In silico studies of the effect of phenolic compounds from grape seed extracts on the activity of phosphoinositide 3-kinase (PI3K) and the farnesoid x receptor (FXR)

In silico studies of the effect of phenolic compounds from grape seed extracts on the activity of phosphoinositide 3-kinase (PI3K) and farnesoid X receptor (FXR)Montserrat Vaqué Marquès En aquesta tesis es pretén aplicar metodologies computacionals (generació de farmacòfors i docking proteïna lligand) en l'àmbit de la nutigenòmica (ciència que pretén entendre, a nivell molecular, com els nutrients afecten la salut). S'aplicaran metodologies in silico per entendre a nivell molecular com productes naturals com els compostos fenòlics presents en la nostra dieta, poden modular la funció d'una diana comportant un efect en la salut. Aquest efecte es creu que podria ser degut a la seva interacció directa amb proteïnes de vies de senyalització molecular o bé a la modificació indirecta de l'expressió gènica. Donat que el coneixement de l'estructura del complex lligand-receptor és bàsic per entendre el mecanisme d'acció d'aquests lligands s'aplica la metodologia docking per predir l'estructura tridimensional del complex. En aquest sentit, un dels programes de docking és AutoGrid/AutoDock (un dels més citats). No obstant, l'automatització d'AutoGrid/AutoDock no és trivial tan per (a) la cerca virtual en una llibreria de lligands contra un grup de possibles receptors, (b) l'ús de flexibilitat, i (c) realitzar un docking a cegues utilitzant tota la superfície del receptor. Per aquest motiu, es dissenya una interfície gràfica de fàcil ús per utilitzar AutoGrid/AutoDock. Blind Docking Tester (BDT) és una aplicació gràfica que s'executa sobre quatre programes escrits en Fortran i que controla les condicions de les execucions d'AutoGrid i AutoDock. BDT pot ser utilitzat per equips d'investigadors en el camp de la química i de ciències de la vida interessats en dur a terme aquest tipus d'experiments però que no tenen suficient habilitats en programació. En la modulació del metabolisme de la glucosa, treballs in vivio i in vitro en el nostre grup de recerca s'han atribuït els efectes beneficiosos de l'extracte de pinyol de raïm en induir captació de glucosa (punt crític pel manteniment de l'homeostasis de la glucosa). No obstant alguns compostos fenòlics no tenen efecte en la captació de la glucosa, d'altres l'inhibeixen reversiblement. En alguns casos aquesta inhibició és el resultat de la competició dels compostos fenòlics amb ATP pel lloc d'unió de l'ATP de la subunitat catalítica de la fosfatidil inositol 3-kinasa (PI3K). Estudis recents amb inhibidors específics d'isoforma han identificat la p110α (la subunitat catalítica de PI3Kα) com la isoforma crucial per la captació de glucosa estimulada per insulina en algunes línies cel·lulars. Els programes computacionals han estat aplicats per tal de correlacionar l'activitat biològica dels compostos fenòlics amb informació estructural per obtenir una relació quantitativa estructura-activitat (3D-QSAR) i obtenir informació dels requeriments estructura-lligand per augmentar l'afinitat i/o selectivitat amb la diana (proteïna). Tot hi haver-se demostrat que l'adició d'extractes de compostos fenòlics en l'aliment pot tenir en general un benefici per la salut, s'ha de tenir en compte que l'estudi 3D-QSAR (construït a partir d'inhibidors sintètics de p110α) prediu que algunes d'aquestes molècules poden agreujar la resistència a la insulina en individus susceptibles dificultant la capatació de glucosa en múscul i teixit adipós i, per tant, produir un efecte secundari indesitjat. Resultats en el nostre grup de recerca han demostrat que compostos fenòlics presents en extractes de llavor de raïm incrementen l'activitat del receptor "farnesoid x receptor" (FXR) de manera dosi depenent quan el lligand natural de FXR (CDCA) és present. Les metodologies in silico, docking i 3D-QSAR, han estat aplicades juntament amb dades biològiques d'agonistes no esteroidals de FXR que s'uneixen a un lloc d'unió proper però diferent al lligand esteroidal 6CDCA. Els resultats han mostrat que els compostos fenòlics no són capaços d'activar FXR per ells mateixos però poden afegir noves interaccions que estabilitzarien la conformació activa de FXR en presència del lligand natural CDCA. Els compostos fenòlics podrien induir canvis conformacionals específics que augmentarien l'activitat de FXR. In silico studies of the effect of phenolic compounds from grape seed extracts on the activity of phosphoinositide 3-kinase (PI3K) and farnesoid X receptor (FXR)Montserrat Vaqué Marquès This thesis was written with the aim of applying computational methods that have already been developed for molecular design and simulation (i.e. pharmacophore generation and protein-ligand docking) to nutrigenomics. So, in silico tools that are routinely used by the pharmaceutical industry to develop drugs have been used to understand, at the molecular level, how natural products such as phenolic compounds (i.e. molecules that are commonly found in fruits and vegetables) can improve health and prevent diseases. Therefore, we first focused on predicting the structure of protein-ligand complexes. The docking algorithms can use the individual structures from receptor and ligand to predict (1) whether they can form a complex and (2) if so, the structure of the resulting complex. This prediction can be made, for instance, with AutoGrid/AutoDock, the most cited docking software in the literature. The automation of AutoGrid/AutoDock is not trivial for tasks such as (1) the virtual screening of a library of ligands against a set of possible receptors; (2) the use of receptor flexibility and (3) making a blind-docking experiment with the whole receptor surface. Therefore, in order to circumvent these limitations, we have designed BDT (i.e. blind-docking tester; http://www.quimica.urv.cat/~pujadas/BDT), an easy-to-use graphic interface for using AutoGrid/AutoDock. BDT is a Tcl/Tk graphic front-end application that runs on top of four Fortran programs and which controls the conditions of the AutoGrid and AutoDock runs. As far as the modulation of the glucose metabolism is concerned, several in vivo and in vitro results obtained by our group have shown that grape seed procyanidin extracts (GSPE) stimulate glucose uptake in 3T3-L1 adipocytes and thus help to maintain their glucose homeostasis. In contrast, it is also well known that although some phenolic compounds do not affect glucose uptake, others reversibly inhibit it in several cell lines. Moreover, for at least some of these phenolic compounds, this inhibition is the result of their competition with ATP for the ATP-binding site in p110α (i.e. the α isoform of the catalytic subunit of phosphoinositide 3-kinase or PI3Kα). Furthermore, recent studies with isoform-specific inhibitors have identified p110α as the crucial isoform for insulin-stimulated glucose-uptake in some cell lines. Therefore, although it has been proved that the addition of phenolic compound extracts to food can have an overall benefit on health, it should be taken into account that some of these molecules may exacerbate insulin resistance in susceptible individuals via impaired glucose uptake in muscle and adipose tissues and, therefore, produce an undesirable side effect. In this context, we have applied computational approaches (i.e. protein-ligand docking and 3D-QSAR) to predict the IC50 (i.e. the concentration that reduces the p110α activity to 50%). Our results agree with previous experimental results and predict that some compounds are potential inhibitors of this enzyme. Recent results in our research group have demonstrated that the phenolic compounds in GSPE increase the activity of the farnesoid X receptor (i.e. FXR) in a dose-dependent way when the natural ligand of FXR (i.e. CDCA) is also present. The phenolic compounds might induce specific conformational changes that increase FXR activity and then contribute to cardioprotection through mechanisms that are independent of their intrinsic antioxidant capacities but that involve direct interaction with FXR to modulate gene expression. Taking into account this hypothesis a 3D-QSAR analysis was made in an attempt to understand how phenolic compounds activate FXR. So, our results explain why phenolic compounds cannot activate FXR by themselves and how they can add new interactions to stabilize the active conformation of FXR when its natural ligand (i.e. CDCA) is present. Therefore, we proposed a mechanism of FXR activation by dietary phenolic compounds in which they may enhance bile acid-bound FXR activity

Sparse algorithms for decoding and identification of neural circuits

The brain, as an information processing machine, surpasses any man-made computational device, both in terms of its capabilities and its efficiency. Neuroscience research has made great strides since the foundational works of Cajal and Golgi. However, we still have very little understanding about the algorithmic underpinnings of the brain as an information processor. Identifying mechanistic models of the functional building blocks of the brain will have significant impact not just on neuroscience, but also on artificial computational systems. This provides the main motivation for the work presented in this thesis, summarily i) biologically-inspired algorithms that can be efficiently implemented in silico, ii) functional identification of the processing in certain types of neural circuits, and iii) a collaborative ecosystem for brain research in a model organism, towards the synergistic goal of understanding functional mechanisms employed by the brain. First, this thesis provides a highly parallelizable, biologically-inspired, motion detection algorithm that is based upon the temporal processing of the local (spatial) phase of a visual stimulus. The relation of the phase based motion detector to the widely studied Reichardt detector model, is discussed. Examples are provided comparing the performance of the proposed algorithm with the Reichardt detector as well as the optic flow algorithm, which is the workhorse for motion detection in computer vision. Further, it is shown through examples that the phase based motion detection model provides intuitive explanations for reverse-phi based illusory motion percepts. Then, tractable algorithms are presented for decoding with and identification of neural circuits, comprised of processing that can be described by a second-order Volterra kernel (quadratic filter). It is shown that the Reichardt detector, as well as models of cortical complex cells, can be described by this structure. Examples are provided for decoding of visual stimuli encoded by a population of Reichardt detector cells and complex cells, as well as their identification from observed spike times. Further, the phase based motion detection model is shown to be equivalent to a second-order Volterra kernel acting on two normalized inputs. Subsequently, a general model that computes the ratio of two non-linear functionals, each comprising linear (first order Volterra kernel) and quadratic (second-order Volterra kernel) filters, is proposed. It is shown that, even under these highly non-linear operations, a population of cells can encode stimuli faithfully using a number of measurements that are proportional to the bandwidth of the input stimulus. Tractable algorithms are devised to identify the divisive normalization model and examples of identification are provided for both simulated and biological data. Additionally, an extended framework, comprising parallel channels of divisively normalized cells each subjected to further divisive normalization from lateral feedback connections, is proposed. An algorithm is formulated for identifying all the components in this extended framework from controlled stimulus presentation and observed outputs samples. Finally, the thesis puts forward the Fruit Fly Brain Observatory (FFBO), an initiative to enable a collaborative ecosystem for fruit fly brain research. Key applications in FFBO, and the software and computational infrastructure enabling them, are described along with case studies

Technology 2002: The Third National Technology Transfer Conference and Exposition, volume 2

Proceedings from symposia of the Technology 2002 Conference and Exposition, December 1-3, 1992, Baltimore, MD. Volume 2 features 60 papers presented during 30 concurrent sessions

Continuous-time temporal logic specification and verification for nonlinear biological systems in uncertain contexts

In this thesis we introduce a complete framework for modelling and verification of biological systems in uncertain contexts based on the bond-calculus process algebra and the LBUC spatio-temporal logic. The bond-calculus is a biological process algebra which captures complex patterns of interaction based on affinity patterns, a novel communication mechanism using pattern matching to express multiway interaction affinities and general kinetic laws, whilst retaining an agent-centric modelling style for biomolecular species. The bond-calculus is equipped with a novel continuous semantics which maps models to systems of Ordinary Differential Equations (ODEs) in a compositional way. We then extend the bond-calculus to handle uncertain models, featuring interval uncertainties in their species concentrations and reaction rate parameters. Our semantics is also extended to handle uncertainty in every aspect of a model, producing non-deterministic continuous systems whose behaviour depends either on time-independent uncertain parameters and initial conditions, corresponding to our partial knowledge of the system at hand, or time-varying uncertain inputs, corresponding to genuine variability in a system’s behaviour based on environmental factors. This language is then coupled with the LBUC spatio-temporal logic which combines Signal Temporal Logic (STL) temporal operators with an uncertain context operator which quantifies over an uncertain context model describing the range of environments over which a property must hold. We develop model-checking procedures for STL and LBUC properties based on verified signal monitoring over flowpipes produced by the Flow* verified integrator, including the technique of masking which directs monitoring for atomic propositions to time regions relevant to the overall verification problem at hand. This allows us to monitor many interesting nested contextual properties and frequently reduces monitoring costs by an order of magnitude. Finally, we explore the technique of contextual signal monitoring which can use a single Flow* flowpipe representing a functional dependency to complete a whole tree of signals corresponding to different uncertain contexts. This allows us to produce refined monitoring results over the whole space and to explore the variation in system behaviour in different contexts

Fifth Annual Workshop on Space Operations Applications and Research (SOAR 1991), volume 2

Papers given at the Space Operations and Applications Symposium, host by the NASA Johnson Space Center on July 9-11, 1991 are given. The technical areas covered included intelligent systems, automation and robotics, human factors and life sciences, and environmental interactions

OIL SPILL MODELING FOR IMPROVED RESPONSE TO ARCTIC MARITIME SPILLS: THE PATH FORWARD

Maritime shipping and natural resource development in the Arctic are projected to increase as sea ice coverage decreases, resulting in a greater probability of more and larger oil spills. The increasing risk of Arctic spills emphasizes the need to identify the state-of-the-art oil trajectory and sea ice models and the potential for their integration. The Oil Spill Modeling for Improved Response to Arctic Maritime Spills: The Path Forward (AMSM) project, funded by the Arctic Domain Awareness Center (ADAC), provides a structured approach to gather expert advice to address U.S. Coast Guard (USCG) Federal On-Scene Coordinator (FOSC) core needs for decision-making. The National Oceanic & Atmospheric Administration (NOAA) Office of Response & Restoration (OR&R) provides scientific support to the USCG FOSC during oil spill response. As part of this scientific support, NOAA OR&R supplies decision support models that predict the fate (including chemical and physical weathering) and transport of spilled oil. Oil spill modeling in the Arctic faces many unique challenges including limited availability of environmental data (e.g., currents, wind, ice characteristics) at fine spatial and temporal resolution to feed models. Despite these challenges, OR&R’s modeling products must provide adequate spill trajectory predictions, so that response efforts minimize economic, cultural and environmental impacts, including those to species, habitats and food supplies. The AMSM project addressed the unique needs and challenges associated with Arctic spill response by: (1) identifying state-of-the-art oil spill and sea ice models, (2) recommending new components and algorithms for oil and ice interactions, (3) proposing methods for improving communication of model output uncertainty, and (4) developing methods for coordinating oil and ice modeling efforts