The effects of intrinsic noise on the behaviour of bistable cell regulatory systems under quasi-steady state conditions

We analyse the effect of intrinsic fluctuations on the properties of bistable stochastic systems with time scale separation operating under1 quasi-steady state conditions. We first formulate a stochastic generalisation of the quasi-steady state approximation based on the semi-classical approximation of the partial differential equation for the generating function associated with the Chemical Master Equation. Such approximation proceeds by optimising an action functional whose associated set of Euler-Lagrange (Hamilton) equations provide the most likely fluctuation path. We show that, under appropriate conditions granting time scale separation, the Hamiltonian can be re-scaled so that the set of Hamilton equations splits up into slow and fast variables, whereby the quasi-steady state approximation can be applied. We analyse two particular examples of systems whose mean-field limit has been shown to exhibit bi-stability: an enzyme-catalysed system of two mutually-inhibitory proteins and a gene regulatory circuit with self-activation. Our theory establishes that the number of molecules of the conserved species are order parameters whose variation regulates bistable behaviour in the associated systems beyond the predictions of the mean-field theory. This prediction is fully confirmed by direct numerical simulations using the stochastic simulation algorithm. This result allows us to propose strategies whereby, by varying the number of molecules of the three conserved chemical species, cell properties associated to bistable behaviour (phenotype, cell-cycle status, etc.) can be controlled.Comment: 33 pages, 9 figures, accepted for publication in the Journal of Chemical Physic

Coupled Stochastic Spatial and Non-Spatial Simulations of ErbB1 Signaling Pathways Demonstrate the Importance of Spatial Organization in Signal Transduction

BACKGROUND: The ErbB family of receptors activates intracellular signaling pathways that control cellular proliferation, growth, differentiation and apoptosis. Given these central roles, it is not surprising that overexpression of the ErbB receptors is often associated with carcinogenesis. Therefore, extensive laboratory studies have been devoted to understanding the signaling events associated with ErbB activation. METHODOLOGY/PRINCIPAL FINDINGS: Systems biology has contributed significantly to our current understanding of ErbB signaling networks. However, although computational models have grown in complexity over the years, little work has been done to consider the spatial-temporal dynamics of receptor interactions and to evaluate how spatial organization of membrane receptors influences signaling transduction. Herein, we explore the impact of spatial organization of the epidermal growth factor receptor (ErbB1/EGFR) on the initiation of downstream signaling. We describe the development of an algorithm that couples a spatial stochastic model of membrane receptors with a nonspatial stochastic model of the reactions and interactions in the cytosol. This novel algorithm provides a computationally efficient method to evaluate the effects of spatial heterogeneity on the coupling of receptors to cytosolic signaling partners. CONCLUSIONS/SIGNIFICANCE: Mathematical models of signal transduction rarely consider the contributions of spatial organization due to high computational costs. A hybrid stochastic approach simplifies analyses of the spatio-temporal aspects of cell signaling and, as an example, demonstrates that receptor clustering contributes significantly to the efficiency of signal propagation from ligand-engaged growth factor receptors

Comparative antilipidemic effect of N-acetylcysteine and sesame oil administration in diet-induced hypercholesterolemic mice

<p>Abstract</p> <p>Background</p> <p>There is an increasing number of novel antilipidemic therapies under consideration. The putative hypolipidemic effect of N-acetylcysteine (NAC) and sesame oil was studied in a mouse model of dietary-induced hypercholesterolemia.</p> <p>Methods</p> <p>Male C57bl/6 mice were assigned to the following groups: (NC) control group, (HC) group receiving test diet supplemented with 2% cholesterol and 0.5% cholic acid for 8 weeks, (HCN) group receiving the test diet with NAC supplementation (230 mg/kg p.o.) and (HCS) group fed the test diet enriched with 10% sesame oil. Total serum cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were assayed at the beginning and at the end of the experiment. Total peroxides and nitric oxide (NO) levels were measured in the serum at the end of the experiment. Hepatic and aortic lesions were evaluated by haematoxylin-eosin staining.</p> <p>Results</p> <p>Higher serum levels of total and LDL-cholesterol were recorded in all groups fed the high cholesterol diet. The HCN group presented reduced lipid levels compared to HC and HCS groups. No differences were observed between HCS and HC groups. Peroxide content in serum was markedly increased in mice consuming high cholesterol diet. NAC and sesame oil administration led to a significant decrease of serum lipid peroxidation in the levels of control group, whereas only NAC restored NO bioavailability. In terms of liver histology, the lesions observed in HCN group were less severe than those seen in the other high cholesterol groups.</p> <p>Conclusion</p> <p>Co-administration of NAC, but not sesame oil, restored the disturbed lipid profile and improved hepatic steatosis in the studied diet-induced hypercholesterolemic mice. Both agents appear to ameliorate serum antioxidant defense.</p

The cyclin-dependent kinase inhibitor p57(Kip2) is epigenetically regulated in carboplatin resistance and results in collateral sensitivity to the CDK inhibitor seliciclib in ovarian cancer

Carboplatin remains a first-line agent in the management of epithelial ovarian cancer (EOC). Unfortunately, platinum-resistant disease ultimately occurs in most patients. Using a novel EOC cell line with acquired resistance to carboplatin: PEO1CarbR, genome-wide micro-array profiling identified the cyclin-dependent kinase inhibitor p57(Kip2) as specifically downregulated in carboplatin resistance. Presently, we describe confirmation of these preliminary data with a variety of approaches

Anabolic androgenic steroids reverse the beneficial effect of exercise on tendon biomechanics: An experimental study

Background The effect of anabolic androgenic steroids on tendons has not yet been fully elucidated. Aim of the present study was the evaluation of the impact of anabolic androgenic steroids on the biomechanical and histological characteristics of Achilles tendons. Methods Twenty-four male Wistar rats were randomized into four groups with exercise and anabolic steroids (nandrolone decanoate) serving as variables. Protocol duration was 12 weeks. Following euthanasia, tendons’ biomechanical properties were tested with the use of a modified clamping configuration. Histological examination with light and electron microscopy were also performed. Results In the group of anabolic steroids and exercise the lowest fracture stress values were observed, while in the exercise group the highest ones. Histological examination by light and electron microscopy revealed areas of collagen dysplasia and an increased epitendon in the groups receiving anabolic steroids and exercise. Conclusions These findings suggest that anabolic androgenic steroids reverse the beneficial effect of exercise, thus resulting in inferior maximal stress values

The preliminary design of a scaled Composite UHBR Fan for a wind tunnel test campaign

AbstractThe ambition of the CA3ViAR project is to design an open test case fan that experiences instability mechanisms, which are representative for ultra-high bypass ratio (UHBR) fans of civil aircrafts, and to perform a comprehensive experimental investigation to measure aerodynamic, aeroelastic and aeroacoustic performance in a wide range of operational conditions. Experimental tests will be performed in the Propulsion-Test-Facility (PTF) of the Institute of Jet Propulsion and Turbomachinery (IFAS) of Technische Universität Braunschweig, Germany. The final objective of the project is to provide an open test case for the entire research community, with geometries, numerical and experimental results to establish a new reference for composite UHBR fan design. This will support the development of new methods and tools for the development of safer, lighter and more efficient composite fans for greener UHBR engines. In this work the preliminary design of the low transonic fan (LTF) to be used as test article, whose main requirement is to be operated in a safe and controlled way in conditions of aerodynamic and/or aeroelastic instability during wind tunnel operations, is presented. More in particular, consolidated aerodynamic design, strategy adopted to drive the structural design, flutter analysis taking into account acoustic reflection at the intake, dynamic and stress analyses, as well as aeroacoustic measurement optimization are presented and discussed. The preliminary mechanical design of composite blades and the rotor hub, together with the rotor instrumentation and related studies to embed sensors in the composite blades, are also part of this article, and complemented by manufacturing trials and demonstration tests give the full picture of all the project activities up to the preliminary design review

Are children with SARS-CoV-2 infection at high risk for thrombosis? Viscoelastic testing and coagulation profiles in a case series of pediatric patients

© 2020 Wiley Periodicals LLC The coagulopathy of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented in adults, with increases in D-dimer and prothrombin time found to be strong predictors of mortality, and anticoagulation shown to decrease this mortality. Viscoelastic parameters such as elevations in maximum clot firmness (MCF) on rotational thromboelastometry (ROTEM) have correlated with a hypercoagulable state in adults with SARS-CoV-2. We report our experience in children infected with SARS-CoV-2, with noted elevations in D-dimer and MCF on ROTEM (indicating hypercoagulability). Exploration of viscoelastic testing to provide additional laboratory-based evidence for pediatric-specific risk assessment for thromboprophylaxis in SARS-CoV-2 is warranted

Correlation between mesenteric fat thickness and serum apolipoproteins in patients with peripheral arterial occlusive disease

BACKGROUND: Visceral fat possesses the most detrimental potential for cardiovascular morbidity through the release of adipokines, as well as metabolic and proinflammatory mediators, which adversely affect metabolic and vascular homeostasis. Among the different types of visceral adipose tissue, mesenteric fat is considered particularly detrimental, due to its close proximity to the portal circulation, affecting directly the liver, which is the main regulator of body metabolic homeostasis. Mesenteric fat can be reliably estimated using abdominal ultrasonography, the only available imaging method able to depict individual mesenteric leaves. Aim of the present study was to investigate the correlation of mesenteric fat thickness (MFT) with serum apolipoprotein levels in patients undergoing digital subtraction angiography in a single center. METHODS: 35 male patients with peripheral arterial disease were examined. After careful examination of the periumbilical area, the mesenteric leaves were identified. The maximal distance between each pair of sequential leaves was measured, and the mean value of the three thickest leaves was determined as the mesenteric fat thickness. Six apolipoprotein fasting serum concentrations were measured using a Luminex proteomics platform (xMAP Multiplex immunoassay): apolipoprotein A-I (apoAI), apolipoprotein A-II (apoAII), apolipoprotein B (apoB), apolipoprotein C-II (apoCII), apolipoprotein C-III (apoCIII) and apolipoprotein E (apoE). RESULTS: MFT correlated with apoAII and apoB serum concentrations. The correlations with apoAII and apoB remained significant following correction for BMI. No correlations were noted between MFT and serum apoAI, apoCII, apoCIII or apoE levels before or after adjustment for BMI. CONCLUSIONS: Our study indicates that MFT is significantly correlated with the concentration of atherogenic low density lipoproteins particles, as well as with apoAII, a determinant of free fatty acids levels. No correlation was observed between mesenteric fat thickness and very low density lipoprotein or chylomicron particles concentration

Recurrent Auto-Encoder Model for Large-Scale Industrial Sensor Signal Analysis

Recurrent auto-encoder model summarises sequential data through an encoder structure into a fixed-length vector and then reconstructs the original sequence through the decoder structure. The summarised vector can be used to represent time series features. In this paper, we propose relaxing the dimensionality of the decoder output so that it performs partial reconstruction. The fixed-length vector therefore represents features in the selected dimensions only. In addition, we propose using rolling fixed window approach to generate training samples from unbounded time series data. The change of time series features over time can be summarised as a smooth trajectory path. The fixed-length vectors are further analysed using additional visualisation and unsupervised clustering techniques. The proposed method can be applied in large-scale industrial processes for sensors signal analysis purpose, where clusters of the vector representations can reflect the operating states of the industrial system.Comment: Accepted paper at the 19th International Conference on Engineering Applications of Neural Networks (EANN 2018