migrations from traditional winter ranges to remnant high-latitude summer sea ice. These impacts will likely affect specific sex and age groups differently and may ultimately preclude bears from seasonally returning to their traditional ranges.
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BFBNIB, FZAB, GIS, IJS, INZLJ, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
The response to mRNA vaccines needs to be sufficient for immune cell activation and recruitment, but moderate enough to ensure efficacious antigen expression. The choice of the cap structure and use ...of N1-methylpseudouridine (m1Ψ) instead of uridine, which have been shown to reduce RNA sensing by the cellular innate immune system, has led to improved efficacy of mRNA vaccine platforms. Understanding how RNA modifications influence the cell intrinsic immune response may help in the development of more effective mRNA vaccines. In the current study, we compared mRNA vaccines in mice against influenza virus using three different mRNA formats: uridine-containing mRNA (D1-uRNA), m1Ψ-modified mRNA (D1-modRNA), and D1-modRNA with a cap1 structure (cC1-modRNA). D1-uRNA vaccine induced a significantly different gene expression profile to the modified mRNA vaccines, with an up-regulation of Stat1 and RnaseL, and increased systemic inflammation. This result correlated with significantly reduced antigen-specific antibody responses and reduced protection against influenza virus infection compared with D1-modRNA and cC1-modRNA. Incorporation of m1Ψ alone without cap1 improved antibodies, but both modifications were required for the optimum response. Therefore, the incorporation of m1Ψ and cap1 alters protective immunity from mRNA vaccines by altering the innate immune response to the vaccine material.
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Tregoning and colleagues compare the impact of incorporation of m1Ψ on an mRNA influenza vaccine. Modifying mRNA for vaccines was critical in their successful deployment during the COVID-19 pandemic. m1Ψ incorporation significantly reduced the expression of potentially inhibitory ISG after vaccination and was associated with greater adaptive immune responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The effects of declining Arctic sea ice on local ecosystem productivity are not well understood but have been shown to vary inter‐specifically, spatially, and temporally. Because marine mammals ...occupy upper trophic levels in Arctic food webs, they may be useful indicators for understanding variation in ecosystem productivity. Polar bears (Ursus maritimus) are apex predators that primarily consume benthic and pelagic‐feeding ice‐associated seals. As such, their productivity integrates sea ice conditions and the ecosystem supporting them. Declining sea ice availability has been linked to negative population effects for polar bears but does not fully explain observed population changes. We examined relationships between spring foraging success of polar bears and sea ice conditions, prey productivity, and general patterns of ecosystem productivity in the Beaufort and Chukchi Seas (CSs). Fasting status (≥7 days) was estimated using serum urea and creatinine levels of 1,448 samples collected from 1,177 adult and subadult bears across three subpopulations. Fasting increased in the Beaufort Sea between 1983–1999 and 2000–2016 and was related to an index of ringed seal body condition. This change was concurrent with declines in body condition of polar bears and observed changes in the diet, condition and/or reproduction of four other vertebrate consumers within the food chain. In contrast, fasting declined in CS polar bears between periods and was less common than in the two Beaufort Sea subpopulations consistent with studies demonstrating higher primary productivity and maintenance or improved body condition in polar bears, ringed seals, and bearded seals despite recent sea ice loss in this region. Consistency between regional and temporal variation in spring polar bear fasting and food web productivity suggests that polar bears may be a useful indicator species. Furthermore, our results suggest that spatial and temporal ecological variation is important in affecting upper trophic‐level productivity in these marine ecosystems.
As an apex predator, polar bear feeding behavior is dependent on sea ice conditions and prey availability. This study examined patterns in polar bear spring foraging, quantified as the probability of fasting >7 days, across three subpopulations. Fasting increased in the two Beaufort Sea subpopulations from 1983–1999 (i) to 2000–2016 (ii), but decreased in the Chukchi Sea. Fasting was related to an index of ringed seal body condition and consistent with variation in primary productivity and the condition and reproduction of other vertebrate consumers. Our results suggest that spatial and temporal ecological variation affect upper trophic‐level productivity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Carbon sequestration with amendments in blue-green infrastructure soils could off-set anthropogenic greenhouse gas emissions to alleviate climate change. In this 3-year study, the effects of wheat ...straw and its biochar on carbon sequestration in an urban landscaping soil were investigated under realistic outdoor conditions using two large-scale lysimeters. Both amendments were carried out by incorporating pellets at 0–15 cm soil depth with an equivalent initial total carbon input of 2% of the dry soil weight. Soil carbon, carbon isotope ratios, dissolved carbon in leachates, CO2–C emissions, carbon fixed in above ground vegetation, soil water content, soil bulk electrical conductivity, and water infiltration rates, were then compared between the 2 lysimeters. After 3 years, we observed that, despite having a 17.2% lower vegetation growth, soil organic and inorganic carbon content was higher by 28.8% and 41.5%, respectively, in biochar as compared to wheat straw amended soil. Carbon isotope analysis confirmed the greater stability of the added carbon in the biochar amended soil. Water content was on average 23.2% and 13.0% in the straw pellet and biochar amended soil, respectively, whereas water infiltration rates were not significantly different between the two lysimeters. Overall, the incorporation of wheat straw biochar into soil could store an estimated 30 tonnes of carbon per hectare in city blue-green infrastructure spaces. Interviews involving institution stakeholders examined the feasibility of this biochar application. Stakeholders recognized the potential of biochar as an environment-friendly means for carbon offsetting, but were concerned about the practicality of biochar production and application into soil and increased maintenance work. Consequently, additional potential benefits of biochar for environmental management such as improving the quality of polluted run-off in stormwater treatment systems should be emphasized to make biochar an attractive proposition in sustainable urban development.
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•Urban soil amended with wheat straw (WP) or biochar (BC) was monitored over 3 years.•Vegetation growth was 17.2% lower for BC, versus WP amendment.•After 3 years, BC amended soil carbon was increased by 2.91 ± 2.48 kg m−2.•After 3 years, WP amended soil carbon was decreased by 0.36 ± 1.92 kg m−2.•30 tonnes·ha−1 soil carbon sequestration resulted from 48 tonnes·ha−1 BC application.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Influenza virus represents a challenge for traditional vaccine approaches due to its seasonal changes and potential for zoonotic transmission. Nucleic acid vaccines can overcome some of these ...challenges, especially through the inclusion of multiple antigens to increase the breadth of response. RNA vaccines were an important part of the response to the COVID-19 pandemic, but for future outbreaks DNA vaccines may have some advantages in terms of stability and manufacturing cost that warrant continuing investigation to fully realize their potential. Here, we investigate influenza virus vaccines made using a closed linear DNA platform, Doggybone™ DNA (dbDNA), produced by a rapid and scalable cell-free method. Influenza vaccines have mostly focussed on Haemagglutinin (HA), but the inclusion of Neuraminidase (NA) may provide additional protection. Here, we explored the potential of including NA in a dbDNA vaccine, looking at DNA optimization, mechanism and breadth of protection. We showed that DNA targeting sequences (DTS) improved immune responses against HA but not NA. We explored whether NA vaccine-induced protection against influenza virus infection was cell-mediated, but depletion of CD8 and NK cells made no impact, suggesting it was antibody-mediated. This is reflected in the restriction of protection to homologous strains of influenza virus. Importantly, we saw that including both HA and NA in a single combined vaccine did not dampen the immune response to either one. Overall, we show that linear dbDNA can induce an immune response against NA, which may offer increased protection in instances of HA mismatch where NA remains more conserved.
ARID1A is a core DNA-binding subunit of the BAF chromatin remodeling complex, and is lost in up to 7% of all cancers. The frequency of ARID1A loss increases in certain cancer types, such as clear ...cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeling complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The therapeutic promise of small interfering RNAs （siRNAs） for specific gene silencing is dependent on the successful delivery of functional siRNAs to the cytoplasm. Their conjugation to an ...established delivery platform, such as gold nanoparticles, offers tremendous potential for treating diseases and advancing our understanding of cellular processes. Their success or failure is dependent on both the uptake of the nanoparticles into the cells and subsequent intracellular release of the functional siRNA. In this study, utilizing gold nanoparticle siRNA-mediated delivery against C-MYC, we aimed to determine if we could achieve knockdown in a cancer cell line with low levels of intracellular glutathione, and determine the influence, if any, of polyethylene glycol （PEG） ligand density on knockdown, with a view to determining the optimal nanoparticle design to achieve C-MYC knockdown. We demonstrate that, regardless of the PEG density, knockdown in cells with relatively low glutathione levels can be achieved, as well as the possible effect of steric hindrance of PEG on the availability of the siRNA for cleavage in the intracellular environment. Gold nanoparticle uptake was demonstrated via transmission electron microscopy and mass spectroscopy, while knockdown was determined at the protein and physiological levels （cells in S-phase） by in-cell westerns and BrdU incorporation, respectively.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The glucocorticoid receptor (GR) is a major drug target in inflammatory disease. However, chronic glucocorticoid (GC) treatment leads to disordered energy metabolism, including increased weight gain, ...adiposity, and hepatosteatosis - all programs modulated by the circadian clock. We demonstrated that while antiinflammatory GC actions were maintained irrespective of dosing time, the liver was significantly more GC sensitive during the day. Temporal segregation of GC action was underpinned by a physical interaction of GR with the circadian transcription factor REVERBa and co-binding with liver-specific hepatocyte nuclear transcription factors (HNFs) on chromatin. REVERBa promoted efficient GR recruitment to chromatin during the day, acting in part by maintaining histone acetylation, with REVERBa-dependent GC responses providing segregation of carbohydrate and lipid metabolism. Importantly, deletion of Reverba inverted circadian liver GC sensitivity and protected mice from hepatosteatosis induced by chronic GC administration. Our results reveal a mechanism by which the circadian clock acts through REVERBa in liver on elements bound by HNF4A/HNF6 to direct GR action on energy metabolism.
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