A 3D printable alloy designed for extreme environments.

Multiprincipal-element alloys are an enabling class of materials owing to their impressive mechanical and oxidation-resistant properties, especially in extreme environments1,2. Here we develop a new oxide-dispersion-strengthened NiCoCr-based alloy using a model-driven alloy design approach and laser-based additive manufacturing. This oxide-dispersion-strengthened alloy, called GRX-810, uses laser powder bed fusion to disperse nanoscale Y2O3 particles throughout the microstructure without the use of resource-intensive processing steps such as mechanical or in situ alloying3,4. We show the successful incorporation and dispersion of nanoscale oxides throughout the GRX-810 build volume via high-resolution characterization of its microstructure. The mechanical results of GRX-810 show a twofold improvement in strength, over 1,000-fold better creep performance and twofold improvement in oxidation resistance compared with the traditional polycrystalline wrought Ni-based alloys used extensively in additive manufacturing at 1,093 °C5,6. The success of this alloy highlights how model-driven alloy designs can provide superior compositions using far fewer resources compared with the 'trial-and-error' methods of the past. These results showcase how future alloy development that leverages dispersion strengthening combined with additive manufacturing processing can accelerate the discovery of revolutionary materials.

A report card approach to describe temporal and spatial trends in parameters for coastal seagrass habitats.

Report cards that are designed to monitor environmental trends have the potential to provide a powerful communication tool because they are easy to understand and accessible to the general public, scientists, managers and policy makers. Given this functionality, they are increasingly popular in marine ecosystem reporting. We describe a report card method for seagrass that incorporates spatial and temporal variability in three metrics-meadow area, species and biomass-developed using long-term (greater than 10 years) monitoring data. This framework summarises large amounts of spatially and temporally complex data to give a numeric score that provides reliable comparisons of seagrass condition in both persistent and naturally variable meadows. We provide an example of how this is applied to seagrass meadows in an industrial port in the Great Barrier Reef World Heritage Area of north-eastern Australia.

Transcriptomic changes underlying EGFR inhibitor resistance in human and mouse models of basal-like breast cancer.

The goals of this study were to identify transcriptomic changes that arise in basal-like breast cancer cells during the development of resistance to epidermal growth factor receptor inhibitors (EGFRi) and to identify drugs that are cytotoxic once EGFRi resistance occurs. Human patient-derived xenografts (PDXs) were grown in immunodeficient mice and treated with a set of EGFRi; the EGFRi erlotinib was selected for more expansive in vivo studies. Single-cell RNA sequencing was performed on mammary tumors from the basal-like PDX WHIM2 that was treated with vehicle or erlotinib for 9 weeks. The PDX was then subjected to long-term erlotinib treatment in vivo. Through serial passaging, an erlotinib-resistant subline of WHIM2 was generated. Bulk RNA-sequencing was performed on parental and erlotinib-resistant tumors. In vitro high-throughput drug screening with > 500 clinically used compounds was performed on parental and erlotinib-resistant cells. Previously published bulk gene expression microarray data from MMTV-Wnt1 tumors were contrasted with the WHIM2 PDX data. Erlotinib effectively inhibited WHIM2 tumor growth for approximately 4 weeks. Compared to untreated cells, single-cell RNA sequencing revealed that a greater proportion of erlotinib-treated cells were in the G1 phase of the cell cycle. Comparison of WHIM2 and MMTV-Wnt1 gene expression data revealed a set of 38 overlapping genes that were differentially expressed in the erlotinib-resistant WHIM2 and MMTV-Wnt1 tumors. Comparison of all three data types revealed five genes that were upregulated across all erlotinib-resistant samples: IL19, KLK7, LCN2, SAA1, and SAA2. Of these five genes, LCN2 was most abundantly expressed in triple-negative breast cancers, and its knockdown restored erlotinib sensitivity in vitro. Despite transcriptomic differences, parental and erlotinib-resistant WHIM2 displayed similar responses to the majority of drugs assessed for cytotoxicity in vitro. This study identified transcriptomic changes arising in erlotinib-resistant basal-like breast cancer. These data could be used to identify a biomarker or develop a gene signature predictive of patient response to EGFRi. Future studies should explore the predictive capacity of these gene signatures as well as how LCN2 contributes to the development of EGFRi resistance.

High-Resolution Environmentally Extended Input-Output Model to Assess the Greenhouse Gas Impact of Electronics in South Korea.

South Korea is a global leader in electronics, but little is known about their climate change impact. Here, we estimate the direct and indirect greenhouse gas (GHG) emissions of Korean electronics by developing a new and high-resolution (∼380 sectors) environmentally extended input-output model, named KREEIO. We find that final demand for Korean electronics led to nearly 8% of national GHG emissions in 2017, mostly because of indirect emissions embodied in the electronics supply chain. Notably, the semiconductor and display sectors contributed 3.2% and 2.4% to national emissions, with capital investment accounting for 17% of the two sectors' total emissions or nearly 1% of national emissions. For other electronic products, scope 1, scope 2, and upstream scope 3 emissions on average accounted for 3%, 10%, and 87% of a sector's GHG intensity, respectively. Detailed contribution analysis suggests that reducing Korean electronics GHG emissions would benefit most from the transition to a low-carbon electricity grid, but mitigation efforts in many other sectors such as metals and chemicals are also important. Overall, our study underscores the significance of electronics GHG emissions in South Korea, especially those from semiconductors and displays, and the mitigation challenges these sectors face as demand continues to grow globally.

Diet-tissue discrimination and turnover of δ13 C and δ15 N in muscle tissue of a penaeid prawn.

RATIONALE: Stable isotopes are used to study trophic and movement ecology in aquatic systems, as they provide spatially distinct, time-integrated signatures of diet. Stable isotope ecology has been used to quantify species-habitat relationships in many important fisheries species (e.g., penaeid prawns), with approaches that typically assume constant values for diet-tissue discrimination and diet-tissue steady state, but these can be highly variable. Here we provide the first report of these processes in Metapenaeus macleayi (eastern school prawn). METHODS: Here we explicitly measure and model carbon (δ13 C) and nitrogen (δ15 N) diet-tissue discrimination and turnover in eastern school prawn muscle tissue as a function of experimental time following a change in diet to an isotopically distinct food source. RESULTS: Diet-tissue discrimination factors were 5 and 0.6‰ for δ13 C and δ15 N, respectively. Prawn muscle tissue reached an approximate steady state after approximately 50 and 30 days for δ13 C and δ15 N. Half-lives indicated faster turnover of δ15 N (~8 days) than δ13 C (~14 days). CONCLUSIONS: Our diet-tissue discrimination factors deviate from 'typical' values with larger values for carbon than nitrogen isotopes, but are generally similar to those measured in other crustaceans. Similarly, our estimates of isotopic turnover align with those in other penaeid species. These findings confirm muscle tissue as a reliable indicator of long-term diet and movement patterns in eastern school prawn.

Targeting ADAM10 in Cancer and Autoimmunity.

Generating inhibitors for A Disintegrin And Metalloproteinase 10 (ADAM10), a zinc-dependent protease, was heavily invested in by the pharmaceutical industry starting over 20 years ago. There has been much enthusiasm in basic research for these inhibitors, with a multitude of studies generating significant data, yet the clinical trials have not replicated the same results. ADAM10 is ubiquitously expressed and cleaves many important substrates such as Notch, PD-L1, EGFR/HER ligands, ICOS-L, TACI, and the "stress related molecules" MIC-A, MIC-B and ULBPs. This review goes through the most recent pre-clinical data with inhibitors as well as clinical data supporting the use of ADAM10 inhibitor use in cancer and autoimmunity. It additionally addresses how ADAM10 inhibitor therapy can be improved and if inhibitor therapy can be paired with other drug treatments to maximize effectiveness in various disease states. Finally, it examines the ADAM10 substrates that are important to each disease state and if any of these substrates or ADAM10 itself is a potential biomarker for disease.

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer.

BACKGROUND: Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma. RESULTS: In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4 T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine's versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6 J E0771 murine breast cancer model. CONCLUSIONS: Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies.

Effects of Spatial Scale on Life Cycle Inventory Results.

Efforts to compile life cycle inventory (LCI) data at more geographically refined scales or resolutions are growing. However, it remains poorly understood as to how the choice of spatial scale may affect LCI results. Here, we examine this question using U.S. corn as a case study. We compile corn production data at two spatial scales, state and county, and compare how their LCI results may differ for state and national level analyses. For greenhouse gas (GHG) emissions, estimates at the two scales are similar (<20% of difference) for most state-level analyses and are basically the same (<5%) for national level analysis. For blue water consumption, estimates at the two scales differ more. Our results suggest that state-level analyses may be an adequate spatial scale for national level GHG analysis and for most state-level GHG analyses of U.S. corn, but may fall short for water consumption, because of its large spatial variability. On the other hand, although county-based LCIs may be considered more accurate, they require substantially more effort to compile. Overall, our study suggests that the goal of a study, data requirements, and spatial variability are important factors to consider when deciding the appropriate spatial scale or pursuing more refined scales.

Environmental Benefits of Engine Remanufacture in China's Circular Economy Development.

China has recently implemented broad strategies aimed at achieving a circular economy by providing subsidies for the remanufacture industry and setting a target of 15% increase in energy efficiency in industrial production across sectors, among other strategies. Here, we examine the environmental implications of these policies in the context of engine remanufacture, using an environmental computable general equilibrium (CGE) model. Results indicate that both the subsidy policy and energy efficiency improvement target can contribute to economic growth and emission reductions, but the subsidy policy is estimated to have far greater impacts. The implementation of both can reinforce each other, generating higher economic and environmental benefits than the sum of each occurrence alone. Another major finding from our model is that an additional remanufactured engine only displaces 0.42 (90% confidence interval from 0.32 to 0.47) of a new engine (comprised of new parts), mainly because the lower prices of remanufactured engines lead to greater consumption. This ratio is much lower than the 1:1 perfect displacement commonly assumed in life cycle assessment (LCA) studies. Overall, our study suggests that the subsidizing of engine remanufacture in China can help promote the industry, improve overall economic welfare, and contribute to environmental targets. Our study also contributes to the estimation of more realistic product displacement ratios in LCA.

Highly Disturbed Populations of Seagrass Show Increased Resilience but Lower Genotypic Diversity.

The response of seagrass systems to a severe disturbance provides an opportunity to quantify the degree of resilience in different meadows, and subsequently to test whether there is a genetic basis to resilience. We used existing data on levels of long-standing disturbance from poor water quality, and the responses of seagrass (Zostera muelleri) after an extreme flood event in Moreton Bay, Queensland, Australia. Sites were grouped into high and low disturbance categories, in which seagrass showed high and low resilience, respectively, as determined by measuring rates of key feedback processes (nutrient removal, suppression of sediment resuspension, and algal grazing), and physiological and morphological traits. Theoretically, meadows with higher genotypic diversity would be expected to have greater resilience. However, because the more resilient meadows occur in areas historically exposed to high disturbance, the alternative is also possible, that selection will have resulted in a narrower, less diverse subset of genotypes than in less disturbed meadows. Levels of genotypic and genetic diversity (allelic richness) based on 11 microsatellite loci, were positively related (R2 = 0.58). Genotypic diversity was significantly lower at highly disturbed sites (R = 0.49) than at less disturbed sites (R = 0.61). Genotypic diversity also showed a negative trend with two morphological characteristics known to confer resilience on seagrass in Moreton Bay, leaf chlorophyll concentrations and seagrass biomass. Genetic diversity did not differ between disturbed and undisturbed sites. We postulate that the explanation for these results is historical selection for genotypes that confer protection against disturbance, reducing diversity in meadows that contemporarily show greater resilience.

Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy.

Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy.

Contrasting effects of ocean warming on different components of plant-herbivore interactions.

There is increasing uncertainty of how marine ecosystems will respond to rising temperatures. While studies have focused on the impacts of warming on individual species, knowledge of how species interactions are likely to respond is scant. The strength of even simple two-species interactions is influenced by several interacting mechanisms, each potentially changing with temperature. We used controlled experiments to assess how plant-herbivore interactions respond to temperature for three structural dominant macrophytes in the Mediterranean and their principal sea urchin herbivore. Increasing temperature differentially influenced plant-specific growth, sea urchin growth and metabolism, consumption rates and herbivore preferences, but not movement behaviour. Evaluating these empirical observations against conceptual models of plant-herbivore performance, it appears likely that while the strength of herbivory may increase for the tested macroalga, for the two dominant seagrasses, the interaction strength may remain relatively unchanged or even weaken as temperatures rise. These results show a clear set of winners and losers in the warming Mediterranean as the complex factors driving species interactions change.

Marginal Emission Factors Considering Renewables: A Case Study of the U.S. Midcontinent Independent System Operator (MISO) System.

Estimates of marginal emission factors (MEFs) for the electricity sector have focused on emitting sources only, assuming nonemitting renewables rarely contribute to marginal generation. However, with increased penetration and improved dispatch of renewables, this assumption may be outdated. Here, we improve the methodology to incorporate renewables in MEF estimates and demonstrate a case study for the Midcontinent Independent System Operator (MISO) system where wind has been commonly dispatched on the margin. We also illustrate spatiotemporal variations of MEFs and explore implications for energy storage technologies. Results show that because the share of renewables in MISO is still relatively low (6.34%), conventional MEFs focused on emitting sources can provide a good estimate in MISO overall, as well as in the Central and South subregions. However, in the MISO North subregion where wind provides 22.5% of grid generation, neglecting nonemitting sources can overestimate MEFs for CO2, SO2, and NOx by about 30%. The application of expanded MEFs in this case also reveals heightened emission increases associated with load shifting of storage technologies. Our study highlights the importance of expanded MEFs in regions with high and growing renewables penetration, particularly as renewable energy policy seeks to incorporate demand-side technologies.

Subnational mobility and consumption-based environmental accounting of US corn in animal protein and ethanol supply chains.

Corn production, and its associated inputs, is a relatively large source of greenhouse gas emissions and uses significant amounts of water and land, thus contributing to climate change, fossil fuel depletion, local air pollutants, and local water scarcity. As large consumers of this corn, corporations in the ethanol and animal protein industries are increasingly assessing and reporting sustainability impacts across their supply chains to identify, prioritize, and communicate sustainability risks and opportunities material to their operations. In doing so, many have discovered that the direct impacts of their owned operations are dwarfed by those upstream in the supply chain, requiring transparency and knowledge about environmental impacts along the supply chains. Life cycle assessments (LCAs) have been used to identify hotspots of environmental impacts at national levels, yet these provide little subnational information necessary for guiding firms' specific supply networks. In this paper, our Food System Supply-Chain Sustainability (FoodS3) model connects spatial, firm-specific demand of corn purchasers with upstream corn production in the United States through a cost minimization transport model. This provides a means to link county-level corn production in the United States to firm-specific demand locations associated with downstream processing facilities. Our model substantially improves current LCA assessment efforts that are confined to broad national or state level impacts. In drilling down to subnational levels of environmental impacts that occur over heterogeneous areas and aggregating these landscape impacts by specific supply networks, targeted opportunities for improvements to the sustainability performance of supply chains are identified.

Seed germination in a southern Australian temperate seagrass.

In a series of experiments, seeds from a temperate seagrass species, Zostera nigricaulis collected in Port Phillip Bay, Victoria, Australia were exposed to a range of salinities (20 PSU pulse/no pulse, 25 PSU, 30 PSU, 35 PSU), temperatures (13 °C, 17 °C, 22 °C), burial depths (0 cm, 1 cm, 2 cm) and site specific sediment characteristics (fine, medium, coarse) to quantify their impacts on germination rate and maximum overall germination. In southern Australia the seagrass Z. nigricaulis is a common subtidal species; however, little is known about the factors that affect seed germination which is a potential limiting factor in meadow resilience to natural and anthropogenic disturbances. Overall seed germination was low (<20%) with germination decreasing to <10% when seeds were placed in the sediment. When germination of Z. nigricaulis seeds was observed, it was enhanced (greater overall germination and shorter time to germination) when seeds were exposed to a 20 PSU pulse for 24 h, maintained at salinity of 25 PSU, temperatures <13 °C, in sediments with fine or medium grain sand and buried at a depth of <1 cm. These results indicate that germination of Z. nigricaulis seeds under in situ conditions may be seasonally limited by temperatures in southern Australia. Seed germination may be further restricted by salinity as freshwater pulses reaching 20 PSU are typically only observed in Port Phillip Bay following large scale rainfall events. As a result, these populations may be particularly susceptible to disturbance with only a seasonally limited capacity for recovery.

Identifying knowledge gaps in seagrass research and management: An Australian perspective.

Seagrass species form important marine and estuarine habitats providing valuable ecosystem services and functions. Coastal zones that are increasingly impacted by anthropogenic development have experienced substantial declines in seagrass abundance around the world. Australia, which has some of the world's largest seagrass meadows and is home to over half of the known species, is not immune to these losses. In 1999 a review of seagrass ecosystems knowledge was conducted in Australia and strategic research priorities were developed to provide research direction for future studies and management. Subsequent rapid evolution of seagrass research and scientific methods has led to more than 70% of peer reviewed seagrass literature being produced since that time. A workshop was held as part of the Australian Marine Sciences Association conference in July 2015 in Geelong, Victoria, to update and redefine strategic priorities in seagrass research. Participants identified 40 research questions from 10 research fields (taxonomy and systematics, physiology, population biology, sediment biogeochemistry and microbiology, ecosystem function, faunal habitats, threats, rehabilitation and restoration, mapping and monitoring, management tools) as priorities for future research on Australian seagrasses. Progress in research will rely on advances in areas such as remote sensing, genomic tools, microsensors, computer modeling, and statistical analyses. A more interdisciplinary approach will be needed to facilitate greater understanding of the complex interactions among seagrasses and their environment.

Spatial variation in reproductive effort of a southern Australian seagrass.

In marine environments characterised by habitat-forming plants, the relative allocation of resources into vegetative growth and flowering is an important indicator of plant condition and hence ecosystem health. In addition, the production and abundance of seeds can give clues to local resilience. Flowering density, seed bank, biomass and epiphyte levels were recorded for the temperate seagrass Zostera nigricaulis in Port Phillip Bay, south east Australia at 14 sites chosen to represent several regions with different physicochemical conditions. Strong regional differences were found within the large bay. Spathe and seed density were very low in the north of the bay (3 sites), low in the centre of the bay (2 sites) intermediate in the Outer Geelong Arm (2 sites), high in Swan Bay (2 sites) and very high in the Inner Geelong Arm (3 sites). In the south (2 sites) seed density was low and spathe density was high. These regional patterns were largely consistent for the 5 sites sampled over the three year period. Timing of flowering was consistent across sites, occurring from August until December with peak production in October, except during the third year of monitoring when overall densities were lower and peaked in November. Seagrass biomass, epiphyte load, canopy height and stem density showed few consistent spatial and temporal patterns. Variation in spathe and seed density and morphology across Port Phillip Bay reflects varying environmental conditions and suggests that northern sites may be restricted in their ability to recover from disturbance through sexual reproduction. In contrast, sites in the west and south of the bay have greater potential to recover from disturbances due to a larger seed bank and these sites could act as source populations for sites where seed production is low.

Optimizing Eco-Efficiency Across the Procurement Portfolio.

Manufacturing organizations' environmental impacts are often attributable to processes in the firm's upstream supply chain. Environmentally preferable procurement (EPP) and the establishment of environmental purchasing criteria can potentially reduce these indirect impacts. Life-cycle assessment (LCA) can help identify the purchasing criteria that are most effective in reducing environmental impacts. However, the high costs of LCA and the problems associated with the comparability of results have limited efforts to integrate procurement performance with quantitative organizational environmental performance targets. Moreover, environmental purchasing criteria, when implemented, are often established on a product-by-product basis without consideration of other products in the procurement portfolio. We develop an approach that utilizes streamlined LCA methods, together with linear programming, to determine optimal portfolios of product impact-reduction opportunities under budget constraints. The approach is illustrated through a simulated breakfast cereal manufacturing firm procuring grain, containerboard boxes, plastic packaging, electricity, and industrial cleaning solutions. Results suggest that extending EPP decisions and resources to the portfolio level, recently made feasible through the methods illustrated herein, can provide substantially greater CO2e and water-depletion reductions per dollar spend than a product-by-product approach, creating opportunities for procurement organizations to participate in firm-wide environmental impact reduction targets.

Further studies on vinamidinium salt amine exchange reactions, borohydride reductions and subsequent transformations.

Studies directed at the amine exchange reaction of vinamidinium salts followed by sodium borohydride reduction to secondary and tertiary allylic amines are described. The tertiary allylic amines were alkylated and subjected to base mediated rearrangement to yield a variety of highly functionalized tertiary homoallylic amines.