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Abstract Background In clinical research, there has been a call to move beyond individual psychosocial factors towards identifying cultural and social factors that inform mental health. Similar calls have been made in the eating disorders (ED) field underscoring the need to understand larger sociocultural influences on EDs. Discrimination is a social stressor that may influence mental health in similar ways to traumatic or adverse childhood experiences (ACEs). Given the high rates of EDs and discrimination among marginalized groups, it is vital to understand the role of discrimination and ACEs as predictors of ED symptoms in these populations. The aim of this study is to examine how perceived discrimination predicts ED pathology when statistically adjusting for gender, race, and ACEs. Methods The diverse study sample consisted of 331 undergraduate students from a longitudinal cohort study (ages 18–24; 66% female; 35% White/non-Hispanic). Participants completed measures of everyday discrimination, ACEs, and ED pathology. Results Following adjustment for multiple statistical comparisons, the frequency of daily discrimination predicted all ED symptoms above and beyond history of ACEs. In follow-up analyses, number of reasons for discrimination predicted cognitive restraint and purging. Differences in ED symptomatology were found based on the reason for discrimination, gender, and race. Specifically, those who experienced weight discrimination endorsed higher scores on all ED symptoms, and those experiencing gender discrimination endorsed higher body dissatisfaction, cognitive restraint, and restriction. People of color endorsed higher restriction, while female participants endorsed higher scores on all ED symptom with the exception of cognitive restraint. Conclusion Discrimination is a salient risk factor for ED symptoms even when accounting for individuals’ history of ACEs. Future research should utilize an intersectional approach to examine how perceived discrimination affects ED pathology over time. (Word count: 234). 

Phagocytic elimination of solid tumors by innate immune cells seems attractive for immunotherapy, particularly because of the possibilities for acquired immunity. However, the approach remains challenging, with blockade of the macrophage checkpoint CD47 working in immunodeficient mice and against highly immunogenic tumors but not in the clinic where tumors are poorly immunogenic. Even when mouse tumors of poorly immunogenic B16F10 melanoma are opsonized to drive engulfment with a suitable monoclonal antibody (mAb), anti-CD47 blockade remains insufficient. Using both in vitro immuno-tumoroids and in vivo mouse models, we show with CRISPR interference (CRISPRi) that a relatively uniform minimum repression of CD47 by 80% is needed for phagocytosis to dominate net growth when combined with an otherwise ineffective mAb (anti-Tyrp1). Heterogeneity enriches for CD47-high cells, but mice that eliminate tumors generate prophagocytic IgGs that increase in titer with CD47 repression and with tumor accumulation of macrophages, although deeper repression does not improve survival. Given well-known limitations of antibody permeation into solid tumors, our studies clarify benchmarks for CD47 disruption that should be more clinically feasible and safer but just as effective as complete ablation. Additionally, safe but ineffective opsonization in human melanoma trials suggests that combinations with deep repression of CD47 could prove effective and initiate durable immunity.

 

Ecologists and evolutionary biologists are increasingly cognizant of rapid adaptation in wild populations. Rapid adaptation to anthropogenic environmental change is critical for maintaining biodiversity and ecosystems services into the future. Anthropogenic salinization of freshwater ecosystems is quickly emerging as a primary threat, which is well documented in the northern temperate ecoregion. Specifically, many northern temperate lakes have undergone extensive salinization because of urbanization and the associated increase in impervious surfaces causing runoff, and the extensive use of road deicing salts (e.g., NaCl). It remains unclear whether increasing salinization will lead to extirpation of species from these systems. Using a “resurrection genomics” approach, we investigated whether the keystone aquatic herbivore,Daphnia pulicaria,has evolved increased salinity tolerance in a severely salinized lake located in Minnesota, USA. Whole-genome resequencing of 54Daphniaclones from the lake and hatched from resting eggs that represent a 25-y temporal contrast demonstrates that many regions of the genome containing genes related to osmoregulation are under selection in the study population. Tolerance assays of clones revealed that the most recent clones are more tolerant to salinity than older clones; this pattern is concomitant with the temporal pattern of stabilizing salinity in this lake. Together, our results demonstrate that keystone species such asDaphniacan rapidly adapt to increasing freshwater salinization. Further, our results indicate that rapid adaptation to salinity may allow lakeDaphniapopulations to persist in the face of anthropogenic salinization maintaining the food webs and ecosystem services they support despite global environmental change.

 

The nucleus in many cell types is a stiff organelle, but fat-filled lipid droplets (FDs) in cytoplasm are seen to indent and displace the nucleus. FDs are phase-separated liquids with a poorly understood interfacial tension γ that determines how FDs interact with other organelles. Here, micron-sized FDs remain spherical as they indent peri-nuclear actomyosin and the nucleus, while causing local dilution of Lamin-B1 independent of Lamin-A,C and sometimes triggering nuclear rupture. Focal accumulation of the cytosolic DNA sensor cGAS at the rupture site is accompanied by sustained mislocalization of DNA repair factors to cytoplasm, increased DNA damage, and delayed cell cycle. Macrophages show FDs and engulfed rigid beads cause similar indentation dilution. Spherical shapes of small FDs indicate a high γ, which we measure for FDs mechanically isolated from fresh adipose tissue as ∼40 mN/m. This value is far higher than that of protein condensates, but typical of oils in water and sufficiently rigid to perturb cell structures including nuclei.

 

In solid tumours, the abundance of macrophages is typically associated with a poor prognosis. However, macrophage clusters in tumour-cell nests have been associated with survival in some tumour types. Here, by using tumour organoids comprising macrophages and cancer cells opsonized via a monoclonal antibody, we show that highly ordered clusters of macrophages cooperatively phagocytose cancer cells to suppress tumour growth. In mice with poorly immunogenic tumours, the systemic delivery of macrophages with signal-regulatory protein alpha (SIRPα) genetically knocked out or else with blockade of the CD47–SIRPα macrophage checkpoint was combined with the monoclonal antibody and subsequently triggered the production of endogenous tumour-opsonizing immunoglobulin G, substantially increased the survival of the animals and helped confer durable protection from tumour re-challenge and metastasis. Maximizing phagocytic potency by increasing macrophage numbers, by tumour-cell opsonization and by disrupting the phagocytic checkpoint CD47–