In this thesis we start by reproducing previous experiments by Zanos et al., where they have shown that it is possible to associate neural signals with specific cytokines. One future aim of this project is to send synthetic neural signals through the efferent arc of the vagus nerve and observe reactions without the corresponding catalyst of the symptoms. We use a variational autoencoder (VAE) in our experiment to create a model able to generate new neural signals, and we introduce a novel clustering technique called VAE-clustering, which will be used to cluster neural signals with their associated cytokines. The focus of this paper is the implementation of this method and applying it on the neural signals. Running VAE-clustering on the MNIST dataset shows it to be viable for finding detailed properties of a dataset. We also find that using a VAE as a generative model for neural signals is a good way for recreating detailed waveforms. / I detta examensarbete börjar vi med att reproducera tidigare experiment av Zanos et al., där dom visat att det är möjligt att associera nervsignaler med specifika cytokiner. Ett framtida mål med detta projekt är att skicka syntetiska nervsignaler till kroppen för att observera reaktioner utan motsvarande katalysator av symptomen. Vi använder en variational autoencoder (VAE) i våra experiment för att skapa en modell kapabel till att generera nya nervsignaler, och vi introducerar en ny klusterings-teknik kallad VAE-klustring, vilken kommer att användas för att klustra nervsignaler med dess associerade cytokiner. Fokuset i detta arbete ligger i implementationen av denna metod och applicerandet på nervsignaler. Efter att ha kört VAE-klustring på MNIST dataset fann vi att det det är användbart för att hitta detaljerade egenskaper hos ett dataset. Vi har även funnit att användningen av en VAE som en generativ modell för nervsignaler är ett bra sätt att återskapa detaljerade vågformer.

In the past decade, characterizing spiking neuron models has been extensively researched as an essential issue in computational neuroscience. In this thesis, we examine the estimation problem of two different neuron models. In Chapter 2, We propose a modified Izhikevich model with an adaptive threshold. In our two-stage estimation approach, a linear least squares method and a linear model of the threshold are derived to predict the location of neuronal spikes. However, desired results are not obtained and the predicted model is unsuccessful in duplicating the spike locations. Chapter 3 is focused on the parameter estimation problem of a multi-timescale adaptive threshold (MAT) neuronal model. Using the dynamics of a non-resetting leaky integrator equipped with an adaptive threshold, a constrained iterative linear least squares method is implemented to fit the model to the reference data. Through manipulation of the system dynamics, the threshold voltage can be obtained as a realizable model that is linear in the unknown parameters. This linearly parametrized realizable model is then utilized inside a prediction error based framework to identify the threshold parameters with the purpose of predicting single neuron precise firing times. This estimation scheme is evaluated using both synthetic data obtained from an exact model as well as the experimental data obtained from in vitro rat somatosensory cortical neurons. Results show the ability of this approach to fit the MAT model to different types of reference data.

Short-term synaptic plasticity (STP) is a phenomenon that has been closely associated with how neurons communicate with each other. I study communication between neurons tied to synapses endowed with short-term plasticity (dynamic synapses). This is achieved by using mathematical models of neural phenomena that align with those found in real neurons. In addition to dynamic synapses, a model of static synapses is created, on which control experiments are performed. The response of postsynaptic neurons, to spiking-sequences from presynaptic neurons, is examined in order to infer how information is transmitted across cells. During these computational experiments, it was found that the range of firing rates to which postsynaptic neurons responded, depends heavily on certain parameters of STP-processes. These parameters are the time constants for short-term synaptic depression and facilitation: the two time-dependent processes that define STP. Some results confirm those of the existing literature, while this work places an added emphasis on the sensitivity of the propagation of rate codes to the aforementioned parameters of synapses. This is relevant because it has been found that real synapses display a wide range of time constants in the nervous system. Hence, understanding how this variation carries a significant impact on rate-coding schemes is vital when engaging in further studies of neural rate codes. / Synaptisk plasticitet på kort sikt (STP) är ett fenomen som har blivit nära förknippat med hur nervceller kommunicerar med varandra. Jag studerar kommunikation mellan nervceller som är kopplade till synapser som är försedda med kortsiktig synaptisk plasticitet (dynamiska synapser). Detta har åstadkommits genom matematisk modellering av fenomen i nervsystemet som är konsekventa med de som är funna i verkliga nervceller. Utöver dynamiska synapser, så skapas även en modell av statiska synapser på vilka kontrollexperiment utövas. Gensvaret av postsynaptiska nervceller, på sekvenser av nervimpulser från presynaptiska nervceller, kartläggs för att studera hur information transmitteras mellan celler. I dessa beräkningsmässiga experiment så var det funnet att spannet av frekvenser för vilka postsynaptiska nervceller visade gensvar, var kraftigt beroende på specifika parametrar för STP-processer. Dessa parametrar är tidskonstanterna för synaptisk depression på kort sikt samt synaptisk facilitering på kort sikt: de två tidsberoende processerna som definierar STP. Vissa resultat bekräftade de som återfinns i den befintliga literaturen, samtidigt som detta arbete placerar adderad tyngd på känsligheten som frekvensmässiga koder uppvisar för ovannämnda synaptiska parametrar. Detta är relevant eftersom det är känt att verkliga synapser uppvisar ett brett spann av tidskonstanter i nervsystemet. Följdaktigen är det centralt att förstå hur denna variation innehar signifikant påverkan på frekvenskoder vid fortsatta studier inom frekvensmässiga neurala koder.

В рамках работы были исследованы методы построения систем планирования и управления предприятием класса ERP-систем. Цель работы – разработка программного инструмента в «1С: ERP Управление предприятием 2», позволяющего вести учет всех заказов, предстоящих и уже выполняющихся на предприятии. В ходе исследования был разработан рабочий прототип учета и планирования производства заказов на предприятии по производству литий-ионных аккумуляторов с использованием ERP-системы «1С-Предприятие». / Within the framework of this work, a study was made of the existing types of scheduler and enterprise resources planning system methods. An analysis of the existing question-answer systems was carried out. The goal of work id development software tool for schedule and resources planning for order control and management of laity-ions buttery base on ERP-system “1C: ERP Enterprise”. In the course of the study, a working prototype of schedule and resources planning for order control and management base on ERP-system “1C: ERP Enterprise” was developed.

Microglial cells, the resident macrophages of the central nervous system (CNS), exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell-damaging factors, they get transformed into an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species, and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia have a number of important physiological functions in the CNS; for example, they shield small disruptions of the blood–brain barrier by their processes, dynamically interact with synaptic structures, and clear surplus synapses during development. In neurodegenerative illnesses, they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction. Therefore, the blockade of this reaction improves the outcome of Alzheimer’s Disease, Parkinson’s Disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. The function of microglia is regulated by a whole array of purinergic receptors classified as P2Y12, P2Y6, P2Y4, P2X4, P2X7, A2A, and A3, as targets of endogenous ATP, ADP, or adenosine. ATP is sequentially degraded by the ecto-nucleotidases and 5′-nucleotidase enzymes to the almost inactive inosine as an end product. The appropriate selective agonists/antagonists for purinergic receptors as well as the respective enzyme inhibitors may profoundly interfere with microglial functions and reconstitute the homeostasis of the CNS disturbed by neuroinflammation.

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Les récepteurs nucléaires font partie d’une famille de protéine multigénique agissant comme facteurs de transcription qui, en réponse à la liaison d’un ligand, régulent l’expression de gènes cibles impliqués dans une variété de fonctions physiologiques. Cependant, les récepteurs nucléaires orphelins, qui n’ont pas de ligand connu, peuvent également être régulées par des modifications post-traductionnelles (PTMs) comme la SUMOylation et la phosphorylation. La famille des NR4A, incluant Nurr1, Nur77 et Nor1, sont des récepteurs orphelins dépendant grandement des PTMs au niveau de l’AF-1 afin de moduler leurs activités essentielles dans la différenciation, le développement et le métabolisme des fonctions neurologiques. En particulier, il est connu que les PTMs permettent le recrutement de cofacteurs comme l’isomérase Pin-1, une enzyme recrutée par des motifs phospho-sérine/thréonine-proline qui catalyse l’isomérisation cis/trans du lien avec la proline. Notre laboratoire a récemment identifié un site de SUMOylation atypique nommé pSuM (phosphorylation-dependent Sumoylation Motif) possédant une extension phosphorylable de motif sérine/thréonine-proline au niveau du domaine AF-1 (Activation Function-1) de certains récepteurs nucléaires, soutenant un processus de régulation transcriptionnelle des récepteurs via la SUMOylation et la phosphorylation. Le récepteur Nor1 possède un motif pSuM dont le rôle exact de la SUMOylation et l'implication de Pin-1 comme régulateurs de l’activité de Nor1 dans les mécanismes de neuroprotection reste inconnu. Ainsi nos objectifs sont de déterminer et caractériser le mécanisme de recrutement et l'impact de Pin-1 sur la régulation de Nor1 ainsi que de déterminer le rôle de Pin-1 sur l’expression des gènes cibles impliqués dans la neuroprotection. Nos résultats démontrent que l’isomérase Pin-1 favorise l’expression de gène impliquées dans la neuroprotection comme Eno3, Nrip1 et Atf3 via un mécanisme dépendant de la SUMOylation et de la phosphorylation qui permet la régulation positive de l’activité transcriptionnelle de Nor1 dans un modèle de cellules neuronales de souris. En conclusion, les résultats de ce travail permettent d’identifier l’isomérase Pin-1 comme un nouveau cofacteur de Nor1 impliqué dans le contrôle de l’expression génique associé à la neuroprotection et démontre un mécanisme de régulation de Nor1 par la SUMOylation et la phosphorylation de l’extension du pSuM. / Nuclear receptors are part of a family of multigene proteins acting as transcription factors that, in response to ligand binding, regulate the expression of target genes involved in various physiological functions. However, orphan nuclear receptors, which have no known ligand, can also be controlled by post-translational changes (PTMs) such as SUMOylation and phosphorylation. The NR4A family, including Nurr1, Nur77, and Nor1, are orphan receptors highly dependent on PTMs at the AF-1 domain to modulate their essential activities in the differentiation, development, and metabolism of neurological functions. The PTMs of nuclear receptors allow the recruitment of cofactors such as the Pin-1 isomerase, an enzyme recruited by phospho-serine/threonine-proline motifs that catalyzes the cis/trans isomerization of the proline. Our laboratory has recently identified an atypical SUMOylation site named pSuM (phosphorylation-dependent Sumoylation Motif) characterized by a phosphorylation-sensitive extension of serine/threonine-proline pattern usually present in the AF-1 (Activation Function-1) domain of receptors and providing transcriptional regulation via SUMOylation and phosphorylation. As of now, the role of SUMOylation and Pin-1 as regulators of Nor1 activity in neuroprotection mechanisms remains unknown. Thus, our objectives were to determine and characterize the recruitment mechanism of Pin-1 and its impact on the transcriptional regulation of Nor1 as well as to determine the role of Pin-1 on the expression of target genes involved in neuronal integrity. Our results have shown that Pin-1 isomerase enhances the expression of genes involved in neuroprotection such as Eno3, Nrip1, and Atf3 through a SUMOylation and phosphorylation mechanism that upregulates the transcriptional activity of Nor1 in neuronal cells. In conclusion, this project identifies Pin-1 as a novel cofactor of Nor1 that is regulated by SUMOylation and phosphorylation of the pSuM extension, thus allowing a tight control over the transcription of genes involved in neuroprotection processes.

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