Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy.

Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving cancer therapy, an understanding of fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.

Advancing gender inclusivity for Two-Spirit, trans, nonbinary and other gender-diverse blood and plasma donors.

Background And Objectives: Two-Spirit, trans, nonbinary and other gender-diverse (2STGD) donors face challenges in donation. While many blood operators aim to address these challenges, to date, no empirical study with these donors has been conducted to guide their efforts. This paper reports 2STGD donors' views on a two-step approach asking donors their gender and sex assigned at birth (SAAB), and expanding gender options in donor registration.

Involving lived experience in regional efforts to address gambling-related harms: going beyond 'window dressing' and 'tick box exercises'.

Background: Lived Experience (LE) involvement has been shown to improve interventions across diverse sectors. Yet LE contributions to public health approaches to address gambling-related harms remain underexplored, despite notable detrimental health and social outcomes linked to gambling. This paper analyses the potential of LE involvement in public health strategy to address gambling-related harms.

What works in advocating for food advertising policy change across an english region - a realist evaluation.

Background: With increasing recognition of the role of commercial determinants of health, local areas in England have sought to restrict the advertising of products high in fat, salt and sugar (HFSS) on council-owned spaces, as part of wider strategies to reduce obesity. While there is some evidence of the impact of such policy change on behaviour, little is known about what works in the process of implementing this policy change.

Methods: Guided by a realist evaluation framework that explores the interaction between context, mechanism and outcomes, this study aims to investigate the factors that influence the restriction of outdoor advertising of HFSS products in one region in England.

The conceptualization and development of critical health literacy in children: a scoping review.

The cognitive and social practices associated with critical health literacy, such as critical appraisal of health messages and participation in political processes to address wider determinants of health, are of lifelong benefit. Understanding how and where critical health literacy development can be supported early in the life course may improve health outcomes now and in the future. This scoping review focuses on how critical health literacy in children is conceptualized and the supportive environments available for its development.

Co-producing principles to guide health research: an illustrative case study from an eating disorder research clinic.

Background: There is significant value in co-produced health research, however power-imbalances within research teams can pose a barrier to people with lived experience of an illness determining the direction of research in that area. This is especially true in eating disorder research, where the inclusion of co-production approaches lags other research areas. Appealing to principles or values can serve to ground collaborative working.

RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia.

Runt-related transcription factor 1 (RUNX1) is oncogenic in diverse types of leukemia and epithelial cancers where its expression is associated with poor prognosis. Current models suggest that RUNX1 cooperates with other oncogenic factors (e.g.

Settings for the development of health literacy: A conceptual review.

Advances in conceptualizing settings in health promotion include understanding settings as complex and interlinked systems with a core commitment to health and related outcomes such as health literacy. Traditional settings for the development of health literacy include health care environments and schools. There is a need to identify and conceptualize non-traditional and emerging settings of twenty-first-century everyday life.

Involving Children in Health Literacy Research.

Despite the volume and breadth of health literacy research related to children, children's involvement in that research is rare. Research with children is challenging, but the principles of involvement and engagement underpin all health promotion work, including health literacy. This commentary reflects on the process of setting up a Children's Advisory Group to consult on an institutional ethnography study of health literacy work from children's standpoint.

Immunohistochemical characteristics of local sites that trigger atrial arrhythmias in response to high-frequency stimulation.

Aims: The response to high frequency stimulation (HFS) is used to locate putative sites of ganglionated plexuses (GPs), which are implicated in triggering atrial fibrillation (AF). To identify topological and immunohistochemical characteristics of presumed GP sites functionally identified by HFS.

Methods And Results: Sixty-three atrial sites were tested with HFS in four Langendorff-perfused porcine hearts.

Public Libraries as Supportive Environments for Children's Development of Critical Health Literacy.

Critical health literacy enables individuals to use cognitive and social resources for informed action on the wider determinants of health. Promoting critical health literacy early in the life-course may contribute to improved health outcomes in the long term, but children's opportunities to develop critical health literacy are limited and tend to be school-based. This study applies a settings-based approach to analyse the potential of public libraries in England to be supportive environments for children's development of critical health literacy.

Digital Health Intervention Design and Deployment for Engaging Demographic Groups Likely to Be Affected by the Digital Divide: Protocol for a Systematic Scoping Review.

Background: Digital health interventions refer to interventions designed to support health-related knowledge transfer and are delivered via digital technologies, such as mobile apps. Digital health interventions are a double-edged sword: they have the potential to reduce health inequalities, for example, by making treatments available remotely to rural populations underserved by health care facilities or by helping to overcome language barriers via in-app translation services; however, if not designed and deployed with care, digital health interventions also have the potential to increase health inequalities and exacerbate the effects of the digital divide.

Objective: The aim of this study is to review ways to mitigate the digital divide through digital health intervention design, deployment, and engagement mechanisms sensitive to the needs of digitally excluded populations.

North American temperate conifer (Tsuga canadensis) reveals a complex physiological response to climatic and anthropogenic stressors.

Rising atmospheric CO (c) is expected to promote tree growth and lower water loss via changes in leaf gas exchange. However, uncertainties remain if gas-exchange regulation strategies are homeostatic or dynamical in response to increasing c, as well as evolving climate and pollution inputs. Using a suite of tree ring-based δC-derived physiological parameters (ΔC, c, iWUE) and tree growth from a mesic, low elevation stand of canopy-dominant Tsuga canadensis in north-eastern USA, we investigated the influence of rising c, climate and pollution on, and characterised the dynamical regulation strategy of, leaf gas exchange at multidecadal scales.

Cross-Priming Dendritic Cells Exacerbate Immunopathology After Ischemic Tissue Damage in the Heart.

Background: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of heart failure. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells, and potentially initiate a persistent autoimmune response against the heart.

Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling.

We describe a human and large animal Langendorff experimental apparatus for live electrophysiological studies and measure the electrophysiological changes due to gap junction uncoupling in human and porcine hearts. The resultant ex vivo intact human and porcine model can bridge the translational gap between smaller simple laboratory models and clinical research. In particular, electrophysiological models would benefit from the greater myocardial mass of a large heart due to its effects on far-field signal, electrode contact issues and motion artefacts, consequently more closely mimicking the clinical setting.

An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo.

Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.

Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity.

Acute leukemias are aggressive malignancies of developmentally arrested hematopoietic progenitors. We sought here to explore the possibility that changes in hematopoietic stem/progenitor cells during development might alter the biology of leukemias arising from this tissue compartment. Using a mouse model of acute T cell leukemia, we found that leukemias generated from fetal liver (FL) and adult bone marrow (BM) differed dramatically in their leukemia stem cell activity with FL leukemias showing markedly reduced serial transplantability as compared to BM leukemias.

RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes.

RUNX1 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). The spectrum of RUNX1 mutations has led to the notion that it acts as a tumor suppressor in this context; however, other studies have placed RUNX1, along with transcription factors TAL1 and NOTCH1, as core drivers of an oncogenic transcriptional program. To reconcile these divergent roles, we knocked down RUNX1 in human T-ALL cell lines and deleted Runx1 or Cbfb in primary mouse T-cell leukemias.

IGF1R Derived PI3K/AKT Signaling Maintains Growth in a Subset of Human T-Cell Acute Lymphoblastic Leukemias.

Insulin-like growth factor 1 receptor (IGF1R) is a prevalent signaling pathway in human cancer that supports cell growth/survival and thus contributes to aggressive biological behavior. Much work has gone into development of IGF1R inhibitors; however, candidate agents including small molecule tyrosine kinase inhibitors and blocking antibodies have yet to fulfill their promise clinically. Understanding cellular features that define sensitivity versus resistance are important for effective patient selection and anticipation of outgrowth of a resistant clone.

Giant reversible anisotropy changes at room temperature in a (La,Sr)MnO3/Pb(Mg,Nb,Ti)O3 magneto-electric heterostructure.

In a model artificial multiferroic system consisting of a (011)-oriented ferroelectric Pb(Mg,Nb,Ti)O3 substrate intimately coupled to an epitaxial ferromagnetic (La,Sr)MnO3 film, electric field pulse sequences of less than 6 kV/cm induce large, reversible, and bistable remanent strains. The magnetic anisotropy symmetry reversibly switches from a highly anisotropic two-fold state to a more isotropic one, with concomitant changes in resistivity. Anisotropy changes at the scale of a single ferromagnetic domain were measured using X-ray microscopy, with electric-field dependent magnetic domain reversal showing that the energy barrier for magnetization reversal is drastically lowered.

CD44 promotes chemoresistance in T-ALL by increased drug efflux.

T-Cell acute lymphoblastic leukemia is considered a largely curable disease in children; however, adult patients and children with refractory or relapsed disease have consistently poor outcomes. On the basis of our prior work highlighting CD44 as a marker of leukemia-initiating cells in animal models and because cancer stem cells are postulated to possess intrinsic resistance to conventional chemotherapy, we examined whether CD44 itself might play a role in mediating chemoresistance. We report here that in both genetically defined mouse models and human cell lines, CD44 expression is associated with chemoresistance, and that this effect is mediated in part through enhanced drug efflux.

Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling.

The Wnt signaling pathway has been shown to play important roles in normal hematopoietic stem cell biology and in the development of both acute and chronic myelogenous leukemia. Its role in maintaining established leukemia stem cells, which are more directly relevant to patients with disease, however, is less clear. To address what role Wnt signaling may play in T-cell acute lymphoblastic leukemia (T-ALL), we used a stably integrated fluorescent Wnt reporter construct to interrogate endogenous Wnt signaling activity in vivo.

Carbon p electron ferromagnetism in silicon carbide.

Ferromagnetism can occur in wide-band gap semiconductors as well as in carbon-based materials when specific defects are introduced. It is thus desirable to establish a direct relation between the defects and the resulting ferromagnetism. Here, we contribute to revealing the origin of defect-induced ferromagnetism using SiC as a prototypical example.

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7.