Locality and order-invariant logics

Malli on logiikassa käytetty abstraktio monille matemaattisille objekteille. Esimerkiksi verkot, ryhmät ja metriset avaruudet ovat malleja. Äärellisten mallien teoria on logiikan osa-alue, jossa tarkastellaan logiikkojen, formaalien kielten, ilmaisuvoimaa malleissa, joiden alkioiden lukumäärä on äärellinen. Rajoittuminen äärellisiin malleihin mahdollistaa tulosten soveltamisen teoreettisessa tietojenkäsittelytieteessä, jonka näkökulmasta logiikan kaavoja voidaan ajatella ohjelmina ja äärellisiä malleja niiden syötteinä. Lokaalisuus tarkoittaa logiikan kyvyttömyyttä erottaa toisistaan malleja, joiden paikalliset piirteet vastaavat toisiaan. Väitöskirjassa tarkastellaan useita lokaalisuuden muotoja ja niiden säilymistä logiikkoja yhdistellessä. Kehitettyjä työkaluja apuna käyttäen osoitetaan, että Gaifman- ja Hanf-lokaalisuudeksi kutsuttujen varianttien välissä on lokaalisuuskäsitteiden hierarkia, jonka eri tasot voidaan erottaa toisistaan kasvavaa dimensiota olevissa hiloissa. Toisaalta osoitetaan, että lokaalisuuskäsitteet eivät eroa toisistaan, kun rajoitutaan tarkastelemaan äärellisiä puita. Järjestysinvariantit logiikat ovat kieliä, joissa on käytössä sisäänrakennettu järjestysrelaatio, mutta sitä on käytettävä siten, etteivät kaavojen ilmaisemat asiat riipu valitusta järjestyksestä. Määritelmää voi motivoida tietojenkäsittelyn näkökulmasta: vaikka ohjelman syötteen tietojen järjestyksellä ei olisi odotetun tuloksen kannalta merkitystä, on syöte tietokoneen muistissa aina jossakin järjestyksessä, jota ohjelma voi laskennassaan hyödyntää. Väitöskirjassa tutkitaan minkälaisia lokaalisuuden muotoja järjestysinvariantit ensimmäisen kertaluvun predikaattilogiikan laajennukset yksipaikkaisilla kvanttoreilla voivat toteuttaa. Tuloksia sovelletaan tarkastelemalla, milloin sisäänrakennettu järjestys lisää logiikan ilmaisuvoimaa äärellisissä puissa.

Visual completion in an illusory figure

The visual systems of humans and animals represent physical reality in a modified way, depending on the specific demands that the species in question has for survival. The ability to perceive visual illusions is found in independently evolved visual systems, from honeybees to humans. In humans, the ability emerges early, at the age of four months. Thus the perception of illusion is likely to reflect visual processes of fundamental importance for object perception in natural vision. The experiments reported in this thesis employed various modifications of the Kanizsa triangle, a drawn configuration composed of three black disks with missing sectors on a white background. The sectors appear to form the tips of a triangle. The visual system completes the physically empty area between the disks, generally called inducers, with giving the perception of an illusory triangle. The illusory triangle consists of an illusory surface bounded by illusory contours; the triangle appears brighter than and to lie above the background. If the sectors are coloured, the colour fills the illusory area, a phenomenon known as neon colour spreading . We investigated spatial limitations on the perception of Kanizsa-type illusions and how other stimuli and viewing parameters affected these limitations. We also studied complex configurations thick, bent, mobile and chromatic inducers - to determine whether illusions combining several attributes can be perceived. The results suggest that the visual system is highly effective in completing a percept. The perception of an illusory figure is spatially scale invariant when perceived at threshold. The processing time and the number of fixations modify the percept, making the perception of the illusion more probable in various viewing conditions. Furthermore, the fact that the illusion can be perceived when only one inducer is physically present at any given moment indicates the potential of single inducers. Apparently, modelling illusory figure perception will require a combination of low-level, local processes and higher-level integrative processes. Our studies with stimuli combining several attributes relevant to object perception demonstrate that the perception of an illusory figure is flexible and is maintained also when it contains colour and volume and when shown in movement. All in all, the results confirm the assumed importance of the visual processes related with the perception of illusory figures in everyday viewing. This is indicated by the variety of inducer modifications that can be made without destroying the percept. Furthermore, the illusion can acquire additional attributes from such modifications. Due to individual differences in the perception of illusory figures, universal values for absolute performance are not always meaningful, but stable trends and general relations do exist.

Cortical processing of speech and non-speech sounds in autism and Asperger syndrome

Autism and Asperger syndrome (AS) are neurodevelopmental disorders characterised by deficient social and communication skills, as well as restricted, repetitive patterns of behaviour. The language development in individuals with autism is significantly delayed and deficient, whereas in individuals with AS, the structural aspects of language develop quite normally. Both groups, however, have semantic-pragmatic language deficits. The present thesis investigated auditory processing in individuals with autism and AS. In particular, the discrimination of and orienting to speech and non-speech sounds was studied, as well as the abstraction of invariant sound features from speech-sound input. Altogether five studies were conducted with auditory event-related brain potentials (ERP); two studies also included a behavioural sound-identification task. In three studies, the subjects were children with autism, in one study children with AS, and in one study adults with AS. In children with autism, even the early stages of sound encoding were deficient. In addition, these children had altered sound-discrimination processes characterised by enhanced spectral but deficient temporal discrimination. The enhanced pitch discrimination may partly explain the auditory hypersensitivity common in autism, and it may compromise the filtering of relevant auditory information from irrelevant information. Indeed, it was found that when sound discrimination required abstracting invariant features from varying input, children with autism maintained their superiority in pitch processing, but lost it in vowel processing. Finally, involuntary orienting to sound changes was deficient in children with autism in particular with respect to speech sounds. This finding is in agreement with previous studies on autism suggesting deficits in orienting to socially relevant stimuli. In contrast to children with autism, the early stages of sound encoding were fairly unimpaired in children with AS. However, sound discrimination and orienting were rather similarly altered in these children as in those with autism, suggesting correspondences in the auditory phenotype in these two disorders which belong to the same continuum. Unlike children with AS, adults with AS showed enhanced processing of duration changes, suggesting developmental changes in auditory processing in this disorder.

Visual search and eye movements: Studies of perceptual span

In visual search one tries to find the currently relevant item among other, irrelevant items. In the present study, visual search performance for complex objects (characters, faces, computer icons and words) was investigated, and the contribution of different stimulus properties, such as luminance contrast between characters and background, set size, stimulus size, colour contrast, spatial frequency, and stimulus layout were investigated. Subjects were required to search for a target object among distracter objects in two-dimensional stimulus arrays. The outcome measure was threshold search time, that is, the presentation duration of the stimulus array required by the subject to find the target with a certain probability. It reflects the time used for visual processing separated from the time used for decision making and manual reactions. The duration of stimulus presentation was controlled by an adaptive staircase method. The number and duration of eye fixations, saccade amplitude, and perceptual span, i.e., the number of items that can be processed during a single fixation, were measured. It was found that search performance was correlated with the number of fixations needed to find the target. Search time and the number of fixations increased with increasing stimulus set size. On the other hand, several complex objects could be processed during a single fixation, i.e., within the perceptual span. Search time and the number of fixations depended on object type as well as luminance contrast. The size of the perceptual span was smaller for more complex objects, and decreased with decreasing luminance contrast within object type, especially for very low contrasts. In addition, the size and shape of perceptual span explained the changes in search performance for different stimulus layouts in word search. Perceptual span was scale invariant for a 16-fold range of stimulus sizes, i.e., the number of items processed during a single fixation was independent of retinal stimulus size or viewing distance. It is suggested that saccadic visual search consists of both serial (eye movements) and parallel (processing within perceptual span) components, and that the size of the perceptual span may explain the effectiveness of saccadic search in different stimulus conditions. Further, low-level visual factors, such as the anatomical structure of the retina, peripheral stimulus visibility and resolution requirements for the identification of different object types are proposed to constrain the size of the perceptual span, and thus, limit visual search performance. Similar methods were used in a clinical study to characterise the visual search performance and eye movements of neurological patients with chronic solvent-induced encephalopathy (CSE). In addition, the data about the effects of different stimulus properties on visual search in normal subjects were presented as simple practical guidelines, so that the limits of human visual perception could be taken into account in the design of user interfaces.

Perception of surface brightness

The human visual system has adapted to function in different lighting environments and responds to contrast instead of the amount of light as such. On the one hand, this ensures constancy of perception, for example, white paper looks white both in bright sunlight and in dim moonlight, because contrast is invariant to changes in overall light level. On the other hand, the brightness of the surfaces has to be reconstructed from the contrast signal because no signal from surfaces as such is conveyed to the visual cortex. In the visual cortex, the visual image is decomposed to local features by spatial filters that are selective for spatial frequency, orientation, and phase. Currently it is not known, however, how these features are subsequently integrated to form objects and object surfaces. In this thesis the integration mechanisms of achromatic surfaces were studied by psychophysically measuring the spatial frequency and orientation tuning of brightness perception. In addition, the effect of textures on the spread of brightness and the effect of phase of the inducing stimulus on brightness were measured. The novel findings of the thesis are that (1) a narrow spatial frequency band, independent of stimulus size and complexity, mediates brightness information (2) figure-ground brightness illusions are narrowly tuned for orientation (3) texture borders, without any luminance difference, are able to block the spread of brightness, and (4) edges and even- and odd-symmetric Gabors have a similar antagonistic effect on brightness. The narrow spatial frequency tuning suggests that only a subpopulation of neurons in V1 is involved in brightness perception. The independence of stimulus size and complexity indicates that the narrow tuning reflects hard-wired processing in the visual system. Further, it seems that figure-ground segregation and mechanisms integrating contrast polarities are closely related to the low level mechanisms of brightness perception. In conclusion, the results of the thesis suggest that a subpopulation of neurons in visual cortex selectively integrates information from different contrast polarities to reconstruct surface brightness.

Inflammation and Complement Activation in Intracranial Artery Aneurysms

Intracranial artery aneurysms (IAs) are estimated to be present in 2.3% of the population. A rupture of an IA causes subarachnoid hemorrhage, with up to 50% mortality. The annual low rupture risk of an IA indicates that most IAs never rupture. The current treatment options are invasive and somewhat risky. Thus rupture-prone IAs should be identified and this requires a better understanding of the IA wall pathobiology. Inflammatory cell infiltrations have been found to precede IA rupture, indicating the role of inflammation in IA wall degeneration and rupture. The complement system is a key mediator of inflammation and house-hold processing of injured tissue. This study aimed at identifying the role of complement activation in IA wall degeneration and the complement activators involved and determining how the complement system is regulated in the IA wall. In immunostainings, the end-product of complement activation, the terminal complement complex (TCC), was located mainly in the outer part of the IA wall, in areas that had also sustained loss of cells. In electron microscopy, the area of maximum TCC accumulation contained cellular debris and evidence of both apoptotic and necrotic cell death. Complement activation correlated with IA wall degeneration and rupture, de-endothelialization, and T-cell and CD163-positive macrophage infiltration. The complement system was found to become activated in all IAs by the classical pathway, with recruitment of alternative pathway amplification. Of the potential activators immunoglobulins G and M and oxidatively modified lipids were found in large areas. Lipid accumulation was observed to clearly colocalize with TCC and C-reactive protein. In the luminal parts of the IA wall, complement activation was limited by cellular expression of protectin (CD59) and extracellular matrix-bound inhibitors, C4b binding protein and factor H whereas the outer part of the wall lacked cells expressing protectin as well as matrix-bound factor H. In single nucleotide polymorphism-analysis, age-related macular degeneration-associated factor H Y402H polymorphism did not associate with the presence of IAs or their rupture The data suggest that complement activation and TCC formation are involved in IA wall degeneration and rupture. Complement seems to become activated by more than one specific activator. The association of complement with de-endothelialization and expression of several complement activators indicate a possible role of endothelial dysfunction and/or impaired clearance mechanisms. Impaired complement regulation seems to be associated with increased complement activation in IA walls. These results stress the role of chronic inflammation in IA wall pathobiology and the regulatory role of complement within this process. Imaging inflammation would possibly enhance the diagnostics of rupture-prone IAs, and targeting IA treatment to prevent chronic inflammation might improve IA treatment in the future.

Array Comparative Genomic Hybridization in Sarcomas

Over the past years, much research on sarcomas based on low-resolution cytogenetic and molecular cytogenetic methods has been published, leading to the identification of genetic abnormalities partially underlying the tumourigenesis. Continued progress in the identification of genetic events such as copy number aberrations relies upon adapting the rapidly evolving high-resolution microarray technology, which will eventually provide novel insights into sarcoma biology, and targets for both diagnostics and drug development. The aim of this Thesis was to characterize DNA copy number changes that are involved in the pathogenesis of soft tissue leiomyosarcoma (LMS), dermatofibrosarcoma protuberans (DFSP), osteosarcoma (OS), malignant fibrous histiocytoma (MFH), and uterine leiomyosarcoma (ULMS) by applying fine resolution array comparative genomic hybridization (aCGH) technology. Both low- and high-grade LMS tumours showed distinct copy number patterns, in addition to sharing two minimal common regions of gains and losses. Small aberrations were detected by aCGH, which were beyond the resolution of chromosomal comparative genomic hybridization (cCGH). DFSP tumours analysed by aCGH showed gains in 17q, 22q, and 21 additional gained regions, but only one region (22q) with copy number loss. Recurrent amplicons identified in OS by aCGH were 12q11-q15, 8q, 6p12-p21, and 17p. Amplicons 12q and 17p were further characterized in detail. The amplicon at 17p was characterized by aCGH in low- and high-grade LMS, OS, and MFH. In all but one case this amplicon, with minimal common regions of gains at 17p11-p12, started with the distal loss of 17p13-pter. OS and high-grade LMS were grouped together as they showed a complex pattern of copy number gains and amplifications at 17p, whereas MFH and low-grade LMS showed a continuous pattern of copy number gains and amplification at 17p. In addition to the commonly gained and lost regions identified in ULMS by aCGH, various biological processes affected by these copy number changes were also indicated by pathway analysis. The three novel findings obtained in this work were: characterization of amplicon 17p in low- and high-grade LMS and MFH, profiles of DNA copy number changes in LMS, and detection of various pathways affected by copy number changes in ULMS. These studies have not been undertaken previously by aCGH technology, thus this Thesis adds new information regarding DNA copy number changes in sarcomas. In conclusion, the aCGH technique used in this Thesis has provided new insights into the genetics of sarcomas by detecting the precise regions affected by copy number changes and some potential candidate target genes within those regions, which had not been uncovered by previously applied low resolution techniques.

Oncolytic Adenoviruses for Gynecologic Cancer

Gene therapy is a promising novel approach for treating cancers resistant to or escaping currently available modalities. Treatment approaches are based on taking advantage of molecular differences between normal and tumor cells. Various strategies are currently in clinical development with adenoviruses as the most popular vehicle. Recent developments include improving targeting strategies for gene delivery to tumor cells with tumor specific promoters or infectivity enhancement. A rapidly developing field is as well replication competent agents, which allow improved tumor penetration and local amplification of the anti-tumor effect. Adenoviral cancer gene therapy approaches lack cross-resistance with other treatment options and therefore synergistic effects are possible. This study focused on development of adenoviral vectors suitable for treatment of various gynecologic cancer types, describing the development of the field from non-replicating adenoviral vectors to multiple-modified conditional replicating viruses. Transcriptional targeting of gynecologic cancer cells by the use of the promoter of vascular endothelial growth factor receptor type 1 (flt-1) was evaluated. Flt-1 is not expressed in the liver and thus an ideal promoter for transcriptional targeting of adenoviruses. Our studies implied that the flt-1 promoter is active in teratocarcinomas.and therefore a good candidate for development of oncolytic adenoviruses for treatment of this often problematic disease with then poor outcome. A tropism modified conditionally replicating adenovirus (CRAd), Ad5-Δ24RGD, was studied in gynecologic cancers. Ad5-Δ24RGD is an adenovirus selectively replication competent in cells defective in the p16/Rb pathway, including many or most tumor cells. The fiber of Ad5-Δ24RGD contains an integrin binding arginine-glycine-aspartic acid motif (RGD-4C), allowing coxackie-adenovirus receptor independent infection of cancer cells. This approach is attractive because expression levels of CAR are highly variable and often low on primary gynecological cancer cells. Oncolysis could be shown for a wide variety of ovarian and cervical cancer cell lines as well as primary ovarian cancer cell spheroids, a novel system developed for in vitro analysis of CRAds on primary tumor substrates. Biodistribution was evaluated and preclinical safety data was obtained by demonstrating lack of replication in human peripheral blood mononuclear cells. The efficicacy of Ad5-Δ24RGD was shown in different orthotopic murine models including a highly aggressive intraperitoneal model of disseminated ovarian cancer cells, where Ad5-Δ24RGD resulted in complete eradication of intraperitoneal disease in half of the mice. To further improve the selectivity and specificity of CRAds, triple-targeted oncolytic adenoviruses were cloned, featuring the cyclo-oxygenase-2 (cox-2) promoter, E1A transcomplementation and serotype chimerism. Those viruses were evaluated on ovarian cancer cells for specificity and oncolytic potency with regard to two different cox2 versions and three different variants of E1A (wild type, delta24 and delta2delta24). Ad5/3cox2Ld24 emerged as the best combination due to enhanced selectivity without potency lost in vitro or in an aggressive intraperitoneal orthotopic ovarian tumor model. In summary, the preclinical therapeutic efficacy of the CRAds tested in this study, taken together with promising biodistribution and safety data, suggest that these CRAds are interesting candidates for translation into clinical trials for gynecologic cancer.

Molecular Genetic Background of Tumours in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a hereditary tumour predisposition syndrome. Its phenotype includes benign cutaneous and uterine leiomyomas (CLM, ULM) with high penetrance and rarer renal cell cancer (RCC), most commonly of papillary type 2 subtype. Over 130 HLRCC families have been identified world-wide but the RCC phenotype seems to concentrate in families from Finland and North America for unknown reasons. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. FH encodes the enzyme fumarase from mitochondrial citric acid cycle. Fumarase enzyme activity or type or site of the FH mutation are unassociated with disease phenotype. The strongest evidence for tumourigenesis mechanism in HLRCC supports a hypoxia inducible factor driven process called pseudohypoxia resulting from accumulation of the fumarase substrate fumarate. In this study, to assess the importance of gene- or exon-level deletions or amplifications of FH in patients with HLRCC-associated phenotypes, multiplex ligation-dependent probe amplification (MLPA) method was used. One novel FH mutation, deletion of exon 1, was found in a Swedish male patient with an evident HLRCC phenotype with CLM, RCC, and a family history of ULM and RCC. Six other patients with CLM and 12 patients with only RCC or uterine leiomyosarcoma (ULMS) remained FH mutation-negative. These results suggest that copy number aberrations of FH or its exons are an infrequent cause of HLRCC and that only co-occurrence of benign tumour types justifies FH-mutation screening in RCC or ULMS patients. Determination of the genomic profile of 11 HLRCC-associated RCCs from Finnish patients was performed by array comparative genomic hybridization. The most common copy number aberrations were gains of 2, 7, and 17 and losses of 13q12.3-q21.1, 14, 18, and X. When compared to aberrations of sporadic papillary RCCs, HLRCC-associated RCCs harboured a distinct DNA copy number profile and lacked many of the changes characterizing the sporadic RCCs. The findings suggest a divergent molecular pathway for tumourigenesis of papillary RCCs in HLRCC. In order to find a genetic modifier of RCC risk in HLRCC, genome-wide linkage and identical by descent (IBD) analysis studies were performed in Finnish HLRCC families with microsatellite marker mapping and SNP-array platforms. The linkage analysis identified only one locus of interest, the FH gene locus in 1q43, but no mutations were found in the genes of the region. IBD analysis yielded no convincing haplotypes shared by RCC patients. Although these results do not exclude the existence of a genetic modifier for RCC risk in HLRCC, they emphasize the role of FH mutations in the malignant tumourigenesis of HLRCC. To study the benign tumours in HLRCC, genome-wide DNA copy number and gene expression profiles of sporadic and HLRCC ULMs were defined with modern SNP- and gene-expression array platforms. The gene expression array suggests novel genes involved in FH-deficient ULM tumourigenesis and novel genes with putative roles in propagation of sporadic ULM. Both the gene expression and copy number profiles of HLRCC ULMs differed from those of sporadic ULMs indicating distinct molecular basis of the FH-deficient HLRCC tumours.