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Background Cancer cells have an imbalance in oxidation-reduction (redox) homeostasis. Understanding the precise mechanisms and the impact of the altered redox microenvironment on the immunologic reaction to tumors is limited. Methods We isolated exosomes from ovarian cancer cells through ultracentrifuge and characterized by Western-blots and Nanoparticle Tracking Analysis. 2D, 3D-coculture tumor model, and 3D live cell imaging were used to study the interactions between tumor cells, macrophages and CD3 T cells in vitro. The role of exosomal miR-155-5p in tumor growth was evaluated in xenograft nude mice models and immune-competent mice models. Flow cytometry and flow sorting were used to determine the expression levels of miR-155-5p and PD-L1 in ascites and splenic macrophages, and the percentages of CD3 T cells subpopulations. Results The elevation of reactive oxygen species (ROS) greatly downregulated exosomal miR-155-5p expression in tumor cells. Neutralization of ROS with N-acetyl-L-cysteine (NAC) increased the levels of miR-155-5p in tumor exosomes that were taken up by macrophages, leading to reduction of macrophage migration and tumor spheroid infiltration. We further found that programmed death ligand 1 (PD-L1) is a functional target of miR-155-5p. Co-culture of macrophages pre-treated with NAC-derived tumor exosomes or exosomal miR-155-5p with T-lymphocytes leading to an increased percentage of CD8 + T-lymphocyte and a decreased CD3 + T cell apoptosis through PD-L1 downregulation. Tumor growth in nude mice was delayed by treatment with NAC-derived tumor exosomes. Delivery of tumor exo-miR-155-5p in immune-intact mice suppressed ovarian cancer progression and macrophage infiltration, and activated CD8 + T cell function. It is of note that exo-miR-155-5p inhibited tumor growth more potently than the PD-L1 antibody, suggesting that in addition to PD-L1, other pathways may also be targeted by this approach. Conclusions Our findings demonstrate a novel mechanism, ROS-induced down-regulation of miR-155-5p, by which tumors modulate the microenvironment that favors tumor growth. Understanding of the negative impact of ROS on the tumor immune response will improve current therapeutic strategies. Targeting miR-155-5p can be an alternative approach to prevent formation of an immunosuppressive TME through downregulation of PD-L1 and other immunosuppressive factors. Graphical Abstract

Using her watercolor artistry and universal accompanying quotes of wisdom, Maryjo Koch has assembled a delightful little book of happy thoughts and images.

Background Current research on the transmission of trauma and eating disorders across generations is limited. However, quantitative studies suggest that the influence of parents’ and grandparents’ eating disorders and their prior exposure to trauma are associated with the development of eating disorders in future generations. Qualitative research exploring personal accounts of the impact of transgenerational trauma on the development of eating disorders has been largely unexplored. The aim of the current qualitative study was to explore the meaning that participants ascribed to their eating disorders in the context of transgenerational trauma across three generations. Methods Six adult female participants who had received a diagnosis of anorexia nervosa and/or bulimia nervosa completed multiple unstructured interviews, informed by a psychoanalytical methodology. Results Four themes were developed from the material that emerged from the interviews: (1) The toll of undigested emotions (2), A need for safety (3), “ It’s not just me” – making connections with the past , and (4) “Last link” in the chain? Conclusions The themes were discussed in respect of previous literature, with a particular emphasis on Gerson’s concept of the dead third , which emphasises an unconscious compulsion to repeat unprocessed transgenerational traumas. Clinical implications of the research underscores the importance of a holistic approach to the treatment of eating disorders, recognising both individual and familial traumas within the family system. Moreover, the research demonstrates the significant impact that mental health clinicians can have in eating disorder treatment by fostering a supportive, safe and trusting therapeutic relationship. Plain English summary Previous research in the field of eating disorders has shown that eating disorders might be passed down through families, possibly because of past unprocessed traumas experienced by parents and grandparents. However, there are few research studies that have asked people who experience eating disorders how they understand the meaning of their eating disorders in the context of their families histories. Six adult women who were diagnosed with anorexia nervosa and/or bulimia nervosa spoke about their thoughts and feelings in relation to their eating disorders in the context of transgenerational trauma. The results showed that for participants in this study, their eating disorders helped them to manage their emotions and to feel safe. Participants struggled with overwhelming emotions and felt a lack of safety in their childhoods. These experiences were connected to the unprocessed traumas that their parents and grandparents experienced. Participants spoke about their hopes of stopping the transmission of transgenerational traumas through their engagement in eating disorder treatment and recovery. Overall, the study highlights the importance of considering both individual and family traumas when treating eating disorders. It also emphasizes how crucial supportive relationships with mental health professionals can be in eating disorder treatment.

Published for a major exhibition at The Museum of Modern Art, this catalog reveals new perspectives on the work of Frank Lloyd Wright. Structured as a series of inquiries into the Frank Lloyd Wright Foundation Archives at Taliesin West, Arizona, the book is a collection of scholarly explorations rather than an attempt to construct a master narrative. Each chapter centers on a key object from the archive that aninvited author has \"unpacked\" -- tracing its meanings and connections, and juxtaposing it with other works from the archive, from MoMA, or from outside collections. The publication aims to open up Wright's work to questions, interrogations and debates, and to highlight interpretations by contemporary scholars, both established Wright experts and others considering this iconic figure from new and illuminating perspectives.

Pulsed Field Ablation (PFA) is a new ablation method being rapidly adopted for treatment of atrial fibrillation, which shows advantages in safety and efficiency over radiofrequency and cryo-ablation. In this study, we used an in vivo swine model (10 healthy and 5 with chronic myocardial infarct) for ventricular PFA, collecting intracardiac electrograms, electro-anatomical maps, native T1-weighted and late gadolinium enhancement MRI, gross pathology, and histology. We used 1000–1500 V pulses, with 1–16 pulse trains to vary PFA dose. Lesions were assessed at 24 h, 7 days, and 6 weeks in healthy and at 48 h in infarcted ventricles. Comparisons of lesion sizes using a numerical model enabled us to determine lethal electric field thresholds for cardiac tissue and its dependence on the number of pulse trains. Similar thresholds were found in normal and infarcted hearts. Numerical modeling and temperature-sensitive MRI confirmed the nonthermal nature of PFA, with less than 2% of a lesion’s volume at the highest dose used being attributed to thermal damage. Longitudinal cardiac MRI and histology provide a comprehensive description of lesion maturation. Lesions shrink between 24 h and 7 days post-ablation and then remain stable out to 6 weeks post-ablation. Periprocedural electrograms analysis yields good correlation with lesion durability and size.

The broad adoption of transgenic crops has revolutionized agriculture. However, resistance to insecticidal proteins by agricultural pests poses a continuous challenge to maintaining crop productivity and new proteins are urgently needed to replace those utilized for existing transgenic traits. We identified an insecticidal membrane attack complex/perforin (MACPF) protein, Mpf2Ba1, with strong activity against the devastating coleopteran pest western corn rootworm (WCR) and a novel site of action. Using an integrative structural biology approach, we determined monomeric, pre-pore and pore structures, revealing changes between structural states at high resolution. We discovered an assembly inhibition mechanism, a molecular switch that activates pre-pore oligomerization upon gut fluid incubation and solved the highest resolution MACPF pore structure to-date. Our findings demonstrate not only the utility of Mpf2Ba1 in the development of biotechnology solutions for protecting maize from WCR to promote food security, but also uncover previously unknown mechanistic principles of bacterial MACPF assembly. The insecticidal protein Mpf2Ba1 shows potent control against corn rootworm. Here, the authors present detailed structural analyses revealing transitions between its three main stages of pore formation. These findings uncover molecular mechanisms of bacterial pore assembly and advance both crop biotechnology and food security.

Background Despite a strong evidence base and policy recommendation supporting the implementation of psychoeducation interventions within the mental health system, equitable access for many service users and family members has not been achieved. To enhance translation, developing an evidence-base around the factors that influence implementation of interventions is critical. Methods The aim of the study was to explore the factors influencing implementation of a group cofacilitated recovery focused psychoeducation intervention. The study design was explorative qualitative descriptive, involving the collection of data through individual and focus group interviews with key stakeholders ( n  = 75) involved with the implementation within 14 mental health sites in the Republic of Ireland. The Consolidation Framework for Implementation Research (CFIR) was used as a conceptual framework to guide data collection and analysis. Results Key enablers and barriers were identified across all CFIR domains of the framework with some factors (depending on context) being both an enabler and a barrier. Important factors in the outer setting domain included structural stability within national systems and the peer payment system, while the extent of a recovery-oriented culture, leadership, implementation readiness, and buy-in were influential factors in the inner setting. The characteristics of the intervention in terms of design, evidence-base and adaptability also shaped the intervention’s implementation as did the knowledge, beliefs and self-efficacy of facilitators. In terms of processes, implementation was influenced by the degree of engagement of key individuals who championed and supported the programme. The results highlight that while some of the barriers were specific to the programme, many reflected systemic and structural challenges within health services more generally. Conclusion Findings from this study provide an enhanced understanding of the different layers of determinants to implementation of an intervention. Overcoming challenges will involve positive and ongoing engagement and collaboration across the full range of stakeholders that are active within each domain, including policy and operational levels. The quality of leadership at each domain level is of crucial importance to successful implementation.

In this article, I engage Athanasius of Alexandria’s invocation of the infamous dismemberment of the unnamed woman found in Judg 19. By the fourth century, this story of gang rape—along with other preserved stories of sexual violence—found in Judges, were scattered throughout early Christian literature. Judges 19 holds a particularly troubling history in the late ancient context. The story of the rape and dismemberment of the unnamed woman in Judg 19 gave life to another story and typified a style of writing that I characterize in the article as a heresiology. The spectacle of Judges, along with other gruesome deaths of women, was one way in which heresiological discourse frames rhetorical arguments for writers like Athanasius of Alexandria. Here, I purposely draw our attention to how Athanasian orthodoxy became reliant on gender-based violence.