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  • 151.
    Gedda, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Fondell, Amelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Park, John
    Department of medicine, Division of Haematology-Oncology, Cancer research institute, University of California San Fransisco, USA.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Experimental radionuclide therapy of HER2-expressing xenografts using two-step targeting Nuclisome-particles2012In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, no 3, p. 480-487Article in journal (Refereed)
    Abstract [en]

    The therapeutic potential of Auger-electron emitting radionuclides is strongly dependent on their close vicinity to DNA, since the energy deposition is mainly localized within a few cubic nanometers around the site of decay. Thus, apart from specificity, successful tumor therapy relies on a nuclear delivery strategy. We recently presented a two-step targeting strategy to transport Auger-electron-emitting radionuclides into the cell nucleus by means of nuclide-filled liposomes (Nuclisome particles), that is, polyethylene glycol-stabilized, tumor-cell-targeting liposomes loaded with (125)I-labeled anthracyclines. In the present study, the survival of mice intraperitoneally inoculated with human HER2-expressing SKOV-3 tumor cells and treated with HER2-targeting Nuclisome particles was studied.

    METHODS:

    BALB/c nu/nu mice were inoculated with 10(7) SKOV-3 cells intraperitoneally and thereafter directly injected with Nuclisome particles with increasing specific radioactivity. Groups of 10-12 mice were treated with 0.01 MBq/mouse up to 2 MBq/mouse, and survival was monitored and compared with that in control groups (n = 33). Organs were analyzed for HER2 expression and radiotoxic effects histologically. Absorbed doses were estimated using dose factors from the online Radiation Dose Assessment Resource model.

    RESULTS:

    The results showed a clear correlation between administered radioactive dose and survival. No such dose-dependent survival was observed for mice treated with Nuclisome particles lacking HER2-targeting ability. With HER2-targeting Nuclisome particles, a significant increase in survival, compared with that of untreated control mice, could already be seen at an administered activity of 0.1 MBq/mouse (P = 0.0301). At the highest activity administered, 2 MBq/mouse (P < 0.0001), 70% of the mice survived the study and most were tumor-free. Neither macroscopic nor microscopic radiotoxic side effects were observed. Dosimetric calculations, assuming nonreceptor targeting, revealed that the radioactive doses to normal tissues were low.

    CONCLUSION:

    Taken together the results show that with successful targeting to the tumor-cell nucleus it is possible to obtain a therapeutic effect from Auger-electron-emitting radionuclides administered at radioactive doses low enough to spare normal tissue from radiotoxic side effects.

  • 152.
    Giandomenico, Valeria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Modlin, Irvin M.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Khan, Mohid S.
    Millar, Robert P.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Borlak, Jurgen
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Nielsen, Bengt
    Baltzer, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Waterton, John C.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Improving the Diagnosis and Management of Neuroendocrine Tumors: Utilizing New Advances in Biomarker and Molecular Imaging Science2013In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 98, no 1, p. 16-30Article in journal (Refereed)
    Abstract [en]

    Neuroendocrine tumors (NET) are malignant solid tumors that arise in hormone-secreting tissue of the diffuse neuroendocrine system or endocrine glands. Although traditionally understood to be a rare disease, the incidence and prevalence of NET have increased greatly in the past 3 decades. However, during this time, progress in diagnosis and outcome of NET has generally been modest. In order to achieve improved outcome in NET, a better understanding of NET biology combined with more reliable serum markers and better techniques to identify tumor localization and small lesions are needed. Although some NET biomarkers exist, sensitive and specific markers that predict tumor growth and behavior are generally lacking. In addition, the integration of new molecular imaging technologies in patient diagnosis and follow-up has the potential to enhance care. To discuss developments and issues required to improve diagnostics and management of NET patients, with specific focus on the latest advances in molecular imaging and biomarker science, 17 global leaders in the fields of NET, molecular imaging and biomarker technology gathered to participate in a 2-day meeting hosted by Prof. Kjell Oberg at the University of Uppsala in Sweden. During this time, findings were presented regarding methods with potential prognostic and treatment applications in NET or other types of cancers. This paper describes the symposium presentations and resulting discussions.

  • 153.
    Gkanatsiou, Eleni
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Mass Spectrometry Based Proteomics: Toward understanding neuropathic pain2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The aim of this project was to get insight into mass spectrometry based proteomics, get familiarized with novel techniques, and obtain the operating skills with modern Orbitrap mass spectrometers. In order to achieve this, the proteome changes in neuropathic pain responses corresponding to nerve injury side in individual rat’s spinal cord were explored. We focused in protein identification and quantification of the expressed proteins in 3 different set of samples, SNL, Sham and Naive rats. 

  • 154.
    Granqvist, Philip
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Undersökning om organisk arsenik kan analyseras i urin med en befintlig metod för oorganisk arsenik i livsmedel med HPLC-ICP-MS2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 155.
    Gromova, Arina
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Zhao, Hongxing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Konzer, Anne
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Falk, Alexander
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Pettersson, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bergström Lind, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Identification of the adenovirus type 2 C-168 protein2017In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 238, p. 110-113Article in journal (Refereed)
    Abstract [en]

    A hitherto predicted but undetected protein, C-168, in adenovirus type 2 (Ad2) has been identified using mass spectrometry (MS) based proteomics. The gene of this 17.7 kDa protein is located on the forward strand in the major late transcription unit between base pairs 9294 and 9797. A tryptic peptide, derived from the C-terminal part of the protein, was identified with high amino acid sequence coverage. A candidate splice site for the corresponding mRNA is also presented. The protein sequence is unusual with repeats of serine, glycine and arginine. A bioinformatics prediction of protein function and localization is presented.

  • 156.
    Grönbladh, Alfhild
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kushnir, Mark M
    ARUP Institute for Clinical and Experimental Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The impact of nandrolone decanoate and growth hormone on biosynthesis of steroids in rats2013In: Steroids, ISSN 0039-128X, E-ISSN 1878-5867, Vol. 78, no 12-13, p. 1192-1199Article in journal (Refereed)
    Abstract [en]

    Growth hormone (GH) and anabolic androgenic steroids (AAS) are commonly used in sports communities. Several studies have suggested an association between GH and AAS. We have investigated the impact of GH in rats treated with nandrolone decanoate (ND). Male Wistar rats received ND (15 mg/kg) every third day during three weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) for ten consecutive days. Plasma samples were collected and peripheral organs (i.e. heart, liver, testis and thymus) were dissected and weighed. Concentration of thirteen endogenous steroids was measured in the rat plasma samples using high specificity LC-MS/MS methods. Seven steroids were detected and quantified, and concentrations of estrone, testosterone, and androstenedione were significantly different among the groups, while concentrations of pregnenolone, DHEA, 17- hydroxyprogesterone and corticosterone were not altered. Administration of rhGH alone altered the plasma steroid distribution, and the results demonstrated significantly increased concentrations of plasma estrone as well as decreased concentrations of testosterone and androstenedione in the ND-treated rats. Administration of rhGH to ND-pretreated rats did not reverse the alteration of the steroid distribution induced by ND. Administration of ND decreased the weight of the thymus, and addition of rhGH did not reverse this reduction. However, rhGH administration induced an enlargement of thymus. Taken together, the plasma steroid profile differed in the four groups, i.e. controls, AAS, rhGH and the combination of AAS and rhGH treatment.

  • 157. Gupta, Bhuvanesh
    et al.
    Krishnanand, Kumar
    Deopura, B. L.
    Atthoff, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Surface modification of polycaprolactone monofilament by low pressure oxygen plasma2013In: Journal of Applied Polymer Science, ISSN 0021-8995, E-ISSN 1097-4628, Vol. 127, no 3, p. 1744-1750Article in journal (Refereed)
    Abstract [en]

    Surface modification of polycaprolactone filament has been carried out using a low pressure oxygen plasma to introduce active centers in the form of radicals, peroxides, and hydroperoxides on the surface. Evaluation by 2, 2-diphenyl-1-picrylhydrazyl method shows that there is an optimum value of exposure time, gas pressure, and discharge power for the generation of the maximum concentration of such groups. The plasma exposure time was thereafter varied to study the extent of the surface modification introduced by the plasma. It was found that only a short time of exposure to the oxygen plasma was necessary to make the surface highly wettable and polar with increased surface energy and work of adhesion. Surface chemical analysis by X-ray photoelectron spectroscopy revealed that this happens because of oxidation of the top layer of the filament, which occurs primarily by the breaking of bonds and incorporation of oxygen containing functionalities. Morphological and topographical observations by scanning electron microscopy and atomic force microscopy revealed that etching is pronounced at longer exposure times leading to a rougher surface with hill-valley features.

  • 158.
    Hanrieder, Jörg
    et al.
    Department of Chemical and Biological Engineering, Analytical Chemistry, Chalmers University of Technology, Gothenburg, Sweden;.
    Ekegren, Titti
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    MALDI Imaging of Post Mortem Human Spinal Cord in Amyotrophic Lateral Sclerosis2013In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 124, no 5, p. 695-707Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressing disease of the central nervous system that is characterized by motor neuron degeneration in the brain stem and the spinal cord. Matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is an emerging powerful technique that allows for spatially resolved, comprehensive and specific characterization of molecular species in situ. In this study we report for the first time, MALDI imaging-based spatial protein profiling and relative quantification of post mortem human spinal cord samples obtained from ALS patients and controls. In normal spinal cord, protein distribution patterns were well in line with histological features. For example, thymosin beta 4, ubiquitin, histone proteins, acyl CoA binding protein, and macrophage inhibitory factor were predominantly localized to the grey matter. Furthermore, unsupervised statistics revealed a significant reduction of two protein species in ALS grey matter. One of these proteins (m/z 8451) corresponds to an endogenous truncated form of ubiquitin (Ubc 1-76), with both C-terminal glycine residues removed (Ubc-T/Ubc 1-74). This region-specific ubiquitin processing suggests a disease-related change in protease activity. These results highlight the importance of MALDI IMS as a versatile approach to elucidate molecular mechanisms of neurodegenerative diseases.

  • 159. Hao, Dong-Xia
    et al.
    Sandstrom, Corine
    Huang, Yong-Dong
    Kenne, Lennart
    Janson, Jan-Christer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ma, Guang-Hui
    Su, Zhi-Guo
    Residue-level elucidation of the ligand-induced protein binding on phenyl-argarose microspheres by NMR hydrogen/deuterium exchange technique2012In: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 8, no 23, p. 6248-6255Article in journal (Refereed)
    Abstract [en]

    Protein-ligand interactions on liquid-solid interfaces governed the design of functional biomaterials. However, accurate residue details of ligand induced protein binding and unfolding on an interface were still unknown by the current ensemble of protein structure characterizations. Here, a hydrogen/deuterium (H/D) approach coupled with analysis of NMR TOCSY spectra and the solvent accessible surface area (SASA) was designed to enable residue level understanding of lysozyme adsorbed at a phenyl-ligand modified surface. Results showed that the binding sites and unfolding of lysozyme molecules on phenyl-agarose microspheres demonstrated significant ligand-density dependence and protein-coverage dependence. Either increasing ligand density or decreasing adsorption coverage would lead to more binding sites and unfolding of the protein molecules. With the multipoint adsorption strengthening, the protein molecule changed from lying end-on to side-on. Finally, Molecular Dock simulation was utilized to evaluate the NMR determined binding sites based on energy ranking of the binding. It confirmed that this NMR approach represents a reliable route to in silico abundant residue-level structural information during protein interaction with biomaterials.

  • 160. Hasson, Dan
    et al.
    Theorell, Tores
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Canlon, Barbara
    Acute Stress Induces Hyperacusis in Women with High Levels of Emotional Exhaustion2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e52945-Article in journal (Refereed)
    Abstract [en]

    Background: Hearing problems is one of the top ten public health disorders in the general population and there is a well-established relationship between stress and hearing problems. The aim of the present study was to explore if an acute stress will increase auditory sensitivity (hyperacusis) in individuals with high levels of emotional exhaustion (EE). Methods: Hyperacusis was assessed using uncomfortable loudness levels (ULL) in 348 individuals (140 men; 208 women; age 23-71 years). Multivariate analyses (ordered logistic regression), were used to calculate odds ratios, including interacting or confounding effects of age, gender, ear wax and hearing loss (PTA). Two-way ANCOVAs were used to assess possible differences in mean ULLs between EE groups pre- and post-acute stress task (a combination of cold pressor, emotional Stroop and Social stress/video recording). Results: There were no baseline differences in mean ULLs between the three EE groups (one-way ANOVA). However, after the acute stress exposure there were significant differences in ULL means between the EE-groups in women. Post-hoc analyses showed that the differences in mean ULLs were between those with high vs. low EE (range 5.5-6.5 dB). Similar results were found for frequencies 0.5 and 1 kHz. The results demonstrate that women with high EE-levels display hyperacusis after an acute stress task. The odds of having hyperacusis were 2.5 (2 kHz, right ear; left ns) and 2.2 (4 kHz, right ear; left ns) times higher among those with high EE compared to those with low levels. All these results are adjusted for age, hearing loss and ear wax. Conclusion: Women with high levels of emotional exhaustion become more sensitive to sound after an acute stress task. This novel finding highlights the importance of including emotional exhaustion in the diagnosis and treatment of hearing problems.

  • 161.
    Hawkes, Jeffrey A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Dittmar, Thorsten
    Carl von Ossietzky Univ Oldenburg, Inst Chem & Biol Marine Environm, Res Grp Marine Geochem, D-26129 Oldenburg, Germany..
    Patriarca, Claudia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Tranvik, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Evaluation of the Orbitrap Mass Spectrometer for the Molecular Fingerprinting Analysis of Natural Dissolved Organic Matter2016In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 88, no 15, p. 7698-7704Article in journal (Refereed)
    Abstract [en]

    We investigated the application of the LTQ-Orbitrap mass spectrometer (LTQ-Velos Pro, Thermo Fisher) for resolving complex mixtures of natural aquatic dissolved organic matter (DOM) and compared this technique to the more established state-of-the-art technique, Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS, Bruker Daltonics), in terms of the distribution of molecular masses detected and the reproducibility of the results collected. The Orbitrap was capable of excellent reproducibility: Bray-Curtis dissimilarity between duplicate measurements was 2.85 +/- 0.42% (mean +/- standard deviation). The Orbitrap was also capable of the detection of most major ionizable organic molecules in typical aquatic mixtures, with the exception of most sulfur and phosphorus containing masses. This result signifies that the Orbitrap is an appropriate technique for the investigation of very subtle biogeochemical processing of bulk DOM. The lower costs (purchase and maintenance) and wider availability of Orbitrap mass spectrometers in university departments means that the tools necessary for research into DOM processing at the molecular level should be accessible to a much wider group of scientists than before. The main disadvantage of the technique is that substantially fewer molecular formulas can be resolved from a complex mixture (roughly one third as many), meaning some loss of information. In balance, most biogeochemical studies that aim at molecularly fingerprinting the source of natural DOM could be satisfactorily carried out with Orbitrap mass spectrometry. For more targeted metabolomic studies where individual compounds are traced through natural systems, FTICR-MS remains advantageous.

  • 162.
    Hawkes, Jeffrey A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Carl von Ossietzky Univ Oldenburg, Inst Chem & Biol Marine Environm ICBM, Res Grp Marine Geochem, D-26129 Oldenburg, Germany..
    Hansen, Christian T.
    Univ Bremen, Dept Geosci, D-28359 Bremen, Germany.;MARUM Ctr Marine Environm Sci, D-28359 Bremen, Germany..
    Goldhammer, Tobias
    MARUM Ctr Marine Environm Sci, D-28359 Bremen, Germany..
    Bach, Wolfgang
    Univ Bremen, Dept Geosci, D-28359 Bremen, Germany.;MARUM Ctr Marine Environm Sci, D-28359 Bremen, Germany..
    Dittmar, Thorsten
    Carl von Ossietzky Univ Oldenburg, Inst Chem & Biol Marine Environm ICBM, Res Grp Marine Geochem, D-26129 Oldenburg, Germany..
    Molecular alteration of marine dissolved organic matter under experimental hydrothermal conditions2016In: Geochimica et Cosmochimica Acta, ISSN 0016-7037, E-ISSN 1872-9533, Vol. 175, p. 68-85Article in journal (Refereed)
    Abstract [en]

    Marine dissolved organic matter (DOM) is a large (660 Pg) pool of reduced carbon that is subject to thermal alteration in hydrothermal systems and sedimentary basins. In natural high-temperature hydrothermal systems, DOM is almost completely removed, but the mechanism and temperature dependence of this removal have not been studied to date. We investigated molecular-level changes to DOM that was solid-phase extracted (SPE-DOM) from the deep ocean of the North Pacific Ocean. This complex molecular mixture was experimentally exposed to temperatures between 100 and 380 degrees C over the course of two weeks in artificial seawater, and was then characterised on a molecular level via ultrahigh-resolution Fourier-transform ion cyclotron mass spectrometry (FT-ICR-MS). Almost 93% of SPE-DOM was removed by the treatment at 380 degrees C, and this removal was accompanied by a consistent pattern of SPE-DOM alteration across the temperatures studied. Higher molecular weight and more oxygen rich compounds were preferentially removed, suggesting that decarboxylation and dehydration of carboxylic acid and alcohol groups are the most rapid degradation mechanisms. Nitrogen containing compounds followed the same overall trends as those containing just C, H and O up to 300 degrees C. Above this temperature, the most highly altered samples contained very little of the original character of marine DOM, instead being mainly composed of very low intensity N- and S-containing molecules with a high H/C ratio (>1.5). Our results suggest that abiotic hydrothermal alteration of SPE-DOM may already occur at temperatures above 68 degrees C. Our experiments were conducted without a sedimentary or mineral phase, and demonstrate that profound molecular alteration and almost complete removal of marine SPE-DOM requires nothing more than heating in a seawater matrix.

  • 163.
    Hawkes, Jeffrey A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Patriarca, Claudia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Sjöberg, Per J. R.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Tranvik, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Extreme isomeric complexity of dissolved organic matter found across aquatic environments2018In: Limnology and Oceanography Letters, E-ISSN 2378-2242, Vol. 3, no 2, p. 21-30Article in journal (Refereed)
    Abstract [en]

    The natural aquatic environment contains an enormous pool of dissolved reduced carbon, present as ultra‐complex mixtures that are constituted by an unknown number of compounds at vanishingly small concentrations. We attempted to separate individual structural isomers from several samples using online reversed‐phase chromatography with selected ion monitoring/tandem mass spectrometry, but found that isomeric complexity still presented a boundary to investigation even after chromatographic simplification of the samples. However, it was possible to determine that the structural complexity differed among samples. Our results also suggest that extreme structural complexity was a ubiquitous feature of dissolved organic matter (DOM) in all aquatic systems, meaning that this diversity may play similar roles for recalcitrance and degradation of DOM in all tested environments.

  • 164.
    Hawkes, Jeffrey A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Radoman, Nikola
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Stockholm Univ, Dept Environm Sci & Analyt Chem, Stockholm, Sweden.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Wallin, Marcus
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Tranvik, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Löfgren, Stefan
    Swedish Univ Agr Sci SLU, Dept Aquat Sci & Assessment, Sect Geochem & Hydrol, Uppsala, Sweden.
    Regional diversity of complex dissolved organic matter across forested hemiboreal headwater streams2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 16060Article in journal (Refereed)
    Abstract [en]

    Dissolved organic matter (DOM) from soils enters the aquatic environment via headwater streams. Thereafter, it is gradually transformed, removed by sedimentation, and mineralised. Due to the proximity to the terrestrial source and short water residence time, the extent of transformation is minimal in headwaters. DOM has variable composition across inland waters, but the amount of variability in the terrestrial end member is unknown. This gap in knowledge is crucial considering the potential impact large variability would have on modelling DOM degradation. Here, we used a novel liquid chromatography –mass spectrometry method to characterise DOM in 74 randomly selected, forested headwater streams in an 87,000 km2 region of southeast Sweden. We found a large degree of sample similarity across this region, with Bray-Curtis dissimilarity values averaging 8.4 ± 3.0% (mean ± SD). The identified variability could be reduced to two principle coordinates, correlating to varying groundwater flow-paths and regional mean temperature. Our results indicate that despite reproducible effects of groundwater geochemistry and climate, the composition of DOM is remarkably similar across catchments already as it leaves the terrestrial environment, rather than becoming homogeneous as different headwaters and sub-catchments mix.

  • 165.
    Hawkes, Jeffrey A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Carl von Ossietzky Univ Oldenburg, Res Grp Marine Geochem, ICBM MPI Bridging Grp, Inst Chem & Biol Marine Environm ICBM, D-26129 Oldenburg, Germany..
    Rossel, Pamela E.
    Carl von Ossietzky Univ Oldenburg, Res Grp Marine Geochem, ICBM MPI Bridging Grp, Inst Chem & Biol Marine Environm ICBM, D-26129 Oldenburg, Germany.;Alfred Wegener Inst, HGF MPG Grp Deep Sea Ecol & Technol, D-27570 Bremerhaven, Germany..
    Stubbins, Aron
    Univ Georgia, Skidaway Inst Oceanog, Marine Sci, Savannah, GA 31411 USA..
    Butterfield, David
    Univ Washington, Joint Inst Study Atmosphere & Oceans, Seattle, WA 98115 USA.;NOAA PMEL, Seattle, WA 98115 USA..
    Connelly, Douglas P.
    Univ Southampton, Natl Oceanog Ctr, Southampton SO14 3ZH, Hants, England..
    Achterberg, Eric P.
    Univ Southampton, Natl Oceanog Ctr, Southampton SO14 3ZH, Hants, England.;GEOMAR Helmholtz Ctr Ocean Res, D-24148 Kiel, Germany..
    Koschinsky, Andrea
    Jacobs Univ Bremen, D-28759 Bremen, Germany..
    Chavagnac, Valerie
    Univ Toulouse, Lab Geosci Environm Toulouse, F-31400 Toulouse, France..
    Hansen, Christian T.
    Univ Bremen, MARUM Ctr Marine Environm Sci, D-28359 Bremen, Germany.;Univ Bremen, Dept Geosci, D-28359 Bremen, Germany..
    Bach, Wolfgang
    Univ Bremen, MARUM Ctr Marine Environm Sci, D-28359 Bremen, Germany.;Univ Bremen, Dept Geosci, D-28359 Bremen, Germany..
    Dittmar, Thorsten
    Carl von Ossietzky Univ Oldenburg, Res Grp Marine Geochem, ICBM MPI Bridging Grp, Inst Chem & Biol Marine Environm ICBM, D-26129 Oldenburg, Germany..
    Efficient removal of recalcitrant deep-ocean dissolved organic matter during hydrothermal circulation2015In: Nature Geoscience, ISSN 1752-0894, E-ISSN 1752-0908, Vol. 8, no 11, p. 856-+Article in journal (Refereed)
    Abstract [en]

    Oceanic dissolved organic carbon (DOC) is an important carbon pool, similar in magnitude to atmospheric CO2, but the fate of its oldest forms is not well understood(1,2). Hot hydrothermal circulation may facilitate the degradation of otherwise un-reactive dissolved organic matter, playing an important role in the long-term global carbon cycle. The oldest, most recalcitrant forms of DOC, which make up most of oceanic DOC, can be recovered by solid-phase extraction. Here we present measurements of solid-phase extractable DOC from samples collected between 2009 and 2013 at seven vent sites in the Atlantic, Pacific and Southern oceans, along with magnesium concentrations, a conservative tracer of water circulation through hydrothermal systems. We find that magnesium and solid-phase extractable DOC concentrations are correlated, suggesting that solid-phase extractable DOC is almost entirely lost from solution through mineralization or deposition during circulation through hydrothermal vents with fluid temperatures of 212-401 degrees C. In laboratory experiments, where we heated samples to 380 degrees C for four days, we found a similar removal efficiency. We conclude that thermal degradation alone can account for the loss of solid-phase extractable DOC in natural hydrothermal systems, and that its maximum lifetime is constrained by the timescale of hydrothermal cycling, at about 40 million years(3).

  • 166.
    Hawkes, Jeffrey A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Sjöberg, Per J. R.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Tranvik, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Complexity of dissolved organic matter in the molecular size dimension: insights from coupled size exclusion chromatography electrospray ionisation mass spectrometry2019In: Faraday discussions (Online), ISSN 1359-6640, E-ISSN 1364-5498, Vol. 218, p. 52-71Article in journal (Refereed)
    Abstract [en]

    This paper investigates the relationship between apparent size distribution and molecular complexity of dissolved organic matter from the natural environment. We used a high pressure size exclusion chromatography (HPSEC) method coupled to UV-Vis diode array detection (UV-DAD) and electrospray ionisation mass spectrometry (ESI-MS) in order to compare the apparent size of natural organic matter, determined by HPSEC-UV and the molecular mass determined online by ESI-MS. We found that there was a clear discrepancy between the two methods, and found evidence for an important pool of organic matter that has a strong UV absorbance and no ESI-MS signal. Contrary to some previous research, we found no evidence that apparently high molecular weight organic matter is constituted by aggregates of low molecular weight (<1000 Da) material. Furthermore, our results suggest that the majority of apparent size variability within the ESI ionisable pool of organic matter is due to secondary interaction and exclusion effects on the HPSEC column, and not true differences in hydrodynamic size or intermolecular aggregation.

  • 167.
    Heiene, Reidun
    et al.
    University of Utrecht.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Neusüß, Christian
    Aalen University.
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Carbamylated hemoglobin project AKI vs CKD- or the magnitude of the chronic component2016Conference paper (Refereed)
  • 168.
    Hellgren, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Edvinsson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olivier, Jocelien D.
    Univ Groningen, Groningen Inst Evolutionary Life Sci, Dept Neurobiol, Unit Behav Neurosci, NL-9700 AB Groningen, Netherlands..
    Fornes, Romina
    Karolinska Inst, Dept Physiol & Pharmacol, S-10401 Stockholm, Sweden..
    Stener-Victorin, Elisabet
    Karolinska Inst, Dept Physiol & Pharmacol, S-10401 Stockholm, Sweden..
    Ubhayasekera, S. J. Kumari A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Tandem mass spectrometry determined maternal cortisone to cortisol ratio and psychiatric morbidity during pregnancy-interaction with birth weight2016In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 69, p. 142-149Article in journal (Refereed)
    Abstract [en]

    Maternal serum cortisol has been suggested to be influenced by psychiatric morbidity, and may also influence fetal growth. However, several studies found equal cortisol levels in depressed and healthy pregnant women. Placental 11-beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) shields the fetus from maternal cortisol by conversion to cortisone, a function that may be compromised by maternal stress. We aimed to compare the serum ratio of cortisone to cortisol, in women with and without psychiatric morbidity during pregnancy. A secondary aim was to investigate whether fetal growth, approximated by infant birth weight, was associated with the cortisone to cortisol ratio. We performed tandem mass spectrometry analysis of serum cortisol and cortisone in late pregnancy in 94 women with antenatal psychiatric morbidity and 122 controls (cohort 1). We also compared the placental gene expression of HSD11B1 and 2 in another group of 69 women with psychiatric morbidity and 47 controls (cohort 2). There were no group differences in cortisol to cortisone ratio, absolute levels of cortisone and cortisol (cohort 1), or expression of HSD11B1 or 2 (cohort 2). However, cortisone to cortisol ratio was positively associated with birth weight in women with psychiatric morbidity, also after adjustment for gestational length, fetal sex, maternal height, smoking, SSRI use, and time of blood sampling (standardized beta = 0.35, p < 0.001), with no association in the healthy controls Thus, the maternal serum cortisone to cortisol ratio does not seem to be affected by psychiatric morbidity, but psychiatric morbidity may increase fetal exposure to cortisol or other metabolic factors influencing fetal growth.

  • 169.
    Heras, Gabriel
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Namuduri, Arvind Venkat
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Traini, Leonardo
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Falk, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Precision Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, China.
    Tian, Geng
    Precision Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, China.
    Gastaldello, Stefano
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;Precision Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, China.
    Muscle RING-finger protein-1 (MuRF1) functions and cellular localization are regulated by SUMO1 post-translational modification2019In: Journal of Molecular Cell Biology, ISSN 1674-2788, E-ISSN 1759-4685, Vol. 11, no 5, p. 356-370Article in journal (Refereed)
    Abstract [en]

    The muscle RING-finger protein-1 (MuRF1) is an E3 ubiquitin ligase expressed in skeletal and cardiac muscle tissues and it plays important roles in muscle remodeling. Upregulation of MuRF1 gene transcription participates in skeletal muscle atrophy, on contrary downregulation of protein expression leads to cardiac hypertrophy. MuRF1 gene point mutations have been found to generate protein aggregate myopathies defined as muscle disorder characterized by protein accumulation in muscle fibers. We have discovered that MuRF1 turned out to be also a target for a new post-translational modification arbitrated by conjugation of SUMO1 and it is mediated by the SUMO ligases E2 UBC9 and the E3 PIASγ/4. SUMOylation takes place at lysine 238 localized at the second coiled-coil protein domain that is required for efficient substrate interaction for polyubiquitination. We provided evidence that SUMOylation is essential for MuRF1 nuclear translocation and its mitochondria accumulation is enhanced in hyperglycemic conditions delivering a stabilization of the overall SUMOylated proteins in cultured myocytes. Thus, our findings add this SUMO1 post-translational modification as a new concept to understand muscle disorders related to the defect in MuRF1 activity.

  • 170.
    Hernroth, Bodil
    et al.
    Royal Swedish Acad Sci, Sven Loven Ctr Marine Sci, Kristineberg 566, SE-45178 Fiskebackskil, Sweden;Kristianstad Univ, Dept Nat Sci, SE-29188 Kristianstad, Sweden.
    Baden, Susanne
    Univ Gothenburg, Dept Biol & Environm Sci, Kristineberg 566, SE-45178 Fiskebackskil, Sweden.
    Tassidis, Helena
    Kristianstad Univ, Dept Nat Sci, SE-29188 Kristianstad, Sweden.
    Hörnaeus, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Guillemant, Julie
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Impact of ocean acidification on antimicrobial activity in gills of the blue mussel (Mytilus edulis) 2016In: Fish and Shellfish Immunology, ISSN 1050-4648, E-ISSN 1095-9947, Vol. 55, p. 452-459Article in journal (Refereed)
    Abstract [en]

    Here, we aimed to investigate potential effects of ocean acidification on antimicrobial peptide (AMP) activity in the gills of Mytilus edulis, as gills are directly facing seawater and the changing pH (predicted to be reduced from ~8.1 to ~7.7 by 2100). The AMP activity of gill and haemocyte extracts was compared at pH 6.0, 7.7 and 8.1, with a radial diffusion assay against Escherichia coli. The activity of the gill extracts was not affected by pH, while it was significantly reduced with increasing pH in the haemocyte extracts. Gill extracts were also tested against different species of Vibrio (V. parahaemolyticus V. tubiashii, V. splendidus and V. alginoyticus) at pH 7.7 and 8.1. The metabolic activity of the bacteria decreased by ~65-90%, depending on species of bacteria, but was, as in the radial diffusion assay, not affected by pH. The results indicated that AMPs from gills are efficient in a broad pH-range. However, when mussels were pre-exposed for pH 7.7 for four month the gill extracts presented significantly lower inhibit of bacterial growth. A full in-depth proteome investigation of gill extracts, using LC-Orbitrap MS/MS technique, showed that among previously described AMPs from haemocytes of Mytilus, myticin A was found up-regulated in response to lipopolysaccharide, 3 h post injection. Sporadic occurrence of other immune related peptides/proteins also pointed to a rapid response (0.5- 3 h p.i.). Altogether, our results indicate that the gills of blue mussels constitute an important first line defence adapted to act at the pH of seawater. The antimicrobial activity of the gills is however modulated when mussels are under the pressure of ocean acidification, which may give future advantages for invading pathogens.

  • 171.
    Hillered, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Dahlin, Andreas P
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Chu, Jiangtao
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Hjort, Klas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Cerebral microdialysis for protein biomarker monitoring in the neurointensive care setting - a technical approach2014In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 5, p. 245-Article in journal (Refereed)
    Abstract [en]

    Cerebral microdialysis (MD) was introduced as a neurochemical monitoring method in the early 1990s and is currently widely used for the sampling of low molecular weight molecules, signaling energy crisis, and cellular distress in the neurointensive care (NIC) setting. There is a growing interest in MD for harvesting of intracerebral protein biomarkers of secondary injury mechanisms in acute traumatic and neurovascular brain injury in the NIC community. The initial enthusiasm over the opportunity to sample protein biomarkers with high molecular weight cut-off MD catheters has dampened somewhat with the emerging realization of inherent methodological problems including protein-protein interaction, protein adhesion, and biofouling, causing an unstable in vivo performance (i.e., fluid recovery and extraction efficiency) of the MD catheter. This review will focus on the results of a multidisciplinary collaborative effort, within the Uppsala Berzelii Centre for Neurodiagnostics during the past several years, to study the features of the complex process of high molecular weight cut-off MD for protein biomarkers. This research has led to new methodology showing robust in vivo performance with optimized fluid recovery and improved extraction efficiency, allowing for more accurate biomarker monitoring. In combination with evolving analytical methodology allowing for multiplex biomarker analysis in ultra-small MD samples, a new opportunity opens up for high-resolution temporal mapping of secondary injury cascades, such as neuroinflammation and other cell injury reactions directly in the injured human brain. Such data may provide an important basis for improved characterization of complex injuries, e.g., traumatic and neurovascular brain injury, and help in defining targets and treatment windows for neuroprotective drug development.

  • 172.
    Hillered, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Dahlin, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Purins, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Wetterhall, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Hjort, Klas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lewen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    New Microdialysis Method for Protein Biomarker Sampling in the Neurointensive Care Setting2014In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 31, no 5, p. A22-A22Article in journal (Refereed)
  • 173.
    Hoja-Łukowicz, Dorota
    et al.
    Institute of Zoology, Jagiellonian University, Krakow, Poland.
    Link-Lenczowski, Paweł
    Institute of Zoology, Jagiellonian University, Krakow, Poland.
    Carpentieri, Andrea
    Department of Organic Chemistry and Biochemistry, School of Biotechnological Sciences, Federico II University of Naples, Italy .
    Amoresano, Angela
    Department of Organic Chemistry and Biochemistry, School of Biotechnological Sciences, Federico II University of Naples, Italy.
    Pocheć, Ewa
    Institute of Zoology, Jagiellonian University, Krakow, Poland.
    Artemenko, Konstantin A
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lityńska, Anna
    Institute of Zoology, Jagiellonian University, Krakow, Poland.
    L1CAM from human melanoma carries a novel type of N-glycan with Galβ1-4Galβ1- motif: Involvement of N-linked glycans in migratory and invasive behaviour of melanoma cells2013In: Glycoconjugate Journal, ISSN 0282-0080, E-ISSN 1573-4986, Vol. 30, no 3, p. 205-225Article in journal (Refereed)
    Abstract [en]

    Dramatic changes in glycan biosynthesis during oncogenic transformation result in the emergence of marker glycans on the cell surface. We analysed the N- linked glycans of L1CAM from different stages of melanoma progression, using high-performance liquid chromatography combined with exoglycosidase sequencing, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry, and lectin probes. L1CAM oligosaccharides are heavily sialylated, mainly digalactosylated, biantennary complex-type structures with galactose β1-4/3-linked to GlcNAc and with or without fucose α1-3/6-linked to GlcNAc. Hybrid, bisected hybrid, bisected triantennary and tetraantennary complex oligosaccharides, and β1-6-branched complex-type glycans with or without lactosamine extensions are expresses at lower abundance. We found that metastatic L1CAM possesses only α2-6-linked sialic acid and the loss of α2-3-linked sialic acid in L1CAM is a phenomenon observed during the transition of melanoma cells from VGP to a metastatic stage. Unexpectedly, we found a novel monoantennary complex-type oligosaccharide with a Galβ1-4Galβ1- epitope capped with sialic acid residues A1[3]G(4)2S 2-3 . To our knowledge this is the first report documenting the presence of this oligosaccharide in human cancer. The novel and unique N- glycan should be recognised as a new class of human melanoma marker. In functional tests we demonstrated that the presence of cell surface α2-3-linked sialic acid facilitates the migratory behaviour and increases the invasiveness of primary melanoma cells, and it enhances the motility of metastatic cells. The presence of cell surface α2-6-linked sialic acid enhances the invasive potential of both primary and metastatic melanoma cells. Complex-type oligosaccharides in L1CAM enhance the invasiveness of metastatic melanoma cells.

  • 174.
    Holfeld, Aleš
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Unlocking the Proteome of Archival Tissue Collections: Proteomic Analysis of Urinary Bladder Cancer Tissues using Mass Spectrometry-based Proteomics2017Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Formalin-fixed and paraffin-embedded (FFPE) and optimal cutting temperature (OCT)-embedded frozen tissue samples have recently gained interest as they exist in vast repositories worldwide and represent a valuable resource for clinical studies. However, unlocking the proteome of these archival tissues has encountered many challenges. Formalin has deleterious effects on protein structure which has been a barrier to use such a tissue material for global discovery and post-translational modification (PTM) analysis using mass spectrometry (MS). Furthermore, a cryopreservation OCT medium composed of polymers, such polyvinyl alcohol and polyethylene glycol, interferes with MS analysis due to ion suppression effects. Recent developments in sample preparation protocols and MS-based proteomics have enabled to investigate these archived samples and opened up the possibility to integrate them into biomarker discovery. In this present study, I demonstrate a streamlined, compatible, reproducible, and high-throughput proteomic workflow for subsequent MS-based ‘shotgun’ and PTM analysis of FFPE and OCT-embedded frozen tissues using nanoLC-MS/MS. For the first time, the comprehensive comparison of protein expression in paired FFPE and OCT-embedded frozen tissues of invasive and non-muscle invasive bladder cancer is presented. Label-free quantification revealed more than 2,000 and 3,000 protein identities in FFPE and OCT-embedded frozen bladder cancer tissues, respectively. In total, 24 and 29 proteins showed differential protein expression in FFPE and OCT/frozen when comparing invasive stage versus non-muscle invasive bladder cancer. Exploring molecular interactions demonstrated that regulated proteins play a crucial role in bladder cancer-associated pathways. These preliminary results, therefore, reveal the potential to apply our optimized proteomic workflow for biomarker and drug target discovery. Furthermore, I tested titanium dioxide phosphopeptide enrichment on paired FFPE and OCT-embedded frozen tissue sample. More than three hundred phosphorylation sites were identified in both types of samples. This proteomic platform could also be a promising tool for PTM analysis in archival tissue samples. 

  • 175.
    Holfeld, Aleš
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Valdés, Alberto
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Parallel Proteomic Workflow for Mass Spectrometric Analysis of Tissue Samples Preserved by Different Methods2018In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 9, p. 5841-5849Article in journal (Refereed)
    Abstract [en]

    Formalin-fixed and paraffin-embedded (FFPE) and optimal cutting temperature (OCT)-embedded and frozen tissue specimens in biobanks are highly valuable in clinical studies but proteomic and post-translational modification (PTM) studies using mass spectrometry (MS) have been limited due to structural arrangement of proteins and contaminations from embedding material. This study aims to develop a parallel proteomic workflow for FFPE and OCT/frozen samples that allows for large-scale, quick, reproducible, qualitative, and quantitative high-resolution MS analysis. The optimized protocol gives details on removal of embedding material, protein extraction, and multienzyme digestion using filter-aided sample preparation method. The method was evaluated by investigating the protein expression levels in nonmuscle-invasive and muscle-invasive bladder cancer samples in two cohorts and MS spectra were carefully reviewed for contaminations. More than 2000 and 3000 proteins in FFPE and OCT/frozen samples, respectively, were identified, and samples could be clustered in different tumor stages based on their protein expression. Furthermore, more than 250 and 400 phosphopeptides could be identified from specific patient samples of FFPE and OCT/frozen, respectively, using titanium dioxide enrichment. The paper presents unique data describing the similarities and differences observed in FFPE and OCT/frozen samples and shows the feasibility to detect proteins and site-specific phosphorylation even after long-term storage of clinical samples.

  • 176. Holst, Bodil S.
    et al.
    Kushnir, Mark M.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Liquid chromatography-tandem mass spectrometry (LC-MS/MS) for analysis of endogenous steroids in the luteal phase and early pregnancy in dogs: a pilot study2015In: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165X, Vol. 44, no 4, p. 552-558Article in journal (Refereed)
    Abstract [en]

    Background Blood samples from dogs are often limited in volume, only allowing few steroids to be quantified with immunoassays. In addition, immunoassays may be compromised by interferences such as anti-reagent antibodies. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) can be used for the simultaneous quantitation of several steroids. This has not been described in dogs before. Objectives The aims were to use LC-MS/MS to study steroid profiles in early pregnancy and luteal phase in dogs, and to determine if differences exist between pregnant (P) and nonpregnant (NP) dogs. Methods Nine female dogs were included, 4 during a NP luteal phase, 4 during a P luteal phase, and one during one NP and one P luteal phase. Blood samples were collected around the time of the LH surge (Day 0) and on Day 26. Serum was analyzed for 5 classes of steroids, including glucocorticoids, androgens, estrogens, pregnanes, and progestins, using LC-MS/MS methods. Results The concentration of progesterone was significantly higher on Day 26 in P than in NP bitches. Distribution of concentrations of glucocorticoids, androgens, estrogens, or pregnanes in P and NP dogs were not statistically different. The predominating glucocorticoid was cortisol, and dihydroepiandrosterone (DHEA) was the predominating androgen. Concentration of estrone was comparable to oestradiol, whereas concentrations of pregnenolone were higher than those of 17-OH pregnenolone. Conclusions Only concentration of progesterone differed between P and NP bitches, being significantly higher on Day 26 in P than in NP bitches. LC-MS/MS offers interesting possibilities for studies of canine reproductive endocrinology.

  • 177.
    Hompland, Ivar
    et al.
    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, POB 4953, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Bruland, Oyvind Sverre
    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, POB 4953, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Ubhayasekhera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Boye, Kjetil
    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, POB 4953, N-0424 Oslo, Norway.;Oslo Univ Hosp, Norwegian Radium Hosp, Dept Tumor Biol, Oslo, Norway..
    Clinical implications of repeated drug monitoring of imatinib in patients with metastatic gastrointestinal stromal tumour2016In: Clinical Sarcoma Research, ISSN 2045-3329, Vol. 6, article id 21Article in journal (Refereed)
    Abstract [en]

    Background: Imatinib mesylate (IM) is the preferred treatment for the majority of patients with metastatic gastrointestinal stromal tumour (GIST). Low trough IM concentration (C-min) values have been associated with poor clinical outcomes in GIST patients. However, there are few studies of repeated measurements of IM levels, and therapeutic drug monitoring is not yet a part of routine clinical practice. This study was conducted to reveal clinical scenarios where plasma concentration measurement of IM trough level (Cmin) is advantageous. Methods: Patients with advanced GIST receiving IM were included from January 2011 to April 2015. Heparin plasma was collected at each follow-up visit. Ninety-six samples from 24 patients were selected for IM concentration measurement. Associations between IM plasma concentration and clinical variables were analyzed by Students't test, univariate and multivariate linear regression analyses. Results: The mean IM Cmin plasma concentrations for patients taking < 400, 400 and > 400 mg daily were 782, 1132 and 1665 ng/mL, respectively (p = 0.010). High IM C-min levels were correlated with age, low body surface area, low haemoglobin concentration, low creatinine clearance, absence of liver metastasis and no prior gastric resection in univariate analysis. In multivariate analysis age, gastric resection and liver metastasis were included in the final model. Eight patients had disease progression during the study, and mean IM levels were significantly lower at time of progression compared to the previous measurement for the same patients (770 and 1223 ng/mL, respectively; p = 0.020). Conclusions: Our results do not support repeated monitoring of IM levels on a routine basis in all patients. However, we have revealed clinical scenarios where drug measurement could be beneficial, such as for patients who have undergone gastric resection, suspicion of non-compliance, subjectively reported side effects, in elderly patients and at the time of disease progression.

  • 178.
    Huang, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Yang, Li
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Sjödin, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Synthesis and Redox Properties of Thiophene Terephthalate Building Blocks for Low-Potential Conducting Redox Polymers2015In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 119, no 49, p. 27247-27254Article in journal (Refereed)
    Abstract [en]

    Terephthalate-substituted thiophene derivatives are promising redox-active components for anode materials in lithium-ion batteries. In this study, we present the synthesis of substituted 2-(thiophen-3-yl)terephthalate derivatives (TTDs) as suitable monomers for thiophene-based conducting redox polymers, along with their characterization by electrochemical and spectroscopic techniques. Density functional theory (DFT) calculations, utilizing the universal solvation model based on solute electron density (SMD), were used to predict both the first and the second reduction potentials of these TTDs. The computational results showed good agreement with the experimental data in nonaqueous acetonitrile solvent, with mean absolute errors of 30 and 40 mV for the first and second reduction steps, respectively. Time-dependent (TD) DFT calculations on TTDs indicated terephthalate local transitions at both 200 and 240 nm and charge-transfer transitions above 300 nm by examination of the involved molecular orbitals.

  • 179.
    Huser, Brian J.
    et al.
    Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, Box 7050, S-75007 Uppsala, Sweden..
    Egemose, Sara
    Univ Southern Denmark, Dept Biol, Campusvej 55, DK-5230 Odense M, Denmark..
    Harper, Harvey
    ERD Environm Res & Design, 3419 Trentwood Blvd,Suite 102, Orlando, FL USA..
    Hupfer, Michael
    Leibniz Inst Freshwater Ecol & Inland Fisheries, Berlin, Germany..
    Jensen, Henning
    Univ Southern Denmark, Dept Biol, Campusvej 55, DK-5230 Odense M, Denmark..
    Pilgrim, Keith M.
    Barr Engn, 4077 77th St, Minneapolis, MN 55304 USA..
    Reitzel, Kasper
    Univ Southern Denmark, Dept Biol, Campusvej 55, DK-5230 Odense M, Denmark..
    Rydin, Emil
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Futter, Martyn
    Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, Box 7050, S-75007 Uppsala, Sweden..
    Longevity and effectiveness of aluminum addition to reduce sediment phosphorus release and restore lake water quality2016In: Water Research, ISSN 0043-1354, E-ISSN 1879-2448, Vol. 97, p. 122-132Article in journal (Refereed)
    Abstract [en]

    114 lakes treated with aluminum (Al) salts to reduce internal phosphorus (P) loading were analyzed to identify factors driving longevity of post-treatment water quality improvements. Lakes varied greatly in morphology, applied Al dose, and other factors that may have affected overall treatment effectiveness. Treatment longevity based on declines in epilimnetic total P (TP) concentration averaged 11 years for all lakes (range of 0-45 years). When longevity estimates were used for lakes with improved conditions through the end of measurements, average longevity increased to 15 years. Significant differences in treatment longevity between deeper, stratified lakes (mean 21 years) and shallow, polymictic lakes (mean 5.7 years) were detected, indicating factors related to lake morphology are important for treatment success. A decision tree developed using a partition model suggested Al dose, Osgood index (01, a morphological index), and watershed to lake area ratio (related to hydraulic residence time, WA:LA) were the most important variables determining treatment longevity. Multiple linear regression showed that Al dose, WA:LA, and 01 explained 47, 32 and 3% respectively of the variation in treatment longevity. Other variables (too data limited to include in the analysis) also appeared to be of importance, including sediment P content to Al dose ratios and the presence of benthic feeding fish in shallow, polymictic lakes.

  • 180.
    Hägglund, Sara
    et al.
    Swedish Univ Agr Sci, Host Pathogen Interact Grp, Dept Clin Sci, Uppsala, Sweden..
    Blodorn, Krister
    Swedish Univ Agr Sci, Host Pathogen Interact Grp, Dept Clin Sci, Uppsala, Sweden..
    Näslund, Katarina
    Swedish Univ Agr Sci, Host Pathogen Interact Grp, Dept Clin Sci, Uppsala, Sweden..
    Vargmar, Karin
    Swedish Univ Agr Sci, Sect Pathol, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Bergström, Sara K.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Universitet.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala Univ, Dept Chem BMC, Sci Life Lab, Analyt Chem, Uppsala, Sweden.;Binzhou Med Univ, Med & Pharm Res Ctr, Yantai, Peoples R China..
    Arainga, Mariluz
    Univ Nebraska Med Ctr, Omaha, NE USA..
    Riffault, Sabine
    Univ Paris Saclay, INRA, Unite Virol & Immunol Mol, Jouy En Josas, France..
    Taylor, Geraldine
    Pirbright Inst, Ash Rd, Pirbright, Surrey, England..
    Pringle, John
    Swedish Univ Agr Sci, Host Pathogen Interact Grp, Dept Clin Sci, Uppsala, Sweden..
    Valarcher, Jean Francois
    Swedish Univ Agr Sci, Host Pathogen Interact Grp, Dept Clin Sci, Uppsala, Sweden..
    Proteome analysis of bronchoalveolar lavage from calves infected with bovine respiratory syncytial virus-Insights in pathogenesis and perspectives for new treatments2017In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 12, no 10, article id e0186594Article in journal (Refereed)
    Abstract [en]

    Human and bovine respiratory syncytial viruses (HRSV/BRSV) are major causes of severe lower respiratory tract infections in children and calves, respectively. Shared epidemiological, clinical, pathological and genetic characteristics of these viruses make comparative research highly relevant. To characterise the host response against BRSV infection, bronchoalveolar lavage supernatant (BAL) from i) non-vaccinated, BRSV-infected ii) vaccinated, BRSV-infected and iii) non-infected calves was analysed by tandem mass spectrometry. Proteins were semi-quantified and protein expression was validated by immunoblotting. Correlations between selected proteins and pathology, clinical signs and virus shedding were investigated. Calves with BRSV-induced disease had increased total protein concentrations and a decreased number of proteins identified in BAL. The protein profile was characterised by neutrophil activation and a reduction in identified antioxidant enzymes. The presence of neutrophils in alveolar septa, the expression level of neutrophil-related or antioxidant proteins and LZTFL1 correlated significantly with disease. Citrullinated histone 3, an indicator of extracellular traps (ETs), was only detected in non-vaccinated, BRSV-infected animals. By bringing disequilibrium in the release and detoxification of reactive oxygen species, generating ETs and causing elastine degradation, exaggerated neutrophil responses might exacerbate RSV-induced disease. Neutrophil-mitigating or antioxidant treatments should be further explored.

  • 181.
    Hörnaeus, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Guillemant, Julie
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Hernroth, Bodil
    The RoyalSwedishAcademyofSciences,SvenLovénCenterforMarineScience.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mass spectrometry data from a quantitative analysis of protein expression in gills of immuno-challenged blue mussels (Mytilus edulis)2016In: Data in Brief, E-ISSN 2352-3409, Vol. 8, p. 470-473Article in journal (Refereed)
    Abstract [en]

    Here, we provide the dataset associated with our research article on the potential effects of ocean acidification on antimicrobial peptide (AMP) activity in the gills of Mytilus edulis, "Impact of ocean acidification on antimicrobial activity in gills of the blue mussel (Mytilus edulis)" [1]. Blue mussels were stimulated with lipopolysaccharides and samples were collected at different time points post injection. Protein extracts were prepared from the gills, digested using trypsin and a full in-depth proteome investigation was performed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Protein identification and quantification was performed using the MaxQuant 1.5.1.2 software, "MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification" [2].

  • 182.
    Jansson, Erik T.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Strategies for analysis of isomeric peptides2018In: Journal of Separation Science, ISSN 1615-9306, E-ISSN 1615-9314, Vol. 41, no 1, p. 385-397Article, review/survey (Refereed)
    Abstract [en]

    This review presents an overview and recent progress of strategies for detecting isomerism in peptides, with focus on D/L epimerization and the various isomers that the presence of an aspartic acid residue may yield in a protein or peptide. While mass spectrometry has become a majorly used method of choice within proteomics, isomerism is inherently difficult to analyze because it is a modification that does not yield any change in mass of the analyte. Here, several techniques used for analysis of peptide isomerism are discussed, including enzymatic assays, liquid chromatography, and capillary electrophoresis. Recent progress in method development using mass spectrometry is also discussed, including labeling strategies, fragmentation techniques, and ion-mobility spectrometry.

  • 183.
    Jansson, Erik T.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Stanford Univ, Dept Chem, Stanford, CA 94305 USA..
    Dulay, Maria T.
    Stanford Univ, Dept Chem, Stanford, CA 94305 USA..
    Zare, Richard N.
    Stanford Univ, Dept Chem, Stanford, CA 94305 USA..
    Monitoring Enzymatic Reactions in Real Time Using Venturi Easy Ambient Sonic-Spray Ionization Mass Spectrometry2016In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 88, no 12, p. 6195-6198Article in journal (Refereed)
    Abstract [en]

    We developed a technique to monitor spatially confined surface reactions with mass spectrometry under ambient conditions, without the need for voltage or organic solvents. Fused-silica capillaries immersed in an aqueous solution, positioned in close proximity to each other and the functionalized surface, created a laminar flow junction with a resulting reaction volume of similar to 5 pL. The setup was operated with a syringe pump, delivering reagents to the surface through a fused silica capillary. The other fused-silica capillary was connected to a Venturi easy ambient sonic-spray ionization source, sampling the resulting analytes at a slightly higher flow rate compared to the feeding capillary. The combined effects of the inflow and outflow maintains a chemical microenvironment, where the rate of advective transport overcomes diffusion. We show proof-of-concept where acetylcholinesterase was immobilized on an organosiloxane polymer through electrostatic interactions. The hydrolysis of acetylcholine by acetylcholinesterase into choline was monitored in real-time for a range of acetylcholine concentrations, fused-silica capillary geometries, and operating flow rates. Higher reaction rates and conversion yields were observed with increasing acetylcholine concentrations, as would be expected.

  • 184.
    Jansson, Erik T.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Stanford Univ, Dept Chem, Stanford, CA 94305 USA..
    Lai, Yin-Hung
    Stanford Univ, Dept Chem, Stanford, CA 94305 USA..
    Santiago, Juan G.
    Stanford Univ, Dept Mech Engn, Stanford, CA 94305 USA..
    Zare, Richard N.
    Stanford Univ, Dept Chem, Stanford, CA 94305 USA..
    Rapid Hydrogen-Deuterium Exchange in Liquid Droplets2017In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, no 20, p. 6851-6854Article in journal (Refereed)
    Abstract [en]

    The rate of hydrogen-deuterium exchange (HDX) in aqueous droplets of phenethylamine has been determined with submillisecond temporal resolution by mass spectrometry using nanoelectrospray ionization with a theta-capillary. The average speed of the micro droplets is measured using microparticle image velocimetry. The droplet travel time is varied from 20 to 320 mu s by changing the distance between the emitter and the heated inlet to the mass spectrometer and the voltage applied to the emitter source. The droplets were found to accelerate by similar to 30% during their observable travel time. Our droplet imaging shows that the theta-capillary produces two Taylor cone-jets (one per channel), causing mixing to take place from droplet fusion in the Taylor spray zone. Phenethylamine (phi CH2CH2NH2) was chosen to study because it has only one functional group (-NH2) that undergoes rapid HDX. We model the HDX with a system of ordinary differential equations. The rate constant for the formation of -NH2D+ from -NH3+ is 3660 +/- 290 s(-1), and the rate constant for the formation of -NHD2+ from -NH2D+ is 3330 +/- 270 s(-1). The observed rates are about 3 times faster than what has been reported for rapidly exchangeable peptide side-chain groups in bulk measurements using stopped-flow kinetics and NMR spectroscopy. We also applied this technique to determine the HDX rates for a small 10-residue peptide, angiotensin I, in aqueous droplets, from which we found a 7-fold acceleration of HDX in the droplet compared to that in bulk solution.

  • 185.
    Jansson, Ronnie
    et al.
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.
    Lau, Cheuk H
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.; Swedish Univ Agr Sci, Dept Chem & Biotechnol, Uppsala, Sweden.
    Ishida, Takuya
    Univ Tokyo, Grad Sch Agr & Life Sci, Dept Biomat Sci, Tokyo, Japan.
    Ramström, Margareta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandgren, Mats
    Swedish Univ Agr Sci, Dept Chem & Biotechnol, Uppsala, Sweden.
    Hedhammar, My
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.; KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, Stockholm, Sweden .
    Functionalized silk assembled from a recombinant spider silk fusion protein (Z-4RepCT) produced in the methylotrophic yeast Pichia pastoris.2016In: Biotechnology Journal, ISSN 1860-6768, E-ISSN 1860-7314, Vol. 11, no 5, p. 687-699Article in journal (Refereed)
    Abstract [en]

    Functional biological materials are a growing research area with potential applicability in medicine and biotechnology. Using genetic engineering, the possibility to introduce additional functions into spider silk-based materials has been realized. Recently, a recombinant spider silk fusion protein, Z-4RepCT, was produced intracellularly in Escherichia coli and could after purification self-assemble into silk-like fibers with ability to bind antibodies via the IgG-binding Z domain. In this study, the use of the methylotrophic yeast Pichia pastoris for production of Z-4RepCT has been investigated. Temperature, pH and production time were influencing the amount of soluble Z-4RepCT retrieved from the extracellular fraction. Purification of secreted Z-4RepCT resulted in a mixture of full-length and degraded silk proteins that failed to self-assemble into fibers. A position in the C-terminal domain of 4RepCT was identified as being subjected to proteolytic cleavage by proteases in the Pichia culture supernatant. Moreover, the C-terminal domain was subjected to glycosylation during production in P. pastoris. These observed alterations of the CT domain are suggested to contribute to the failure in fiber assembly. As alternative approach, Z-4RepCT retrieved from the intracellular fraction, which was less degraded, was used and shown to retain ability to assemble into silk-like fibers after enzymatic deglycosylation.

  • 186.
    Jerlström-Hultqvist, Jon
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Einarsson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Xu, Feifei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Hjort, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ek, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Steinhauf, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Andersson, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Svärd, Staffan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Spironucleus mitochondrial remnants suggest that hydrogenosomes are ancient organellesIn: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490Article in journal (Refereed)
  • 187.
    Jerlström-Hultqvist, Jon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Einarsson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Xu, Feifei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Hjort, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ek, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Steinhauf, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hultenby, Kjell
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Andersson, Jan O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Hydrogenosomes in the diplomonad Spironucleus salmonicida2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 2493-Article in journal (Refereed)
    Abstract [en]

    Acquisition of the mitochondrion is a key event in the evolution of the eukaryotic cell, but diversification of the organelle has occurred during eukaryotic evolution. One example of such mitochondria-related organelles (MROs) are hydrogenosomes, which produce ATP by substrate- level phosphorylation with hydrogen as a byproduct. The diplomonad parasite Giardia intestinalis harbours mitosomes, another type of MRO. Here we identify MROs in the salmon parasite Spironucleus salmonicida with similar protein import and Fe-S cluster assembly machineries as in Giardia mitosomes. We find that hydrogen production is prevalent in the diplomonad genus Spironucleus, and that S. salmonicida MROs contain enzymes characteristic of hydrogenosomes. Evolutionary analyses of known hydrogenosomal components indicate their presence in the diplomonad ancestor, and subsequent loss in Giardia. Our results suggest that hydrogenosomes are metabolic adaptations predating the split between parabasalids and diplomonads, which is deeper than the split between animals and fungi in the eukaryotic tree.

  • 188.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Palmblad, Magnus
    Deelder, Andre M.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Identification of genetic variants influencing the human plasma proteome2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 12, p. 4673-4678Article in journal (Refereed)
    Abstract [en]

    Genetic variants influencing the transcriptome have been extensively studied. However, the impact of the genetic factors on the human proteome is largely unexplored, mainly due to lack of suitable high-throughput methods. Here we present unique and comprehensive identification of genetic variants affecting the human plasma protein profile by combining high-throughput and high-resolution mass spectrometry (MS) with genome-wide SNP data. We identified and quantified the abundance of 1,056 tryptic-digested peptides, representing 163 proteins in the plasma of 1,060 individuals from two population-based cohorts. The abundance level of almost one-fifth (19%) of the peptides was found to be heritable, with heritability ranging from 0.08 to 0.43. The levels of 60 peptides from 25 proteins, 15% of the proteins studied, were influenced by cis-acting SNPs. We identified and replicated individual cis-acting SNPs (combined P value ranging from 3.1 x 10(-52) to 2.9 x 10(-12)) influencing 11 peptides from 5 individual proteins. These SNPs represent both regulatory SNPs and nonsynonymous changes defining well-studied disease alleles such as the epsilon 4 allele of apolipoprotein E (APOE), which has been shown to increase risk of Alzheimer's disease. Our results show that high-throughput mass spectrometry represents a promising method for large-scale characterization of the human proteome, allowing for both quantification and sequencing of individual proteins. Abundance and peptide composition of a protein plays an important role in the etiology, diagnosis, and treatment of a number of diseases. A better understanding of the genetic impact on the plasma proteome is therefore important for evaluating potential biomarkers and therapeutic agents for common diseases.

  • 189.
    Jonsson, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Validation of mercury free methods for analysis of Chemical Oxygen Demand in municipial wastewater2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Water is used every day in society and to be able to recycle this water we depend upon efficient wastewater treatment. It is vital to test the wastewater based on different parameters. One parameter is the Chemical Oxygen Demand (COD), which defines the amount of organic substances that can be chemically oxidized within the water. The Swedish standardized analytical method for COD (SS-028142), COD(Cr) is dependent on mercury, a substance which was banned according to Swedish regulations in year 2009 but is still used due to time limited dispensations.

    This report is a part of a pre-procurement innovative project initiated by the Swedish Water and Wastewater Association (SWWA) in order to bring forward and evaluate mercury free analytical methods for COD for municipal wastewater. The aim was to validate three analytical methods for COD: Chloride Determination, Chloride Elimination and PeCOD and compare the analytical results to the standardized COD(Cr). Three laboratories, Käppala (Stockholm), Gryaab (Gothenburg) and Komlab (Örnsköldsvik) were included in the validation process by providing analytical data. The validation was conducted using the data as input for the statistical methods regression, correlation and analysis of variance to investigate the performance of the individual methods. As a complement to the statistical results, comments regarding the methods brought up by the laboratory staff were compiled in order to reflect on the usability and robustness of the methods. 

    The results indicated that the method Chloride Determination was the method most similar to the COD(Cr) method, when investigating obtained COD concentrations, required analytical time and implementation steps needed to obtain a final COD value. This result was evident by high coefficient of determination values for influent wastewater samples. The PeCOD method, which was submitted in two versions, one manual and one automatic was only able to analyze soluble COD. It was found that the PeCOD methods obtained lower COD concentrations compared to the standardized method when analyzing filtered samples. Due to highly variable correlation coefficients between the PeCOD and COD(Cr) for various types of samples indicated that no uniform linear relation between the methods was present. Analysis with the Chloride Elimination method was halted early in the validation process, but was found to receive approximately 50 percent lower COD values than the reference method  COD(Cr). Finally it can be said that the input data for conducting the statistical test were limited and further analysis should be recommended in order to validate the results with a higher certainty. 

  • 190.
    Jose Farre, Maria
    et al.
    Univ Girona, Catalan Inst Water Res, ICRA, H2O Bldg,Sci & Technol Pk, Girona 17003, Spain.
    Jaen-Gil, Adrian
    Univ Girona, Catalan Inst Water Res, ICRA, H2O Bldg,Sci & Technol Pk, Girona 17003, Spain.
    Hawkes, Jeffrey A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Petrovic, Mira
    Univ Girona, Catalan Inst Water Res, ICRA, H2O Bldg,Sci & Technol Pk, Girona 17003, Spain;Catalan Inst Res & Adv Studies, ICREA, Barcelona 08010, Spain.
    Catalan, Nuria
    Univ Girona, Catalan Inst Water Res, ICRA, H2O Bldg,Sci & Technol Pk, Girona 17003, Spain.
    Orbitrap molecular fingerprint of dissolved organic matter in natural waters and its relationship with NDMA formation potential2019In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 670, p. 1019-1027Article in journal (Refereed)
    Abstract [en]

    N-nitrosodimethylamine (NDMA) is a disinfection byproduct that has been classified as probable human carcinogen by the US Environmental Protection Agency. According to the published literature, natural dissolved organic matter (DOM) can be a source of NDMA precursors in drinking water. New advances in chemical characterization of DOM with high resolution mass spectrometry (HRMS) are allowing researchers to understand these ultra-complex mixtures. The objective of this study is to investigate analytical methodologies based on HRMS to explore NDMA formation from natural waters. To this aim, different waters from drinking water reservoirs in Spain containing NDMA precursors (quantified by means of NDMA formation potential) in concentrations between 17 and 60 ng/L have been studied. The workflow includes DOM solid-phase extraction and Orbitrap analysis with and without chromatographic separation. Here, we show that the molecular composition of DOM across the studied drinking water reservoirs is correlated with the NDMA formation potential. In particular, we found that NDMA formation potential is associated with compounds with high hydrogen saturation (H/C >= 1.5), corresponding also to reservoirs with higher background nutrient concentrations and wastewater indicators. Further chromatographic fractionation did not allow better definition of these possible precursors as they were present in different fractions of the chromatogram, suggesting that they were isomerically complex. 

  • 191.
    Kaihola, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Gülen Yaldir, Fatma
    Centre of Reproduction, Uppsala University Hospital Uppsala, Sweden.
    Hreinson, Julius
    IVF-Clinic Falun Falun, Sweden.
    Hörnaeus, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Olivier, Jocelien
    Unit Behavioural Neuroscience, Department of Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen Groningen, Netherlands.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Effects of fluoxetine on human embryo development2016In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 10, article id 160Article in journal (Other academic)
    Abstract [en]

    The use of antidepressant treatment during pregnancy is increasing, and selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressants in pregnant women. Serotonin plays a role in embryogenesis, and serotonin transporters are expressed in two-cell mouse embryos. Thus, the aim of the present study was to evaluate whether fluoxetine, one of the most prescribed SSRI antidepressant world-wide, exposure influences the timing of different embryo developmental stages, and furthermore, to analyze what protein, and protein networks, are affected by fluoxetine in the early embryo development. Human embryos (17 = 48) were randomly assigned to treatment with 0.25 or 0.5 IiM fluoxetine in culture medium. Embryo development was evaluated by time-lapse monitoring. The fluoxetine-induced human embryo proteome was analyzed by shotgun mass spectrometry. Protein secretion from fluoxetine-exposed human embryos was analyzed by use of high-multiplex immunoassay. The lower dose of fluoxetine had no influence on embryo development. A trend toward reduced time between thawing and start of cavitation was noted in embryos treated with 0.5 it M fluoxetine (p = 0.065). Protein analysis by shotgun mass spectrometry detected 45 proteins that were uniquely expressed in fluoxetine-treated embryos. These proteins are involved in cell growth, survival, proliferation, and inflammatory response. Culturing with 0.5 p M, but not 0.25 p M fluoxetine, caused a significant increase in urokinase-type plasminogen activator (uPA) in the culture medium. In conclusion, fluoxetine has marginal effects on the timing of developmental stages in embryos, but induces expression and secretion of several proteins in a manner that depends on dose. For these reasons, and in line with current guidelines, the lowest possible dose of SSRI should be used in pregnant women who need to continue treatment.

  • 192.
    Kakehashi, R.
    et al.
    Organic Materials Research Division, Osaka Municipal Technical Research Institute, 1-6-50 Morinomiya, Joto-ku, Osaka 836-8553, Japan.
    Tokai, N.
    Organic Materials Research Division, Osaka Municipal Technical Research Institute, 1-6-50 Morinomiya, Joto-ku, Osaka 836-8553, Japan.
    Kohno, T.
    Department of Applied Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Omiya, Asahi-ku, Osaka 535-8585, Japan.
    Nakatsuji, Y.
    Department of Applied Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Omiya, Asahi-ku, Osaka 535-8585, Japan.
    Yamamura, S.
    Organic Materials Research Division, Osaka Municipal Technical Research Institute, 1-6-50 Morinomiya, Joto-ku, Osaka 836-8553, Japan.
    Karlsson, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Protonation Behavior and Solution Properties of Amine Oxide Surfactants Containing a Pyridyl Group2013In: Journal of Oleo Science, ISSN 1345-8957, E-ISSN 1347-3352, Vol. 62, no 3, p. 123-132Article in journal (Refereed)
    Abstract [en]

    Hydrogen bonding between surfactant molecules plays an important role in self-assembly formation. For long alkyl chain amine oxide surfactants, the specific protonation degree dependence of some solution properties has been considered to be due to hydrogen bonding between protonated and deprotonated species. In addition to this type of hydrogen bonding, we introduced a pyridyl group into an alkylamine oxide molecule as a new hydrogen-bonding site. The pyridyl group has three different structural isomers based on the position of the substituent. An amine oxide group in pyridylamine oxides was preferentially protonated. In addition, protonation of the pyridyl group revealed a pronounced substituent position effect on the critical micelle concentration, micellar size, and solubilization of oil-soluble dye into micelles. The intermolecular or intramolecular hydrogen bond formation could be controlled by altering the substituent position.

  • 193.
    Kallak, Theodora Kunovac
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Baumgart, J.
    Department of Obstetrics and Gynecology, Örebro University Hospital, Sweden.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Moby, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kask, Kristiina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Norjavaara, E.
    Gothenburg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Sweden .
    Kushnir, M. M.
    ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, USA.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Nilsson, K.
    The School of Health and Medical Sciences, Örebro University, Sweden.
    Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients2012In: Climacteric, ISSN 1369-7137, E-ISSN 1473-0804, Vol. 15, no 5, p. 473-480Article in journal (Refereed)
    Abstract [en]

    Objective

    Vaginal estradiol is considered contraindicated in aromatase inhibitor (AI)-treated patients because of the risk of elevated estrogen levels. This leaves limited treatment options for patients experiencing gynecological symptoms. However, in clinical practice, no precise estimation has been performed of circulating estrogens and aromatase index in postmenopausal breast cancer patients on long-lasting AI or tamoxifen treatment. 

    Methods

    Steroid hormones were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) and extraction radioimmunoassay (RIA). Postmenopausal AI-treated patients (n =33) were compared with tamoxifen-treated patients (n =34) and controls without vaginal treatment (n =56), with vaginal estradiol (n =25), or with estriol (n =11) treatment. 

    Results

    By use of LC-MS/MS, median (range) estradiol plasma concentrations were 16.7 (2.4-162.6), 31.0 (13.4-77.1), 27.2 (7.8-115.8) and 33.3 (20.3-340.1) pmol/l in AI-treated breast cancer patients, tamoxifen-treated breast cancer patients, postmenopausal controls and postmenopausal controls on vaginal estradiol, respectively. The AI-treated group and subgroups had significantly lower estradiol and estrone concentrations than all other groups(p <0.05). There was extensive interindividual variation in estradiol concentration within the AI-treated group, measured using both LC-MS/MS (2.3-182.0 pmol/l) and extraction RIA (2.4-162.6 pmol/l). The AI-treated group had lower aromatase index compared to all other groups (p <0.05-0.001).  

    Conclusion

    Circulating estrogen levels may have been underestimated in previous longitudinal studies of AI-treated breast cancer patients. Additional studies are required to further evaluate the role of circulating estrogens in breast cancer patients suffering from gynecological symptoms.

  • 194.
    Kallak, Theodora Kunovac
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Sandelin-Francke, Lotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Campbell, Rebecca E
    Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Medical Sciences, Dunedin, New Zealand.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain2017In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 177, no 4, p. 379-388Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Prenatal androgen exposure has been suggested to play a role in polycystic ovary syndrome. Given the limited information on what maternal characteristics influence maternal testosterone levels, and the even less explored routes by which female fetus androgen exposure would occur, the aim of this study was to investigate the impact of maternal age, BMI, weight gain, depressed mood and aromatase SNPs on testosterone levels in maternal serum and amniotic fluid of female fetuses.

    METHODS: Blood samples from pregnant women (n = 216) obtained in gestational weeks 35-39, and pre-labor amniotic fluid samples from female fetuses (n = 56), taken at planned Caesarean section or in conjunction with amniotomy for induction of labor, were analyzed. Maternal serum testosterone and amniotic fluid testosterone and cortisol were measured by tandem mass spectrometry.

    RESULTS: Multiparity (β = -0.28, P < 0.001), self-rated depression (β = 0.26, P < 0.001) and weight gain (β = 0.18, P < 0.05) were independent explanatory factors for the maternal total testosterone levels. Maternal age (β = -0.34, P < 0.001), weight gain (β = 0.19, P < 0.05) and amniotic fluid cortisol levels (β = 0.44, P < 0.001) were independent explanatory factors of amniotic fluid testosterone in female fetuses, explaining 64.3% of the variability in amniotic fluid testosterone.

    WIDER IMPLICATIONS OF THE FINDINGS: Young maternal age and excessive maternal weight gain may increase the prenatal androgen exposure of female fetuses. Further studies are needed to explore this finding.

  • 195.
    Karademir, Betul
    et al.
    Marmara Univ, Sch Med, Dept Biochem, Genet & Metab Dis Res & Invest Ctr, Istanbul, Turkey.
    Sari, Gulce
    Marmara Univ, Sch Med, Dept Biochem, Genet & Metab Dis Res & Invest Ctr, Istanbul, Turkey;Okan Univ, Fac Engn, Dept Genet & Bioengn, Istanbul, Turkey.
    Jannuzzi, Ayse Tarbin
    Istanbul Univ, Fac Pharm, Dept Pharmaceut Toxicol, Istanbul, Turkey.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Grune, Tilman
    German Inst Human Nutr Potsdam Rehbruecke DIfE, Dept Mol Toxicol, D-14558 Nuthetal, Germany;German Ctr Diabet Res DZD, D-85764 Munich, Germany;German Ctr Cardiovasc Res DZHK, D-10117 Berlin, Germany.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Binzhou Med Univ, Med & Pharm Res Ctr, Yantai, Peoples R China.
    Hacioglu-Bay, Husniye
    Marmara Univ, Sch Med, Dept Anat, Istanbul, Turkey.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Jung, Tobias
    German Inst Human Nutr Potsdam Rehbruecke DIfE, Dept Mol Toxicol, D-14558 Nuthetal, Germany;German Ctr Diabet Res DZD, D-85764 Munich, Germany;German Ctr Cardiovasc Res DZHK, D-10117 Berlin, Germany.
    Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 16318Article in journal (Refereed)
    Abstract [en]

    The proteasomal system is responsible for the turnover of damaged proteins. Because of its important functions in oncogenesis, inhibiting the proteasomal system is a promising therapeutic approach for cancer treatment. Bortezomib (BTZ) is the first proteasome inhibitor approved by FDA for clinical applications. However neuropathic side effects are dose limiting for BTZ as many other chemotherapeutic agents. Therefore second-generation proteasome inhibitors have been developed including carfilzomib (CFZ). Aim of the present work was investigating the mechanisms of peripheral neuropathy triggered by the proteasome inhibitor BTZ and comparing the pathways affected by BTZ and CFZ, respectively. Neural stem cells, isolated from the cortex of E14 mouse embryos, were treated with BTZ and CFZ and mass spectrometry was used to compare the global protein pool of treated cells. BTZ was shown to cause more severe cytoskeletal damage, which is crucial in neural cell integrity. Excessive protein carbonylation and actin filament destabilization were also detected following BTZ treatment that was lower following CFZ treatment. Our data on cytoskeletal proteins, chaperone system, and protein oxidation may explain the milder neurotoxic effects of CFZ in clinical applications.

  • 196.
    Karlsson, Ida
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Analysis of active botulinumtoxin in biological matrices for applications in veterinary botulism outbreaks2018Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Botulinum neurotoxins (BoNTs), produced by the bacteria Clostridium botulinum,are the deadliest toxins known to mankind, causing the disease botulism. Thecurrently golden standard for detection of active BoNTs is the mouse bioassay(MBA). The ethical concern of the MBA has however encouraged the development ofother methods for detecting BoNTs. At the National Veterinary Institute (SVA) anEndopep-MS method for qualitative detection of active botulinum neurotoxins inhuman and chicken serum has been validated. Endopep-MS is an endopeptidasemethod that uses MALDI-TOF MS (Matrix-assisted laser desorption ionization–timeof flight mass spectrometry) for detection. The method is based on the toxins ownprotease activity and has been proven to be a promising, selective and sensitivemethod for detection of active BoNTs. The purpose with this study was to adapt andfurther develop SVA's validated Endopep-MS method for detection of BoNT-C, D andtheir mosaics C/D and D/C to new matrices such as liver, excrement and feed. Themain focus has been on avian liver samples that, as suspected, contained a lot ofendogenous proteases. By using the combination of a 2 M sodium chloride salt washsolution and the addition of 4μ L of a protease inhibitor cocktail to the endopepreaction buffer the activity of the proteases was successfully reduced withoutinhibiting the activity of the BoNTs.

  • 197.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Lindström, Anna-Karin
    Hanrieder, Jorg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arnerup, Gunnel
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neonatal Exposure to the Cyanobacterial Toxin BMAA Induces Changes in Protein Expression and Neurodegeneration in Adult Hippocampus2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 130, no 2, p. 391-404Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial toxin -N-methylamino-l-alanine (BMAA) has been proposed to contribute to neurodegenerative disease. We have previously reported a selective uptake of BMAA in the mouse neonatal hippocampus and that exposure during the neonatal period causes learning and memory impairments in adult rats. The aim of this study was to characterize effects in the brain of 6-month-old rats treated neonatally (postnatal days 910) with the glutamatergic BMAA. Protein changes were examined using the novel technique Matrix-Assisted Laser Desorption Ionization (MALDI) imaging mass spectrometry (IMS) for direct imaging of proteins in brain cryosections, and histological changes were examined using immunohistochemistry and histopathology. The results showed long-term changes including a decreased expression of proteins involved in energy metabolism and intracellular signaling in the adult hippocampus at a dose (150mg/kg) that gave no histopathological lesions in this brain region. Developmental exposure to a higher dose (460mg/kg) also induced changes in the expression of S100, histones, calcium- and calmodulin-binding proteins, and guanine nucleotide-binding proteins. At this dose, severe lesions in the adult hippocampus including neuronal degeneration, cell loss, calcium deposits, and astrogliosis were evident. The data demonstrate subtle, sometimes dose-dependent, but permanent effects of a lower neonatal dose of BMAA in the adult hippocampus suggesting that BMAA could potentially disturb many processes during the development. The detection of BMAA in seafood stresses the importance of evaluating the magnitude of human exposure to this neurotoxin.

  • 198.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Quality measures of imaging mass spectrometry aids in revealing long-term striatal protein changes induced by neonatal exposure to the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA)2014In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 13, p. 93-104Article in journal (Refereed)
    Abstract [en]

    Many pathological processes are not directly correlated to dramatic alterations in protein levels. The changes in local concentration of important proteins in a subset of cells or at specific loci is likely to play a significant role in the disease etiologies, but the precise location might be unknown or too small to be adequately sampled for the purpose of traditional proteomic techniques. In this respect, matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) is a unique analytical method that combines analysis of multiple molecular species and their distribution in one single platform. As reproducibility is essential for successful biomarker discovery it is important to systemically assess data quality in biologically relevant MALDI IMS experiments. In the present study, we applied four simple tools to study the reproducibility for individual sections, within group variation and between group variations of data acquired from brain sections of 21 animals divided into three treatment groups. We also characterized protein changes in distinct regions of the striatum from six month-old rats treated neonatally (PND; postnatal days 9-10) with the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) that has been implicated in neurodegenerative diseases. The results showed that optimized experimental settings can render high quality MALDI IMS data with relatively low variation (14-15 %CV) that allows characterization of subtle changes in protein expression in various subregions of the brain. This was further exemplified by the dose-dependent reduction of MBP (myelin basic protein) in the caudate putamen and the nucleus accumbens of adult rats neonatally treated with BMAA (150 and 460 mg/kg). The MBP reduction was confirmed with immunohistochemistryand indicates that developmental exposure to BMAA may induce structural effects on axonal growth and/or directly on proliferation of oligodendrocytes and myelination, which might be important for the previously shown BMAA-induced long-term cognitive impairments.

  • 199.
    Karunasekera, Hasanthi
    et al.
    Swedish Univ Agr Sci, Dept Forest Prod Wood Sci, Box 7008, SE-75007 Uppsala, Sweden.
    Pettersson, Jean
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Daniel, Geoffrey
    Swedish Univ Agr Sci, Dept Forest Prod Wood Sci, Box 7008, SE-75007 Uppsala, Sweden.
    Copper tolerance of the soft-rot fungus Phialophora malorum grown in-vitro revealed by microscopy and global protein expression2019In: International Biodeterioration & Biodegradation, ISSN 0964-8305, E-ISSN 1879-0208, Vol. 137, p. 147-152Article in journal (Refereed)
    Abstract [en]

    In this study, we used proteomics in conjunction with microscopy to study differences in the proteome and hyphal morphology of the copper tolerant soft rot fungus Phialophora malorum grown in media containing 0.064, 0.64% Cu as CuSO4. Unique proteins were found in the control and the copper-treated (0.064% CuSO4) samples. Of five unique proteins found in the 0.064% CuSO4 treated cultures, ATP synthase subunit alpha is considered to play an important role in copper tolerance as it is involved in the biosynthesis of fatty acids and steroids and may relate to morphological changes associated with hyphal cell walls of the fungus when grown in the presence of copper. ICP-AES analyses showed total mycelial Cu to increase with media Cu with 5246- and 16535 mu g Cu/g dry wt mycelia respectively found in 0.064 and 0.64% Cu-cultures after 6 weeks growth. Rubeanic acid staining of 0.064% mycelia showed Cu bound in intracellular bodies while most Cu was found as extracellular precipitates on the surfaces of hyphae in 0.64% Cu. SEM showed hyphal surfaces enrobed in fibrillar polysaccharides to which Cu was bound.

  • 200.
    Kask, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Hörnaeus, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Åberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Jorsback, A.
    GE Healthcare, Uppsala, Sweden..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Proteomic, functional and receptor studies of growth differentiation factor 15, GDF-152018In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 114, p. S76-S76Article in journal (Other academic)
1234567 151 - 200 of 439
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