Дисертації: "SILICO STUDIES"

1

ROCCO, A. GUERINI. "IN SILICO STUDIES ON MODELS OF SYNTHETIC HDL." Doctoral thesis, Università degli Studi di Milano, 2008. http://hdl.handle.net/2434/51223.

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The major protein components of high-density lipoproteins (HDL) are apolipoprotein (apo) A-I and apoA-II. Sixty-three different mutations of apoA-I are known. Among them, apoA-IMilano (IM) and apoA-IParis (IP) are characterized by an R-C substitution, leading to the formation of disulfide-linked homodimers and of heterodimers with apoA-II. From observations in humans and in animal models apoA-IM and apoA-IP behave as molecules with an intrinsic antiatherogenic activity. No experimental structure at atomic resolution of lipid-bound apoA-I is available. In this thesis I present four molecular models of synthetic HDL containing a lipidic core of palmitoyloleoyl- phosphatidylcholine and either two molecules of wild type apoA-I, or one apoA-IM homodimer, or one apoA-IP homodimer, or two molecules of apoA-IM–apoA-II heterodimer. On all the systems I computed molecular dynamics simulations to obtain reliable data about the behavior of apoA-I in a lipidic environment and to sharpen the understanding of its molecular functions in regulating cholesterol homeostasis. In all the four models of s- HDL the increase with time in the number of favorable interactions between apoA-I and phospholipids was the driving force for the structural reorganization and stabilization of s-HDL. I found a strong correspondence between computed and experimental properties, which supports the reliability of my results.

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2

Rücker, Pia Maria [Verfasser], and Heinrich [Akademischer Betreuer] Sticht. "In silico Studies of Viral Proteins : Structure, Design, and Dynamics = In-silico-Studien viraler Proteine / Pia Maria Rücker. Betreuer: Heinrich Sticht." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2012. http://d-nb.info/1019250631/34.

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3

Canbäck, Björn. "In silico Studies of Early Eukaryotic Evolution." Doctoral thesis, Uppsala universitet, Evolutionsbiologi, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3075.

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A question of great interest in evolutionary biology is how and why the eukaryotic cell evolved. Several hypotheses have been proposed, ranging from an early emergence of a primitive eukaryotic cell, to various fusion models like the hydrogen hypothesis. Within this context, relevant bacterial gene families and genomes are examined in this thesis. The mitochondrion, the energy producing organelle in the eukaryotic cell, is generally believed to be of α-proteobacterial descent. To learn more about mitochondrial evolution, and therefore eukaryotic evolution, the genomes of the α-proteobacteria Bartonella henselae and Bartonella quintana were sequenced. Software was developed and used in the annotation of these genomes. Several gene products of nuclear-encoded genes are exported to the mitochondrion. Many of these genes are thought to originate from the emerging organelle. An analysis of the more than 400 genes encoding proteins targeted to the yeast mitochondrion indicates that one set of genes originated from the bacterial symbiont, while the eukaryotic host contributed another. Thus, the mitochondrial proteome has a dual origin. The hydrogen hypothesis postulates that the glycolytic genes belong to the group of genes that were transferred from symbiont to host. These genes are thoroughly analysed from a phylogenetic perspective. Contrary to the predictions of the hydrogen hypothesis, the results provide no support for a close relationship between nuclear genes encoding glycolytic enzymes and their α-proteobacterial homologs. In general, it is thought that intensive gene transfers may limit our ability to reconstruct gene and species evolution, especially among microbes. A phylogenetic analysis of a large cohort of genes from the AT-rich genome of the γ-proteobacterium Buchnera aphidicola (Sg) resulted in a high fraction of atypical tree topologies, previously interpreted as horizontal gene transfers. By applying methods that accommodate for asymmetric nucleotide substitutions, it is shown that many well-supported gene topologies are drastically altered, so that they now agree with the rRNA topology. The conclusion is that atypical topologies may not necessarily be evidence for horizontal gene transfers.

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4

Cascone, Sara. "In silico and in vitro models in pharmacokinetic studies." Doctoral thesis, Universita degli studi di Salerno, 2015. http://hdl.handle.net/10556/2026.

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2011 - 2012
One of the aims of the thesis was to design and realize an in vitro device able to reproduce the gastrointestinal behavior. To reproduce the temperature and pH history an USP apparatus II coupled with a control system was used. The temperature was kept constant using the USP apparatus, a pH probe was inserted in the dissolution medium to measure the pH. The measured pH was compared (by a software) with a set point. Proportionally at the mean error, a quantity of an acidic or basic solution was inserted, by pumps, in the dissolution medium adjusting the pH at the desired value. Using the real pH history of the gastrointestinal tract, which provide a decrease in the pH value from 4.8 to about 2.0 during the first two hours of dissolution, and then an increase to 6.8, the release pattern from tablets was evaluated. The release patterns of these tablets obtained with the new device were compared with those obtained using the conventional method (which provides a pH 1 during the first two hours of dissolution, and then the neutralization at pH 6.8) and it was found that the drug released during the first two hours was higher in the case in which the real pH history was reproduced. This is due to the fact that the higher pH in the first stage damages the coating of the tablet. Once the chemical and thermal conditions were reproduced, the reproduction of the transport across the intestinal membrane was faced. An high throughput device which is able to reproduce continuously the exchange between the compartments has been necessary. The USP apparatus was equipped with a device composed by an hollow filter (which simulate the intestinal wall) and two pumps for the fluids simulating the intestinal content and the circulatory system surrounding the gastrointestinal tract content. The fluids enter in contact in the filter and the fluid rich in drug content (that simulates the intestinal content) gives the drug to the fluid poor in drug (simulating the blood content). The release patterns obtained by the use of this device were studied and compared with those obtained following the conventional dissolution method. Moreover these release patterns obtained using the real pH evolution were coupled with the effect of mass exchange and compared with those obtained using the conventional methods. The results showed that the effect of the real history of pH is higher in the first stage of dissolution, than the effect of the mass exchange is dominant. The reproduction of the mechanical history of the stomach is than faced. The peristaltic waves were reproduced using a lattice bag (elastic and compressible) connected to a camshaft which, with its rotation ensured the contraction of the bag. The bag was shrunk by connectors and the right position was ensured by guides. Changing the rotation speed of the shaft, the frequency of the contractions could be adjusted. The release pattern of a commercial tablet in the new device was evaluated and compared with the conventional one. The results showed that the non-perfect mixing of the stomach was satisfactory reproduced and this lead to a release pattern completely different. Moreover, the effect of the frequency of the contractions on the release pattern was evaluated. Second, but not secondary, aim of the thesis was to develop an in silico model (physiologically based) which is able to simulate the plasma concentration of drugs. The model is composed by seven compartments, which simulate the human organ, tissue, or a group of them. The compartments are interconnected between them and seven differential equations (with their initial conditions) describe their behavior. Once the parameter are obtained (by fitting or in literature), using an in vitro release pattern, the model is able to simulate the concentrations in all the compartments, including the plasma compartment. The plasma concentration are simulated both in the case in which the new release pattern (with the real pH history) is used as input, and the case in which the conventional one is used. The results show that in the real case the plasma concentration is very different both in value and in shape than the expected. The model then was used to simulate the fate of several molecules simultaneously in the human body (i.e. if a racemic mixture is administered or if the drug is metabolized to another molecule). The system of differential equations is expanded to describe the fate of each molecule. Then, the physiological parameters, such as gender and age, were integrated in the model; in this way, the dependence of the model parameter on the physiological parameter was evaluated. Finally, the gastrointestinal concentration simulated with the in silico model was successfully compared with the drug concentration measured with the in vitro model. It could be concluded that the combined approach which uses the in vitro and the in silico models is a powerful tool in the pharmacokinetic studies. [edited by Author]
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5

Börjesson, Anders. "In silico studies of carbon nano tubes and metal clusters." Doctoral thesis, Högskolan i Borås, Institutionen Ingenjörshögskolan, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:hb:diva-3565.

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Carbon nanotubes have been envisioned to become a very important material in various applications. This is due to the unique properties of carbon nanotubes which can be exploited in applications on length scales spanning from the nano world to our macroscopic world. For example, the electronic properties of carbon nanotubes makes them utterly suitable for nano electronics while the strength of them makes them suitable for reinforcements in plastics. Both of these applications do however require... mer the ability for systematic production of carbon nanotubes with certain properties. This is called selective carbon nanotube growth and today this has not been achieved with total success. In the work presented in the thesis several diﬀerent computational methods have been applied in our contribution to the systematic search for selective carbon nanotube growth. Put in a context of previous knowledge about carbon nanotube growth our results provide valuable clues to which parameters that control the carbon nanotube growth. In association with the latest results we even dare to, with all modesty, speculate about a plausible control mechanism. The studies presented in the thesis addressed diﬀerent stages of carbon nanotube growth, spanning from the properties aﬀecting the initiation of the growth to the parameters aﬀecting the termination of the growth. In some more detail this included studies of the melting temperatures of nanoscaled metal clusters. The expected size dependence of the melting temperatures was conﬁrmed and the melting temperatures of clusters on substrates were seen to depend both on the material and shape of the surface. As this constitute the premises prior to the carbon nanotube growth it was followed by studies of the interaction between carbon nanotubes and metal clusters of diﬀerent size and constitution. This was done using diﬀerent computational methods and at diﬀerent temperatures. It soon became apparent that the clusters adapted to the carbon nanotube and not vice versa. This held true irrespectively of the constitution of the cluster, that is for both pure metal and metal carbide. It was also seen that there exist a minimum cluster size that prevent the carbon nanotube end from closing. Closure of the carbon nanotube end is likely to lead to the termination of the growth which lead to studies of other reasons for growth termination, e.g., Ostwald ripening of the catalyst particles. This was investigated with the result that the rate of the Ostwald ripening may depend on both the chirality and diameter of the carbon nanotubes. It is suggested that this may provide some answers to the controlled growth of carbon nanotubes.

Disputationen sker fredagen den 3 december 2010, kl. 10:15, Kollektorn, Kemivägen 9

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6

Noailly, Jérôme. "Model developments for in silico studies of the lumbar spine biomechanics." Doctoral thesis, Universitat Politècnica de Catalunya, 2009. http://hdl.handle.net/10803/6067.

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La present tesi investiga l'ús de la modelització amb elements finits per a l'estudi de la biomecànica lumbar per a l'avaluació clínica. Els estudis bibliogràfics del capítol 1 mostren relacions funcionals clares entre les forces externes i les estructures i formes del teixit lumbar. Els estudis clínics demostraren que independentment del seu origen, el dolor lumbar pot veure's empitjorat per sobrecàrregues dels teixits. Les mesures experimentals són insuficients per descriure la distribució de càrrega entre els diferents teixits lumbars, és així que s'han utilitzat models d'elements finits. No obstant, la fiabilitat dels models a l'hora de predir les càrregues locals en els teixits no ha estat demostrada, essent aquest un dels objectes d'estudi.

En el Capítol 2 s'elaborà un model bisegment de la columna lumbar. El model inicial es completà incloent el còrtex vertebral, una definició complerta de les juntes sinovials, les plaques terminals de cartílag i una descripció millorada de l'estructura de l'anell. Es van simular càrregues simplificades per als estudis in vitro per calcular les distribucions de tensions, deformacions i energia. El model bisegment és vàlid per interpretar les distribucions de càrrega funcionals a L3-L5 en el cas d'estructures conegudes de teixit, però el conjunt de la geometria L3-L5 necessitava ser millorat.

Així al Capítol 3 es creà un model geomètric bisegment precís de L3-L5. El nou model incloïa les corregides: dimensions i formes, alçades de disc, localitzacions del nucli, formes posteriors de l'os, i distribució dels lligaments. Després de comparar a nivell biomecànic l'antiga geometria amb la nova, els resultats mostraren que els rols relatius dels teixits modelats depenen de la geometria. En general, les distribucions de càrrega predites eren més fisiològiques en el nou model. En canvi, ambdós models, reprodueixen rangs experimentals de moviment, així doncs la seva validació hauria de tenir en compte les transferències de càrrega locals.

El Capítol 4 es centra en la variabilitat dels angles creuats del col·lagen de l'anell. Es crearen quatre models bisegment amb organitzacions d'anell fibrós basats en la bibliografia comparant-se sota diverses càrregues. A més es proposà un paràmetre d'estabilització de l'anell per analogia a un tub de parets gruixudes. La biomecànica del model depenia en gran mesura de l'organització de l'anell fibrós, però el paràmetre d'estabilització era soviet contradictori amb les tensions i forces predites. Així, s'assumí que la geometria de la columna i l'organització de l'anell fibrós estaven lligades. Les xarxes d'anell de col·lagen adaptades es poden determinar numèricament, però els models d'anell haurien d'estar bastats en relacions mecanobiològiques.

Al Capítol 5 es presenta un model de disc artificial acoblat amb el model de L3-L5. Models bisegment amb i sense implant van ser comparats amb càrregues controlades per força o desplaçament, incloent o no l'aproximació del pes del cos. La rigidesa de la pròtesi alterava generalment les distribucions de càrrega i les rotacions controlades per desplaçament conduint a grans efectes adjacents. Incloent el pes del cos les condicions de contorn semblaven més fisòlogiques que sense. Malgrat la rigidesa del nou disc, aquest sembla més prometedor que altres dispositius comercials.
En aquesta tesi s'han creat sis models nous elements finits de la columna lumbar osteoligamentosa. Les simulacions han mostrat que l'ús fiable dels models requereix d'una descripció precisa de les càrregues locals i respostes mecàniques de teixits. Les prediccions locals van estar limitades qualitativament degudes al desconeixement de les estructures de teixit tou, equacions constitutives i condicions de contorn. En canvi, els models poden ser emprats com a laboratoris in silico per superar aquestes limitacions. Basat en la informació numèrica i experimental, s'ha proposat un procediment jeràrquic per al desenvolupament qualitativament fiable de models elements finits de la columna lumbar.
This PhD thesis investigated the use of finite element modelling to study lumbar spine biomechanics for clinical assessment. Bibliographic studies reported in the first Chapter showed clear functional relations between external forces and lumbar spine tissue structures and shapes. Clinical research revealed that independently of its origin, low back pain may be worsened by altered tissue mechanical environments. Experimental measurements alone cannot truly describe the load distributions between the different lumbar spine tissues. Thus, finite element models have been used in the past. But model reliability in predicting local tissue loadings is still not manifest and has been explored in this thesis as described in the following chapters.

In Chapter 2, a L3-L5 lumbar spine bi-segment model was built. An initial model was completed to include the vertebral cortex, a full definition of the facet joints, the cartilage endplates, and an improved description of the annulus fibre-reinforced structure. Simplified load-cases used for in vitro studies were simulated to calculate stress and strain energy distributions. Predictions within the L3-L5 lumbar spine bi-segment model could be interpreted in terms of functional load distributions related to known tissue structures, but the overall L3-L5 bisegment model geometry needed further update.

Thus, in Chapter 3, a geometrically accurate L3-L5 lumbar spine bi-segment model was created. The new model included corrected L3 and L5 body shapes and dimensions, corrected disc heights and nucleus placements, corrected posterior bone shapes, dimensions, and orientations, and corrected ligament distributions. The new and old geometries were biomechanically compared. Results showed that the relative roles of modelled tissues greatly depend on the geometry. Predicted load distributions were generally more physiological in the new model. However, new and old models could both reproduce experimental ranges of motion, meaning that their validation should take into account local load transfers.

Chapter 4 focuses on the variability of the annulus collagen criss-cross angles. Four bi-segment models with literature-based annulus fibre organizations were created and compared under diverse loads. Moreover, an annulus stabilization parameter was proposed by analogy to a thick walled pipe. Model biomechanics greatly depended on the annulus fibre organization, but annulus stabilization parameter was often contradictory with the predicted stresses and strains. Spine geometry and annulus fibrous organization were hypothesized to be linked together. Adapted annulus collagen networks may be numerically determined, but annulus modelling should be based on mechano-biological relationships.

In Chapter 5, a case-study of a novel artificial disc design coupled with the L3-L5 lumbar spine model is presented. Bi-segment models with and without implant were compared under load- or displacement-controlled rotations, with or without body-weight like load. Prosthesis stiffness generally altered the load distributions and displacement-controlled rotations led to strong adjacent level effects. Including body weight-like loads seemed to give more realistic results. Although the novel disc substitute is too stiff, it is more promising than other existing commercial devices.

In this thesis, six new osteoligamentous lumbar spine bi-segment finite element models were created. Simulations showed that reliable use of lumbar spine finite element models requires precise descriptions of local tissue loading and response. Local predictions were qualitatively mainly limited by a lack of knowledge about soft tissue structural organisations, constitutive equations, and boundary conditions. However, models can be used as in silico laboratories to overcome such limitations. A hierarchical procedure for the development of qualitatively reliable lumbar spine finite element models was proposed based on available numerical and experimental inputs.

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7

Vasudevan, Sridhar Ramaswamy. "Physiology of NAADP : insights from in silico and in vitro studies." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491748.

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In this thesis, I have explored the physiological role and the mode of synthesis of the Ca2-'--releasing second messenger, Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP). I demonstrate ill my work, the presence of a NAADP synthesizing enzyme; NAADP synthase, that is specific for NAADl> production and is regulated by Ca2+. This was demonstrated with use of biochemical, HPLC and confocal microscopy techniques. Followed by this, I show the ability ofNAADP to release Ca2 -!- from sea urchin spenn. As an extension to this study, I demonstrate the presence of NAADP-binding sites and explore the nature of the NAADP-sensitive Ca2 -!- stores involved. This study was conducted using techniques such as 4$Ca2-:- flux assays, Mn2 .,.-quench assays, e2p]NAADP binding assays and confocal microscopy. In the third part ofmy study, I study the possibility of NAADP being an endogenous cellular messenger in neurons by studying its ability to release Cal -'- using confocal microscopy, electroporation and phannacological studies. These results provide comprehensive insights into the roles of NAADP in CaZ+ signalling, the nature of theÃ‚Â· stores NAADP acts upon and the nature of its receptor in a range of cell types such as in spenn as well as neurons. Research on NAADP signalling would benefit greatly from the development of pharmacological modulators ofNAADP signalling cascade. As no such molecules are available, in the final part ofmy study, I make USe of computer-aided drug design to develop novel phaImacological tools to modulate NAADP signalling. I have developed, thus far, an NAADP-receptor antagonist, an NAADPÃ‚Â·phosphatase inhibitor and a partial agonist for inositolÃ‚Â·l,4,S-trisphosphate-receptor. These successes have added greatly to our toolkit for NAADP research and possibly to nlture dmg discovery efforts.

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8

Maughan, C. N. "Experimental and in silico computational studies of novel nanoparticle vaccine adjuvants." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1546603/.

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This thesis applies inorganic chemistry to develop new nanoparticulate vaccine adjuvants, entities added to a vaccine to inculcate robust immunity. The Introduction sets out the background to this work, and the Experimental Methods chapter reviews the techniques applied. Chapter 3 then reports the preparation of AlO(OH) using a continuous hydrothermal synthetic pathway – with sub-100 °C temperatures and atmospheric pressure – to produce nanoscale particles. A variety of experimental parameters was explored, and some degree of particle engineering could be achieved albeit over a narrow range of sizes and shapes. There was some evidence of particle size influencing the response of macrophages to the samples. Chapter 4 and Chapter 5 aim to engineer the size and shape of hydroxyapatite and zinc oxide nanoparticles, respectively, through different continuous hydrothermal processes. Several different morphologies (spheres, and mixtures of spheres/rods/platelets) could be produced. The morphology and particle size appear to affect cytokine production in vitro. Chapter 6 explores layered double hydroxides (LDHs) as inorganic adjuvants. A series of materials were prepared and characterised, and the effect of changing the LDH chemical composition on adjuvanticity determined. It was found that the size of the guest anion influences the immune response. Further, computational models were developed to aid the in silico prediction of immunogenicity, with calculated energy values being a suitable proxy for the zeta potential. The related hydroxy double salt (HDS) materials are investigated as adjuvants in Chapter 7. A series of materials was prepared and their chemical composition found to markedly effect the immune response in vitro. Computational models were sought with the same in silico aim as the LDH materials, however with limited success owing to a lack of detailed structural knowledge in the literature. Finally, overarching conclusions and suggestions for the future outlook of this area of research are given in Chapter 8.

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9

Husby, J. "In silico studies of nucleic acid complexes with proteins, and therapeutic small molecules." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1379540/.

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In silico approaches to nucleic acid targeted drug discovery have been used in order to study duplex DNA, in complexes with proteins as well as more unusual form of G-rich DNA folded into higher-order structures termed as G-quadruplexes, in complexes with therapeutic small molecules. The overall aim of this work has been to provide insight into the stability, recognition, energetics of binding and dynamic behavior of these DNAs in complexes with the STAT3βtc homodimer:DNA complex and with therapeutic small molecules in G-quadruplex/pyridostatin and G-quadruplex/fragment complexes by means of combined in silico approaches. The techniques of explicit solvent molecular dynamics (MD) simulations, and subsequent calculations of the free energies of binding, molecular docking, and 3D-pharmacophore modeling have been applied to study STAT3 and G-quadruplex DNA, promising targets for anticancer therapeutic intervention. Analysis of the data obtained from multiple 50-ns MD simulations of the STAT3-DNA complexes has suggested how the transcription factor STAT3 interacts with duplex DNA, the nature of the conformational changes, and ways in which func- tion may be affected. A majority of known pathologic mutations affecting the DNA-biding region of the STAT3 have been found at the protein-DNA interface, and they have been mapped in detail. The STAT3 conformations obtained from these MD simulations have been subsequently used as a basis for a comparative multiple-target molecular docking study with an in-house library of potential STAT3 inhibitors, providing a rational of their binding in the absence of structural data. A novel “dynamic docking” approach (robust platform of numerous MD simulations) has been developed to address the G-quadruplex receptor and ligand flexibility issue, and subsequent conformational change upon binding. The strength of binding at different regions and both sites of the G-quadruplex were then closely examined. An in silico study of a fragment-based approach towards G-quadruplex stabilizing ligands has also been explored, in parallel with experimental studies, to assess whether this could provide a reliable rapid approach to finding hit fragments in the case of the c-MYC promoter quadruplex.

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10

Platania, Chiara Bianca Maria. "Implications of dopamine D3 receptor for glaucoma: in-silico and in-vivo studies." Doctoral thesis, Università di Catania, 2014. http://hdl.handle.net/10761/1515.

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Glaucoma is a progressive optic neuropathy and it is considered by the World Health Organization to be the cause of 12% of visual impairment and 2% of blindness. Glaucoma is characterized by alterations of optic disc and visual field. High intraocular pressure (IOP) is the main risk factor of glaucoma. IOP reduction represents the first step in the management of glaucoma which is eventually followed by laser surgery of the trabecular meshwork (TM) and glaucoma-filtering surgery. Currently, there are five main classes of approved ocular hypotensive drugs: beta-blockers, carbonic anhydrase inhibitors, prostaglandin analogs, sympathomimetics and miotics. However, there is still the need to have more potent medications available for this disease. In the panorama of pharmacological targets for regulation of IOP, there are some interesting G protein coupled receptors (GPCRs) such as dopaminergic receptors. The work of the present thesis has been focused on GPCRs and in particular on dopamine D3 receptor as pharmacological target for ocular hypotensive drugs. Cabergoline, bromocriptine, cianergoline and legotrile, classical D2 receptor agonists, have been shown to decrease intraocular pressure. D3 receptor belongs to the D2 class of dopaminergic receptors, along with D2 and D4 receptor. It shares high sequence homology and identity with D2 receptor and several efforts have been carried out in order to design selective ligands for either D3 or D2 subtype. Drug design and discovery, based on structure based approach, need the knowledge of the tertiary structure of the target protein. In 2010 the x-ray structure of human D3 receptor (mutated hD3-lysozime chimera) was solved, then this structure was used to carry out the homology modeling of wild-type (wt) hD3 and hD2L receptors. The homology models of these receptors were not able to discriminate selective ligands by a molecular docking study, thus these structures have been subjected to optimization by means of molecular dynamics in a water-membrane environment. After optimization the structures differentiated in the binding pockets and have been validated, strengthen the validity and reliability of the in silico approach. A similar computational approach was carried out in order to study the structure differences between the D3 receptors and 5HT1A, 5HT2A-C receptors, known to be involved in regulation of intraocular pressure. The role of D3 receptor activation by cabergoline in lowering IOP was confirmed in C57BL/6J wt and D3-/- mice, using a pharmacological approach along with D3 gene deletion. Cabergoline was not effective in ocular hypertensive D3-/- mice, whereas exerted a greater and longer hypotensive effect in ocular hypertensive wt mice, in comparison to normotensive animals. The in silico approach, validated for D3 and D2L receptors, has been used to model and optimize the structures of 5HT1A, 5HT2A-B-C receptors which are other putative ocular targets of cabergoline. In silico results showed that cabergoline binds in a similar way into pockets of D3 and 5HT2A-C and it has higher affinity for D3 receptor in comparison to serotonergic receptors, according to experimental affinity data. Moreover docking revealed that binding of cabergoline into D3 and 5HT1A receptors is associated with a better desolvation energy in comparison to 5HT2A C binding. The structure-based computational approach hereby adopted was able to build, refine, and validate structure models of homologous dopaminergic and serotonergic receptors that may be of interest for structure-based drug discovery of ligands, with dopaminergic selectivity or with multi-pharmacological profile, potentially useful to treat optic neuropathies such as glaucoma. Finally, the present work represents an excellent example of successful integration of two different approaches to biomedical research, in silico and in vivo, which are not in contrast but complementary.

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11

Groß, Christine [Verfasser], Kay [Akademischer Betreuer] Hamacher, and Gerhard [Akademischer Betreuer] Thiel. "In Silico Studies on Proteins for Synthetic Biology / Christine Groß ; Kay Hamacher, Gerhard Thiel." Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2019. http://d-nb.info/1176701967/34.

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12

Hsieh, Heidi. "Investigating Zinc Toxicity In Olfactory Neurons: In Silico, In Vitro, And In Vivo Studies." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447070598.

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13

Durdagi, Serdar [Verfasser]. "In silico drug design studies of bioactive cannabinoid and [60]fullerene derivatives / Serdar Durdagi." Berlin : Freie Universität Berlin, 2009. http://d-nb.info/1023624370/34.

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14

Panigrahi, P. "In silico structure-function, specificity and stability studies of N-terminal nucleophile hydrolase enzymes." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2015. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2019.

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15

Brodaczewska, Natalia Anna. "NMR and in silico studies of fucosylated chondroitin sulfate (fCS) and its interactions with selectins." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31232.

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This thesis describes structural studies on the interactions between the fucosylated chondroitin sulfate (fCS) oligosaccharides and human proteins known as selectins. fCS is a carbohydrate obtained from sea cucumbers, that can be classified as a branched glycosaminoglycan (GAG). It has attracted much attention due to its anti-coagulant, anti-inflammatory, antimetastatic and anti-HIV properties and its structure was previously determined by NMR. Selectins constitute a family of proteins involved in cell adhesion processes, such as inflammation, attachment of viral particles and migration of tumour cells. fCS oligosaccharides have been shown to bind to selectins, which is likely a reason behind their biological activity. However, the mechanism of this interaction is currently unknown. The initial part of the thesis describes the experimental work on expression and purification of the recombinant L- and P-selectin constructs in Pichia pastoris, Escherichia coli and HEK 293 cells. The aim of these experiments was to produce two constructs for each selectin, a single domain construct, consisting of the C-type lectin domain only, and a double domain construct, consisting of both the C-type lectin and the EGF-like domains. The intention was that the recombinant proteins would be labelled with 13C and 15N to allow for the in-depth structural NMR studies on the fCS-selectin interaction. Various experimental approaches have been explored, including the use of different cell lines, modifications to construct design, as well as alterations to expression and purification conditions. Although it was not possible to produce soluble selectin constructs in either bacterial or yeast cells, protein expression tests in HEK293 cells, performed in collaboration with the Oxford Protein Production facility (OPPF), led to production of a soluble L-selectin construct, consisting of the L-selectin C-type lectin domain. The produced L-selectin construct, as well as two commercially available constructs of the Land P-selectin extracellular domains, were used in the Saturation Transfer Difference (STD) NMR experiments to provide new information about the nature of the fCS-selectin binding. The STD experiments allowed to identify the regions within the fCS oligosaccharides that are in direct contact with the protein and likely play an important role in this interaction. Experiments on different protein constructs allowed the comparison of fCS binding to P-selectin and to two different recombinant constructs of L-selectin. Results of these studies suggest that the binding occurs via a similar mechanism for both L- and P-selectins and that the fCS oligosaccharides bind to one-domain L-selectin construct with similar affinity as to a larger construct, consisting of the entire extracellular region of the protein. Alongside the experimental work, theoretical in silico studies on the fCS-selectin binding were undertaken as part of this project. The existing X-ray structures of selectin complexes were subjected to Molecular Dynamics (MD) simulations, which allowed to explore the dynamic behaviour of E-selectin upon binding to sialyl Lewis x (sLex). It was found that sLex forms a more favourable interaction with the extended conformation of E-selectin and that the protein in this conformation is characterised by a high degree of interdomain flexibility, with a new type of interdomain movement observed in the MD studies on this complex. In further in silico studies, the fCS oligosaccharides were docked to the existing P-selectin structures. The docking tests were performed on the computationally produced fCS trisaccharides with fucose branches either 2,4 or 3,4-sulfated. Results were evaluated with MD simulations and analysed in the light of current knowledge of selectin-ligand binding and the STD NMR experimental results. The in silico studies allowed to identify a subset of P-selectin residues that are likely involved in the interaction with fCS oligosaccharides in vivo. The conformational behaviour of P-selectin upon binding to fCS was also explored and it was found that the interdomain hinge is flexible during this interaction and allows transition from bent to extended conformational state. Finally, a new NMR method was developed to facilitate the studies of complex carbohydrates, incorporating the concepts of G-matrix Fourier Transform (GFT) NMR into 2D HSQC and 2D HSQC-TOCSY experiments. The method allows to separate peaks in the regions of high spectral overlap, providing information that can simplify the assignment process. The new experiments facilitated the structural evaluation of a sample containing a mixture of oligosaccharides resulting from the depolymerisation of fCS polysaccharide.

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16

Oshota, Olusegun James. "A systems biology approach to the production of biotechnological products through systematic in silico studies." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/a-systems-biology-approach-to-the-production-of-biotechnological-products-through-systematic-in-silico-studies(724d8446-b270-4558-b4d0-974cf18a7a0a).html.

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Background: Currently, the development of microbial strains for biotechnological production of chemicals and materials can be improved by using a rational metabolicengineering that may involve genetic engineering and/or systems biology techniques. Elementary ux mode analysis (EFM) and Flux balance analysis (FBA) are the twomost commonly used methods for probing the microbial network system properties for metabolic engineering purposes. EFM can be used to identify all possible pathways. However, combinatorial explosion of the number of EFMs obtained during EFM analysis, especially for large reaction networks, hinders the use of EFM data fordeveloping gene knockout strategies. The objective of this project was to identify interesting target products and design `proof of principle' Saccharomyces cerevisiaestrains capable of overproducing a target product; in this case lysine was chosen. Methods: EFMs were calculated for a reaction network from S. cerevisiae. In order to make sense of the large EFM solution space, a novel approach based on com-putational reduction and clustering of EFM datasets into subsets was developed,which aided the prediction of knockouts for lysine production. A Pattern analysismethod, based on regular expression matching, was also developed to interpret the EFM data. FBA frameworks, OptKnock and GDLS, were used to design in silcoproduction strains based on genome-scale models of yeast. Double and triple S. cerevisiae lysine producing strains were constructed using a PCR-based deletion method. Absolute and relative metabolome measurements for lysine and other metabolites in the single and double mutants were achieved using GC-TOF-MS.Results: The new computational and clustering methodology aided significantly the EFM-based in silico design of S. cerevisiae strains for enhanced yield of lysine andother value chemicals. Ethanol and lysine overproducing in silico strains were also developed by OptKnock and GDLS. Remarkably, the production strains with singledeletions, lsc2 and glt1, excreted into the medium five times the amount of lysine than the control strain. Five S. cerevisiae double mutant strains were successfullyconstructed. Two-fold increase in flux towards lysine production was demonstrated by S. cerevisiae double mutant M1, while both S. cerevisiae double mutants M4 andM5 showed about four-fold increase in lysine production. Conclusion: The general modelling and data reduction approaches developed here contributed in obviating the enormous problems associated with trying to obtainthe EFMs from large reaction network models and interpreting the resulting of large number of EFMs. EFM analysis aided the development of single and double S.cerevisiae mutant strains, capable of increased yield of lysine. The computational method was validated by construction of strains that are able to produce several foldmore lysine than the original strain.

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17

Lam, Ming-Chi. "In silico dynamic optimisation studies for batch/fed-batch mammalian cell suspension cultures producing biopharmaceuticals." Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/45465.

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Mammalian cell cultures are valuable for synthesis of therapeutic proteins and antibodies. They are commonly cultivated in bioindustry in form of large-scale suspension fed-batch cultures. The structure and regulatory responses of mammalian cells are complex, making it challenging to model them for practical process optimisation. The adjustable degrees of freedom in the cell cultures can be continuous variables as well as binary-type variables. The binary-type variables may be irreversible in cases such as cell-cycle arrest. The main aim of this study was to develop a general model for mammalian cell cultures using extracellular variables and capturing major changes in cellular responses between batch and fed-batch cultures. The model development started with a simple model for a hybridoma cell culture using first-principle equations. The growth kinetics was only linked to glucose and glutamine and the cell population was divided into three cell-cycle phases to study the phenomenon of cell-cycle arrest. But there were certain deficiencies in predicting growth rates in the death phase in fed-batch cultures although it was successful to simultaneously optimise a combination of continuous and binary-irreversible degrees of freedom. Thus, the growth kinetics was further related to amino acids concentration and cellular responses to high versus low concentration of glutamine and glucose based on a Chinese hamster ovary cell-line where amino acids data were available. The model contained 192 parameters with 26 measured cell culture variables. Most of the sensitive parameters were able to be identified using the Sobol' method of Global Sensitivity Analysis. The model could capture the main trends of key variables and be used to search for the optimal working range of the controllable variables. But uncertainties in the sensitive model parameters caused non-negligible variations in the model-based optimisation results. It is recommended to couple such off-line optimisation with on-line measurements of a few major variables to tackle the real-time uncertain nature of the complex cell culture system.

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18

Javierre, Guilhem. "Understand the inversion mechanism of P-stereogenic compound using kinetic studies and in silico modeling." Thesis, Ecole centrale de Marseille, 2018. http://www.theses.fr/2018ECDM0001/document.

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La thèse consiste en l'étude de la racémisation d'hydrogéno-phénylphosphinates d'alkyle, des molécules centrées sur un phosphore stéréogénique. Pour cela, nous avons synthétisé les composés d'intérêt puis étudié leur cinétique de racémisation en utilisant l'HPLC chirale et la RMN du phosphore. La première étude théorique (SMD//M06-2X/6-31++G**) sur l’énantiomérisation d’un phosphinate d’alkyle après une SN2 par un alcool a montré comme mécanisme le plus favorable une syn-addition de l’alcool sur la double liaison P=O du phosphinate à l’opposé du groupement alkoxy. Les études cinétiques d’inversion du phosphinate d’éthyle dans l’éthanol à reflux ont montré une barrière de 135 kJ.mol-1 en moyenne, en excellent accord avec ce modèle (136 kJ.mol-1). L’ajout de base lors de l’étude cinétique ont montré une accélération de l’inversion avec une barrière maximum mesurée à 121,5 kJ.mol-1 montrant un effet de catalyse basique. Les modèles cinétiques et théoriques réalisés à ce jour ont suggéré que la base activerait l’alcool pour faciliter son addition. Les premiers résultats sur l’influence du groupement alkyle ont montré une dépendance globale de l’inversion à la taille du groupement, mais certains modèles DFT, notamment avec l’adamantyle, n’étaient pas en accord avec cette hypothèse
This thesis is about the racemization of alkyl hydrogeno-phenylphosphinate, a molecule centered on a stereogenic phosphorus atom. We have synthetized compounds of interest, and studied their kinetic of racemization with chiral HPLC and phosphorus NMR. The first theoretical study (SMD//M06-2X/6-31++G**) about the enantiomerization of alkyl phosphinate after an SN2 with an alcohol have shown that the most favored mechanism was a syn-addition of the alcohol onto the double bond P=O on the opposite side of the alkoxy group. Kinetic studies with ethyl phosphinate in ethanol under reflux have shown an inversion barrier around 135 kJ.mol-1, in excellent agreement with this model (136 kJ.mol-1). The addition of a basic compound during kinetic measurements has shown a decreasing of the barrier to 121.5 kJ.mol-1, showing a catalytic effect. Kinetic and theoretical models have suggested that the mechanism would go through an activation of the alcohol by the basic compound which would facilitate its addition. The first tests about the nature of the alkyl group of phosphinate and alcohol have shown a general dependency of the barrier with the hindrance, but some DFT models, especially with adamantyl, have been in disagreement with this hypothesis

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19

Rivas, Santos Pep. "Design and synthesis of engineered peptides to target undruggable PPIs: from in silico to in vitro studies." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668150.

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Major unsolved diseases such as Cancer, cardiopathies or neurodegenerative disorders are frequently related with the malunction of complex protein networks. These networks are integrated by the interaction of multiple proteins that in case of a misregulation can trigger an undesired effect. Therefore, disruption of protein-protein interactions (PPIs), that are involucrated in a protein signalling cascade which is relevant for a particular diseases, is a hot topic in pharmaceutical industry. Unfortunately, traditional small molecules have been found to not be the most suitable inhibitiors of these therapeutic targets as PPI interfaces are characterized by a flat area with a lack of cavities that can fit a small molecule. In this scenario, peptides has called the attention in the drug discovery field for be a more appropiate candidates to target PPIs. Peptides are found in the chemical space between small molecules and antibodies, usullay contain between 2-50 amino acids and have an approximated weight of 250-10.000 Da. Then, their medium size allows a efficient recognition of the target protein without the need of well formed cavieties on the protein surface. However, peptides are characterized by a poor permeability and low stability in blood stream which had limited their therapeutic application in the past. Opportunately, introduction of non-natural amino acids and D-amino acids, N-alkylations of peptide backbone, cyclization and N-terminal and C-terminal modified cappings improve the biophysical properties along with the affinity for the receptor protein. Then, the use of engineered peptides, so-called peptidomimetics, is a promissing approach to target PPIs that can improve the binding potency of natural peptides and overcoming their major drawbacks at the same time. This thesis was carried out at Iproteos, a biotech company positioned in the use of peptidomimetics to target intracellular PPIs. The company has developed an in-house technology coined IPROTech, which is a platform that applys different in silico tools that are focused in the design of peptidomimetics, which are synthesized manually, quantified and finally evaluated in vitro. The experimental results are reintroduced in the platform and the process is repeated iteratively until achieve a final lead candidate. Hence, in the present work, IPROTech was applied to found de novo peptidomimetic molecules that inhibit the interaction of 4 different PPIs that are considered of therapeutic importance, Talin- Vinculin (Cancer), Rad51-BRCA2 (Cancer), Ras-Effectors (Cancer) and Retromer-L2 (HPVs infection). For each PPI, a collabration project with an academic group expert in field was setted up. Iproteos was in charge of the in silico studies of the target protein in order to design and synthesized a set peptidomimetic sequences that were predicted to disrupt the PPI of interest. On the other hand, the collaborators were responsible of the experimental evualtion of the synthesized compounds. In this terms, at least 1 hit was found for each PPI when evaluated in vitro, demonstrating an outsanding overall succes-rate of 31 % when all synthesized peptidomimetics were evaluated in vitro. Additinoally, the inclusion of new fancy builduing blocks into the compounds sintheysis, N-alkylation of the peptidomimetics backbone, pearmeability across biological barriers or the use of cyclodextrins as solvating excipient were other points studied as well.
Trobar nous fàrmacs capaços de trencar interaccions proteïna-proteïna, que d’alguna manera estan involucrades amb una malaltia, és de gran interès en el camp de la indústria farmacèutica. No obstant això, aquest tipus de diana terapèutica normalment no presenten cap cavitat ben definida a la seva superfície, característica necessària per albergar les tradicionals molècules petites. Per aquest motiu, la utilització de pèptids com a possibles fàrmacs és una aproximació molt prometedora perquè en tenir una mida molecular superior poden establir més interaccions amb la proteïna receptora afavorint així la seva unió. Però, aquesta aproximació està limitada per les propietats bioquímiques dels pèptids, ja que normalment són poc permeables i amb una baixa estabilitat un cop administrats. Afortunadament, els avanços fets en la síntesi de pèptids ha permès afegir modificacions sobre la seqüència dels pèptids per tal de millora les seves propietats, això inclou amino àcids no naturals, N-alquilacions, diferent tipus de N-terminals i C-terminals, entre altres. Els compostos obtinguts quan s’aplica aquesta enginyeria es coneixen com a peptidomimetics. Aquesta tesi es va realitzar a Iproteos. Iproteos és una petita empresa biotecnològica, focalitzada en l’ús de peptidomimetics per tal d’inhibir IPPs relacionades amb alguna malaltia. Per fer possible aquesta tasca, Iproteos ha creat una tecnologia, IPROTech, que agrupa tècniques computacionals per tal de cribrar la proteïna d’interès i genera estructures peptidometiques que més tard són sintetitzades, purificades i quantificades. Per aquesta tesi, es va aplicar la tecnologia IPROTech per trobar peptidomimetics amb la capacitat d’inhibir quatre IPP de rellevància terapèutica, Talina-Vinculina (càncer), Rad51- BRCA2 (càncer), Ras-Effectors (càncer) i Retromer-L2 (HPVs). Per cadascuna d’aquestes dianes, a Iproteos es va realitzar els estudis in silico i la síntesi dels peptidomimetics mentre que l'avaluació experimental la van fer grups acadèmics experts en cada camp. En tots els casos es va trobar almenys un compost capaç de trencar amb la interacció. Addicionalment propietats com la solubilitat, permeabilitat o estabilitat van ser avaluades per aquells compostos actius. Finalment, gràcies a les dades generades, alguns d’aquests compostos es van poder optimitzar obtenint un candidat final més potent encara.

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20

Turpeinen, M. (Miia). "Cytochrome P450 enzymes—in vitro, in vivo, and in silico studies." Doctoral thesis, University of Oulu, 2006. http://urn.fi/urn:isbn:9514282205.

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Abstract Metabolism is a major determinant of the pharmacokinetic properties of most drugs and is often behind bioavailability problems, drug-drug interactions, and metabolic idiosyncrasies. Cytochrome P450 (CYP) enzymes are a superfamily of microsomal hemoproteins catalysing the metabolic reactions of several exogenous compounds. The majority of crucial steps within drug metabolism are in connection with CYP enzymes. In the present study, in vivo, in vitro, and in silico approaches were applied and characterised to evaluate the effects of chemical entities on CYP-mediated metabolism. CYP2B6 was used as a target enzyme for these studies. For evaluation of the CYP inhibition potential of new chemical entities, a novel in vitro test system utilising the n-in-one approach was developed. This method proved to be robust and applicable to screening purposes. Validation of the n-in-one assay was done by comparing its performance to commonly used in vitro techniques using six structurally diverse drugs. All assay types yield remarkably similar results with the majority of the CYP forms tested. Several chemicals were screened in vitro and in silico in order to find potent and selective chemical inhibitors for CYP2B6. Ticlopidine, thioTEPA and 4-(4-chlorobenzylpyridine) were found to be highly effective inhibitors of CYP2B6. The selectivity of thioTEPA proved to be very high, whereas ticlopidine and 4-(4-chlorobenzylpyridine) also inhibited other CYPs. At a concentration level of 1 μM for ticlopidine and 0.1 μM for 4-(4-chlorobenzylpyridine), the inhibitory effect towards other CYPs was negligible. Due to wide clinical use and relevance, clopidogrel and ticlopidine were selected for further in vivo interaction studies. Both clopidogrel and ticlopidine significantly inhibited the CYP2B6-catalysed bupropion hydroxylation and patients receiving either clopidogrel or ticlopidine are likely to need dose adjustments when treated with drugs primarily metabolised by CYP2B6. The effect of impaired kidney function on CYP2B6 activity and on bupropion pharmacokinetics was also explored. In patients with kidney disease, the bupropion AUC and Cmax were significantly higher and the apparent oral clearance of bupropion was notably lower compared to healthy controls. The present results indicate that the in silico and in vitro methods used are helpful in predicting in vivo drug-drug interactions. The effective utilisation of these models in the early phases of drug discovery could therefore help to target the in vivo studies and to eliminate metabolically unfavourable drug candidates.

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21

Sustarsic, Marko. "In vitro, in silico and in vivo studies of the structure and conformational dynamics of DNA polymerase I." Thesis, University of Oxford, 2016. http://ora.ox.ac.uk/objects/uuid:ea317d58-00f7-4fc4-b71b-866b4becf0f7.

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DNA polymerases are a family of molecular machines involved in high-fidelity DNA replication and repair, of which DNA polymerase I (Pol) is one the best-characterized members. Pol is a strand-displacing polymerase responsible for Okazaki fragment synthesis and base-excision repair in bacteria; it consists of three protein domains, which harbour its 5’-3' polymerase, 3’-5’ exonuclease and 5’ endonuclease activities. In the first part of the thesis, we use a combination of single-molecule Förster resonance energy transfer (smFRET) and rigid-body docking to probe the structure of Pol bound to its gapped-DNA substrate. We show that the DNA substrate is highly bent in the complex, and that the downstream portion of the DNA is partly unwound. Using all-atom molecular dynamics (MD) simulations, we identify residues in the polymerase important for strand displacement and for downstream DNA binding. Moreover, we use coarse-grained simulations to investigate the dynamics of the gapped-DNA substrate alone, allowing us to propose a model for specific recognition and binding of gapped DNA by Pol. In the second part of the thesis, we focus on the catalytically important conformational change in Pol that involves the closing of the ‘fingers’ subdomain of the protein around an incoming nucleotide. We make use of the energy decomposition method (EDM) to predict the stability-determining residues for the closed and open conformations of Pol, and test their relevance by site-directed mutagenesis. We apply the unnatural amino acid approach and a single-molecule FRET assay of Pol fingers-closing, to show that substitutions in the stability-determining residues significantly affect the conformational equilibrium of Pol. In the final part of the thesis, we attempt to study Pol in its native environment of the living cell. We make use of the recently developed method of internalization by electroporation, and optimize it for organically labelled proteins. We demonstrate the internalization and single-molecule tracking of Pol, and provide preliminary data of intra-molecular FRET in Pol, both at the single-cell and single-molecule levels. Finally, by measuring smFRET within an internalized gapped-DNA construct, we observe DNA binding and bending by endogenous Pol, confirming the physiological relevance of our in vitro Pol-DNA structure.

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22

Wicha, Sebastian Georg [Verfasser]. "Integrated in vitro and in silico studies for optimisation of broad-spectrum antibiotic combination therapy / Sebastian Georg Wicha." Berlin : Freie Universität Berlin, 2015. http://d-nb.info/1080171118/34.

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23

Mento, Federico. "Development of Lung Ultrasound Quantitative Approaches and Automatic Semi-Quantitative Strategies: In Silico, In Vitro, and Clinical Studies." Doctoral thesis, Università degli studi di Trento, 2022. https://hdl.handle.net/11572/354762.

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Lung ultrasound (LUS) is a relatively novel application of ultrasound technology, which is increasingly expanding since the nineties. However, contrary to standard ultrasound imaging, which was primarily developed for imaging noninvasively the anatomy of internal body parts, LUS is mainly based on the visual interpretation of imaging artifacts. Among which, the so-called vertical artifacts are particularly important as they correlate with various pathologies. The main limitations associated with this type of pattern analysis remain its subjectivity and limited reproducibility. Moreover, the understanding and exploitation of the mechanisms behind the genesis of vertical artifacts are just in their beginnings. In this context, the most diffused and utilized strategies in LUS analyses are the so-called semi-quantitative techniques, which are based on the visual interpretation of LUS patterns, where a score is assigned based on visual interpretation of LUS patterns, which correlate with the state of lung. However, these techniques are strongly operator dependent. To this end, the use of artificial intelligence (AI) to automatically score LUS data could be instrumental to reduce the subjectivity in the evaluation of LUS patterns. For this reason, as a first novel contribution, we proposed a technique to automatically classify LUS videos by means of an aggregation strategy based on a deep learning (DL) frame-based classification. However, given the strong subjectivity of the task, it is not reliable to expect levels of agreement between AI and human operators at video or frame level around 90-100%. Indeed, the use of AI algorithms could lead to more reproducible analyses but cannot completely avoid subjectivity, as AI training remains based on the subjective labeling performed by clinicians. Another important aspect to be considered in semi-quantitative techniques is the proper definition and standardization of acquisition protocols. As an example, the number and spatial distribution of areas of the chest to be scanned are often defined arbitrarily and not following an evidence-based approach. For this reason, after having proposed (in a study of March 2020 I coauthored) a standardized imaging protocol specifically designed for the coronavirus disease 2019 (COVID-19) patients based on 14 scanning areas, we evaluated the impact of changing the scanning areas on the evaluation of COVID-19 (second novel contribution) and post-COVID-19 (third novel contribution) patients. In addition, to properly define the imaging settings to be used in a LUS examination and, in parallel, to develop quantitative LUS techniques specifically designed for lung, the mechanisms behind the genesis of vertical artifacts (whose comprehension is just in its beginnings) should be deeply understood. To better understand the dependence of vertical artifacts on imaging parameters, we performed two experimental studies (fourth and fifth novel contributions), where we assessed the dependence of vertical artifacts' intensity on different imaging parameters. On one hand, the presented results showed how there exist different confounding factors (e.g., focal point and angle of incidence of ultrasound beam) that should be reduced when developing a LUS approach. On the other hand, the results showed how a frequency characterization of vertical artifacts could be exploited to develop a LUS quantitative approach, as these artifacts seemed to be associated with specific resonance phenomena. Specifically, the acoustic traps' theory suggested that vertical artifacts originate from multiple reflections of ultrasound waves trapped within channels that can form between alveoli when lung tissue becomes pathological. By exploiting this concept, the frequency characterization of these artifacts could be used to indirectly estimate the size of acoustic channels (or traps). To further evaluate the possibility to estimate these channels' size with a multi-frequency approach, we performed a numerical study with the k-wave MATLAB toolbox (sixth novel contribution). The main advantage of in silico studies consists of the possibility to control the disposition of alveoli, which can be located at precise distances between each other. Therefore, with this kind of studies, it is possible to look for a correlation between the vertical artifacts' intensity as a function of frequency and the alveolar disposition. In the final novel contribution of this thesis, we performed a clinical study in humans showing the potentiality to exploit a quantitative multi-frequency approach to differentiate patients affected by pulmonary fibrosis (PF) from patients with other lung pathologies. Specifically, the frequency characterization of vertical artifacts along with their intensity was able to differentiate patients with PF with a specificity and sensitivity of 92%. In conclusion, quantitative approaches represent the future of LUS, as they could provide a physical metric able to characterize the lung surface by applying an acquisition technique specifically designed for the lung. Nevertheless, to develop these techniques, the genesis of vertical artifacts needs to be more deeply investigated and understood by means of controlled in vitro and in silico studies. In the meantime, semi-quantitative approaches based on image analysis techniques should be exploited to estimate the state of lungs by detecting and recognizing specific LUS patterns that do signal different levels of aeration. However, to reduce the impact of confounding factors, the standardization of the imaging protocols and scoring systems is essential.

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24

Yu, Wenying. "Computational, Synthetic, Biochemical and Biological Studies and Characterization on STAT3 Inhibitors for Potential Anticancer Therapy." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373328058.

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25

Borley, Daryl W. "Epitope dominance studies with serotype O foot-and-mouth disease." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:4adc3373-1d89-41d9-b1ce-7d8cbb0e817a.

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Foot-and-mouth disease virus (FMDV) is an economically devastating and highly contagious livestock pathogen. It exists as seven serotypes, comprising numerous antigenically distinct subtypes. The large amount of antigenic heterogeneity has confounded attempts at developing broadly reactive vaccines. In order to overcome this issue the fundamentals of the interactions between the virus and the host humoral immune response must first be understood. Previous work in this area using monoclonal antibody (mAb) escape mutants has identified five antigenic sites for the O serotype and efforts have been made to quantify their relative importance. However, this does not represent a complete picture of serotype O antigenicity. The work conducted in this thesis demonstrates the role of a limited number of dominant substitutions in mediating the antigenic diversity of serotype O Foot-and-Mouth disease virus. Two alternative but complementary methods for identifying epitopes were developed. The first used a mathematical model to analyse newly generated serological and sequence data from 105 viruses, cultured for this purpose (and cross-reacted to 5 reference antisera), in the context of an existing crystallographic structure to identify and quantify the antigenic importance of sites on the surface of the virus. The second approach was purely structural, using existing B cell epitope prediction tools to develop a method for predicting FMDV epitopes using existing crystallographic structures of FMDV. These techniques were validated by the use of reverse genetics, which confirmed the impact on cross reactivity of two predicted novel serotype O antigenic residues, with a further four novel residues identified by looking in depth at the interactions between two genetically close, but antigenically distant viruses. This increased knowledge of the antigenic composition of serotype O FMDV contributes to our understanding of the nature of vaccine efficacy and the breadth of protection, which, in the longer term, will aid in the goal of developing vaccines to better protect livestock from such a highly antigenically variable disease.

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26

Paul, George Ajay Abisheck [Verfasser]. "In Silico Facets of Biochemical Research: Accounts from Protein Folding and Protein-Ligand Interaction Studies / Ajay Abisheck Paul George." Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1219140031/34.

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27

Sousa, Mariana Côrtes de. "Estudos de modelagem molecular para previsão In Silico dos prováveis metabólitos de fase I de flavonóides." Universidade Federal de Goiás, 2012. http://repositorio.bc.ufg.br/tede/handle/tede/4259.

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Flavonoids are an important class of natural products candidate drugs, and low molecular weight polyphenols, widely distributed throughout the plant kingdom. Investigations on its activities over the past 30 years, demonstrated a potential to prevent several diseases, among them cardiovascular diseases, inflammatory disorders, viral infections, diabetes and neurological disorders, in addition to its known antioxidant. The family of cytochrome P450 (CYP) is composed of monooxygenases, which play a crucial role in the metabolism of endogenous and exogenous substances, and participates in the metabolism of flavonoids. In this paper we describe the application of a methodology for exploring combined in silico prediction of sites of metabolism of quercetin, rutin, naringin and naringenin, found in abundance in nature. A methodology used was ligand based drug design (LBDD) to predict the sites of metabolism (SOM) and the program MetaPrint2D most likely estimate of the metabolites, combined with the method structure based drug design (SBDD) by using molecular docking and energy minimization, to predict the interaction of quercetin, rutin, naringin and naringenin with the isoforms CYP2C9 and CYP1A2. Metabolites were found several Phase I with catalytically active distance (<5 Å) and interaction sites described in the literature, with hydroxylation reactions of aliphatic, aromatic hydroxylation, dealkylation and O-dealkylation. The proposed in silico metabolic hydroxylation at the position corresponding to the C3' were consistent with studies in vitro and in vivo experiments described in the literature for naringin and naringenin. Amino acids of the active site of CYP isoforms have been identified as important in the positioning of the flavonoids quercetin, rutin, naringin and naringenin toward the heme, confirming the involvement of these isoforms in the metabolism of flavonoids.
Os flavonóides representam uma importante classe de produtos naturais candidatos à fármacos, sendo polifenóis de baixo peso molecular, amplamente distribuídos no reino vegetal. Investigações sobre suas atividades, nos últimos 30 anos, demonstraram uma prevenção potencial de diversas patologias, dentre elas doenças cardiovasculares, desordens inflamatórias, infecções virais, diabetes e desordens neurológicas, além de sua conhecida ação antioxidante. A família do citocromo P450 (CYP) é composta de monooxigenases, que desempenham um papel crucial no metabolismo de substâncias endógenas e exógenas, e participa do metabolismo de flavonóides. Neste trabalho, descrevemos a aplicação de uma metodologia in silico combinada para explorar a previsão dos sítios de metabolismo dos flavonóides quercetina, rutina, naringenina e naringina, encontrados em abundância na natureza. Utilizou-se uma metodologia baseada nos ligantes (LBDD) para previsão dos sítios de metabolismo (SOM) pelo programa MetaPrint2D e previsão dos metabólitos mais prováveis, combinado à metodologia baseada na estrutura do receptor (SBDD) através da utilização de docking molecular e minimização de energia, para prever a interação de quercetina, rutina, naringenina e naringina com as isoformas CYP2C9 e CYP1A2. Foram encontrados diversos metabólitos de Fase I, com distâncias cataliticamente ativas (< 5 Å) e sítios de interação descritos na literatura, apresentando reações de hidroxilação alifática, hidroxilação aromática, desalquilação e O-desalquilação. Os metabólitos propostos in silico correspondentes à hidroxilação na posição C3’ foram com coerentes com estudos in vitro e in vivo descritos na literatura para naringenina e naringina. Aminoácidos do sítio ativo das isoformas de CYP foram identificados como importantes no posicionamento dos flavonóides quercetina, rutina, naringenina e naringina em direção ao heme, confirmando a participação dessas isoformas no metabolismo de flavonóides.

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Schmelzer, Constance [Verfasser]. "Effects of coenzyme Q10 on gene expression and inflammation : results from in silico, in vitro and in vivo studies / Constance Schmelzer." Kiel : Universitätsbibliothek Kiel, 2010. http://d-nb.info/1019904569/34.

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Ferreira, Carolina Martins André Oliveira. "Utilização de modelos farmacocinéticos de base fisiológica em estudos toxicológicos." Master's thesis, [s.n.], 2015. http://hdl.handle.net/10284/5154.

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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
Os efeitos adversos decorrentes das interações de substâncias químicas com os organismos, devido a exposição voluntária ou involuntária, são objeto de grande preocupação por parte das autoridades de saúde e da população em geral. Atualmente, os efeitos tóxicos são ainda, responsáveis por uma percentagem significativa das falhas na fase final no desenvolvimento de fármacos. A toxicocinética é normalmente descrita usando dois tipos de modelos - modelos empíricos ou modelos farmacocinéticos de base fisiológica (PBPK). Estes últimos traduzem o corpo humano como um conjunto de vários compartimentos, sendo que cada um representa fisiologicamente os órgãos, tecidos e outros espaços fisiológicos. Nos modelos PBPK, o organismo interage com os compostos químicos, como um sistema integrado, isto é, um efeito que ocorra num desses compartimentos do corpo pode influenciar o que ocorre num outro compartimento completamente distinto. Estes modelos têm vindo a ser aperfeiçoados, o que tem permitido progressos muito importantes no esclarecimento da ADMET (absorção, distribuição, metabolização, excreção e toxicidade), tanto em estudos de desenvolvimento de novos fármacos, como na compreensão da toxicocinética de certas substâncias, entre as quais os poluentes ambientais. Mediante a modelação com base em modelos de base fisiológica, torna-se possível a obtenção de informações importantes, tais como a melhor via de administração ou posologia, mas também o conhecimento de variações que ocorram em função de determinadas patologias, vias de excreção, principais locais de distribuição e efeitos adversos. Esta abordagem apresenta, ainda, baixo custo e rapidez na obtenção de resultados, baseia-se, geralmente, em dados humanos e permite, facilmente, a investigação de compostos hipotéticos. Estas vantagens fazem com que a modelação baseada em modelos PBPK possua, atualmente, um papel preponderante na investigação toxicológica e que as variadas agências nacionais de regulação e avaliação de medicamentos e produtos de saúde recomendem os métodos in silico como complemento aos testes realizados em animais. The adverse effects resulting from the interactions of chemical substances with the human body, due to voluntary or involuntary exposure, are object of great concern by health authorities and the general population. Nowadays, the toxic effects still account for a significant percentage of the final phase faults in drug development. The toxicokinetics is usually described by two types of models - empiric models or physiologically-based pharmacokinetic models (PBPK). The later describe the human body as a set of compartments corresponding to specific organs, tissues or other physiologic spaces. In a PBPK model the organism is pictured like an integrated system, thus an effect that occurs in one of the compartments can influence other effect that occurs in another completely different compartment. These models have been improved during the last three decades, which has allowed very significant progress in clarifying the ADMET (absorption, distribution, metabolism, excretion, toxicity), in drug development studies and in the knowledge of toxicokinetics of substances such as environmental pollutants. Modeling with physiologically-based pharmacokinetic models has contributed to obtain important information, such as the best route of administration or dosage, but also the knowledge of variations occurring under certain conditions, excretion routes, main distribution sites and adverse effects. This approach is also low cost and swifter in achieving results, it is generally based on human data and allows the investigation of hypothetical compounds easily. For all these reasons, modeling based in PBPK models currently has a leading role in toxicological research and the various national regulatory agencies and evaluation of medicines and health products recommend methods in silico as complementary to animal testing.

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Chiaranussati, Preeyanuj. "NMR studies of silicas and platinum/ silica catalysts." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319580.

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Vaqué, Marquès Montserrat. "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)." Doctoral thesis, Universitat Rovira i Virgili, 2007. http://hdl.handle.net/10803/8664.

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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.

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Mohammadi, Azadeh. "Apolipoprotein E isoform specific differences on their tertiary structure and on their interaction with amyloid-β peptide: Structural and dynamics studies by cross-linking mass spectrometry and in silico modeling". Doctoral thesis, Universite Libre de Bruxelles, 2017. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/257269.

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La maladie d’Alzheimer (MA) est un désordre neuro-dégénératif chronique fatal et la forme la plus répandue des démences chez l’adulte qui touchent plus de 28 millions de personnes dans le monde. En absence de traitement pour les démences neurodégénérative dont la maladie d’Alzheimer, le coût de celles-ci est estimé à 1 trillion d’USD en 2018 ce qui représente des enjeux économiques et sociétaux majeurs au niveau national et mondial. La MA est une forme d’amylose qui est caractérisée par l’agrégation du peptide amyloïde beta (Aβ) dans le cerveau des patients. Le facteur de risque génétique principal de la forme tardive (après 65 ans) de cette maladie est l’isoforme E4 de l’apolipoprotéine E (apoE) qui intervient dans le transport et le métabolisme des lipides et interagit avec le peptide Aβ. La modulation de la structure des isoformes d’apoE et de leur interaction avec l’Aβ apparaît comme une cible prometteuse dans la conception rationnelle de thérapies de la maladie. Celle-ci nécessite néanmoins une compréhension approfondie des propriétés structurales et dynamiques des deux partenaires moléculaires. Dans le cadre de cette thèse, nous avons étudié la structure de trois isoformes (E2, E3 et E4) de l’apoE par différentes techniques de biologie structurale et principalement par la réticulation chimique couplée à la spectrométrie de masse (CXMS) quantitative et par la bioinformatique structurale. Ces données complémentées par la spectroscopie infrarouge ont permis de construire des modèles structuraux de l’apoE2, E3 et E4. Nous avons mis en évidence l’interaction des domaines N- et C-terminal et la présence de multiples conformations de l’apoE chez les trois isoformes. Nos données suggèrent un équilibre entre deux principales conformations de l’apoE dont la population relative diffère entre les trois isoformes. Nous proposons les interfaces à cibler dans le cadre de thérapie visant à moduler les propriétés structurales des isoformes de l’apoE.Nous avons également mis en évidence que chaque isoforme d’apoE (E2, E3 et E4) interfère avec l’agrégation d’Aβ. Le peptide interagit avec les deux domaines N- et C- terminal de l’apoE. L’étude quantitative de l’interaction par CXMS a révélé des différences entre les cross-links formés en présence des isoformes. La modélisation du complexe apoE-Aβ a permis de mettre en évidence les interfaces impliquées dans l’interaction. Celle-ci possède une composante hydrophobe et électrostatique qui diffère chez les isoformes d’apoE. Nous proposons un mécanisme de l’interaction apoE-Aβ qui est initié par les propriétés hydrophobes des deux partenaires et qui est stabilisé par la suite via des contacts électrostatiques. Par ailleurs, une étude permettant d’explorer le potentiel de la nouvelle chimie de réticulation des résidues acides de protéine dans des applications en protéomique structurale a été effectuée.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished

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33

Deng, Xin, and 鄧欣. "Positron studies of silicon and germanium nanocrystals embedded in silicon dioxide." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B41508749.

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Deng, Xin. "Positron studies of silicon and germanium nanocrystals embedded in silicon dioxide." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B41508749.

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Singhon, Rattiya. "Adsorption of Cu(II) and Ni(II) Ions on Functionalized Colloidal Silica Particles Model Studies for Wastewater Treatment." Thesis, Besançon, 2014. http://www.theses.fr/2014BESA2077/document.

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Ce doctorat porte sur la fonctionnalisation de silices colloïdales en vue de la rétention de micropolluants métalliques dans des effluents. Les nanoparticules et microparticules ouvrent des potentialités d’application dans de nombreux secteurs industriels (chimie, environnement, pharmacie...). Ainsi, ces travaux de recherche portent sur la synthèse et la caractérisation de matériaux composites submicroniques : il s’agit de silices colloïdales sur lesquelles sont greffés des silanes ou supportés des polysaccharides. Une des applications de ces travaux de recherche porte sur l’adsorption de métaux de transition sur ces composites en solution aqueuse. Dans le cadre de ce doctorat, les caractéristiques des composites sont définies par leur morphologie de surface, par l’étude des groupements fonctionnels présents, par détermination de leurs surfaces spécifiques ainsi qu’en solution aqueuse par détermination de leurs diamètres hydrodynamiques et de leurs potentiels zéta. Dans un premier temps, la fonctionnalisation de la silice a permis le greffage de groupements carboxyliques et amines dont tes taux de greffage obtenus ont été respectivement de 0,47 µmol/m² et 3,86 µmol/m². En présence de groupements amines, le potentiel  des composites est positif jusqu’ à pH 9 alors qu’il est négatif dès pH 3 pour des silices non fonctionnalisées. Dans un second temps, la silice est supportée par du chitosane dont le degré de désacétylation est de 77%. Conjointement, l’encapsulation de la silice est réalisées par du chitosane sur lequel des fonctions carboxyliques ont été greffées. La morphologie des particules est alors modifiée, leurs diamètres hydrodynamiques sont plus élevés et leurs potentiels  sont positifs jusqu’ à pH basique. La rétention d’ions métalliques (Cu(II) et Ni(II)) par ces composites à différents pH est ensuite étudiée. Pour chacun des cations métalliques, les capacités d’adsorption sont déterminées ainsi que les cinétiques d’adsorption. L’application de plusieurs modèles d’isotherme d’équilibre a été réalisée. Dans le cas de Cu(II), à pH 5, les meilleures capacités d’adsorption sont obtenues pour des silices supportées par du chitosane greffé : la capacité de rétention des ions Cu(II) est de 270 mg/g à pH 5. De même, c’est ce composite qui permet la meilleurs rétention des ions Ni(II) à pH 7 avec une capacité d’adsorption de 263 m/g. Concernant la cinétique, le modèle de réaction de surface du pseudo-second ordre s’applique bien aux résultats expérimentaux
This study is focused on the preparation of three types of silica-based composites for the capture of Cu(II) and Ni(II) ions. The first strategy consists in coating chitosan on colloidal fumed silica after acidic treatment yielding the composite SiO2+CS. The second strategy can be separated into two routes: the first one involves surface grafting of silica with aminopropyltriethoxysilane to obtaining silica particles covered by amino groups (SiO2(NH2)). The second one involves in surface condensation of triethoxysilylbutyronitrile, followed by acidic hydrolysis of the surface-bound nitrile groups affording silica particles covered by carboxyl groups (SiO2(CO2H)). In the last step, chitosan has been grafted on the surface bound NH2 or -CO2H groups yielding the composites SiO2(NH2)+CS or SiO2(CO2H)+CS. The third strategy involves in the modified CS surface with -CO2H groups, followed by coating onto the non-modified silica nanoparticles to obtain the composite SiO2+CS(CO2H). The novel hybrid materials were characterized by IR spectroscopy, scanning electron microscopy, atomic force microscopy, and zeta potential measurements. Batch experiments were conducted to study the sorption performance of these composites for Cu(II) and Ni(II) removal from aqueous solution at optimum pH at 298 K. The kinetics were evaluated utilizing pseudo-first-order, pseudo-second-order, and intraparticle diffusion models. The adsorption kinetics followed the mechanism of the pseudo-second-order equation for all types of adsorbents. The adsorption isotherms were evaluated utilizing Langmuir, Freundlich, and Temkin models. The best interpretation for equilibrium data was given by Langmuir isotherm model. This study demonstrates that the adsorption capacities for Cu(II) ion is more efficient for the SiO2+CS (256 mg g-1) compared to SiO2(NH2) (75 mg g-1). However, the carboxyl grafted CS-coated silica (SiO2+CS(CO2H) exhibited an excellent adsorption capacity (333 mg g-1). In case of Ni(II), based on Langmuir isotherm the maximum adsorption capacity found to be 182 mg g-1for SiO2+CS, and 210 mg g-1 for SiO2(CO2H) + CS. Using single-metal solutions, these adsorbents were found to have an affinity for metal ions in order as Cu(II) > Ni(II). The adsorption of Cu(II) ion by SiO2+CS was affected by the nature of the respective anion. Application of these composite materials to remove Cu(II) and Ni(II) from aqueous solution was shown to be more efficient than the adsorption capacities of many sorbents probed by other research groups

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Aljohny, Bassam Ouda. "Studies on silicon microbiology." Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548645.

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37

Glaser, K. J. "Computational studies of silica." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1333222/.

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There are three areas of research in this thesis. The first is concerned with the silica polymorph, tridymite, with simulations carried out using three computational methods: free energy minimisation, molecular dynamics and Density Functional Theory. A number of tridymite structures with different atomic configurations have been found in nature. The simulations explore various properties of these different forms of tridymite and investigate whether it is possible to distinguish between them using the three computational techniques. It was found that the interatomic potential and simulation technique used, rather than the simulation temperature, were the main factors affecting the resulting structure. There are a number of possible explanations for this result: The techniques may not be sensitive enough to deal with an energy landscape as at as in the case of tridymite. Another reason is that the potentials have been parameterised to distinguish between structures which have reconstructive transitions (where bonds are broken and formed) and may not be able to deal with displacive transitions (where only angles between atoms change) as with tridymite. The final possible explanation is that a number of the known structures may be meta-stable and/or poorly characterised. For the second research area molecular dynamics simulations using a rigid ion two body potential were carried out in order to investigate the properties of silica melts and glasses. A number of different silica crystals were melted to see whether the melts are all similar or whether their properties can be differentiated according to the original crystal structure. At sufficiently high temperatures the starting structure did not affect the properties of the melt. Several properties of silica melts and glasses were investigated: mean square displacement, autocorrelation functions, pair distribution functions, the extent to which silicon and oxygen atoms move together, Arrhenius plots, coordination number, bond lengths and angles. Investigations were also carried out as to whether it is possible to use a shell model to simulate a silica melt. Various properties were calculated and it was found that agreement with experiment was not as accurate as when using the rigid ion model. The third research area is an exploration of the properties of amorphous silica at elevated pressures and a range of temperatures, using molecular dynamics with a rigid ion two body potential. Calculations show that, at low temperatures, the distortion of the tetrahedra is not recovered upon decompression whereas experimental results find complete recovery of the tetrahedra. There is little available experimental data on the behaviour of silica at both high pressures and temperatures. Calculations show that at high temperatures all properties of the initial structure before compression are recovered.

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38

Anthony, Carl John. "Oxide interface studies on silicon and silicon carbide." Thesis, University of Newcastle Upon Tyne, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424150.

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39

Yoshida, Hisao. "Studies on Photocatalysis by Silica and Silica - Based Materials." Kyoto University, 1998. http://hdl.handle.net/2433/157038.

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本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものである
Kyoto University (京都大学)
0048
新制・論文博士
博士(工学)
乙第9830号
論工博第3320号
新制||工||1114(附属図書館)
UT51-98-G429
(主査)教授吉田鄕弘, 教授川﨑昌博, 教授横尾俊信
学位規則第4条第2項該当

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40

McFarlan, Andrew J. "Infrared studies of silica surfaces." Thesis, University of Ottawa (Canada), 1991. http://hdl.handle.net/10393/7852.

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The silanol distributions on "as received" aerosil and precipitated silica have been studied (1) by using time-resolved infrared spectroscopy in order to follow a reaction with AlMe$\sb3$, TiCl$\sb4$, or BCl$\sb3$, (2) by spectroscopically comparing the accessibility of probe molecules having different steric dimensions, that react with surface silanols (SiOH) either by chemisorption or H/D exchange, and (3) by gravimetrically measuring surface silanol densities using vacuum microbalance techniques. The results have been used to compare and characterize these non-porous silicas of similar surface area. Initially, H-bonded silanols are relatively more reactive than isolated silanols in the order of reagents, BCl$\sb3$ $>$ TiCl$\sb4$ $>$ AlMe$\sb3$. In the fully hydroxylated "as received" state, the number of silanol groups on either silica which react with various hydrogen sequestering (HS) agents decreases as the size of the agent increases (ZnMe$\sb2$, BCl$\sb3$, TiCl$\sb4$, AlMe$\sb3$ and Me$\sb3$SiNHSiMe$\sb3$ (HMDS) in increasing size). The number of silanols that undergo H/D exchange also decreases as the size of the probe molecule increases (D$\sb2$O, ND$\sb3$, and deuterated methanol, i-propanol and t-butanol). The reaction between HMDS and H-bonded silanols occurs preferentially with the terminal silanols of a chain, and we propose that these silanols occupy sites which are inherently more accessible to this bulky reactant. By following the evolution of the SiOH bands on both silicas in all three spectral regions for 450, 600, and 800$\sp\circ$C activation, we have assigned bands to two types of isolated silanols. The type I silanols are preferentially eliminated between 450 and 800$\sp\circ$C activation and are more abundant on precipitated silica than on aerosil. Type II silanols (isolated single silanols) dominate the surface of highly activated aerosil or precipitated silica. The vibrational spectra are reported for the physically adsorbed complexes, SiOH...X (X = CO, N$\sb2$, and CH$\sb4$) and the nature of their specific interaction with surface SiOH is discussed. Mechanisms are proposed for the room-temperature reaction between SiOH and TMP to produce DMP, and the SiOH catalyzed isomerization of TMP to DMMP. (Abstract shortened by UMI.)

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41

Wielgosz, R. I. "Electrochemical studies of porous silicon." Thesis, University of Bath, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296302.

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42

Tyou, Sonbeku. "STUDIES ON BIOACTIVITY OF SILICA." Kyoto University, 1997. http://hdl.handle.net/2433/202316.

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43

González, Fernández Alfredo A. "Studies and integration of Silicon-based light emitting systems." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/285863.

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This project presents the study of luminescent devices and materials based on silicon for its use in the fabrication of an optical system that integrates light emitter, waveguide, and light sensor in a single chip obtained by the use of standard CMOS techniques and materials. The atomic and structural characteristics of the materials are analysed and related to its luminescent response. Taking into account the results from the active material characterization, the design, fabrication, and characterization of electroluminescent devices based on such materials is presented. Finally, the design, fabrication and characterization of a complete CMOS compatible Integrated Optical System consisting of a transceiver, is discussed and analysed. The active materials used for light emission were different Silicon Rich Silicon Dioxide(SRO) and SRO-Si3 N4 bi-layers, obtained by a variety of CMOS compatible techniques and fabrication parameters. Two contributing mechanisms to photoluminescence in SRO were identified in all cases, respectively linked to the presence of radiative defects, and to Quantum Confinement phenomena. It is proposed and tested a model to describe the latter, based on the effective mass approximation, and the relation between the amount of Si-Si links and the volume of nano-agglomerates present in the material. In bi-layer samples, an additional luminescence band was observed, found to be generated in the transition material between silicon nitride and dioxide, and related to energy states introduced by defects. Samples with SRO thickness ten times higher than that of nitride, presented a clear dominance of the photoluminescence related to the dioxide. The centres responsible for electroluminescence in the electronicd evices were found to be fundamentally the same as those for photoluminescence despite the differences in measured spectra, and it was concluded that the influence of the architecture on the light output is of significant importance. It was shown that bi-layered devices delivered better results in terms of efficiency, light emission control, distribution and stability. The carrier transport mechanisms observed in the devices were dominated by material breakdown in single-layered devices, and Trap-assisted Tunnelling in the bi-layers. The Optical System integrating the light emitter, a waveguide, and a light detector, was designed and fabricated based on the results from the fabrication and analysis of the stand alone light emitting devices. During the design stage, it was corroborated by computer simulations that the characteristics of thelight emittedby thedevices thatpresented thehighest e.ciency and reliability, were suitable for its transmission trough the proposed waveguide architecture. The detection capabilities of the designed light sensors were also theoretically corroborated to be appropriated for the detection of the emitted light type. The proper functioning of the elements conforming the finally fabricated system was probed. Differences were found in the operation of the stand alone light emitting devices and those integrated, but the resulting luminescence was within the boundaries of the transmittable spectrum. The operation of the Integrated Optical System was tested and preliminarily studied, obtaining positive results in its stimulus-detection response, fulfilling the main objective of the work, and opening the door for further studies which can lead to the optimization of the design for particular applications.
Este proyecto aborda el estudio de dispositivos y materiales luminiscentes basados en silicio para su uso en la fabricación de un sistema óptico que integre emisor de luz, guía de ondas, y sensor en un solo chip obtenido mediante el uso de técnicas y materiales estándar para la fabricación CMOS. Las características atómicas y estructurales de los materiales son analizados y relacionados con su respuesta luminiscente. Considerando los resultados de la caracterización del material activo, se presenta el diseño, fabricación, y caracterización de dispositivos electroluminiscentes basados en dichos materiales. Finalmente, se discute y analizan el diseño, fabricación, y caracterización de un transceptor como Sistema Óptico Integrado. Los materiales activos para la emisión de luz fueron distintos Dióxidos de Silicio enriquecidos con Silicio (SRO por sus siglas en inglés) y bi-capas SRO-Si3 N4, obtenidos mediante una variedad de técnicas compatibles con los procesos CMOS y distintos parámetros para los mismos. Se identificaron dos mecanismos que contribuyen a la fotoluminiscencia del SRO en todos los casos, relacionados con defectos radiativos y fenómenos de Confinamiento Cuántico, respectivamente. Se sugiere y pone a prueba un modelo para describir este último, basado en la aproximación de la masa efectiva y la relación entre la cantidad de enlaces Si-Si y el volumen de nano-aglomerados. En muestras bi-capa, se observó una banda adicional de luminiscencia, cuya generación fue identificada en el material de transición entre el nitruro de silicio y el óxido, y relacionada con estados de energía introducidos por defectos. Muestras con un espesor de SRO diez veces mayores a aquel del nitruro presentaron una clara dominación de la luminiscencia relacionada con el óxido. Se halló que los centros responsables por la electroluminiscencia en los dispositivos electrónicos son fundamentalmente los mismos que los responsables de la fotoluminiscencia a pesar de las diferencias en los espectros medidos, y se concluyó que la influencia de la arquitectura sobre el espectro de salida es de importancia significativa. Se mostró que dispositivos bi-capa entregan mejores resultados en términos de eficiencia, control sobre la luz emitida, distribución de la misma, y estabilidad en el funcionamiento. Se observó que los mecanismos de transporte de carga hallados en los dispositivos están dominados por ruptura del material en el caso de dispositivos de una sola capa, y Tuneleo Asistido por Trampas en el caso de dispositivos bi-capa. El Sistema Óptico que integra el emisor, una guía de ondas, y el detector de luz, fue diseñado y fabricado con base en los resultados de la fabricación y análisis de los dispositivos emisores de luz aislados. Durante la etapa de diseño, se corroboró mediante simulaciones por computadora que las características de la luz emitida por los dispositivos que presentaron la máxima eficiencia y fiabilidad fueran apropiadas para su transmisión a través de la guía de ondas propuesta. También se corroboró teóricamente que las capacidades de detección de los sensores diseñados fuera la adecuada para el tipo de luz emitida. Se exploró el apropiado funcionamiento de los elementos del sistema finalmente fabricado. Se encontraron diferencias en la operación de los dispositivos emisores de luz aislados y aquellos integrados, pero la luminiscencia resultante se halló dentro de los límites del espectro transmisible. La operación del Sistema Óptico Integrado fue probada y estudiada de manera preliminar, con la obtención de resultados positivos en su respuesta estímulo-detección, cumpliendo así con el objetivo principal del trabajo, y abriendo la puerta para estudios posteriores que pueden guiar a la optimización del diseño del sistema para aplicaciones particulares.

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44

Raghavan, Srikanth. "Comparative studies of 6H-SiC surface preparation." Morgantown, W. Va. : [West Virginia University Libraries], 2008. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=5766.

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Thesis (M.S.)--West Virginia University, 2008.
Title from document title page. Document formatted into pages; contains xii, 56 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 51-53).

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45

Sharratt, Andrew Paul. "Silica supported nickel catalysts : tracer studies." Thesis, University of Surrey, 1991. http://epubs.surrey.ac.uk/843407/.

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A series of silica supported catalysts were prepared by impregnation of the support materials with a nickel(II) nitrate precursor under standard conditions. The catalysts and silicas were characterised using temperature programmed reduction (TPR) techniques, neutron diffraction, small angle neutron scattering, and 29Si magic angle spinning nuclear magnetic resonance (MAS-NMR). These analyses revealed one significant variable in the silicas:- the surface concentration of strained siloxane rings containing three silicon atoms. The catalysts were tested using ethene as a probe molecule and the amination of ethanol as a test reaction in conjunction with various tracers (2H, 3H, 13C and 15N). Significant differences in behaviour and activity were observed, these differences correlated with the surface concentration of the strained three membered rings. Possible interactions between reactants and the rings were proposed to explain the observed differences in behaviour. Based on the tracer studies it was possible to propose a mechanism for the animation reaction over the catalysts. The role of the silica surfaces in influencing the activity of the catalysts was illustrated in terms of the proposed reaction mechanism.

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46

Sotthibandhu, Sakuntala. "Radiation damage studies of silicon detectors." Thesis, Imperial College London, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339072.

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47

Weston, P. J. "Studies on semi-insulating polycrystalline silicon." Thesis, Swansea University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.636580.

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The properties of Semi-Insulating Polycrystalline Silicon (SIPOS) have been investigated for a wide range of oxygen content. This thesis details and discusses results pertaining to its growth, its structural composition, its electrical characteristics, and the modelling of its electrical characteristics. SIPOS was grown using Low Pressure Chemical Vapour Deposition of silane and nitrous oxide. The ratio of the flow rates of these gases was found to control the oxygen content and growth rate of the SIPOS. The structural composition was investigated using Auger Electron Spectroscopy. This showed that SIPOS is a two-phase mixture of silicon and silicon dioxide. The electrical characteristics were investigated by measuring current as a function of voltage applied to a vertical SIPOS structure. Measurements were also made of current as a function of temperature with a constant applied voltage. The results showed that current flow in SIPOS is a Poole Frenkel or Schottky type process. Modelling of the current flow in SIPOS as a function of voltage, oxygen content, and temperature, was on the basis of series connected dual dielectrics and the continuity of current flow in silicon and silicon dioxide. The results showed that percolation effects need to be accounted for.

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48

Al-Wajeeh, Khaled Mohsen. "Studies on the microbiology of silicon." Thesis, University of Sheffield, 1999. http://etheses.whiterose.ac.uk/10225/.

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A study was made of the interactions between the element silicon, mainly as silicic acid, and various microbial processes. The effect of silicon compounds on fungal growth was determined under both oligotrophic and nutrient-rich (copiotrophic) conditions. Mycelium of Aspergillus oryzae was grown from a spore inoculum added to ultra-pure water (upw) containing silicon compounds, but not in upw alone. Growth of other fungi also only occurred in upw when silicon compounds were added. Increased growth of fungi also followed the addition of silicon compounds to Czapek Dox medium. Silicic acid also increased the protein content of fungi grown under such nutrient-rich conditions. The fungi solubilised the insoluble silicon compounds under both oligotrophic and copiotrophic conditions. Silicon was not however, accumulated by fungi as electron-dense hyphal bodies. Addition of silicic acid to nutrient rich media also increased the growth of species of Streptomyces but decreased the chlorophyll content of the alga, Dunaliella parva; the growth of two yeasts and the bacteria, E. colt and S. aureus also was not affected by silicon addition; the observed stimulatory effect therefore appears to be restricted to filamentous microorganisms. The effect of silicon compounds on various microbial processes was also investigated. Silicic acid stimulated the production of citric acid by Aspergillus niger, but decreased nitrification and sulphur oxidation in this fungus. Silicic acid addition also led to a reduction in antibiotic production by species of Streptomyces. Studies were initiated to study the possibility that fungi and bacteria can erode the surface of both bulk and porous silicon wafers. While no such surface erosion was evident, we observed that E. coif underwent extensive extreme pleomorphism when growing under starvation conditions for up to 14 days. Such pleomorphism consisted of the formation of bulbous protrusions from the normal rod, dumbbell-shaped cells and long filaments, these were up to 50g in length (compared to the normal 1-3μ, rods). Such filamentation was clearly caused by the inability of the bacterial cells (rods) to separate on division. The observed bacterial pleomorphism was not however, silicon-specific, as it was also found to occur on titanium and glass surfaces. Such extreme pleomorphism may have important implications in relation to the growth of E. coli in low nutrient environments and may influence the bacterium's ability to affect pathogenesis. While the microbiology of silicon has largely been neglected the results of this thesis show that there is considerable interaction between this element and microbial growth. Future studies should in particular be directed towards determining if silicon can be used as an energy source by microorganisms. Additionally, the observed phenomenon of extreme pleomorphism in E. coil is clearly worthy of further study.

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49

Li, Jun. "Silicon Phthalocyanines for Photodynamic Therapy Studies." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1193850866.

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50

Mason, Ruth Elizabeth. "Positron studies of ion implanted silicon." Thesis, University of Bath, 2006. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434067.

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Дисертації з теми "SILICO STUDIES"

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