Identifying Factors of Microparticles Modified with Arginine Derivatives That Induce Phenotypic Shifts in Macrophages

Macrophages are key players in the progression of many diseases, ranging from rheumatoid arthritis to cancer. Drug delivery systems have the potential not only to transport payloads to diseased tissue but also to influence cell behavior. Here, poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAm-co-AAc) microparticles were modified with 14 different arginine derivatives. These particles were then incubated with interleukin-4 or lipopolysaccharide-stimulated macrophages or naïve macrophages (RAW 264.7). The phenotypic state of the macrophages was assessed by measuring arginase activity, tumor necrosis factor-α (TNF-α) secretion, and nitrite production. Partial least-squares analysis revealed material properties and descriptors that shifted the macrophage phenotype for the three cell conditions in this study. Material descriptors relating to secondary bonding were suggested to play a role in shifting phenotypes in all three macrophage culture conditions. These findings suggest that macrophage responses could be altered through drug delivery vehicles, and this method could be employed to assist in screening potential candidates

Twenty first century changes in Antarctic and Southern Ocean surface climate in CMIP6

Two decades into the 21st century there is growing evidence for global impacts of Antarctic and Southern Ocean climate change. Reliable estimates of how the Antarctic climate system would behave under a range of scenarios of future external climate forcing are thus a high priority. Output from new model simulations coordinated as part of the Coupled Model Intercomparison Project Phase 6 (CMIP6) provides an opportunity for a comprehensive analysis of the latest generation of state‐of‐the‐art climate models following a wider range of experiment types and scenarios than previous CMIP phases. Here the main broad‐scale 21st century Antarctic projections provided by the CMIP6 models are shown across four forcing scenarios: SSP1‐2.6, SSP2‐4.5, SSP3‐7.0 and SSP5‐8.5. End‐of‐century Antarctic surface‐air temperature change across these scenarios (relative to 1995–2014) is 1.3, 2.5, 3.7 and 4.8°C. The corresponding proportional precipitation rate changes are 8, 16, 24 and 31%. In addition to these end‐of‐century changes, an assessment of scenario dependence of pathways of absolute and global‐relative 21st century projections is conducted. Potential differences in regional response are of particular relevance to coastal Antarctica, where, for example, ecosystems and ice shelves are highly sensitive to the timing of crossing of key thresholds in both atmospheric and oceanic conditions. Overall, it is found that the projected changes over coastal Antarctica do not scale linearly with global forcing. We identify two factors that appear to contribute: (a) a stronger global‐relative Southern Ocean warming in stabilisation (SSP2‐4.5) and aggressive mitigation (SSP1‐2.6) scenarios as the Southern Ocean continues to warm and (b) projected recovery of Southern Hemisphere stratospheric ozone and its effect on the mid‐latitude westerlies. The major implication is that over coastal Antarctica, the surface warming by 2100 is stronger relative to the global mean surface warming for the low forcing compared to high forcing future scenarios

Beta cell extracellular vesicle miR-21-5p cargo is increased in response to inflammatory cytokines and serves as a biomarker of type 1 diabetes

AIMS/HYPOTHESIS: Improved biomarkers are acutely needed for the detection of developing type 1 diabetes, prior to critical loss of beta cell mass. We previously demonstrated that elevated beta cell microRNA 21-5p (miR-21-5p) in rodent and human models of type 1 diabetes increased beta cell apoptosis. We hypothesised that the inflammatory milieu of developing diabetes may also increase miR-21-5p in beta cell extracellular vesicle (EV) cargo and that circulating EV miR-21-5p would be increased during type 1 diabetes development. METHODS: MIN6 and EndoC-βH1 beta cell lines and human islets were treated with IL-1β, IFN-γ and TNF-α to mimic the inflammatory milieu of early type 1 diabetes. Serum was collected weekly from 8-week-old female NOD mice until diabetes onset. Sera from a cross-section of 19 children at the time of type 1 diabetes diagnosis and 16 healthy children were also analysed. EVs were isolated from cell culture media or serum using sequential ultracentrifugation or ExoQuick precipitation and EV miRNAs were assayed. RESULTS: Cytokine treatment in beta cell lines and human islets resulted in a 1.5- to threefold increase in miR-21-5p. However, corresponding EVs were further enriched for this miRNA, with a three- to sixfold EV miR-21-5p increase in response to cytokine treatment. This difference was only partially reduced by pre-treatment of beta cells with Z-VAD-FMK to inhibit cytokine-induced caspase activity. Nanoparticle tracking analysis showed cytokines to have no effect on the number of EVs, implicating specific changes within EV cargo as being responsible for the increase in beta cell EV miR-21-5p. Sequential ultracentrifugation to separate EVs by size suggested that this effect was mostly due to cytokine-induced increases in exosome miR-21-5p. Longitudinal serum collections from NOD mice showed that EVs displayed progressive increases in miR-21-5p beginning 3 weeks prior to diabetes onset. To validate the relevance to human diabetes, we assayed serum from children with new-onset type 1 diabetes compared with healthy children. While total serum miR-21-5p and total serum EVs were reduced in diabetic participants, serum EV miR-21-5p was increased threefold compared with non-diabetic individuals. By contrast, both serum and EV miR-375-5p were increased in parallel among diabetic participants. CONCLUSIONS/INTERPRETATION: We propose that circulating EV miR-21-5p may be a promising marker of developing type 1 diabetes. Additionally, our findings highlight that, for certain miRNAs, total circulating miRNA levels are distinct from circulating EV miRNA content

Wise practices: Indigenous-settler relations in Laurentian Great Lakes fishery governance and water protection

Ongoing tensions between Indigenous and non-Indigenous communities working in support of the protection and management of fish and water in North America have necessitated a shift from current structures towards relationships built upon and driven by respect, relevance, reciprocity, and responsibility. Similarly, the cumulative and evolving effects of climate change, industrialization, resource extraction, and displacement of Indigenous Peoples from their traditional and contemporary lands and waters requires purposeful application of decolonizing methods in aquatic systems management and protection, which in turn aids in the re-establishment of agency to Indigenous Peoples. This article endeavors to outline critical differences in ‘best practices’ and ‘wise practices’ in Laurentian Great Lakes fisheries management, water protection, and Indigenous-settler working relations through dialogue on experiences of Indigenous working relationships with colonial governmental bodies. We discuss critical misunderstandings, and the need for creating room for and profoundly respecting Indigenous ways of knowing and being. This work brings together lessons, stories, and knowledge from a panel of Indigenous and allied scholars and community members from the International Association for Great Lakes Research annual conference in May 2021, and subsequently uses a conversation-based methodology to preserve the voices and teachings of panelists. The lessons shared in this work are vital to the future of Laurentian Great Lakes fish and water health

The R-process Alliance: First Magellan/MIKE Release from the Southern Search for R-Process-enhanced Stars

Extensive progress has been recently made into our understanding of heavy element production via the $r$-process in the Universe, specifically with the first observed neutron star binary merger (NSBM) event associated with the gravitational wave signal detected by LIGO, GW170817. The chemical abundance patterns of metal-poor $r$-process-enhanced stars provides key evidence into the dominant site(s) of the $r$-process, and whether NSBMs are sufficiently frequent or prolific $r$-process sources to be responsible for the majority of $r$-process material in the Universe. We present atmospheric stellar parameters (using a Non-Local Thermodynamic Equilibrium analysis) and abundances from a detailed analysis of 141 metal-poor stars, carried out as part of the $R$-Process Alliance (RPA) effort. We obtained high-resolution "snapshot" spectroscopy of the stars using the MIKE spectrograph on the 6.5m Magellan Clay telescope at Las Campanas Observatory in Chile. We find 10 new highly enhanced $r$-II (with [Eu/Fe] $> +1.0$), 62 new moderately enhanced $r$-I ($+0.3 <$ [Eu/Fe] $\le +1.0$) and 17 new limited-$r$ ([Eu/Fe] $< +0.3$) stars. Among those, we find 17 new carbon-enhanced metal-poor (CEMP) stars, of which five are CEMP-no. We also identify one new $s$-process-enhanced ([Ba/Eu ]$> +0.5$), and five new $r/s$ ($0.0 <$ [Ba/Eu] $< +0.5$) stars. In the process, we discover a new ultra metal-poor (UMP) star at [Fe/H]=$-$4.02. One of the $r$-II stars shows a deficit in $\alpha$ and Fe-peak elements, typical of dwarf galaxy stars. Our search for $r$-process-enhanced stars by RPA efforts, has already roughly doubled the known $r$-process sample.Comment: 17 pages, 9 figures, 6 tables, Accepted for publication in Ap

Reconstruction of the historic time course of blood‐borne virus contamination of clotting factor concentrates, 1974–1992

Factor VIII and IX clotting factor concentrates manufactured from pooled plasma have been identified as potent sources of virus infection in persons with hemophilia (PWHs) in the 1970s and 1980s. To investigate the range and diversity of viruses over this period, we analysed 24 clotting factor concentrates for several blood‐borne viruses. Nucleic acid was extracted from 14 commercially produced clotting factors and 10 from nonremunerated donors, preserved in lyophilized form (expiry dates: 1974–1992). Clotting factors were tested by commercial and in‐house quantitative PCRs for blood‐borne viruses hepatitis A, B, C and E viruses (HAV, HBV, HCV, HEV), HIV‐ types 1/2, parvoviruses B19V and PARV4, and human pegiviruses types 1 and 2 (HPgV‐1,‐2). HCV and HPgV‐1 were the most frequently detected viruses (both 14/24 tested) primarily in commercial clotting factors, with frequently extremely high viral loads in the late 1970s–1985 and a diverse range of HCV genotypes. Detection frequencies sharply declined following introduction of virus inactivation. HIV‐1, HBV, and HAV were less frequently detected (3/24, 1/24, and 1/24 respectively); none were positive for HEV. Contrastingly, B19V and PARV4 were detected throughout the study period, even after introduction of dry heat treatment, consistent with ongoing documented transmission to PWHs into the early 1990s. While hemophilia treatment is now largely based on recombinant factor VIII/IX in the UK and elsewhere, the comprehensive screen of historical plasma‐derived clotting factors reveals extensive exposure of PWHs to blood‐borne viruses throughout 1970s‐early 1990s, and the epidemiological and manufacturing parameters that influenced clotting factor contamination