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Abstract Moral injury has emerged as a construct of interest in healthcare workers’ (HCW) occupational stress and health. We conducted one of the first multidisciplinary, longitudinal studies evaluating the relationship between exposure to potentially morally injurious events (PMIEs), burnout, and turnover intentions. HCWs (N = 473) completed surveys in May of 2020 (T1) and again in May of 2021 (T2). Generalized Linear Models (robust Poisson regression) were used to test relative risk of turnover intentions, and burnout at T2 associated with PMIE exposure, controlling for T1 covariates. At T1, 17.67% reported they had participated in a PMIE, 41.44% reported they witnessed a PMIE and 76.61% reported feeling betrayed by healthcare or a public health organization. In models including all T1 PMIE exposures and covariates, T2 turnover intentions were increased for those who witnessed a PMIE at T1 (Relative Risk [RR] = 1.66, 95% Confidence Interval [CI] 1.17–2.34) but not those that participated or felt betrayed. T2 burnout was increased for those who participated in PMIE at T1 (RR = 1.38, 95%CI 1.03–1.85) but not those that witnessed or felt betrayed. PMIE exposure is highly prevalent among HCWs, with specific PMIEs associated with turnover intentions and burnout. Organizational interventions to reduce and facilitate recovery from moral injury should account for differences in the type of PMIE exposures that occur in healthcare work environments.

Although U.S. schools grapple with persistent racial inequities, niceness, a socioemotional way of being that privileges whiteness, regularly impedes equity efforts in K-12 and teacher education settings. In the Midwest, niceness is uniquely rooted in a historical "obsession with public civility" (Cayton & Gray, 2002, p. 159) that advances whiteness through a "demure white supremacy" (Cleveland, 2021, para. 6), particularly in education. Here, the authors theorize Midwestern educational niceness, a regionally produced and enacted phenomenon "nicely" instantiated by the overwhelmingly white, Midwestern teacher workforce that stymies equity efforts. The authors conceptualize the ways whiteness, through niceness, works through other phenomena including color-evasiveness (Annamma et al., 2017; Bonilla-Silva, 2006), white fragility (DiAngelo, 2018), and emotionalities of whiteness (Matias, 2016). Countering the insidiousness of Midwestern educational niceness will require a recognition that this regional form of niceness and equity are incommensurate.

Abstract CAR-T therapy is a promising, novel treatment modality for B-cell malignancies and yet many patients relapse through a variety of means, including loss of CAR-T cells and antigen escape. To investigate leukemia-intrinsic CAR-T resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screens in an immunocompetent murine model of B-cell acute lymphoblastic leukemia (B-ALL) utilizing a modular guide RNA library. We identified IFNγR/JAK/STAT signaling and components of antigen processing and presentation pathway as key mediators of resistance to CAR-T therapy in vivo; intriguingly, loss of this pathway yielded the opposite effect in vitro (sensitized leukemia to CAR-T cells). Transcriptional characterization of this model demonstrated upregulation of these pathways in tumors relapsed after CAR-T treatment, and functional studies showed a surprising role for natural killer (NK) cells in engaging this resistance program. Finally, examination of data from B-ALL patients treated with CAR-T revealed an association between poor outcomes and increased expression of JAK/STAT and MHC-I in leukemia cells. Overall, our data identify an unexpected mechanism of resistance to CAR-T therapy in which tumor cell interaction with the in vivo tumor microenvironment, including NK cells, induces expression of an adaptive, therapy-induced, T-cell resistance program in tumor cells.

Abstract Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family β-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.

Abstract The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human disease. Structures of LRRK2 have recently been determined, but the structure and molecular mechanisms regulating the activity of the LRRK1 as well as differences in the regulation of LRRK1 and LRRK2 remain unclear. Here, we report a cryo-EM structure of the LRRK1 monomer and a lower-resolution cryo-EM map of the LRRK1 dimer. The monomer structure, in which the kinase is in an inactive conformation, reveals key interdomain interfaces that control kinase activity as we validate experimentally. Both the LRRK1 monomer and dimer are structurally distinct compared to LRRK2. Overall, our results provide structural insights into the activation of the human LRRKs, which advance our understanding of their physiological and pathological roles.

Blood vessels in different vascular beds vary in size, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vessel size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow, eventually leading to the DA collapse. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA size in she mutants correlated with an increased endothelial expression of claudin 5a (cldn5a), which encodes a protein enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates vessel and lumen size during vascular tubulogenesis.

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Introduction: Cannabinoids including cannabidiol (CBD) have attracted enormous interest as bioactive ingredients for various dermatological and/or cosmeceutical uses. However, topical applications of cannabinoids might be limited without a fundamental understanding of their skin permeability. Herein, we aimed to evaluate the skin permeability of CBD and its topical formulations using artificial skin membrane assays. The solubility and stability of CBD in various surfactants that are commonly used in topical applications were also evaluated. Methods: CBD and two CBD-incorporated topical formulations (cream and gel) were prepared for this study. Computational predictions (SwissADME and DERMWIN™) and the parallel artificial membrane permeability assay (PAMPA) were used to evaluate the skin permeability of CBD isolate. The Franz cell diffusion (in vitro release testing) assay was used to evaluate the skin permeability of CBD formulations. The solubility and stability of CBD in surfactants were assessed by high-performance liquid chromatography and mass spectrometry analysis. Results: CBD isolate showed favorable skin permeability in the SwissADME and DERMWIN™ predictions (−Log Kp of 3.6 and 5.7 cm/s, respectively) and PAMPA (−LogPe value of 5.0 at pH of 6.5 and 7.4). In addition, CBD had higher solubility (378.4 μg/mL) in surfactant Tween 20 as compared to its solubility in polyisobutene. In an acidic environment (pH 5 and 6), Tween 20 maintained the CBD content at 81% and 70% over 30 days, respectively. CBD in the formulations of cream and gel also had moderate skin permeability in the Franz cell diffusion assay. Conclusion: Data from artificial membrane-based assays support that CBD is a skin permeable cannabinoid and the permeability and stability of its formulations may be influenced by several factors such as surfactant and pH environment. Findings from our study suggest that CBD may have suitable skin permeability for the development of dermatological and/or cosmeceutical applications but further studies using in vivo models are warranted to confirm this.

Coronary bifurcation lesions and treatment with two-stent techniques have been developed, including the double kissing (DK) crush technique. The use of this technique in children or noncoronary vessels, including pulmonary arteries, has not been described. We present a 12-year-old girl with Alagille syndrome, a ventricular septal defect (VSD), and complex bilateral pulmonary artery (PA) stenoses who is status post six catheterizations for PA angioplasty and stenting to improve her marked right ventricular hypertension. With collaboration between the congenital and structural teams, she successfully underwent the DK crush technique for a complex lesion in her PA. This improved pulmonary flow and allowed for successful surgical VSD closure.

Anthropogenically fragmented populations may have reduced fitness due to loss of genetic diversity and inbreeding. The extent of such fitness losses due to fragmentation and potential gains from conservation actions are infrequently assessed together empirically. Controlled crosses within and among populations can identify whether populations are at risk of inbreeding depression and whether inter-population crossing alleviates fitness loss. Because fitness depends on the environment and life stage, studies quantifying cumulative fitness over a large portion of the lifecycle in conditions that mimic natural environments are most informative. To assess the fitness consequences of habitat fragmentation, we leveraged controlled within-family, within-population, and between-population crosses to quantify inbreeding depression and heterosis in seven populations of Echinacea angustifolia within a 6,400-ha area. We then assessed cumulative offspring fitness after 14 yr of growth in a natural experimental plot (N  = 1,136). The mean fitness of progeny from within-population crosses varied considerably, indicating genetic differentiation among source populations, even though these sites are all less than 9 km apart. The fitness consequences of within-family and between-population crosses varied in magnitude and direction. Only one of the seven populations showed inbreeding depression of high effect, while four populations showed substantial heterosis. Outbreeding depression was rare and slight. Our findings indicate that local crossings between isolated populations yield unpredictable fitness consequences ranging from slight decreases to substantial increases. Interestingly, inbreeding depression and heterosis did not relate closely to population size, suggesting that all fragmented populations could contribute to conservation goals as either pollen recipients or donors. [ABSTRACT FROM AUTHOR]

We report on commissioning experiments at the high-energy, high-temperature (HHT) target area at the GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany, combining for the first time intense pulses of heavy ions from the SIS18 synchrotron with high-energy laser pulses from the PHELIX laser facility. We demonstrate the use of X-ray diagnostic techniques based on intense laser-driven X-ray sources, which will allow probing of large samples volumetrically heated by the intense heavy-ion beams. A new target chamber as well as optical diagnostics for ion-beam characterization and fast pyrometric temperature measurements complement the experimental capabilities. This platform is designed for experiments at the future Facility for Antiproton and Ion Research in Europe GmbH (FAIR), where unprecedented ion-beam intensities will enable the generation of millimeter-sized samples under high-energy-density conditions. [ABSTRACT FROM AUTHOR]

Chemical screening libraries often feature natural product extracts (NPEs) due to the intriguing biological activities they possess and the structural diversity found in their individual components. A research project originally designed to create an extract library of every specimen in the University of Rhode Island (URI) Heber W. Youngken Jr. Medicinal Garden soon turned into a laboratory-based teaching project in which upper-division undergraduate students generated and analyzed extracts in an academic minisemester project. Additionally, motivated upper-division undergraduates carried out independent research isolating biologically active molecules. Hands-on laboratory activities enhanced students' knowledge of methodologies and workflows associated with extract analysis and biological evaluation of botanical extracts. The synergy of the laboratory course with the independent study contributed to workforce preparation and library generation.