Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations.

Modelling the generation of customised poetry in Jess

The present paper presents an application that composes formal poetry in Spanish in a semiautomatic interactive fashion. JASPER is a forward reasoning rule-based system that obtains from the user an intended message, the desired metric, a choice of vocabulary, and a corpus of verses; and, by intelligent adaptation of selected examples from this corpus using the given words, carries out a prose-to-poetry translation of the given message. In the composition process, JASPER combines natural language generation and a set of construction heuristics obtained from formal literature on Spanish poetry.

Numerical modelling of braided fibres for reinforced concrete

Fire has been always a major concern for designers of steel and concrete structures. Designing fire-resistant structural elements is not an easy task due to several limitations such as the lack of fire-resistant construction materials. Concrete reinforcement cover and external insulation are the most commonly adopted systems to protect concrete and steel from overheating, while spalling of concrete is minimised by using HPFRC instead of standard concrete. Although these methodologies work very well for low rise concrete structures, this is not the case for high-rise and inaccessible buildings where fire loading is much longer. Fire can permanently damage structures that cost a lot of money. This is unsafe and can lead to loss of life. In this research, the author proposes a new type of main reinforcement for concrete structures which can provide better fire-resistance than steel or FRP re-bars. This consists of continuous braided fibre rope, generally made from fire-resistant materials such as carbon or glass fibre. These fibres have excellent tensile strengths, sometimes in excess of ten times greater than steel. In addition to fire-resistance, these ropes can produce lighter and corrosive resistant structures. Avoiding the use of expensive resin binders, fibres are easily bound together using braiding techniques, ensuring that tensile stress is evenly distributed throughout the reinforcement. In order to consider braided ropes as a form of reinforcement it is first necessary to establish the mechanical performance at room temperature and investigate the pull-out resistance for both unribbed and ribbed ropes. Ribbing of ropes was achieved by braiding the rope over a series of glass beads. Adhesion between the rope and concrete was drastically improved due to ribbing, and further improved by pre-stressing ropes and reducing the slacked fibres. Two types of material have been considered for the ropes: carbon and aramid. An implicit finite element approach is proposed to model braided fibres using Total Lagrangian formulation, based on the theory of small strains and large rotations. Modelling tows and strands as elastic transversely isotropic materials was a good assumption when stiff and brittle fibres such as carbon and glass fibres are considered. The rope-to-concrete and strand-to-strand bond interaction/adhesion was numerically simulated using newly proposed hierarchical higher order interface elements. Elastic and linear damage cohesive models were used effectively to simulate non-penetrative 'free' sliding interaction between strands, and the adhesion between ropes and concrete respectively. Numerical simulation showed similar de-bonding features when compared with experimental pull-out results of braided ribbed rope reinforced concrete.

Modelling and PI Control of an Irrigation Canal

The main goal of this paper is to expose and validate a methodology to design efficient automatic controllers for irrigation canals, based on the Saint-Venant model. This model-based methodology enables to design controllers at the design stage (when the canal is not already built). The methodology is applied on an experimental canal located in Portugal. First the full nonlinear PDE model is calibrated, using a single steady-state experiment. The model is then linearized around a functioning point, in order to design linear PI controllers. Two classical control strategies are tested (local upstream control and distant downstream control) and compared on the canal. The experimental results show the effectiveness of the model.

Modelling and studies of the spectral response of some optoelectronic components

Solar radiation takes in today's world, an increasing importance. Different devices are used to carry out spectral and integrated measurements of solar radiation. Thus the sensors can be divided into the fallow types: Calorimetric, Thermomechanical, Thermoelectric and Photoelectric. The first three categories are based on components converting the radiation to temperature (or heat) and then into electrical quantity. On the other hand, the photoelectric sensors are based on semiconductor or optoelectronic elements that when irradiated change their impedance or generate a measurable electric signal. The response function of the sensor element depends not only on the intensity of the radiation but also on its wavelengths. The radiation sensors most widely used fit in the first categories, but thanks to the reduction in manufacturing costs and to the increased integration of electronic systems, the use of the photoelectric-type sensors became more interesting. In this work we present a study of the behavior of different optoelectronic sensor elements. It is intended to verify the static response of the elements to the incident radiation. We study the optoelectronic elements using mathematical models that best fit their response as a function of wavelength. As an input to the model, the solar radiation values are generated with a radiative transfer model. We present a modeling of the spectral response sensors of other types in order to compare the behavior of optoelectronic elements with other sensors currently in use.

Assessment of PV Systems Performance in the Madeira Island Using Typical Meteorological Year Data

This paper focus on the development of an algorithm using Matlab to generate Typical Meteorological Years from weather data of eight locations in the Madeira Island and to predict the energy generation of photovoltaic systems based on solar cells modelling. Solar cells model includes the effect of ambient temperature and wind speed. The analysis of the PV system performance is carried out through the Weather Corrected Performance Ratio and the PV system yield for the entire island is estimated using spatial interpolation tools.

Contribution to the diffuse radiation modelling in Évora, Portugal

Solar radiation data is crucial for the design of energy systems based on the solar resource. Since diffuse radiation measurements are not always available in the archive data series, either due to the inexistence of measuring equipment, shading device misplacement or missing data, models to generate these data are needed. In this work, one year of hourly and daily horizontal solar global and diffuse irradiation measurements in Évora are used to establish a new relation between the diffuse radiation and the clearness index. The proposed model includes a fitting parameter, which was adjusted through a simple optimization procedure to minimize the Least Square Error as compared to measurements. A comparison against several other fitting models presented in the literature was also carried out using the Root Mean Square Error as statistical indicator, and it was found that the present model is more accurate than the previous fitting models for the diffuse radiation data in Évora.

Control and Supervision of Wind Energy Conversion Systems

This paper is about a PhD thesis and includes the study and analysis of the performance of an onshore wind energy conversion system. First, mathematical models of a variable speed wind turbine with pitch control are studied, followed by the study of different controller types such as integer-order controllers, fractional-order controllers, fuzzy logic controllers, adaptive controllers and predictive controllers and the study of a supervisor based on finite state machines is also studied. The controllers are included in the lower level of a hierarchical structure composed by two levels whose objective is to control the electric output power around the rated power. The supervisor included at the higher level is based on finite state machines whose objective is to analyze the operational states according to the wind speed. The studied mathematical models are integrated into computer simulations for the wind energy conversion system and the obtained numerical results allow for the performance assessment of the system connected to the electric grid. The wind energy conversion system is composed by a variable speed wind turbine, a mechanical transmission system described by a two mass drive train, a gearbox, a doubly fed induction generator rotor and by a two level converter.

AgroDB - integration of database management systems with crop models.

2016

Statistical Analysis and Modelling Aspects of Thermally Driven Turbulence

The present work aims to provide a deeper understanding of thermally driven turbulence and to address some modelling aspects related to the physics of the flow. For this purpose, two idealized systems are investigated by Direct Numerical Simulation: the rotating and non-rotating Rayleigh-Bénard convection. The preliminary study of the flow topologies shows how the coherent structures organise into different patterns depending on the rotation rate. From a statistical perspective, the analysis of the turbulent kinetic energy and temperature variance budgets allows to identify the flow regions where the production, the transport, and the dissipation of turbulent fluctuations occur. To provide a multi-scale description of the flows, a theoretical framework based on the Kolmogorov and Yaglom equations is applied for the first time to the Rayleigh-Bénard convection. The analysis shows how the spatial inhomogeneity modulates the dynamics at different scales and wall-distances. Inside the core of the flow, the space of scales can be divided into an inhomogeneity-dominated range at large scales, an inertial-like range at intermediate scales and a dissipative range at small scales. This classic scenario breaks close to the walls, where the inhomogeneous mechanisms and the viscous/diffusive processes are important at every scale and entail more complex dynamics. The same theoretical framework is extended to the filtered velocity and temperature fields of non-rotating Rayleigh-Bénard convection. The analysis of the filtered Kolmogorov and Yaglom equations reveals the influence of the residual scales on the filtered dynamics both in physical and scale space, highlighting the effect of the relative position between the filter length and the crossover that separates the inhomogeneity-dominated range from the quasi-homogeneous range. The assessment of the filtered and residual physics results to be instrumental for the correct use of the existing Large-Eddy Simulation models and for the development of new ones.

Intelligent Sensor Systems for Structural Health Monitoring Applications

The convergence between the recent developments in sensing technologies, data science, signal processing and advanced modelling has fostered a new paradigm to the Structural Health Monitoring (SHM) of engineered structures, which is the one based on intelligent sensors, i.e., embedded devices capable of stream processing data and/or performing structural inference in a self-contained and near-sensor manner. To efficiently exploit these intelligent sensor units for full-scale structural assessment, a joint effort is required to deal with instrumental aspects related to signal acquisition, conditioning and digitalization, and those pertaining to data management, data analytics and information sharing. In this framework, the main goal of this Thesis is to tackle the multi-faceted nature of the monitoring process, via a full-scale optimization of the hardware and software resources involved by the {SHM} system. The pursuit of this objective has required the investigation of both: i) transversal aspects common to multiple application domains at different abstraction levels (such as knowledge distillation, networking solutions, microsystem {HW} architectures), and ii) the specificities of the monitoring methodologies (vibrations, guided waves, acoustic emission monitoring). The key tools adopted in the proposed monitoring frameworks belong to the embedded signal processing field: namely, graph signal processing, compressed sensing, ARMA System Identification, digital data communication and TinyML.

Modelling and Uncertainty Quantification application to SA simulation codes in advanced SMR

In the framework of a global transition to a low-carbon energy mix, the interest in advanced nuclear Small Modular Reactors (SMRs) has been growing at the international level. Due to the high level of maturity reached by Severe Accident Codes for currently operating rectors, their applicability to advanced SMRs is starting to be studied. Within the present work of thesis and in the framework of a collaboration between ENEA, UNIBO and IRSN, an ASTEC code model of a generic IRIS reactor has been developed. The simulation of a DBA sequence involving the operation of all the passive safety systems of the generic IRIS has been carried out to investigate the code model capability in the prediction of the thermal-hydraulics characterizing an integral SMR adopting a passive mitigation strategy. The following simulation of 4 BDBAs sequences explores the applicability of Severe Accident Codes to advance SMRs in beyond-design and core-degradation conditions. The uncertainty affecting a code simulation can be estimated by using the method of Input Uncertainty Propagation, whose application has been realized through the RAVEN-ASTEC coupling and implementation on an HPC platform. This probabilistic methodology has been employed in a study of the uncertainty affecting the passive safety system operation in the DBA simulation of ASTEC, providing a further characterization of the thermal-hydraulics of this sequence. The application of the Uncertainty Quantification method to early core-melt phenomena has been investigated in the framework of a BEPU analysis of the ASTEC simulation of the QUENCH test-6 experiment. A possible solution to the encountered challenges has been proposed through the application of a Limit Surface search algorithm.

A take on complexity: bio-molecules and human metabolism interaction modelling for health and nutrition with machine learning

The advent of omic data production has opened many new perspectives in the quest for modelling complexity in biophysical systems. With the capability of characterizing a complex organism through the patterns of its molecular states, observed at different levels through various omics, a new paradigm of investigation is arising. In this thesis, we investigate the links between perturbations of the human organism, described as the ensemble of crosstalk of its molecular states, and health. Machine learning plays a key role within this picture, both in omic data analysis and model building. We propose and discuss different frameworks developed by the author using machine learning for data reduction, integration, projection on latent features, pattern analysis, classification and clustering of omic data, with a focus on 1H NMR metabolomic spectral data. The aim is to link different levels of omic observations of molecular states, from nanoscale to macroscale, to study perturbations such as diseases and diet interpreted as changes in molecular patterns. The first part of this work focuses on the fingerprinting of diseases, linking cellular and systemic metabolomics with genomic to asses and predict the downstream of perturbations all the way down to the enzymatic network. The second part is a set of frameworks and models, developed with 1H NMR metabolomic at its core, to study the exposure of the human organism to diet and food intake in its full complexity, from epidemiological data analysis to molecular characterization of food structure.

An efficient Jeans modelling of axisymmetric galaxies with multiple stellar components

Dynamical models of stellar systems represent a powerful tool to study their internal structure and dynamics, to interpret the observed morphological and kinematical fields, and also to support numerical simulations of their evolution. We present a method especially designed to build axisymmetric Jeans models of galaxies, assumed as stationary and collisionless stellar systems. The aim is the development of a rigorous and flexible modelling procedure of multicomponent galaxies, composed of different stellar and dark matter distributions, and a central supermassive black hole. The stellar components, in particular, are intended to represent different galaxy structures, such as discs, bulges, halos, and can then have different structural (density profile, flattening, mass, scale-length), dynamical (rotation, velocity dispersion anisotropy), and population (age, metallicity, initial mass function, mass-to-light ratio) properties. The theoretical framework supporting the modelling procedure is presented, with the introduction of a suitable nomenclature, and its numerical implementation is discussed, with particular reference to the numerical code JASMINE2, developed for this purpose. We propose an approach for efficiently scaling the contributions in mass, luminosity, and rotational support, of the different matter components, allowing for fast and flexible explorations of the model parameter space. We also offer different methods of the computation of the gravitational potentials associated of the density components, especially convenient for their easier numerical tractability. A few galaxy models are studied, showing internal, and projected, structural and dynamical properties of multicomponent galaxies, with a focus on axisymmetric early-type galaxies with complex kinematical morphologies. The application of galaxy models to the study of initial conditions for hydro-dynamical and $N$-body simulations of galaxy evolution is also addressed, allowing in particular to investigate the large number of interesting combinations of the parameters which determine the structure and dynamics of complex multicomponent stellar systems.

Modelling, simulation and control of rotary-wing aircraft in multi-agent scenario

The topic of this thesis is the design and the implementation of mathematical models and control system algorithms for rotary-wing unmanned aerial vehicles to be used in cooperative scenarios. The use of rotorcrafts has many attractive advantages, since these vehicles have the capability to take-off and land vertically, to hover and to move backward and laterally. Rotary-wing aircraft missions require precise control characteristics due to their unstable and heavy coupling aspects. As a matter of fact, flight test is the most accurate way to evaluate flying qualities and to test control systems. However, it may be very expensive and/or not feasible in case of early stage design and prototyping. A good compromise is made by a preliminary assessment performed by means of simulations and a reduced flight testing campaign. Consequently, having an analytical framework represents an important stage for simulations and control algorithm design. In this work mathematical models for various helicopter configurations are implemented. Different flight control techniques for helicopters are presented with theoretical background and tested via simulations and experimental flight tests on a small-scale unmanned helicopter. The same platform is used also in a cooperative scenario with a rover. Control strategies, algorithms and their implementation to perform missions are presented for two main scenarios. One of the main contributions of this thesis is to propose a suitable control system made by a classical PID baseline controller augmented with L1 adaptive contribution. In addition a complete analytical framework and the study of the dynamics and the stability of a synch-rotor are provided. At last, the implementation of cooperative control strategies for two main scenarios that include a small-scale unmanned helicopter and a rover.