DNA metüülimise roll kokaiini poolt põhjustatud käitumusliku sensitisatsiooni kujunemises

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Ravimsõltuvust iseloomustab vastupandamatu tung tarbida psühhotroopseid aineid hoolimata sellega kaasuvatest tõsistest kõrvaltoimetest. Uuringud on näidanud, et ravimsõltuvus kujuneb välja järk-järgult ja sõltuvusega seotud neurobioloogilised muutused võivad jääda püsima ka pärast psühhotroopsete ainete tarvitamise lõppu. Korduv psühhostimulaatori (nt. kokaiini) manustamine põhjustab katseloomadel suurenenud käitumusliku vastuse. Sellist fenomeni nimetatakse psühhomotoorseks ehk käitumuslikuks sensitisatsiooniks ning see modelleerib adiktiivset käitumist ja psühhostimulaatorite psühhootilisi komplikatsioone inimesel. Kuna käitumuslikule sensitisatsioonile on iseloomulikud püsivad muutused katseloomade käitumises, siis arvatakse, et osaliselt on selle põhjuseks lühi- ja pikaajalised geeniekspressiooni muutused, mis omakorda mõjutavad närviimpulsi ülekannet, sünapsite moodustamist ja närviringide funktsioneerimist. Mitmed uuringud viitavad, et epigeneetilised mehhanismid, eriti geeni promootori piirkonna DNA metüülimine, mille korral liidetakse DNA metüültransferaasi (DNMT) vahendusel metüülrühm tsütosiin-guanosiin (CpG) dinukleotiidsele järjestusele, on seotud pikaajaliste geeniekspressiooni muutustega. Käesoleva töö eesmärgiks oli uurida DNA metüülimise rolli kokaiini poolt põhjustatud käitumusliku sensitisatsiooni kujunemises hiirtel ja rottidel. Töö tulemused näitasid, et kokaiini manustamine suurendas dünaamiliselt Dnmt3a ja Dnmt3b ekspressiooni täiskasvanud hiirte naalduvas tuumas (nucleus accumbens) ja hipokampuses; põhjustas valitud markergeenide promootori piirkonnas nii DNA metüülimist kui ka demetüülimist ning DNMT inhibiitori, zebulariini, manustamine normaliseeris hüpermetüülitud geeni transkriptsiooni täiskasvanud hiirte naalduvas tuumas ja pidurdas käitumusliku sensitisatsiooni teket. Samuti leidsime, et keskkonnategurid, nagu metüülrühma doonor S-adenosüülmetioniin (SAM) ja varajases elueas kogetud stress, võivad DNA metüülimise kaudu soodustada psühhostimulaatoritest tingitud ravimsõltuvuse teket nii hiirtel kui ka rottidel.Drug addiction is a chronic relapsing disorder characterised by a pattern of compulsive drug seeking and taking behaviour despite severe adverse consequences. Prolonged abuse of drugs, such as psychostimulants, may contribute to behavioural abnormalities that can last for months or even years after discontinuing drug consumption. Repeated administration of psychostimulants (such as cocaine) induces an enhanced behavioural response to subsequent drug exposure, a phenomenon known as psychomotor or behavioural sensitisation. Psychostimulant-induced behavioural sensitisation in rodents provides a model for addictive behaviours, such as those associated with craving and relapse, and for the psychotic complications of psychostimulant abuse. Behavioural sensitisation is remarkably persistent phenomenon. In rodents, it can persist from months to years after drug treatment is discontinued. Persistent behavioural sensitisation indicates that drug-induced short- and long-term changes in gene expression may be involved. Accumulating data suggest that epigenetic mechanisms, such as DNA methylation (catalysed by DNA methyltransferases - DNMTs), are critical regulators of persistent gene expression changes and may be related to behavioural disorders. The aim of this study was to investigate the role of DNA methylation in the development of cocaine-induced behavioural sensitisation in mice and rats. Our data demonstrated that cocaine treatment caused a dynamic increase in Dnmt3a and Dnmt3b expression levels in the nucleus accumbens (NAc) and hippocampus of adult mice; induced both DNA methylation/demethylation in the promoter regions of the selected genes; and intracerebroventricular treatment with the DNMT inhibitor zebularine normalised hypermethylated gene transcription in the NAc of adult mice and delayed the development of cocaine-induced behavioural sensitisation. We also found that environmental factors, such as methyl group donor S-adenosylmethionine (SAM) and early life stress, may promote, via DNA methylation, the development of psychostimulant-induced drug addiction in mice and rats

On Infinitely Many Rational Approximants to ζ(3)

A set of second order holonomic difference equations was deduced from a set of simultaneous rational approximation problems. Some orthogonal forms involved in the approximation were used to compute the Casorati determinants for its linearly independent solutions. These solutions constitute the numerator and denominator sequences of rational approximants to ζ(3) . A correspondence from the set of parameters involved in the holonomic difference equation to the set of holonomic bi-sequences formed by these numerators and denominators appears. Infinitely many rational approximants can be generated.The research of J.A. was funded by Agencia Estatal de Investigación of Spain, grant number PGC-2018-096504-B-C33 and Comunidad Autónoma de Madrid, grant number CC-G08-UC3M/ESP-4516

Detailed analysis of the lattice Boltzmann method on unstructured grids

The lattice Boltzmann method has become a standard for efficiently solving problems in fluid dynamics. While unstructured grids allow for a more efficient geometrical representation of complex boundaries, the lattice Boltzmann methods is often implemented using regular grids. Here we analyze two implementations of the lattice Boltzmann method on unstructured grids, the standard forward Euler method and the operator splitting method. We derive the evolution of the macroscopic variables by means of the Chapman-Enskog expansion, and we prove that it yields the Navier-Stokes equation and is first order accurate in terms of the temporal discretization and second order in terms of the spatial discretization. Relations between the kinetic viscosity and the integration time step are derived for both the Euler method and the operator splitting method. Finally we suggest an improved version of the bounce-back boundary condition. We test our implementations in both standard benchmark geometries and in the pore network of a real sample of a porous rock.Comment: 42 page

Principios, Normas y Procedimientos de Contabilidad Gubernamental en el Ministerio Agropecuario y Forestal MAG FOR del Departamento de Matagalpa y Delegación Central en el primer semestre del año 2010

El presente seminario de graduación consiste en una investigación sobre la aplicación de los Principios, Normas y Procedimientos de Contabilidad Gubernamental en el Ministerio Agropecuario y Forestal del departamento de Matagalpa y Delegación Central en el primer semestre del año. Se procedió al análisis de la información teórica recopilada mediante la aplicación de tres niveles de lectura, donde se demuestra con ejemplos de aplicación de cada uno de los principios, normas y procedimientos que el MAG FOR da cumplimiento razonablemente a dichos enunciados. Luego se analizo la aplicación contable, la descripción conceptual de las leyes que rigen a las entidades del estado y los diferentes manuales que compone la estructura organizativa y financiera de la institución. También se procedió a realizar una simulación contable que lleva el Ministerio Agropecuario y Forestal en un mes de su ejecución presupuestaria, partiendo de la asignación del crédito presupuestario recibido del Ministerio de Hacienda y Crédito Público, realizar el gasto de acuerdo a la planificación mensual previamente establecida, después reunir todos los documentos soportes necesarios para la rendición de cuentas suficientes para la asignación del crédito presupuestario para el siguiente mes, afectando todas las área que están involucradas en la elaboración y ejecución de estos procedimientos basándose en los mandatos de ley pertinentes y los manuales de procedimientos. El propósito de este trabajo es servir de guía a generaciones futuras de estudiantes de las ciencias económicas de las universidades de Nicaragua, para que conozcan de manera general la función primordial de la Contabilidad Gubernamental en el desarrollo del paí

Creating BIM model from point cloud data for building maintenance by the example of the Estonian National Museum

Magistritöö Geodeesia õppekavalMagistritöö eesmärgiks on uurida skaneeritud punktipilve alusel modelleeritud BIM haldusmudeli kvaliteeti geodeedi seisukohast. Turunõudlusest tulenevalt püüavad geodeedid tulla välja paremate ja huvitavamate ideedega, et leida uusi kliente ja tõsta geodeesia valdkonna väärtust. Hoonemudelite järgi on olemas vajadus ja selle vastu tunnevad kliendid aina rohkem huvi. Töö eesmärgi täitmiseks anti ülevaade teadusartiklitest ja autori kogemusest BIM haldusmudeli loomise protsessist. Töös on uurimisobjektiks Eesti Rahva Muuseum (ERM), mille BIM-mudeli loomine koosnes kahest osast: andmete kogumisest ja mudeli modelleerimisest. Andmete kogumise olulisem etapp on hoone laserskaneerimine, lisaks kasutatakse veel tahhümeetri ja ortofoto mõõdistusandmeid ning BIM-elemendid otsitakse BIM-kataloogidest. Enne skaneerimist ja mudeldamist määratakse lähteülesanne, kus kirjeldatakse mudeli maht, detailsus ja väljanägemine. Uurimistöö metoodikaks on juhtumiuuring (case study), kus peamiseks analüüsiüksuseks on üksikjuhtum ehk ERM BIM haldusmudel. Kogutakse hulgaliselt olulisi fakte uurimisobjekti kohta ja võrreldakse teiste andmetega, antud juhul projekti ja teostusjoonistega. Töö teostamiseks kasutati Revit tarkvara, kus hetkel puudub võimalus kontrollida mudeli täpsust. Punktipilvest modelleerimisel viidi läbi andmete võrdlus projekti, teostusjooniste ja BIM-mudeli vahel. Mudelis peavad ruumi pindalad jääma tellija poolt ette antud 2% lubatud piiri sisse. Analüüsis selgus, et kõige rohkem peaks tähelepanu pöörama modelleerimisel väikestele ja eri-tasapinnalistele ruumidele ja seinte kõrgustele. Lisaks mõjusid seinte erinevustele ruumi suurus ja kuju. Vigade põhjusteks võisid olla probleemid Reviti modelleerimistööriistade kasutamisega, mittesobivate elementide kasutamine ja info kadumine andmete üleviimisel ühest programmist teise. Skaneerimiskäigu suunalisi ja korruste kaupa seinte vigade kuhjumist ei avaldanud ja klaasipindade peegeldumised mudelis suuri erinevusi ei tekitanud. BIM-mudeli koostamine võiks olla uus väljund geodeesia ettevõtetele. Parima tulemuse saavutamiseks peaks BIM-mudeli modelleerimise protsessi kaasama lisaks geodeedile veel arhitekti, ehitaja, projekteerija, kinnisvarahalduri ja tehnosüsteemide spetsialisti. Kokkuvõtteks võib öelda, et BIMmudeli koostamine on geodeedi pärusmaa või vähemalt osa sellest protsessis, näiteks punktipilvede koostamise ja modelleerimise näol. Geodeet võiks vastutada eelkõige mudeli täpsuse eest.Master's thesis aim is to explore the creating process from scanned point cloud based BIM model for management of facilities in different ways of data collection and to control the quality of the model in terms of surveyor. There is a necessity and customers are more and more interested in building 3D-models. In order to expand the surveyor work, the author explores the possibilities of BIM model creation by g surveyor. For the first time in Estonia, there were ordered the management of building information model at the national level in 2016. Riigi Kinnisvara AS (RIKAS) ordered the procurement procedure of the model from Hades Geodeesia OÜ. There name of the procurement is: "Estonian National Museum, creating a model of facilities management," which has also been the subject of this study. To reach the goal, the author of this work describes the scientific articles and the author's experiences how to do the point cloud based BIM model. The main data collection method is Terrestrial Laser Scanning. Another method was using the total station, the survey data and BIMelements were searched in BIM-catalogues. Creating a BIM model is divided into two. Firstly, Lasers-scanning and modeling. Before scanning and modeling, it has to be determined by the reference, which describes the model volume, the level of detail and appearance. The methodology of conducting the research is based on the case study, Estonian National Museum BIM model of facilities management. The author has collected a lot of important information about the object and compared with other data, in this case, with the execution of drawings and project data. Revit software has no way to verify the model, it will be control data analysis. Space area differences must be below 2%, which is required by RKAS. The analysis showed that most attention should have the modeling of small rooms and rooms on different levels and choosing the correct height of walls. In addition, the differences in the walls where effected by room size and the its shape of geometry. Error may have been causes by the problems in using Revit modeling tools, using not suitable elements, or loss of information in data transfer. Creating the BIM model could be a new output in geodesy, but it takes a lot of time to train the BIM Specialist. In order to have the best results, it is necessary for BIM modeling process to involve, in addition to surveyor, the architects, builders, designers, real estate managers and technical systems specialist. In conclusion it can be said that the surveyor is one of the most important specialist in creating BIM model, or at least in part of this process, for example in forming the point cloud draft and in modeling. The surveyor should be primarily responsible for the accuracy of the model

Local yield stress statistics in model amorphous solids

We develop and extend a method presented in [S. Patinet, D. Vandembroucq, and M. L. Falk, Phys. Rev. Lett., 117, 045501 (2016)] to compute the local yield stresses at the atomic scale in model two-dimensional Lennard-Jones glasses produced via differing quench protocols. This technique allows us to sample the plastic rearrangements in a non-perturbative manner for different loading directions on a well-controlled length scale. Plastic activity upon shearing correlates strongly with the locations of low yield stresses in the quenched states. This correlation is higher in more structurally relaxed systems. The distribution of local yield stresses is also shown to strongly depend on the quench protocol: the more relaxed the glass, the higher the local plastic thresholds. Analysis of the magnitude of local plastic relaxations reveals that stress drops follow exponential distributions, justifying the hypothesis of an average characteristic amplitude often conjectured in mesoscopic or continuum models. The amplitude of the local plastic rearrangements increases on average with the yield stress, regardless of the system preparation. The local yield stress varies with the shear orientation tested and strongly correlates with the plastic rearrangement locations when the system is sheared correspondingly. It is thus argued that plastic rearrangements are the consequence of shear transformation zones encoded in the glass structure that possess weak slip planes along different orientations. Finally, we justify the length scale employed in this work and extract the yield threshold statistics as a function of the size of the probing zones. This method makes it possible to derive physically grounded models of plasticity for amorphous materials by directly revealing the relevant details of the shear transformation zones that mediate this process