Molecular genetics of X-linked cone-rod dystrophy and Åland Island eye disease

Inherited retinal diseases are the most common cause of vision loss among the working population in Western countries. It is estimated that ~1 of the people worldwide suffer from vision loss due to inherited retinal diseases. The severity of these diseases varies from partial vision loss to total blindness, and at the moment no effective cure exists. To date, nearly 200 mapped loci, including 140 cloned genes for inherited retinal diseases have been identified. By a rough estimation 50% of the retinal dystrophy genes still await discovery. In this thesis we aimed to study the genetic background of two inherited retinal diseases, X-linked cone-rod dystrophy and Åland Island eye disease. X-linked cone-rod dystrophy (CORDX) is characterized by progressive loss of visual function in school age or early adulthood. Affected males show reduced visual acuity, photophobia, myopia, color vision defects, central scotomas, and variable changes in fundus. The disease is genetically heterogeneous and two disease loci, CORDX1 and CORDX2, were known prior to the present thesis work. CORDX1, located on Xp21.1-11.4, is caused by mutations in the RPGR gene. CORDX2 is located on Xq27-28 but the causative gene is still unknown. Åland Island eye disease (AIED), originally described in a family living in Åland Islands, is a congenital retinal disease characterized by decreased visual acuity, fundus hypopigmentation, nystagmus, astigmatism, red color vision defect, myopia, and defective night vision. AIED shares similarities with another retinal disease, congenital stationary night blindness (CSNB2). Mutations in the L-type calcium channel α1F-subunit gene, CACNA1F, are known to cause CSNB2, as well as AIED-like disease. The disease locus of the original AIED family maps to the same genetic interval as the CACNA1F gene, but efforts to reveal CACNA1F mutations in patients of the original AIED family have been unsuccessful. The specific aims of this study were to map the disease gene in a large Finnish family with X-linked cone-rod dystrophy and to identify the disease-causing genes in the patients of the Finnish cone-rod dystrophy family and the original AIED family. With the help of linkage and haplotype analyses, we could localize the disease gene of the Finnish cone-rod dystrophy family to the Xp11.4-Xq13.1 region, and thus establish a new genetic X-linked cone-rod dystrophy locus, CORDX3. Mutation analyses of candidate genes revealed three novel CACNA1F gene mutations: IVS28-1 GCGTC>TGG in CORDX3 patients, a 425 bp deletion, comprising exon 30 and flanking intronic regions in AIED patients, and IVS16+2T>C in an additional Finnish patient with a CSNB2-like phenotype. All three novel mutations altered splice sites of the CACNA1F gene, and resulted in defective pre-mRNA splicing suggesting altered or absent channel function as a disease mechanism. The analyses of CACNA1F mRNA also revealed novel alternative wt splice variants, which may enhance channel diversity or regulate the overall expression level of the channel. The results of our studies may be utilized in genetic counseling of the families, and they provide a basis for studies on the pathogenesis of these diseases. In the future, the knowledge of the genetic defects may be used in the identification of specific therapies for the patients.

Half-occlusion processing in stereoscopic vision

This study investigated questions related to half-occlusion processing in human stereoscopic vision: (1) How does the depth location of a half-occluding figure affect the depth localization of adjacent monocular objects? (2) Is three-dimensional slant around vertical axis (geometric effect) affected by half-occlusion constraints? and (3) How the half-occlusion constraints and surface formation processes are manifested in stereoscopic capture? Our results showed that the depth localization of binocular objects affects the depth localization of discrete monocular objects. We also showed that the visual system has a preference for a frontoparallel surface interpretation if the half-occlusion configuration allows multiple interpretation alternatives. When the surface formation was constrained by textures, our results showed that a process of rematching spreading determines the resulting perception and that the spreading can be limited by illusory contours that support the presence of binocularly unmatched figures. The unmatched figures could be present, if the inducing figures producing the illusory surface contained binocular image differences that provided cues for quantitative da Vinci stereopsis. These findings provide evidence of the significant role of half-occlusions in stereoscopic processing.

Feature integration in human vision

The earliest stages of human cortical visual processing can be conceived as extraction of local stimulus features. However, more complex visual functions, such as object recognition, require integration of multiple features. Recently, neural processes underlying feature integration in the visual system have been under intensive study. A specialized mid-level stage preceding the object recognition stage has been proposed to account for the processing of contours, surfaces and shapes as well as configuration. This thesis consists of four experimental, psychophysical studies on human visual feature integration. In two studies, classification image a recently developed psychophysical reverse correlation method was used. In this method visual noise is added to near-threshold stimuli. By investigating the relationship between random features in the noise and observer s perceptual decision in each trial, it is possible to estimate what features of the stimuli are critical for the task. The method allows visualizing the critical features that are used in a psychophysical task directly as a spatial correlation map, yielding an effective "behavioral receptive field". Visual context is known to modulate the perception of stimulus features. Some of these interactions are quite complex, and it is not known whether they reflect early or late stages of perceptual processing. The first study investigated the mechanisms of collinear facilitation, where nearby collinear Gabor flankers increase the detectability of a central Gabor. The behavioral receptive field of the mechanism mediating the detection of the central Gabor stimulus was measured by the classification image method. The results show that collinear flankers increase the extent of the behavioral receptive field for the central Gabor, in the direction of the flankers. The increased sensitivity at the ends of the receptive field suggests a low-level explanation for the facilitation. The second study investigated how visual features are integrated into percepts of surface brightness. A novel variant of the classification image method with brightness matching task was used. Many theories assume that perceived brightness is based on the analysis of luminance border features. Here, for the first time this assumption was directly tested. The classification images show that the perceived brightness of both an illusory Craik-O Brien-Cornsweet stimulus and a real uniform step stimulus depends solely on the border. Moreover, the spatial tuning of the features remains almost constant when the stimulus size is changed, suggesting that brightness perception is based on the output of a single spatial frequency channel. The third and fourth studies investigated global form integration in random-dot Glass patterns. In these patterns, a global form can be immediately perceived, if even a small proportion of random dots are paired to dipoles according to a geometrical rule. In the third study the discrimination of orientation structure in highly coherent concentric and Cartesian (straight) Glass patterns was measured. The results showed that the global form was more efficiently discriminated in concentric patterns. The fourth study investigated how form detectability depends on the global regularity of the Glass pattern. The local structure was either Cartesian or curved. It was shown that randomizing the local orientation deteriorated the performance only with the curved pattern. The results give support for the idea that curved and Cartesian patterns are processed in at least partially separate neural systems.

The Emerging Phenotype: Ecological Genetics of Color, Form and Sex in the Common Frog

One of the main aims of evolutionary biology is to explain why organisms vary phenotypically as they do. Proximately, this variation arises from genetic differences and from environmental influences, the latter of which is referred to as phenotypic plasticity. Phenotypic plasticity is thus a central concept in evolutionary biology, and understanding its relative importance in causing the phenotypic variation and differentiation is important, for instance in anticipating the consequences of human induced environmental changes. The aim of this thesis was to study geographic variation and local adaptation, as well as sex ratios and environmental sex reversal, in the common frog (Rana temporaria). These themes cover three different aspects of phenotypic plasticity, which emerges as the central concept for the thesis. The first two chapters address geographic variation and local adaptation in two potentially thermally adaptive traits, namely the degree of melanism and the relative leg length. The results show that although there is an increasing latitudinal trend in the degree of melanism in wild populations across Scandinavian Peninsula, this cline has no direct genetic basis and is thus environmentally induced. The second chapter demonstrates that although there is no linear, latitudinally ordered phenotypic trend in relative leg length that would be expected under Allen s rule an ecogeographical rule linking extremity length to climatic conditions there seems to be such a trend at the genetic level, hidden under environmental effects. The first two chapters thus view phenotypic plasticity through its ecological role and evolution, and demonstrate that it can both give rise to phenotypic variation and hide evolutionary patterns in studies that focus solely on phenotypes. The last three chapters relate to phenotypic plasticity through its ecological and evolutionary role in sex determination, and consequent effects on population sex ratio, genetic recombination and the evolution of sex chromosomes. The results show that while sex ratios are strongly female biased and there is evidence of environmental sex reversals, these reversals are unlikely to have caused the sex ratio skew, at least directly. The results demonstrate that environmental sex reversal can have an effect on the evolution of sex chromosomes, as the recombination patterns between them seem to be controlled by phenotypic, rather than genetic, sex. This potentially allows Y chromosomes to recombine, lending support for the recent hypothesis suggesting that sex-reversal may play an important role on the rejuvenation of Y chromosomes.

Functional imaging of peripheral vision and dorsal stream function in the human cerebral cortex

Visual information processing in brain proceeds in both serial and parallel fashion throughout various functionally distinct hierarchically organised cortical areas. Feedforward signals from retina and hierarchically lower cortical levels are the major activators of visual neurons, but top-down and feedback signals from higher level cortical areas have a modulating effect on neural processing. My work concentrates on visual encoding in hierarchically low level cortical visual areas in human brain and examines neural processing especially in cortical representation of visual field periphery. I use magnetoencephalography and functional magnetic resonance imaging to measure neuromagnetic and hemodynamic responses during visual stimulation and oculomotor and cognitive tasks from healthy volunteers. My thesis comprises six publications. Visual cortex forms a great challenge for modeling of neuromagnetic sources. My work shows that a priori information of source locations are needed for modeling of neuromagnetic sources in visual cortex. In addition, my work examines other potential confounding factors in vision studies such as light scatter inside the eye which may result in erroneous responses in cortex outside the representation of stimulated region, and eye movements and attention. I mapped cortical representations of peripheral visual field and identified a putative human homologue of functional area V6 of the macaque in the posterior bank of parieto-occipital sulcus. My work shows that human V6 activates during eye-movements and that it responds to visual motion at short latencies. These findings suggest that human V6, like its monkey homologue, is related to fast processing of visual stimuli and visually guided movements. I demonstrate that peripheral vision is functionally related to eye-movements and connected to rapid stream of functional areas that process visual motion. In addition, my work shows two different forms of top-down modulation of neural processing in the hierachically lowest cortical levels; one that is related to dorsal stream activation and may reflect motor processing or resetting signals that prepare visual cortex for change in the environment and another local signal enhancement at the attended region that reflects local feed-back signal and may perceptionally increase the stimulus saliency.

Search for new color-octet vector particle decaying to t tbar in p pbar collisions at sqrt{s} = 1.96 TeV

We present the result of a search for a massive color-octet vector particle, (e.g. a massive gluon) decaying to a pair of top quarks in proton-antiproton collisions with a center-of-mass energy of 1.96 TeV. This search is based on 1.9 fb$^{-1}$ of data collected using the CDF detector during Run II of the Tevatron at Fermilab. We study $t\bar{t}$ events in the lepton+jets channel with at least one $b$-tagged jet. A massive gluon is characterized by its mass, decay width, and the strength of its coupling to quarks. These parameters are determined according to the observed invariant mass distribution of top quark pairs. We set limits on the massive gluon coupling strength for masses between 400 and 800 GeV$/c^2$ and width-to-mass ratios between 0.05 and 0.50. The coupling strength of the hypothetical massive gluon to quarks is consistent with zero within the explored parameter space.

I kläm mellan vision och verklighet - en etnografisk fallstudie av en webbredaktion

I avhandlingen analyseras arbetsprocesserna vid en webbredaktion. Undersökningen är en etnografisk fallstudie där Hufvudstadsbladets webbproduktion fungerar som case. Den övergripande frågeställningen är hur växelverkan mellan tidningsredaktionen och webbredaktionen fungerar och varför. Syftet var att hitta och synliggöra de underliggande spänningar i organisationen som bimedialiteten kan ha gett upphov till, och analysera produktionen mot bakgrund av tidigare forskning. Analysen behandlar tre områden som ofta återkommer i mediekonvergensforskningen, det vill säga organisation, innehåll och inställning. Forskningsmaterialet är insamlat med hjälp av observation, intervjuer och en e-postenkät. Arbetet på redaktionen observerades under sex arbetsskift. Webbreporterns arbete observerades, observationerna antecknades och efter varje arbetsskift bandades en intervju med webbreportern. Utöver dessa intervjuer gjordes ytterligare tre intervjuer med två nyhetschefer och chefredaktören. En e-postenkät med öppna frågor skickades ut till samtliga redaktionsmedlemmar. Avhandlingen tar avstamp i mediekonvergensforskning, redaktionsforskning och aktivitetsteori. Eftersom den teoretiska utgångspunkten delvis ligger inom aktivitetsteori och utvecklande arbetsforskning räknades samtidigt störningar i arbetsprocessen för att kunna identifiera underliggande spänningar i organisationen. Alla händelser som innebar ett längre eller kortare avbrott i arbetsprocessen antecknades och delades in i kategorier. Sammanlagt sextio störningar identifierades, varav den största andelen, en tredjedel, konstaterades bero på organisations- och kommunikationsfaktorer, främst till följd av bristfällig intern kommunikation. Slutsatserna är webbproduktionen till följd av heterogena objekt i aktivitetssystemet - oklara mål och oklarhet gällande webbens roll i organisationen sitter fast i klyftan mellan ledningens vision och verkligheten på redaktionen. Ett flertal motstridiga uppfattningar om webbproduktionens roll råder på redaktionen. Det leder till störningar i arbetsprocessen som i sin tur gör att produktionen haltar och inte utvecklas. Oklarheten kring målen leder till oklarhet kring konkret praxis, kommunikationssvårigheter, missförstånd och en sned arbetsfördelning, som samtliga inverkar på smidigheten i produktionen.

Vision based indoor positioning in a retail environment

Modern smart phones often come with a significant amount of computational power and an integrated digital camera making them an ideal platform for intelligents assistants. This work is restricted to retail environments, where users could be provided with for example navigational in- structions to desired products or information about special offers within their close proximity. This kind of applications usually require information about the user's current location in the domain environment, which in our case corresponds to a retail store. We propose a vision based positioning approach that recognizes products the user's mobile phone's camera is currently pointing at. The products are related to locations within the store, which enables us to locate the user by pointing the mobile phone's camera to a group of products. The first step of our method is to extract meaningful features from digital images. We use the Scale- Invariant Feature Transform SIFT algorithm, which extracts features that are highly distinctive in the sense that they can be correctly matched against a large database of features from many images. We collect a comprehensive set of images from all meaningful locations within our domain and extract the SIFT features from each of these images. As the SIFT features are of high dimensionality and thus comparing individual features is infeasible, we apply the Bags of Keypoints method which creates a generic representation, visual category, from all features extracted from images taken from a specific location. A category for an unseen image can be deduced by extracting the corresponding SIFT features and by choosing the category that best fits the extracted features. We have applied the proposed method within a Finnish supermarket. We consider grocery shelves as categories which is a sufficient level of accuracy to help users navigate or to provide useful information about nearby products. We achieve a 40% accuracy which is quite low for commercial applications while significantly outperforming the random guess baseline. Our results suggest that the accuracy of the classification could be increased with a deeper analysis on the domain and by combining existing positioning methods with ours.