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McDowell, Chester Dale. "Potential heterogeneity in p53/S100B(ββ) complex." Thesis, Kansas State University, 2012. http://hdl.handle.net/2097/13845.
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Master of ScienceDepartment of Biochemistry
Jianhan Chen
Paul E. Smith
Intrinsically disordered proteins have been shown to be important in many physiological processes, including cell signaling, translation, and transcription. They are also associated with cancer, and neurodegenerative diseases. The tumor suppressor p53 contains several disordered regions, including the C-terminal negative regulatory domain (NRD). In cancer the function of p53 has been shown to be repressed by S100B(ββ) binding to p53-NRD. Binding of S100B(ββ) blocks acetylation and phosphorylation sites in the p53-NRD, which leads to tetramer dissociation and prevents p53 activation. NMR studies have shown that p53-NRD binds S100B(ββ) in a stable α-helix conformation. Interestingly, despite the well-converged and apparent rigid nature of the NMR structure ensemble, a majority of intermolecular NOEs used to calculate the NMR ensemble are very weak (≥6 Å). The final NMR structures also contains unsatisfied buried charged residues at the binding interface. It’s plausible that the p53-S100B(ββ) complex is more dynamic than previously believed. The goal of the study is to determine the potential conformational heterogeneity in p53-S100B(ββ) complex using molecular modeling. For this, five diverse structures were selected from the 40-member NMR ensemble. For each initial conformation, we performed 100 ns molecular dynamic simulations in explicit solvent to explore the structure and dynamics of the p53-NRD in complex with S100B(ββ). Several analytical tools were used to characterize the p53-NRD conformation, including root-mean squared deviation (RMSD), root-mean squared fluctuation (RMSF), and residue helicity. The accuracy of the simulations was mainly assessed by comparing with experimental NOEs. The results show that, even though the ensemble is heterogeneous it satisfies 82% of the experimental NOEs. Clustering analysis further suggests that many conformational sub-states coexist for this complex, and individual clusters appear to satisfy only subsets of NOE distances. Importantly, the buried surface analysis demonstrates that the heterogeneous ensemble generated from MD provides similar shielding of key residues, which include post-translational modification residues needed for p53 activation. This study also demonstrates that atomistic simulations can provide important insights into structure and dynamics of IDPs for understanding their biological function.
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Mukhtar, Musawwadah. "State-dependent disordered potential for studies of Anderson transition with ultracold atoms." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLO001/document.
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Dans ce manuscrit, nous présentons notre avancement pour réaliser une méthode spectroscopique pour étudier la transition d’Anderson avec des atomes froids. Cela repose sur la réalisation d'un potentiel désordonné sélectif en état de spin, le désordre n'étant significatif que pour l'un des deux états de spin impliqués. En combinant cela avec la technique de transfert par radiofréquence d’un état insensible au désordre à un état exclusivement sensible au désordre, il devient possible de charger une onde de matière dans le désordre dans des états d’énergie bien définies. Pour prouver le concept, nous avons effectué des mesures des fonctions spectrales d’atomes ultra-froids dans des potentiels désordonnés, qui sont directement proportionnels au taux de transfert des atomes. Nous présentons les résultats en montrant un excellent accord avec les calculs numériques. Cela a ouvert des perspectives pour d’autres études sur la transition d’Anderson. En particulier, nous cherchons à observer la transition entre les états diffusifs et les états localisés séparés par une énergie critique, appelée le seuil de mobilité. Une telle étude nécessite la réalisation d’un désordre sélectif en état de spin qui permet un long temps de propagation dans le désordre afin de distinguer les deux phases. À cette fin, nous présentons un nouveau schéma du désordre sélectif en état de spin avec deux lasers du speckle (speckle bichromatique). Cela ouvre la voie à une approche spectroscopique de la transition d’Anderson avec des atomes froids avec une résolution en énergie bien supérieure à celles des expériences précédentesIn this manuscript, we present our progress towards realizing a spectroscopic method to study of Anderson transition with ultracold atoms. This relies on the realization of state-dependent disordered potential whereby the disorder is significant only for one of two involved spin-states. Combined with technique of radio-frequency transfer from the disorder-free state to the state with controlled disorder, it becomes possible to load a matter wave in the disorder in a well-defined energy states. As a proof of principle, we have performed measurements of the spectral functions of ultracold atoms in disordered potentials, which are directly proportional to the transfer rate of the atoms. We present the results showing excellent agreement with numerical calculations. This has opened up prospects for further studies of the Anderson transition. In particular we seek to observe transition between the diffusive and the localized states separated by a critical energy, the so-called mobility edge. Such study requires realization of state-dependent disorder which allows long propagation time in the disorder in order to distinguish the two phases. For this purpose, we present a new scheme of the state-dependent disorder with two laser speckles (bichromatic laser speckle). This paves the way towards spectroscopic approach of Anderson transition with ultracold atoms with energy resolution much higher than those in the previous experiments
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Felix, Moscoso Monica, Galvan Jack Denegri, Loayza Fernando Ortega, and Adrian V. Hernandez. "Respiratory Therapy in Chronic Heart Failure Patients Complicated With Sleep-Disordered Breathing: Potential Study Bias." Journal of the Japanese Circulation Society, 2016. http://hdl.handle.net/10757/611825.
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Cadel, Agnese. "Disordered models: Spin Glasses and Directed Polymers." Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3425541.
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Disordered systems are among the most difficult and most fascinating problems in statistical mechanics.
One speaks of disordered (or complex) system when the dynamics, or the structures that appears within the system, exhibits a rich variety of behaviours, while the microscopic entities the system is made of, and the interactions among these entities, are a priori simple. In this thesis we consider two famous examples of these systems: spin glasses and directed polymers in random environments.
In the first part of the thesis we study a variant of the Sherrington-Kirkpatrick (SK) model, the SK model with ferromagnetic interactions. More precisely the Hamiltonian that describes the model is a combination of a SK and Curie-Weiss Hamiltonian. Our aim is to extend the well known results obtained in the SK model, trying to describe this new model in the high temperature region. The main result is that the two key parameters, the magnetization and the overlap, are asymptotically close to constants ? and q, That are the unique solutions of the so-called replica symmetric equations of this model. We then use this result to study the thermodynamical limit of the free energy and the behaviour of the Gibbs measure.
In the second part of the thesis we consider two models of directed polymers in random environment. First of all we consider a Brownian polymer in a Gaussian environment, fully determined by its covariance function. In this case it is known that the thermodynamical limit of the free energy exists and it is expected that the polymer is in the strong disorder regime for low temperatures. We give a better estimate of the limit of the free energy in order to quantify how far we are from the weak disorder regime. Then we modify the hypothesis on the covariance of the environment, to determine if one ever leaves the strong disorder regime. After this we consider a continuous time random walk in a white noise potential, making a link between the last result and this new model.
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Li, Yuting. "Simulations and Electronic Structure of Disordered Silicon and Carbon Materials." Ohio University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1395410498.
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Lellouch, Samuel. "Collective localization transitions in interacting disordered and quasiperiodic Bose superfluids." Thesis, Palaiseau, Institut d'optique théorique et appliquée, 2014. http://www.theses.fr/2014IOTA0017/document.
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Ce mémoire présente une étude théorique des propriétés de localisation collective dans les superfluides de Bose désordonnés ou quasipériodiques. S'il est connu depuis Anderson que le désordre peut localiser les particules libres, comprendre ses effets dans les systèmes quantiques en interaction, où il est à l'origine de transitions de phase et d'effets de localisation non-Triviaux, représente aujourd'hui un défi majeur. En nous focalisant sur le cas d'un gaz de Bose dans le régime de faibles interactions, bien décrit par la théorie de Bogoliubov, nous étudions les transitions de localisation de ses excitations collectives dans différents contextes. Dans le cas d'un vrai désordre dans l'espace continu tout d'abord, nous développons un formalisme de désordre fort allant au-Delà des études antérieures, aboutissant à une description complète des propriétés de localisation des excitations en dimension arbitraire. Nous présentons un diagramme de localisation générique, et une interprétation microscopique de la propagation des excitations dans le désordre. Dans un second temps, nous considérons le cas d'un potentiel quasipériodique unidimensionel, aux propriétés intermédiaires entre un vrai désordre et un potentiel périodique. Notre traitement analytique et numérique du problème révèle une transition de localisation collective, que nous caractérisons et interprétons en termes de localisation dans un potentiel effectif multiharmonique. Pour finir, nous considérons le cas d'un gaz de Bose à deux composants. Nous développons le formalisme général pour étudier ces questions et décrivons la physique de base de ces systèmes qui présentent leurs propres spécificitésIn this thesis, we theoretically investigate the collective localization properties of weakly-Interacting Bose superfluids subjected to disordered or quasiperiodic potentials. While disorder has been recognized since Anderson to induce single-Particle localization, the interplay between disorder and interactions in quantum systems is today among the most challenging questions in the field, and underlies fascinating phase transitions and non-Trivial localization effetcs. Focusing on Bose gases in the weakly-Interacting regime for which the Bogoliubov theory proves a successful tool, we study the localization transitions of collective excitations in several contexts. First, in the case of a continuous true disorder, we develop a strong-Disorder formalism going beyond previous studies, providing us with a complete description of the localization behaviour of collective excitations in arbitrary dimension. A generic localization diagram is obtained and the transport of excitations in the disorder is microscopically interpreted. Secondly, we consider the case of one-Dimensional quasiperiodic potentials, which are known to display intermediate properties between periodic and disordered ones. We perform a numerical and analytical treatment of the localization problem of collective excitations, allowing us to quantitatively characterize and interpret the localization transition in terms of an effective multiharmonic problem. Finally, we set up the general inhomogeneous formalism to address such issues in multicomponent Bose gases, and enlighten the basic physic of such systems, which are known to exhibit their own specific features
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Schwabe, Nikolai F. "Weighted two-particle Green's functions in the coherent-potential approximation and perturbation effects in tunneling systems out of equilibrium." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318916.
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Laubie, Hadrien Hyacinthe. "Elastic properties and failure behavior of disordered porous solids : a potential-of-mean-force-based lattice element approach." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/111443.
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Thesis: Ph. D. in Mechanics of Materials, Massachusetts Institute of Technology, Department of Civil and Environmental Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 165-175).
The effective mechanical properties of multiphase materials not only depend on the volume fraction and chemical composition of their constituents but also on details of their local texture. Yet, most homogenization methods do not take this texture effect into account. Understanding how local texture affects the overall elastic and failure properties of heterogeneous solids is the focus of this thesis. Emphasis is placed on porous media that are critical for many industry sectors, that either aim at engineering the porosity and its distribution in synthesized materials to reach desired properties; or at predicting the behavior of naturally-occurring porous materials given porosity and porosity fluctuations. To this end, a discrete simulation tool -coined lattice element method (LEM)- was implemented. Akin to potential-of-mean-force approaches used in soft-matter physics, a solid structure is discretized into mass points interacting with the nearest neighbors through effective interaction potentials. Depending on the choice of the local interactions, a phase's effective behavior can be linear or non-linear; isotropic or anisotropic. Introducing two different failure criteria, the fracture behavior is shown to be in perfect agreement with classical theories. A detailed LEM calibration procedure is provided. By means of extensive simulations, the role of textural properties on the mechanical behavior of random porous materials is investigated. Starting from an ordered configuration, it is found that a gradual increase in disorder can considerably deteriorate both stiffness and failure resistance of disordered porous solids. Specifically, it is shown that this disorder-induced strength and stiffness degradation results from a transition from a state governed by a single-pore stress concentration to a state controlled by multi-pore interactions, with the tail length of stress distribution being correlated with disorder. We propose that classical homogenization methods based on first or second-order averaging methods are amended to consider the found higher-order stress-distribution characteristics for highly disordered porous materials.
by Hadrien Laubie.
Ph. D. in Mechanics of Materials
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Lang, Brittany. "A Longitudinal Exploration of Drive for Leanness: Potential Uniqueness, Sex Neutrality, Adaptive Nature, and Sociocultural Fit." Scholar Commons, 2018. https://scholarcommons.usf.edu/etd/7537.
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Historically disordered eating research has been gendered with models focusing on women’s pursuit of a thin ideal, as well as men’s attempts to obtain a muscular ideal. The motivations to achieve these ideals are called the drive for thinness (DT) and drive for muscularity (DM). More recently, a cultural shift has been noted in that ideal bodies are converging across sexes to a lean ideal, with the associated motivation being labeled the drive for leanness (DL). As DL is a nascent construct, little is known about its relationships with DT and DM, or if it predicts or is predicted by the same variables that are associated with DT and DM. This study aimed to expand what is known about DL in four ways: 1) ascertain the uniqueness of DL from DT and DM; 2) explore whether DL is sex neutral; 3) investigate the extent to which DL is more or less adaptive than DT and/or DM in terms of health-related outcomes; and 4) explore associations between DL and established predictors from sociocultural models of disordered eating. Analyses evidenced support for DL’s distinctiveness from DT and DM, partial support for DL’s sex neutrality, partial support discerned via relationships with health-related outcomes for DL’s adaptive nature in comparison to DT or DM, and support for DL’s relationships with sociocultural predictors being similar to that seen between these predictors with DT and DM. This study adds to the literature by broadening what is known about DL’s uniqueness, sex neutrality, adaptive nature, and sociocultural fit in relation to the other drives within a theory based framework, providing a potential basis for future DL model building and research in general.
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Rowlands, Derwyn Andrew. "The Korringa-Kohn-Rostoker nonlocal coherent-potential approximation : a new method for calculating the electronic structure of disordered metallic systems." Thesis, University of Warwick, 2004. http://wrap.warwick.ac.uk/59515/.
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The limitations of the current 'first-principles' effective medium approach to calculating the electronic structure of disordered systems are described. These limitations can be addressed by a cluster theory, and only very recently the first satisfactory cluster theory, the nonlocal coherent potential approximation, has been developed within a tight-binding framework. However an approach based on KKR multiple scattering is needed in order to treat the problem from first principles for ab-initio calculations. In this thesis, these ideas are reformulated in terms of multiple scattering theory and the Korringa-Kohn-Rostoker non-local coherent potential approximation (KKR-NLCPA) is introduced for describing the electronic structure of disordered systems. The KKR-NLCPA systematically provides a hierarchy of improvements upon the widely used local mean-field KKR-CPA approach and includes nonlocal correlations in the disorder configurations by means of a self-consistently embedded cluster. The KKR-NLCPA method satisfies all of the requirements for a successful cluster generalisation of the KKR-CPA; it determines a site-to-site translationally-invariant effective medium, it is herglotz analytic, becomes exact in the limit of large cluster sizes, reduces to the KKR-CPA for a single-site cluster, is straightforward to implement numerically, and enables the effects of short-range order upon the electronic structure to be investigated. In particular, it is suitable for combination with electronic density functional theory to give an ab-initio description of disordered systems. Future applications to charge correlation and lattice displacement effects in alloys and spin fluctuations in magnets amongst others are very promising. The method is illustrated by application to a simple one-dimensional model.
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Iceta, Sylvain. "Repenser la désinhibition alimentaire dans l’obésité, sous l’angle de l’hypothèse de l’addiction à l’alimentation." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1003/document.
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L’addiction à l’alimentation (AA) est un concept ancien, mais encore sujet de controverses qui toucherait 18 à 24 % des obèses. Dans cette thèse, nous nous sommes intéressés aux intrications entre régulations du comportement alimentaire, addiction et AA, afin de mieux comprendre les mécanismes liés à la désinhibition de la prise alimentaire. Notre travail a conduit à plusieurs résultats : 1) Une revue de la littérature a permis de montrer l’existence d’interaction étroite entre les niveaux de régulation du comportement alimentaire et comment AA pourrait en être un exemple de dérégulation. 2) Une étude de cohorte a permis de démontrer l’existence de caractéristiques cliniques communes entre addictions et AA et celle d’un probable transfert d’addiction de la nicotine vers l’alimentation. 3) Sur le plan expérimental, nous avons montré qu’il existe des perturbations des ondes P300 et N200, dans l’obésité et la désinhibition alimentaire, proches de celles observées dans les addictions. 4) Enfin, nos résultats suggèrent le rôle potentiel de la ghréline comme marqueur de risque de trouble du comportement alimentaire. Ce travail ouvre des perspectives sur le plan expérimental, avec la suggestion de groupes contrôles plus pertinents ; cliniques, avec la création d’un potentiel test de dépistage rapide ; thérapeutiques, avec la mise en place d’un essai thérapeutique par tDCSFood addiction (FA) is an old concept, but still subject to controversy. It affects 18 to 24% of obese people. In this thesis, we are interested in overlaps between food behavior regulation, addiction and FA, in order to better understand the mechanisms linked to food intake disinhibition. Our work leads to several results: 1) A review of the literature has shown the existence of close interaction between eating behavior regulation levels and how FA could be an example of their disturbance. 2) A cohort study demonstrated the existence of common clinical features between addiction and FA and a probable addiction transfer from nicotine to food. 3) From an experimental point of view, we have shown that there are disturbances of P300 and N200 ERP, in obesity and food disinhibition, close to those observed in addictions. 4) Finally, our results suggest the potential role of ghrelin as a marker for eating disorders increased risk. This work opens experimental perspectives, with the suggestion of more relevant control groups; clinical perspectives, with the creation of a screening tool; therapeutics perspectives, with the establishment of a therapeutic trial by tDCS
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Gulenko, Anastasia. "Etude structurale du verre de TeO₂ et de la variété désordonnée TeO₂-δ par dynamique moléculaire." Thesis, Limoges, 2014. http://www.theses.fr/2014LIMO0013/document.
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Ce travail a pour but d’améliorer la description structurale du verre de TeO2 pur et d’étudier en profondeur la structure de la phase désordonnée δ-TeO2 au moyen de la dynamique moléculaire (DM). Nous avons établi des potentiels interatomiques (IAP), simples mais non triviaux, prenant en compte la polarisabilité des atomes de tellure et d’oxygène à l'aide du modèle cœur-coquille. Nous avons démontré le rôle important de la paire libre électronique de l'atome de Te dans la formation d'unités asymétriques TeOx. Les IAPs précis reproduisent 17 structures cristallines à base de TeO2 et sont appropriés pour les simulations par DM des systèmes désordonnés. Les simulations des structures de la phase vitreuse pure et de δ-TeO2 ont été effectuées par DM. Il a été démontré que le verre de TeO2 est principalement constitué d'unités structurales TeO3 et TeO4, et un grand nombre d'atomes d’oxygène non-pontant (NBO) est observé. La coordinence des atomes de tellure est plus faible dans le verre que dans les structures cristallines pures.Dans la phase δ-TeO2, les atomes de tellure forment un réseau cristallin (CFC) bien défini et les atomes d'oxygène présentent un grand désordre de position. Cette phase est caractérisée par une population d’unités structurales, une coordinence des atomes de tellure et une proportion d'atomes d’oxygène non pontant typique du verre. Par conséquent, la structure δ-TeO2 est plus proche de celle du verre que des structures d'autres polymorphes cristallines de TeO2 puresThis work aims to improve the structural description of the pure TeO2 glass and to give a deep insight into the structure of the disordered δ-TeO2 phase by means of molecular dynamics (MD) simulations.We derived simple but nontrivial interatomic potentials (IAPs), which take into account the polarisability of tellurium and oxygen atoms using the core-shell model. We demonstrated the important role of the electronic lone pair of the tellurium atoms in the formation of asymmetrical TeOx units. The accurate IAPs is able to reproduce 17 crystalline TeO2-based structures and are appropriate for MD simulations of disordered systems.The MD simulations of the pure glass and δ-TeO2 phase structures were carried out. It was demonstrated that the TeO2-glass consists of mainly TeO3 and TeO4 structural units and a large number of non-bridging oxygen (NBO) atoms is observed. The coordination number of the tellurium atoms in the glass is less than in the pure crystalline structures.In the δ-TeO2 phase, the tellurium atoms form a well-defined crystalline (FCC) lattice and the oxygen atoms exhibit a large positional disorder. This phase has a structural units distribution and a tellurium coordination number and a proportion of NBO atoms similar to those of the glass. Hence, the structure of δ-TeO2 is closer to that of glass than to the structures of other pure TeO2 crystalline polymorphs
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Jendrzejewski, Fred. "Quantum transport of ultracold atoms in disordered potentials." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00809290.
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In this thesis we study the quantum transport of matter waves with ultracold atoms. Such ultracold atom systems provide a very good control and a high flexibility of the parameters of the systems like the interactions, its dimensionality and the external potentials. This makes them a great tool for the investigation of several fundamental concepts of condensed matter physics. We focus on the quantum transport in disordered media. It differs to classical transport by the fundamental role played by inference phenomena, which can eventually lead to the suppression of transport; known as Anderson Localization. Observing the expansion of a Bose-Einstein condensate in a strong light disorder, we show evidence for Localization of ultracold atoms in three dimensions. In the last part of this manuscript we discuss the observation of Coherent Backscattering of ultracold atoms, which is a direct signal of the role of quantum coherence in quantum transport in disordered media. We observe the time evolution of the momentum distribution of a cloud of ultra-cold atoms, launched with a narrow velocity distribution in a disordered potential. A peak emerges in the backwards direction, corresponding to the CBS signal.
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Kuhn, Robert. "Coherent transport of matter waves in disordered optical potentials." [S.l.] : [s.n.], 2007. http://opus.ub.uni-bayreuth.de/volltexte/2007/287.
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Kiang, Michael Wai Jong. "Event-rated brain potential studies of semantic processing in schizophrenia and schizotypal personality." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3283453.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed November 7, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Farrow, Maree J., and maree farrow@med monash edu au. "Brain electrical activity topography in attention-deficit/hyperactivity disorder." Swinburne University of Technology, 2003. http://adt.lib.swin.edu.au./public/adt-VSWT20050406.141958.
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Attention-deficit/hyperactivity disorder (ADHD) is a common childhood psychiatric disorder characterized by developmentally inappropriate levels of inattentiveness, impulsivity and hyperactivity. Current theories of ADHD cite evidence from neuropsychological and brain imaging studies suggesting that abnormalities in the structure and function of the frontal lobes and connected brain regions are associated with impaired behavioural inhibition, constituting the primary deficit in ADHD. While most reviewers conclude that neuropsychological studies have failed to find specific deficits in various aspects of attention in ADHD, poor performance on attentional tasks, including the continuous performance task (CPT), is a common finding and previous electrophysiological studies suggest evidence of impaired attentional processing. This study aimed to investigate the cortical activity associated with attentional processes in children with and without ADHD, using steady-state probe topography (SSPT). Seventeen boys diagnosed with ADHD and seventeen age matched control boys participated. Changes in the amplitude and latency of the steady-state visually evoked potential (SSVEP) associated with correct responses to targets in the �X� and �AX� versions of the CPT were examined. At critical time points in both tasks, the control group demonstrated SSVEP changes suggesting increased activation and increased speed of neural processing. These effects occurred predominantly in medial frontal, right prefrontal, right parietal and occipital regions, suggesting enhanced activity in regions previously shown to be involved in attentional processes. The ADHD group demonstrated much smaller increases in activation and processing speed in frontal regions and predominantly reduced activation and slower processing in parieto-occipital regions. Group differences suggesting reduced activity in the ADHD group were observed in response to the presentation of both cues and targets, as well as in the intervals leading up to target presentation, especially in the cued CPT-AX. These results suggest that processing of task relevant stimuli as well as preparatory and motor processes may be associated with dysfunctional activation of brain networks of attention in ADHD, involving deficits in both frontal and parietal cortical regions. These regions may also be involved in the maintenance of information required for correct task performance and the results also suggest possible deficits in these processes in ADHD. The findings are consistent with others of reduced activation and cognitive deficits in ADHD involving these brain regions and networks, and with the idea that ADHD may be associated with a diminished ability to regulate levels of arousal and activation appropriate to task demands.
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PISANÒ, CLARISSA ANNA. "Therapeutic potential of RGS4 blockade in movement disorders." Doctoral thesis, Università degli studi di Ferrara, 2020. http://hdl.handle.net/11392/2478812.
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Le proteine regolatrici del signaling delle proteine G (RGS - Regulators of G-protein signaling) sono una classe di regolatori che modula negativamente i pathway intracellulari innescati dalle proteine G.
Le RGS legano la subunità Gα del trimero proteina G e accelerano la velocità di idrolisi del GTP, spegnendo il segnale del GPCR (G-protein coupled receptor). Usare le RGS come target terapeutico può significare potenziare l’attività di agonisti endogeni o esogeni, incrementandone selettività o tessuto-specificità. RGS4 è la proteina RGS più studiata ed è principalmente espressa in aree cerebrali come corteccia e gangli della base (BG). È stato dimostrato il coinvolgimento di RGS4 in diverse patologie come schizofrenia, malattia di Parkinson (MP) e discinesie indotte da L-Dopa (LID - L-Dopa induced dyskinesia). La presente tesi amplia queste conoscenze, mostrando evidenze sperimentali sul ruolo di RGS4 nel parkinsonismo indotto da neurolettici (Studio I) e sull’interazione di RGS4 e il recettore NOP fornendo un nuovo approccio terapeutico per le LID (Studio II). Nello Studio I, è stata investigata l’abilità di due inibitori di RGS4 di invertire l’acinesia indotta da raclopride, un neurolettico. Grazie alla tecnica della microdialisi, è stato possibile monitorare il rilascio di glutammato nella sostanza nera parte reticolata, al fine di verificare l’impatto dei composti sull’attività della via indiretta. Successivamente, è stato analizzato l’effetto dell’inibizione di RGS4 sul signaling D2, attraverso l’analisi di specifici marker molecolari. Infine, è stato condotto uno studio preliminare allo scopo di identificare il GPCR, modulato da RGS4, che media l’effetto anti-acinetico degli inibitori di RGS4. Inizialmente, abbiamo proposto il recettore glutamatergico mGlu5 come possibile target. Questo studio ha messo in luce che gli inibitori di RGS4 attenuano il NIP (neuroleptic-induced parkinsonism), agendo a livello striatale per ridurre la disinibizione della via indiretta mediata dall’azione del neurolettico. A livello striatale, l’inibizione di RGS4 comporta un aumento dell’attivazione della cascata delle MAPK indotta dal neurolettico. Nello Studio II, si è cercato di allargare la finestra terapeutica di un agonista NOP attraverso l’interazione RGS4-recettore NOP. In primo luogo, l’interazione di RGS4 con il recettore NOP è stata dimostrata in un modello cellulare e confermata in fettine di striato. Come readout biochimico dell’attività NOP, è stata usata l’inibizione dell’accumulo di cAMP nelle cellule e dell’aumento di neuroni pERK- positivi nelle fettine, stimolati da agonista D1. L'impatto dell'inibitore RGS4, CCG-203920, sull'effetto antidiscinetico dell'agonista del recettore della Nocicettina/orfanina FQ (N/OFQ), AT-403, è stato quindi valutato in un modello di ratto di LID. È stata valutata la capacità di CCG-203920 di potenziare l'effetto antidiscinetico rispetto all'effetto sedativo di AT-403. Al fine di indagare l'impatto di CCG-2003920 sulle vie molecolari alla base delle LID, grazie alla tecnica del Western blot, è stato possibile analizzare i livelli di pERK e pGluR1. Con la stessa tecnica, sono stati monitorati i livelli di RGS4 nello striato a seguito della deplezione di dopamina e del trattamento cronico con L-Dopa. I principali risultati dello Studio II sono stati la dimostrazione che RGS4 modula negativamente la funzione del recettore NOP e che l'inibizione dell'RGS4 potenzia l'effetto antidiscinetico dell'agonista del recettore NOP, senza amplificarne gli effetti sedativi. Infine, i nostri risultati suggeriscono che l'inibizione di RGS4 potrebbe anche essere utile per annullare la sovraespressione di RGS4 nello striato che si verifica durante l'espressione delle LID. Entrambi gli studi hanno confermato il coinvolgimento di RGS4 nelle disfunzioni dei GB e il potenziale terapeutico degli inibitori di RGS4 nel trattamento del NIP e della LID.Regulators of G-protein signaling (RGS) are a class of protein which negatively modulate the intracellular pathways evoked by G-proteins. RGS proteins bind the Gα subunit of the heterotrimer G-protein and accelerate the hydrolysis of GTP, turning the GPCR (G-protein coupled receptor) signal off. Targeting an RGS protein could potentiate the activity of an endogenous or exogenous agonist, improving its selectivity or tissue-specificity. RGS4 is the most studied among RGS proteins. It is mostly expressed in brain areas, such as cortex and basal ganglia (BG). The involvement of RGS4 in various pathological conditions, such as schizophrenia, Parkinson’s disease (PD) and L-Dopa induced dyskinesia (LID) has been proven. This thesis adds to these findings, providing evidence of an involvement of RGS4 in neuroleptic-induced parkinsonism (Study I) and disclosing for the first time an RGS4-NOP receptor interaction which can be targeted in LID therapy (Study II). In Study I, the ability of two RGS4 inhibitors in reversing raclopride-induced akinesia was investigated. Dual probe microdialysis was used to monitor in vivo glutamate release in the substantia nigra reticulata to assess whether these inhibitors impact the activity of the indirect pathway and to identify their site of action. Biochemical signatures of D2 signalling pathway activation following RGS4 inhibition were studied. A preliminary attempt to identify the GPCR targeted by RGS4 was made by challenging RGS4 inhibitors with an mGlu5 receptor antagonist. The main findings were that both RGS inhibitors attenuate neuroleptic-induced parkinsonism, acting at the striatal and nigral levels to attenuate the neuroleptic-induced disinhibition of the indirect pathway. At the striatal level, RGS4 inhibition potentiated the neuroleptic-induced activation of MAPK pathway and did not involve mGlu5 receptors. LID is a cluster of abnormal involuntary movements (AIMs), caused by chronic administration of L-Dopa, which represent the most disabling complication of dopamine replacement therapy of PD. In Study II, an attempt was made to widen the therapeutic window of a NOP receptor agonist by leveraging the RGS4-NOP receptor interaction. The interaction of RGS4 with the NOP receptor was first demonstrated in a cell model, then in striatal slices. Biochemical readouts of NOP activity were the D1 receptor-stimulated cAMP accumulation in cell lines, and the D1 receptor-stimulated number of pERK-positive neurons in slices. The impact of the RGS4 inhibitor CCG-203920 on the antidyskinetic effect of the Nociceptin/orphanin FQ (N/OFQ) opioid peptide (NOP) receptor agonist AT-403 was then evaluated in a rat model of LID. The ability of CCG-203920 to potentiate the antidyskinetic effect relative to the sedative effect of AT-403 was assessed, and the interference of CCG-2003920 with the molecular pathways underlying LID was evaluated using Western analysis of pERK and pGluR1 levels. Finally, Western analysis was also used to monitor levels of RGS4 in the striatum following dopamine-depletion and chronic L-Dopa treatment. The main findings of Study II were the demonstration that RGS4 negatively modulates NOP receptor function, and that RGS4 inhibition potentiates the antidyskinetic effect of the NOP receptor agonist without amplifying its sedative effects. RGS4 inhibition might also be useful to correct the upregulation of RGS4 levels in striatum occurring during dyskinesia expression. In conclusion, these studies confirmed the involvement of RGS4 in basal ganglia dysfunction and the therapeutic potential of RGS4 inhibitors for treating neuroleptic-induced parkinsonism and LID. Targeting signaling molecules downstream of GPCRs, i.e. RGS proteins, can prove a novel tool to improve drug safety and clinical profile.
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Taylor, Rachael Louise. "Vestibular Evoked Myogenic Potential Characteristics in Common Vestibular Disorders." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/15856.
Full textAbstract:
Intense sound and vibration evokes small reflexes from the neck and eye muscles, reflecting activation of vestibular-otolith receptors. These responses provide the basis for two clinical tests of balance function, referred to as cervical- and ocular- vestibular evoked myogenic potentials (cVEMPs and oVEMPs). As relatively new tests, their diagnostic role has not been fully explored. The primary aim of this thesis was to identify test and stimulus combinations that improve the sensitivity and specificity of VEMP testing, whilst differentiating between different causes of vertigo and imbalance. Patients with Ménière’s disease, vestibular migraine, superior canal dehiscence, vestibular schwannoma, and vestibular neuritis were recruited from neurology outpatient clinics at the Royal Prince Alfred Hospital in Sydney, Australia from 2009-2015. Each study identified specific stimulus/VEMP combinations that enhanced the sensitivity of VEMP testing, as well as revealing patterns of otolith dysfunction that characterised each disorder. Ménière’s disease was characterised by impaired saccular and largely preserved utricular function, whereas in vestibular migraine otolith function was usually preserved and symmetrical. Superior canal dehiscence was unique with its high frequency augmentation effects and prolonged oVEMP latencies to skull-tap stimulation. For vestibular schwannoma larger than 14 mm, impaired function of both otolith organs was common. Abnormal utricular, but spared saccular function, was most often observed in patients with vestibular neuritis. The findings of this thesis provide new insight into how test parameters can be manipulated to enhance the sensitivity of VEMP testing in the clinical setting. The different patterns of saccular and utricular involvement contribute significantly to the clinician’s ability to separate different vestibular disorders.
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Breitfeld, Jörg [Verfasser]. "Identification of Potential Biomarkers for Depressive Disorders / Jörg Breitfeld." Bonn : Universitäts- und Landesbibliothek Bonn, 2017. http://d-nb.info/1149154330/34.
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Taliaferro, Linda Kay. "Psychiatric Disorders as Potential Predictors in Medical Disease Development." ScholarWorks, 2011. https://scholarworks.waldenu.edu/dissertations/939.
Full textAbstract:
Millions of individuals suffer disability or death from immune-based inflammatory diseases. If psychiatric disorders could be empirically linked to the prediction of immune-based inflammatory diseases, there would be a basis for promoting disease prevention measures for individuals diagnosed with one of four psychiatric disorders. Psychoneuroimmunology provided the theoretical base for understanding emotionally induced medical disease development. In this quantitative study, a parallel archival research design was used to investigate the degree to which generalized anxiety disorder, posttraumatic stress disorder, major depression recurrent, and dysthymic disorder predicted the presence of atherosclerosis, cardiovascular heart disease, rheumatoid arthritis, cancer, and type II diabetes. There were 1,209 electronic medical records of adult patients obtained through purposive stratified sampling. A secondary data analysis was employed using descriptive cross tabulation, chi-square test of independence, and multinomial logistic regression. The findings revealed major depression recurrent was a statistically significant predictor for atherosclerosis, rheumatoid arthritis, type II diabetes and cancer. Generalized anxiety disorder was a statistically significant predictor for cancer. The results can promote positive social change by providing information that could be used to develop assessment plans that identity individuals who are at risk of developing the comorbid diseases. The prevention programs could effectively be used to minimize the subsequent development of inflammatory diseases, which in turn could decrease the onset of the medical diseases among individuals with psychiatric disorders.
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Rogers, Dave Edward. "Event-related potentials in obsessive-compulsive disorder." Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.696168.
Full textAbstract:
A meta-analysis of event-related potential (ERP) studies between controls and high-OCD groups was conducted to examine whether there is a consistent relationship between differences in P300 amplitude and latency following exposure to OCD-related stimuli.After applying exclusion and inclusion criteria, 10 studies remained. The overall effect size for amplitudinal P300 differences was non-significant and results were heterogeneous, while the overall findings for latency were significant. There is therefore tentative evidence from this meta-analysis that reduced P300 latency is a neural correlate for late onset attentional bias in OCD. In the large scale study, a control group of low OCS participants ,was compared to nonclinical high OCS participants on dependent variables of event-related potential amplitude and response time. EEG differences in P100 and ipsilateral invalid negativity (IIN) were investigated as neural correlates of the facilitated attention and disengagement biases respectively. Significant differences were found between groups across IIN amplitude only, suggesting effortful disengagement only occurred in the high OCD groups under selected conditions. The implication is that delayed disengagement is the main attentional bias associated with OCD symptomatology.
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Williams, Kimberley Clare. "Differences in visual attention processing: An event-related potential comparative analysis within psychotic disorders." University of the Western Cape, 2019. http://hdl.handle.net/11394/6706.
Full textAbstract:
>Magister Scientiae - MScINTRODUCTION: Sustained attention is known to be dysfunctional in psychotic disorders. Sustained attention is the ability to remain focused on a specific time-locked stimulus within a task. We aimed to determine whether there are specific group differences between CON and three psychotic disorders: SCZ, MPD and BPD, then to determine differences between these psychotic disorders. This included differences in behavioural performance and prominent electrophysiological event-related potential (ERP) wave components during cueing and target processing of a visual sustained attention task. Further we aimed to characterize ERP waveform component relationships across and within these groups for demographics, substance use, behavioural performance, and clinical variables, the last limited to the psychotic groups. Lastly, we investigated the effects of prescribed medications on ERP wave components within the psychotic groups. METHODOLOGY: 103 participants (29 schizophrenia (SCZ), 28 bipolar disorder with a history of psychosis (BPD), 21 methamphetamine-induced psychotic disorder (MPD), and 30 controls (CON)) underwent electroencephalography (EEG) record while completing a visual continuous performance task. Participants were presented with 60 trials with three consecutive S’s, the presentation of the third S required a behavioural response. Prominent ERP waveform components were extracted from cues and target stimulus. Group differences were determined by ANOVA with Bonferroni post-hoc correction or multivariate Kruskal-Wallis test dependent on data distribution. Relationships between ERP wave components were determined appropriate with Spearman’s Rank order correlation analyses. RESULTS: (1) MPD reported higher use of substances compared to CON, SCZ and BPD. SCZ behavioural performance was poorer compared to CON which was shown by their longer response times, reduced accuracy and increased errors of omission. Clinically, MPD was found to have a shorter duration of illness compared to SCZ. Then SCZ was found to have more positive symptoms compared to BPD whereas BPD had more negative symptoms compared to SCZ. For the first cue, wave component differences were found only over the left hemisphere, for P100 amplitude over the frontal cortex, P300 amplitude over the central cortex, and N170 amplitude over the parietal cortex. For the presentation of the second cue, differences noted for all groups were localised to the frontal and central brain regions, for P100 and N170 ERP waveforms. For the target stimulus wave component differences were found over the prefrontal, frontal and parietal brain regions, within CON, SCZ, BPD and MPD. (2) For the first cue, education positively correlated with the N170 left parietal amplitude in CON and P300 right parietal amplitude in MPD. During the second cue, the left parietal N170 latency in SCZ correlated positively with education and the left central P300 latency correlated negatively with education in MPD. The age on the day of testing correlated positively with the target left frontal P300 latency in MPD. For the first cue, substance use positively correlated with the left and right parietal P300 latency and negatively for the right parietal P100 amplitude in SCZ. In MPD, a negative correlation was noted across left and right prefrontal N170 and P300 amplitudes, and positive correlation for the left prefrontal P300 latency in MPD. For the target stimulus, correlations were evident for the left and right parietal N70, N170 amplitudes, P300 latency, the right parietal P100 amplitude and left central P300 latency in SCZ. For the first cue, in SCZ PANSS total score correlated positively with left and right central P300 amplitudes and the left parietal P300 amplitude. For the second cue; in MPD, the PANSS negative symptom score, positively correlated with the P100 and N170 left parietal amplitude, left and right parietal P150 amplitude, left central and right parietal P300 amplitude. For the target, the Hamilton depression rating scale correlated positively with the left and right frontal P300 amplitude in MPD and then negatively with the right parietal P300 amplitude in SCZ. Behavioural performance in CON, positively correlated with the left parietal N70, P100, P150 and N170 amplitude the number of correct responses, and left central N170 amplitude. While the number of impulsive responses correlated negatively with the left parietal N70, P100, P150 and N170 and the left central N170 amplitude of CON. For the second cue, behavioural performance was related to the fronto-parietal relationship across all groups. For the target stimulus, impulsive responses positively correlated with the left parietal N70 latency in SCZ. Overall response time negatively correlated with the right parietal P300 latency for SCZ. (3) Medication was found to affect ERP wave components during the sustained visual attention task. For the first cue FGA’s increased the left central P100 amplitude in both SCZ and BPD and decreased the left parietal P100 amplitude in SCZ only. The use of antipsychotics increased the right parietal N70 and left central P100 amplitudes in BPD, specifically the right prefrontal N170 amplitude was increased with the use of SGA’s. Then clozapine use increased the left frontal P100 amplitude in SCZ. For the second cue, SGA’s decreased the right parietal P150 amplitude in SCZ but in MPD the right parietal P150 amplitude was increased with haloperidol use, and FGA. SGA’s increased the left parietal P300 latency in BPD and sodium valproate decreased the left prefrontal P300 latency. For the target stimulus, SGA’s decreased the right parietal P100, P150 and left parietal P150 amplitudes and increased the left central P300 latency in BPD. CONCLUSION: (1) sustained attentional performance is poorer in SCZ. Our study adds to previous studies showing attention processing deficits in SCZ, are evident during cueing of a sustained attention tasks; (2) substance use was found to slow cognitive processing, education improved executive function and information processing, and symptom severity was associated with dysfunction of prefrontal and frontal cortices; (3) antipsychotic medication was related to improved processing of salient information. These data support the current literature and provide novel insights to the attentional processing deficits during cueing in the psychotic disorders.
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Eisenbrandt, Lydia L., Alyssa P. Gretak, Brittany S. Sharma, and Jill D. Stinson. "Externalizing Disorders as a Potential Risk Factor for Adolescent Males." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/7883.
Full textAbstract:
Externalizing disorders, as described by DSM-V (2013), are an empirically supported group of mental health conditions characterized by impulsiveness, antisocial behaviors, and disruptive conduct. These include Conduct Disorder (CD), Oppositional Defiant Disorder (ODD), Attention-Deficit/Hyperactivity Disorder (ADHD), and Impulse Control Disorders (ICDs). Symptoms often emerge during childhood or adolescence, when brain development is still ongoing. A prematurely-developed prefrontal cortex, paired with reward-seeking and emotional responses in youth, can contribute to impulsive behaviors and limited ability to predict the consequences of one’s actions (Casey, Jones, & Hare, 2008). Compared to females, males tend to be diagnosed with higher rates of externalizing disorders (Kerr, Reinke, & Eddy, 2013), which may place them at higher risk for engaging in risky and/or harmful behaviors.
Research indicates that youth with externalizing disorders engage in a number of risky/harmful behaviors that could have negative consequences. A meta-analysis by Allely (2014) suggests that certain externalizing disorders, such as ADHD, may be a risk factor for self-harm behaviors in child, adolescent, and adult populations. Further, those with externalizing disorders in late childhood tend to have co-morbid depression and are more prone to suicidal ideation and suicide attempts during late adolescence and early adulthood (Kerr, Reinke, & Eddy, 2013). Others have also found a strong connection between externalizing disorders and suicidal behaviors among youth (Beautrais, 2000; Goldston et al., 1998; Hills, Cox, McWilliams, & Sareen, 2005; Verona & colleagues, 2000; 2001; 2004).
Moreover, externalizing disorders, such as ADHD or CD, are correlated with sexual offending behaviors, which may be a result of sexual disinhibition (Kafka, 2012). While diverse, persons who have engaged in sexually abusive behavior often evidence antisocial behaviors and diagnoses of ADHD and CD (Prendergast, 2004; Shields, 1995). Grant et al. (2009) additionally indicated that the presence of trauma may also contribute to behavioral problems that resemble externalizing disorders.
The current study aims to investigate male adolescents with and without externalizing disorders (i.e., ADHD, ODD, CD, and ICDs) by investigating a sample of youth in a residential treatment facility for sexually abusive behaviors (N = 295). Data related to adolescents’ self-harm behaviors, suicidal ideation and/or attempts, sexual offending behaviors, arrest histories, and diagnostic mental health histories were gathered from archival records. Within the sample, 234 participants were diagnosed with at least one externalizing disorder, including ADHD (n = 209), ODD (n = 91), CD (n = 102), and ICDs (n = 50). Chi-square analyses and one-way ANOVAs will be conducted to explore relationships among externalizing disorders, presence and frequency of self-harm behaviors and/or suicide attempts, frequency and types of sexual offenses committed, and frequency and types of arrest. Presence of PTSD diagnoses and Adverse Childhood Experiences (ACE) will also be taken into consideration, as previous literature suggests that early sexual, physical, and emotional trauma may also contribute to behavioral problems and sexual offending behaviors in adolescents (Grant et al., 2009).
The goal of the current study is to fill gaps within the literature by identifying areas of concern among adolescents with externalizing disorders. The findings from the current study will be discussed in terms of clinical implications regarding risk reduction, prevention, and treatment.
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Xiang, Ping. "Quantum control of dynamics of quasiparticles in periodic and disordered lattice potentials." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/49995.
Full textAbstract:
This thesis describes research on controlling the dynamics of quasiparticles in
periodic and disordered lattice potentials. Working with model systems of arrays of atoms and molecules trapped in optical lattices,
I focus on, but not limited to, the rotational excitons of polar molecules and propose to use external fields to
control the binding and propagation of quasiparticles.
First, we study the binding of rotational excitons in a periodic potential. We show that non-linear interactions of such excitons can
be controlled by an electric field. The exciton-exciton interactions can be tuned
to induce exciton pairing, leading to the formation of biexcitons and three-body bound states of excitons. In addition, we propose a non-optical way to create biexcitons by splitting a high-energy exciton into two
low-energy excitons.
Second, we present schemes to control the propagation of a collective
excited state in ordered and disordered aggregates of coupled particles. We demonstrate that the dynamics of these excitations can be controlled by
applying a transient external potential which modifies the phase of the quantum
states of the individual particles. The method is based on an interplay of adiabatic
and sudden time scales in the quantum evolution of the many-body states. We show
that specific phase transformations can be used to accelerate or decelerate quantum
energy transfer and spatially focus delocalized excitations onto different parts of
arrays of quantum particles. For the model systems of atoms and molecules trapped in an optical lattice, we consider possible experimental implementations
of the proposed technique and study the effect of disorder, due to the presence of
impurities, on its fidelity. We further show that the proposed technique can allow
control of energy transfer in completely disordered systems.
Finally, in an effort to refine the theoretical tools to study dynamics of quasiparticles, I extend calculations of lattice
Green's functions to disordered systems. We develop a generic algorithm that can
be easily adapted to systems with long-range interactions and high dimensionalities. As an application of the method, we propose
to use the Green's function to study the tunneling of biexciton states through
impurities.Science, Faculty of
Chemistry, Department of
Graduate
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Zoltowska, Katarzyna Marta. "Novel pathogenic mechanisms of myasthenic disorders and potential therapeutic approaches." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:e817f50a-0318-4944-bf67-773af523c4c3.
Full textAbstract:
Congenital myasthenic syndrome (CMS) and myasthenia gravis (MG) are, respectively, inherited or autoimmunological disorders caused by aberrant neuromuscular transmission, which manifests as fatiguable muscle weakness. A novel subtype of CMS, resulting from mutations in GFPT1 and characterised by a limb girdle pattern of muscle weakness, has been described. The gene encodes L glutamine:D fructose-6-phosphate amidotransferase 1 (GFAT1) – a key rate limiting enzyme in the hexosamine biosynthetic pathway, providing building blocks for glycosylation of proteins and lipids. The research focused on the molecular bases of the CMS resulting from mutations in the ubiquitously expressed gene, but with symptoms largely restricted to the neuromuscular junction (NMJ). The work has established a link between the NMJ and GFPT1 CMS by demonstrating that the AChR cell surface is decreased in GFPT1 patient muscle cells and in GFPT1-silenced cell lines. The decrease is likely to be caused by reduced steady-state levels of individual AChR α, δ and ε, but not β, subunits. To optimise treatment for myasthenic disorders, a comparative in vivo trial of therapy with pyridostigmine bromide and salbutamol sulphate, and pyridostigmine bromide alone, was conducted. Supplementation of the AChE inhibitor-based therapy with the β2-adrenergic receptor agonist had a beneficial effect. This offers promise for more effective treatments for CMS and MG affected individuals. Molecular causes of MG were also investigated. The search for novel antibody targets was conducted with the use of a designed cell-based assay for the detection of anti COLQ autoimmunoglobulins in MG patient sera. The antibodies were detected in 24 out of 418 analysed samples, but their pathogenicity has not been determined.
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Berglof, Hollie K. "Differential Diagnosis of Attention Deficit Hyperactivity Disorder and Depression: Potential Bias and Misdiagnosis." DigitalCommons@USU, 2003. https://digitalcommons.usu.edu/etd/6189.
Full textAbstract:
This study investigated whether psychologists are attempting to distinguish between attention deficit hyperactivity disorder (ADHD) and depression in youth. Findings indicate that, overall, clinicians are conducting comprehensive evaluations and considering ADHD and depression as likely diagnoses. Clinicians were more likely to use self-report depression measures if the client was female or adolescent than if the child was male or school age; however, they were equally likely to incorporate ADHD-related measures with males and females , and 8 year olds and 15 year olds . Clinicians were more likely to consider adolescents than school-age children and females than males to have a mood disorder. Doctoral-level clinicians were more likely to consider a mood disorder and ADHD than master's- level clinicians. Clinicians who had completed a child psychopathology course were more likely to consider ADHD than those who had not completed such a course. The implications of these findings for child-oriented clinicians are discussed.
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Mohamad, Zaini Zuraiza Binti. "Chromosomal instability in oral potentially malignant disorders." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/chromosomal-instability-in-oral-potentially-disorders(bc361088-778f-4089-94c5-86e277eede62).html.
Full textAbstract:
Oral cancer is one of only four major cancers whose predicted mortality rate will significantly increase in the next 15 years. Many patients have potential precursor lesions but the methods for predicting the small number at high risk of cancer do not have sufficient predictive value or are labour intensive. The aim of this project is to investigate tests capable of predicting malignant transformation through detection of chromosomal instability. Image-based DNA image-based cytometry (‘ploidy analysis’) has been used routinely in the diagnostic Oral Pathology Unit but has not been tested on lesions clinically suspected as having high risk and its predictive values are not known for targeted use. Follow up data was compiled for 252 patients with risk lesions from local databases and cancer registries and a follow up study of malignant transformation was performed. Over than half of the dysplastic lesions, which transformed into cancer were aneuploid. Real time qPCR and QuantiGene Plex DNA assays were applied to samples of oral none dysplastic and dysplastic lesions to detect alterations in gene copy number using markers identified in previous studies in the laboratory. Discrepancies between methods were found, with inconsistent results caused by normalised to different housekeeping genes; RnaseP for qPCR, TPM1 for QGPlex and TERT in both techniques. Both these techniques were found to be insufficiently reliable for clinical use. Fluorescence in situ hybridization (FISH) was applied against Cen3/TP63, Cen7/EGFR, Cen8/PTK2, Cen11/CCND1 and 20ptel/MMP9. This proved almost as effective as image based ploidy analysis but was too labour intensive and time consuming for routine use. FISH revealed previously unrecognized zones of variation within dysplastic lesions and variation in clonal structure within them. Our data show that DNA image-based ploidy analysis combined with dysplasia assessment is the most predictive technique for use in a diagnostic setting and should be considered the reference standard.
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Roberts, Leanne. "Cannabinoids as potential new therapeutics of gastrointestinal motility and inflammatory disorders." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/14092/.
Full textAbstract:
Cannabinoids show potential as new treatments for inflammatory bowel disease (IBD),exerting several favourable effects in the gut, including anti-inflammatory and antimotilityeffects. The main difficulty with cannabinoids is their psychotropic side effects,but access to the brain may be prevented by conjugating the cannabinoid to a bulkygroup such as a dendrimer. The aims of this thesis were to investigate the mechanism by which cannabinoids reduce gut motility and to investigate whether cannabinoids protect the intestine from inflammatory-damage. A further aim was to determine whether cannabinoids remain pharmacologically active when conjugated to a dendrimer. All cannabinoids used (apart from arachidonoylcyclopropylamide and (-)WIN 55,212-2) caused a concentration-dependent reduction in the size of electrically-stimulated contractions in the guinea-pig ileum. The responses were not blocked by CB1, CB2, CBe(putative endothelial cannabinoid receptor) or GPR55 antagonists, suggesting that none of these receptors were involved in mediating cannabinoid responses. PSN 375963 reduced carbachol-induced contraction, suggesting that the GPR119 may be present on ileum smooth muscle. (+)WIN 55,212-2 was shown to protect the guinea-pig ileum from hydrogen peroxide-induced damage but this protection was not blocked by CB1, CB2, CBe or GPR55 antagonists, suggesting that the protective effects were not mediated through these receptors. Conjugation of JWH007 to a spacer (GA003) abolished activity in the guinea-pig ileum and the conjugation of JWH007 to a spacer and dendrimer (GA006) was found to be toxic in the macrophage assay. These studies show that cannabinoid-mediated inhibition of guinea-pig ileum contractions is not mediated through the CB1, CB2, CBe or GPR55 receptor. These receptors were not involved in the (+)WIN 55,212-2 mediated protection against hydrogen peroxide-induced damage in the ileum. The approach of attaching a dendrimer to JWH007 to prevent central nervous system (CNS) penetration does not appear to be a feasible approach because the cannabinoid-dendrimer was unexpectedly cytotoxic.
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DiSilvestro, David Joel. "Encapsulation of Genetically Modified Preadipocytes for Potential Treatment of Metabolic Disorders." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449090087.
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Brown, Lecia Ashanna Moya. "The Potential Role of Antiretroviral Efavirenz in HIV Associated Neurocognitive Disorders." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6685.
Full textAbstract:
The prevalence of milder forms of HIV-associated neurocognitive disorders (HAND) is rising despite combination antiretroviral therapy (cART). Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, but causes neurological symptoms that may interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HAND in patients on cART. Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human “Swedish” mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production (Chapter 3). Treatment with EFV or the EFV containing regimen generated significantly increased soluble Aβ, and promoted increased β-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aβ - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aβ generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aβ phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aβ promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aβ peptide.
Further (Chapter 4), there is evidence that neural stem cells (NSCs) can migrate to sites of brain injury such as those caused by inflammation and oxidative stress, which are pathological features of HAND. Thus, reductions in NSCs may contribute to HAND pathogenesis. Since the HIV non-nucleoside reverse transcriptase inhibitor EFV has previously been associated with cognitive deficits and promotion of oxidative stress pathways, we examined its effect on NSCs in vitro as well as in C57BL/6J mice. Here we report that EFV induced a decrease in NSC proliferation in vitro as indicated by MTT assay, as well as BrdU and nestin immunocytochemistry. In addition, EFV decreased intracellular NSC adenosine triphosphate (ATP) stores and NSC mitochondrial membrane potential (MMP). Further, we found that EFV promoted increased lactate dehydrogenase (LDH) release, activation of p38 mitogen-activated protein kinase (MAPK), and increased Bax expression in cultured NSCs. Moreover, EFV reduced the quantity of proliferating NSCs in the subventricular zone (SVZ) of C57BL/6 mice as suggested by BrdU, and increased apoptosis as measured by active caspase-3 immunohistochemistry. If these in vitro and in vivo models translate to the clinical syndrome, then a pharmacological or cell-based therapy aimed at opposing EFV-mediated reductions in NSC proliferation may be beneficial to prevent or treat HAND in patients receiving EFV.
1 Portions of this abstract have been previously published (Brown LAM, et al., 2014; Jin, J, et al, 2016) and are utilized with permission of the publisher.1
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1248530.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1263904.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1264024.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1263926.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1248550.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1263964.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1263986.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1264046.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1265284.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1248611.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1265264.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1266688.
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ROCCHETTI, MATTEO. "AUTISM SPECTRUM DISORDERS IN ADULTS: CLINICAL DIAGNOSIS AND POTENTIAL SERUM BIOMARKER." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1265364.
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Schulze, Katja Kristina. "Event-related potentials in bipolar disorder : a family study." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437286.
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Harris, Gregory Glenn. "Potential role of social support systems and post traumatic stress disorder." Huntington, WV : [Marshall University Libraries], 2005. http://www.marshall.edu/etd/descript.asp?ref=579.
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Morgan, Charlie David. "Olfactory event-related potentials in Alzheimer's disease /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2000. http://wwwlib.umi.com/cr/ucsd/fullcit?p9974114.
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Boltz, Horst-Holger [Verfasser], Jan [Akademischer Betreuer] Kierfeld, and Joachim [Gutachter] Stolze. "Semiflexible polymers in disordered potentials / Horst-Holger Boltz. Betreuer: Jan Kierfeld. Gutachter: Joachim Stolze." Dortmund : Universitätsbibliothek Dortmund, 2016. http://d-nb.info/1112736662/34.
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Joshi, Gururaj. "MULTIFUNCTIONAL POTENTIAL THERAPEUTICS TOWARDS OXIDATIVE STRESS MEDIATED NEURODEGENERATIVE DISORDERS AND MODELS THEREOF." UKnowledge, 2006. http://uknowledge.uky.edu/gradschool_diss/298.
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The studies described in this dissertation were performed with the goal of understandingthe function of antioxidant compounds delivered in vivo to rodents and the implication of theresults towards oxidative stress (OS)-related neurodegenerative disorders with particularemphasis on Alzheimer's disease (AD). OS has been implicated in AD and is characterized byextensive oxidative damage to protein, lipids and DNA. A major thrust of this dissertation workwas to gain insight into antioxidant properties of compounds used in the following studies andtheir efficacy as potential therapeutics for treatment of OS-related disorders.D609, a glutathione (GSH) mimetic is known to trap OH. Radicals, scavenge H2O2 andreduce the A?? (1-42)-induced OS and cytotoxicity in neurons. The present dissertation studyshowed in vivo protective effect of D609 in synaptosomes and mitochondria isolated fromgerbils against OS mediated by Fe2+/H2O2, AAPH, and A?? (1-42). Upon intraperitonial (i.p.)injection of gerbils, D609 showed protection of subsequently isolated brain moieties against OS.In vivo administration of D609 also modulates brain GSH levels and increases the activity of keyGSH-related enzymes, thereby likely provides a protection against OS.Adriamycin (ADR), a quinone-containing chemotherapeutic, is known to produce ROS inheart. Patients under treatment with ADR often show persistent changes in cognitive function(effect called as chemobrain by patients). Upon i.p. injection, ADR causes OS, increasesexpression of multidrug resistant protein-1 (MRP-1) in brain and alters GSH levels and itsrelated enzyme activities. ??-Glutamyl cysteinyl ethyl ester (GCEE) is known to increase GSHlevels in brain, in vivo. Research reported in this dissertation shows that in vivo GCEE reversesthe ADR-mediated OS in mice brain.N-acetylcysteine (NAC), a GSH precursor provides the limiting substrate cysteine inGSH synthesis. Previously, our laboratory showed increased GSH levels post i.p. injection ofNAC and reduces OS in synaptosomes treated with acrolein. The present study showed thatNAC given in drinking water to APP/PS-1 mice, a model of AD can significantly reduce OS.These results provide a potential therapeutic intervention by antioxidants that can modulateGSH in OS-mediated neurodegenerative disorders.
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Gray, James Andrew Russell. "Modulating the heat-shock response : a potential therapy for lysosomal storage disorders." Thesis, University of Oxford, 2014. https://ora.ox.ac.uk/objects/uuid:d9b746c9-9026-4a6e-97b5-00bb848100d7.
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Lysosomal storage disorders (LSDs) comprise a broad disease group of inherited metabolic disorders, the majority of which are associated with CNS pathology, significant disability and reductions in life expectancy. LSDs are caused by mutations in genes encoding proteins critical for the correct functioning of lysosomal homeostasis. The disruption of lysosomal homeostasis results in the abnormal accumulation of lysosomal content, initiating intracellular pathological events, including calcium dysregulation and lysosomal membrane permeablisation (LMP) affecting cell function and inducing cellular death mechanisms. These pathological events are particularly damaging within the CNS, due to its limited capacity for regeneration. Despite intensive scientific research into these disorders, and an increased understanding of the pathological events underlying these diseases, effective treatments are still lacking for most LSDs. Several therapeutic approaches have been investigated in the last 30 years, including enzyme replacement therapy, bone marrow transplantation, substrate reduction therapy, chemical chaperones and gene therapy. However, the CNS pathology in many of the LSDs remains unaddressed due to the restricted ability of many therapeutic agents to cross the blood-brain barrier. The heat-shock response (HSR) is an emerging element involved in the pathogenesis of a variety of disorders. The HSR is a physiological response to a wide range of cellular stresses. It functions to protect the cell from the aggregation of misfolded proteins and LMP. Of the HSR, several key players are integral to mounting a heat shock response, these include the heat-shock factor 1 (HSF-1) and HSP70. In this thesis, we provide proof-of-principle for the use of recombinant HSP70, and the small molecule up-regulator of the HSR, arimoclomol in treatment of a range of LSDs. We show that HSP70 is able to access the CNS, and increase the degradative capacity of lysosomal hydrolases. This provides differential behavioural, biochemical and survival effects in LSD models of Niemann-Pick type C, Sandhoff and Fabry disease. Additional studies using the HSF-1 upregulator arimoclomol, show a complex dose-response between the different models, possibly reflecting essential differences in the calcium dysregulation between these disease states.
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Scotto, Rosato Anna. "TRPML1 : role in autophagy and potential target to treat lysosomal storage disorders." Thesis, Open University, 2018. http://oro.open.ac.uk/55296/.
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The view of the lysosome as the terminal end of cellular catabolic pathways has been challenged by recent studies showing a central role of this organelle in the control of cell function. Here we show that a lysosomal Ca2+ signaling mechanism controls the activities of the phosphatase calcineurin and of its substrate TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. Lysosomal Ca2+ release via mucolipin 1 (TRPML1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation. Induction of autophagy and lysosomal biogenesis via TFEB required TRPML1-mediated calcineurin activation, linking lysosomal calcium signaling to both calcineurin regulation and autophagy induction. In addition to the role of TRPML1 on sustaining transcriptional autophagy program, through the activation of TFEB, we also found that TRPML1-activation induces the recruitment of PtdIns(3)P-binding proteins to the nascent autophagosome, whereas genetic or pharmacological inhibition of TRPML1 channel inhibits autophagy initiation. Importantly, alteration of this function has pathological consequences, and thus we found that autophagosome formation is impaired in human fibroblasts from patients affected of mucolipidosis IV (MLIV; a severe lysosomal storage disorder caused by mutations in TRPML1). By using specific compound inhibitors during starvation, we found that TRPML1-mediated induction of autophagosome biogenesis requires calmodulin, CaMKKβ, and the PtdIns(3)-generating enzyme VPS34. Therefore, we hypothezise that during starvation, TRPML1 activation releases lysosomal calcium that activates a calcium-depedent pathway involving CaMKKβ and the induction of two essential protein complexes involved in autophagy initiation such as ULK1 and PIK3C3 complexes. In parallel studies, we used high content (HC) screening approaches to identify small molecules able to ameliorate the MLIV phenotype. In one of them, we tested whether previously identified drugs (150 FDA compounds) inducing TFEB translocation and cellular clearance might be active in MLIV patient cells. This screening resulted in the identification of 3 drugs able to induce TFEB nuclear translocation confirming the importance of the TRPML1-mediated signalling to promote TFEB activity. In addition, only one of these hits were able to reduce the pathological accumulation of autophagic substrates such as p62 and NBR1 in MLIV human fibroblasts. In a second independent HC-screening, we developed a cell-based assay to identify FDA-drugs able to reduce cholesterol accumulation in MLIV cells. We identify 8 small molecules able to reduce cholesterol accumulation in MLIV human fibroblasts that will need further characterization to define their ability to ameliorate the phenotype of this devastating disease. In summary, we found two novel signaling pathways triggered by TRPML1-dependent lysosomal calcium release that regulate cellular homeostasis by both promoting autophagy initiation and sustaining transcriptional programs inducing autophagic and lysosomal genes during starvation. Finally, we use part of this knowledge to develop cell-based high content screening assays that identified 9 FDA-approved compounds able to ameliorate the autophagic impairment and reduce lipid storage in MLIV disease cells.