Broad Changes Research Articles

Mechanisms of school-based peer education interventions to improve young people's health literacy or health behaviours: A realist-informed systematic review.

Peer education interventions are widely used in secondary schools with an aim to improve students' health literacy and/or health behaviours. Although peer education is a popular intervention technique with some evidence of effectiveness, we know relatively little about the key components that lead to health improvements among young people, or components that may be less helpful. This review aims to identify the main mechanisms involved in school-based peer education health interventions for 11-18-year-olds. Five electronic databases were searched for eligible studies during October 2020, an updated search was then conducted in January 2023 to incorporate any new studies published between November 2020 and January 2023. To be included in the review, studies must have evaluated a school-based peer education intervention designed to address aspects of the health of students aged 11-18 years old and contain data relevant to mechanisms of effect of these interventions. No restrictions were placed on publication date, or country but only manuscripts available in English language were included. Forty papers were identified for inclusion with a total of 116 references to intervention mechanisms which were subsequently grouped thematically into 10 key mechanisms. The four most common mechanisms discussed were: 1) Peerness; similar, relatable and credible 2) A balance between autonomy and support, 3) School values and broader change in school culture; and 4) Informal, innovative and personalised delivery methods. Mechanisms were identified in quantitative, qualitative and mixed methods intervention evaluations. This study highlights a number of key mechanisms that can be used to inform development of future school-based peer education health interventions to maximise effectiveness. Future studies should aim to create theories of change or logic models, and then test the key mechanisms, rather than relying on untested theoretical assumptions. Future work should also examine whether particular mechanisms may lead to harm, and also whether certain mechanisms are more or less important to address different health issues, or whether a set of generic mechanisms always need to be activated for success.

Widespread, depth-dependent cortical microstructure alterations in pediatric focal epilepsy.

Tissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes or treatment-related side effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilized quantitative magnetic resonance imaging (MRI), which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug-resistant focal epilepsy and, secondarily, whether changes were related to disease severity. To assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug-resistant focal epilepsy (age range = 4-18 years) and 46 typically developing children (age range = 2-18 years). We assessed depth-dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof-of-concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically defined abnormalities (MRI positive) and healthy controls, and tested whether this could classify patients without reported radiological abnormalities (MRI negative). We uncovered depth-dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 71.4% at 89.4% specificity on held-out MRI-negative patients. These findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically identified abnormalities.

Repeated Activation of Pyramidal Neurons in the Prefrontal Cortex Alters Microglial Phenotype in Male Mice.

Aberrant neuronal activity in the cortex alters microglia phenotype and function in several contexts, including chronic psychologic stress and neurodegenerative disease. Recent findings even suggest that heightened levels of neuronal activity spur microglia to phagocytose synapses, with potential impacts on cognition and behavior. Thus, the present studies were designed to determine if activation of neurons alone-independent of disease or dysfunction-is sufficient to alter microglial phenotype in the medial prefrontal cortex (mPFC), a brain region critical in emotion regulation and cognition. In these studies, we used both an adeno-associated virus-mediated and Cre-dependent chemogenetic [designer receptors exclusively activated by designer drugs (DREADD)] approach to repeatedly activate excitatory pyramidal neurons (CaMKIIa+) neurons in the mPFC. Various molecular, cytometric, and behavioral endpoints were examined. Recurrent DREADD-induced neuronal activation led to pronounced changes in microglial density, clustering, and morphology in the mPFC and increased microglia-specific transcripts implicated in synaptic pruning (e.g., Csf1r, Cd11b). Further analyses revealed that the magnitude of DREADD-induced neuronal activation was significantly correlated with measures of microglial morphology in the mPFC. These alterations in microglial phenotype coincided with an increase in microglial lysosome volume in the mPFC and selective deficits in working memory function. Altogether, these findings indicate that repeated neuronal activation alone is sufficient to drive changes in microglia phenotype and function in the mPFC. Future studies using optogenetic and chemogenetic approaches to manipulate neural circuits need to consider microglial and other nonneuronal contributions to physiologic and behavioral outcomes. SIGNIFICANCE STATEMENT: Microglia are highly attuned to fluctuations in neuronal activity. Here we show that repeated activation of pyramidal neurons in the prefrontal cortex induces broad changes in microglia phenotype; this includes upregulation of pathways associated with microglial proliferation, microglia-neuron interactions, and lysosome induction. Our findings suggest that studies using chemogenetic or optogenetic approaches to manipulate neural circuits should be mindful of indirect effects on nonneuronal cells and their potential contribution to measured outcomes.

Technical and Organisational Change in UK Construction

This paper examines the broad technological and organisational change trends in the UK construction sector. This uses the information from the input-output balances to track the key inputs to construction from the production and services sectors, along with self-input from construction. The inputs to the UK construction sector from 1997 through to 2020, based on the current supply and use tables, form the basis for the analysis. Changes in the inputs from the key commodity groups for materials and services are presented as a time series. Regression analysis is used to evaluate the relationship of the input coefficients against time to see if the slope is significantly different from zero. The changes in the material and service sector inputs are also discussed. The results demonstrate that most of the twelve material groups showed downward trends over the period studied, while most of the five service groups showed increases. This shows that materials provide a declining share of inputs to construction while most services sector inputs, along with self-input from construction, absorb higher shares. This is used to throw some light on changing trends in construction technology and organisational change in areas such as subcontracting, off-site prefabrication, and plant hire. The approach is limited because it can only identify changes between the various broad groups used in the supply and use tables. The analysis confirms certain of the well-documented technological changes in construction. These include the ongoing replacement of traditional brick-build structures with timber-framed technology. It does confirm the continued expansion of the use of subcontracting in construction. It also shows increased inputs from technology and information services and architectural and consultancy services. More surprisingly it does not indicate any rise in off-site prefabrication. Keywords: Construction economics, input-output analysis, organisational change, technical change.

Can Civil Courts Save the Climate? Strategic Climate-change Litigation Before Civil Courts

Climate change is an urgent global problem, and national legislatures must enhance their efforts to reduce carbon dioxide emissions drastically. Individuals and NGOs have filed public law actions against national legislators before international courts (prominently the ECHR) and several constitutional courts to allege violations of constitutional and human rights. In a more recent development, civil courts too are being seized with climate‑change litigation. In 2021, a Dutch court ruling on an action by an NGO against the Royal Dutch Shell Group held that Shell is obliged to reduce its CO2 emissions considerably. This judgment, based on the Dutch Civil Code’s general tort regulations, has triggered a wave of similar actions before German courts. Such cases of individual plaintiffs, supported by NGOs, suing private companies for damages or for an immediate reduction of emissions are examples of ‘strategic litigation’ aimed at bringing about broad societal changes beyond the scope of the individual case at hand. The article analyses the political implications, tackles the question of whether general tort law is a suitable instrument to address the climate‑change problem, and discusses how civil courts may handle these cases. Climate change is a complex, multi-stakeholder issue that requires a difficult process of balancing social, legal, and economic interests – which is the task of democratically legitimised parliaments, not primarily a task of courts.

A mouse model of oral contraceptive exposure: Depression, motivation, and the stress response

Hormonal contraceptives, including oral contraceptives (OCs), regulate hormonal cycles and broadly affect physiological processes, including stress responsivity. Whereas many users describe overall improved mood, up to 10 % of OC users experience adverse effects, including depression and anxiety. Given the link between regulation of hypothalamic-pituitary-adrenal (HPA) axis, stress exposure, and risk for depression, it is likely that OC-effects on stress mediate increased risk or increased resilience to these disorders. In this study, we developed and characterized a tractable mouse model of OC exposure with which to identify the mechanisms underlying OC modulation of brain, behavior, and mood. Specifically, we aimed to determine whether translationally relevant doses of OC-hormones in mice mimic changes in stress responsivity observed in humans taking OCs and describe behavioral changes during OC exposure. Young adult female C57Bl/6 N mice received daily ethinyl estradiol (EE) and levonorgestrel (LVNG) in 10 % sucrose, EE and drospirenone (DRSP) in 10 % sucrose, or 10 % sucrose alone. Translationally relevant doses of EE + LVNG-exposure, but not EE + DRSP, suppressed the acute stress response, consistent with effects observed in human OC users. EE + LVNG caused a specific anhedonia-like effect, without broad changes in stress-coping behavior, other depression-like behaviors, or anxiety-like behaviors. The suppression of regular estrous cycling, together with the blunting of the corticosterone response to acute stress, demonstrate the utility of this model for future studies to identify the mechanisms underlying OC interactions with stress, motivation, and risk for depression.

US Medicaid program: An analysis of the spending and utilization patterns for antidepressants from 2017 to 2021

BackgroundMajor depressive disorder (MDD) is a serious mental health condition that contributes to health complications, financial burden and death. In 2020, about one in five US adults had a lifetime diagnosis of MDD. With Major Depressive Disorder (MDD) being a common mental health concern, it is important to understand treatment patterns within public health systems like Medicaid, as they play a crucial role in providing care to diverse populations. ObjectiveThe study investigated antidepressant usage and market distribution in the Medicaid Program. By doing so, the study aimed to provide insights into how these trends reflect broader changes in mental health treatment practices and policy implications within the Medicaid system during the study period. MethodsPublic Medicaid data from 2017 to 2021 were analyzed, focusing on 30 FDA-approved antidepressants. Spending and prescription data were aggregated using Excel and Python. ResultsThe total US Medicaid expenditure on antidepressants increased from about $1 billion dollars in 2017 to $1.12 billion dollars in 2021, an increase of about 10%. Consistently, SSRIs were the class of antidepressants that Medicaid spent the most on. The highest Medicaid spending on a single antidepressant in 2017 and 2018 was bupropion. During the remaining years of the study (2019, 2020, 2021) Medicaid appropriated most funds toward Vortioxetine. The total number of antidepressant prescriptions increased from 52 million scripts to 59 million scripts (an increase of about 14%). ConclusionsThe increase in Medicaid spending on antidepressants during the study period can be explained by an increase in utilization (a 14% increase in antidepressant prescriptions from 2017 to 2021), and a shift toward prescribing newer more costly antidepressants (like SSRIs and others) and away from prescribing older, less costly antidepressants like monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs).”

Single-cell RNA sequencing uncovers the cell type-dependent transcriptomic changes in the retrosplenial cortex after peripheral nerve injury

The retrosplenial cortex (RSC) is a vital area for storing remote memory and has recently been found to undergo broad changes after peripheral nerve injury. However, little is known about the role of RSC in pain regulation. Here, we examine the involvement of RSC in the pain of mice with nerve injury. Notably, reducing the activities of calcium-/calmodulin-dependent protein kinase type II-positive splenial neurons chemogenetically increases paw withdrawal threshold and extends thermal withdrawal latency in mice with nerve injury. The single-cell or single-nucleus RNA-sequencing results predict enhanced excitatory synaptic transmissions in RSC induced by nerve injury. Local infusion of 1-naphthyl acetyl spermine into RSC to decrease the excitatory synaptic transmissions relieves pain and induces conditioned place preference. Our data indicate that RSC is critical for regulating physiological and neuropathic pain. The cell type-dependent transcriptomic information would help understand the molecular basis of neuropathic pain.

Long-term biocrust responses to wildfires in Washington, USA.

Dryland ecosystems in the western United States are affected by invasive species, wildfires, livestock grazing, and climate change in ways that are difficult to distinguish. Biocrusts perform important ecological roles in these systems and are sensitive to all of these pressures. We revisited a Washington, USA, site sampled for biocrusts in 1999 to focus on effects of exotic annual grass invasion and wildfires in the absence of livestock grazing. We examined changes between 1999 and 2020 using a Bayesian directed acyclic graph (DAG) to interpret direct and indirect causal impacts of wildfire on perennial bunchgrasses, exotic annual grasses, and biocrusts. Between 1999 and 2020, exotic annual grass cover increased in all plots and in unburned plots by 16% and 18%, respectively, bunchgrass cover decreased by 21% and 25%, and biocrust cover decreased by 8.9% and 9.8%. Our DAG suggested that decreases in bunchgrass increased exotic annual grass, which reduced biocrust cover. Wildfires did not directly influence changes in bunchgrass, exotic annual grass, or biocrust cover. Areas dominated by exotic annual grass had less abundant and diverse biocrusts than areas with less exotic annual grass. Biocrust community changes were more strongly related to increasing exotic annual grasses than to wildfires. Changes may relate to other soil disturbances or broad-scale changes in climate or air quality. The minimal influence of wildfire on exotic annual grass and biocrusts suggests that apparent negative impacts of wildfire at other sites may be due to exacerbation by livestock grazing or other surface disturbance.

Ketocarotenoid production in tomato triggers metabolic reprogramming and cellular adaptation: The quest for homeostasis.

Plants are sessile and therefore have developed an extraordinary capacity to adapt to external signals. Here, the focus is on the plasticity of the plant cell to respond to new intracellular cues. Ketocarotenoids are high-value natural red pigments with potent antioxidant activity. In the present study, system-level analyses have revealed that the heterologous biosynthesis of ketocarotenoids in tomato initiated a series of cellular and metabolic mechanisms to cope with the formation of metabolites that are non-endogenous to the plant. The broad multilevel changes were linked to, among others, (i) the remodelling of the plastidial membrane, where the synthesis and storage of ketocarotenoids occurs; (ii) the recruiting of core metabolic pathways for the generation of metabolite precursors and energy; and (iii) redox control. The involvement of the metabolites as regulators of cellular processes shown here reinforces their pivotal role suggested in the remodelled 'central dogma' concept. Furthermore, the role of metabolic reprogramming to ensure cellular homeostasis is proposed.

Transformasi Makna Kata Serapan Bahasa Arab Pada Bahasa Indonesia Dalam Istilah Agama Islam dari Aspek Bahasa dan Budayanya

This research aims to describe Arabic loan words in Indonesian which focuses on terms contained in the Islamic religion and analyze changes in meaning based on linguistic and cultural factors of the source language. This research uses a qualitative descriptive research approach, namely the Systematic Literature Review method with a number of research objects. The data sources used include previous research articles and journals that examine the transformation of language meaning.
 The research results identified three types of meaning changes in Arabic vocabulary that were adopted into Indonesian. The three types of meaning changes include broad meaning changes, narrowed meaning changes, and total meaning changes. This research provides in-depth insight into how words in Arabic interact with the Islamic religion and are then absorbed into Indonesian, and how these meanings change over time and context in aspects of language and culture.

Distinct Temporal Dynamic Serum Metabolite Profiles Characterize Treatment Response and Early Toxicity after B-Cell Lymphoma Directed CAR-T-Cell Therapy

Introduction: CD19 chimeric antigen receptor T-cell therapy (CD19.CAR-T) has profoundly improved treatment options for patients with relapsed/refractory B-cell lymphomas (r/r BCL), but is also associated with distinct toxicities. To elucidate host-intrinsic immunometabolic factors contributing to clinical benefit or immunotoxicity, we recently demonstrated that an increase of metabolically high-risk adipose tissue mass is associated with an elevated cytokine release syndrome (CRS) risk but also with improved survival (Haematologica 2022, CIR 2023). To gain further insights into the underlying immunometabolic mechanisms, we analyzed temporal dynamic changes of serum metabolites in r/r BCL patients during the first 14 days of CD19.CAR-T treatment. Methods: In this single-center analysis, we studied patients receiving CD19.CAR-T for r/r large BCL or mantle cell lymphoma (MCL) between 01/2019 and 12/2021 in a real-world setting. All patients were consecutively treated in our department (LMU University Hospital) and serum was prospectively collected in the morning hours from fasted patients beginning at the day of CAR-T infusion (D0), and 3-5 and 14 days later. Using liquid chromatography mass-spectrometry, we quantitatively analyzed a total of 305 water-soluble metabolites and 734 lipids. Metabolomic data was integrated with clinical patient records including CRS, 1-year progression-free survial (PFS) and amount of visceral adipose tissue (VAT). Results: In total, we measured 170 serum samples from 55 r/r LBCL and 4 r/r MCL patients, of which 52 had serial samples at all three time points (D0: 55, D3-5: 59, D14: 56). The following CAR-T products were administered: axi-cel (n = 26), tisa-cel (n = 29) and brexu-cel (n = 4). 25 (42.4%) patients developed a CRS grade ≥ 2, while 34 patients had a CRS grade 0-1. The best 90-day overall response rate was 52.5%, with a complete remission rate of 42.4%. At 1 year, 67.8% of patients progressed. From the 1039 metabolites measured, 525 metabolites passed quality control. Metabolite values were normalized and auto-scaled for further analysis. A partial least square differential analysis based on the collected time points led to a clear separation of samples with uric acid, desoxy-ribose-5-phosphate (dRibose-P), essential amino acids and (phospho)lipids having the strongest impact. Whereas 56 metabolites showed a significant increase from D0 to D14 led by uric and essential amino acids, 34 metabolites decreased over the course of treatment with the strongest reduction in dRibose-P and sphingosine phosphate. Performing a metabolic pathway enrichment analysis based on the most altered metabolite levels, we detected 22 significantly affected metabolic pathways and programs including aerobic glycolysis, urea cycle, amino acid and lipid metabolism (FDR < 0.1, Fig. 1A). To further delineate metabolite changes in regards to CRS, 1-year PFS and amount of VAT, we conducted a multivariate empirical bayes analysis of variance to specifically detect metabolites with differential temporal dynamics and considered all metabolites with an FDR < 0.1. Patients who developed a CRS ≥ 2° showed increased levels of kynurenine, phosphatidylethanolamides and lysophosphatidylserines, and decreased levels of ornithine and phosphatidylinositols. 1-year progressors showed a significant increase of several phosphatidylinositols beginning at D3-5 after CAR-T infusion, and decreased levels of phosphatidylcholines. For VAT, we used a threshold of 144 cm² which was derived from previously conducted computer tomography segmentation analyses. As expected, VAT cohorts mostly differed in fatty acid metabolism-associated metabolites including (acyl)carnitines, cholesterol esters, triglycerides and xanthine. In order to identify metabolites being associated with multiple outcomes, we looked for mutual metabolites among distinct cohort profiles. Here, one example is phosphatidylinositol-(22:5/16:0), which was increased in CRS 0-1° and 1y-progressors ( Fig. 1B). Conclusions: Our study highlights that CD19.CAR-T treatment is accompanied by broad changes in the serum metabolome of r/r BCL patients, which can be used to profile patients being affected by CAR-T-related immunotoxicity and their response to treatment. In ongoing analyses, we evaluate the use of these profiles for predictive models, and assess their impact on CAR-T cell function in-vitro.

Bone Marrow Cytokines Concentrations in Myelodysplastic Neoplasms: Its Correlation with the Immune Populations and Clonal Hematopoiesis

Background: Myelodysplastic neoplasms (MDS) are a clonal, heterogenic disease of the hematopoietic stem cell. Pathophysiology is mainly related to intrinsic myeloid abnormalities, epigenetic changes and immune system deregulation that leads to changes in the bone marrow microenvironment. MDS patients have shown broad and heterogenic changes in cytokine concentrations compared to controls. An elevation of pro-apoptotic and inflammatory cytokines and chemokines has been described. Nevertheless, the role of inflammatory soluble factors is still poorly understood. We aim to describe cytokine concentrations in the bone marrow of MDS patients and how it correlates with the immune population and clonal hematopoiesis. Methods: We prospectively analyzed 60 bone marrow plasma samples. Forty-four MDS patients without RS or 5q deletion, 8 healthy donors (HD) and 9 cytopenia of unknown significance (CUS). Cytokine/chemokine concentration were analyzed with ThermoFisher commercial kit ProcartaPlexTM Multiplex immunoassay of 32-PLEX (EGF/eotaxin/FGF-2/G-CSF/GM-CSF/HGF/INFalpha/ IFNgamma/IL-1alpha,/IL1-b/IL-10/IL-12/IL-13/IL-15/IL-17a/IL-1RA/IL-2/IL-22 /IL3 /IL-4/IL-5/IL-6/IL-7/IL-8/IL-9), carried out by Luminex® platform. Furthermore, we analyzed NK subpopulations differentiating an immature population (CD56 brigthCD16 −) from a mature one (CD56 dimCD16+). Lymphocyte T sub-populations were studied in PB samples determined as CD45+CD3+ and the different expression of the following monoclonal antibodies CD4/CD8/CCR7/CD45RA/CD27/CD28/CD25/CD127/CXCR3/CXCR6. The analysis was performed, by flow cytometry, on fresh samples, following a membrane staining protocol with 10-colors/3 lasers. Finally, molecular analysis was performed by NGS using the Oncomine Myeloid Research Assay included 40 genes. Results: A total of 60 subjects were included (median age was 71 years-old and 35% were female). Auto-immune disease was present in 6.6% (Figure 1). Regarding chemokines, CCL11 a pro-inflammatory chemokine was increased in MDS (59.73pg/ml) compared to CUS (41.24pg/ml) and HD (22.63pg/ml), also CXCL9, with a complex role in tumor progression, being 29.08pg/ml in MDS, 17.14pg/ml in CUS and 1.13pg/ml in HD. On the other hand, CCL2 and CCL4 showed lower concentrations in MDS vs HD but higher than CUS (Figure 2). Interleukins analysis showed, IL-1RA higher concentrations in MDS (139.9pg/ml), than HD (36.4pg/mL) and no detection in CUS. IL- 2 was detected only in HD (7.61pg/mL) and IL-3 showed greater concentrations in HD and CUS (20.75pg/ml) compared to MDS (13.84pg/ml). IL-6 did not showed differences among the three groups; in 18.3% subjects (11/60) concentrations were ≥10pg/ml and 8 were MDS. IL-8, a pro-inflammatory/proangiogenic cytokine, showed increased concentrations in only 23% subjects (14/60); 13 were MDS. Regarding growth factors, we observed EGF only in HD (28.16%), whilst HGF and VEGF-A showed higher concentrations in MDS. Mature NK sub-populations were increased in CUS (76.16%) vs MDS (11.58%), (p=0.006) and HD (10.66%), (p=0.01). Moreover, CD8+ T lymphocytes between CUS 49.79% vs MDS 14.29% and HD 1.68 (p=0.05) and Th2 in MDS of 22.71% vs CUS 17.5 (p=0.031) without differences to HD 22.54%. Forty-six MDS subjects presented ≥3 somatic mutations, those presented higher concentrations of CCL11 (73.56pg/mL), HGF (497.7pg/mL), CCL2 (95.3pg/ml) and VEGF-A (506pg/mL). Interestingly, we found that among CUS subjects 66.6% (6/9) presented mutations, 2 DMT3A (VAF < 5%), 1 IDH1 (VAF 3.7%), 1 SRSF2 (VAF 38.9%), 1 TET2 (VAF 39.5%), 1 ZRSR2 (VAF 35%), 1 PHF6 (VAF 39.8%). Finally, regarding IPSS-R risk, we observed higher concentrations of inhibitory proteins like IL-10 and cytokines involved in the regulation of tumor microenvironment like CXCL10 or CCL2 in HR-MDS, while in LR-MDS we observed a more cytotoxic and inflammatory profile (Figure 2). Conclusions: Our study describes a heterogenic background of MDS. Suggesting an increase in some cytokines related to cell recruitment, migration, and proliferation in the bone marrow of MDS and an exhaustive and inhibitory environment in those patients with high-risk characteristics, pointing out the important role of immune subpopulations and environment in the clonal progression.

IRF4 Expression in Germinal Center and Lymphoma B Cells Regulates Antigen-Dependent Immune Response

A substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. We showed that this unfavorable group displays increased expression of IRF4, dysregulated immune signaling and an immunosuppressive microenvironment. At the molecular level, IRF4 controls expression of antigen presentation and immune molecules (e.g. HLA-DR, CD40, PDL1). Furthermore, silencing of IRF4 triggers anti-lymphoma immunity ( Mondello P et al, Blood 2022;140 Suppl 1:168-169). However, little is known on the molecular mechanisms whereby IRF4 controls the crosstalk between B and T cells. To address this question, first we performed RNA-seq, ATAC-seq and CUT&TAG of active (H3K27Ac, H3K4me3) and repressive (H3K27me3, H3K4me1) histone marks in TMD8 and HBL1 (lymphoma cells with high IRF4 expression) transfected with two pairs of siIRF4 or siCtr for 72 hours. Gene expression revealed a broad change in transcription, with 432 upregulated genes and 136 downregulated genes in siIRF4 compared to siCtr. Notably, the genes with increased expression following IRF4 silencing coded for antigen presentation, immune molecules and cytokines (e.g. HLA-DR, CD86, IL6, IL10). Accordingly, we observed significant enrichment of antigen presentation, interferon and immune response signatures ( Fig 1A). Integrating RNA-seq with chromatin accessibility showed a significant shift towards transcriptional upregulation at genes nearest to upregulated ATAC peaks, with significant enrichment at enhancers (n=771). Conversely, transcriptional suppression was enriched at enhancers (n=2,458) of downregulated peaks. k-means analyses of all union peaks, generated by merging ATAC with CUT&TAG peaks, revealed a significant gain of H3K4me3, with concordant loss of H3K4me1 at enhancers with upregulated gene expression. In contrast, H3K4me3 was severely decreased at suppressed peaks. TF motif analysis revealed an enrichment for PU.1 and E2A at IRF4-bound regions, suggesting their cooperation in regulating immune signaling. Since antigen presentation and other immune molecules are critical components of the immune synapse, we explored the role of IRF4 on the interaction between germinal center (GC) B and T cells by crossing irf4 fl/fl mice with conditional deletion of irf4 ( Klein et al, Nat Immunol 2006) and Cγ 1cre mice ( Cγ 1cre; irf4 fl/fl) to induce recombination in GC B cells. After 10 days of immunization (GC reaction peak), Cγ 1cre; irf4 fl/fl and Cγ 1cre; irf4 fl/+ GC B cells showed significant increase of HLA-DR and CD40 expression compared to WT. As expected, Cγ 1cre; irf4 fl/fl mice displayed a significantly skewed light-zone:dark-zone ratio in favor of increased dark-zone, which are the cells that most reflect the action of BCL6, with concordant suppression of plasma cells. Additionally, we observed a significant increase of CD4 + T cells after partial or complete deletion of irf4, with upregulation of T FH cells and decrease of T reg cells ( Fig 1B). Notably, mice with loss of irf4 showed a significant decrease in exhausted T FH cells. To test if this effect was dependent on MHC:TCR interaction, we cocultured CD4 + T cells with TMD8 cells transfected with two siIRF4 or siCtr in presence of blocking antibodies for MHC class I, MHC class II or both. Blocking one or the other MHC class I or II partially rescued the IRF4 effect on T reg and T FH cells respectively as well as reduced anti-lymphoma cytotoxicity. Further experiments blocking IRF4-dependent IL6 and IL10 identified these two cytokines as responsible for the additional effects on T cells. To confirm this as an antigen-dependent immune response we coculture sorted GC B cells from NP-OVA-immunized Cγ 1cre; irf4 fl/fl, Cγ 1cre; irf4 fl/+ and WT mice with CSFE-labeled OVA-specific OT-II CD4 + T cells at a ratio of 2:1 in an organoid system for 5 days. We observed induced antigen specific proliferation of CD4 + T cells in the presence of Cγ 1cre; irf4 fl/fl and Cγ 1cre; irf4 fl/+ GC B cellscompared to WT,as indicated by decrease in CSFE expression . We confirmed an increase of T FH cells and a decrease of T reg cells, supporting the conclusion that IRF4 directly controls the antigen-dependent immune response . In summary, IRF4 expression in GC and lymphoma B cells regulates immune signaling with PU.1 and E2A, thereby modulating antigen-dependent immune responses with potential implications for lymphomagenesis. Future studies investigating targeting of IRF4 in lymphoma are warranted.

Evaluation of Serum Homocysteine and Nitric Oxide Levels in Women with Polycystic Ovarian Syndrome and Periodontal Diseases

Polycystic ovary syndrome (PCOS) and periodontal diseases are common chronic inflammatory disorders. PCOS is a complicated condition affects overall health and causes broad spectrum changes that affect periodontal health status. Available evidence suggests that oxidative stress might comprise a link for the association between periodontal diseases and components of the metabolic syndrome. Both homocysteine (Hcy) and nitric oxide (NO) are considered to reflect the strength of oxidative stress. The aims of the study were to compare the periodontal health condition among the study groups (gingivitis, gingivitis +PCOS, chronic periodontitis (CP) and CP + PCOS group) by measuring the clinical periodontal parameters (Plaque Index (PLI), Gingival Index (GI), Bleeding on Probing (BOP), Probing Pocket Depth (PPD) and Clinical Attachment Level (CAL), and measure serum (Hcy) and (NO) and compare their levels between study groups , then correlate between these parameters with each other and with clinical periodontal parameters in order to determine the effect of PCOS on periodontal health status and levels of serum Hcy and NO.

Implementation of a Clinical Entrustment Scale and Feedback Form in an Academic Veterinary Medical Center: An Empirical Analysis of Goal Oriented Learner Driven-Entrustment (GOLD-E) Assessment Tool.

This paper presents findings from an empirical analysis conducted on the initial implementation of Goal Oriented Learner Driven-Entrustment (GOLD-E). Specifically, researchers examined the following questions: How do faculty, technicians, and residents/interns integrate GOLD-E into their assessment process? Is GOLD-E user friendly (e.g., form and functionality)? How do faculty, technicians, and residents/interns navigate the shift from evaluator to coach? Researchers incorporated a number of mixed, overlapping methodologies consisting of both qualitative and quantitative survey responses and focus group interactions. The use of these multiple data representations allowed researchers to gather layered and complex data to provide for a fuller understanding of the initial implementation of the GOLD-E tool. The empirical analysis demonstrates the need for revisions in the GOLD-E assessment tool as well as broad systemic changes to drive transformation in the culture of assessment.

Inter-colony variation in predation, mercury burden and adult survival in a declining seabird

Migratory species with disjunct and localized breeding distributions, including many colonial marine birds, pose challenges for management and conservation as their dynamics are shaped by both broad oceanographic changes and specific factors affecting individual breeding colonies. We compare six colonies of the declining Leach's storm-petrel, Hydrobates leucorhous, across their core range in Atlantic Canada using standard capture-mark-recapture methods to estimate annual survival of individually marked populations of breeding adults. Over the period analysed (5–20 years per colony; 2003–2022), mean annual survival varied among colonies (0.81–0.88) and annually (process error σ ranging from 0.01 to 0.09), though annual fluctuations were not synchronous across colonies. Two colonies with limited natural predation showed higher survival, and there was a decline in survival with increasing colony-specific total mercury burden. Our work shows that colony-specific pressures and regional contaminant burdens are potentially important contributors to current population declines, and highlights the importance of monitoring demographic rates at multiple sites for species that congregate at key life-history stages.

From L.A. to Boise: How Migration Has Changed During the COVID-19 Pandemic

AbstractWe examine how broad changes in work arrangements and lifestyles brought on by the COVID-19 pandemic have affected households’ location decisions. Using data on over 360,000 residential, interstate moves over the last 5 years, we find that more than 12% of moves were directly influenced by the pandemic. Among pandemic-influenced movers, over 15% of households cite that remote work influenced their move. Lifestyle-related (job-related) migration increased (decreased) significantly, particularly for the set of households who are likely to have access to remote work. We further find that these changes in migration patterns are positively related to post-pandemic economic growth.

EPCO-33. H3K4 METHYLATION IS A PREREQUISITE OF CELL FATE CHANGE DURING IDH-MUTANT GLIOMAGENESIS

Abstract RATIONALE: Low grade gliomas (LGGs) are defined by isocitrate dehydrogenase (IDH)-mutations that mediate broad epigenetic changes. However, additional determinants of low-grade gliomagenesis remain unknown, including factors necessary for the activation of LGG gene programs. Here, we aim at identifying epigenetic prerequisites of IDH-dependent gliomagenesis by modulating key chromatin modifiers in a conditionally IDHR132H-expressing immortalized human astrocyte (IHA) model system. METHODS: Using chemical compounds, we targeted key histone modifications and DNA methylation in an inducibly IDHR132H expressing IHA cell line. Flow cytometry for the LGG-associated marker L1CAM served as a primary read-out. Compound candidates were further assessed with RNA-Seq and mass spectrometry. Phenotypic evaluation included sphere formation, clonogenicity, cell viability and invasion assays. Relevant findings were additionally assessed in established LGG cell lines TS603, NCH612 and NCH1681. RESULTS: L1CAM was significantly altered by DOT1L inhibitor EPZ00477, MLL1 inhibitor MM-102, and EZH2 inhibitor GSK-126. MM-102 treatment was associated with broad transcriptional downregulation. Intersecting data from MM-102 and GSK126 treated cells, we identified potential bivalent genes directly affected by inhibitor treatment that were enriched for Wnt signaling and developmental transcription factors implicated in gliomagenesis. Overlapping transcriptional and proteomics data, MM-102-treated cells exhibited a signature of predominantly downregulated genes associated with invasion/migration, extracellular matrix (ECM) and cholesterol metabolism. Fittingly, cells showed impaired invasion, clonal proliferation and sphere forming capacity. The negative effect on sphere formation tracked inversely with aggressiveness of established LGG cell lines. CONCLUSION: Interfering with histone H3K4 methylation through MLL1 inhibition is associated with broad downregulation of gene sets related to cell identity and ECM/migration, reflected by disruption of clonal proliferation in IDHR132H astrocytes and LGG cell lines. This points to deposition of H3K4 methylation as a prerequisite of cell fate change in LGG development. Persisting effects on established LGG cell lines warrant its investigation as a potential therapeutic target.

European public opinion: united in supporting Ukraine, divided on the future of NATO

Abstract • How strong is public support for Ukraine in Europe? Given reports that Russian President Vladimir Putin may be ‘playing for time’ in the hopes that weary publics will demand an end to supporting Ukraine, this is an important question. • In February 2023, we conducted a survey of public attitudes in ten major European countries: France, Germany, the United Kingdom, Estonia, Hungary, Poland, Finland, Sweden, Italy and Spain. • Our findings suggest that Europeans are (almost) unanimous in blaming Russia for the war and strongly in favour of standing by Ukraine in its war effort. • Only minorities of respondents are of the opinion that Ukraine should be urged to accept territorial losses that could help end the war, or that economic sanctions against Russia should be lifted. Even in countries where support for Ukraine is lower (Hungary and Italy), or among more sceptical groups, we typically find a majority or plurality on Ukraine's side (or, at worst, we find only a small majority are pro-Russia). • Regarding NATO, there is no widespread appetite for increasing its presence in eastern Europe (except in Poland and Estonia), and even less support for Ukraine joining the alliance. At least in the eyes of the public, fighting a war in Ukraine is perceived as a goal in itself that does not necessarily elicit broader changes to existing security alliances like NATO. • Looking ahead, if the gap between the expectations audiences had for the Ukrainian counter-offensive and what it actually delivers is too great, we would expect public support for Ukraine in the conflict to weaken overall. • If governments wish to keep support levels high, we recommend targeting communications to reach groups we have found to be less supportive. This could include utilizing non-traditional media platforms to reach younger audiences, or members of populist right-wing groups.