Ejektionsfraktion (EF) är ett mått på den globala systoliska vänsterkammarens funktion. EF är en viktig parameter för den systoliska vänsterkammare funktionen eftersom de terapeutiska samt prognostiska fattade besluten bygger på bland annat detta mått, vilket normalt är ≥ 55 % av slutdiastolisk volym. Vid beräkning av EF används bland annat tvådimensionell (2D) ekokardiografi (2D-EKO) samt myokardscintigrafi i vila (GSPECT). Utifrån 2D-EKO erhålls EF med Biplan Simpson metoden tillämpad i fyrkammarvy och tvåkammarvy i slutdiastole och slutsystole. Med GSPECT i vila erhålls EF värden utifrån QPS och QGS bilderna efter att en automatisk utlinjering av endokardiets konturer genomförts med hjälp av Hermes Medical solution. Syftet med studien var att se om det föreligger en signifikant skillnad för uppmätt EF mellan Myokardscintigrafi (GSPECT) och 2D Ekokardiografi i vila. Studien innefattade 30 deltagare. Deltagarnas uppgifter avidentifierades och inhämtades från tidigare genomförd 2D-EKO respektive GSPECT i vila, med högst 6 månaders mellanrum av legitimerade Biomedicinsk Analytiker. Resultatet av studien förevisade ett p – värde (p=0,000) <0,1% samt r-värde (r = 0,65.) Vilket indikerar på en stark och signifikant korrelation däremot förekommer det en bristande uppnåelse av överstämmelse mellan metoderna utifrån spridningsdiagrammet som ger ( r^2= 0,42). Bland Altmandiagammet noterar att ett gott samband mellan metoderna föreligger och även så gör standardavvikelse för 2D-EKO samt GSPECT som påvisade (50.1±¬¬10,8) respektive (49,1± 15,1). Studien förevisade goda övergripande korrelationer mellan EF härstammande från 2D-EKO och GSPECT. Sammantaget visade studien att metoderna överensstämmer med varandra vid mätning av EF. / Ejection fraction (EF) is a measure of the global systolic left chamber function. EF is a significant parameter for the systolic left ventricle function since therapeutic and prognostic conclusions are based on the left chamber ejection fraction. EF is normally ≥ 55% of the end-diastolic volume. Left ventricle ejection fraction can be determined non-invasively by 2D echocardiography (2D – ECHO) and gated single photon emission computed tomography. Based on 2D echocardiography (2D-ECHO), EF was obtained using the biplane Simpson method applied in four-chamber view and two- chamber views in both end diastole and end systole. With myocardial perfusion (GSPECT), EF values were obtained based on the QPS- and QGS- images after an automatic orientation of endocarditis contours were carried out by Hermes Medical solution. The purpose of this report was to see if there is a significant difference in (EF) between (GSPECT) and (2D-ECHO) at rest. The study included 30 participants. EF values were attained by licensed biomedical scientist. Participants' data were de-characterized and obtained from previously performed Echocardiography (2D-ECHO) and myocardial perfusion (GSPECT) at rest examination at intervals of no more than 6 months. The outcomes of the study showed (p=0.000) <0.1% and (r = 0.65) thus representing a strong and significant correlation, however there is a lack of consistency between the methods based on the scattering chart that gives (r^2 = 0.42). Bland Altman's illustration state that a good correlation between the methods exists and so does standard deviation for 2D-ECHO and Myocardial perfusion (GSPECT) as demonstrated (50.1±10.8) and (49.1±15.1) respectively. The study showed good overall correlations between EF derived from (2D ECHO) and Myocardial perfusion (GSPECT). In conclusion, the statistics demonstrated that the methods are comparable to each other when measuring EF.

Le Sarcome d'Ewing est un cancer pédiatrique rare, principalement dû à l'expression de l'oncogène de jonction EWS-Fli1, et dont les traitements médicamenteux ont peu évolué au cours des dernières décennies. Nous nous intéressons à une nouvelle approche thérapeutique utilisant des siRNA, ciblant spécifiquement l'oncogène EWS-Fli1, et permettant l'inhibition de la croissance tumorale. Durant mon travail de thèse, j'ai utilisé des nanocristaux de diamant issus soit de détonation (DND), soit de synthèse haute pression-haute température (NDHPHT) pour vectoriser les siRNA, accrochés par interaction électrostatique. Pour ce faire, les NDs ont été rendus cationiques par différentes méthodes: (i) hydrogénation assistée par plasma, (ii) par recuit thermique, ou (iii) par traitement chimique pour les DNDs, ou (iv) greffage covalent d'un polymère cationique sur des NDHPHT (COP-NDHPHT).Mes travaux ont comporté deux axes: (i) étude in vitro des complexes ND:siRNA (caractérisations physico-chimiques des NDs et étude de l'efficacité d'inhibition de l'oncogène par les complexes); (ii) distribution tissulaire de COP-NDHPHT, injectés dans des souris, grâce à des NDHPHT fluorescents, contenant des défauts azote-lacune. Pour les détecter individuellement dans des coupes d'organes de souris portant une tumeur xénogreffée sous-cutanée, nous avons développé un système d'imagerie en épifluorescence à grande ouverture numérique, et résolu en temps afin de rejeter l'autofluorescence tissulaire (de durée de vie plus courte que celle des NDs). Nous avons quantifié le nombre, l'état d'agrégation et la localisation cellulaire de ces vecteurs (grâce à un marquage histopathologique imagé simultanément) 24h après injection. Les NDs ont été clairement détectés dans les différents organes, dont la tumeur, ouvrant la voie à un contrôle de la progression tumorale grâce au siRNA. / Ewing Sarcoma is a rare pediatric cancer, caused in the majority of the cases by the expression of the fusion oncogene EWS-Fli1. Current treatments have not much evolved over the past decades. We are investigating a new therapy based on siRNA specifically targeting the oncogene and inhibiting the tumor growth. During my PhD thesis, I have tested different types of synthetic nanodiamonds (ND) used to vectorize siRNA electrostatically bound at their surface: ND produced by detonation (DND) or by High Pressure-High Temperature synthesis (NDHPTH). Their surfaces have been cationized by various processes: (i) plasma or (ii) thermal hydrogenation, (ii) chemical treatment, or (iv) covalent grafting of a copolymer (COP-NDHPHT).My PhD work included two main axis: (i) in vitro study of ND:siRNA complexes (NDs physico-chemical characterization and oncogene inhibition efficacy by the complexes); (ii) tissue distribution of COP-NDHPHT, injected into mice, using fluorescent NDHPHT containing nitrogen-vacancy defects. To detect them individually in sections of mouse organs carrying a subcutaneous xenograft tumor, we developed an epifluorescence imaging system with large numerical aperture and resolved in time to reject tissue autofluorescence (of a shorter lifetime than NDs). We quantified the number, the aggregation state and the cell localization (thanks to simultaneous histopathological imaging) of these vectors 24 hours after injection. NDs have been clearly detected in different organs, including the tumor, paving the way for tumor progression control with siRNA.

Syftet med denna uppsats är att analysera hur människors val av boplats påverkar segregationen i Stockholm ur ett antropolgiskt perspektiv. Jag har valt att använda den välkänt fashionabla Stockholmsförorten Djursholm som exempel. Vad utgör exklusiviteten? Hur ser Djursholmarna på sig själva? Jag har använt mig av antropologisk litteratur och exempel från intervjuer ur professor Mikael Holmqvists bok Djursholm: Sveriges ledarsamhälle. I samband med detta har jag gjort egna observationer och fotograferat. Djursholm bygger på tradition, förutsägbarhet och en symbolisk gemenskap. Många villor har stora parkliknande trädgårdar omgärdade av häckar, staket och grindar. Min tes är att Djursholm kan betraktas som ett grindsamhälle – en översättning från det kända engelska begreppet "Gated Community" – och bidrar på så vis till segregationen vilket jag kommer att utforska.

Att sträva efter en hållbar samhällsutveckling sett till ekonomiska, ekologiska och sociala aspekter är en målsättning som ges stor tonvikt inom svensk politik och planering. Den påtagliga boendesegregationen som präglar det svenska samhället utgör dock ett problem i arbetet för att nå den sociala hållbarheten, vilket inte minst tydliggörs genom att det varit en fråga på den politiska agendan sedan 1970-talet. För att försöka minska segregationen eftersträvar kommuner ofta att skapa blandade bostadsområden, planera för mötesplatser samt bygga bort barriärer mellan olika stadsdelar för att öka integrationen och minska både geografiska och sociala avstånd mellan människor. Sedan avregleringen på bostadsmarknaden har de privata aktörernas roll i bostadsförsörjningen ökat, vilket resulterat i att nya bostadskoncept etablerats i Sverige. Undersökningsobjektet för denna studie, nämligen gated communities, utgör ett av de allra senaste koncepten. Det finns många varianter av gated communities runt om i världen, men en generell beskrivning är att det rör sig om bostadsområden som hägnas in med hjälp av fysiska barriärer så som murar, stängsel eller grindar. Bostadskonceptet är väletablerat i exempelvis USA och Sydamerika, men på den svenska bostadsmarknaden har det ännu inte slagit igenom. Under andra halvan av 2000-talet har det dock byggts ett antal inhägnade bostadsområden runt om i landet, vilket skapat en medial debatt kring huruvida gated communities kan komma att se en framtida utveckling även i Sverige.  Detta masterarbete syftar till att undersöka och analysera vad gated communities kan komma att innebära för den socialt hållbara bostads- och samhällsutveckling som politik och planering strävar efter att uppnå. Syftet är också att undersöka hur ett antal kommuner i deras strategiska arbete ser på bostadskonceptet och vilka konsekvenser som en ökad utveckling kan medföra. Detta har undersökts genom en flerfallstudie, där två bostadsområden och två kommuner utgör fallen i studien. Empirin i studien, vilken i huvudsak kommer från intervjuer med politiker, planerare och byggherrar samt genom dokumentstudier av olika planhandlingar, har analyserats genom en kvalitativ innehållsanalys. Studien visar att inhägnade bostadsområden i en svensk kontext existerar i två former, nämligen inhägnade bostadsrättsområden och exklusiva gated communities där boende ges privat tillgång till funktioner och service. Studiens huvudsakliga slutsats är att båda formerna skapar ytterligare en dimension till den rådande boendesegregationen genom att fysiska barriärer förs upp och förtydligar gränser i rummet som tidigare endast varit mentala. Exklusiva gated communities som riktas åt socioekonomiskt starka grupper och erbjuder funktioner som parker, lekplatser och andra fritidsaktiviteter riskerar att minska dessa gruppers incitament till att nyttja de offentliga mötesplatserna som kommunerna skapar i förhoppning om att få olika befolkningsgrupper att mötas. En ökad utveckling av gated communities riskerar därmed att skapa ännu tydligare ”vi och dom” – uppdelningar i samhället och utmana de svenska strategierna som använts för att försöka minska boendesegregationen sedan 1970-talet. Trots detta visar studien även att det finns ett visst kommunalt intresse i bostadskonceptet, vilket kan bero på att kommuner kan öka sina skatteintäkter och göra kostnadsbesparingar genom etableringen av gated communities.

Today, we are living in a data-driven world. Due to a surge in data generation, there is a need for efficient and accurate techniques to analyze data. One such kind of data which is needed to be analyzed are text reviews given for movies. Rather than classifying the reviews as positive or negative, we will classify the sentiment of the reviews on the scale of one to ten. In doing so, we will compare two recurrent neural network algorithms Long short term memory(LSTM) and Gated recurrent unit(GRU). The main objective of this study is to compare the accuracies of LSTM and GRU models. For training models, we collected data from two different sources. For filtering data, we used porter stemming and stop words. We coupled LSTM and GRU with the convolutional neural networks to increase the performance. After conducting experiments, we have observed that LSTM performed better in predicting border values. Whereas, GRU predicted every class equally. Overall GRU was able to predict multiclass text data of movie reviews slightly better than LSTM. GRU was computationally expansive when compared to LSTM.

Pentameric ligand-gated ion channels are critical mediators of electrochemical signal transduction in neurons and other excitable cells, causing them to be important targets of psychoactive drugs. Structural data for these complex proteins are limited, particularly among eukaryotic family members and for the functionally critical open state. These data limitations cause knowledge gaps regarding the mechanisms of ion channel opening, gating, and modulation. However, a newly discovered bacterial family member, known as sTeLIC, shares numerous structural features with its eukaryotic relatives in our central nervous system. A recently solved electron microscopy structure depicts sTeLIC in an apparent open state with binding pockets in its extracellular domain, compatible with binding a drug with structural similarities to amphetamines, like the 4-bromoamphetamine. This project aims to provide the first structure-function evidence for direct modulation of a pentameric ligand-gated ion channel by an amphetamine. The two most essential tools used in this project to examine the effects of 4-bromoamphetamine on sTeLIC were Xenopus laevis oocytes and two-electrode voltage-clamp. These tools were necessary for the collection of gating and modulation data. Ion channel activities can be analysed by clamping sTeLIC injected Xenopus laevis oocytes into the two-electrode voltage-clamp since it can artificially control the membrane voltage of oocytes. Modulation data show that 4-bromoamphetamine is a bimodal allosteric potentiator, as well as an allosteric agonist. Residues Y104 and W75, located in the binding pocket, were selected by comparing the published open state model with an AlphaFold-generated non-conducting model. Mutating these into valine or alanine reduces the potentiation. One explanation may be that removing tyrosine's aromatic ring complicates retaining essential interactions in the binding pocket while swapping tryptophan for smaller residues could make it easier for the drug to stabilise the closed state.

<p>The miniaturization of a MOSFET is the constant driving force in semiconductor technology over the decades. This scaling enables the realization of the ever complex and functional integration on a single chip where over tens of billions of transistors densely packed. Silicon (Si) is always the golden performer until recent years when the shrinking of a transistor becomes more and more difficult, due to phenomena such as short channel effect and mobility degradation, which is a challenge especially for atomic level scaling. The dawning of low dimensional materials, such as graphene, transition metal dichalcogenides (TMDs), black phosphorus (BP), with their natural atomically thin two-dimension (2D) layered structure and other novel properties, might serve as an alternative solution for ultimate scaling. However, the understanding of the electronic transport in these Van der Waals materials is still lacking. </p><p> In this research, the exploration of this material was first initiated on the vertical heterojunctions where two materials’ interfaces meet. Many previous literatures claimed this hetero-interface creates a P/N junction that results in a diode-like rectification. Yet, by careful analysis and comparing with our “real” vertical structures where the lateral components were eliminated, it is proved this rectification is a direct result from the contact region. The Schottky barrier on the drain side together with the gate effect is the true culprit.</p><p> Realizing how the Schottky barrier could be dominating in these 2D FETs, the second study is the Schottky barrier effect on the contact resistances and furthermore the mobility of the device. Because of the existence of the Schottky barrier between the channel and contact, the contact resistance is not negligible, unlike the ohmic contact for conventional Si MOSFETs. By comparing the intrinsic and extrinsic mobilities of TMD materials, It is found that the contact resistance’s response to the back gate, namely, the rate of how it changes with the back gate has a huge factor in determining whether the extrinsic field-effect mobility underestimates or overestimates its intrinsic mobility. This opens a new insight on the understanding of the transport mechanism under contacts for different TMDs.</p> With the understanding of the Schottky barrier FETs, lastly, the flexibility of these 2D materials is utilized to create high performance three-dimensionally stacked multi-channel FETs, from the inspiration of the Si gate-all-around nanosheet structure. A first-ever 3D integrated high performance MoS₂ device with two channels on top of each other was designed and fabricated, where the current is doubled with an extra layer of channel. The potential of these novel material to be implemented on the future generations of high-performance devices is demonstrated, shedding light on the prospect for extending the Moore’s Law with proper assistance from new materials.

The brain network is a multiscale hierarchical organization from neurons and local circuits to macroscopic brain areas. The precise synaptic transmission at each synapse is therefore crucial for neural communication and the generation of orchestrated behaviors. Activation of presynaptic voltage-gated calcium channels (CaV2) initiates synaptic vesicle release and plays a key role in neurotransmission. In this dissertation, I have aimed to uncover how CaV2 activity affects synaptic transmission, circuit function and behavioral outcomes using Caenorhabditis elegans as a model. The C. elegans genome encodes an ensemble of highly conserved neurotransmission machinery, providing an opportunity to study the molecular mechanisms of synaptic function in a powerful genetic system. I identified a novel gain of function CaV2α1 mutation that causes CaV2 channels to activate at a lower membrane potential and slow the inactivation. Cell-specific expression of these gain-of-function CaV2 channels is sufficient to hyper-activate neurons of interest, offering a way to study their roles in a given circuit. CaV2(gf) mutants display behavioral hyperactivity and an excitation-dominant synaptic transmission. Imbalanced excitation and inhibition of the nervous system have been associated with several neurological disorders, including Familial Hemiplegic Migraine type 1 (FHM1) which is caused by gain- of-function mutations in the human CaV2.1α1 gene. I showed that animals carrying C. elegans CaV2α1 transgenes with corresponding human FHM1 mutations recapitulate the hyperactive behavioral phenotype exhibited by CaV2(gf) mutants, strongly suggesting the molecular function of CaV2 channels is highly conserved from C. elegans to human. Through performing a genome-wide forward genetic screen looking for CaV2α(gf) suppressors, we isolated new alleles of genes that required for CaV2 trafficking, localization and function. These regulators include subunits of CaV2 channel complex, components of synaptic and dense core vesicle release machinery as well as predicted extracellular proteins. Taken together, this work advances the understanding of CaV2 malfunction at both cellular and circuit levels, and provides a genetically amenable model for neurological disorders associated with excitation-inhibition imbalance. Additionally, through identifying regulators of CaV2, this research provides new avenues for understanding the CaV2 channel mediated neurotransmission and potential pharmacological targets for the treatments of calcium channelopathies.

Philosophiae Doctor - PhD / Neurodegenerative disorders are characterised by progressive loss of the brain’s physiological functions as a result of gradual degeneration of neurons in the central nervous system. Even though they are classified as diseases of the elderly, occurrence earlier in life is possible, but that would suggest the influence of genetic and/or environmental factors. Due to the continuous rise in modernisation and industrialisation over the years, there has been an increase in incidence and prevalence of neurodegenerative disorders. With the advances in technology and life expectancy, the rates of the common forms (Alzheimer’s disease and Parkinson’s disease), are expected to increase exponentially by 2050. Unfortunately, there is still no clinically approved treatment or therapy to slow down or halt the degenerative process as most registered drugs only offer symptomatic relief. Confounding this issue is the lack of definite mechanism of neurodegeneration, which is still poorly defined and not completely understood. Nonetheless, the pathology of most neurodegenerative disorders is believed to be a combination of interrelated processes that eventually leads to neuronal cell death. Among the postulated processes, the impact of excitotoxicity mediated by NMDA receptor over-activation is prominent and it is implicated in virtually all neurodegenerative disorders. With this basic insight, it is believed that molecules capable of inhibiting NMDA receptors and associated calcium channels, without affecting the normal physiological functions of the brain, could potentially serve as good neuroprotective drugs. Competitive and uncompetitive blockers (MK-801 and ketamine) have been explored, but none were clinically accepted due to undesirable side effects such as hallucinations, sedation and depression. However, NGP1-01, a polycyclic cage molecule, has been shown to be neuroprotective through modulation of NMDA receptors and voltage gated calcium channels and attenuation of MPP+ -induced toxicity. A similar approach could be useful in the design and development of new neuroprotective drugs. The aim of this study was to synthesise a series of open and rearranged cage-like molecules and explore their neuroprotective potential in neuroblastoma SH-SY5Y cells. The proposed structures, with norbornane scaffolds that contained different moieties, were designed to structurally resemble NGP1-01 and MK-801. Once synthesised, the compounds were purified and characterised, and were evaluated for their biological activities. Compounds were first screened for cytotoxicity at different concentrations. Thereafter, they were evaluated for neuroprotective effects against MPP+ -induced excitotoxicity and for calcium flux modulatory effects on NMDA receptor and voltage gated calcium channels. The norbornane derivatives were synthesised and characterised, and all final products were afforded in sufficient yields. All compounds with the exception of two compounds displayed good cytotoxic profiles towards the SH-SY5Y neuroblastoma cells at 10 µM, 50 µM and 100 µM concentrations as they demonstrated percentage cell viabilities close to 100% (control treated cells). Only two compounds showed percentage cell viability of 51% and 59% at 100 µM. Utilising the same cell line, all compounds, tested at 10 µM, attenuated MPP+ -induced toxicity after 24 hours of exposure to a neurotoxin. This was evident in the 23% to 53% enhancement (significant with p < 0.05) in cell viability when compared to the MPP+ only treated cells. In comparison to known NMDA receptor and/or voltage gated calcium channel blockers (MK-801, NGP1-01 or nimodipine), the synthesised compounds demonstrated mono or dual inhibition of calcium channels as they effectively attenuated calcium influx by blocking NMDA receptors and/or voltage gated calcium channels expressed in neuroblastoma SHSY5Y cells. This group of compounds were found to be more potent NMDA receptor inhibitors, probably due to similarities with MK-801 and memantine, than voltage gated calcium channel inhibitors. All compounds demonstrated moderate to good calcium inhibitory effects at NMDA receptors in the range of 23% to 70% while a selected few displayed very little or no activity at the voltage gated calcium channels. In conclusion, 27 compounds with norbornane scaffolds were successfully synthesised and evaluated for cytotoxicity and neuroprotection. The abilities of the synthesised compounds to protect neurons from the neurotoxin MPP+ and reduce calcium flux into neuronal cells were successfully demonstrated. These characteristics are essential in neuroprotection as they may prove significant in halting or slowing down the disease progression. The compounds showing a good cytotoxicity profile, neuroprotective effects and ability to reduce calcium overload, could potentially act as neuroprotective agents with good safety profiles or contribute as lead structures to the development and design of structurally related molecules that could clinically benefit people with neurodegenerative disorders.

This dissertation focuses on the development of analytical methods based on Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and their applications for separation and structural characterization of oligosaccharides. Porous graphitized carbon liquid chromatography (PGC-LC), gated-trapped ion mobility spectrometry (Gated-TIMS), and electronic excitation dissociation tandem mass spectrometry (EED MS/MS) are three essential techniques employed here. First, the EED method was optimized to generate more informative glycan tandem mass spectra for accurate structural analysis. Glycans were reduced and permethylated or labeled with a reducing-end fixed charge to increase sensitivity, avoid gas-phase structural rearrangement, and facilitate spectral interpretation. EED of glycans produced nearly complete series of Z-, Y- and 1,5X-ions, that appear in the spectra as triplets with characteristic spacing, thus facilitating accurate determination of the glycan topology. Additional radical-driven dissociation pathways were identified, from which different types of linkage-diagnostic ions (cross-ring, secondary, or internal fragments) were generated. The results demonstrated that linkage analysis can be accomplished by utilizing one or a combination of several linkage-diagnostic fragments. EED MS/MS was then implemented, in conjunction with PGC-LC or Gated-TIMS, for on-line separation and characterization of complex mixtures of glycans. These two methods were successfully applied for high-throughput and detailed structural analysis of N-glycans released from human serum, O-glycans released from bovine submaxillary mucin and free oligosaccharides. The performance of these methods was tested and improved through analysis of different types of glycans from a variety of biological sources. Finally, in collaboration with bioinformaticians, a spectral interpretation algorithm, GlycoDeNovo, has been developed for automated and de novo glycan topology reconstruction from their tandem mass spectra. A large number of EED tandem spectra of glycan standards generated in house were used as the training dataset to establish appropriate IonClassifiers for candidate ranking. GlycoDeNovo is capable of identifying correct topologies from MS/MS spectra of glycans in different derivatized forms. Several aspects of this collaborative project were covered in this thesis, including glycan derivatization, data acquisition and manual spectral interpretation to guide the development and evaluate the performance of the automated approach. In this thesis research, integrated approaches utilizing PGC-LC–EED-MS/MS and Gated-TIMS–EED-MS/MS, and the appropriate bioinformatics software, have been established for structural analysis of glycan mixtures. They hold great potential for comprehensive, automated, and de novo glycome characterization.