Computational modelling of the regulation of Insulin signalling by oxidative stress

BACKGROUND: Existing models of insulin signalling focus on short term dynamics, rather than the longer term dynamics necessary to understand many physiologically relevant behaviours. We have developed a model of insulin signalling in rodent adipocytes that includes both transcriptional feedback through the Forkhead box type O (FOXO) transcription factor, and interaction with oxidative stress, in addition to the core pathway. In the model Reactive Oxygen Species are both generated endogenously and can be applied externally. They regulate signalling though inhibition of phosphatases and induction of the activity of Stress Activated Protein Kinases, which themselves modulate feedbacks to insulin signalling and FOXO. RESULTS: Insulin and oxidative stress combined produce a lower degree of activation of insulin signalling than insulin alone. Fasting (nutrient withdrawal) and weak oxidative stress upregulate antioxidant defences while stronger oxidative stress leads to a short term activation of insulin signalling but if prolonged can have other effects including degradation of the insulin receptor substrate (IRS1) and FOXO. At high insulin the protective effect of moderate oxidative stress may disappear. CONCLUSION: Our model is consistent with a wide range of experimental data, some of which is difficult to explain. Oxidative stress can have effects that are both up- and down-regulatory on insulin signalling. Our model therefore shows the complexity of the interaction between the two pathways and highlights the need for such integrated computational models to give insight into the dysregulation of insulin signalling along with more data at the individual level. A complete SBML model file can be downloaded from BIOMODELS (https://www.ebi.ac.uk/biomodels-main) with unique identifier MODEL1212210000. Other files and scripts are available as additional files with this journal article and can be downloaded from https://github.com/graham1034/Smith2012_insulin_signalling

Rat mammary carcinogenesis following neutron- or X-radiation

Female 61 to 63 - day - old Sprague-Dawley rats were exposed once to a single dose of either 0.43 - MeV neutrons or 250 - kVX - rays . For neutrons 23 rats were exposed in plastic tubes rotated around and 31 c m from a water-cooled tritium impregnated target bombarded with 2.45 - MeV protons from a V a n de Graaff generator. The mean kerma was measured at the rat location by integrating the response of a rat - sized homogeneous tissue equivalent ionization chamber of minimum mass. The ratio between absorbed dose and kerma is under investigation and is anticipated to be approximately 0.7. A compensated GM gamma-ray dosimeter indicated that the gamma - ray doses were 3.5% of the total dose. All rats were examined weekly for the presence of breast tumours and these were removed, fixed, stained and verified histologically as mammary neoplasms. At 10 months after exposure 98<7ο of the rats were a live . The neutron kerma, the per cent of rats with mammary neoplasia, and the number of rats were, respectively: 0.125 rads, 8.2°}o, 182; 0.5 rads, 9.0^0, 89; 2 rads, 20. 6,68; and 8 rads, 31.1%, 45. The X - ray results were: 30 R, 1.4% 95; 60 R, 27. l°Io, 48; and 90 R, 35.4%, 48. A 3. O^o incidence was found in 167 control rats. At 10 months after exposure the mammary neoplastic response after 8 rads of neutrons corresponds approximately to that after 60 - 90 R of X - rays . Similarly, the response after 2 rads of neutrons was intermediate between 30 and 60 R of X - rays and the response after 0 . 125 and 0.5 rads of neutrons was similar to that after 30 R of X - rays . This demonstrates that the RBE for 0.43 - MeV neutrons is much lower at high doses than at low doses. Determination of the confidence limits for the dose-RBE dependence and dose-incidence relationship will be determined as additional data are collected

Systems modelling predicts chronic inflammation and genomic instability prevent effective mitochondrial regulation during biological ageing

The regulation of mitochondrial turnover under conditions of stress occurs partly through the AMPK-NAD+-PGC1α-SIRT1 signalling pathway. This pathway can be affected by both genomic instability and chronic inflammation since these will result in an increased rate of NAD+ degradation through PARP1 and CD38 respectively. In this work we develop a computational model of this signalling pathway, calibrating and validating it against experimental data. The computational model is used to study mitochondrial turnover under conditions of stress and how it is affected by genomic instability, chronic inflammation and biological ageing in general. We report that the AMPK-NAD+-PGC1α-SIRT1 signalling pathway becomes less responsive with age and that this can prime for the accumulation of dysfunctional mitochondria

Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones

ACKNOWLEDGMENTS This work was funded by The BBSRC (BB/D004659/1) the Wellcome Trust (080980/Z/06/Z) and the Medical Research Council (G0701003).Peer reviewedPublisher PD

Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

BackgroundPatients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database.MethodsAn IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA.ResultsMedian survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. &gt;30% present in the worst prognostic group (GI-GPA of ≤1.0).ConclusionsBrain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com

A meta-study of relationships between fluvial channel-body stacking pattern and aggradation rate: implications for sequence stratigraphy

A quantitative comparison of 20 literature case studies of fluvial sedimentary successions tests common assumptions made in published models of alluvial architecture concerning (1) inverse proportionality between channel-deposit density and floodplain aggradation rates, and (2) resulting characteristics of channel-body geometries and connectedness. Our results do not support the relationships predicted by established stratigraphy models: the data suggest that channel-body density, geometry, and stacking pattern are not reliable diagnostic indicators of rates of accommodation creation. Hence, these architectural characteristics alone do not permit the definition of accommodation-based “systems tracts” and “settings”, and this calls into question current sequence stratigraphic practice in application to fluvial successions