37 resultados para Proteins in human nutrition


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The Arctic peoples are currently faced with the challenge of adapting to climate change. Adaptive strategies have been central for the survival of the Northern communities also in the past. This doctoral dissertation is a comparative study of how two Northern societies, the Faroe Islands and Greenland, have responded to challenges caused by the interplay of environmental, political and socio-economic changes. Its main objective is to describe the characteristics of respective adaptive strategies developed in the two societies and to show which connections exist between adaptation and the development of the settlement patterns. This study is based on document analysis, supported by an analysis of demographic and economic statistics. For the field work, the empirical method of landscape-reading was applied. A narrative approach was used to explain interrelations between adaptive strategies and societal developments in the Faroe Islands and Greenland. Maps illustrating development and changes in settlement patterns in different time periods are central for this study because they illustrate the impacts of adaptation on settlement development. The results of this dissertation show that people in the Faroe Islands and Greenland have consciously developed their settlements and used this as an adaptive strategy: different types of settlements were established depending on which kind of resource base was available. Strong dependency on a single resource is likely to increase the probability that settlement development was impacted by it. The interrelation of natural resource use and settlement pattern development has weakened in the Faroe Islands and Greenland from the mid-1900s. Since then, the importance of the government settlement policies has become pronounced and the existing settlement pattern, including settlements without prospects for genuine economic viability, has been preserved. Currently, the Northern communities are increasingly dependent on worldwide developments. In the light of this study, the communities can respond to challenges of globalization and climate change and develop new kind of adaptive strategies, such as diversification of their economic activities. This dissertation shows that it is important to extend studies about community adaptation in the High North to consider the overall development of the Northern settlement patterns.

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Plasma membrane adopts myriad of different shapes to carry out essential cellular processes such as nutrient uptake, immunological defence mechanisms and cell migration. Therefore, the details how different plasma membrane structures are made and remodelled are of the upmost importance. Bending of plasma membrane into different shapes requires substantial amount of force, which can be provided by the actin cytoskeleton, however, the molecules that regulate the interplay between the actin cytoskeleton and plasma membrane have remained elusive. Recent findings have placed new types of effectors at sites of plasma membrane remodelling, including BAR proteins, which can directly bind and deform plasma membrane into different shapes. In addition to their membrane-bending abilities, BAR proteins also harbor protein domains that intimately link them to the actin cytoskeleton. The ancient BAR domain fold has evolved into at least three structurally and functionally different sub-groups: the BAR, F-BAR and I-BAR domains. This thesis work describes the discovery and functional characterization of the Inverse-BAR domains (I-BARs). Using synthetic model membranes, we have shown that I-BAR domains bind and deform membranes into tubular structures through a binding-surface composed of positively charged amino acids. Importantly, the membrane-binding surface of I-BAR domains displays an inverse geometry to that of the BAR and F-BAR domains, and these structural differences explain why I-BAR domains induce cell protrusions whereas BAR and most F-BAR domains induce cell invaginations. In addition, our results indicate that the binding of I-BAR domains to membranes can alter the spatial organization of phosphoinositides within membranes. Intriguingly, we also found that some I-BAR domains can insert helical motifs into the membrane bilayer, which has important consequences for their membrane binding/bending functions. In mammals there are five I-BAR domain containing proteins. Cell biological studies on ABBA revealed that it is highly expressed in radial glial cells during the development of the central nervous system and plays an important role in the extension process of radial glia-like C6R cells by regulating lamellipodial dynamics through its I-BAR domain. To reveal the role of these proteins in the context of animals, we analyzed MIM knockout mice and found that MIM is required for proper renal functions in adult mice. MIM deficient mice displayed a severe urine concentration defect due to defective intercellular junctions of the kidney epithelia. Consistently, MIM localized to adherens junctions in cultured kidney epithelial cells, where it promoted actin assembly through its I-BAR andWH2 domains. In summary, this thesis describes the mechanism how I-BAR proteins deform membranes and provides information about the biological role of these proteins, which to our knowledge are the first proteins that have been shown to directly deform plasma membrane to make cell protrusions.

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Two types of antigen-presenting cells (APCs), macrophages and dendritic cells (DCs), function at the interface of innate and adaptive immunity. Through recognition of conserved microbial patterns, they are able to detect the invading pathogens. This leads to activation of signal transduction pathways that in turn induce gene expression of various molecules required for immune responses and eventually pathogen clearance. Cytokines are among the genes induced upon detection of microbes. They play an important role in regulating host immune responses during microbial infection. Chemotactic cytokines, chemokines, are involved in migratory events of immune cells. Cytokines also promote the differentiation of distinct T cell responses. Because of the multiple roles of cytokines in the immune system, the cytokine network needs to be tightly regulated. In this work, the induction of innate immune responses was studied using human primary macrophages or DCs as cell models. Salmonella enterica serovar Typhimurium served as a model for an intracellular bacterium, whereas Sendai virus was used in virus experiments. The starting point of this study was that DCs of mouse origin had recently been characterized as host cells for Salmonella. However, only little was known about the immune responses initiated in Salmonella-infected human DCs. Thus, cellular responses of macrophages and DCs, in particular the pattern of cytokine production, to Salmonella infection were compared. Salmonella-induced macrophages and DCs were found to produce multiple cytokines including interferon (IFN) -gamma, which is conventionally produced by T and natural killer (NK) cells. Both macrophages and DCs also promoted the intracellular survival of the bacterium. Phenotypic maturation of DCs as characterized by upregulation of costimulatory and human leukocyte antigen (HLA) molecules, and production of CCL19 chemokine, were also detected upon infection with Salmonella. Another focus of this PhD work was to unravel the regulatory events controlling the expression of cytokine genes encoding for CCL19 and type III IFNs, which are central to DC biology. We found that the promoters of CCL19 and type III IFNs contain similar regulatory elements that bind nuclear factor kappaB (NF-kappaB) and interferon regulatory factors (IRFs), which could mediate transcriptional activation of the genes. The regulation of type III IFNs in virus infection resembled that of type I IFNs a cytokine class traditionally regarded as antiviral. The induction of type I and type III IFNs was also observed in response to bacterial infection. Taken together, this work identifies new details about the interaction of Salmonella with its phagocytic host cells of human origin. In addition, studies provide information on the regulatory events controlling the expression of CCL19 and the most recently identified IFN family genes, type III IFN genes.

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The purpose of this work was to elucidate the ontogeny of interleukin-10 (IL-10) secretion from newborn mononuclear cells (MCs), and to examine its relation to the secretion of interferon-g (IFN-g) and immunoglobulins (Igs). The initial hypothesis was that the decreased immunoglobulin (Ig) synthesis of newborn babies was the result of immature cytokine synthesis regulation, which would lead to excessive IL-10 production, leading in turn to suppressed IFN-g secretion. Altogether 57 full-term newborns and 34 adult volunteers were enrolled. Additionally, surface marker compositions of 29 premature babies were included. Enzyme-linked immunoassays were used to determine the amount of secreted IL-10, IFN-g, and Igs, and the surface marker composition of MC were analyzed with a FACScan flow cytometer. The three most important findings were: 1. Cord blood MC, including CD5+ B cells, are able to secrete IL-10. However, when compared with adults, the secretion of IL-10 was decreased. This indicates that reasons other than excessive IL-10 secretion are responsible of reduced IFN-g secretion in newborns. 2. As illustrated by the IL-10 and IFN-g secretion pattern, newborn cytokine profile was skewed towards the Th2 type. However, approximately 25% of newborns had an adult like cytokine profile with both good IL10 and IFN-g secretion, demonstrating that fullterm newborns are not an immunologically homogenous group at the time of birth. 3. There were significant differences in the surface marker composition of MCs between individual neonates. While gestational age correlated with the proportion of some MC types, it is evident that there are many other maternal and fetal factors that influence the maturity and nature of lymphocyte subpopulations in individual neonates. In conclusion, the reduced ability of neonates to secrete Ig and IFN-g is not a consequence of high IL-10 secretion. However, individual newborns differ significantly in their ability to secrete cytokines as well as Igs.

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Tactile sensation plays an important role in everyday life. While the somatosensory system has been studied extensively, the majority of information has come from studies using animal models. Recent development of high-resolution anatomical and functional imaging techniques has enabled the non-invasive study of human somatosensory cortex and thalamus. This thesis provides new insights into the functional organization of the human brain areas involved in tactile processing using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). The thesis also demonstrates certain optimizations of MEG and fMRI methods. Tactile digit stimulation elicited stimulus-specific responses in a number of brain areas. Contralateral activation was observed in somatosensory thalamus (Study II), primary somatosensory cortex (SI; I, III, IV), and post-auditory belt area (III). Bilateral activation was observed in secondary somatosensory cortex (SII; II, III, IV). Ipsilateral activation was found in the post-central gyrus (area 2 of SI cortex; IV). In addition, phasic deactivation was observed within ipsilateral SI cortex and bilateral primary motor cortex (IV). Detailed investigation of the tactile responses demonstrated that the arrangement of distal-proximal finger representations in area 3b of SI in humans is similar to that found in monkeys (I). An optimized MEG approach was sufficient to resolve such fine detail in functional organization. The SII region appeared to contain double representations for fingers and toes (II). The detection of activations in the SII region and thalamus improved at the individual and group levels when cardiac-gated fMRI was used (II). Better detection of body part representations at the individual level is an important improvement, because identification of individual representations is crucial for studying brain plasticity in somatosensory areas. The posterior auditory belt area demonstrated responses to both auditory and tactile stimuli (III), implicating this area as a physiological substrate for the auditory-tactile interaction observed in earlier psychophysical studies. Comparison of different smoothing parameters (III) demonstrated that proper evaluation of co-activation should be based on individual subject analysis with minimal or no smoothing. Tactile input consistently influenced area 3b of the human ipsilateral SI cortex (IV). The observed phasic negative fMRI response is proposed to result from interhemispheric inhibition via trans-callosal connections. This thesis contributes to a growing body of human data suggesting that processing of tactile stimuli involves multiple brain areas, with different spatial patterns of cortical activation for different stimuli.