Evolution of the Aging Brain Transcriptome and Synaptic Regulation

Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes

Comparison of TGFβ expression in healthy and diseased human tendon

Introduction: Diseased tendons are characterised by fibrotic scar tissue, which adversely affects tendon structure and function and increases the likelihood of reinjury. The mechanisms and expression profiles of fibrosis in diseased tendon is understudied compared to pulmonary and renal tissues, where TGFβ and its associated superfamily are known to be key drivers of fibrosis and modulate extracellular matrix homeostasis. We hypothesised that differential expression of TGFβ superfamily members would exist between samples of human rotator cuff tendons with established disease compared to healthy control tendons. Methods: Healthy and diseased rotator cuff tendons were collected from patients presenting to an orthopaedic referral centre. Diseased tendinopathic (intact) and healthy rotator cuff tendons were collected via ultrasound-guided biopsy and torn tendons were collected during routine surgical debridement. Immunohistochemistry and qRT-PCR were used to investigate the protein and gene expression profiles of TGFβ superfamily members in these healthy and diseased tendons. Results: TGFβ superfamily members were dysregulated in diseased compared to healthy tendons. Specifically, TGFβ-1, TGFβ R1 and TGFβ R2 proteins were reduced (p<0.01) in diseased compared to healthy tendons.At the mRNA level, TGFβ R1 was significantly reduced in samples of diseased tendons, whereas TGFβ R2 was increased (p<0.01). BMP-2, BMP-7 and CTGF mRNA remained unchanged with tendon disease. Conclusions: We propose down-regulation of TGFβ pathways in established tendon disease may be a protective response to limit disease-associated fibrosis. The disruption of the TGFβ axis with disease suggests associated downstream pathways may be important for maintaining healthy tendon homeostasis. The findings from our Page 3 of 26 study suggest that patients with established tendon disease would be unlikely to benefit from therapeutic TGFβ blockade, which has been investigated as a treatment strategy in several animal models. Future studies should investigate the expression profile of fibrotic mediators in earlier stages of tendon disease to improve understanding of the targetable mechanisms underpinning tendon fibrosis

Clinical, financial and social impacts of COVID-19 and their associations with mental health for mothers and children experiencing adversity in Australia

Background Australia has maintained low rates of SARS-COV-2 (COVID-19) infection, due to geographic location and strict public health restrictions. However, the financial and social impacts of these restrictions can negatively affect parents\u27 and children\u27s mental health. In an existing cohort of mothers recruited for their experience of adversity, this study examined: 1) families\u27 experiences of the COVID-19 pandemic and public health restrictions in terms of clinical exposure, financial hardship family stress, and family resilience (termed \u27COVID-19 impacts\u27); and 2) associations between COVID-19 impacts and maternal and child mental health. Methods Participants were mothers recruited during pregnancy (2013-14) across two Australian states (Victoria and Tasmania) for the \u27right@home\u27 trial. A COVID-19 survey was conducted from May-December 2020, when children were 5.9-7.2 years old. Mothers reported COVID-19 impacts, their own mental health (Depression, Anxiety, Stress Scales short-form) and their child\u27s mental health (CoRonavIruS Health and Impact Survey subscale). Associations between COVID-19 impacts and mental health were examined using regression models controlling for pre-COVID-19 characteristics. Results 319/406 (79%) mothers completed the COVID-19 survey. Only one reported having had COVID-19. Rates of self-quarantine (20%), job or income loss (27%) and family stress (e.g., difficulty managing children\u27s at-home learning (40%)) were high. Many mothers also reported family resilience (e.g., family found good ways of coping (49%)). COVID-19 impacts associated with poorer mental health (standardised coefficients) included self-quarantine (mother: β = 0.46, child: β = 0.46), financial hardship (mother: β = 0.27, child: β = 0.37) and family stress (mother: β = 0.49, child: β = 0.74). Family resilience was associated with better mental health (mother: β = -0.40, child: β = -0.46). Conclusions The financial and social impacts of Australia\u27s public health restrictions have substantially affected families experiencing adversity, and their mental health. These impacts are likely to exacerbate inequities arising from adversity. To recover from COVID-19, policy investment should include income support and universal access to family health services