👤 Jo Salmon

Aging and male sex are major risk factors for abdominal aortic aneurysm (AAA), a disease characterized by vascular cell phenotypic switching and aortic wall remodeling. Mitochondrial oxidative stress has been implicated in these changes. We previously demonstrated that NOX4 (NADPH oxidase 4) expression and activity increase with age in cardiovascular cells, promoting mitochondrial oxidative stress and vascular dysfunction. This study investigates whether NOX4-driven mitochondrial oxidative stress and DNA damage promote AAA development through vascular cell reprogramming. We used mitochondria-targeted NOX4-dependent mitochondrial DNA damage and activation of DNA-sensing pathways promote SMC phenotypic switching, inflammation, and aortic wall remodeling in AAA. Targeting NOX4 and enhancing mitochondrial function may offer therapeutic strategies for AAA prevention. Show less

Diverse haematological neoplasms are driven by tyrosine kinase (TK) fusion genes formed by recurrent or non-recurrent genomic rearrangements. The resulting chimeric proteins often present excellent targets for treatment with kinase inhibitors, and the fusion transcripts or genomic junctions can be used as specific targets for molecular monitoring. Whilst the TK genes involved are generally well characterised (e.g. ABL1, PDGFRA, FGFR1), the fusion partners are very diverse, presenting a challenge for detection and characterisation of these structural variants (SV) using current diagnostic methods. We assessed the ability of targeted nanopore sequencing using adaptive sampling to detect fusion genes in myeloid neoplasms. We sequenced genomic DNA from patients (n = 20) with a known or suspected TK gene fusion and identified rearrangements in 18 cases, including all cases with a known TK fusion, typical and atypical BCR::ABL1 rearrangements, an 843Kb deletion causing a FIP1L1::PDGFRA fusion, novel AGAP2::PDGFRB and NFIA::PDGFRB fusions, and a complex CCDC88C::PDGFRB rearrangement with multiple translocation events. The approach was fast (<72 h/sample from DNA to result), flexible with minimal hands-on laboratory time, and provided accurate, patient-specific characterisation of genomic breakpoints. Show less

Adolescent psychological wellbeing is a critical determinant of lifelong health. Global data suggest a concerning decline in adolescent wellbeing. While the 24-hour movement behaviours, moderate to vigorous physical activity (MVPA), light physical activity (LPA), sedentary time, and sleep, have been linked to mental health outcomes; their associations with specific domains of adolescent psychological wellbeing remain underexplored. This study used compositional data analysis (CoDA) to examine how time-use relate to domain-specific wellbeing in Australian secondary school adolescents. Data were drawn from 124 adolescents (aged 13–17 years) participating in the TransformUs Secondary effectiveness trial. Wrist worn Actigraph GT9X accelerometer captured 24-hour movement behaviour over at least three valid days (≥ 16 h/day). Wellbeing was assessed using the EPOCH Measure of Adolescent Wellbeing, which includes five domains: engagement, perseverance, optimism, connectedness, and happiness. CoDA was used to examine associations between the composition of daily movement behaviours and EPOCH domains using isometric log-ratio (ILR) transformations. A compositional time reallocation analysis (30-minutes) was also performed to explore hypothetical associations with wellbeing outcomes. The average daily time-use composition was 680.9 min (47.3%) sedentary time, 473.0 min (32.8%) sleep, 250.7 min (17.4%) LPA, and 35.3 min (2.5%) MVPA. Greater time spent in LPA relative to other behaviours was significantly associated with higher happiness scores ( Adolescent daily movement behaviour composition was associated with domain-specific psychological wellbeing, particularly happiness. LPA was a potential contributor to positive psychological wellbeing. These findings suggest that even modest changes in daily routines, such as replacing sedentary time and LPA, may support adolescent flourishing. Future research should confirm these findings longitudinally and employ in intervention studies. The online version contains supplementary material available at 10.1186/s44167-025-00094-8. Show less

There is increasing interest in the importance of patterns of accumulation and overall daily time-use composition of physical activity (PA) and sedentary time (SED) for children's cardiometabolic health. This study examined cross-sectional associations between the time-use composition of PA and SED patterns with cardiometabolic risk factors in 4-year-olds. Data were drawn from the Barwon Infant Study 4-year review (n = 467). Accelerometer data were classified into short (≤ 1-minute) and long (> 1-min) SED, light-, moderate-, and vigorous-intensity PA (LPA, MPA, VPA) bouts. A waking time-use composition of eight distinct components (total volumes plus short and long bouts of SED, LPA MPA, VPA) was constructed using compositional data analysis. Linear mixed models examined associations between composition patterns and body mass index (BMI), percent body fat, triceps and subscapular skinfold thickness, blood pressure, heart rate, carotid-femoral pulse wave velocity, and aortic and carotid intima-media thickness. Adjusted models indicated a higher ratio of long versus short LPA bouts was associated with higher z-BMI (β = 1.69, SE = 0.83, p = 0.04), percent body fat (β = 10.72, SE = 3.71, p = 0.004), and z-triceps (β = 1.90, SE = 0.93, p = 0.04). A higher ratio of long versus short MPA bouts was associated with lower z-BMI (β = - 0.99, SE = 0.46, p = 0.03) and percent body fat (β = - 4.63, SE = 1.93, p = 0.02). A higher total volume of MPA versus VPA was associated with higher percent body fat (β = 4.07, SE = 1.63, p = 0.01) and z-triceps (β = 1.05, SE = 0.43, p = 0.01). Other outcomes showed no associations (p ≥   0.05). In preschoolers, accumulating LPA in shorter bursts, MPA in longer bursts, and maintaining a higher proportion of VPA may support healthier adiposity profiles. These findings underscore the importance of minimizing prolonged sedentary time and encouraging sustained, high-intensity PA from early childhood. Show less

Thoracic aortic aneurysms (TAA) are a progressive disease characterized by inflammation, smooth muscle cell activation and matrix degradation. We hypothesized that mesenchymal stem cells (MSCs) can immunomodulate vascular inflammation and remodeling via altered microRNA (miRNAs) expression profile to attenuate TAA formation. C57BL/6 mice underwent topical elastase application to form descending TAAs. Mice were also treated with MSCs on days 1 and 5 and aortas were analyzed on day 14 for aortic diameter. Cytokine array was performed in aortic tissue and total RNA was tagged and hybridized for miRNAs microarray analysis. Immunohistochemistry was performed for elastin degradation and leukocyte infiltration. Treatment with MSCs significantly attenuated aortic diameter and TAA formation compared to untreated mice. MSC administration also attenuated T-cell, neutrophil and macrophage infiltration and prevented elastic degradation to mitigate vascular remodeling. MSC treatment also attenuated aortic inflammation by decreasing proinflammatory cytokines (CXCL13, IL-27, CXCL12 and RANTES) and upregulating anti-inflammatory interleukin-10 expression in aortic tissue of elastase-treated mice. TAA formation demonstrated activation of specific miRNAs that are associated with aortic inflammation and vascular remodeling. Our results also demonstrated that MSCs modulate a different set of miRNAs that are associated with decrease leukocyte infiltration and vascular inflammation to attenuate the aortic diameter and TAA formation. These results indicate that MSCs immunomodulate specific miRNAs that are associated with modulating hallmarks of aortic inflammation and vascular remodeling of aortic aneurysms. Targeted therapies designed using MSCs and miRNAs have the potential to regulate the growth and development of TAAs. Show less