| 1. |
- Ahlsten, Nanna, 1982-
(författare)
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Transition metal-catalysed isomerisation of allylic alcohols : Applications to C−C, C−F and C−Cl bond formation
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The focus of this thesis has been to develop selective and atom-economical methods for carbon-carbon and carbon-heteroatom bond formation, and to some extent improve on existing findings in this area. More specifically, methods for the catalytic generation of enolates from allylic alcohols and their in situ functionalisation with electrophilic reagents are described. In the first part of this thesis, a method for the Rh-catalysed redox-isomerisation of allylic alcohols into carbonyl compounds under environmentally benign conditions is described. The reaction takes place at room temperature, in the absence of acids or bases, using water as the only solvent, and it is applicable to both primary and secondary allylic alcohols.The second part describes the combination of an isomerisation reaction of allylic alcohols with a C−C bond formation, catalysed by a rhodium complex. In this way, allylic alcohols were coupled with aldehydes and N-tosylimines to give aldol and Mannich-type products. In addition to allylic alcohols, homoallylic and bishomoallylic alcohols could be used as enolate precursors, and this is the first report where the latter two substrate types have been used in such a reaction. In the remaining parts of the thesis, an iridium-catalysed isomerisation of allylic alcohols has been combined with an electrophilic halogenation step to provide a conceptually new method for the synthesis of α-halogenated carbonyl compounds. In this way, α-fluoro and α-chloroketones have been synthesised as single constitutional isomers, with the regiochemistry of the final products determined by the position of the double bond in the allylic alcohols. The reactions are tolerant to air, run in water-organic solvent mixtures, and proceed at room temperature.
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| 2. |
- Alsehli, Ahmed
(författare)
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The role of HMG-coenzyme A reductase (HMGCR) and statin medication in the Central Nervous System : Cognitive Functions, Metabolism, Feeding and Sleep Behaviour
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Millions of people are currently on statin medications (HMGCR inhibitors) to prevent cardiovascular diseases. Despite considerable central nervous system expression, little is known about HMGCR function in the brain. In Paper I, we used Drosophila and rodent models and found that inhibiting Hmgcr expression in the insulin-producing cells of the Drosophila hypothalamus equivalent, known as the pars intercerebralis (PI), throughout development, significantly reduces the expression of Insulin–like peptides 2 and 3 (ILP2 and ILP3), severely decreasing insulin signalling. This reduction causes decreased body size, hyperglycemia, increased lipid storage, and hyperphagia. We also discovered that Farnesyl pyrophosphate synthase (Fpps), an enzyme downstream of Hmgcr in the mevalonate pathway, is required for ILP2 expression in the PI. In rodents, acute inhibition of hypothalamic Hmgcr stimulates food intake as well. Furthermore, in rats, we found two regions within the hypothalamus that had significantly increased neural activity, the paraventricular nucleus and arcuate nucleus, which are known to regulate food intake. In Paper II, we explored the effects of statins on cognition and performed an observational study on a population-based sample from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups. Subjects were classified depending on age (up to 65 and over 65 years). The effect of statin use differed between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. In Paper III, we examined association of single nucleotide polymorphisms within the HMGCR gene, rs17238484 and rs12916, with self-reported insomnia symptoms. We found that statin users are associated with a higher risk for self-reported insomnia. The HMGCR genetic variants were also associated with self-reported insomnia, but in different manner. Carriers the rs12916-T risk allele had a protective effect from insomnia symptoms. No associations were found for either statin takers or carriers of these HGCMR risk alleles and late evening chronotype. The increased risk of insomnia noted with statins is partially explained by a mechanism that might be independent of HMGCR inhibition. In Paper IV, we discovered a novel role for Hmgcr in sleep regulation in Drosophila, where lacking of pan-neuronal Hmgcr expression causes sleep-promoting effects. We also found that loss of Hmgcr expression specifically in the PI insulin-producing cells, recapitulates the effect of pan-neuronal Hmgcr inhibition. Conversely, inhibiting Hmgcr in only six PI DH44 expressing neurons has the opposite effect on sleep, increasing sleep latency and decreasing sleep duration. This bi-functional property of Hmgcr in the fly brain underlies its importance in sleep regulation. Furthermore, loss of Hmgcr showed no effect on circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock.
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| 3. |
- Cao, Hao
(författare)
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Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Most species are constantly exposed to xenobiotic chemicals through multiple routes. Among all categories of xenobiotics, phthalates and bisphenols are two of the most widely used plasticizers and can be found in polyvinyl chloride (PVC) materials, medical devices and even drinking water. In paper I, we found that bis-(2-ethylhexyl) phthalate (DEHP) exposure caused a significant decrease in circulating carbohydrates and insulin-related genes. The Multidrug-Resistance like Protein 1 (MRP1, MRP in Drosophila) belongs to the ATP-binding cassette transporter family, and previous studies revealed the importance of MRP1 for transporting xenobiotics. However, the function of MRP1 in metabolism and other biological processes is still unclear. Therefore, in paper II, we showed that knocking down MRP expression in Malpighian tubules, the physiological equivalence of the vertebrate kidney, led to disrupted lipid homeostasis and oxidative resistance. In paper III and IV, we initially used whole transcriptome sequencing to assess the genetic interferences of exposure to Dibutyl Phthalate (DBP) and Bisphenol A Diglycidyl Ether (BADGE). The reproductive and developmental disruptions of DBP had been reported in many studies. However, the mechanism is still unclear. In paper III, we observed that DBP interfered with neuronal systems associated circadian genes, including in vrille (vri, human NFIL3), timeless (tim, human TIMELESS), period (per, human PER3) and Pigment-dispersing factor (Pdf). Furthermore, we demonstrated that the evolutionarily conserved gene, Hormone receptor-like in 38 (Hr38, human NR4A2) was involved in responding to DBP and regulated Pdf expression as a consequence. In paper IV, BADGE, a BPA-substitute, was tested for its disruptive effects on Drosophila. Based on the transcriptome sequencing, we found that several mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), had detectable overexpression by BADGE exposure. Developmental exposure to BADGE induced a large increase of hemocytes in fly 3rd instar larvae, while it did not damage the morphological structure of lymph gland and blood circulation. To summarize, our studies describe the potential disruptions of the industrial xenobiotics and provide the mechanistic hints for future investigations.
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| 4. |
- Fröcklin, Sara, 1981-
(författare)
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Women in the Seascape : Gender, Livelihoods and Management of Coastal and Marine Resources in Zanzibar, East Africa
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- All over the world, coastal populations depend on, and influence, the environment in pursue of their livelihoods. Managing the environment, while meeting the growing demand for marine resources, is a challenge. It further requires knowledge about all actors. Women's contribution is often overlooked in research, policy and management of marine and coastal resources. This thesis aims to reduce this gap; a gender analysis is applied to differentiate women and men's access and use of the seascape and to address key gender issues in coastal livelihoods in Zanzibar, Tanzania. Paper I shows that men are typically engaged in fisheries and have access to the whole seascape, whereas women engage in less economically viable activities, such as seaweed farming and invertebrate harvesting, in near-shore areas. A limitation for women to reach the whole seascape is a general lack of boat transport, swimming skills and fishing gear. Paper II analyzes occupational health within seaweed farming and shows that women seaweed farmers suffer from a variety of problems, such as eye infections, musculoskeletal pains, respiratory problems and fatigue, because of poor working conditions. Paper III addresses social and ecological aspects of invertebrate harvesting. This activity lacks proper management and over a five-year period (2005 to 2010), invertebrate abundance and species richness have decreased. It also reveals gender disparities in access to invertebrate collecting grounds and species of higher economic value. Paper IV examines gender within fish trade; women traders have less access to markets, high-value fish, a diverse customer-base, cold-storing facilities and fish trade associations. Income data shows that women's income is always lower. The management system is found to be androcentric and this thesis thus argues for the need to look at the "bigger picture"; the whole seascape, both men and women, and their interests should be considered in coastal and marine management.
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| 5. |
- Heil, Katharina F., 1987-
(författare)
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A Systems Biological Approach to Parkinson's Disease
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s Disease (PD) is the second most common neurodegenerative disease in the Western world. Itshows a high degree of genetic and phenotypic complexity with many implicated factors, various diseasemanifestations but few clear causal links. Ongoing research has identified a growing number of molecularalterations linked to the disease.Dopaminergic neurons in the substantia nigra, specifically their synapses, are the key-affected region in PD.Therefore, this work focuses on understanding the disease effects on the synapse, aiming to identify potentialgenetic triggers and synaptic PD associated mechanisms. Currently, one of the main challenges in this area isdata quality and accessibility.In order to study PD, publicly available data were systematically retrieved and analysed. 418 PD associatedgenes could be identified, based on mutations and curated annotations. I curated an up-to-date and completesynaptic proteome map containing a total of 6,706 proteins. Region specific datasets describing thepresynapse, postsynapse and synaptosome were also delimited. These datasets were analysed, investigatingsimilarities and differences, including reproducibility and functional interpretations.The use of Protein-Protein-Interaction Network (PPIN) analysis was chosen to gain deeper knowledgeregarding specific effects of PD on the synapse. Thus I generated a customised, filtered, human specificProtein-Protein Interaction (PPI) dataset, containing 211,824 direct interactions, from four public databases.Proteomics data and PPI information allowed the construction of PPINs. These were analysed and a set oflow level statistics, including modularity, clustering coefficient and node degree, explaining the network’stopology from a mathematical point of view were obtained.Apart from low-level network statistics, high-level topology of the PPINs was studied. To identify functionalnetwork subgroups, different clustering algorithms were investigated. In the context of biological networks, theunderlying hypothesis is that proteins in a structural community are more likely to share common functions.Therefore I attempted to identify PD enriched communities of synaptic proteins. Once identified, they werecompared amongst each other. Three community clusters could be identified as containing largely overlappinggene sets. These contain 24 PD associated genes. Apart from the known disease associated genes in thesecommunities, a total of 322 genes was identified. Each of the three clusters is specifically enriched for specificbiological processes and cellular components, which include neurotransmitter secretion, positive regulation ofsynapse assembly, pre- and post-synaptic membrane, scaffolding proteins, neuromuscular junctiondevelopment and complement activation (classical pathway) amongst others.The presented approach combined a curated set of PD associated genes, filtered PPI information andsynaptic proteomes. Various small- and large-scale analytical approaches, including PPIN topology analysis,clustering algorithms and enrichment studies identified highly PD affected synaptic proteins and subregions.Specific disease associated functions confirmed known research insights and allowed me to propose a newlist of so far unknown potential disease associated genes. Due to the open design, this approach can be usedto answer similar research questions regarding other complex diseases amongst others.
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| 6. |
- Juremalm, Mikael, 1968-
(författare)
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The Role of Chemokines in Mast Cell Migration
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mast cells are very potent multifunctional effector cells of the immune system normally distributed throughout connective tissues. An accumulation of mast cells has been described in several pathological conditions such as allergic- and autoimmune inflammations and in certain tumours. This necessitates two different processes: 1) Recruitment of mast cell progenitors from peripheral blood; 2) Accretion of mature mast cells at sites of inflammation and tumour areas. Both processes are depending on the local production of chemotactic factors. The aim of this study was to investigate the role of chemokines and their corresponding receptors in mast cell chemotaxis. By cloning and mRNA-screening of cord blood derived mast cells several chemokine receptors were found to be expressed. Functional expression was confirmed of chemokine receptors CXCR4, CCR1 and CCR4. CXCL12, the only known ligand for CXCR4, acted as a mast cell chemotaxin and induced migration of progenitor cells with capacity to differentiate into mast cells. Of several ligands known to bind CCR1 and CCR4, only CCL5 induced migration of mast cells. The migration to CCL5 was mediated through both CCR1 and CCR4. In contrast, the ligands to CCR4, CCL17 and CCL22, could inhibit CCL5-induced migration. Expression of CCR1 and CCR4 could also be confirmed on mast cells in lung from asthmatic patients. Furthermore, we could demonstrate that mast cells were attracted by CCL5 produced by tumour cells in Hodgkin´s lymphoma.In conclusion, the work in this thesis has identified two chemokines that regulates mast cell migration. This knowledge helps us understand the mechanisms behind homing of mast cell progenitors from the blood into the tissue and the accumulation of mature mast cells at sites of inflammation and tumourigenesis.
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| 7. |
- Lin, Xionghui, 1976-
(författare)
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Hematopoiesis in a Crustacean
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hemocytes (blood cells) play an important role in the immune response in invertebrates, and thus the regulation of hemocyte homeostasis (hematopoiesis) is essential for the host survival against pathogens. Astakine 1, a homologue to vertebrate prokineticins, was first identified in the freshwater crayfish Pacifastacus leniusculus as a cytokine, and was found to be necessary for new hemocyte synthesis and release in vivo, and also to induce spreading and proliferation of Hematopoietic tissue cells (Hpt cells, precursor of hemocytes) in vitro. The work of this thesis is aimed to further our understanding of the molecular mechanisms involved in astakine 1 induced hematopoiesis.Crayfish transglutaminase (Tgase) has been identified in the hemocytes, and is essential for the coagulation reaction. Interestingly this enzyme is exceedingly abundant in the Hpt cells, and the spreading of Hpt cells induced by astakine 1 was accompanied by sequential loss of TGase activity from the surface of these cells. This loss of TGase activity may be an important effect of astakine 1, resulting in recruiting new hemocytes into the circulatory system. Although astakine 1 contain a prokineticin domain, it lacks the conserved N-terminal AVIT motif present in its vertebrate homologues. This motif is important for vertebrate prokineticins to interact with their receptors, indicating a different receptor interaction for crayfish astakine 1. Astakine 1 was indeed found to interact with a completely different receptor, the β-subunit of ATP synthase, on a portion of Hpt cells, and subsequently block its extracellular ATP formation. Surface ATP synthase has been reported on numerous mammalian cells, but now for the first time in an invertebrate. The activity of ATP synthase on the Hpt cells may be important for the survival and proliferation of Hpt cells, but the underlying mechanisms remain further study. With the finding of a second type of astakine in crayfish, invertebrate astakines can be divided into two groups: astakine 1 and astakine 2. The properties of astakine 2 are different from those of astakine 1 both in structure and function. In primary cell culture of Hpt cells, only astakine 1 can promote proliferation as well as differentiation into semigranular cells, whereas astakine 2 may play a potential role in the maturation of granular cells. Moreover, a novel cysteine rich protein, Pacifastacus hematopoiesis factor (PHF), was found to be one target gene of astakine 1 in Hpt cells. Down regulation of PHF results in increased apoptosis in Hpt cells in vitro, and in vivo silencing PHF leads to a severe loss of hemocytes in the animal. Therefore astakine 1 acquires the anti-apoptosis ability by inducing its downstream gene PHF in the Hpt cells. With its ability to promote the survival, proliferation and differentiation of Hpt cells, astakine 1 is proven to be an important hematopoietic growth factor.
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| 8. |
- Raddock, Elisabeth, 1975-
(författare)
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Listen how the wise one begins construction of a house for Viṣṇu : vijānatā yathārabhyaṃ gṛhaṃ vaiṣṇavaṃ śṛṇv evaṃ. Chapters 1-14 of the Hayaśīrṣa Pañcarātra
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation consists of a translation of the first fourteen chapters of Hayaśirṣa Pañcarātra and a detailed analysis aiming at its contextualization in historical, cultural, and theological milieus. The Hayaśirṣa Pañcarātra is a Sanskrit text from approximately the ninth century A.D. primarily dealing with rituals concerning the construction of a temple to the god Viṣṇu. The text is probably from Eastern India, most likely Bengal or Orissa. The Hayaśirṣa Pañcarātra belongs to the Pāñcarātra tradition, a Viṣṇu centered movement within what we today call Hinduism. The Hayaśirṣa Pañcarātra has incorporated older texts, most of which are no longer extant, and has also been a source-text for later works, most notably the Agni Purāṇa and the Hari Bhakta Vilāsa. The text is named after Hayaśirṣa, the horse-headed incarnation of Viṣṇu, who represents Viṣṇu’s divine character as revealer of śruti. This is the first time that the Hayaśirṣa Pañcarātra has been translated. The text is important for Sanskrit textual history, art history, cultural history, religious history of the subcontinent, but unavailable to even most Sanskrit scholars because of a lack of access to the Sanskrit text. The translated chapters deal with preliminary work including choosing the participants for the undertaking. They list, therefore, prerequisites and qualifications, particularly of the ācārya, the specific qualities required of the site, and for digging the foundation. The Hayaśirṣa Pañcarātra situates the temple at the center of the universe by means of the vāstupuruṣamaṇḍala. The vāstupuruṣamaṇḍala is, I argue, both a ritual and a practical diagram: it is used ritually to locate the temple at the center of the universe; and it is used practically to plan the layout of the temple. The rituals marking the beginning of temple construction, like ritual plowing, can be traced to Vedic ceremonial practice, including, but not limited to, ritual plowing in the Vedic fire altar. The text focuses on certain moments within the construction because of the ritual function of these moments. The text is primarily a ritual text, possibly written for the ācārya. The Hayaśirṣa Pañcarātra is central to the understanding of temple construction and the rituals around it making the view of these more complete.
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| 9. |
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