Two decades of event-related potential (ERP) research have established that the most consistent correlates of the onset of visual consciousness are the early visual awareness negativity (VAN), a negative component in the N2 time range over posterior electrode sites, and the late positivity (LP), a positive component in the P3 time range over fronto-parietal electrode sites. A review by Koivisto & Revonsuo (2010) had looked at 39 studies and concluded that the VAN is the earliest and most reliable correlate of visual phenomenal consciousness, whereas the LP probably reflects later processes associated with reflective/access consciousness. However, an “early” vs. “late” debate still persists. This thesis provides an update to that earlier review. All ERP and MEG studies that have appeared since 2010 and directly compared ERPs of aware and unaware conditions are considered. The result corroborates the view that VAN is the earliest and most consistent signature of visual phenomenal consciousness, and casts further doubt on the LP as an ERP correlate of consciousness. Important new methodological, empirical, and theoretical developments in the field are described, and the empirical results are related to the theoretical background debates.

Traffic flow predictions are an important part of an Intelligent Transportation System as the ability to forecast accurately the traffic conditions in a transportation system allows for proactive rather than reactive traffic control. Providing accurate real-time traffic predictions is a challenging problem because of the nonlinear and stochastic features of traffic flow. An increasingly widespread deployment of traffic sensors in a growing transportation system produces greater volume of traffic flow data. This results in problems concerning fast, reliable and scalable traffic predictions.The thesis explores the feasibility of increasing the scalability of real-time traffic predictions by partitioning the transportation system into smaller subsections. This is done by using data collected by Trafikverket from traffic sensors in Stockholm and Gothenburg to construct a traffic sensor graph of the transportation system. In addition, three graph partitioning algorithms are designed to divide the traffic sensor graph according to vehicle travel time. Finally, the produced transportation system partitions are used to train multi-layered long shortterm memory recurrent neural networks for traffic density predictions. Four different types of models are produced and evaluated based on root mean squared error, training time and prediction time, i.e. transportation system model, partitioned transportation models, single sensor models, and overlapping partition models.Results of the thesis show that partitioning a transportation system is a viable solution to produce traffic prediction models as the average prediction accuracy for each traffic sensor across the different types of prediction models are comparable. This solution tackles scalability issues that are caused by increased deployment of traffic sensors to the transportation system. This is done by reducing the number of traffic sensors each prediction model is responsible for which results in less complex models with less amount of input data. A more decentralized and effective solution can be achieved since the models can be distributed to the edge of the transportation system, i.e. near the physical location of the traffic sensors, reducing prediction and response time of the models. / Prognoser för trafikflödet är en viktig del av ett intelligent transportsystem, eftersom möjligheten att prognostisera exakt trafiken i ett transportsystem möjliggör proaktiv snarare än reaktiv trafikstyrning. Att tillhandahålla noggrann trafikprognosen i realtid är ett utmanande problem på grund av de olinjära och stokastiska egenskaperna hos trafikflödet. En alltmer utbredd använding av trafiksensorer i ett växande transportsystem ger större volym av trafikflödesdata. Detta leder till problem med snabba, pålitliga och skalbara trafikprognoser.Avhandlingen undersöker möjligheten att öka skalbarheten hos realtidsprognoser genom att dela transportsystemet i mindre underavsnitt. Detta görs genom att använda data som samlats in av Trafikverket från trafiksensorer i Stockholm och Göteborg för att konstruera en trafiksensor graf för transportsystemet. Dessutom är tre grafpartitioneringsalgoritmer utformade för att dela upp trafiksensor grafen enligt fordonets körtid. Slutligen används de producerade transportsystempartitionerna för att träna multi-layered long short memory neurala nät för förspänning av trafiktäthet. Fyra olika typer av modeller producerades och utvärderades baserat på rotvärdes kvadratfel, träningstid och prediktionstid, d.v.s. transportsystemmodell, partitionerade transportmodeller, enkla sensormodeller och överlappande partitionsmodeller.Resultat av avhandlingen visar att partitionering av ett transportsystem är en genomförbar lösning för att producera trafikprognosmodeller, eftersom den genomsnittliga prognoser noggrannheten för varje trafiksensor över de olika typerna av prediktionsmodeller är jämförbar. Denna lösning tar itu med skalbarhetsproblem som orsakas av ökad användning av trafiksensorer till transportsystemet. Detta görs genom att minska antal trafiksensorer varje trafikprognosmodell är ansvarig för. Det resulterar i mindre komplexa modeller med mindre mängd inmatningsdata. En mer decentraliserad och effektiv lösning kan uppnås eftersom modellerna kan distribueras till transportsystemets kant, d.v.s. nära trafiksensorns fysiska läge, vilket minskar prognosoch responstid för modellerna.

Liminal sites are those on the verge of change, between boundaries and in a temporary state of ambiguity. Throughout my practice as an architect I was aware of the existence of such spaces. I was also aware that they were rarely the product of my intentional design effort. Because of that to me these spaces were precious. They represent moments in space of ambiguous function and questionable beauty but also moments I sought out everyday. This masters research is my way of refocusing my practice to engage with these types of spaces. The sense that this search will take me outside of my understanding of architecture lead me to chose to undertake it as a masters in landscape architecture. My main research question is: How can a designer construct a liminal site? The research concentrates on four central themes - development of a definition of the term

The distribution of the expressed genotype is moved around in the population over time byevolution. Natural selection is one of the forces that act on the phenotype to change the patterns ofnucleotide variation underlying those distributions. How the phenotype changes over aheterogeneous environment describes the type of evolutionary force acting on this trait and thisshould be reflected in the variation at loci underlying this trait. While the variation in phenotypesand at the nucleotide level in a population indicates the same evolutionary force, it does notnecessarily mean that they are connected. In natural populations the continuous shifting of geneticmaterial through recombination events break down possible associations between loci facilitates theexamination of possible causal loci to single base pair differences in DNA-sequences. Connecting thegenotype and the phenotype thus provides an important step in the understanding the geneticarchitecture of complex traits and the forces that shape the observed patterns.This thesis examines the European aspen, Populus tremula, sampled from subpopulations overan extensive latitudinal gradient covering most of Sweden. Results show a clear geneticdifferentiation in the timing of bud set, a measure of the autumnal cessation of growth, betweendifferent parts of Sweden pointing at local adaptation. In the search for candidate genes thatunderlie the local adaptation found, most genes (25) in the photoperiodic gene network wereexamined for signals of selection. Genes in the photoperiodic network show an increase in theheterogeneity of differentiation between sampled subpopulations in Sweden. Almost half (12) of theexamined genes are under some form of selection. Eight of these genes show positive directionalselection on protein evolution and the gene that code for a photoreceptor, responsible for mediatingchanging light conditions to downstream targets in the network, has the hallmarks of a selectivesweep. The negative correlation between positive directional selection and synonymous diversityindicates that the majority of the photoperiod gene network has undergone recurrent selectivesweeps. A phenomenon that likely has occurred when P. tremula has readapted to the northern lightregimes during population expansion following retracting ice between periods of glaciations. Two ofthe genes under selection also have single nucleotide polymorphisms (SNP) that associate with budset, two in the PHYB2 gene and one in the LHY2 gene. Furthermore, there is an additional SNP inLHY1 that explain part of the variation in timing of bud set, despite the lack of a signal of selection atthe LHY1 gene. Together these SNPs explain 10-15% of the variation in the timing of bud set and 20-30% more if accounting for the positive co-variances between SNPs. There is thus rather extensiveevidence that genes in the photoperiod gene network control the timing of bud set, and reflect localadaptation in this trait.

Κύριος στόχος της εργασίας ήταν η συγκριτική μελέτη της παλίνδρομης αναστολής μεταξύ του ραχιαίου και του κοιλιακού πόλου του ιππόκαμπου αρουραίου. Χρησιμοποιήθηκε η μεθοδολογία της in vitro διατήρησης τομών ιππόκαμπου και εξωκυττάριων καταγραφών προκλητών δυναμικών πεδίου. Τα αποτελέσματά μας έδειξαν ότι η GABAA εξαρτώμενη παλίνδρομη αναστολή είναι ασθενέστερη, έχει μικρότερη διάρκεια και φθίνει πιο γρήγορα στον κοιλιακό σε σχέση με το ραχιαίο ιππόκαμπο. Χρησιμοποιώντας διάφορα φάρμακα που δρουν ενισχυτικά στον GABAA υποδοχέα δείξαμε ότι υπάρχει λειτουργική διαφοροποίηση του GABAA εξαρτώμενου ανασταλτικού μηχανισμού μεταξύ των δύο πόλων του ιππόκαμπου, ενισχύοντας την υπόθεση της λειτουργικής διαφοροποίησης στο επίπεδο του υποδοχέα μεταξύ των δύο πόλων. Στην in vivo μελέτη, χρησιμοποιώντας το μοντέλο επαγωγής επιληπτικών κρίσεων με χορήγηση πεντυλενοτετραζόλης, δείξαμε ότι η ενίσχυση της GABAA εξαρτώμενης αναστολής απο τα κατασταλτικά φάρμακα συσχετίζεται με το μέγεθος της αντιεπιληπτικής τους δράσης. Επιπλέον, η βιταμίνη D δεν παρουσίασε αντιεπιληπτική δράση στους C57BL/6J μύες, ούτε ενίσχυσε την αναστολή, κάτι που δείχνει ότι δεν έχει επίδραση στον GABAA υποδοχέα ή, τουλάχιστον, στους υπότυπούς του στον ιππόκαμπο. / The major aim of this work was the comparative study of recurrent inhibition between the dorsal and ventral pole of the rat hippocampus. We used the methodology of in vitro maintenance of hippocampal slices and recording of evoked field potentials. We showed that the GABAA mediated recurrent inhibition is weaker, lasts less and decays faster in ventral than in dorsal hippocampus. Using various drugs that act as positive allosteric modulators of the GABAA receptor, we showed that there is a functional differentiation of the GABAA inhibitory mechanism between the two hippocampal poles, strengthening the hypothesis of the functional differentiation at the level of the receptor between the two poles. In the in vivo study, using the pentylenetetrazole model for inducing epileptic seizures, we showed that the enhancement of the GABAA mediated recurrent inhibition correlates with the strength of antiepileptic action of the sedative drugs used. In addition vitamin D did not show antiepileptic action in C57BL/6J mice. Moreover it didn’t enhance recurrent inhibition, showing that it doesn’t have any action on the GABAA receptor or, at least, on its subtypes in hippocampus.

Συναπτική διέγερση και αναστολή βρίσκονται σε συνεχή δυναμική ισορροπία, απαραίτητη για την καλή λειτουργία του ΚΝΣ. Ένα από τα βασικά ανασταλτικά κυκλώματα του εγκεφάλου είναι αυτό της παλίνδρομης αναστολής. Το πιο χαρακτηριστικό, ίσως, παράδειγμα του κυκλώματος αυτού βρίσκεται στη CA1 περιοχή του ιππόκαμπου, η οποία προσφέρεται για ηλεκτροφυσιολογικές μελέτες in vitro, λόγω της στρωματοειδούς οργάνωσης των κυκλωμάτων ιππόκαμπου. Πρόσφατες έρευνες έχουν δείξει διαφορές στη δομή και λειτουργία των δύο πόλων του ιππόκαμπου, καθιστώντας αναγκαία τη συγκριτική τους μελέτη. Στην εργασία αυτή χρησιμοποιήθηκαν εξωκυττάριες καταγραφές από την πυραμιδική στοιβάδα σε συνδυασμό με το πρωτόκολλο διπλού ορθόδρομου ερεθισμού (περιορισμένα) και το πρωτόκολλο αντίδρομου-ορθόδρομου ερεθισμού (εκτενέστερα) για τη μελέτη του πλάτους και της διάρκειας της παλίνδρομης αναστολής σε τομές ραχιαίου και κοιλιακού ιππόκαμπου από αρσενικούς επίμυες, καθώς και της επίδρασης επί αυτής μιας σειράς καταπραϋντικών φαρμάκων που δρουν ως αλλοστερικοί ενισχυτές του GABAA υποδοχέα. Τα αποτελέσματα των πειραμάτων έδειξαν: Επαλήθευση της στρωματοειδούς οργάνωσης των κυκλωμάτων του ιππόκαμπου, με μεγαλύτερη κατευθυντικότητα των ανασταλτικών κυκλωμάτων στο ραχιαίο σε σχέση με τον κοιλιακό πόλο. Μεγαλύτερο πλάτος και διάρκεια και πιο αργή μείωση της παλίνδρομης αναστολής γενικά, και της GABAA συνιστώσας της ειδικότερα, στο ραχιαίο σε σχέση με τον κοιλιακό ιππόκαμπο. Ενίσχυση της παλίνδρομης αναστολής και στους δύο πόλους του ιππόκαμπου από διαζεπάμη, μιδαζολάμη, ζολπιδέμη, φαινοβαρβιτάλη, θειοπεντάλη, πεντοβαρβιτάλη, αλφαξαλόνη και προποφόλη. Συσχέτιση της αύξησης του πλάτους της αναστολής και της διάρκειας της ενίσχυσής της με την κλινική δράση της κάθε συγκέντρωσης φαρμάκου. Ενίσχυση της αποκλειστικά GABAA εξαρτώμενης αναστολής από υψηλές συγκεντρώσεις θειοπεντάλης και αλφαξαλόνης που δοκιμάστηκαν ενδεικτικά πολύ πέρα από τα φυσιολογικά χρονικά όριά της. Μεγαλύτερη διάρκεια ενίσχυσης της συναπτικής αναστολής από τις σχετικά υψηλότερες δόσεις φαρμάκων στο ραχιαίο σε σχέση με τον κοιλιακό πόλο. Έλλειψη δράσης του νευροστεροειδούς αλλοπρεγνανολόνη και των συνθετικών παραγώγων του στη συναπτική αναστολή. Περιορισμένος αριθμός in vivo πειραμάτων εκτίμησης της επίδρασης της αλλο-πρεγνανολόνης και των παραγώγων της στην αναστολή με το μοντέλο ελέγχου επιληπτικών κρίσεων που προκαλούνται από PTZ έδειξε πως, ενώ τα συνθετικά παράγωγα δεν είχαν καμία δράση, η αλλοπρεγνανολόνη είχε σημαντική θετική δράση / Synaptic excitation and inhibition are maintained in dynamic equilibrium, necessary for the proper function of the CNS. One of the basic inhibitory circuits of the brain is that of recurrent inhibition. The most distinctive example of recurrent inhibition occurs in the CA1 region of the hippocampus, a region particularly suited to in vitro electrophysiological investigations because of the unique lamellar organization of hippocampal circuits. Recent research has uncovered considerable differences in the structure and function of the two poles of the hippocampus necessitating a comparative study. In this study we used extracellular recordings from the pyramidal cell layer of dorsal and ventral rat hippocampal slices, in conjunction with limited use of the double orthodromic and more extensive use of the paired antidromic-orthodromic stimulation protocol in order to study the CA1 recurrent inhibition and the effects of a series of sedative drugs, with GABAA allosteric modulator properties, on it. The results of these experiments showed: A verification of the lamellar organization of hippocampal circuits. Dorsal pole inhibitory circuits showed a greater orientation specificity than ventral pole ones. A greater size and duration and a slower decay of recurrent inhibition in general, and of its GABAA-mediated component in particular, in dorsal compared to ventral hippocampus. An enhancement of recurrent inhibition in both hippocampal poles produced by diazepam, midazolam, zolpidem, phenobarbital, thiopental, pentobarbital, alfaxalone and propofol. A correlation between the enhancement of the size of recurrent inhibition or the duration of its enhancement and the clinical actions of every drug concentration tested. An enhancement of the exclusively GABAA-mediated recurrent inhibition by representative high concentrations of thiopental and alfaxalone well beyond its normal duration. A greater duration of recurrent inhibition enhancement by the relatively higher drug concentrations in dorsal compared to ventral hippocampus. A lack of action on synaptic inhibition by the neurosteroid allopregnanolone and its synthetic derivatives. A limited number of in vivo experiments assessing the effect of allopregnanolone and its derivatives on synaptic inhibition, measured as their ability to control epileptic seizures induced by acute injections of PTZ, showed that the synthetic derivatives had no effect whereas allopregnanolone had a significant positive effect.

Diabetes disproportionately affects minority populations. Social support, and more specifically marriage, has been found to buffer the negative effects of diabetes and depression. Data collected from African Americans with type 2 diabetes in Atlanta and NHANES data were compared to examine whether marriage affects health status and mental health. Approximately, 1742 African Americans aged 18-80 were included in this study. Chi square analysis revealed that married men had lower rates of depression (15.9% vs. 24.7%) compared to unmarried men (p < 0.05), but the same effect was not found in women. The findings show that marriage was not associated with HbA1c, but was associated with rates of depression. The lack of association of HbA1c with marriage may be because marriage may not be the best proxy of social support in the African American community. Future research should focus on alternative forms of social support such as cohabitation, extend family, and friend.

La plupart des molécules d’ARN doivent se replier en structure tertiaire complexe afin d’accomplir leurs fonctions biologiques. Cependant, les déterminants d’une chaîne de polynucléotides qui sont nécessaires à son repliement et à ses interactions avec d’autres éléments sont essentiellement inconnus. L’établissement des relations structure-fonction dans les grandes molécules d’ARN passe inévitablement par l’analyse de chaque élément de leur structure de façon individuelle et en contexte avec d’autres éléments. À l’image d’une construction d’immeuble, une structure d’ARN est composée d’unités répétitives assemblées de façon spécifique. Les motifs récurrents d’ARN sont des arrangements de nucléotides retrouvés à différents endroits d’une structure tertiaire et possèdent des conformations identiques ou très similaires. Ainsi, une des étapes nécessaires à la compréhension de la structure et de la fonction des molécules d’ARN consiste à identifier de façon systématique les motifs récurrents et d’en effectuer une analyse comparative afin d’établir la séquence consensus. L’analyse de tous les cas d’empaquetage de doubles hélices dans la structure du ribosome a permis l’identification d’un nouvel arrangement nommé motif d’empaquetage le long du sillon (AGPM) (along-groove packing motif). Ce motif est retrouvé à 14 endroits dans la structure du ribosome de même qu’entre l’ARN ribosomique 23S et les molécules d’ARN de transfert liées aux sites ribosomaux P et E. Le motif se forme par l’empaquetage de deux doubles hélices via leur sillon mineur. Le squelette sucre-phosphate d’une hélice voyage le long du sillon mineur de l’autre hélice et vice versa. Dans chacune des hélices, la région de contact comprend quatre paires de bases. L’empaquetage le plus serré est retrouvé au centre de l’arrangement où l’on retrouve souvent une paire de bases GU dans une hélice interagissant avec une paire de bases Watson-Crick (WC) dans l’autre hélice. Même si la présence des paires de bases centrales GU versus WC au centre du motif augmente sa stabilité, d’autres alternatives existent pour différents représentants du motif. L’analyse comparative de trois librairies combinatoires de gènes d’AGPM, où les paires de bases centrales ont été variées de manière complètement aléatoire, a montré que le contexte structural influence l’étendue de la variabilité des séquences de nucléotides formant les paires de bases centrales. Le fait que l’identité des paires de bases centrales puisse varier suggérait la présence d’autres déterminants responsables au maintien de l’intégrité du motif. L’analyse de tous les contacts entre les hélices a révélé qu’en dehors du centre du motif, les interactions entre les squelettes sucre-phosphate s’effectuent via trois contacts ribose-ribose. Pour chacun de ces contacts, les riboses des nucléotides qui interagissent ensemble doivent adopter des positions particulières afin d’éviter qu’ils entrent en collision. Nous montrons que la position de ces riboses est modulée par des conformations spécifiques des paires de bases auxquelles ils appartiennent. Finalement, un autre motif récurrent identifié à l’intérieur même de la structure de trois cas d’AGPM a été nommé « adenosine-wedge ». Son analyse a révélé que ce dernier est lui-même composé d’un autre arrangement, nommé motif triangle-NAG (NAG-triangle). Nous montrons que le motif « adenosine-wedge » représente un arrangement complexe d’ARN composé de quatre éléments répétitifs, c’est-à-dire des motifs AGPM, « hook-turn », « A-minor » et triangle-NAG. Ceci illustre clairement l’arrangement hiérarchique des structures d’ARN qui peut aussi être observé pour d’autres motifs d’ARN. D’un point de vue plus global, mes résultats enrichissent notre compréhension générale du rôle des différents types d’interactions tertiaires dans la formation des molécules d’ARN complexes. / Most RNA molecules have to adopt a complex tertiary structure to accomplish their biological functions. However, the important determinants of a polynucleotide chain that are required for its proper folding and its interactions with other elements are essentially unknown. The establishment of structure-function relationships in large RNA molecules goes inevitably through the analysis of each element of their structure separately and in context with other elements. Like a building, an RNA structure is built of repetitive pieces that are glued together in a specific way. These repetitive elements, instead of being bricks, are recurrent motifs. Recurrent RNA motifs are arrangements of nucleotides found in different parts of a tertiary structure and have identical or very similar conformations. Thus, a necessary step toward the understanding of RNA structure and function consists in the systematic identification of recurrent motifs, followed by their comparative analysis and establishment of their sequence consensus. The analysis of all instances of helical packing within the ribosome structure led to the identification of a new structural arrangement, named the along-groove packing motif (AGPM), which is found in 14 places of the ribosome structure as well as between the 23S ribosomal RNA and the transfer RNA molecules bound to the P and E sites. The motif is formed by the packing of two double helices via their minor grooves. The sugar-phosphate backbone of one helix goes along the minor groove of the other helix and vice versa. In each helix, the contact region includes four base pairs. The closest packing occurs in the center where one can often see a GU base pair packed against a WC base pair. While the presence of the central base pairs GU versus WC in the core of the motif enhances its stability, other alternatives are also present among available structures of the motif. A comparative analysis of three different combinatorial gene libraries of AGPM, in which the central base pairs were fully randomized, shows that the structural context influences the scope of nucleotide sequence variability of the central base pairs. The fact that the identity of the central base pairs can vary suggested that there are other determinants responsible of the motif’s integrity. Analysis of all other inter-helix contacts has shown that outside the center of the motif the interactions between backbones are made via three ribose-ribose contacts. Within each of these contacts, the riboses of the nucleotides that are in touch adopt particular positions in order to provide for collision-free interactions between them. We show that the position of these riboses is modulated by the specific base pair conformation in which it belongs. Finally, another recurrent arrangement that occurs within the structure of three cases of AGPM was identified and called the adenosine-wedge. Analysis has shown that the latter motif is itself composed of a smaller arrangement, called the NAG-triangle motif. We show that the adenosine-wedge motif represents a complex RNA arrangement composed of four repetitive elements, AGPM, the hook-turn, the A-minor and the NAG-triangle, which clearly illustrates the hierarchical organisation of the structure that could also occur in other RNA motifs as well. Altogether, my results enrich our general understanding of the role of different types of tertiary interactions in the formation of large RNA molecules.

No description available.

Hypothyroidism is a common endocrine disorder affecting women of reproductive age. On a global level, iodine deficiency is still the most common cause of hypothyroidism. Also genetic variations, in particular SNP rs4704397 in the PDE8B gene, are responsible for a significant proportion of TSH variations.  Untreated hypothyroidism has significant adverse effects on pregnancy and fetal outcome. Most international guidelines suggest targeted thyroid testing in pregnant women with risk factors for thyroid disturbances. In a case-control study, an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage was found. The explanation for this association is unknown. In a nationwide survey, all guidelines for thyroid testing and management of hypothyroidism during pregnancy in Sweden were collected and compared with international guidelines. The local guidelines were variable and poorly compliant with the international guidelines. In a follow-up in one district, 5,254 pregnant women were included for subsequent review of their medical reports. We found a targeted thyroid testing rate of 20.1% in clinical practice, with an overall frequency of women with trimester-specific elevated TSH of 18.5%. More disturbingly, half of the women who were on levothyroxine treatment at the time of conception had an elevated TSH level at thyroid testing. In a subsequent cohort study of the 5,254 women, we found the prevalence of trimester-specific elevated TSH and overt hypothyroidism to be equal in targeted thyroid tested and untested women. In a cross-sectional study, a median urinary iodine concentration (UIC) of 98 μg/l was found in the study population. According to WHO/UNICEF/IGN criteria, the population-based median UIC during pregnancy should be 150-249 μg/l. In conclusion, genetic variations may contribute to adverse pregnancy outcomes. In clinical practice, thyroid testing and the management of hypothyroidism during pregnancy is unsatisfactory, regarding the whole chain from development of local guidelines to their implementation and to targeted thyroid testing. Moreover, our results indicate insufficient iodine status in the pregnant population of Sweden.