| 1. |
- Ament-Velásquez, Sandra Lorena, M.Sc. 1988-
(författare)
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Drivers of evolutionary change in Podospora anserina
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Genomic diversity is shaped by a myriad of forces acting in different directions. Some genes work in concert with the interests of the organism, often shaped by natural selection, while others follow their own interests. The latter genes are considered “selfish”, behaving either neutrally to the host, or causing it harm. In this thesis, I focused on genes that have substantial fitness effects on the fungus Podospora anserina and relatives, but whose effects are very contrasting. In Papers I and II, I explored the evolution of a particular type of selfish genetic elements that cause meiotic drive. Meiotic drivers manipulate the outcome of meiosis to achieve overrepresentation in the progeny, thus increasing their likelihood of invading and propagating in a population. In P. anserina there are multiple meiotic drivers but their genetic basis was previously unknown. In Paper I, we demonstrated that drive is caused by members of the Spok gene family. We discovered two new Spok genes, Spok3 and Spok4, which locate in different chromosomes in different strains. In Paper II, we showed that Spok3 and Spok4 are found on a gigantic (up to 247 Kb long) variant of Enterprise, a Crypton-like transposable element. Enterprise likely mobilize through the action of a putative tyrosine-recombinase that we call Kirc. When carrying the Spoks, this element has double selfish properties: transposition and meiotic drive. In addition, we found that homologs of the Spoks (Paper I) and of Kirc (Paper II) are widespread in fungi but their phylogenies are discordant with that of the species, suggesting that they have undergone horizontal gene transfer. In Papers III and IV, I turned the focus into genes that have an adaptive function. In fungi, the het genes control conspecific self/non-self recognition. Such genes are expected to evolve under frequency-dependent balancing selection. In Paper III, we found evidence of balancing selection acting on some het genes across the P. anserina species complex. Unexpectedly, we also discovered that het genes of the HNWD gene family are duplicated in a transposon-like manner, broadening our understanding of their potential fitness effects. Finally, in Paper IV we show how het genes with pleiotropic effects on sexual recognition lead to the evolution of strong reproductive isolation, and hence speciation. Overall, the results of my thesis highlight the functional intersection between mobile selfish genetic elements and other genes, either selfish or adaptive, and their effects on genome architecture and population structure.
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| 2. |
- Bengtsson, Inger M., 1944
(författare)
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Psychosocial and stress-related aspects on ischemic heart disease
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To study different aspects of ischemic heart disease (IHD) i.e. stress related risk factors, biochemical markers of stress, in particular the cortisol awakening response (CAR) and outcome in terms of health related quality of life (HRQoL). Methods: 72 myocardial infarction (AMI) patients took part in the HRQoL studies. From a subsample of a population-based cohort of Swedish adults 194 men and women, 15% with the metabolic syndrome (MetS), took part in awakening cortisol sampling. The risk factor study was conducted on 290 previous chest pain patients. Assessment of HRQoL was via questionnaires (SF-36, CHP, Zung). CAR was performed by measuring salivary cortisol and medical records or death certificates were read identifying ischemic heart or cerebrovascular disease during 14-years of follow-up. Results: Patients < 59 years improved in SF-36 Physical Component scores (PCS) but not in Mental Component scores (MCS), and scored significantly below community norms in both PCS, mean (CI) = 44.7 (40.6–48.7) vs. 50.3 (49.3–51.4) and MCS = 45.9 (41.8–49.9) vs. 51.3 (50.3–52.4) at 6 months. Predictors for MCS were age (p=0.03) and Vitality (p=0.02). Predictors for PCS were Physical Function (p=0.01) and CCS angina scores (p < 0.001). Angina was negatively related to HRQoL. Patients < 59 years reached community norms in PCS after 2 years but scored significantly below norms in MCS throughout with an effect size of -0.5 (CI -0.88 to -0.14) at 2 years. In patients ≥ 59 years, no changes took place after 6 months. A significant difference in CAR% was found between men and women with MetS, mean (±SE) = 38.5 (13.1)% and 91.4 (17.0)%, p=0.02. Women with the MetS awoke with the lowest cortisol level, mean (± SE) = 8.92 (0.96) nmol/l. Women without MetS had a CAR% of 36.5 (5.7)% and a awakening cortisol level of 12.33 (0.69) nmol/l. The values for men were 38.5 (13.1)% and 36.0 (6.1)%. 74 patients had died or been hospitalised with a diagnosis of IHD or cerebrovascular disease. Age (OR 1.1, CI 1.1–1.2), previous history of angina pectoris (OR 9.7, CI 2.1–71.6), pathological ECG at ED (OR 3.3, CI 1.2–8.7), hypertension (OR 5.0, CI 1.9–13.8) and smoking (OR 3.0, CI 1.3–7.6) were all associated with future IHD or cerebrovascular events. Noradrenalin (NA) levels were highest in the event group compared with the non-event group, mean (± SD) = 2.44 (1.02) versus 1.90 (0.75) and lowest in the non-participants 1.80 (0.61) nmol/l. Cortisol values were lowest in the event group, mean ± (SD) = 377(133) nmol/l. Conclusion: Inferior health in younger compared to older AMI patients in mental health domains of HRQoL was detected as was a sex difference in the cortisol awakening response between men and women with MetS. Traditional risk factors were found to predict future diagnosis of ischemic heart or cerebrovascular disease 14 years after a hospital visit for chest pain.
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| 3. |
- Bengtsson, Jörgen, 1976-
(författare)
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Developmental Aspects of Drug Transport Across the Blood-Brain Barrier
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The developmental aspect of drug transport across the blood-brain barrier (BBB) was investigated. Microdialysis was used to study unbound morphine BBB transport at different ages in sheep. An in vitro study was performed to find differentially expressed genes in brain capillary-rich fractions of the brain in rats of different ages. Microdialysis and brain-to-plasma ratios were used to study the contribution of breast cancer resistance protein (Bcrp) to the transport of nitrofurantoin (NTF) across the BBB of rats during development as well as in adult rats and mice. A method of analysing morphine and its metabolites in plasma and microdialysis samples was developed and validated. The in vivo recovery of deuterated morphine, used as a calibrator in microdialysis experiments, was not affected by the presence of morphine in the tissue. A net influx of morphine was observed in premature lambs and adult sheep, in contrast to the efflux seen in other species. This influx decreased with age, indicating that the morphine transport across the BBB changes with age. In contrast, the transport of the morphine metabolite morphine-3-glucuronide (M3G) did not change with age. Microarray data indicated that several active transporters are differentially expressed with age. Moreover, the mRNA expression levels of Abcg2 (Bcrp) and Slc22a8 (organic anion transporter 3) changed with age when quantified using real-time polymerase chain reaction. In contrast, the expression of Abcb1 (P-glycoprotein) and occludin (a tight junction protein) did not change with age. In rats, the brain distribution of NTF decreased with age due to increased protein binding in plasma. The concentration ratio of unbound NTF across the BBB was low in the adult rat, due to intra-brain metabolism and/or efflux by other transporters. Bcrp did not appear to have a significant contribution in the developing rat or in knock-out mice compared to wild-type controls with regard to NTF BBB transport. In conclusion, in vitro studies showed that the expression levels of some genes changed with age, presumably affecting subsequent drug distribution to the brain. Further, in vivo studies showed that distribution across the BBB changed with age for morphine but not for M3G or NTF.
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| 4. |
- Bengtsson, Magnus Wilhelm, 1977-
(författare)
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Effects of Orexins, Guanylins and Feeding on Duodenal Bicarbonate Secretion and Enterocyte Intracellular Signaling
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The duodenal epithelium secretes bicarbonate ions and this is regarded as the primary defence mechanism against the acid discharged from the stomach. For an efficient protection, the duodenum must also function as a sensory organ identifying luminal factors. Enteroendocrine cells are well-established intestinal “taste” cells that express signaling peptides such as orexins and guanylins. Luminal factors affect the release of these peptides, which may modulate the activity of nearby epithelial and neural cells.The present thesis considers the effects of orexins and guanylins on duodenal bicarbonate secretion. The duodenal secretory response to the peptides was examined in anaesthetised rats in situ and the effects of orexin-A on intracellular calcium signaling by human as well as rat duodenal enterocytes were studied in vitro.Orexin-A, guanylin and uroguanylin were all stimulants of bicarbonate secretion. The stimulatory effect of orexin-A was inhibited by the OX1-receptor selective antagonist SB-334867. The muscarinic antagonist atropine on the other hand, did not affect the orexin-A-induced secretion, excluding involvement of muscarinic receptors. Orexin-A induced calcium signaling in isolated duodenocytes suggesting a direct effect at these cells. Interestingly, orexin-induced secretion and calcium signaling as well as mucosal orexin-receptor mRNA and OX1-receptor protein levels were all substantially downregulated in overnight fasted rats compared with animals with continuous access to food. Further, secretion induced by Orexin-A was shown to be dependent on an extended period of glucose priming.The uroguanylin-induced bicarbonate secretion was reduced by atropine suggesting involvement of muscarinic receptors. The melatonin receptor antagonist luzindole attenuated the secretory response to intra-arterially administered guanylins but had no effect on secretion when the guanylins were given luminally. In conclusion, the results suggest that orexin-A as well as guanylins may participate in the regulation of duodenal bicarbonate secretion. Further, the duodenal orexin system is dependent on the feeding status of the animals.
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| 5. |
- Niazi, M. Khalid Khan, 1978-
(författare)
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Image Filtering Methods for Biomedical Applications
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Filtering is a key step in digital image processing and analysis. It is mainly used for amplification or attenuation of some frequencies depending on the nature of the application. Filtering can either be performed in the spatial domain or in a transformed domain. The selection of the filtering method, filtering domain, and the filter parameters are often driven by the properties of the underlying image. This thesis presents three different kinds of biomedical image filtering applications, where the filter parameters are automatically determined from the underlying images.Filtering can be used for image enhancement. We present a robust image dependent filtering method for intensity inhomogeneity correction of biomedical images. In the presented filtering method, the filter parameters are automatically determined from the grey-weighted distance transform of the magnitude spectrum. An evaluation shows that the filter provides an accurate estimate of intensity inhomogeneity.Filtering can also be used for analysis. The thesis presents a filtering method for heart localization and robust signal detection from video recordings of rat embryos. It presents a strategy to decouple motion artifacts produced by the non-rigid embryonic boundary from the heart. The method also filters out noise and the trend term with the help of empirical mode decomposition. Again, all the filter parameters are determined automatically based on the underlying signal.Transforming the geometry of one image to fit that of another one, so called image registration, can be seen as a filtering operation of the image geometry. To assess the progression of eye disorder, registration between temporal images is often required to determine the movement and development of the blood vessels in the eye. We present a robust method for retinal image registration. The method is based on particle swarm optimization, where the swarm searches for optimal registration parameters based on the direction of its cognitive and social components. An evaluation of the proposed method shows that the method is less susceptible to becoming trapped in local minima than previous methods.With these thesis contributions, we have augmented the filter toolbox for image analysis with methods that adjust to the data at hand.
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| 6. |
- Olsen, Jessica M., 1986-
(författare)
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β-Adrenergic Signalling Through mTOR
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adrenergic signalling is part of the sympathetic nervous system and is activated upon stimulation by the catecholamines epinephrine and norepinephrine. This regulates heart rate, energy mobilization, digestion and helps to divert blood flow to important organs. Insulin is released to regulate metabolism of carbohydrates, fats and proteins, mainly by taking up glucose from the blood. The insulin and the catecholamine hormone systems are normally working as opposing metabolic regulators and are therefore thought to antagonize each other.One of the major regulators involved in insulin signalling is the mechanistic target of rapamycin (mTOR). There are two different complexes of mTOR; mTORC1 and mTORC2, and they are essential in the control of cell growth, metabolism and energy homeostasis. Since mTOR is one of the major signalling nodes for anabolic actions of insulin it was thought that catecholamines might oppose this action by inhibiting the complexes. However, lately there are studies demonstrating that this may not be the case. mTOR is for instance part of the adrenergic signalling pathway resulting in hypertrophy of cardiac and skeletal muscle cells and inhibition of smooth muscle relaxation and helps to regulate browning in white adipose tissue and thermogenesis in brown adipose tissue (BAT).In this thesis I show that β-adrenergic signalling leading to glucose uptake occurs independently of insulin in skeletal muscle and BAT, and does not activate either Akt or mTORC1, but that the master regulator of this pathway is mTORC2. Further, my co-workers and I demonstrates that β-adrenergic stimulation in skeletal muscle and BAT utilizes different glucose transporters. In skeletal muscle, GLUT4 is translocated to the plasma membrane upon stimulation. However, in BAT, β-adrenergic stimulation results in glucose uptake through translocation of GLUT1. Importantly, in both skeletal muscle and BAT, the role of mTORC2 in β-adrenergic stimulated glucose uptake is to regulate GLUT-translocation.
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