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Fluoropolymers are a distinct class of per- and polyfluoroalkyl substances (PFAS), high molecular weight (MW) polymers with fluorine attached to their carbon-only backbone. Fluoropolymers possess a unique combination of properties and unmatched functional performance critical to the products and manufacturing processes they enable and are irreplaceable in many uses. Fluoropolymers have documented safety profiles; are thermally, biologically, and chemically stable, negligibly soluble in water, nonmobile, nonbioavailable, nonbioaccumulative, and nontoxic. Although fluoropolymers fit the PFAS structural definition, they have very different physical, chemical, environmental, and toxicological properties when compared with other PFAS. This study describes the composition, uses, performance properties, and functionalities of 14 fluoropolymers, including fluoroplastics and fluoroelastomers, and presents data to demonstrate that they satisfy the widely accepted polymer hazard assessment criteria to be considered polymers of low concern (PLC). The PLC criteria include physicochemical properties, such as molecular weight, which determine bioavailability and warn of potential hazard. Fluoropolymers are insoluble (e.g., water, octanol) solids too large to migrate into the cell membrane making them nonbioavailable, and therefore, of low concern from a human and environmental health standpoint. Further, the study results demonstrate that fluoropolymers are a distinct and different group of PFAS and should not be grouped with other PFAS for hazard assessment or regulatory purposes. When combined with an earlier publication by Henry et al., this study demonstrates that commercial fluoropolymers are available from the seven participating companies that meet the criteria to be considered PLC, which represent approximately 96% of the global commercial fluoropolymer market. Integr Environ Assess Manag 2022;00:1-29. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental ToxicologyChemistry (SETAC).

Supplementary Methods

Acute leukemias are systemic malignancies associated with a dire outcome. Because of low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages toward a tumor-promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates antileukemic immunity and elicits effective and lasting natural killer cell– and T cell–dependent immune response against naïve and treatment-resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD-1 checkpoint blockade in PD-1–refractory leukemias. Finally, we provide proof-of-concept that a clinical-grade AXL inhibitor can be used in combination with standard-of-care therapy to cure established leukemia, regardless of AXL expression in malignant cells.Significance:Alternatively primed myeloid cells predict negative outcome in leukemia. By demonstrating that leukemia cells actively evade immune control by engaging AXL receptor tyrosine kinase in macrophages and promoting their alternative priming, we identified a target which blockade, using a clinical-grade inhibitor, is vital to unleashing the therapeutic potential of myeloid-centered immunotherapy.This article is highlighted in the In This Issue feature, p. 2659

Supplementary Figures and Figure legends

The cellular mechanisms required to ensure homeostasis of the hematopoietic niche and the ability of this niche to support hematopoiesis upon stress remain elusive. We here identify Wnt5a in Osterix+ mesenchymal progenitor and stem cells (MSPCs) as a critical factor for niche-dependent hematopoiesis. Mice lacking Wnt5a in MSPCs suffer from stress-related bone marrow (BM) failure and increased mortality. Niche cells devoid of Wnt5a show defective actin stress fiber orientation due to an elevated activity of the small GTPase CDC42. This results in incorrect positioning of autophagosomes and lysosomes, thus reducing autophagy and increasing oxidative stress. In MSPCs from patients from BM failure states which share features of peripheral cytopenia and hypocellular BM, we find similar defects in actin stress fiber orientation, reduced and incorrect colocalization of autophagosomes and lysosomes, and CDC42 activation. Strikingly, a short pharmacological intervention to attenuate elevated CDC42 activation in vivo in mice prevents defective actin-anchored autophagy in MSPCs, salvages hematopoiesis and protects against lethal cytopenia upon stress. In summary, our study identifies Wnt5a as a restriction factor for niche homeostasis by affecting CDC42-regulated actin stress-fiber orientation and autophagy upon stress. Our data further imply a critical role for autophagy in MSPCs for adequate support of hematopoiesis by the niche upon stress and in human diseases characterized by peripheral cytopenias and hypocellular BM.

Highlight of the multimodal characterization of corrosion behaviour of microgram quantities of UO2, enabled by a novel particle-attached microfluidic electrochemical cell.

Multiple CubeSat altimeters can work independently or corporately to form altimeter constellations. Different configurations of the constellations can acquire distinguished advantages: improved spatial/temporal sampling and high cross-track resolution, which will be helpful for observations of oceanic small-scale structures and weather forecasting. Compared to single conventional altimeters, CubeSat altimeter constellations may achieve better performances with lower costs. To fully understand these systems, this article focuses on the performance analysis and methodology for CubeSat altimeter constellations. Besides the typical analyses of the resolution, revisit, and absolute sea surface height (SSH) accuracy, the performance analysis was conducted by considering the characteristics of multiple measurements provided by CubeSat altimeter constellations. Local and global spatial sampling performances are investigated for various constellations and compared by sampling density and swath size. Moreover, relative SSH accuracy is introduced and evaluated based on the spatial structure functions of errors to effectively evaluate the measurement performance. Related system requirements on power, delta-v, etc., to achieve the performance are also discussed, which ensures that the analysis fits the boundary conditions of implementation. Finally, different concepts of the CubeSat altimeter constellations are compared, where their limitations and possible solutions are also discussed.

Bone marrow samples from discarded femoral heads are often used as healthy controls in studies investigating the in vitro characteristics of cells from patients with hematologic malignancies. Since patient samples are usually derived from iliac crest aspirates, this carries the risk that the properties of the cells from both sources might be different due to the site and method of harvesting. Comparing BM cells from iliac crest aspirates and femoral heads from age-matched healthy donors, we show that, while mesenchymal stromal cells have indistinguishable properties between both sources, hematopoietic stem and progenitor cells (HSPC) from femoral heads show a considerable proliferative advantage in vitro. These data therefore suggest that experiments comparing leukemic cells from the iliac crest to healthy HSPC obtained from femoral heads should be interpreted with caution.

A conflict of interest occurs when parasites manipulate the behavior of their host in contradictory ways. In grass shrimp (Palaemonetes pugio), trematode parasites cause the shrimp to be more active than usual around predators, while bopyrid isopod parasites elicit the opposite response. Since these parasites are altering the host’s behavior in opposing directions, a conflict of interest should occur in doubly infected shrimp. Natural selection should favor attempts to resolve this conflict through avoidance, killing, or sabotage. In a field survey of shrimp populations in four tidal creeks in the Cape Fear River, we found a significant negative association between the two parasites. Parasite abundance was negatively correlated in differently sized hosts, suggesting avoidance as a mechanism. Subsequent mortality experiments showed no evidence of early death of doubly infected hosts. In behavior trials, doubly infected shrimp did not show significantly different behavior from other infection statuses, suggesting that neither parasite sabotages the manipulation of the other. Taken together, our results suggest that rather than sabotaging one another directly, bopyrid and trematode parasites reduce conflict by preferentially infecting differently sized hosts. Because grass shrimp exist at high biomass in salt marsh ecosystems and are infected at high prevalence, our findings have implications for ecosystem structure and function.

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone–derived cells as healthy experimental controls.

PurposeHypereosinophilia represents a heterogenous group of severe medical conditions characterized by elevated numbers of eosinophil granulocytes in peripheral blood, bone marrow or tissue. Treatment options for hypereosinophilia remain limited despite recent approaches including IL-5-targeted monoclonal antibodies and tyrosine kinase inhibitors.MethodsTo understand aberrant survival patterns and options for pharmacologic intervention, we characterized BCL-2-regulated apoptosis signaling by testing for BCL-2 family expression levels as well as pharmacologic inhibition using primary patient samples from diverse subtypes of hypereosinophilia (hypereosinophilic syndromen = 18, chronic eosinophilic leukemia not otherwise specifiedn = 9, lymphocyte-variant hypereosinophilian = 2, myeloproliferative neoplasm with eosinophilian = 2, eosinophilic granulomatosis with polyangiitisn = 11, reactive eosinophilian = 3).ResultsContrary to published literature, we found no difference in the levels of the lncRNAMorrbidand its targetBIM. Yet, we identified a near complete loss of expression of pro-apoptoticPUMAas well as a reduction in anti-apoptoticBCL-2. Accordingly,BCL-2inhibition using venetoclax failed to achieve cell death induction in eosinophil granulocytes and bone marrow mononuclear cells from patients with hypereosinophilia. In contrast,MCL1inhibition using S63845 specifically decreased the viability of bone marrow progenitor cells in patients with hypereosinophilia. In patients diagnosed with Chronic Eosinophilic Leukemia (CEL-NOS) or Myeloid and Lymphatic Neoplasia with hypereosinophilia (MLN-Eo) repression of survival was specifically powerful.ConclusionOur study shows thatMCL1inhibition might be a promising therapeutic option for hypereosinophilia patients specifically for CEL-NOS and MLN-Eo.

Host density shapes infection risk through two opposing phenomena. First, when infective stages are subdivided among multiple hosts, greater host densities decrease infection risk through ‘safety in numbers’. Hosts, however, represent resources for parasites, and greater host availability also fuels parasite reproduction. Hence, host density increases infection risk through ‘density-dependent transmission’. Theory proposes that these phenomena are not disparate outcomes but occur over different timescales. That is, higher host densities may reduce short-term infection risk, but because they support parasite reproduction, may increase long-term risk. We tested this theory in a zooplankton-disease system with laboratory experiments and field observations. Supporting theory, we found that negative density–risk relationships (safety in numbers) sometimes emerged over short timescales, but these relationships reversed to ‘density-dependent transmission’ within two generations. By allowing parasite numerical responses to play out, time can shift the consequences of host density, from reduced immediate risk to amplified future risk.

The precise modeling of the de-excitation of Gd isotopes is of great interest for experimental studies of neutrinos using Gd-loaded organic liquid scintillators. The FIFRELIN code was recently used within the purposes of the STEREO experiment for the modeling of the Gd de-excitation after neutron capture in order to achieve a good control of the detection efficiency. In this work, we report on the recent additions in the FIFRELIN de-excitation model with the purpose of enhancing further the de-excitation description. Experimental transition intensities from EGAF database are now included in the FIFRELIN cascades, in order to improve the description of the higher energy part of the spectrum. Furthermore, the angular correlations between {\gamma} rays are now implemented in FIFRELIN, to account for the relative anisotropies between them. In addition, conversion electrons are now treated more precisely in the whole spectrum range, while the subsequent emission of X rays is also accounted for. The impact of the aforementioned improvements in FIFRELIN is tested by simulating neutron captures in various positions inside the STEREO detector. A repository of up-to-date FIFRELIN simulations of the Gd isotopes is made available for the community, with the possibility of expanding for other isotopes which can be suitable for different applications., Comment: Corrected typos on author names on arXiv metadata

Humans live in complex socio-ecological systems where we interact with parasites and pathogens that spend time in abiotic and biotic environmental reservoirs (e.g., water, air, soil, other vertebrate hosts, vectors, intermediate hosts). Through a synthesis of published literature, we reviewed the life cycles and environmental persistence of 150 parasites and pathogens tracked by the World Health Organization's Global Burden of Disease study. We used those data to derive the time spent in each component of a pathogen's life cycle, including total time spent in humans versus all environmental stages. We found that nearly all infectious organisms were “environmentally mediated” to some degree, meaning that they spend time in reservoirs and can be transmitted from those reservoirs to human hosts. Correspondingly, many infectious diseases were primarily controlled through environmental interventions (e.g., vector control, water sanitation), whereas few (14%) were primarily controlled by integrated methods (i.e., combining medical and environmental interventions). Data on critical life history attributes for most of the 150 parasites and pathogens were difficult to find and often uncertain, potentially hampering efforts to predict disease dynamics and model interactions between life cycle time scales and infection control strategies. We hope that this synthetic review and associated database serve as a resource for understanding both common patterns among parasites and pathogens and important variability and uncertainty regarding particular infectious diseases. These insights can be used to improve systems-based approaches for controlling environmentally mediated diseases of humans in an era where the environment is rapidly changing.

Dead animal biomass (carrion) is present in all terrestrial ecosystems, and its consumption, decomposition, and dispersal can have measurable effects on vertebrates, invertebrates, microbes, parasites, plants, and soil. But despite the number of studies examining the influence of carrion on food webs, there has been no attempt to identify how general ecological processes around carrion might be used as an ecosystem indicator. We suggest that knowledge of scavenging and decomposition rates, scavenger diversity, abundance, and behavior around carrion, along with assessments of vegetation, soil, microbe, and parasite presence, can be used individually or in combination to understand food web dynamics. Monitoring carrion could also assist comparisons of ecosystem processes among terrestrial landscapes and biomes. Although there is outstanding research needed to fully integrate carrion ecology and monitoring into ecosystem management, we see great potential in using carrion as an ecosystem indicator of an intact and functional food web., We argue that information about the processes and organisms involved with the consumption and decomposition of dead animal matter (carrion) can provide insights into the broader health and integrity of ecosystems.

A dopamine D2 receptor mutation was recently identified in a family with a novel hyperkinetic movement disorder. Compared to the wild type D2 receptor, the novel allelic variant D2-I(212)F activates a Gα(i1)β(1)γ(2) heterotrimer with higher potency and modestly enhanced basal activity in human embryonic kidney (HEK) 293 cells, and has decreased capacity to recruit arrestin3. We now report that omitting overexpressed G protein-coupled receptor kinase-2 (GRK2) decreased the potency and efficacy of quinpirole for arrestin recruitment. The relative efficacy of quinpirole for arrestin recruitment to D2-I(212)F compared to D2-WT was considerably lower without overexpressed GRK2 than with added GRK2. D2-I(212)F exhibited higher basal activation of Gα(oA) than Gα(i1), but little or no increase in the potency of quinpirole relative to D2-WT. Other signs of D2-I(212)F constitutive activity for G protein-mediated signaling, in addition to basal activation of Gα(i/o), were enhanced basal inhibition of forskolin-stimulated cyclic AMP accumulation that was reversed by the inverse agonists sulpiride and spiperone and a ~4-fold increase in the apparent affinity of D2-I(212)F for quinpirole, determined from competition binding assays. In mouse midbrain slices, inhibition of tonic current by the inverse agonist sulpiride in dopamine neurons expressing D2-I(212)F was consistent with our hypothesis of enhanced constitutive activity and sensitivity to dopamine relative to D2-WT. Molecular dynamics simulations with D2 receptor models suggested that an ionic lock between the cytoplasmic ends of the third and sixth α-helices that constrains many G protein-coupled receptors in an inactive conformation spontaneously breaks in D2-I(212)F. Overall, these results confirm that D2-I(212)F is a constitutively active and signaling-biased D2 receptor mutant, and also suggest that the effect of the likely pathogenic variant in a given brain region will depend on the nature of G protein and GRK expression.

Development of coastal New England has led to the replacement of up to 37% of salt marshes with degraded freshwater wetlands, primarily through tidal restrictions. Removing these restrictions to restore salt marsh ecology would improve water quality, increase flood and storm protection, nutrient filtration, erosion control, and carbon sequestration. However, such restorations replace functional freshwater wetlands and could potentially impact freshwater species. Freshwater-dependent wildlife species such as the spotted turtle (Clemmys guttata), may be especially vulnerable to rapid changes in habitat resulting from tidal reintroduction due to their high site fidelity and limited ability to disperse quickly. Conservation of genetically and physically isolated spotted turtle populations as well as the restoration of salt marshes to mitigate climate change impacts are both high priorities on Nantucket Island. These two priorities conflicted in a project to restore tidal hydrology to an impounded freshwater marsh known to host a robust spotted turtle population. We evaluated changes to spotted turtle home range size and location and habitat use in response to salt marsh restoration over eight years. Home range size did not change but the location of home ranges shifted into bordering wetlands landward of the tidal salt water influence. Spotted turtles selected remaining freshwater marshes and shrub swamps while avoiding developed land and areas of establishing salt marsh within areas that had previously been high quality habitat. This study suggests prioritizing conservation of wetlands adjacent to planned salt marsh restoration to provide habitat for freshwater species to migrate.

Clonal hematopoiesis (CH) is characterized by somatic mutations in blood cells of individuals without hematologic disease. While the mutational landscape of CH in peripheral blood (PB) has been well characterized, detailed analyses addressing its spatial and cellular distribution in the bone marrow (BM) compartment are sparse. We studied CH driver mutations in healthy individuals (n = 261) across different anatomical and cellular compartments. Variant allele frequencies were higher in BM than PB and positively correlated with the number of driver variants, yet remained stable during a median of 12 months of follow-up. In CH carriers undergoing simultaneous bilateral hip replacement, we detected ASXL1-mutant clones in one anatomical location but not the contralateral side, indicating intra-patient spatial heterogeneity. Analyses of lineage involvement in ASXL1-mutated CH showed enriched clonality in BM stem and myeloid progenitor cells, while lymphocytes were particularly involved in individuals carrying the c.1934dupG variant, indicating different ASXL1 mutations may have distinct lineage distribution patterns. Patients with overt myeloid malignancies showed higher mutation numbers and allele frequencies and a shifting mutation landscape, notably characterized by increasing prevalence of DNMT3A codon R882 variants. Collectively, our data provide novel insights into the genetics, evolution, and spatial and lineage-specific BM involvement of CH.

To reach the Sustainable Development Goals, we may need to act on synergies between some targets while mediating trade-offs between other targets. But what, exactly, are synergies and trade-offs, and how are they related to other outcomes, such as ‘win–win’ solutions? Finding limited guidance in the existing literature, we developed an operational method for distinguishing win–wins from eight other possible dual outcomes (lose–lose, lose–neutral and so on). Using examples related to human health and conservation, we illustrate how interdisciplinary problem-solvers can use this framework to assess relationships among targets and compare multi-target interventions that affect people and nature. Reaching the Sustainable Development Goals requires recognizing trade-offs and synergies among targets. Focusing on conservation and human health, this Perspective suggests how to productively distinguish win–wins from other outcomes.

Cell-free systems contain many proteins and metabolites required for complex functions such as transcription and translation or multi-step metabolic conversions. Research into expanding the delivery of these systems by drying or by embedding into other materials is enabling new applications in sensing, point-of-need manufacturing, and responsive materials. Meanwhile, silk fibroin from the silk worm, Bombyx mori, has received attention as a protective additive for dried enzyme formulations and as a material to build biocompatible hydrogels for controlled localization or delivery of biomolecular cargoes. In this work, we explore the effects of silk fibroin as an additive in cell-free protein synthesis (CFPS) reactions. Impacts of silk fibroin on CFPS activity and stability after drying, as well as the potential for incorporation of CFPS into hydrogels of crosslinked silk fibroin are assessed. We find that simple addition of silk fibroin increased productivity of the CFPS reactions by up to 42%, which we attribute to macromolecular crowding effects. However, we did not find evidence that silk fibroin provides a protective effects after drying as previously described for purified enzymes. Further, the enzymatic crosslinking transformations of silk fibroin typically used to form hydrogels are inhibited in the presence of the CFPS reaction mixture. Crosslinking attempts did not impact CFPS activity, but did yield localized protein aggregates rather than a hydrogel. We discuss the mechanisms at play in these results and how the silk fibroin-CFPS system might be improved for the design of cell-free devices.

Our present understanding of surface dissolution of nuclear fuels such as uranium dioxide (UO2) is limited by the use of non-local characterization techniques. Here we discuss the use of state-of-the-art scanning transmission electron microscopy (STEM) to reveal atomic–scale changes occurring to a UO2 thin film subjected to anoxic dissolution in deionised water. No amorphisation of the UO2 film surface during dissolution is observed, and dissolution occurs preferentially at surface reactive sites that present as surface pits which increase in size as the dissolution proceeds. Using a combination of STEM imaging modes, energy-dispersive X-ray spectroscopy (STEM-EDS), and electron energy loss spectroscopy (STEM-EELS), we investigate structural defects and oxygen passivation of the surface that originates from the filling of the octahedral interstitial site in the centre of the unit cells and its associated lattice contraction. Taken together, our results reveal complex pathways for both the dissolution and infiltration of solutions into UO2 surfaces.

The sequestration of metal ions into the crystal structure of minerals is common in nature. To date, the incorporation of technetium(IV) into iron minerals has been studied predominantly for systems under carefully controlled anaerobic conditions. Mechanisms of the transformation of iron phases leading to incorporation of technetium(IV) under aerobic conditions remain poorly understood. Here we investigate granular metallic iron for reductive sequestration of technetium(VII) at elevated concentrations under ambient conditions. We report the retarded transformation of ferrihydrite to magnetite in the presence of technetium. We observe that quantitative reduction of pertechnetate with a fraction of technetium(IV) structurally incorporated into non-stoichiometric magnetite benefits from concomitant zero valent iron oxidative transformation. An in-depth profile of iron oxide reveals clusters of the incorporated technetium(IV), which account for 32% of the total retained technetium estimated via X-ray absorption and X-ray photoelectron spectroscopies. This corresponds to 1.86 wt.% technetium in magnetite, providing the experimental evidence to theoretical postulations on thermodynamically stable technetium(IV) being incorporated into magnetite under spontaneous aerobic redox conditions. For the geological disposal of radionuclides through immobilization within minerals, naturally aerobic conditions need to be considered. Here the authors report a quantitative reduction of Tc7+ and partial structural incorporation of Tc4+ into in situ formed nonstochiometric magnetite under ambient conditions.