| 1. |
- Åberg, Veronica, 1976-, et al.
(författare)
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Carboxylic acid isosteres improve the activity of ring-fused 2-pyridones that inhibit pilus biogenesis in E. coli
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier Ltd. - 0960-894X. ; 18:12, s. 3536-3540
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Tidskriftsartikel (refereegranskat)abstract
- Ring-fused 2-pyridones, termed pilicides, are small synthetic compounds that inhibit pilus assembly in uropathogenic Escherichia coli. Their biological activity is clearly dependent upon a carboxylic acid functionality. Here, we present the synthesis and biological evaluation of carboxylic acid isosteres, including, for example, tetrazoles, acyl sulfonamides, and hydroxamic acids of two lead 2-pyridones. Two independent biological evaluations show that acyl sulfonamides and tetrazoles significantly improve pilicide activity against uropathogenic E. coli.
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| 2. |
- Altincekic, Nadide, et al.
(författare)
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Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies
- 2024
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 19:2, s. 563-574
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Tidskriftsartikel (refereegranskat)abstract
- The main protease Mpro, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with Mpro. These investigations resulted in the four-armed compound 35b that binds directly to Mpro. 35b could be cocrystallized with Mpro revealing its noncovalent binding mode, which fills all four active site subpockets. Herein, we describe the NMR-derived fragment-to-hit pipeline and its application for the development of promising starting points for inhibitors of the main protease of SCoV2.
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| 3. |
- Anugwom, Ikenna, et al.
(författare)
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Esterified Lignin from Construction and Demolition Waste (CDW) as a Versatile Additive for Polylactic-Acid (PLA) Composites-The Effect of Artificial Weathering on its Performance
- 2022
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Ingår i: Global Challenges. - : Wiley-VCH Verlagsgesellschaft. - 2056-6646. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Demand for sustainable packaging and building materials has increased the need for biobased additives. Biocomposites can often be exposed to different weather conditions and UV irradiation. Thus, additives to prevent the negative impact of weathering are generally added to composites. This study aims to evaluate using esterified lignin as an additive against weathering effects in polylactic-acid (PLA) composites. Lignin is extracted from construction and demolition waste (CDW) wood using a deep eutectic solvent then esterified and tested as an additive in the fabrication of biobased composites. For comparison, lignin from birch is used as a raw material for an additive. Esterification is confirmed by solid-state N MR analysis. Samples are exposed to artificial weathering for 700 hours and their impact strength and color change properties are measured. The results indicate that esterified lignin from CDW (CDW e-lignin) as an additive protects the biocomposite from the weathering impact. The sample containing the CDW e-lignin as an additive suffers only a 4.3% of reduction of impact strength, while the samples that contain commercial additives lose clearly more of their impact strength (from 23.1% to 61.1%). Based on the results CDW e-lignin is a good additive to prevent weathering. As a conclusion, the esterified lignin from CDW, is a versatile additive for composite production.
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| 4. |
- Chambi, Diego, et al.
(författare)
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Production of Exopolysaccharides by Cultivation of Halotolerant Bacillus atrophaeus BU4 in Glucose- and Xylose-Based Synthetic Media and in Hydrolysates of Quinoa Stalks
- 2022
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Ingår i: Fermentation. - : MDPI AG. - 2311-5637. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- A halotolerant, exopolysaccharide-producing bacterium isolated from the Salar de Uyuni salt flat in Bolivia was identified as Bacillus atrophaeus using next-generation sequencing. Comparisons indicate that the genome most likely (p-value: 0.0024) belongs to a subspecies previously not represented in the database. The growth of the bacterial strain and its ability to produce exopolysaccharides (EPS) in synthetic media with glucose or xylose as carbon sources, and in hydrolysates of quinoa stalks, was investigated. The strain grew well in all synthetic media, but the growth in glucose was better than that in xylose. Sugar consumption was better when initial concentrations were low. The growth was good in enzymatically produced cellulosic hydrolysates but was inhibited in hemicellulosic hydrolysates produced using hydrothermal pretreatment. The EPS yields were up to 0.064 g/g on initial glucose and 0.047 g/g on initial xylose, and was higher in media with relatively low sugar concentrations. The EPS was isolated and purified by a sequential procedure including centrifugation, cold ethanol precipitation, trichloroacetic acid treatment, dialysis, and freeze-drying. Glucose and mannose were the main sugars identified in hydrolyzed EPS. The EPS was characterized by size-exclusion chromatography, Fourier-transform infrared (FTIR) spectroscopy, heteronuclear single-quantum coherence nuclear magnetic resonance (HSQC NMR) spectroscopy, scanning electron microscopy, X-ray diffraction, and thermogravimetric analysis. No major differences were elucidated between EPS resulting from cultivations in glucose- or-xylose-based synthetic media, while some divergences with regard to molecular-weight averages and FTIR and HSQC NMR spectra were detected for EPS from hydrolysate-based media.
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| 5. |
- Derba-Maceluch, Marta, et al.
(författare)
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Xylan glucuronic acid side chains fix suberin-like aliphatic compounds to wood cell walls
- 2023
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Ingår i: New Phytologist. - : John Wiley & Sons. - 0028-646X .- 1469-8137. ; 238:1, s. 297-312
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Tidskriftsartikel (refereegranskat)abstract
- Wood is the most important repository of assimilated carbon in the biosphere, in the form of large polymers (cellulose, hemicelluloses including glucuronoxylan, and lignin) that interactively form a composite, together with soluble extractives including phenolic and aliphatic compounds. Molecular interactions among these compounds are not fully understood.We have targeted the expression of a fungal α-glucuronidase to the wood cell wall of aspen (Populus tremula L. × tremuloides Michx.) and Arabidopsis (Arabidopsis thaliana (L.) Heynh), to decrease contents of the 4-O-methyl glucuronopyranose acid (mGlcA) substituent of xylan, to elucidate mGlcA's functions.The enzyme affected the content of aliphatic insoluble cell wall components having composition similar to suberin, which required mGlcA for binding to cell walls. Such suberin-like compounds have been previously identified in decayed wood, but here, we show their presence in healthy wood of both hardwood and softwood species. By contrast, γ-ester bonds between mGlcA and lignin were insensitive to cell wall-localized α-glucuronidase, supporting the intracellular formation of these bonds.These findings challenge the current view of the wood cell wall composition and reveal a novel function of mGlcA substituent of xylan in fastening of suberin-like compounds to cell wall. They also suggest an intracellular initiation of lignin–carbohydrate complex assembly.
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| 6. |
- Dominguez, Pia Guadalupe, et al.
(författare)
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Sucrose synthase determines carbon allocation in developing wood and alters carbon flow at the whole tree level in aspen
- 2021
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Ingår i: New Phytologist. - : John Wiley & Sons. - 0028-646X .- 1469-8137. ; 229:1, s. 186-198
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Tidskriftsartikel (refereegranskat)abstract
- Despite the ecological and industrial importance of biomass accumulation in wood, the control of carbon (C) allocation to this tissue and to other tree tissues remain poorly understood. We studied sucrose synthase (SUS) to clarify its role in biomass formation and C metabolism at the whole tree level in hybrid aspen (Populus tremula x tremuloides). To this end, we analysed source leaves, phloem, developing wood, and roots ofSUSRNAitrees using a combination of metabolite profiling, 13CO2 pulse labelling experiments, and long-term field experiments. The glasshouse grownSUSRNAitrees exhibited a mild stem phenotype together with a reduction in wood total C. The 13CO2 pulse labelling experiments showed an alteration in the C flow in all the analysed tissues, indicating that SUS affects C metabolism at the whole tree level. This was confirmed when theSUSRNAitrees were grown in the field over a 5-yr period; their stem height, diameter and biomass were substantially reduced. These results establish that SUS influences C allocation to developing wood, and that it affects C metabolism at the whole tree level.
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| 7. |
- Ekstrand, Eva-Maria, 1985-, et al.
(författare)
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Methane potentials and organic matter characterization of wood fibres from pulp and paper mills : The influence of raw material, pulping process and bleaching technique
- 2020
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Ingår i: Biomass and Bioenergy. - : Elsevier. - 0961-9534 .- 1873-2909. ; 143
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Tidskriftsartikel (refereegranskat)abstract
- During the process of pulp- and papermaking, large volumes of fibre-rich primary sludge are generated. Anaerobic digestion of primary sludge offers a substantial potential for methane production as an alternative approach to the inefficient energy recoveries by commonly used incineration techniques. However, a systematic study of the importance of upstream process techniques for the methane potential of pulp fibres is lacking. Therefore, biochemical methane potentials were determined at mesophilic conditions for 20 types of fibres processed by a variety of pulping and bleaching techniques and from different raw materials. This included fibres from kraft, sulphite, semi-chemical, chemical thermo-mechanical (CTMP) and thermo-mechanical pulping plants and milled raw wood. The pulping technique was clearly important for the methane potential, with the highest potential achieved for kraft and sulphite fibres (390–400 Nml CH4 g VS−1). For raw wood and CTMP, hardwood fibres gave substantially more methane than the corresponding softwood fibres (240 compared to 50 Nml CH4 g VS−1 and 300 compared to 160 Nml CH4 g VS−1, respectively). Nuclear magnetic resonance characterization of the organic content demonstrated that the relative lignin content of the fibres was an important factor for methane production, and that an observed positive effect of bleaching on the methane potential of softwood CTMP fibres was likely related to a higher degree of deacetylation and improved accessibility of the hemicellulose. In conclusion, fibres from kraft and sulphite pulping are promising substrates for methane production irrespective of raw material or bleaching, as well as fibres from CTMP pulping of hardwood.
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| 8. |
- Fernández-Domínguez, David, et al.
(författare)
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Deciphering the contribution of microbial biomass to the properties of dissolved and particulate organic matter in anaerobic digestates
- 2023
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Ingår i: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 877
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Tidskriftsartikel (refereegranskat)abstract
- The recalcitrant structures either from substrate or microbial biomass contained in digestates after anaerobic digestion (AD) highly influence digestate valorization. To properly assess the microbial biomass contribution to the digested organic matter (OM), a combination of characterization methods and the use of various substrate types in anaerobic continuous reactors was required. The use of totally biodegradable substrates allowed detecting soluble microbial products via fluorescence spectroscopy at emission wavelengths of 420 and 460 nm while the protein-like signature was enhanced by the whey protein. During reactors' operation, a transfer of complex compounds to the dissolved OM from the particulate OM was observed through fluorescence applied on biochemical fractionation. Consequently, the fluorescence complexity index of the dissolved OM increased from 0.59–0.60 to 1.06–1.07, whereas it decreased inversely for the extractable soluble from the particulate OM from 1.16–1.19 to 0.42–0.54. Accordingly, fluorescence regional integration showed differences among reactors based on visual inspection and orthogonal partial latent structures (OPLS) analysis. Similarly, the impact of the substrate type and operation time on the particulate OM was revealed by 13C nuclear magnetic resonance using OPLS, providing a good model (R2X = 0.93 and Q2 = 0.8) with a clear time-trend. A high signal resonated at ∼30 ppm attributed to CH2-groups in the aliphatic chain of lipid-like structure besides carbohydrates intensities at 60–110 ppm distinguished the reactor fed with whey protein from the other, which was mostly biomass related. Indeed, this latter displayed a higher presence of peptidoglycan (δH/C: 1.6–2.0/20–25 ppm) derived from microbial biomass by 1H-13C heteronuclear single-quantum coherence (HSQC) nuclear magnetic resonance. Interestingly, the sample distribution obtained by non-metric multidimensional scaling of bacterial communities resembled the attained using 13C NMR properties, opening new research perspectives. Overall, this study discloses the microbial biomass contribution to digestates composition to improve the OM transformation mechanism knowledge.
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| 9. |
- Hedenström, Mattias, 1976-
(författare)
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NMR as a tool in drug research : Structure elucidation of peptidomimetics and pilicide-chaperone complexes
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the last decades NMR spectroscopy has become an invaluable tool both in academic research and in the pharmaceutical industry. This thesis describes applications of NMR spectroscopy in biomedicinal research for structure elucidation of biologically active peptides and peptidomimetics as well as in studies of ligand-protein interactions. The first part of this thesis describes the theory and methodology of structure calculations of peptides using experimental restraints derived from NMR spectroscopy. This methodology has been applied to novel mimetics of the peptide hormones desmopressin and Leu-enkephalin. The results of these studies highlight the complicating issue of conformational exchange often encountered in structural determination of peptides and how careful analysis of experimental data as well as optimization of experimental conditions can enable structure determinations in such instances. Although the mimetics of both desmopressin and Leu-enkephalin were found to adopt the wanted conformations, they exhibited no or very poor biological activity. These results demonstrate the difficulties in designing peptidomimetics without detailed structural information of the receptors. A stereoselective synthetic route towards XxxΨ[CH2O]Ala pseudodipeptides is also presented. Such pseudodipeptides can be used as isosteric amide bond replacements in peptides in order to increase their resistance towards proteolytic degradation. The second part of this thesis describes the study of the interaction between compounds that inhibit pilius assembly, pilicides, and periplasmic chaperones from uropathogenic Escherichia coli. Periplasmic chaperones are key components in assembly of pili, i.e. hair-like protein complexes located on the surface of Escherichia coli that cause urinary tract infections. Detailed knowledge about this interaction is important in understanding how pilicides can inhibit pilus assembly by binding to chaperones. Relaxation-edited NMR experiments were used to confirm the affinity of the pilicides for the chaperones and chemical shift mapping was used to study the pilicide-chaperone interaction surface. These studies show that at least two interaction sites are present on the chaperone surface and consequently that two different mechanisms resulting in inhibition of pilus assembly may exist.
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| 10. |
- Jamroskovic, Jan, et al.
(författare)
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Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:6, s. 2876-2888
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Tidskriftsartikel (refereegranskat)abstract
- The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.
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