Biology subjects

Anderson, R.

Publications and source records attributed to Anderson, R..

4 recordsLinked to original sources

bioRxiv2018

Length-independent telomere damage drives cardiomyocyte senescence

Ageing is the biggest risk factor for cardiovascular health and is associated with increased incidence of cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate if clearance of senescent cells attenuates age related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction, and crucially can occur independently of cell-division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a and results in a non-canonical senescence-associated secretory phenotype. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features of cardiac ageing, and promotes cardiomyocyte regeneration. Our data describes a mechanism by which senescence can occur and contribute to ageing in post-mitotic tissues.

cell biology↗

bioRxiv2018

Role of IQGAP1 in Head and Neck Carcinogenesis

Head and neck squamous cell carcinoma (HNSCC) is a common cancer in humans. Phosphoinositide 3-kinase (PI3K)/AKT signaling, along with its downstream effector mTOR, is one of the most frequently altered pathways in HNSCC, and is downstream of growth factor signaling including that mediated by epidermal growth factor receptor (EGFR), which is also commonly upregulated in HNSCC. Recently, IQ motif-containing GTPase activation protein 1 (IQGAP1) has been reported to function as a scaffold for the enzymes involved in the PI3K/AKT signaling pathway. Iqgap1 gene expression is increased in human HNSCCs, raising the hypothesis that it acts as an oncogene in this cancer. Whether IQGAP1 is necessary for HNSCC development as well as what is its underlying mechanism are both unknown. Here we report on the role of IQGAP1 in HNSCC by performing a combination of in vitro studies using human cancer cell lines, and in vivo studies using a well-validated preclinical mouse model for HNSCC that is known to depend upon EGFR signaling. Cells knocked out for IQGAP1 lost AKT signaling. Disruption of IQGAP1-scaffolded PI3K/AKT signaling using a peptide that interferes with the ability of IQGAP1 to bind to PI3K reduced HNSCC cell survival. In vivo studies utilizing Iqgap1-null (Iqgap1-/-) mice demonstrated that IQGAP1 is necessary for efficient PI3K signaling upon EGF-stimulation. Treatment of Iqgap1-/- mice with the oral carcinogen, 4-nitroquinoline 1-oxide (4NQO), Iqgap1-/- led to significantly lower multiplicities of cancer foci as well as significantly lower numbers of high grade cancers than observed in similarly treated Iqgap1+/+ mice. IQGAP1 protein was increased in its expression in HNSCCs arising in the Iqgap1+/+ mice, consistent with that seen in human HNSCCs. We also observed a significant down-regulation of PI3K signaling in 4NQO-induced HNSCCs arising in the Iqgap1-/- mice, consistent with IQGAP1 contributing to carcinogenesis by promoting PI3K signaling. Our studies, therefore, support the hypothesis that IQGAP1 acts as an oncogene in head and neck carcinogenesis, and provide mechanistic insight into its role.

cancer biology↗

bioRxiv2017

Cost evaluation during decision making in patients at early stages of psychosis

Jumping to conclusions during probabilistic reasoning is a cognitive bias reliably observed in psychosis, and linked to delusion formation. Although the reasons for this cognitive bias are unknown, one suggestion is that psychosis patients may view sampling information as more costly. However, previous computational modelling has provided evidence that patients with chronic schizophrenia jump to conclusion because of noisy decision making. We developed a novel version of the classical beads-task, systematically manipulating the cost of information gathering in four blocks. For 31 individuals with early symptoms of psychosis and 31 healthy volunteers, we examined the numbers of draws to decision when information sampling had no, a fixed, or an escalating cost. Computational modelling involved estimating a cost of information sampling parameter and a cognitive noise parameter. Overall patients sampled less information than controls. However, group differences in numbers of draws became less prominent at higher cost trials, where less information was sampled. The attenuation of group difference was not due to floor effects, as in the most costly block participants sampled more information than an ideal Bayesian agent. Computational modelling showed that, in the condition with no objective cost to information sampling, patients attributed higher costs to information sampling than controls (Mann-Whiney U=289, p=0.007), with marginal evidence of differences in noise parameter estimates (t=1.86 df=60, p=0.07). In patients, individual differences in severity of psychotic symptoms were statistically significantly associated with higher cost of information sampling (rho=0.6, p=0.001) but not with more cognitive noise (rho=0.27, p=0.14); in controls cognitive noise predicted aspects of schizotypy (preoccupation and distress associated with delusion-like ideation on the Peters Delusion Inventory). Using a psychological manipulation and computational modelling, we provide evidence that early psychosis patients jump to conclusions because of attributing higher costs to sampling information, not because of being primarily noisy decision makers.

neuroscience↗

bioRxiv2017

Epidemiological and ecological modelling reveal diversity in microbial population structures from a cross-sectional community swabbing study

Respiratory tract infections (RTI) are responsible for over 4 million deaths per year worldwide with pathobiont carriage a required precursor to infection. Through a cross-sectional community-based nasal self-swabbing study we sought to determine carriage epidemiology for respiratory pathogens amongst bacteria (Streptococcus pneumoniae, Haemophilus influenza, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa and Neisseria meningitidis) and viruses (RSV, Influenza viruses A and B, Rhinovirus/Enterovirus, Coronavirus, Parainfluenza viruses 1-3 and Adenovirus (ADV)). Carriage of bacterial and viral species was shown to vary with participant age, recent RTI and the presence of other species. The spatial structure of microbial respiratory communities was less nested (more disordered) in the young (0-4 years) and those with recent RTI. Species frequency distributions were flatter than random expectation in young individuals (X2 = 20.42, p = 0.002), indicating spatial clumping of species consistent with facilitative relationships amongst them. Deviations from a neutral model of ecological niches were observed for samples collected in the summer and from older individuals (those aged 5-17, 18-64 and [≥]65 years) but not in samples collected from winter, younger individuals (those aged 0-4 years), individuals with recent RTI and individuals without recent RTI, demonstrating the importance of both neutral and niche processes in respiratory community assembly. The application of epidemiological methods and ecological theory to sets of respiratory tract samples has yielded novel insights into the factors that drive microbial community composition, such as seasonality and age, as well as species patterns and interactions within the nose.

microbiology↗