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- Yeshanew, Fitsum Girum, 1984-
(författare)
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Crustal evolution of the Arabian–Nubian Shield : Insights from zircon geochronology and Nd–Hf–O isotopes
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Arabian–Nubian Shield (ANS) represents a major site of juvenile Neoproterozoic crustal addition on Earth and documents Neoproterozoic tectonics bracketed by two supercontinent cycles, namely the fragmentation of Rodinia and the amalgamation of Gondwana. There is general consensus that the ANS formed by juvenile magmatic arc accretion and subsequent shield–wide post–tectonic magmatism. However, detailed understanding about the timing of events and the nature of magma sources in parts of the shield are lacking. To date, there are no isotopic data from the Paleozoic sedimentary sequences of the ANS, except those from the northern part. New zircon U–Pb, δ18O and whole–rock Nd isotopes are presented for plutonic rocks from the eastern Ethiopia, Yemen and southernmost Arabian Shield in Saudi Arabia. This thesis also presents the first combined in situ zircon U–Pb–O–Hf isotope data on the Cambrian–Ordovician sandstones of the Arabian Shield. The results are used to elucidate the crustal evolution of these parts of the ANS and to evaluate terrane correlations. Specifically, the nature of crustal growth, i.e., relative proportions of juvenile magmatic additions vs. crustal reworking, nature of the magma source and mechanism of crust formation (plume material vs. subduction zone enrichment) and understanding the provenance of the Cambrian–Ordovician sandstone sequences were important research questions addressed.The results from Paper I suggest that the eastern Ethiopian Precambrian basement is dominated by reworking of pre-Neoproterozoic supracrustal material unlike contemporaneous rocks in the remaining parts of Ethiopia— indicating the presence of two distinct lithospheric blocks of contrasting isotopic compositions in Ethiopia. Metamorphic age distributions suggest that the eastern Ethiopian block was amalgamated with the juvenile Western Ethiopian Shield during ca. 580–550 Ma. Importantly, the suture between them may represent the northern continuation of a major suture identified further south in Africa along which Gondwana amalgamated. Similarly, the Abas terrane in Yemen (Paper II) is dominated by reworking of pre–Neoproterozoic crust and shows age and isotopic compositions that are inconsistent with the Afif terrane of Saudi Arabia, precluding correlation between the two regions. The trace element systematics of plutonic rocks from the southernmost Arabian Shield (paper III) point to enrichment due to subduction component, bear no evidence of a plume component, and are consistent with the adakite-like chemistry of some of the subduction–related plutonic samples. This reinforces the notion that the shield grew through juvenile magmatic arc additions. The combined zircon U–Pb–O–Hf data of the Cambrian–Ordovician sandstones (Paper IV) indicate their derivation from both the adjacent juvenile ANS and the more southerly crustal blocks that are dominated by reworking of pre–Neoproterozoic crust. The remarkable similarity in age spectra and homogeneity of Cambrian sandstones deposited across the northern margin of Gondwana point to continental–scale sediment mixing and dispersal regulated by the supercontinent cycle.
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- 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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- Baumann, Martin J.
(författare)
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Xyloglucan-active enzymes : properties, structures and applications
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cellulosabaserade material är världens rikligast förekommande förnyelsebara råvara. Växters cellväggar är naturliga kompositmaterial där den kristallina cellulosan är inbäddad i en väv av hemicellulosa, strukturproteiner och lignin. Xyloglukaner är en viktig hemicellulosagrupp som omger och korslänkar den kristallina cellulosan i cellväggarna. I denna avhandling undersöks undersöks sambanden mellan struktur och funktion hos olika xyloglukan-aktiva enzymer. En modell för effektiv enzymatisk omvandling av biomassa ges av cellulosomen hos den anaeroba prokaryota organismen Clostridium thermocellum. Cellulosomen är ett proteinkomplex med hög molmassa och flera olika enzymaktiviteter, bl.a. det inverterande xyloglukan-endohydrolaset CtXGH74A. Proteinstrukturen för CtXGH74A har lösts i komplex med xyloglukanoligosackarider, som stabliliserar vissa loopar/slingor som är oordnade i apostrukturen. Ytterligare detaljerade kinetiska och produktananalyser har genomförts för att entydigt visa att CtXGH74A är ett endoxyloglukanas vars slutliga nedbrytningsprodukt är Glc4-baserade xyloglukanoligosackarider. Som jämförelse innehåller glykosidhydrolasfamilj 16 (GH16) såväl hydrolytiska endoxyloglukanaser som xyloglukantransglykosylaser (XETs) från växter. För att utreda vad som bestämmer förhållandet mellan transglykosylering och hydrolys i xyloglukanaktiva enzymer från familj GH 16 jämfördes struktur och kinetik hos ett strikt transglykosylas, PttXET16-34 från hybridasp, med ett nära besläktat hydrolytiskt enzym, NXG1 från krasse. I NXG1 identifierades en viktig förlängningsloop, som vid trunkering gav ett muterat enzym med högre transglykosyleringshastighet och minskad hydrolytisk aktivitet. Kinetikstudierna genomfördes med hjälp av nyutvecklade känsliga provmetoder med väldefinerade XGO:er och ett antal kromogena XGO-arylglykosider. En detaljerad förståelse av enzymologin inom GH16 möjliggjorde utvecklingen av en ny kemoenzymatisk metod för biomimetisk fiberytmodifiering med hjälp av PttXET16-34s translgykosyleringsaktivitet. Aminoalditolderivat av xyloglukanoligosackarider användes som nyckelintermediärer för att introducera ny kemisk funktionalitet hos xyloglukan, såsom kromoforer, reaktiva grupper, proteinligander och initiatorer för polymeriseringsreaktioner. Tekniken innebär ett nytt och mångsidigt verktyg för fiberytmodifiering.
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- Dalmo, Erika
(författare)
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Glioblastoma heterogeneity and plasticity : Investigating the roles of BMP4 and SOX2
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The malignant primary brain tumor glioblastoma has a dismal prognosis and is distinguished by its heterogeneous character. Current treatment with surgical resection, radiotherapy and adjuvant chemotherapy with the alkylating agent temozolomide does not provide a cure, but simply prolongs survival by a few months. Since the tumors recur, cells remaining after treatment can act as cancer stem cells and are able to reform the tumor. This thesis provides insights into glioblastoma heterogeneity and how dominant transcriptional programs have a substantial impact on glioblastoma cell responses to altered levels of the intrinsic proteins BMP4 and SOX2. SOX2 has a role as a stem cell transcription factor in the normal nervous system and in glioblastoma, while BMP4 acts as a cue for astrocytic differentiation during normal nervous system development. As a response to BMP4, we find a wide spectrum of growth-inhibition across 40 human glioblastoma cell lines and correlate the extent of the response with baseline gene expression in the cells. We discover a connection between high SOX2 expression and a more pronounced growth-inhibitory response and establish a causative relationship between SOX2 downregulation and reduced proliferation in BMP4-responsive cell lines. We also find how BMP4 can induce a senescence-like phenotype in glioblastoma and connect it to a mesenchymal phenotype on a proneural-mesenchymal scale by investigating clonally derived cultures from the same tumor. Through elimination of senescent cells by senolytic treatment and generation p21-knockout cells we also establish a p21-dependence for BMP4-induced senescence.Studies on cellular organization identify a hierarchical cell-state pattern which the cells move through during culture and show that external perturbations (here by BMP4 and temozolomide) alter this hierarchy, demonstrating a substantial cellular plasticity.Also, we establish a strategy to eradicate endogenous SOX2 with the inducible exogenous SOX2-system present, demonstrating that SOX2 is not an essential transcription factor in all glioblastomas. In summary, this thesis highlights several aspects of inter- and intratumoral heterogeneity as well as cellular plasticity, providing valuable insights that could help guide the glioblastoma community in the pursuit of more effective therapies against glioblastoma.
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- Giummarella, Nicola, 1984-
(författare)
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Fundamental Aspects of Lignin Carbohydrate Complexes (LCC) : Mechanisms, Recalcitrance and Material concepts
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Covalent bonds between lignin and carbohydrates, forming a matrix referred to as lignin carbohydrate complexes (LCC), remain one of the most controversial topics in wood chemistry. A key issue is whether they are formed during chemical and mechanical pretreatments of the compact wood structure or actually present in wood prior to isolation. A fundamental understanding of their origin and reactivity is vital to unravel their role in wood formation and recalcitrance. Recalcitrance, specifically, has affected the successful development of effective and clean fractionation of wood polymers.To address the above-mentioned concerns, we have developed a novel mild universal and quantitative fractionation protocol of LCC that, when combined with robust spectroscopic analytical tools, including a variety of NMR techniques, GC MS and SEC, reveals deeper insights into the molecular structure of LCC.This method was applied to both hardwood and softwood LCCs and revealed interesting findings on molecular-level regulatory mechanism for lignin carbohydrate (LC) bond formation such as the role of acetylation in hemicelluloses. Moreover, the role of LC bonds on recalcitrance during subcritical water extraction was unveiled.Bio-mimicking in vitro lignin polymerization was adopted to investigate whether LC bonds are native or formed during isolation from wood. For the first time, direct evidence lending support that they are formed in wood cells was demonstrated, thus corroborating the mechanisms suggested in the literature. Furthermore, based on the overall LCC study, we suggest a sequence for how LC bonds may form in vitro.Finally, of special interest to material science, the unveiled LC bond formation mechanism inspired a green, biomimetic, one-pot synthesis of functionalized lignin starting from monomeric components. Excellent selectivity of functionalization is reported and production of lignin-based recyclable materials, based on the premise of this functionalization philosophy, is discussed.
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- Holmgren, Klas, 1989-
(författare)
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Permanent stoma after anterior resection for rectal cancer : prevalence and mechanisms
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- While sphincter-saving surgery constitutes standard treatment for rectal cancer, anterior resection still harbours a significant risk of a permanent stoma in the long run. Although anastomotic leakage plays a major role in this surgical dilemma, the exact mechanisms are not known, while surveys indicate a stoma-free outcome is essential for a majority of patients. To address this issue, the overall aim of the present thesis was to investigate the permanent stoma prevalence in patients undergoing anterior resection for rectal cancer in Sweden, and to identify plausible mechanisms that impede prospects of a stoma-free outcome.In a population-based cohort, chart review of patients who had anterior resection for rectal cancer in the Northern healthcare region in Sweden between 2007 and 2013 showed that 75 out of 316 (24%) patients ended up with a permanent stoma. Of 274 patients (87%) primarily defunctioned with a stoma, 229 underwent stoma closure, 21 (9%) of whom suffered major complications that required return to theatre or worse. A permanent stoma was shown to be more common among patients with anastomotic leakage and an advanced tumour stage.A registry-based method to estimate nationwide stoma outcome after anterior resection for rectal cancer was developed, using data from the Swedish Colorectal Cancer Registry and the National Patient Registry. With a chart-reviewed cohort as reference, stoma outcome was assessed with a positive predictive value of 85.1%, and a negative predictive value of 100.0%. In patients operated in Sweden between 2007 and 2013, the registry-based method determined that 942 out of 4768 (19.8%) had a permanent stoma, while stoma rates varied substantially between different healthcare regions.In a 1:1 matched case-control study of 82 patients who had curative resection for non-disseminated colorectal cancer, a subgroup analysis of 34 patients with rectal cancer displayed biomarker aberrations in serum measured preoperatively in those with anastomotic leakage. Compared to complication-free controls, 15 proteins related to inflammation were elevated, of which two (C-X-C motif chemokine 6, and C-C motif chemokine 11) remained significant after adjustment for multiple testing.Based on a cohort of 4529 patients who had anterior resection, tumour height served as a proxy to determine the extent of mesorectal excision, while long-term stoma outcome was classified using a previously validated registry-based method. Defunctioning stomas significantly decreased chances of a stoma-free outcome, especially in patients undergoing partial mesorectal excision; for these patients, faecal diversion was also least beneficial in terms of reducing anastomotic leakage.In conclusion, every fifth patient undergoing anterior resection for rectal cancer in Sweden eventually ends up with a permanent stoma. Although construction of a defunctioning stoma decreases the risk of symptomatic anastomotic leakage, subsequent takedown surgery carries a substantial risk of major complications, while chances of a long-term stoma-free outcome become significantly reduced. To facilitate selective use of faecal diversion, novel markers to identify high-risk anastomoses prior to surgery have been identified, but require validation in larger prospective settings. Anterior resection without a defunctioning stoma should be considered in appropriately informed patients for whom a stoma-free outcome is of importance. In particular, this holds true for patients eligible for partial mesorectal excision, where anastomotic dehiscence is less frequent and the advantageous effects of a defunctioning stoma are limited.
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- Ilanidis, Dimitrios, 1986-
(författare)
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Biochemical conversion of biomass : hydrothermal pretreatment, by-product formation, conditioning, enzymatic saccharification, and fermentability
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lignocellulosic residues have great potential as feedstocks for production of bio-based chemicals and fuels. One of the main routes is biochemical conversion, which typically includes pretreatment, enzymatic saccharification, microbial fermentation of sugars, and valorization of hydrolysis lignin. Utilization of a broad variety of lignocellulosic feedstocks and development of more efficient conversion processes are advantageous for making bio-based commodities affordable. Biochemical conversion of lignocellulosic biomass was investigated with the overall aim to understand how variations in pretreatment conditions affected yields, formation of bioconversion inhibitors, enzymatic digestibility of pretreated materials, and fermentability. Experiments included estimation of pseudo-lignin content and quantitation of recently discovered microbial inhibitors, such as formaldehyde and p-benzoquinone. Conditioning of pretreated material to improve the efficiency of reactions with biocatalysts was further investigated.Hydrothermal pretreatment of sugarcane bagasse was investigated by using both autocatalyzed and sulfuric-acid-catalyzed pretreatment and by varying temperature and time in such a way that the severity factor was maintained at one of three predetermined values. For autocatalyzed pretreatments, the enzymatic digestibility of the pretreated solids was directly proportional to the severity. Pretreatment conditions that were just harsh enough to almost quantitatively solubilize hemicelluloses gave the best results. Potential effects of the redox environment during hydrothermal pretreatment were investigated by addition of oxygen gas or nitrogen gas in experiments with sugarcane bagasse and Norway spruce. The investigation demonstrated that gas addition, and especially addition of oxygen gas, can be used to modulate the severity of acidic hydrothermal pretreatment. Hydrothermal pretreatment of wheat straw was investigated to evaluate the impact of pretreatment conditions on newly discovered inhibitors, enzymatic digestibility, and fermentation. An increase of the temperature up to 190 °C in autocatalyzed pretreatment led to high combined glucose and xylose yields; up to ~480 kg/ton (dry weight) raw wheat straw. A correlation between enzymatic digestibility and removal of hemicelluloses was observed. A techno-economical evaluation of several conditioning methods for slurries of steam-pretreated spruce indicated that treatment with sodium sulfite was the most favorable option. Treatments with sulfite and dithionite successfully decreased the concentration of formaldehyde. Results also indicate that increased temperature in conditioning of hydrolysate could to some extent compensate for using lower dosages of sodium dithionite.
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