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Sökning: L4X0:0346 6612 > (2005-2009)

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51.
  • Dahlin, Erika, 1981- (författare)
  • Train your brain : updating, transfer, and neural changes
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • An initial aim of this thesis was to determine whether training of a specific executive function (updating) produces improvements in performance on trained and transfer tasks, and whether the effects are maintained over time. Neural systems underlying training and transfer effects were also investigated and one question considered is whether transfer depends on general or specific neural overlap between training and transfer tasks. An additional aim was to identify how individual differences in executive functioning are mapped to functional brain changes. In Study I, significant training-related changes in performance on the letter memory criterion task were found in both young and older adults after 5 weeks of updating training. Transfer to a 3-back test of updating was also demonstrated in the young adults. Functional Magnetic Resonance Imaging (fMRI) revealed overlapping activity in letter memory and 3-back tasks in fronto-parietal areas and striatum pre-training, and a joint training-related activity increase for the tasks in a striatal region. No transfer was observed to a task (Stroop) that engaged fronto-parietal areas, but not the striatal region and updating per se. Moreover, age-related striatal changes imposed constraints on transfer. In Study II, additional transfer tasks and a test of long-term maintenance were included. Results revealed that training-related gains in performance were maintained 18 months post-training in both young and older adults, whereas transfer effects were limited to tasks requiring updating and restricted to young participants. In Study III, analyses of brain activity and performance during n-back (1/2/3-back) were executed. This task enables manipulation of executive demand, which permits examination of how individual differences in executive functioning can be mapped to functional brain changes. Relative to a young high- performing group, capacity constraints in executive functioning were apparent between 1–2-back for the elderly participants and between 2–3-back for a young low-performing group. Capacity constraints in neural activity followed this pattern by showing a monotonically increasing response in the parietal cortex and the thalamus for young high performers, whereas activity levelled off at 1-back for elderly performers and at 2-back for young low performers. The response in the dorsal frontal cortex followed a similar pattern. Together, these findings indicate that fronto-parietal as well as sub-cortical areas are important for individual differences in executive functioning, training of updating and transfer effects.
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52.
  • Dahlqvist, Vera, 1954- (författare)
  • Samvete i vården : att möta det moraliska ansvarets röster
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The overall aim of this thesis is twofold: first, to develop and validate questionnaires that could be used for investigating relationships between perceptions of conscience, moral sensitivity and burnout and second, to describe patterns of self-comfort used to ease stress and illuminate meanings of living with a troubled conscience. The thesis comprises five studies and is based on both quantitative and qualitative data.In study I, a questionnaire was constructed to assess perceptions of conscience; the Perceptions of Conscience Questionnaire (PCQ). This 15 item-questionnaire was distributed to 444 care providers. Statistical analyses of responses showed sufficient distribution and a stable six factor solution congruent with reviewed literature. The six factors were labelled: ‘the voice of authority’, ‘warning signal’, ‘demanding sensitivity’, ‘asset’, ‘burden’ and ‘depending on culture’. The findings suggest that the PCQ is a valid questionnaire. The aim of study II was further development of an existing questionnaire assessing care providers’ moral sensitivity, enabling its use in various care contexts. The revised nine-item questionnaire, the Moral Sensitivity Questionnaire Revised version (MSQ-R), was distributed to 278 care providers with various professional backgrounds. Statistical analyses of responses showed sufficient distribution and a three-factor solution congruent with reviewed literature. The three factors were labelled: ‘sense of moral burden’, ‘sense of moral strength,’ and ‘sense of moral responsibility.’ The findings suggest that MSQ-R is valid for use in various healthcare contexts. In study III, the PCQ, the MSQ-R and the Maslach Burnout Inventory (MBI) were distributed to a population of psychiatric care providers (n=101) to investigate relationships between perceptions of conscience and moral sensitivity and levels of burnout. The hierarchical cluster analysis shows two clusters with Pearson’s r >.50. Cluster A comprising items such as: being sensitive, interpreting and following the voice of conscience that warns us against hurting other or ourselves and developing as human beings was labelled ‘experiencing a sense of moral integrity’. Cluster B comprising items such as: feeling inadequate, doing more than one has strengths for, feeling always responsible, having difficulties to deal with wearing feelings, perceiving that conscience gives wrong signals and express social values, having to deaden one’ conscience, were all related to scores of the MBI subscales emotional exhaustion (EE) and depersonalisation (DP). Cluster B was labelled ‘experiencing a burdening accountability’. The results show that levels of ‘experiencing a burdening accountability’ are closely related to levels of being at risk of burnout.The aim of study IV was to describe patterns of self-comforting measures used to ease stress. The written accounts of 168 care providers and healthcare students were analysed by means of qualitative content analysis. The findings disclose two dimensions: an ability to use early learned measures to take care of oneself (ingression) and an ability to feel intimately related to life, other human beings and universe or God (transcendence). The findings provide valuable knowledge about self-comfort as a coping strategy. The aim of study V was to illuminate meanings of living with a troubled conscience. Ten psychiatric care providers, respondents of study III with various perceptions of conscience were interviewed. The interviews were interpreted using a phenomenological - hermeneutical method. The findings show that one meaning of living with a troubled conscience is being confronted with inadequacy and struggling to view oneself as ‘good enough.’ The comprehensive understanding indicates that inadequacy, both one’s own and that of organization one represents, infuse feelings of shame rather than feelings of guilt. Shame concerns one’s identity and need of reconciliation.Conclusions: The results reveal two ways of encountering a troubled conscience. One is being unable to interpret the ethical demand from a troubled conscience. This is indicated by connections between levels of moral burden and levels of burnout. The other way is being able to interpret the ethical demand and using one’s troubled conscience to develop practical wisdom. This means facing shame of feeling inadequate, reconciling images of the ideal self and self-contempt, and becoming realistic about what one can do. In this process comfort seems to be a mediator of reconciliation.
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53.
  • Dalheim-Englund, Ann-Charlotte (författare)
  • Skydda och frigöra : en studie av föräldrar till barn med astma och av professionella vårdare
  • 2005
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Aim: The overall aim of this thesis is, from the point of view of parents of a child with asthma, to describe meanings of being a parent, parents’ quality of life, and to describe how family relations are influenced by their child’s disease. The aim is also to increase the understanding of what strategies professional caregivers use in their work with teenagers suffering from asthma. Methods: Informants in the three qualitative studies were 29 parents (17 mothers and 12 fathers) of children with asthma and 7 professional caregivers. Informants in a quantitative quality of life study were 371 parents. The data collections were undertaken by means of interviews, observations and a questionnaire. The data was analysed by means of a phenomenological-hermeneutic method, grounded theory and statistics. Results: A meaning of being a parent of a child with asthma is to live a strenuous life and to fear that the child might die during a severe asthma attack. The parents’ actions involve both protecting and liberating and their feelings involve sadness as well as acceptance. Mostly the mothers act in a protecting manner and express feelings of sadness. The fathers mostly act in a liberating manner and express feelings of acceptance. The core concern in families of a child with asthma was found to be disease-engendered uncertainty. The mothers describe that feelings of uncertainty always are present owing to the unpredictability of the disease. These feelings make the mothers more or less available for family members. For the child with asthma the mothers’ experience that they are always available. Thus, control and tight bonds characterize the mother-child relationships. The mothers’ constant availability for the child with asthma is experienced to lead to a decreased availability for other family members and theses relationships are characterised by feelings of forsakenness and lack of understanding. However, when parents of children with asthma estimate their quality of life by a questionnaire, they estimate it as comparatively high. In the same family the parents scoring of separate items was to a large extent similar. The result also shows that professional caregivers’ central concern is to assist teenagers with asthma to conquer life. This gives rise to five strategies: showing respect, being at hand, promoting personal sense of responsibility, promoting exceeding boundaries, and promoting reflections. In professional caregivers’ attempt to assist teenagers to conquer life some differences are seen in the way they support boys and girls. Conclusion: One conclusion drawn from this thesis is that being a parent of a child with asthma involves feelings of uncertainty. In meeting the parents in question, caregivers should reflect upon these feelings and consider how the parents could be assisted. As mothers and fathers describe different attitudes in relation to the care of the child, it is also important to reflect upon how professional caregivers can assist the balance between the mothers’ protecting and the fathers’ liberating attitudes. It is also important for professional caregivers to reflect upon how they meet teenage girls and boys with asthma respectively, and to take their needs and understanding of the situation into consideration.
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54.
  • Danielson, Patrik, 1980- (författare)
  • Innervation patterns and locally produced signal substances in the human patellar tendon : of importance when understanding the processes of tendinosis
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Tendinosis is a condition of chronic pain that afflicts several human tendons, not least the patellar tendon, in which case it is often clinically referred to as ‘jumper’s knee’. The exact mechanisms behind tendinosis are yet not fully understood. One draw-back in the case of patellar tendinosis has been the lack of knowledge of the innervation patterns of the human patellar tendon. It cannot be excluded that the processes of tendinosis are influenced by nerve mediators, released from nerve endings or from stimulated cells inside the tendon. Thus, the studies of the present thesis aimed to 1) map the general, sensory, cholinergic and sympathetic innervation patterns of the human patellar tendon, in both the tendon tissue proper and the loose paratendinous connective tissue surrounding the tendon, and 2) investigate the possible existence of a production of signal substances, traditionally associated with neurons, in non-neuronal tendon cells, and to see if there are signs of local cholinergic and catecholaminergic signaling pathways. Biopsies of both normal pain-free patellar tendons and patellar tendons from patients with chronic painful tendinosis were collected and investigated. The main method utilized was immunohistochemistry, using antibodies directed against synthesizing enzymes for acetylcholine and catecholamines, against muscarinic and adrenergic receptors, and against markers of general and sensory innervation. In situ hybridization (ISH) to detect mRNA for the cholinergic/catecholaminergic synthesizing enzymes was also used. It was found that the loose paratendinous connective tissue of the patellar tendon was rather richly innervated by nerve structures. These consisted of large nerve fascicles, as well as perivascular innervation in the walls of some of the larger arteries and smaller blood vessels. It was found that part of the nerve structures corresponded to sensory afferents, and that some conformed to cholinergic and, especially, sympathetic nerve fibers. The tendon tissue proper was strikingly less innervated than the paratendinous tissue. The sparse innervation that was found in the tendon tissue proper was seen in narrow zones of loose connective tissue and blood vessels, interspersed between the collagen bundles. The overall impression was that the patterns of distribution of the general, sensory, and autonomic innervations of tendinosis tendon tissue were similar to those of normal tendon tissue proper. The most pioneering findings were the immunohistochemical observations of an expression of enzymes related to production of both acetylcholine and catecholamines within the tendon cells (tenocytes) themselves, as well as of a presence of the receptors for these substances on the same cells; features that were predominantly seen in tendinosis tendons. The observations of the synthesizing enzymes for acetylcholine and catecholamines in tenocytes were confirmed by ISH findings of mRNA for these enzymes in the tenocytes. Immunoreactions for muscarinic and adrenergic receptors were also found in blood vessel walls and in some of the nerve fascicles. In summary, this thesis presents novel information on the innervation patterns of the human patellar tendon, in healthy individuals with pain-free tendons as well as in patients with chronic painful tendinosis. Furthermore, it gives the first evidence of the presence of a local, non-neuronal production in the tendon tissue of signal substances normally seen in neurons, and a basis for these substances to affect the tenocytes as these cells also display muscarinic and adrenergic receptors. Thus, the results indicate an existence of autocrine and/or paracrine cholinergic/catecholaminergic systems in the tendon tissue; systems that seem to be up-regulated in tendinosis. This is of great interest as it is known that stimulation of receptors for both catecholamines and acetylcholine can lead to cell proliferation, interfere with pain sensation, influence collagen production, and take part in vasoregulation, as well as, in the case of adrenergic receptors, promote cell degeneration and apotosis. All these processes represent biological functions/events that are reported to be affected in tendinosis. In conclusion, despite the fact that there is very limited innervation within the patellar tendon tissue proper, it is here shown that effects of signal substances traditionally associated with neurons seem to occur in the tissue, via a local production of these substances in tenocytes.
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55.
  • Desta, Menelik, 1955- (författare)
  • Epidemiology of child psychiatric disorders in Addis Ababa, Ethiopia
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Although mental disorders are common among children all over the world, information on the extent and types of child psychiatric disorders in Ethiopia is extremely limited. A study was conducted in an urban setting of Ethiopia to look at the prevalence of child psychiatric disorders and their correlates. A two-phase survey was performed. In the first phase, parents of 5000 children in Addis Ababa, the capital city of Ethiopia, were interviewed using the Reporting Questionnaire for Children (RQC). In the second phase, parents of all screen-positive children (n=864) and parents of 1537 screen-negative children were interviewed using the revised parent version of the Diagnostic Interview for Children and Adolescents (DICA-R), a semi-structured diagnostic instrument that is based on the third revised edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-III-R). This thesis discusses the results of that study in comparison with other child mental health studies in Ethiopia and elsewhere. At the recommended cut-off score of 1, the sensitivity, specificity, predictive values and likelihood ratios of the RQC to DICA-R diagnoses were acceptable. The RQC had high accuracy with a misclassification rate of 17%. The weighted prevalence for any DSM-III-R diagnosis was 17%. The most prevalent condition was enuresis (12.1%) followed by simple phobia (5.5%). The prevalence rates of all other identified conditions were below 1%. Children's age, severe economic problems, and single parenthood were found to be risk factors for any DSM-III-R diagnosis in children. Male sex, younger age, and lower achieved educational grade of the child were all independently associated with childhood enuresis. The odds of having enuresis were significantly higher for children in families with extreme poverty and in children from single-parent homes. The risk of having enuresis was significantly higher in children who had anxiety disorders (AD) and disruptive behaviour disorders (DBD). Sex was significantly associated with disruptive behaviour disorders while grade level, age, family size, ethnicity, poverty, and single parenthood were not. Anxiety disorders were significantly associated with sex, ethnicity, and extreme poverty but not with the other socio-demographic variables. The absence of mood disorders and somatoform disorders, of which symptoms are often encountered in both children and adults at clinical settings and the low prevalence rates of most identified conditions, were probably related to the lack of awareness or alternative explanations at the community level regarding the understanding of behaviour changes. Campaigns of public mental health education with the aim of providing scientific information to society are highly recommended. While Ethiopia works towards mainstreaming mental health into its health care system, training health care workers in applying simple screening tools like the RQC is recommended.
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56.
  • Dimitriou, Michael, 1979- (författare)
  • Discharges in human muscle afferents during manual tasks
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Muscle spindles are complex sensory organs that have been strongly implicated in the control and perception of movements. Human muscle spindles in relaxed muscles behave as stretch receptors, responding to the length and velocity of their parent muscles. However, it has been unclear how they discharge during active movements since their discharges are also affected by fusimotor activity and extrafusal contractions. The vast majority of neurophysiological recordings of muscle afferents have been obtained under passive conditions, or active but behaviourally restricted conditions. These restrictions prevent predictions of human muscle afferent activity during purposeful multi-joint movements, naturally occurring during tasks such as hand shaping, grasping or key-pressing. An experimental protocol was therefore developed which allowed recordings of muscle receptor afferent activity using microneurography during unrestrained wrist and digit movements. Along with single afferent discharges, recordings were obtained of electromyographic activity of major forearm muscles and the kinematics of the wrist and digits. This approach allowed investigations of the factors shaping afferent discharge during everyday manual tasks, i.e., block-grasping and pressing sequences of keys, and during active sinusoidal joint movements. The afferents’ ability to encode information concerning the state of the muscle and joint kinematics during these tasks was also assessed. The responses of spindle afferents from load-bearing muscles were approximatelly 90 degrees more phase-advanced than expected on the length of their parent muscles. That is, the discharges of primary muscle spindle afferents were significantly affected by both velocity and acceleration, the discharges of secondary afferents by velocity, and neither afferent type was particularly affected by static muscle length. Accordingly, these afferents failed to encode length, encoded velocity well and acceleration poorly. The representation of muscle length and velocity was, however, significantly improved when the discharge activity of Golgi tendon afferents was taken into consideration along with muscle spindle activity. The discharge of primary afferents during both key-pressing and block-grasping was best correlated to the muscle velocities observed ~100-160 ms in the future. This predictive ability went beyond what could be expected from the spindles’ simultaneous sensitivity to velocity and acceleration, and could thus only be explained by implicating the fusimotor drive. In addition, evidence is presented that the fusimotor control of spindles was contingent on entire movement sequences during the key-pressing task. It is proposed that the phase relationship between the discharge rate of spindle afferents and the length of their parent muscles is load dependent. Moreover, muscle spindles seem to act as forward sensory models of their parent muscle, which makes sensorial feedback control possible despite neural delays.
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57.
  • Domkin, Dmitry (författare)
  • Perception and control of upper limb movement: Insights gained by analysis of sensory and motor variability
  • 2005
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Chronic neck-shoulder pain is associated with impairments of proprioception and motor control. Thus, assessment of proprioceptive and motor function may be powerful tools both for research and clinical practice. However, insufficient knowledge of certain features of human sensorimotor control hampers both development and interpretation of results of clinically relevant tests. For example, evidence is lacking which proprioception submodalities are reflected in common tests of proprioception. For testing motor function, a better understanding of the control of goal directed arm movements is needed. The purpose of the thesis was to gain further insights into the sensorimotor control of the upper limb in healthy subjects, with implications for clinical testing. The main aims were: (1) to study relationships of outcomes of different tests of shoulder proprioception and (2) to study control strategies in bimanual pointing tasks by analysis of the structure of joint angle variability with the Uncontrolled Manifold (UCM) method. Correlations between proprioceptive acuity in different variants of ipsilateral position-matching and velocity-discrimination were studied. The main finding was that two uncorrelated mechanisms based either on perception of position or movement might underlie perception of limb location in ipsilateral position-matching. The results provided important information for interpretation of common and development of novel tests of shoulder proprioception. The structure of joint angle variance was computed with respect to several task variables during bimanual pointing. Joint angle variability was decomposed in variance affecting and not affecting a task variable. The results showed that the variance in joint space was structured according to the predictions of the UCM hypothesis. It was also shown that the arms were united into one synergy to significantly larger degree than joints within each arm were united into single-arm synergies. It was concluded that the UCM approach might quantify components of motor variability during repetitive motor tasks.
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58.
  • Drobni, Peter, 1975- (författare)
  • Papillomavirus binding and entry : The heparan sulfate receptor and inhibition by lactoferrin
  • 2005
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Papillomaviruses (PVs) infect epithelial cells and are the main causative agent of cervical carcinoma. There are today more than a hundred different PV types and these can be divided into high risk and low risk types. They infect differentiating epithelial cells which make it cumbersome to propagate and produce human papillomavirus (HPV) virions. A common method to study HPV infection is to use HPV virus like particles (VLPs) produced in recombinant eukaryotic expression systems. Glycosaminoglycans (GAGs) have been described as an initial attachment receptor for several viruses. Our aim was to study the interactions between HPV VLPs and different GAGs to determine how these could affect binding and internalization. We found that soluble heparin was the best GAG inhibitor of HPV-16 VLP binding followed by heparan sulfate of mucosal origin. We could also see that CHO cells deficient in GAG expression had a reduced ability to bind VLPs, as did cells pretreated with heparinase III. Our results suggested a primary interaction between HPV and heparin sulfate. To be able to study the early steps of internalization we developed a method where we conjugated the CFDA-SE dye to the surface of VLPs. CFDA-SE is activated by cellular esterases inside the cell. This renders the particle fluorescent and thereby visible in flow cytometry analysis. With this new technique we found that entry of the mucosal HPV-6 and HPV-16 was inhibited by heparin. We could also detect differences between mucosal HPV-16 and cutaneous HPV-5 when these where pre-incubated together with GAGs. The cutaneous PV type was not inhibited by heparin to as high degree as the mucosal type. This might be explained by charge differences in the capsid. The mucosal capsid seems to be more positively charged than the epithelial type which should result in a higher affinity for the negatively charged GAGs. Also, we report for the first time that HPV-5 uses a clathrin mediated internalization process. It has been reported for other viruses such as herpes simplex virus (HSV) that lactoferrin, a protein found in high concentrations in breast milk and vaginal fluids could inhibit infection. Interestingly, HSV also use heparan sulfate as a primary attachment molecule. We wanted to investigate if lactoferrin and lactoferricin could have an effect on HPV binding and internalization. We pre-treated HPV-16 VLPs with lactoferrin of bovine or human origin before infection. After incubation we could detect reduced levels of both bound and internalized HPV VLPs to HaCaT cells. In this case, lactoferrin of bovine origin proved to be more efficient in inhibiting both binding and internalization. To further investigate this we used the N-terminal part of lactoferrin, lactoferricin, to study any possible inhibitory effects. Here we found that lactoferricin of bovine origin was a more potent inhibitor of binding, while human lactoferricin was more effective in inhibiting internalization. This could in part be explained by folding differences between these two related proteins. This work further strengthens the proposed interaction between HS and PV for initial interaction and for the first time show charge depending differences between cutaneous and mucosal type binding and internalization and also that lactoferrin and lactoferricin, parts of the innate immune system inhibit PV binding and internalization in vivo.
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59.
  • Duarte, Nádia, 1977- (författare)
  • Molecular and cellular mechanisms contributing to the pathogenesis of autoimmune diabetes
  • 2005
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Type 1 diabetes is an autoimmune disorder determined both by genetic and environmental factors. The Non-obese diabetic (NOD) mouse is one of the best animal models of this disease. It spontaneously develops diabetes through a process resembling the human pathogenesis. The strong association of NOD Type 1 diabetes to the MHC region and the existence of other diabetes susceptibility loci are also in parallel with the human disease. The identity of the genetic factors and biological function mediated by these loci remain, however, largely unknown. Like in other autoimmune diseases, defects in tolerance mechanisms are thought to be at the origin of type 1 diabetes. Accordingly, defects in both central and peripheral tolerance mechanisms have been reported in the NOD mouse model. Using a subphenotype approach that aimed to dissect the disease into more simple phenotypes, we have addressed this issue. In paper I, we analyzed resistance to dexamethasone-induced apoptosis in NOD immature thymocytes previously mapped to the Idd6 locus. Using a set of congenic mice carrying B6-derived Idd6 regions on a NOD background and vice-versa we could restrict the Idd6 locus to an 8cM region on the telomeric end of chromosome 6 and the control of apoptosis resistance to a 3cM region within this area. In paper II, further analysis of diabetes incidence in these congenic mice separated the genes controlling these two traits, excluding the region controlling the resistance to apoptosis as directly mediating susceptibility to diabetes. These results also allowed us to further restrict the Idd6 locus to a 3Mb region. Expression analysis of genes in this chromosomal region highlighted the Lrmp/Jaw1 gene as a prime candidate for Idd6. Lrmp encodes an endoplasmatic reticulum resident protein. Papers III and IV relate to peripheral tolerance mechanisms. Several T cell populations with regulatory functions have been implicated in type 1 diabetes. In paper III, we analyzed NOD transgenic mice carrying a diverse CD1d-restricted TCR αVa3.2b9), named 24abNOD mice. The number of nonclassical NKT cells was found to be increased in these mice and almost complete protection from diabetes was observed. These results indicate a role for nonclassical NKT cells in the regulation of autoimmune diabetes. In paper IV, we studied the effects of introducing the diverse CD1d-restricted TCR (Va3.2b9) in immunodeficient NOD Rag-/- mice (24abNODRag-/- mice). This resulted in a surprising phenotype with inflammation of the ears and augmented presence of mast cells as well as spleenomegaly and hepatomegaly associated with extended fibrosis and increased numbers of mast cells and eosinophils in the tissues. These observations supported the notion that NKT cells constitute an “intermediary” cell type, not only able to elicit the innate immune system to mount an inflammatory response, but also able to interact with the adaptive immune system affecting the action of effector T cells in an autoimmune situation. In this context the 24abNODRag-/- mice provide an appropriate animal model for studying the interaction of NKT cells with both innate and adaptive components of the immune systemα.
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60.
  • Dubbaka Venu, Pradeep Reddy, 1982- (författare)
  • Molecular studies of intra-oocyte phosphatidylinositol 3 kinase (PI3K) signaling pathway in controlling female fertility
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The primordial follicle pool is the main source of developing follicles in the ovary. The length of reproductive life and the onset of menopause are governed by the amount of primordial follicles in the ovary. The genetic factors and molecular mechanisms that maintain the primordial follicles in a dormant and surviving state for the whole of reproductive life are not well understood. The phosphatidylinositol 3 kinase (PI3K) signaling pathways in the oocyte that control oocyte growth and early follicular development are largely unknown. The major aim of this thesis was to investigate the functional role of the intra-oocyte PI3K pathway in the regulation of primordial follicle activation and survival.  Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a major negative regulator of PI3K. The conditional deletion of Pten in the oocytes of primordial follicles led to the overgrowth of oocytes and activation of the entire pool of primordial follicles. There were higher numbers of activated primordial follicles at postnatal day 8 (PD8) in ovaries lacking PTEN in oocytes; by PD35 all the primordial follicles were activated and all the follicles were depleted by 12 weeks, causing premature ovarian failure (POF). In addition, the rate of follicular death that occurs during sexual maturity is reduced in ovaries that lack PTEN in oocytes. Further mechanistic studies revealed that loss of Pten in oocytes resulted in elevated Akt signaling and upregulation of both expression and activation of ribosomal protein S6 (rpS6). The overactivation of primordial follicles in ovaries that lack PTEN in oocytes is believed to be due to elevated expression and activation of rpS6. PTEN in oocytes is indispensable for the maintenance of primordial follicles in dormancy.  To study the role of the intra-oocyte PI3K signaling pathway in controlling the survival and maintenance of primordial follicles, 3-phosphoinositide-dependent protein kinase-1 (PDK1) was deleted in oocytes of primordial follicle. The loss of Pdk1 in oocytes led to the depletion of most primordial follicles around the onset of sexual maturity, causing POF during early adulthood. Furthermore, the activation of Akt, p70 S6 kinase 1 (S6K1), and rpS6 was impaired in oocytes that lacked PDK1. The suppressed PDK1–Akt–S6K1–rpS6 signaling in oocytes appears to be responsible for the loss of primordial follicles. The excessive activation of primordial follicles seen in the absence of Pten in oocytes could be reversed by concurrent deletion of Pdk1. In addition, the elevated activation of Akt and S6K1 in the absence of PTEN in oocytes was not observed in PTEN and PDK1 double mutant mice. Similarly, the hyperphosphorylation of rpS6 in oocytes that lack PTEN was prevented in double mutant mice, which was most likely due to downregulation of S6K1 activation. Thus, inactivation of rpS6 in double mutant mice might be the reason for the prevention of excessive primordial follicular activation and survival.  PTEN and PDK1 in oocytes are essential for the maintenance of quiescence and survival of primordial follicles. The molecular network involving PI3K/PTEN–PDK1 signaling in oocyte controls the survival, loss, and activation of primordial follicles, which together govern reproductive aging and determine the length of reproductive life in females. The results of the above studies indicate that the mammalian oocyte serves as the seat of programming of follicular activation and survival.
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