Long-lasting Changes Research Articles

New Perspectives in Immunotherapy: Dendritic Cell Training for Recurrent Respiratory Tract Infections

Specific allergen immunotherapy (AIT) is the only treatment option currently available that has a disease-modifying effect which persists after treatment is stopped. Recent advancements involve using adjuvants with glycoconjugated allergens derived from Saccharomyces cerevisiae to enhance AIT by improving allergen immunogenicity and directing immune responses towards Th1 or regulatory profiles. Novel studies have also demonstrated that these glycoconjugates induce long-lasting epigenetic changes in dendritic cells (DCs), initiating a trained immunity effect that extends protection against subsequent microbial exposures in a process referred to as trained immunity. This process not only broadens the immune response to target antigens but also provides an enhanced response to subsequent microbial challenges, representing a significant breakthrough in the treatment of recurrent or multiple infections. Moreover, respiratory tract infections, among the most frequent causes of illness worldwide, often rely on antibiotics for management, despite many being of viral origin. The rampant abuse of antibiotics has led to an unstoppable growth in multidrug resistance, underscoring the urgent need for new strategies to provide an effective and safe alternative for managing recurrent respiratory tract infections (RRTIs).

Reclaiming Pleasure: Does Satisfying Consensual Sexual Activity Predict Next-Day Positive Affect Among Women with a History of Sexual Assault?

ABSTRACT Substantial research documents the psychosocial benefits of sexual activity, including heightened positive affect and lowered negative affect following sexual encounters. However, it is important to examine whether affective benefits of consensual sexual activity are present among individuals who have also experienced non-consensual sexual activity (i.e. sexual assault), given that sexual assault may have harmful consequences for sexual functioning and pleasure during consensual encounters. This study tested consensual sexual activity and satisfaction as predictors of next-day positive and negative affect among 82 women sexual assault survivors. Participants completed ecological momentary assessment measures for three weeks, including measures of past-day dyadic (i.e. partnered) sexual activity and satisfaction in the morning and current affect in the afternoon. As hypothesized, dyadic sexual activity and greater than usual sexual satisfaction predicted increased next-day positive affect after controlling for past-day positive affect. In contrast, and partially supporting hypotheses, sexual satisfaction, but not activity alone, predicted lowered next-day negative affect after controlling for past-day negative affect. At the between person level, greater sexual satisfaction (but not overall frequency of dyadic sexual activity) was associated with greater positive and lower negative affect on average after controlling for several covariates. Findings indicate that satisfying dyadic sexual encounters lead to relatively long-lasting positive affect changes in women who have experienced sexual assault.

Sex-dependent effects of acute stress in adolescence or adulthood on appetitive motivation.

Intensely stressful experiences can lead to long-lasting changes in appetitive and aversive behaviors. In humans, post-traumatic stress disorder increases the risk of comorbid appetitive disorders including addiction and obesity. We have previously shown that an acute stressful experience in adult male rats suppresses motivation for natural reward. We examine the impact of sex and age on the effects of intense stress on action-based (instrumental) and stimulus-based (Pavlovian) motivation for natural reward (food). Rats received 15 unsignaled footshocks (stress) in a single session followed by appetitive training and testing in a distinct context. In Experiment 1, stress occurred in either adolescence (PN28) or adulthood (PN70) with appetitive training and testing beginning on PN71 for all rats. In Experiment 2, stress and appetitive training/testing occurred in adolescence. Acute stress in adolescent females suppressed instrumental motivation assessed with progressive ratio testing when testing occurred in late adolescence or in adulthood, whereas in males stress in adolescence did not suppress instrumental motivation. Acute stress in adulthood did not alter instrumental motivation. In contrast, Pavlovian motivation assessed with single-outcome Pavlovian-to-instrumental transfer (SO-PIT) was consistently enhanced in females following adolescent or adult stress. In males, however, stress in adolescence had no effect, whereas stress in adulthood attenuated SO-PIT. Acute stress in adolescence or adulthood altered instrumental motivation and stimulus-triggered Pavlovian motivation in a sex and developmentally specific manner. These findings suggest that the persistent effects of acute stress on Pavlovian and instrumental motivational processes differ in females and males, and that males may be less vulnerable to the deleterious effects of intense stress during adolescence on appetitive motivation.

Fetal brain response to maternal inflammation requires microglia.

In utero infection and maternal inflammation can adversely impact fetal brain development. Maternal systemic illness, even in the absence of direct fetal brain infection, is associated with an increased risk of neuropsychiatric disorders in affected offspring. The cell types mediating the fetal brain response to maternal inflammation are largely unknown, hindering the development of novel treatment strategies. Here, we show that microglia, the resident phagocytes of the brain, highly express receptors for relevant pathogens and cytokines throughout embryonic development. Using a rodent maternal immune activation (MIA) model in which polyinosinic:polycytidylic acid is injected into pregnant mice, we demonstrate long-lasting transcriptional changes in fetal microglia that persist into postnatal life. We find that MIA induces widespread gene expression changes in neuronal and non-neuronal cells; importantly, these responses are abolished by selective genetic deletion of microglia, indicating that microglia are required for the transcriptional response of other cortical cell types to MIA. These findings demonstrate that microglia play a crucial durable role in the fetal response to maternal inflammation, and should be explored as potential therapeutic cell targets.

Circular Economy in Haiti and Least Developed Countries to Improve Social Justice The Missing Aspects of The Circular Economy Discourse

Current development aid methods implemented by NGOs have demonstrated to generate negative consequences as for example to weaken the role of state, create dependency and reproduce imperialistic power relations. Furthermore, despite great efforts, good wills and a lot of money spent by NGOs and international agencies for development aid projects in Haiti all along the last few decades, little to no results have been reached in a long-term perspective. The purpose of this work is therefore to present and evaluate a new strategy for the field of developmental aid, which is based in this case on the circular economy principles and that is intended to produce a long-lasting change. Circular economy is a relatively new method of thinking about production which will lead the economy of the future, however, its positive effects have been analyzed only in relation to the industrialized and industrializing world, while for the moment no studies have been produced to understand its applicability in the least developed countries of the world. Therefore, this article is of exploratory nature and aims to start a discussion on this subject and to contribute to the understanding of the benefits that circular economy-based projects could generates in fragile and failed states like Haiti. The method utilized has been the one of bibliographic research and a case study, which deeply describe a social-eco enterprise that works in Haiti applying circular economy principles to its projects, is provided. The results confirmed our hypothesis and sustained the idea that to generate long lasting changes and to improve social justice in Haiti and in the other least developed countries of the world, these kind of projects are more than necessary. While the main limit of our method is that we have been able to presents a single case study only, to conclude, we suggest that further studies in this direction and the provision of more case studies by other researchers could better contribute to the solving of the questions generated by this research and could provide more data in support of our assumptions.

An integrative sensor of body states: how the mushroom body modulates behavior depending on physiological context.

The brain constantly compares past and present experiences to predict the future, thereby enabling instantaneous and future behavioral adjustments. Integration of external information with the animal's current internal needs and behavioral state represents a key challenge of the nervous system. Recent advancements in dissecting the function of the Drosophila mushroom body (MB) at the single-cell level have uncovered its three-layered logic and parallel systems conveying positive and negative values during associative learning. This review explores a lesser-known role of the MB in detecting and integrating body states such as hunger, thirst, and sleep, ultimately modulating motivation and sensory-driven decisions based on the physiological state of the fly. State-dependent signals predominantly affect the activity of modulatory MB input neurons (dopaminergic, serotoninergic, and octopaminergic), but also induce plastic changes directly at the level of the MB intrinsic and output neurons. Thus, the MB emerges as a tightly regulated relay station in the insect brain, orchestrating neuroadaptations due to current internal and behavioral states leading to short- but also long-lasting changes in behavior. While these adaptations are crucial to ensure fitness and survival, recent findings also underscore how circuit motifs in the MB may reflect fundamental design principles that contribute to maladaptive behaviors such as addiction or depression-like symptoms.

A cold laboratory hyperspectral imaging system to map grain size and ice layer distributions in firn cores

Abstract. The Greenland and Antarctic ice sheets are covered in a layer of porous firn. Knowledge of firn structure improves our understanding of ice sheet mass balance, supra- and englacial hydrology, and ice core paleoclimate records. While macroscale firn properties, such as firn density, are relatively easy to measure in the field or lab, more intensive measurements of microstructural properties are necessary to reduce uncertainty in remote sensing observations of mass balance, model meltwater infiltration, and constrain ice age – gas age differences in ice cores. Additionally, as the duration and extent of surface melting increases, refreezing meltwater will greatly alter firn structure. Field observations of firn grain size and ice layer stratigraphy are required to test and validate physical models that simulate the ice-sheet-wide evolution of the firn layer. However, visually measuring grain size and ice layer distributions is tedious, is time-consuming, and can be subjective depending on the method. Here we demonstrate a method to systematically map firn core grain size and ice layer stratigraphy using a near-infrared hyperspectral imager (NIR-HSI; 900–1700 nm). We scanned 14 firn cores spanning ∼ 1000 km across western Greenland’s percolation zone with the NIR-HSI mounted on a linear translation stage in a cold laboratory. We leverage the relationship between effective grain size, a measure of NIR light absorption by firn grains, and NIR reflectance to produce high-resolution (0.4 mm) maps of effective grain size and ice layer stratigraphy. We show the NIR-HSI reproduces visually identified ice layer stratigraphy and infiltration ice content across all cores. Effective grain sizes change synchronously with traditionally measured grain radii with depth, although effective grains in each core are 1.5× larger on average, which is largely related to the differences in measurement techniques. To demonstrate the utility of the firn stratigraphic maps produced by the NIR-HSI, we track the 2012 melt event across the transect and assess its impact on deep firn structure by quantifying changes to infiltration ice content and grain size. These results indicate that NIR-HSI firn core analysis is a robust technique that can document deep and long-lasting changes to the firn column from meltwater percolation while quickly and accurately providing detailed firn stratigraphy datasets necessary for firn research applications.

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Toward a Better Understanding of the Construction Impacts of a Light Rail System in Montréal, Canada

Large-scale transport infrastructure projects generate long-lasting changes in the built environment and alter the lives of nearby residents. It is crucial to understand public perceptions of public-transit projects and associated construction impacts, as they influence the social acceptance and eventual success of such projects. To characterize the construction-phase experiences of a new light rail in Montréal, Canada—the Réseau express métropolitain (REM)—we analyzed data from 1,236 respondents from the Greater Montréal region who self-reported ongoing construction activities near their homes. This study employs an exploratory factor and k-means cluster analysis to group residents by their different experiences and perceptions of the REM and its associated construction impacts. The analysis returned five clusters with distinct construction experiences: construction-concerned travelers, REM-critical respondents, neutral travelers, REM enthusiasts, and rerouted travelers. Subsequently, the acceptability of the impacts during the construction phase on each cluster is assessed by comparing perceptions of the impact of neighborhood change on their quality of life and their intention to use the REM. Finally, we derive targeted policy recommendations to help promote increased social acceptability of light-rail transit (LRT) projects, including mitigating disruptions in construction zones, public information campaigns, and inclusive decision-making processes. Findings from this study can benefit policymakers and transport planners as they aim to reduce the disruptions associated with the construction of LRT systems and promote increased social acceptability.

Cannabidiol (CBD) facilitates cocaine extinction and ameliorates cocaine-induced changes to the gut microbiome in male C57BL/6JArc mice

Cocaine use disorder (CUD) is a global health problem with no approved medications. One potential treatment target is the gut microbiome, but it is unknown if cocaine induces long-lasting effects on gut microbes. A novel therapeutic candidate for CUD, cannabidiol (CBD), can improve gut function in rodent models. It is possible that protective effects of CBD against cocaine use are mediated by improving gut health. We examined this question in this experiment. Cocaine conditioned place preference (CPP) was conducted in adult male C57BL/6JArc mice. Mice were treated with vehicle or 20 mg/kg CBD prior to all cocaine CPP sessions (N = 11–13/group). Mice were tested drug free 1, 14 and 28 days after cessation of cocaine and CBD treatment. Fecal samples were collected prior to drug treatment and after each test session. Gut microbiome analyses were conducted using 16 s rRNA sequencing and correlated with behavioural parameters. We found a persistent preference for a cocaine-environment in mice, and long-lasting changes to gut microbe alpha diversity. Cocaine caused persistent changes to beta diversity which lasted for 4 weeks. CBD treatment reduced cocaine-environment preference during abstinence from cocaine and returned gut beta diversity measures to control levels. CBD treatment increased the relative abundance of Firmicutes phyla and Oscillospira genus, but decreased Bacteroidetes phyla and Bacteroides acidifaciens species. Preference score in cocaine-treated mice was positively correlated with abundance of Actinobacteria, whereas in mice treated with CBD and cocaine, the preference score was negatively correlated with Tenericutes abundance. Here we show that CBD facilitates cocaine extinction memory and reverses persistent cocaine-induced changes to gut microbe diversity. Furthermore, CBD increases the abundance of gut microbes which have anti-inflammatory properties. This suggests that CBD may act via the gut to reduce the memory of cocaine reward. Our data suggest that improving gut health and using CBD could limit cocaine abuse.

Proteomic and phosphoproteomic characterization of cardiovascular tissues after long term exposure to simulated space radiation.

Introduction: It may take decades to develop cardiovascular dysfunction following exposure to high doses of ionizing radiation from medical therapy or from nuclear accidents. Since astronauts may be exposed continually to a complex space radiation environment unlike that experienced on Earth, it is unresolved whether there is a risk to cardiovascular health during long-term space exploration missions. Previously, we have described that mice exposed to a single dose of simplified Galactic Cosmic Ray (GCR5-ion) develop cardiovascular dysfunction by 12months post-radiation. Methods: To investigate the biological basis of this dysfunction, here we performed a quantitative mass spectrometry-based proteomics analysis of heart tissue (proteome and phosphoproteome) and plasma (proteome only) from these mice at 8months post-radiation. Results: Differentially expressed proteins (DEPs) for irradiated versus sham irradiated samples (fold-change ≥1.2 and an adjusted p-value of ≤0.05) were identified for each proteomics data set. For the heart proteome, there were 87 significant DEPs (11 upregulated and 76 downregulated); for the heart phosphoproteome, there were 60 significant differentially phosphorylated peptides (17 upregulated and 43 downregulated); and for the plasma proteome, there was only one upregulated protein. A Gene Set Enrichment Analysis (GSEA) technique that assesses canonical pathways from BIOCARTA, KEGG, PID, REACTOME, and WikiPathways revealed significant perturbation in pathways in each data set. For the heart proteome, 166 pathways were significantly altered (36 upregulated and 130 downregulated); for the plasma proteome, there were 73 pathways significantly altered (25 upregulated and 48 downregulated); and for the phosphoproteome, there were 223 pathways significantly affected at 0.1 adjusted p-value cutoff. Pathways related to inflammation were the most highly perturbed in the heart and plasma. In line with sustained inflammation, neutrophil extracellular traps (NETs) were demonstrated to be increased in GCR5-ion irradiated hearts at 12-month post irradiation. NETs play a fundamental role in combating bacterial pathogens, modulating inflammatory responses, inflicting damage on healthy tissues, and escalating vascular thrombosis. Discussion: These findings suggest that a single exposure to GCR5-ion results in long-lasting changes in the proteome and that these proteomic changes can potentiate acute and chronic health issues for astronauts, such as what we have previously described with late cardiac dysfunction in these mice.

Neonatal brain inflammation enhances methamphetamine-induced reinstated behavioral sensitization in adult rats analyzed with explainable machine learning

Neonatal brain inflammation produced by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) results in long-lasting brain dopaminergic injury and motor disturbances in adult rats. The goal of the present work is to investigate the effect of neonatal systemic LPS exposure (1 or 2 mg/kg, i.p. injection in postnatal day 5, P5, male rats)-induced dopaminergic injury to examine methamphetamine (METH)-induced behavioral sensitization as an indicator of drug addiction. On P70, subjects underwent a treatment schedule of 5 once daily subcutaneous (s.c.) administrations of METH (0.5 mg/kg) (P70–P74) to induce behavioral sensitization. Ninety-six hours following the 5th treatment of METH (P78), the rats received one dose of 0.5 mg/kg METH (s.c.) to reintroduce behavioral sensitization. Hyperlocomotion is a critical index caused by drug abuse, and METH administration has been shown to produce remarkable locomotor-enhancing effects. Therefore, a random forest model was used as the detector to extract the feature interaction patterns among the collected high-dimensional locomotor data. Our approaches identified neonatal systemic LPS exposure dose and METH-treated dates as features significantly associated with METH-induced behavioral sensitization, reinstated behavioral sensitization, and perinatal inflammation in this experimental model of drug addiction. Overall, the analysis suggests that the implementation of machine learning strategies is sensitive enough to detect interaction patterns in locomotor activity. Neonatal LPS exposure also enhanced METH-induced reduction of dopamine transporter expression and [3H]dopamine uptake, reduced mitochondrial complex I activity, and elevated interleukin-1β and cyclooxygenase-2 concentrations in the P78 rat striatum. These results indicate that neonatal systemic LPS exposure produces a persistent dopaminergic lesion leading to a long-lasting change in the brain reward system as indicated by the enhanced METH-induced behavioral sensitization and reinstated behavioral sensitization later in life. These findings indicate that early-life brain inflammation may enhance susceptibility to drug addiction development later in life, which provides new insights for developing potential therapeutic treatments for drug addiction.

Amphetamine Exposure during Embryogenesis Alters Expression and Function of Tyrosine Hydroxylase and the Vesicular Monoamine Transporter in Adult C. elegans.

Amphetamines (Amph) are psychostimulants broadly used as physical and cognitive enhancers. However, the long-term effects of prenatal exposure to Amph have been poorly investigated. Here, we show that continuous exposure to Amph during early development induces long-lasting changes in histone methylation at the C. elegans tyrosine hydroxylase (TH) homolog cat-2 and the vesicular monoamine transporter (VMAT) homologue cat-1 genes. These Amph-induced histone modifications are correlated with enhanced expression and function of CAT-2/TH and higher levels of dopamine, but decreased expression of CAT-1/VMAT in adult animals. Moreover, while adult animals pre-exposed to Amph do not show obvious behavioral defects, when challenged with Amph they exhibit Amph hypersensitivity, which is associated with a rapid increase in cat-2/TH mRNA. Because C. elegans has helped reveal neuronal and epigenetic mechanisms that are shared among animals as diverse as roundworms and humans, and because of the evolutionary conservation of the dopaminergic response to psychostimulants, data collected in this study could help us to identify the mechanisms through which Amph induces long-lasting physiological and behavioral changes in mammals.

Prolonged HPA axis dysregulation in postpartum depression associated with adverse early life experiences: A cross-species translational study.

Childhood and adolescent stress increase the risk of postpartum depression (PPD), often providing an increased probability of treatment refractoriness. Nevertheless, the mechanisms linking childhood/adolescent stress to PPD remain unclear. Our study investigated the longitudinal effects of adolescent stress on the hypothalamic-pituitary-adrenal (HPA) axis and postpartum behaviors in mice and humans. Adolescent social isolation prolonged glucocorticoid elevation, leading to long-lasting postpartum behavioral changes in female mice. These changes were unresponsive to current PPD treatments but improved with post-delivery glucocorticoid receptor antagonist treatment. Childhood/adolescent stress significantly impacted HPA axis dysregulation and PPD in human females. Repurposing glucocorticoid receptor antagonists for some cases of treatment-resistant PPD may be considered.

The selective D3Receptor antagonist VK4-116 reverses loss of insight caused by self-administration of cocaine in rats

Chronic psychostimulant use causes long-lasting changes to neural and cognitive function that persist after long periods of abstinence. As cocaine users transition from drug use to abstinence, a parallel transition from hyperactivity to hypoactivity has been found in orbitofrontal-striatal glucose metabolism and striatal D2/D3-receptor activity. Targeting these changes pharmacologically, using highly selective dopamine D3-receptor (D3R) antagonists and partial agonists, has shown promise in reducing drug-taking, and attenuating relapse in animal models of cocaine and opioid use disorder. However, much less attention has been paid to treating the loss of insight, operationalized as the inability to infer likely outcomes, associated with chronic psychostimulant use. Here we tested the selective D3R antagonist VK4-116 as a treatment for this loss in rats with a prior history of cocaine use. Male and female rats were first trained to self-administer cocaine or a sucrose liquid for 2 weeks. After 4 weeks of abstinence, performance was assessed using a sensory preconditioning (SPC) learning paradigm. Rats were given VK4-116 (15 mg/kg, i.p.) or vehicle 30 min prior to each SPC training session, thus creating four drug-treatment groups: sucrose-vehicle, sucrose-VK4-116, cocaine-vehicle, cocaine-VK4-116. The control groups (sucrose-vehicle, sucrose-VK4-116) showed normal sensory preconditioning, whereas cocaine use (cocaine-vehicle) selectively disrupted responding to the preconditioned cue, an effect that was reversed in the cocaine-VK4-116 group, which demonstrating responding to the preconditioned cue at levels comparable to controls. These preclinical findings demonstrate that highly selective dopamine D3R antagonists, particularly VK4-116, can reverse the long-term negative behavioral consequences of cocaine use.

Genetic control of MRI contrast using the manganese transporter Zip14.

Gene-expression reporter systems, such as green fluorescent protein, have been instrumental to understanding biological processes in living organisms at organ system, tissue, cell, and molecular scales. More than 30 years of work on developing MRI-visible gene-expression reporter systems has resulted in a variety of clever application-specific methods. However, these techniques have not yet been widely adopted, so a general-purpose expression reporter is still required. Here, we demonstrate that the manganese ion transporter Zip14 is an in vivo MRI-visible, flexible, and robust gene-expression reporter to meet this need. Plasmid constructs consisting of a cell type-specific promoter, gene coding for human Zip14, and a histology-visible tag were packaged into adeno-associated viruses. These viruses were intracranially injected into the mouse brain. Serial in vivo MRI was performed using a vendor-supplied 3D-MPRAGE sequence. No additional contrast agents were administered. Animals were sacrificed after the last imaging timepoint for immunohistological validation. Neuron-specific overexpression of Zip14 produced substantial and long-lasting changes in MRI contrast. Using appropriate viruses enabled both anterograde and retrograde neural tracing. Expression of Zip14 in astrocytes also enabled MRI of glia populations in the living mammalian brain. The flexibility of this system as an MRI-visible gene-expression reporter will enable many applications of serial, high-resolution imaging of gene expression for basic science and therapy development.

Repeatedly experiencing the McGurk effect induces long-lasting changes in auditory speech perception

In the McGurk effect, presentation of incongruent auditory and visual speech evokes a fusion percept different than either component modality. We show that repeatedly experiencing the McGurk effect for 14 days induces a change in auditory-only speech perception: the auditory component of the McGurk stimulus begins to evoke the fusion percept, even when presented on its own without accompanying visual speech. This perceptual change, termed fusion-induced recalibration (FIR), was talker-specific and syllable-specific and persisted for a year or more in some participants without any additional McGurk exposure. Participants who did not experience the McGurk effect did not experience FIR, showing that recalibration was driven by multisensory prediction error. A causal inference model of speech perception incorporating multisensory cue conflict accurately predicted individual differences in FIR. Just as the McGurk effect demonstrates that visual speech can alter the perception of auditory speech, FIR shows that these alterations can persist for months or years. The ability to induce seemingly permanent changes in auditory speech perception will be useful for studying plasticity in brain networks for language and may provide new strategies for improving language learning.

Determinants, mechanisms and consequences of UN SDGs reporting by universities: conceptual framework and avenues for future research

PurposeThe purpose of this paper is to present a conceptual framework that explores the determinants, mechanisms and consequences of reporting on the United Nations Sustainable Development Goals (UN SDGs) by universities. The framework considers the relationship between reporting on the SDGs and the three main activities of universities: research, teaching and service. As universities hold a unique position in society, understanding their experiences with SDG reporting offers insights into the promotion and integration of SDGs into reporting and practice more broadly.Design/methodology/approachThe paper adopts a conceptual approach and draws on existing literature to develop a framework for understanding reporting on the UN SDGs by universities. The framework considers the challenges faced by universities in providing sustainability information and examines the motivations and outcomes associated with reporting. It also explores the coordination and collaboration necessary across departments within universities and discusses the risks associated with greenwashing.FindingsThe paper highlights that reporting on the UN SDGs can enhance university engagement with stakeholders, improve their reputation, and foster innovation and transdisciplinary research ideas. However, universities encounter challenges such as limited data availability, resource constraints, lack of coordination and competing priorities. The growing scepticism surrounding reporting motives has led to increased allegations of greenwashing within the sector.Originality/valueThis paper contributes to the accounting literature by presenting a comprehensive framework that explores the determinants, mechanisms and consequences of reporting on the UN SDGs by universities. The framework offers insights into how reporting on SDGs can lead to embedding the SDGs in research, teaching and service activities and can be adapted to other organisational contexts. The paper also emphasises the need for further research on the mechanisms of reporting, which play a crucial role in driving long-lasting change.

Abstract 164: Genetic elimination of β-catenin using a doxycycline-regulated GEM model fails to restore checkpoint blockade efficacy due to persistent M2-like macrophages

Abstract Response to checkpoint blockade immunotherapy (CBI) is not universal, partly due to a wide variation in baseline immune cell infiltration in the tumor microenvironment (TME). One mechanism contributing to this variability is tumor cell-intrinsic activation of the β-catenin signaling pathway, which has previously been shown to result in a non-T cell-inflamed TME. Constitutive β-catenin signaling resulted in reduced Batf3-lineage dendritic cell (cDC1) recruitment, leading to reduced T cell activation and infiltration and loss of anti-CTLA-4+anti-PD-L1 therapeutic efficacy. Efforts to target the Wnt/β-catenin pathway to enhance immune responses in β-catenin-active tumors have seen limited success. A genetic experiment eliminating β-catenin expression after establishment of a non-T cell-inflamed TME might illustrate the maximal biologic effect that could be expected with blockade of the pathway. We developed a genetically engineered mouse (GEM) model that allows for dynamic regulation of β-catenin on and off. This model employs tyrosinase-driven tamoxifen-regulated Cre-recombinase to activate the BRAF V600E oncogene and delete the tumor suppressor gene PTEN, along with a transactivator for doxycycline-regulated expression of a non-degradable β-catenin. Topical application of 4-hydroxytamoxifen resulted in melanoma formation, and administration of doxycycline resulted in robust nuclear expression of melanocyte-specific β-catenin compared to non-treated controls. This was accompanied by a significant reduction in CD3+ T cell infiltration within the TME, confirming the link between active β-catenin signaling and T cell exclusion. Discontinuing doxycycline treatment led to complete reduction of nuclear β-catenin expression in the tumor cells within seven days and a substantial return of CD3+ T cells into the TME. However, despite the re-infiltration of CD3+ T cells, the tumors previously expressing β-catenin (ex-β-catenin tumors) did not regain therapeutic responsiveness to anti-CTLA-4+anti-PD-L1. Single cell RNA sequencing of the ex-β-catenin tumors indicated the presence of an immunosuppressive-like macrophage population, characterized by the expression of Ccl8, Gas6 and Cd163. This finding suggests that the prior presence of β-catenin may induce long-lasting changes in the TME that suppress the immune response even after β-catenin levels are reduced. These data corroborate previous findings on the role of β-catenin in modulating the immunological landscape of melanoma and extend it by demonstrating the long-term persistence of immune evasion by suppressive myeloid cells even after β-catenin signaling is eliminated. These insights have implications for clinical strategies aiming to block Wnt/β-catenin signaling, which may additionally require myeloid cell modulation to restore immunotherapy efficacy. Citation Format: Alexandra Cabanov, Ruxandra Tonea, Jason Shapiro, Anna Martinez, Yuanyuan Zha, Thomas F. Gajewski. Genetic elimination of β-catenin using a doxycycline-regulated GEM model fails to restore checkpoint blockade efficacy due to persistent M2-like macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 164.

Epigenetic Mechanisms Modulated by Glucocorticoids With a Focus on Cushing Syndrome.

In Cushing syndrome (CS), prolonged exposure to high cortisol levels results in a wide range of devastating effects causing multisystem morbidity. Despite the efficacy of treatment leading to disease remission and clinical improvement, hypercortisolism-induced complications may persist. Since glucocorticoids use the epigenetic machinery as a mechanism of action to modulate gene expression, the persistence of some comorbidities may be mediated by hypercortisolism-induced long-lasting epigenetic changes. Additionally, glucocorticoids influence microRNA expression, which is an important epigenetic regulator as it modulates gene expression without changing the DNA sequence. Evidence suggests that chronically elevated glucocorticoid levels may induce aberrant microRNA expression which may impact several cellular processes resulting in cardiometabolic disorders. The present article reviews the evidence on epigenetic changes induced by (long-term) glucocorticoid exposure. Key aspects of some glucocorticoid-target genes and their implications in the context of CS are described. Lastly, the effects of epigenetic drugs influencing glucocorticoid effects are discussed for their ability to be potentially used as adjunctive therapy in CS.