Objectives/Goals: Monensin is FDA approved for use in veterinary medicine. Recent studies pointed to its potent anticancer activity. Since de novo drug discovery process typically takes 10 to 15 years and requires an investment of approximately $1.3 to $3 billion, drug repositioning can bypass several steps in this process and increase the potential for success. Methods/Study Population: Cell viability assays were conducted on human MDA-MB-231, MDA-MB-468, and MCF10A breast cancer cell lines and mouse EO771 and 4T1 breast cancer cell lines. MDA-MB-231 cell line was used in all the studies unless specified otherwise. Time course levels of Bcl-2, Bak, p62, and LC3II were assessed via Western blotting with GAPDH as a loading control. Proteomics analysis was conducted by the IDEA National Resource for Quantitative Proteomics. Time course levels of major histocompatibility complex (MHC) I and II and calreticulin were evaluated using flow cytometry. At least three biological replicates have been conducted for each experiment. Results/Anticipated Results: Monensin and several of its novel analogs were potent toward human and mouse breast cancer cell lines. Furthermore, they induced apoptotic cell death as evidenced by Annexin V/PI assay, downregulation of Bcl-2, and upregulation of Bak in MDA-MB-231 cells. Proteomics analysis revealed that several molecular pathways related to MHC class I and II antigen presentation were significantly altered following treatment with these compounds. Additionally, monensin and its analogs significantly increased the expression of MHC class I and II. Our studies also showed that monensin and its analogs increase the surface calreticulin levels. Treatment of MDA-MB-231 cells with these compounds also resulted in an increase in p62 and LC3II expression, suggesting a disruption of the autophagic process. Discussion/Significance of Impact: These results suggest that monensin and its analogs not only exhibit anti-breast cancer cell activity but also modulate immune-related pathways. By disrupting autophagy and enhancing calreticulin levels, these compounds may potentiate antitumor immune responses, providing a promising avenue for drug repositioning in cancer therapy.

The recommended first-line treatment for insomnia is cognitive behavioral therapy for insomnia (CBTi), but access is limited. Telehealth- or internet-delivered CBTi are alternative ways to increase access. To date, these intervention modalities have never been compared within a single study. Further, few studies have examined (a) predictors of response to the different modalities, (b) whether successfully treating insomnia can result in improvement of health-related biomarkers, and (c) mechanisms of change in CBTi. This protocol was designed to compare the three CBTi modalities to each other and a waitlist control for adults aged 50–65 years (N = 100). Participants are randomly assigned to one of four study arms: in-person- (n = 30), telehealth- (n = 30) internet-delivered (n = 30) CBTi, or 12-week waitlist control (n = 10). Outcomes include self-reported insomnia symptom severity, polysomnography, circadian rhythms of activity and core body temperature, blood- and sweat-based biomarkers, cognitive functioning and magnetic resonance imaging.

We present a 1000 km transect of phase-sensitive radar measurements of ice thickness, basal reflection strength, basal melting and ice-column deformation across the Ross Ice Shelf (RIS). Measurements were gathered at varying intervals in austral summer between 2015 and 2020, connecting the grounding line with the distant ice shelf front. We identified changing basal reflection strengths revealing a variety of basal conditions influenced by ice flow and by ice–ocean interaction at the ice base. Reflection strength is lower across the central RIS, while strong reflections in the near-front and near-grounding line regions correspond with higher basal melt rates, up to 0.47 ± 0.02 m a−1 in the north. Melting from atmospherically warmed surface water extends 150–170 km south of the RIS front. Melt rates up to 0.29 ± 0.03 m a−1 and 0.15 ± 0.03 m a−1 are observed near the grounding lines of the Whillans and Kamb Ice Stream, respectively. Although troublesome to compare directly, our surface-based observations generally agree with the basal melt pattern provided by satellite-based methods but provide a distinctly smoother pattern. Our work delivers a precise measurement of basal melt rates across the RIS, a rare insight that also provides an early 21st-century baseline.

While the pathophysiology affecting patients after Fontan palliation versus those with orthostatic intolerance is quite different, a common therapeutic approach exists. Exercise training, specifically augmenting the lower extremity skeletal muscle pump, improves the suboptimal haemodynamics of “preload failure” and thus clinical outcomes for each patient group. In this review, we will describe the problematic physiology affecting these patients, examine the anatomy and haemodynamics of the skeletal muscle pump, and finally review how exercise benefits both groups of patients through augmentation of musculovenous force.

Entrenched ethnoracial hierarchies that persist alongside formal democratic rules threaten commitments to democracy. Previous research has shown how marginalization and oppression harm minoritized group members, but has rarely considered the potential harm entrenched group-based hierarchies pose for democratic society overall. This paper offers two innovations. First, we argue that ethnoracial hierarchies have society-wide implications. Entrenched systems of ethnoracial marginalization undermine support for democracy and respect for democratic rights, even among members of privileged groups. Second, group consciousness conditions the effects of ethnoracial hierarchy among minoritized group members. Specifically, when minoritized individuals hold a structural dimension of group consciousness, they tend to sustain commitments to democracy. Insights from interviews with Indigenous and Afrodescendant activists and policy makers conducted during field research in Peru facilitate development of these theoretical expectations. Subsequent analysis of survey data cross-nationally throughout Latin America and over time in Bolivia demonstrates that ethnoracial hierarchies are associated with weaker democratic commitments across society, while reducing these hierarchies strengthens support for democracy. Among minoritized group members, however, structural group consciousness helps to mitigate these negative effects. This paper contributes a theoretical framework and empirical evidence concerning the challenges ethnoracial hierarchies pose for democratic commitments not only among those who belong to minoritized groups, but for people across society.

Psilocybin therapy has recently emerged as a promising new treatment for depression and other mental health disorders. This chapter summarizes the most recent data on its safety and efficacy. The delivery of psilocybin therapy and its subjective effects are also presented. Furthermore, this chapter outlines our current understanding of psilocybin’s pharmacology and neurobiological effects. Other similar psychedelic substances with encouraging therapeutic potential are briefly presented.

An implementation of the Gauss-Newton algorithm for the analysis of covariance structures that is specifically adapted for high-level computer languages is reviewed. With this procedure one need only describe the structural form of the population covariance matrix, and provide a sample covariance matrix and initial values for the parameters. The gradient and approximate Hessian, which vary from model to model, are computed numerically. Using this approach, the entire method can be operationalized in a comparatively small program. A large class of models can be estimated, including many that utilize functional relationships among the parameters that are not possible in most available computer programs. Some examples are provided to illustrate how the algorithm can be used.

University students often make less healthful dietary choices whilst at university however, do not typically receive advice and support to help them eat more healthily(1,2). A tool which could be provided to students to promote more favourable dietary behaviours is the eNutri web-based app which includes a food frequency questionnaire (FFQ) and delivers automated personalised nutrition advice (PNA) and a diet quality score (DQS) consisting of 11 food/nutrient components(3). The PNA includes scores and general advice for each component and, for the user’s three lowest scoring components, recommends which foods to eat more/less frequently to improve their DQS. As part of a 4-week intervention study, we aimed to explore the perceptions of the eNutri PNA in UK university students.

As part of this intervention, 14 students from the Universities of Reading and Hertfordshire completed the eNutri FFQ and received their PNA. At the end of the study, they rated how much they agreed with statements about the perceived value and benefit (if any) of the eNutri PNA tool, on a 6-point scale ranging from strongly disagree to strongly agree. The percentage of respondents reported is the total number who responded “somewhat agree”, “agree”, or “strongly agree” to each statement.

Of the 14 students, 79% were female with a mean age of 25y (range = 18-37y) and mean BMI of 24.7kg/m2 (range = 19.4-31.9kg/m2). At baseline, the average importance of a healthy diet to the participants (n = 13) was rated at 7.2 out of 10 (with 0 being ‘not important at all’ and 10 being ‘very important’). In total, 57% of respondents indicated that they felt they ‘were eating a healthier diet because of the eNutri advice received’ and only 14% reported that ‘the advice did not motivate them to make changes to their diet’. Furthermore, 64% of respondents indicated that the ‘eNutri PNA gave them confidence in their ability to make changes to their diet’ and that it ‘supported them to do so’. Half of the students agreed that ‘they would want to use eNutri long term to track their progress and receive regular PNA’. In addition, 79% agreed that ‘eNutri should be offered to all university students to help them make healthier food choices’, and that if eNutri was offered to them for free by their university, ‘it would be a valuable student benefit’ and they ‘would want to use it again’.

In general, university students indicated the eNutri PNA tool supported them to eat healthier and providing access to the wider student population would be beneficial to encourage healthy eating at university. These findings along with the quantitative data from the PNA intervention which is currently being analysed will support the development of larger, suitably-powered studies to confirm these findings.

The gut microbiome is impacted by certain types of dietary fibre. However, the type, duration and dose needed to elicit gut microbial changes and whether these changes also influence microbial metabolites remain unclear. This study investigated the effects of supplementing healthy participants with two types of non-digestible carbohydrates (resistant starch (RS) and polydextrose (PD)) on the stool microbiota and microbial metabolite concentrations in plasma, stool and urine, as secondary outcomes in the Dietary Intervention Stem Cells and Colorectal Cancer (DISC) Study. The DISC study was a double-blind, randomised controlled trial that supplemented healthy participants with RS and/or PD or placebo for 50 d in a 2 × 2 factorial design. DNA was extracted from stool samples collected pre- and post-intervention, and V4 16S rRNA gene sequencing was used to profile the gut microbiota. Metabolite concentrations were measured in stool, plasma and urine by high-performance liquid chromatography. A total of fifty-eight participants with paired samples available were included. After 50 d, no effects of RS or PD were detected on composition of the gut microbiota diversity (alpha- and beta-diversity), on genus relative abundance or on metabolite concentrations. However, Drichlet’s multinomial mixture clustering-based approach suggests that some participants changed microbial enterotype post-intervention. The gut microbiota and fecal, plasma and urinary microbial metabolites were stable in response to a 50-d fibre intervention in middle-aged adults. Larger and longer studies, including those which explore the effects of specific fibre sub-types, may be required to determine the relationships between fibre intake, the gut microbiome and host health.