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Explicit Runge--Kutta (RK) methods are susceptible to a reduction in the observed order of convergence when applied to an initial boundary value problem with time-dependent boundary conditions. We study conditions on explicit RK methods that guarantee high order convergence for linear problems; we refer to these conditions as weak stage order conditions. We prove a general relationship between the method's order, weak stage order, and number of stages. We derive explicit RK methods with high weak stage order and demonstrate, through numerical tests, that they avoid the order reduction phenomenon up to any order for linear problems and up to order three for nonlinear problems. 

Abstract Members of advantaged groups are more likely than members of disadvantaged groups to think, feel, and behave in ways that reinforce their group's position within the hierarchy. This study examined how children's status within a group‐based hierarchy shapes their beliefs about the hierarchy and the groups that comprise it in ways that reinforce the hierarchy. To do this, we randomly assigned children (4–8 years;N = 123; 75 female, 48 male; 21 Asian, 9 Black, 21 Latino/a, 1 Middle‐Eastern/North‐African, 14 multiracial, 41 White, 16 not‐specified) to novel groups that differed in social status (advantaged, disadvantaged, neutral third‐party) and assessed their beliefs about the hierarchy. Across five separate assessments, advantaged‐group children were more likely to judge the hierarchy to be fair, generalizable, and wrong to challenge and were more likely to hold biased intergroup attitudes and exclude disadvantaged group members. In addition, with age, children in both the advantaged‐ and disadvantaged‐groups became more likely to see membership in their own group as inherited, while at the same time expecting group‐relevant behaviors to be determined more by the environment. With age, children also judged the hierarchy to be more unfair and expected the hierarchy to generalize across contexts. These findings provide novel insights into how children's position within hierarchies can contribute to the formation of hierarchy‐reinforcing beliefs. Research HighlightsA total of 123 4–8‐year‐olds were assigned to advantaged, disadvantaged, and third‐party groups within a hierarchy and were assessed on seven hierarchy‐reinforcing beliefs about the hierarchy.Advantaged children were more likely to say the hierarchy was fair, generalizable, and wrong to challenge and to hold intergroup biases favoring advantaged group members.With age, advantaged‐ and disadvantaged‐group children held more essentialist beliefs about membership in their own group, but not the behaviors associated with their group.Results suggest that advantaged group status can shape how children perceive and respond to the hierarchies they are embedded within. 

Projecting ecological and evolutionary responses to variable and changing environments is central to anticipating and managing impacts to biodiversity and ecosystems. Current modeling approaches are largely phenomenological and often fail to accurately project responses due to numerous biological processes at multiple levels of biological organization responding to environmental variation at varied spatial and temporal scales. Limited mechanistic understanding of organismal responses to environmental variability and extremes also restricts predictive capacity. We outline a strategy for identifying and modeling the key organismal mechanisms across levels of biological organization that mediate ecological and evolutionary responses to environmental variation. A central component of this strategy is quantifying timescales and magnitudes of climatic variability and how organisms experience them. We highlight recent empirical research that builds this information and suggest how to design future experiments that can produce more generalizable principles. We discuss how to create biologically informed projections in a feasible way by combining statistical and mechanistic approaches. Predictions will inform both fundamental and practical questions at the interface of ecology, evolution, and Earth science such as how organisms experience, adapt to, and respond to environmental variation at multiple hierarchical spatial and temporal scales. 

Abstract Alternative end joining (alt-EJ) mechanisms, such as polymerase theta-mediated end joining, are increasingly recognized as important contributors to inaccurate double-strand break repair. We previously proposed an alt-EJ model whereby short DNA repeats near a double-strand break anneal to form secondary structures that prime limited DNA synthesis. The nascent DNA then pairs with microhomologous sequences on the other break end. This synthesis-dependent microhomology-mediated end joining (SD-MMEJ) explains many of the alt-EJ repair products recovered following I-SceI nuclease cutting in Drosophila. However, sequence-specific factors that influence SD-MMEJ repair remain to be fully characterized. Here, we expand the utility of the SD-MMEJ model through computational analysis of repair products at Cas9-induced double-strand breaks for 1100 different sequence contexts. We find evidence at single nucleotide resolution for sequence characteristics that drive successful SD-MMEJ repair. These include optimal primer repeat length, distance of repeats from the break, flexibility of DNA sequence between primer repeats, and positioning of microhomology templates relative to preferred primer repeats. In addition, we show that DNA polymerase theta is necessary for most SD-MMEJ repair at Cas9 breaks. The analysis described here includes a computational pipeline that can be utilized to characterize preferred mechanisms of alt-EJ repair in any sequence context. 

The wide-scale use of liposomal delivery systems is challenged by difficulties in obtaining potent liposomal suspensions. Passive and active loading strategies have been proposed to formulate drug encapsulated liposomes but are limited by low efficiencies (passive) or high drug specificities (active). Here, we present an efficient and universal loading strategy for synthesizing therapeutic liposomes. Integrating a thermal equilibration technique with our unique liposome synthesis approach, co-loaded targeting nanovesicles can be engineered in a scalable manner with potencies 200-fold higher than typical passive encapsulation techniques. We demonstrate this capability through simultaneous co-loading of hydrophilic and hydrophobic small molecules and targeted delivery of liposomal Doxorubicin to metastatic breast cancer cell line MDA-MB-231. Molecular dynamic simulations are used to explain interactions between Doxorubicin and liposome membrane during thermal equilibration. By addressing the existing challenges, we have developed an unparalleled approach that will facilitate the formulation of novel theranostic and pharmaceutical strategies. 

Abstract Symbiosis with protists is common among cnidarians such as corals and sea anemones and is associated with homeostatic and phenotypic changes in the host that could have epigenetic underpinnings, such as methylation of CpG dinucleotides. We leveraged the sensitivity to base modifications of nanopore sequencing to probe the effect of symbiosis with the chlorophyte Elliptochloris marina on methylation in the sea anemone Anthopleura elegantissima. We first validated the approach by comparison of nanopore-derived methylation levels with CpG depletion analysis of a published transcriptome, finding that high methylation levels are associated with CpG depletion as expected. Next, using reads generated exclusively from aposymbiotic anemones, a largely complete draft genome comprising 243 Mb was assembled. Reads from aposymbiotic and symbiotic sea anemones were then mapped to this genome and assessed for methylation using the program Nanopolish, which detects signal disruptions from base modifications as they pass through the nanopore. Based on assessment of 452,841 CpGs for which there was adequate read coverage (approximately 8% of the CpGs in the genome), symbiosis with E. marina was, surprisingly, associated with only subtle changes in the host methylome. However, we did identify one extended genomic region with consistently higher methylation among symbiotic individuals. The region was associated with a DNA polymerase zeta that is noted for its role in translesion synthesis, which opens interesting questions about the biology of this symbiosis. Our study highlights the power and relative simplicity of nanopore sequencing for studies of nucleic acid base modifications in non-model species.