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  • 101. Nordberg, Agneta
    et al.
    Rinne, Juha O.
    Kadir, Ahmadul
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    The use of PET in Alzheimer disease2010In: Nature Reviews Neurology, ISSN 1759-4758, Vol. 6, no 2, p. 78-87Article, review/survey (Refereed)
    Abstract [en]

    In Alzheimer disease (AD), which is the most common cause of dementia, the underlying disease pathology most probably precedes the onset of cognitive symptoms by many years. Thus, efforts are underway to find early diagnostic markers as well as disease-modifying treatments for this disorder. PET enables various brain systems to be monitored in living individuals. In patients with AD, PET can be used to investigate changes in cerebral glucose metabolism, various neurotransmitter systems, neuroinflammation, and the protein aggregates that are characteristic of the disease, notably the amyloid deposits. These investigations are helping to further our understanding of the complex pathophysiological mechanisms that underlie AD, as well as aiding the early and differential diagnosis of the disease in the clinic. In the future, PET studies will also be useful for identifying new therapeutic targets and monitoring treatment outcomes. Amyloid imaging could be useful as early diagnostic marker of AD and for selecting patients for anti-amyloid-beta therapy, while cerebral glucose metabolism could be a suitable PET marker for monitoring disease progression. For the near future, multitracer PET studies are unlikely to be used routinely in the clinic for AD, being both burdensome and expensive; however, such studies are very informative in a research context.

  • 102.
    Nordqvist, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Endometrial gene expression related to recurrent miscarriage2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    A woman’s uterus is a safe place for the baby to grow and get nourished which is not always the case since the endometrium can, due to some underlying causes repel the fertilised egg which in other words means that the woman undergoes miscarriage. Recurrent miscarriage is defined as three or more pregnancy losses before 22 weeks of gestation. Multiple etiologies is thought to cause recurrent miscarriage although still 50 % of these cases remains unknown. The aim of this study was to measure the gene expression of DKK1, STC1, TK1, IL8 and OLFM1 in the endometrium of women with recurrent miscarriage compared to fertile women by using quantitative real-time PCR (qPCR) with TaqMan probes and primers. Immunohistochemical staining of paraffin embedded endometrium tissue was performed with a primary antibody anti-IL8 for detection of the IL8-protein. No significant difference was seen in mRNA expression between the two groups, only the IL8 mRNA showed a tendency to significant difference between the groups, p=0,063. On protein level, the immunohistochemical staining of IL8 showed few stained cells in both groups. Interestingly, the number of cells was clearly more abundant in women with recurrent miscarriage than in fertile women, p=0,036. The main conclusion from this study is that the high number of IL8 produced cells in the endometrium may be a contributing factor to recurrent miscarriage and need to be investigated further.

  • 103.
    Obaidur, Rahman
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Erlandsson, Maria
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Blom, Elisabeth
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Långström, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Automated synthesis of 18F-labelled analogues of etomidate, vorozole and harmine using commercial synthesizer TRACERLab FXFNManuscript (Other academic)
    Abstract [en]

    18F-Labelled analogues of three biologically interesting compounds, ethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (ETO), 6-[(S)-(4-chlorophenyl)-(1H)-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole (VOZ) and 7-methoxy-1-methyl-9H-β-carboline (HAR) were synthesized by one-step nucleophilic fluorination. The 18F-labelled products were obtained with 20–30% isolated decay-corrected radiochemical yields and the radiochemical purities were over 99% in all cases. The labelling syntheses were performed using fully automated commercial synthesizer TRACERLab FXFN. The automation of the syntheses of these three promising PET tracers using a commercial synthesizer will make them accessible for clinical applications.       

  • 104.
    Ohgaki, Ryuichi
    et al.
    Osaka University, Graduate School of Medicine, Department of Bio-system Pharmacology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. The University of Tokyo, Department of Bioengineering.
    Hayashi, Daichi
    Osaka University, Graduate School of Medicine, Department of Bio-system Pharmacology.
    Quan, Lili
    Osaka University, Graduate School of Medicine, Department of Bio-system Pharmacology.
    Okuda, Suguru
    Osaka University, Graduate School of Medicine, Department of Bio-system Pharmacology.
    Nagamori, Shushi
    Osaka University, Graduate School of Medicine, Department of Bio-system Pharmacology.
    Takai, Madoka
    The University of Tokyo, Department of Bioengineering.
    Kanai, Yoshikatsu
    Osaka University, Graduate School of Medicine, Department of Bio-system Pharmacology.
    Ratiometric fluorescence imaging of cell surface pH by poly(ethylene glycol)-phospholipid conjugated with fluorescein isothiocyanate2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17484Article in journal (Refereed)
    Abstract [en]

    Various physiological and pathological processes are accompanied with the alteration of pH at extracellular juxtamembrane region. Accordingly, the methods to analyze the cell surface pH have been demanded in biological and medical sciences. In this study, we have established a novel methodology for cell surface pH imaging using poly(ethylene glycol)-phospholipid (PEG-lipid) as a core structure of ratiometric fluorescent probes. PEG-lipid is a synthetic amphiphilic polymer originally developed for the cell surface modification in transplantation therapy. Via its hydrophobic alkyl chains of the phospholipid moiety, PEG-lipid is, when applied extracellularly, spontaneously inserted into the plasma membrane and retained at the surface of the cells. We have demonstrated that the PEG-lipid conjugated with fluorescein isothiocyanate (FITC-PEG-lipid) can be used as a sensitive and reversible cell-surfacea-nchored pH probe between weakly alkaline and acidic pH with an excellent spatiotemporal resolution. The remarkably simple procedure for cell-surface labeling with FITC-PEG-lipid would also be advantageous when considering its application to high-throughput in vitro assay. This study further indicates that various probes useful for the investigation of juxtamembrane environments could also be developed by using PEG-lipid as the core structure for bio-membrane anchoring.

  • 105.
    Ohman, L
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hesselager, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Larsson, R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nister, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stigbrand, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wester, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    A new antibody recognizing the vIII mutation of human epidermal growthfactor receptor.2002In: Tumour Biol, Vol. 23, p. 61-Article in journal (Refereed)
  • 106.
    Olsson, P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Collins, VP
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Liu, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Liljegren, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Internalisation and retention of EGF-dextran associated radioactivity intransfected Chinese hamster ovary cells expressing the human EGF-receptor.2002In: Int J Oncol, Vol. 20, p. 1057-Article in journal (Refereed)
  • 107.
    Olsson, P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Goike, H
    Liu, L
    Collins, P
    Ponten, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    In vitro and in vivo studies of a boronated epidermal growth factor (EGF)-dextran conjugate1996In: Seventh International Symposium on Neutron Capture Therapy for Cancer, p. 145-Article, book review (Other academic)
  • 108.
    Olsson, P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Goike, H
    Liu, L
    Collins, VP
    Ponten, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    In vitro and in vivo studies of a boronated epidermal growth factor (EGF)-dextran conjugate.1997Conference paper (Other academic)
  • 109.
    Olsson, P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Goike, H
    Liu, L
    Collins, VP
    Ponten, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Uptake of a boronated epidermal growth factor-dextran conjugate in CHOtor expression.1998In: Anti-Cancer Drug Des., Vol. 13, p. 279-Article in journal (Refereed)
  • 110.
    Patriksson, Alexandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    From Solution into Vacuum - Structural Transitions in Proteins2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Information about protein structures is important in many areas of life sciences, including structure-based drug design. Gas phase methods, like electrospray ionization and mass spectrometry are powerful tools for the analysis of molecular interactions and conformational changes which complement existing solution phase methods. Novel techniques such as single particle imaging with X-ray free electron lasers are emerging as well. A requirement for using gas phase methods is that we understand what happens to proteins when injected into vacuum, and what is the relationship between the vacuum structure and the solution structure.

    Molecular dynamics simulations in combination with experiments show that protein structures in the gas phase can be similar to solution structures, and that hydrogen bonding networks and secondary structure elements can be retained. Structural changes near the surface of the protein happen quickly (ns-µs) during transition from solution into vacuum. The native solution structure results in a reasonably well defined gas phase structure, which has high structural similarity to the solution structure.

    Native charge locations are in some cases also preserved, and structural changes, due to point mutations in solution, can also be observed in vacuo. Proteins do not refold in vacuo: when a denatured protein is injected into vacuum, the resulting gas phase structure is different from the native structure.

    Native structures can be protected in the gas phase by adjusting electrospray conditions to avoid complete evaporation of water. A water layer with a thickness of less than two water molecules seems enough to preserve native conditions.

    The results presented in this thesis give confidence in the continued use of gas phase methods for analysis of charge locations, conformational changes and non-covalent interactions, and provide a means to relate gas phase structures and solution structures.

    List of papers
    1. Reproducible polypeptide folding and structure prediction using molecular dynamics simulations
    Open this publication in new window or tab >>Reproducible polypeptide folding and structure prediction using molecular dynamics simulations
    2005 In: J. Mol. Biol., Vol. 354, p. 173-183Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-96398 (URN)
    Available from: 2007-11-09 Created: 2007-11-09 Last updated: 2014-09-26Bibliographically approved
    2. Prediction of N-Cα bond cleavage frequencies in lectron capture dissociation of Trp-cage dications by force-field molecular dynamics simulations
    Open this publication in new window or tab >>Prediction of N-Cα bond cleavage frequencies in lectron capture dissociation of Trp-cage dications by force-field molecular dynamics simulations
    Show others...
    2006 In: Int. J. Mass Spectrom., Vol. 248, p. 124-135Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-96399 (URN)
    Available from: 2007-11-09 Created: 2007-11-09Bibliographically approved
    3. Probing Solution-Phase and Gas-Phase Structures of Trp-cage Cations by Chiral Substitution and Spectroscopic Techniques
    Open this publication in new window or tab >>Probing Solution-Phase and Gas-Phase Structures of Trp-cage Cations by Chiral Substitution and Spectroscopic Techniques
    Show others...
    2006 (English)In: International Journal of Mass Spectrometry, ISSN 1387-3806, E-ISSN 1873-2798, Vol. 253, no 3, p. 263-273Article in journal (Refereed) Published
    Abstract [en]

    The relevance of gas-phase protein structure to its solution structure is of the utmost importance in studying biomolecules by mass spectrometry. D-Amino acid substitutions within a minimal protein. Trp-cage. were used to correlate solution-phase properties as measured by circular dichroism with solution/gas-phase conformational features of protein cations probed via charge state distribution (CSD) in electrospray ionization. and gas-phase features revealed by tandem mass spectrometry (MS/MS). The gas-phase features were additionally supported by force-field molecular dynamics simulations. CD data showed that almost any single-residue D-substitution destroys the most prominent CD feature of the "native" all-L isomer, alpha-helicity. CSD was able to qualitatively assess the degree of compactness of solution-phase molecular structures. CSD results were consistent with the all-L form being the most compact in solution among all studied stereoisomers except for the D-Asn(1) isomer. D-substitutions of the aromatic Y(3), W(6) and Q(5) residues generated the largest deviations in CSD data among single amino acid substitutions. consistent with the critical role of these residues in Trp-cage stability. Electron capture dissociation of the stereoisomer dications gave an indication that some gas-phase structural features of Trp-cage are similar to those in solution. This result is supported by MDS data oil five of the studied stereoisomer dications in the gas-phase. The MDS-derived minimum-energy structures possessed more extensive hydrogen bonding than the solution-phase structure of the native form, deviating from the latter by 3-4 angstrom and were not 'inside-out' compared to native structures. MDS data could be correlated with CD data and even with ECD results. which aided in providing a long-range structural constraint for MDS. The overall conclusion is the general resemblance, despite the difference on the detailed level, of the preferred structures in both phases for the mini protein Trp-cage.

    Keywords
    solution structure; gas-phase structure; chirality; electron capture dissociation; charge state distribution
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-95865 (URN)10.1016/j.ijms.2006.04.012 (DOI)000238967500014 ()
    Available from: 2007-05-07 Created: 2007-05-07 Last updated: 2017-12-14Bibliographically approved
    4. Proteins structures under electrospray conditions
    Open this publication in new window or tab >>Proteins structures under electrospray conditions
    2007 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 4, p. 933-945Article in journal (Refereed) Published
    Abstract [en]

    During electrospray ionization (ESI), proteins are transferred from solution into vacuum, a process that influences the conformation of the protein. Exactly how much the conformation changes due to the dehydration process, and in what way, is difficult to determine experimentally. The aim of this study is therefore to monitor what happens to protein structures as the surrounding waters gradually evaporate, using computer simulations of the transition of proteins from water to vacuum. Five different proteins have been simulated with water shells of varying thickness, enabling us to mimic the entire dehydration process. We find that all protein structures are affected, at least to some extent, by the transfer but that the major features are preserved. A water shell with a thickness of roughly two molecules is enough to emulate bulk water and to largely maintain the solution phase structure. The conformations obtained in vacuum are quite similar and make up an ensemble which differs from the structure obtained by experimental means, and from the solution phase structure as found in simulations. Dehydration forces the protein to make more intramolecular hydrogen bonds, at the expense of exposing more hydrophobic area (to vacuum). Native hydrogen bonds usually persist in vacuum, yielding an easy route to refolding upon rehydration. The findings presented here are promising for future bio-imaging experiments with X-ray free electron lasers, and they strongly support the validity of mass spectrometry experiments for studies of intra- and intermolecular interactions.

    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-96401 (URN)10.1021/bi061182y (DOI)000243682700001 ()
    External cooperation:
    Available from: 2007-11-09 Created: 2007-11-09 Last updated: 2017-12-14Bibliographically approved
    5. Fluorescence probe of Trp-cage protein conformation in solution and in gas phase
    Open this publication in new window or tab >>Fluorescence probe of Trp-cage protein conformation in solution and in gas phase
    2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 21, p. 6726-6735Article in journal (Refereed) Published
    Abstract [en]

    Measurements of protein unfolding in the absence of solvent, when combined with unfolding studies in solution, offer a unique opportunity to measure the effects of solvent on protein structure and dynamics. The experiments presented here rely on the fluorescence of an attached dye to probe the local conformational dynamics through interactions with a Trp residue and fields originating on charge sites. We present fluorescence measurements of thermal fluctuations accompanying conformational change of a miniprotein, Trp-cage, in solution and in gas phase. Molecular dynamics (MD) simulations are performed as a function of temperature, charge state, and charge location to elucidate the dye-protein conformational dynamics leading to the changes in measured fluorescence. The results indicate that the stability of the unsolvated protein is dominated by hydrogen bonds. Substituting asparagine for aspartic acid at position 9 results in a dramatic alteration of the solution unfolding curve, indicating that the salt bridge involving Lys8, Asp9, and Arg16 (+ - +) is essential for Trp-cage stability in solution. In contrast, this substitution results in minor changes in the unfolding curve of the unsolvated protein, showing that hydrogen bonds are the major contributor to the stability of Trp-cage in gas phase. Consistent with this hypothesis, the decrease in the number of hydrogen bonds with increasing temperature indicated by MD simulations agrees reasonably well with the experimentally derived enthalpies of conformational change. The simulation results display relatively compact conformations compared with NMR structures that are generally consistent with experimental results. The measured unfolding curves of unsolvated Trp-cage ions are invariant with the acetonitrile content of the solution from which they are formed, possibly as a result of conformational relaxation during or after desolvation. This work demonstrates the power of combined solution and gas-phase studies and of single-point mutations to identify specific noncovalent interactions which contribute to protein-fold stability. The combination of experiment and simulation is particularly useful because these approaches yield complementary information which can be used to deduce the details of structural changes of proteins in the gas phase.

    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-96402 (URN)10.1021/ja065092s (DOI)000246686700032 ()17487969 (PubMedID)
    Available from: 2007-11-09 Created: 2007-11-09 Last updated: 2017-12-14Bibliographically approved
    6. A direct comparison of protein structure in the gas and solution phase - the Trp-cage
    Open this publication in new window or tab >>A direct comparison of protein structure in the gas and solution phase - the Trp-cage
    Show others...
    2007 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 46, p. 13147-13150Article in journal (Refereed) Published
    Abstract [en]

    Molecular dynamics simulations of zwitterions of the Trp-cage protein in the gas phase show that the most stable ion in vacuo has preserved the charge locations acquired in solution. A direct comparison of the gas and solution-phase structures reveals that, despite the similarity in charge location, there is significant difference in the structures, with a substantial increase in hydrogen bonds and exposure of hydrophobic parts in the gas phase. The structure of the salt bridge in the gas phase is also much more stable than in the (experimental) solution structure.

    Keywords
    Gas phase, Hydrophobic parts, Salt bridge, Solution phase, Zwitterions
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-96403 (URN)10.1021/jp709901t (DOI)000250967900002 ()17973523 (PubMedID)
    Available from: 2007-11-09 Created: 2007-11-09 Last updated: 2017-12-14Bibliographically approved
    7. A temperature calculator for replica exchange molecular dynamics simulations
    Open this publication in new window or tab >>A temperature calculator for replica exchange molecular dynamics simulations
    In: Phys. Chem. Chem. PhysArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-96404 (URN)
    Available from: 2007-11-09 Created: 2007-11-09Bibliographically approved
  • 111.
    Pierozan, Paula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jernerén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ransome, Yusuf
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    The Choice of Euthanasia Method Affects Metabolic Serum Biomarkers2017In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 21, p. 113-118Article in journal (Refereed)
    Abstract [en]

    The impact of euthanasia methods on endocrine and metabolic parameters in rodent tissues and biological fluids is highly relevant for the accuracy and reliability of the data collected. However, few studies concerning this issue are found in the literature. We compared the effects of three euthanasia methods currently used in animal experimentation (i.e. decapitation, CO2 inhalation and pentobarbital injection) on the serum levels of corticosterone, insulin, glucose, triglycerides, cholesterol and a range of free fatty acids in rats. The corticosterone and insulin levels were not significantly affected by the euthanasia protocol used. However, euthanasia by an overdose of pentobarbital (120 mg/kg intraperitoneal injection) increased the serum levels of glucose, and decreased cholesterol, stearic and arachidonic acids levels compared with euthanasia by CO2 inhalation and decapitation. CO2 inhalation appears to increase the serum levels of triglycerides, while euthanasia by decapitation induced no individual discrepant biomarker level. We conclude that choice of the euthanasia methods is critical for the reliability of serum biomarkers and indicate the importance of selecting adequate euthanasia methods for metabolic analysis in rodents. Decapitation without anaesthesia may be the most adequate method of euthanasia when taking both animal welfare and data quality in consideration.

  • 112.
    Quach, Jon
    et al.
    Murdoch Childrens Res Inst, Parkville, Vic, Australia; Univ Melbourne, Carlton, Vic, Australia; Univ Melbourne, Carlton, Vic, Australia.
    Sarkadi, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Murdoch Childrens Res Inst, Parkville, Vic, Australia.
    Napiza, Natasha
    Murdoch Childrens Res Inst, Parkville, Vic, Australia; Univ Melbourne, Carlton, Vic, Australia.
    Wake, Melissa
    Murdoch Childrens Res Inst, Parkville, Vic, Australia; Univ Melbourne, Carlton, Vic, Australia; Univ Auckland, Auckland, New Zealand.
    Loughman, Amy
    Murdoch Childrens Res Inst, Parkville, Vic, Australia.
    Goldfeld, Sharon
    Murdoch Childrens Res Inst, Parkville, Vic, Australia; Royal Childrens Hosp, Parkville, Vic, Australia; Univ Melbourne, Carlton, Vic, Australia.
    Do Fathers' Home Reading Practices at Age 2 Predict Child Language and Literacy at Age 4?2018In: Academic pediatrics, ISSN 1876-2859, E-ISSN 1876-2867, Vol. 18, no 2, p. 179-187Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Maternal shared reading practices predict emergent literacy, but fathers' contributions are less certain. We examined whether fathers' shared home reading activities at 2 years (1) predict language and emergent literacy at age 4 years, when controlling for maternal contributions; and (2) differentially benefit these outcomes in disadvantaged children.

    METHODS: Design: Two-parent families recruited from 5 relatively disadvantaged communities for the universal Let's Read literacy promotion population-based trial (ISRCTN 04602902) in Melbourne, Australia. Exposure, 2 years: Home reading practices via self-reported maternal and paternal StimQ-Toddler questionnaires, dichotomised at study median (high vs. low). Outcomes, 4 years: Receptive and expressive language (Clinical Evaluation of Language Fundamentals-4), emergent literacy (Sunderland Phonological Awareness Test-Revised).

    ANALYSES: Aim 1: Linear regression, adjusted for mothers' home reading, 2-year-old vocabulary and communication skills and family disadvantage. Aim 2: Interaction of disadvantage [yes vs. no] with high home reading by (a) fathers and (b) at least one parent.

    RESULTS: Data were available for 405 (62.3%) families. High father reading at 2 years (reference: low) predicted better expressive (mean difference 8.0, 95%CI 4.5 to 11.5) and receptive (mean difference 7.3, 95%CI 4.1 to 10.5) language at 4 years (both p<0.001) but not emergent literacy skills. Similar patterns were observed in families with at least one parent with high home reading. Father reading did not differentially benefit outcomes in disadvantaged children.

    CONCLUSION: Fathers' involvement in reading at 2 years predicted better language but not emergent literacy at 4 years, and did not protect against adverse effects of socioeconomic disadvantage.

  • 113.
    Ramachandran, Mohanraj
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dyczynski, Matheus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Pathol & Oncol, CCK, Stockholm, Sweden..
    Baskaran, Sathishkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lulla, Aleksei
    Institute of Technology, University of Tartu, Estonia..
    Lulla, Valeria
    Institute of Technology, University of Tartu, Estonia..
    Saul, Sirle
    Institute of Technology, University of Tartu, Estonia..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Merits, Andres
    Institute of Technology, University of Tartu, Estonia..
    Leja-Jarblad, Justyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus2017In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 6, p. 1519-1530Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Glioblastoma multiforme (GBM) and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)-β-resistant Semliki Forest virus (SFV)-4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient-derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT-2A, GL261) and syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFN-β in inhibiting therapeutic efficacy was investigated.

    RESULTS:

    The introduction of microRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured 4 of 8 mice (50%) with NXS2 and 3 of 11 mice (27%) with CT-2A, but not for GL261 tumor bearing mice. In vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFN-β by respective cells upon SFV4 infection in vitro Similarly, killing efficacy of HGCC lines inversely correlated to IFN-β response and interferon-α⁄β receptor (IFNAR)-1 expression.

    CONCLUSIONS:

    SFV4miRT has reduced neurovirulence, while retaining its oncolytic potential. SFV4miRT is an excellent candidate for treatment of GBMs and neuroblastomas with low IFN-β secretion.

  • 114.
    Rasmussen, Ib
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Berggren, U
    Arvidsson, D
    Ljungdahl, M
    Haglund, U
    Effects of pneumoperitoneum on splanchnic hemodynamics: an experimental study in pigs.1995In: European Journal of Surgery, ISSN 1102-4151, E-ISSN 1741-9271, Vol. 161, no 11, p. 819-26Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the effects on splanchnic haemodynamics of pneumoperitoneum induced by carbon dioxide insufflation.

    DESIGN: Controlled experimental study.

    ANIMALS: 11 Pigs weighing 19-30 kg.

    INTERVENTION: The animals were divided into a control group (n = 4) and a experimental group (n = 7). Experimental animals were subjected to stepwise increasing intra-abdominal pressure from 0 mm Hg to 25 mm Hg by carbon dioxide insufflation.

    MAIN OUTCOME MEASURES: Portal venous blood flow, portal venous blood pressure, portal/hepatic vascular resistance, and gastrointestinal vascular resistance.

    RESULTS: At 25 mm Hg portal venous blood flow was reduced (66% of baseline), and portal venous blood pressure and portal/hepatic vascular resistance were increased (360% and 650% of baseline, respectively). The increase in gastrointestinal vascular resistance was less pronounced.

    CONCLUSIONS: Increased intra-abdominal pressure caused significant changes in the splanchnic haemodynamics. The risk was greater if the intra-abdominal pressure exceeded 15 mm Hg.

  • 115.
    Ring, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Characterization of Retinal Progenitor Cells: Focus on Proliferation and the GABAA Receptor System2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    One strategy to repair an injured or degenerated retina is to stimulate the replacement of damaged or dead neurons with cells derived from endogenous stem- or progenitor cells. A successful strategy requires knowledge about how the proliferation and differentiation of the endogenous cells are regulated. In particular, this knowledge will be important in the establishment of protocols that produce sufficient numbers of specific neurons. The main aim of this thesis was to find and characterise factors regulating the proliferation and differentiation of retinal progenitor cells (RPCs) and hence, contribute to the knowledge of how to use progenitor cells for retinal repair.   

    The major result in this thesis is that GABA contributes to and maintains RPC proliferation. Inhibition of GABAA receptors decreases the proliferation of non-pigmented ciliary epithelial (NPE) cells and RPCs in the intact retina. We propose that this effect is mediated through changes in the membrane potential and voltage-gated calcium channels, which in turn regulate components of the cell cycle. Furthermore, we show that one of the endogenous RPC sources, the Müller cells, consists of two subpopulations based on Pax2 expression. This is interesting because Pax2 may suppress the neurogenic potential, characterised by de-differentiation and proliferation, in Müller cells. Finally, we show that over-expression of FoxN4 induces differentiation-associated transcription factors in the developing chick retina. However, FoxN4 over-expression did not trigger differentiation of NPE cells. These results indicate that the intrinsic properties of the RPCs are determinant for FoxN4-induced differentiation.

    The results presented in this thesis advance our understanding of how specific cells may be generated from different sources of RPCs. Our results show that the different sources are highly diverse in their potential to proliferate and produce neurons. GABA, Pax2 and FoxN4 may be factors to consider when designing strategies for retinal repair. However, the results indicate that the specific responses to these factors are highly associated with the specific properties of the progenitor cells.

    List of papers
    1. Pax2 Is Expressed in a Subpopulation of Muller Cells in the Central Chick Retina
    Open this publication in new window or tab >>Pax2 Is Expressed in a Subpopulation of Muller Cells in the Central Chick Retina
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    2010 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 239, no 6, p. 1858-1866Article in journal (Refereed) Published
    Abstract [en]

    Muller cells in the chick retina are generally thought to be a homogeneous population. We show that the transcription factor Pax2 is expressed by Muller cells in the central chick retina and its expression was first observed at stage 32 (embryonic day [E] 7.5). Birth-dating indicated that the majority of Pax2-positive Muller cells are generated between stage 29 and 33 (E5.5-E8). At stage 42 (E16), several Muller cell markers, such as Sox2 and 2M6, had reached the peripheral retina, while the Pax2 labeling extended approximately half-way. A similar pattern was maintained in the 6-month-old chicken. Neither the Pax2-positive nor the Pax2-negative Muller cells could be specifically associated to proliferative responses in the retina induced by growth factors or N-methyl-D-aspartate. Pax2 was not detected in Muller cells in mouse, rat, guinea-pig, rabbit, or pig retinas; but the zebrafish retina displayed a similar pattern of central Pax2-expressing Muller cells.

    Keywords
    avascular, development, EdU, glia, Muller glia, regeneration, Sox2, zebrafish
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-136282 (URN)10.1002/dvdy.22309 (DOI)000278761700027 ()
    Available from: 2010-12-11 Created: 2010-12-11 Last updated: 2017-12-11Bibliographically approved
    2. Increased A-to-I RNA editing of the transcript for GABAA receptor subunit α3 during chick retinal development
    Open this publication in new window or tab >>Increased A-to-I RNA editing of the transcript for GABAA receptor subunit α3 during chick retinal development
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    2010 (English)In: Visual Neuroscience, ISSN 0952-5238, E-ISSN 1469-8714, Vol. 27, no 5-6, p. 149-157Article in journal (Refereed) Published
    Abstract [en]

    Adenosine-to-inosine (A-to-I) RNA editing is a cotranscriptional or posttranscriptional gene regulatory mechanism that increases the diversity of the proteome in the nervous system. Recently, the transcript for GABA type A receptor subunit α3 was found to be subjected to RNA editing. The aim of this study was to determine if editing of the chicken α3 subunit transcript occurs in the retina and if the editing is temporally regulated during development. We also raised the question if editing of the α3 transcript was temporally associated with the suggested developmental shift from excitation to inhibition in the GABA system. The editing frequency was studied by using Sanger and Pyrosequencing, and to monitor the temporal aspects, we studied the messenger RNA expression of the GABAA receptor subunits and chloride pumps, known to be involved in the switch. The results showed that the chick α3 subunit was subjected to RNA editing, and its expression was restricted to cells in the inner nuclear and ganglion cell layer in the retina. The extent of editing increased during development (after embryonic days 8–9) concomitantly with an increase of expression of the chloride pump KCC2. Expression of several GABAA receptor subunits known to mediate synaptic GABA actions was upregulated at this time. We conclude that editing of the chick GABAA subunit α3 transcript in chick retina gives rise to an amino acid change that may be of importance in the switch from excitatory to inhibitory receptors.

    Keywords
    Chloride ion channel, GABA(A) subunits, GABA receptor, KCC2, mRNA expression, Posttranscriptional modification
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-143655 (URN)10.1017/S0952523810000180 (DOI)000285477900002 ()20843408 (PubMedID)
    Available from: 2011-01-24 Created: 2011-01-24 Last updated: 2017-12-11Bibliographically approved
    3. GABA maintains the proliferation of progenitors in the developing chick ciliary marginal zone and non-pigmented ciliary epithelium:      
    Open this publication in new window or tab >>GABA maintains the proliferation of progenitors in the developing chick ciliary marginal zone and non-pigmented ciliary epithelium:      
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    2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e36874-Article in journal (Refereed) Published
    Abstract [en]

    GABA is more than the main inhibitory neurotransmitter found in the adult CNS. Several studies have shown that GABA regulates the proliferation of progenitor and stem cells. This work examined the effects of the GABA(A) receptor system on the proliferation of retinal progenitors and non-pigmented ciliary epithelial (NPE) cells. qRT-PCR and whole-cell patch-clamp electrophysiology were used to characterize the GABA(A) receptor system. To quantify the effects on proliferation by GABA(A) receptor agonists and antagonists, incorporation of thymidine analogues was used. The results showed that the NPE cells express functional extrasynaptic GABA(A) receptors with tonic properties and that low concentration of GABA is required for a baseline level of proliferation. Antagonists of the GABA(A) receptors decreased the proliferation of dissociated E12 NPE cells. Bicuculline also had effects on progenitor cell proliferation in intact E8 and E12 developing retina. The NPE cells had low levels of the Cl-transporter KCC2 compared to the mature retina, suggesting a depolarising role for the GABA(A) receptors. Treatment with KCl, which is known to depolarise membranes, prevented some of the decreased proliferation caused by inhibition of the GABA(A) receptors. This supported the depolarising role for the GABA(A) receptors. Inhibition of L-type voltage-gated Ca2+ channels (VGCCs) reduced the proliferation in the same way as inhibition of the GABA(A) receptors. Inhibition of the channels increased the expression of the cyclin-dependent kinase inhibitor p27(KIP1), along with the reduced proliferation. These results are consistent with that when the membrane potential indirectly regulates cell proliferation with hyperpolarisation of the membrane potential resulting in decreased cell division. The increased expression of p27(KIP1) after inhibition of either the GABA(A) receptors or the L-type VGCCs suggests a link between the GABA(A) receptors, membrane potential, and intracellular Ca2+ in regulating the cell cycle. 

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-172512 (URN)10.1371/journal.pone.0036874 (DOI)000305336100070 ()
    Available from: 2012-04-11 Created: 2012-04-10 Last updated: 2018-01-12Bibliographically approved
    4. Forkhead box N4 (FoxN4) triggers context-dependent differentiation in the developing chick retina and neural tube
    Open this publication in new window or tab >>Forkhead box N4 (FoxN4) triggers context-dependent differentiation in the developing chick retina and neural tube
    (English)In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436Article in journal (Refereed) Submitted
    Keywords
    Chicken, retinal development, Lim1, Prox1, retinal progenitor cells, Sox2
    National Category
    Neurosciences
    Research subject
    Developmental Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-180007 (URN)
    Available from: 2012-08-28 Created: 2012-08-28 Last updated: 2018-01-12Bibliographically approved
  • 116.
    Röjerdal, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Långtidsbehandling av ADHD hos vuxna: en jämförelse av information om medicineringen på apotek och i vården2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Attention Deficit Hyperactivity Disorder (ADHD) blir en allt vanligare diagnos hos vuxna, då dels patienterna på behandlingen med metylfenidat (MPH) och atomoxetin (ATX) går över till långtidsanvändning upp i vuxenålder och dels allt fler nydiagnostiserade patienter uppdagas i vuxen ålder. Syfte Syftet med denna uppsats var att analysera evidens för MPH och ATX, för långtidsbehandling hos vuxna med ADHD, för att förstå behandlingsstrategin för vuxna och jämföra informationen som ges till vuxna på apotek respektive inom vården rörande behandlingen, för att belysa eventuella skillnader i informationen mellan apotek och vården. Metod: Primära undersökningar gjordes genom litteraturinsamling i PubMed för evidens bakom MPH och ATX samt att kvalitativa intervjuer genomfördes med farmaceuter och vårdgivare. Resultat: I de 12 analyserade artiklarna återgavs 28 olika behandlingsresultat vid långtidsanvändning av MPH eller ATX vid ADHD hos vuxna. Alla visade positiv förbättring hos patienterna med behandling varav 22 resultat var signifikant förbättrade. (p<0,05 - p<0,0001). Sammanlagt 10 intervjuer genomfördes. Intervjuerna visade att det finns en brist hos samtliga intervjuade i kunskap om vad den andra yrkesgruppen faktiskt informerar om. Konklusion: Långtidsanvändning av MPH och ATX, hos vuxna med ADHD är effektivt och säkert. Fler studier behövs vid fortsatt användning för mer förståelse om diagnosen. Ökad samverkan mellan yrkesgrupperna är önskvärd inför framtiden.

  • 117.
    Römsing, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Bökman, Fredrik
    Department of Clinical Chemistry, Falun Central Hospital, Falun, Sweden.
    Berqvist, Yngve
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Determination of melatonin in saliva using automated solid-phase extraction, high-performance liquid chromatography and fluorescence detection2006In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 66, no 3, p. 181-190Article in journal (Refereed)
    Abstract [en]

    A sensitive bioanalytical method for the determination of melatonin in saliva by solid‐phase extraction (SPE), high‐performance liquid chromatography (HPLC) and fluorescence detection has been developed and validated. Saliva was collected with a Salivette® sampling device (Sarstedt) and a mixed‐mode SPE column was used for the extraction of melatonin and internal standard (N‐acetyl‐6‐methoxytryptamine) from the saliva. Chromatographic separation was performed using a HyPurity C18 LC column (150×2.1mm) with mobile phase acetonitrile – ammonium hydrogen carbonate buffer, 0.015M, pH6.8 (23:77, v/v). Excitation and emission wavelengths were set to 285nm and 345nm, respectively. The within‐day precision for the method at 50pmol/L was 7.9 % and the between‐day precision was 10.5 %. The limit of quantification was 50pmol/L.

  • 118.
    Römsing, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Lindegardh, Niklas
    Faculty of Tropical Medicine, Mahidol University, Bangkol, Thailand, Nuffield Department of Clinical Medicined, Center for Tropical Medicine, University of Oxford, Oxford, U.K..
    Bergqvist, Yngve
    Dalarna University College, Borlänge, Sweden, Center for Clinical Research Dalarna, Falun, Sweden.
    Determination of Tafenoquine in plasma and dried blood spots using liquid chromatography and fluorescence detectionManuscript (preprint) (Other academic)
  • 119.
    Sarsam, Ziyad Basil Yacoub
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Optimering av läkemedelsdosering vid fetma och obesitaskirurg2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Fetma, som är ett större och större problem i värden, leder till flera kroniska sjukdomar och därmed ett ökat medicineringsbehov. Obesitaskirurgi har visat sig vara ett effektivt sätt att minska vikten. Det finns bristande information vad gäller riktlinjer och optimering av läkemedelsdoseringen för dessa patienter, båda vid fetma och efter obesitaskirurgi, så att läkemedelsdosen hamnar inom det terapeutiska fönstret. Syfte: Syftet med studien är att utforska nuvarande kunskap om läkemedelsdosering hos personer med fetma och efter obesitaskirurgi, för att öka medvetenheten om optimal behandling för dessa grupper. Metod: Information i denna studie erhölls genom litteratursökning av vetenskapliga artiklar i PubMed, böcker och information från pålitliga webbsidor. Resultatet: Förutom substansernas egenskaper, finns det flera farmakokinetiska och fysiologiska faktorer som påverkar läkemedelsomsättningen i kroppen vid fetma och efter genomgått obesitaskirurgi. Fetma påverkar inte absorptionen, men distributionen, metabolismen och den renala eliminationen, och därmed läkemedelsexponering. Därför behöver läkemedelsdoseringen optimeras. Direkt efter obesitaskirurgi finns det ett tillfälligt behov av att modifiera doseringen tills mag-tarmkanalen har anpassat sig, eftersom läkemedelsabsorptionen påverkas beroende på typen av genomförd obesitaskirurgi. Konklusion: Förändringarna i läkemedelsomsättning och absorption är läkemedelsspecifika. Därför kan optimeringen av läkemedelsdoseringen inte förutsägas med hjälp av någon algoritm eller normaliseras med något viktmått utan behöver anpassas för varje läkemedel.

  • 120. Schaffran, Tanja
    et al.
    Li, Jingyu
    Karlsson, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry.
    Winterhalter, Mathias
    Gabel, Detlef
    Interaction of N,N,N-trialkylammonioundecahydro-closo-dodecaborates with dipalmitoyl phosphatidylcholine liposomes2010In: Chemistry and Physics of Lipids, ISSN 0009-3084, E-ISSN 1873-2941, Vol. 163, no 1, p. 64-73Article in journal (Refereed)
    Abstract [en]

    N,N,N-Trialkylammonioundecahydrododecaborates (1-), a novel class of compounds of interest for use as anions in ionic liquids, interact with DPPC liposomes. Increasing compound concentration causes an increasing negative zeta potential. Dissociation constants demonstrate that the binding capacity increases strongly with longer chain length. N,N,N-Trialkylammonioundecahydrododecaborates with longer alkyl chains show a detergent-like behavior: the compounds incorporate into the liposome membrane and differential scanning calorimetric experiment show already low concentrations cause a complete disappearance of the peak representing the gel-to-liquid crystalline phase transition. In contrast, compounds with shorter alkyl chains only interact with the headgroups of the lipids. Investigations by means of cryo-TEM reveal that all derivatives induce significant morphological changes of the liposomes. N,N,N-Trialkylammonioundecahydrododecaborates with short alkyl chains produce large bilayer sheets, whereas those with longer alkyl chains tend to induce the formation of open or multi-layered liposomes. We propose that the binding of N,N,N-trialkylammonioundecahydrododecaborates is mainly due to electrostatic interactions between the doubly negatively charged cluster unit and the positively charged choline headgroup; the positively charged ammonium group might be in contact with the deeper-lying negatively charged phosphate. For N,N,N-trialkylammonioundecahydrododecaborates with longer alkyl chains hydrophobic interactions with the non-polar hydrocarbon part of the membrane constitute an additional important driving force for the association of the compounds to the lipid bilayer.

  • 121.
    Schedin-Weiss, Sophia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Richard, Benjamin
    Olson, Steven T.
    Kinetic evidence that allosteric activation of antithrombin by heparin is mediated by two sequential conformational changes2010In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 504, no 2, p. 169-176Article in journal (Refereed)
    Abstract [en]

    The serpin, antithrombin, requires allosteric activation by a sequence-specific pentasaccharide unit of heparin or heparan sulfate glycosaminoglycans to function as an anticoagulant regulator of blood clotting proteases. Surprisingly, X-ray structures have shown that the pentasaccharide produces similar induced-fit changes in the heparin binding site of native and latent antithrombin despite large differences in the heparin affinity and global conformation of these two forms. Here we present kinetic evidence for similar induced-fit mechanisms of pentasaccharide binding to native and latent antithrombins and kinetic simulations which together support a three-step mechanism of allosteric activation of native antithrombin involving two successive conformational changes. Equilibrium binding studies of pentasaccharide interactions with native and latent antithrombins and the salt dependence of these interactions suggest that each conformational change is associated with distinct spectroscopic changes and is driven by a progressively better fit of the pentasaccharide in the binding site. The observation that variant antithrombins that cannot undergo the second conformational change bind the pentasaccharide like latent antithrombin and are partially activated suggests that both conformational changes contribute to allosteric activation, in agreement with a recently proposed model of allosteric activation.

  • 122.
    Schutzer, Steven E.
    et al.
    University of Medicine And Dentistry of New Jersey, US.
    Liu, Tao
    Pacific Northwest National Laboratory, US.
    Natelson, Benjamin H.
    University of Medicine And Dentistry of New Jersey, US.
    Angel, Thomas E.
    Pacific Northwest National Laboratory, US.
    Schepmoes, Athena A.
    Pacific Northwest National Laboratory, US.
    Purvine, Samuel O.
    Pacific Northwest National Laboratory, US.
    Hixson, Kim K.
    Pacific Northwest National Laboratory, US.
    Lipton, Mary S.
    Pacific Northwest National Laboratory, US.
    Camp, David G.
    Pacific Northwest National Laboratory, US.
    Coyle, Patricia K.
    State University of New York-Sony Brook, US.
    Smith, Richard D.
    Pacific Northwest National Laboratory, US.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Establishing the proteome of normal human cerebrospinal fluid2010In: PloS ONE, ISSN 1932-6203, Vol. 5, no 6, p. e10980-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Knowledge of the entire protein content, the proteome, of normal human cerebrospinal fluid (CSF) would enable insights into neurologic and psychiatric disorders. Until now technologic hurdles and access to true normal samples hindered attaining this goal. METHODS AND PRINCIPAL FINDINGS: We applied immunoaffinity separation and high sensitivity and resolution liquid chromatography-mass spectrometry to examine CSF from healthy normal individuals. 2630 proteins in CSF from normal subjects were identified, of which 56% were CSF-specific, not found in the much larger set of 3654 proteins we have identified in plasma. We also examined CSF from groups of subjects previously examined by others as surrogates for normals where neurologic symptoms warranted a lumbar puncture but where clinical laboratory were reported as normal. We found statistically significant differences between their CSF proteins and our non-neurological normals. We also examined CSF from 10 volunteer subjects who had lumbar punctures at least 4 weeks apart and found that there was little variability in CSF proteins in an individual as compared to subject to subject. CONCLUSIONS: Our results represent the most comprehensive characterization of true normal CSF to date. This normal CSF proteome establishes a comparative standard and basis for investigations into a variety of diseases with neurological and psychiatric features.

  • 123.
    Sebastiano, Roberto
    et al.
    Polytechnic of Milan, Department of Chemistry, Materials and Chemical Engineering.
    Righetti, Pier Giorgio
    Polytechnic of Milan, Department of Chemistry, Materials and Chemical Engineering.
    Citterio, Attilio
    Polytechnic of Milan, Department of Chemistry, Materials and Chemical Engineering.
    Mendieta, Martha E.
    Polytechnic of Milan, Department of Chemistry, Materials and Chemical Engineering.
    Knob, Radim
    Department of Analytical Chemistry, Palack´y University in Olomouc, Czech Republic.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Easy Silica Capillary Coatings and EOF Modulation for Analysis of Chemicals, Drugs and Biological Molecules in CE and CE-MS2010In: Book of abstracts / [ed] Danilo Corradini, Antonella De Rossi, Isabella Nicoletti, 2010, p. 126-126Conference paper (Refereed)
  • 124.
    Seid Tahir, Seid Hosen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    COMPARATIVE STUDY OF HYDROLYSIS PERFORMED WITH MODERN MICROWAVE TECHNIQUE AND THE TRADITIONAL METHOD2012Independent thesis Basic level (university diploma), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Proteins are vital to all cells in the body. They consist of long chains of amino acids. To be able to study the amino acid composition of a protein it is necessary to hydrolyse it, followed by separation and quantification. When the protein is hydrolysed, in this case ß-lactoglobulin, the protein is divided into individual amino acids. The method that traditionally has been used to hydrolyse proteins takes 24-72 hours to complete. Recently a new microwave heating technique was introduced. With the Ethos1 microwave oven it takes less than one hour to hydrolyse proteins. The objective of this study was to see if the result of the hydrolysis with the new microwave oven technique had the same quality as the previously used method. If the microwave technique can hydrolyse proteins with as good results as the old oven, then it will significantly reduce test turnaround times. The result of this study indicates that the microwave technique is just as reliable as the older method, and thus a good and time saving alternative.

  • 125.
    Shevchenko, Denys V.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Photochemistry and Molecular Science.
    Kokozay, Vladimir N.
    Krasovska, Marina V.
    Shishkin, Oleg V.
    Direct template synthesis of a heterometallic Co-III/Zn-II complex: The advantage of using a metal powder as a starting material2008In: Inorganic Chemistry Communications, ISSN 1387-7003, E-ISSN 1879-0259, Vol. 11, no 10, p. 1209-1211Article in journal (Refereed)
    Abstract [en]

    The heterometallic complex [Co(L-1)Cl-2][ZnCl3(DMF)] (L-1 = 4,6,6-trimethyl-1,9-diamino-3,7-diazanon-3-ene) has been obtained by direct template synthesis from cobalt powder, zinc oxide, zinc chloride, ethylenediamine dihydrochloride and acetone in dimethylformamide and characterized by X-ray crystallographic analysis. The mechanism of the complex formation is suggested.

  • 126.
    Sida, Abdulhak
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Immunohistochemical study of hemoglobin-related proteins in endometrium from fertile and infertile women2012Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    In couples diagnosed with unexplained infertility, the woman has normal ovulatory cycles and no organic pathology, and the man has normal semen. The period during which the implantation of an embryo can occur is defined as the window of implantation (WOI). For infertile women, disturbances in the endometrium maturation are hypothesized to impair the uterine receptivity for embryo implantaition. However, there are still no methods found to predict endometrial receptivity.

    Hemoglobin related-proteins hypothesized to be involved in embryo implantation have been found in the endometrium in both fertile and infertile women. The aim of this study was to determine whether there were differences in the expression of hemoglobin-related proteins, hemoglobin-α, cytoglobin, fetal hemoglobin and haptoglobin in the endometrium of fertile and infertile women. Immunohistchemical staining was used. Haptoglobin showed negative expression in glands, luminal epithelium and strong expression in stroma for both gruops. The expression of the hemoglobin-related proteins, hemoglobin-α, cytoglobin, fetal hemoglobin intensity were stronger in fertile than infertile women.

    More studies are required to find other factors that may have an effect on fertility.

  • 127. Sjoberg, S
    et al.
    Carlsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ghaneolhosseini, H
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hartman, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Malmquist, J
    Naeslund, C
    Olsson, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tjarks, W
    Chemistry and biology of some low molecular weight boron compounds forboron neutron capture therapy.1997In: J Neurooncol, Vol. 33, p. 41-Article in journal (Refereed)
  • 128.
    Sundbom, Renée
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Surgical Stress in Rats: The Impact of Buprenorphine on Postoperative Recovery2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During surgery, both anesthesia and tissue damage cause physiological stress responses in the body. The hypothalamic-pituitary-adrenal (HPA) axis is activated with increased levels of glucocorticoids. After surgical procedures the stress response may be a cause of postoperative morbidity and pre-emptive analgesic treatment can attenuate the stress response during the postoperative period. In laboratory animals, buprenorphine is a commonly used analgesic. Subcutaneous (s.c.) administration of buprenorphine is most common, but oral administration would be preferable in many cases, enabling administration without any handling of the rat.

    In this thesis we studied the surgical stress response in laboratory rats during surgery and in the postoperative period, and its modulation by s.c. injection and oral voluntary ingestion (VI) of buprenorphine. Corticosterone levels and the clinical parameters body weight, water intake and behavior were observed. The concentration of buprenorphine in plasma was measured as well as stock-related differences in postoperative recovery.

    During surgery and anesthesia there was a higher corticosterone release during a more severe surgery and corticosterone levels were reduced more effectively after buprenorphine treatment than after lidocaine treatment.

    Buprenorphine treatment, independent of the route of administration, led to better postoperative recovery in body weight and water intake compared to local anesthetics. VI of buprenorphine resulted in a suppression of plasma corticosterone levels compared to s.c. buprenorphine treatment and treatment with local anesthetics during the first day after surgical catheterization. The corticosterone levels of all buprenorphine treated groups had, by the second postoperative day, reverted to the normal diurnal rhythm of corticosterone secretion. Buprenorphine treatment increased locomotor activity in non-operated rats only. The effect of buprenorphine in operated rats could not be detected via the monitoring of locomotor activity or the time spent resting in the present study.

    Treatment with buprenorphine by VI has similar effects on postoperative plasma corticosterone levels in both Wistar and Sprague-Dawley rats. VI of buprenorphine resulted in a buprenorphine concentration in plasma at least as high as by s.c. treatment.

    Thus, administration by VI of buprenorphine appears to be an effective stress-reducing method for administrating postoperative analgesia to laboratory rats.

    List of papers
    1. Effect of subcutaneous injection and oral voluntary ingestion of buprenorphine on post-operative serum corticosterone levels in male rats
    Open this publication in new window or tab >>Effect of subcutaneous injection and oral voluntary ingestion of buprenorphine on post-operative serum corticosterone levels in male rats
    2008 (English)In: European Surgical Research, ISSN 0014-312X, E-ISSN 1421-9921, Vol. 41, no 3, p. 272-278Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Adequate peri-operative analgesia may reduce post-operative stress response and improve recovery in laboratory animals. We have established a method involving repeated automated blood sampling, allowing quantification of serum corticosterone levels in rats for stress assessment without stress-inducing handling or restraint. In the present study, the effects of the commonly used route of buprenorphine administration (0.05 mg/kg injected subcutaneously) were compared with oral administration (0.4 mg/kg mixed with Nutella and orally administered by voluntary ingestion) in male Sprague-Dawley rats. METHODS: A catheter was placed in the jugular vein and attached to an Accusampler for automated blood sampling. During 96 h after surgery, blood was collected at specified time points. Pre- and post-operative body weights and water consumption were registered. RESULTS: Buprenorphine significantly suppressed levels of circulating corticosterone after the oral but not after the subcutaneous treatment. Both buprenorphine treatments had a positive impact on maintenance of body weight and water consumption, compared to the control group that received no buprenorphine. CONCLUSION: The present investigation suggests that oral voluntary ingestion ad libitum is an efficacious, convenient and non-invasive way of administering peri-operative buprenorphine to rats, as judged by corticosteroid response and effects on body weight and water consumption.

    Keywords
    Surgical stress, Analgesia, Rats
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102299 (URN)10.1159/000142372 (DOI)000260241300004 ()18596376 (PubMedID)
    Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2017-12-13Bibliographically approved
    2. Impact of Surgical Severity and Analgesic Treatment on Plasma Corticosterone in Rats during Surgery
    Open this publication in new window or tab >>Impact of Surgical Severity and Analgesic Treatment on Plasma Corticosterone in Rats during Surgery
    Show others...
    2010 (English)In: European Surgical Research, ISSN 0014-312X, E-ISSN 1421-9921, Vol. 44, no 2, p. 117-123Article in journal (Refereed) Published
    Abstract [en]

    Tissue injury and anaesthesia during surgery induce a stress response associated with increased glucocorticoid secretion from the adrenal glands. This response alters the normal physiology and may cause postoperative morbidity, as well as affect the results during acute experiments. The aim of the present investigation was to study the effect of surgical severity and analgesic treatment on circulating corticosterone in male Sprague-Dawley rats. Male rats were treated with either lidocaine infiltrated during surgery, buprenorphine (0.05 or 0.1 mg/kg subcutaneously) or saline subcutaneously. Each treatment group was subjected to either arterial catheterisation or arterial catheterisation and laparotomy. A catheter was inserted in the common carotid artery and blood was collected during surgery and during anaesthesia 6 h after surgery. Lidocaine treatment reduced the corticosterone levels compared to saline treatment after catheterisation but not after laparotomy. Buprenorphine treatment reduced the corticosterone levels during the first hour after surgery after both catheterisation and laparotomy. The higher buprenorphine dose led to an earlier and more pronounced reduction, especially after laparotomy. In the present study, the corticosterone response during surgery in laboratory rats is correlated with the severity of the procedure, and buprenorphine reduces the surgical stress response more effectively than lidocaine treatment.

    Keywords
    Surgical stress, Corticosterone, Analgesia, Lidocaine, Buprenorphine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-144507 (URN)10.1159/000264962 (DOI)000275045800007 ()20145406 (PubMedID)
    Available from: 2011-02-01 Created: 2011-01-31 Last updated: 2017-12-11Bibliographically approved
    3. Effects of Voluntarily-ingested Buprenorphine on Plasma Corticosterone Levels, Body Weight, Water Intake, and Behaviour in Permanently Catheterised Rats
    Open this publication in new window or tab >>Effects of Voluntarily-ingested Buprenorphine on Plasma Corticosterone Levels, Body Weight, Water Intake, and Behaviour in Permanently Catheterised Rats
    2010 (English)In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 24, no 2, p. 131-135Article in journal (Refereed) Published
    Abstract [en]

    This study investigated the peri- and postoperative effect of pre-emptive analgesia through voluntary ingestion of buprenorphine in Nutella (R), in male Sprague-Dawley rats. An arterial catheter was inserted and the rats were connected to an automated blood sampling device (AccuSampler (R)). Blood samples were drawn up to 18 h after surgery and the plasma concentrations of corticosterone were quantified. Postoperative changes in water intake and body weight were recorded, and the behaviour of the rats was analysed during two 30-min periods. Pre-emptive oral buprenorphine treatment reduced the plasma corticosterone levels in the postoperative period, compared to controls treated with local anaesthetics. Buprenorphine-treated rats consumed more water and maintained body weight better. Behavioural observations indicated that buprenorphine changed the behaviour in non-operated rats but there was no difference in the operated rats. The present study strengthens the hypothesis that pre-emptive oral buprenorphine in Nutella is suitable for treatment of postoperative pain in rats.

    Keywords
    Buprenorphine, surgery, corticosterone, behaviour, rats
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-136659 (URN)000275974100002 ()20363983 (PubMedID)
    Available from: 2010-12-14 Created: 2010-12-14 Last updated: 2017-12-11Bibliographically approved
    4. Plasma concentrations of corticosterone and buprenorphine in rats subjected to jugular vein catheterization
    Open this publication in new window or tab >>Plasma concentrations of corticosterone and buprenorphine in rats subjected to jugular vein catheterization
    Show others...
    2010 (English)In: Laboratory Animals. Journal of the Laboratory Animal Science Association, ISSN 0023-6772, E-ISSN 1758-1117, Vol. 44, no 4, p. 337-343Article in journal (Refereed) Published
    Abstract [en]

    The present study investigated the postoperative plasma concentrations of corticosterone and buprenorphine in male Wistar and Sprague-Dawley rats, treated with buprenorphine administered either through subcutaneous (SC) injection or through voluntary ingestion (VI). The animals were treated with buprenorphine for pre-emptive analgesia prior to surgical placement of a jugular catheter, followed by automated blood sampling during 96 h. Buprenorphine was administered on a regular basis throughout the experiment, and blood was collected on selected time points. Body weight was measured before and 96 h after surgery. It was found that the two rat stocks responded in a similar manner to both buprenorphine treatments, with the exception of body weight change in Wistar rats, in which body weight was reduced after SC treatment. The plasma concentration of corticosterone was significantly higher in the SC-treated animals than in the VI-treated animals during the first 18 h of the study, while plasma buprenorphine concentration was at least as high and more even over time after VI treatment. The present study shows that buprenorphine administration through VI is suitable for both Wistar and Sprague-Dawley rats, with lower stress response and higher plasma concentrations of buprenorphine than after the traditional SC route of administration.

    Keywords
    Rats, catheterization, analgesia, buprenorphine, surgical stress, corticosterone
    National Category
    Biomedical Laboratory Science/Technology
    Identifiers
    urn:nbn:se:uu:diva-133727 (URN)10.1258/la.2010.009115 (DOI)000283457500008 ()
    Available from: 2010-11-18 Created: 2010-11-15 Last updated: 2017-12-12Bibliographically approved
  • 129. Tedelind, Sofia
    et al.
    Poliakova, Kseniia
    Valeta, Amanda
    Hunegnaw, Ruth
    Yemanaberhan, Eyoel Lemma
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kurebayashi, Junichi
    Weber, Ekkehard
    Kopitar-Jerala, Natasa
    Turk, Boris
    Bogyo, Matthew
    Brix, Klaudia
    Nuclear cysteine cathepsin variants in thyroid carcinoma cells2010In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 391, no 8, p. 923-935Article in journal (Refereed)
    Abstract [en]

    The cysteine peptidase cathepsin B is important in thyroid physiology by being involved in thyroid prohormone processing initiated in the follicular lumen and completed in endo-lysosomal compartments. However, cathepsin B has also been localized to the extrafollicular space and is therefore suggested to promote invasiveness and metastasis in thyroid carcinomas through, e. g., ECM degradation. In this study, immunofluorescence and biochemical data from subcellular fractionation revealed that cathepsin B, in its single- and two-chain forms, is localized to endo-lysosomes in the papillary thyroid carcinoma cell line KTC-1 and in the anaplastic thyroid carcinoma cell lines HTh7 and HTh74. This distribution is not affected by thyroid stimulating hormone (TSH) incubation of HTh74, the only cell line that expresses a functional TSH-receptor. Immunofluorescence data disclosed an additional nuclear localization of cathepsin B immunoreactivity. This was supported by biochemical data showing a proteolytically active variant slightly smaller than the cathepsin B proform in nuclear fractions. We also demonstrate that immunoreactions specific for cathepsin V, but not cathepsin L, are localized to the nucleus in HTh74 in peri-nucleolar patterns. As deduced from co-localization studies and in vitro degradation assays, we suggest that nuclear variants of cathepsins are involved in the development of thyroid malignancies through modification of DNA-associated proteins.

  • 130.
    Tedesco-Silva, Helio
    et al.
    Division of Nephrology, Hospital do Rim, Universidade Federal de São Paulo, São Paulo, Brazil.
    Pascual, Julio
    Viklicky, Ondrej
    Basic-Jukic, Nikolina
    Cassuto, Elisabeth
    Kim, Dean Y
    Cruzado, Josep M
    Sommerer, Claudia
    Adel Bakr, Mohamed
    Garcia, Valter D
    Uyen, Huynh-Do
    Russ, Graeme
    Soo Kim, Myoung
    Kuypers, Dirk
    Buchler, Matthias
    Citterio, Franco
    Hernandez Gutierrez, Maria Pilar
    Bernhardt, Peter
    Chadban, Steve
    Department of Renal Medicine, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.
    Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study2019In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, no 9, p. 1953-1963Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail.

    METHODS: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids.

    RESULTS: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA.

    CONCLUSIONS: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.

  • 131. Tjarks, W
    et al.
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Silvander, M
    Mars, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ghaneolhosseini, H
    Henssen, C
    Olsson, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sjoberg, S
    Carlsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, B
    Edwards, K
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical Chemistry.
    Carboranyl phenantridinium analogues: Synthesis and biological evaluation.1997Conference paper (Other academic)
  • 132. Tjarks, W
    et al.
    Ghaneolhosseini, H
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Mars, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olsson, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sjoberg, S
    Carlsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, B
    Carboranyl phenanthridinium analogues: synthesis and biological evaluation.1996In: Seventh International Symposium on Neutron Capture Therapy for Cancer, p. 74-Article, book review (Other academic)
  • 133. Tjarks, W
    et al.
    Malmquist, J
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sjoberg, S
    Carlsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Synthesis and initial biological evaluation of carborane-containing phenanthridinium derivatives.1996In: Cancer Neutron Capture Therapy for Cancer, Mishima Y, Plenum Press, New York , 1996, Vol. chapter 15, p. 121-Chapter in book (Other academic)
  • 134.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Does Feed Containing Trans Fatty Acids Influence the Cholesterol and Oxycholesterols Levels in Chicken?2011In: Nutrition Focus Newsletter, Nutrition Society of Sri Lanka, no 3, p. 5-Article in journal (Other (popular science, discussion, etc.))
  • 135.
    Velikyan, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bulenga, Thomas N
    Selvaraju, Ram Kumar
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Espes, Daniel
    Rosenström, Ulrika
    Eriksson, Olof
    Dosimetry of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 - impact on the feasibility of insulinoma internal radiotherapy.2015In: American journal of nuclear medicine and molecular imaging, ISSN 2160-8407, Vol. 5, no 2, p. 109-26Article in journal (Refereed)
    Abstract [en]

    [(68)Ga]-DO3A-VS-Cys(40)-Exendin-4 has been shown to be a promising imaging candidate for targeting glucagon like peptide-1 receptor (GLP-1R). In the light of radiotheranostics and personalized medicine the (177)Lu-labelled analogue is of paramount interest. In this study we have investigated the organ distribution of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 in rat and calculated human dosimetry parameters in order to estimate the maximal acceptable administered radioactivity, and thus potential applicability of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 for internal radiotherapy of insulinomas. Nine male and nine female Lewis rats were injected with [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 for ex vivo organ distribution study at nine time points. The estimation of human organ/total body absorbed and total effective doses was performed using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1). Six more rats (male: n = 3; female: n = 3) were scanned by single photon emission tomography and computed tomography (SPECT-CT). The renal function and potential cell dysfunction were monitored by creatinine ISTAT and glucose levels. The fine uptake structure of kidney and pancreas was investigated by ex vivo autoradiography. Blood clearance and washout from most of the organs was fast. The kidney was the dose-limiting organ with absorbed dose of 5.88 and 6.04 mGy/MBq, respectively for female and male. Pancreatic beta cells demonstrated radioactivity accumulation. Renal function and beta cell function remained unaffected by radiation. The absorbed dose of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 to kidneys may limit the clinical application of the agent. However, hypothetically, kidney protection and peptidase inhibition may allow reduction of kidney absorbed dose and amplification of tumour absorbed doses.

  • 136. Venkatakrishnan, K.
    et al.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ouellet, D.
    Mettetal, J. T.
    Stein, A.
    Troconiz, I. F.
    Bruno, R.
    Mehrotra, N.
    Gobburu, J.
    Mould, D. R.
    Optimizing Oncology Therapeutics Through Quantitative Translational and Clinical Pharmacology: Challenges and Opportunities2015In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 97, no 1, p. 37-54Article in journal (Refereed)
    Abstract [en]

    Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety.

  • 137.
    Viklund, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    PREVALENCE OF HPV IN ANAL CARCINOMA AS REVEALED BY P16IMMUNOHISTOCHEMISTRY – A RETROSPECTIVE STUDY2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background

    Squamous cell carcinoma of the anus is often considered related to chronic infection of

    oncogene HPV types, primarily HPV16 and HPV18. P16 is a tumor suppressing protein

    involved in the cell cycle. This protein is normally inhibited by the pRB (retinoblastoma)

    protein, however HPV produces the protein E7 which binds to pRB and inactivates it.

    Overexpression of p16 therefore indicates HPV-infection.

    Purpose

    The purpose of this study was to determine the likelihood of HPV-infection being the cause of

    squamous cell carcinoma of the anus.

    Materials and methods

    The method used was immunohistochemistry using antibody towards p16-antigen. A

    pathologist evaluated the tissues and graded them depending on the percentage of cancer cells

    showing presence of p16. Tissues from 63 patients, 49 women, 14 men, were used.

    Results

    The results showed that 81 % of patients tested positive for p16. Cases showed positive

    results in 85.7 % for women versus 64.3 % for men. Mann-Whitney U-test showed a

    difference between genders with a two-tailed p value of 0.00386. Spearman’s rho test showed

    no statistical monotone correlation between degree of overexpression of p16 and patient age.

    Conclusion

    In conclusion this study has shown that HPV-infection in 81 % of cases was the cause of

    squamous cell carcinoma of the anus. The study further showed higher likelihood of

    HPV-infection being the cause of the disease among female patients. The study could not

    show patient age being a factor in likelihood of HPV-infection being the cause.

  • 138.
    Webb, Matthew J
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Palmgren, Pål
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Surface and Interface Science.
    Pal, Prabir
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Surface and Interface Science.
    Karis, Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Surface and Interface Science.
    Grennberg, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    A simple method to produce almost perfect graphene on highly oriented pyrolytic graphite2011In: Carbon, ISSN 0008-6223, E-ISSN 1873-3891, Vol. 49, no 10, p. 3242-3249Article in journal (Refereed)
  • 139.
    Wei, Q
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kullberg, EB
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Trastuzumab-conjugated boron-containing liposomes for tumor-celltargeting; development and cellular studies.2003In: Int J Oncol, Vol. 23, p. 1159-Article in journal (Refereed)
  • 140.
    Westerberg, Per-Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tivesten, Åsa
    Wallenberg Laboratory for Cardiovascular Research, University of Göteborg, Göteborg, Sweden.
    Karlsson, Magnus
    Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences and Orthopedic Surgery, Lund University, Skåne University Hospital, Sweden..
    Mellström, Dan
    Center for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, the Sahlgrenska Academy at Göteborg University, Göteborg, Sweden..
    Ohlsson, Claes
    Center for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, the Sahlgrenska Academy at Göteborg University, Göteborg, Sweden..
    Larsson, Tobias
    Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm,.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Klotho polymorphisms, FGF23 and mortality among elderly men (Swedish MrOs).Manuscript (preprint) (Other academic)
    Abstract [en]

     

    Westerberg, P-A and Kindmark, A contributed equally in preparation of the manuscript.

    Introduction. α-Klotho is the co receptor for Fibroblast growth factor(FGF)23and crucial for phosphate and vitamin D metabolism. Variants in the KLOTHO (KL) gene are associated with longevity and cardiovascular morbidities. Primary aim of this study is to examine if variations in  KL affect mortality risk in a cohort of elderly men. Secondary aims are to examine associations with serum levels of FGF23, phosphate and renal function.

    Methods and results. 27 single nucleotide polymorphisms (SNP) in KLOTHO were genotyped using single base primer extension mass array technique on samples from 2924 men, aged 69 to 81 years, included in Swedish MrOs. After in average 6.1 years of follow up 584 had died, 214 of cardiovascular cause.  After quality analyses and tagging of haplotypes 11 SNPs were analyzed for variation in  mortality risk, serum levels of FGF23, phosphate, calcium and renal function. There were no associations with mortality of all cause. One SNP, (rs398655), in proximity to the promoter, demonstrated an increased Hazard ratio (95% Confidence interval(CI)) of 53% (95% CI, 8-118%) for death due to CVD in heterozygotes compared to homozygotes. Analysis using a dominant model showed an association between SNPs in the 5’ end of the gene and eGFR, phosphate level and logFGF23 (P=0.01).

    Conclusion. KL polymorphisms are associated with variation in FGF23 and phosphate.

  • 141.
    Wiberg, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Granstam, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Harkonen, T.
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland..
    Knip, M.
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland.;Folkkhalsan Res Ctr, Helsinki, Finland.;Tampere Univ Hosp, Dept Pediat, Tampere, Finland..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies2015In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 182, no 3, p. 278-288Article in journal (Refereed)
    Abstract [en]

    In this study we aim to describe the characteristics of non-diabetic organ donors with circulating diabetes-associated autoantibodies collected within the Nordic Network for Islet Transplantation. One thousand and thirty organ donors have been screened in Uppsala for antibodies against glutamic acid decarboxylase (GADA) and islet antigen-2 (IA-2A). The 32 non-diabetic donors that tested positive for GADA (33% of all non-diabetic donors) were studied in more detail, together with 32 matched controls. Mean age among the autoantibody-positive donors was 526 (range 21-74), family history of type 1 diabetes (T1D) was unknown, and no donor was genetically predisposed for T1D regarding the human leucocyte antigen (HLA) locus. Subjects were analysed for islet cell antibodies (ICA), insulin autoantibodies (IAA) and zinc transporter 8 antibodies (ZnT8A), and pancreas morphology and clinical data were examined. Eight non-diabetic donors tested positive for two antibodies and one donor tested positive for four antibodies. No insulitis or other signs of a diabetic process were found in any of the donors. While inflammatory cells were present in all donors, subjects with high GADA titres had significantly higher CD45 cell numbers in exocrine tissue than controls. The extent of fibrosis was more pronounced in autoantibody-positive donors, even in subjects with lower GADA titres. Notably, it is possible that events not related directly to T1D (e.g. subclinical pancreatitis) may induce autoantibodies in some cases.

  • 142.
    Widenkvist, Erika
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Quinlan, Ronald A.
    Dept of Applied Science.
    Holloway, Brian C.
    Luna Innovations Nano Works Division.
    Grennberg, Helena
    Dept of biochemistry and organic chemistry.
    Jansson, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Synthesis of Nanostructed Tungsten Oxide Thin Films2008In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 8, no 10, p. 3750-3753Article in journal (Refereed)
    Abstract [en]

    A facile and inexpensive method to produce thin films of nanostructured tungsten oxide is described. A nanocrystalline tungstite (WO3·H2O) film is spontaneously formed when a tungsten substrate is immersed in nitric acid at elevated temperatures. The resulting thin film is composed of plate-like tungstite crystals with edges preferentially directed out from the substrate surface. The tungstite can easily be transformed into WO3 by annealing. Patterned WO3·H2O/W structures can be obtained by a combination of lithographic techniques and etching. In this study, the effect of exposure time, acid concentration, and temperature on the microstructure of the films has been investigated. The potential of this inexpensive synthesis method to produce large-area coatings of nanostructured tungsten oxide as well as patterned films makes it interesting for several different applications, such as batteries, gas sensors, and photocatalysts.

  • 143.
    Yang, Wenzhi
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Widenkvist, Erika
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Inorganic Chemistry.
    Jansson, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Inorganic Chemistry.
    Grennberg, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry.
    Stirring-induced aggregation of graphene in suspension2011In: New Journal of Chemistry, ISSN 1144-0546, E-ISSN 1369-9261, Vol. 35, no 4, p. 780-783Article in journal (Refereed)
    Abstract [en]

    Graphene in suspension undergoes stirring-induced aggregation that leads to reversible agglomeration and folding/scrolling, all of which affects the Raman spectra; the findings are of importance in all solution-based protocols for graphene preparation and processing.

  • 144.
    Zhu, Jun
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Dahlstrand, Christian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Smith, Joshua R.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Villaume, Sebastien
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Ottosson, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    On the Importance of Clar Structures of Polybenzenoid Hydrocarbons as Revealed by the n-Contribution to the Electron Localization Function2010In: Symmetry, ISSN 2073-8994, E-ISSN 2073-8994, Vol. 2, no 3, p. 1653-1682Article in journal (Refereed)
    Abstract [en]

    The degree of p-electron (de)localization and aromaticity of a series of polybenzenoid hydrocarbons (PBHs) has been analyzed through the π-contribution to the electron localization function (ELFπ), calculated at the B3LYP/6-311G(d,p) hybrid density functional theory level. The extent of p-electron delocalization in the various hexagons of a PBH was determined through analysis of the bifurcation values of the ELFp basins (BV(ELFp)), the spans in the bifurcation values in each hexagon (ΔBV(ELFπ)), and the ring-closure bifurcation values of the ELFπ (RCBV(ELFπ)). These computed results were compared to the qualitative description of local aromaticities of the different hexagons in terms of Clar structures with p-sextets. Benzene, [18]annulene, and thirty two PBHs were analyzed at their equilibrium geometries, and benzene and triphenylene were also analyzed at bond length distorted structures. In general, the description of PBHs in terms of Clar valence structures is supported by the ELFp properties, although there are exceptions. For PBHs at their equilibrium geometries there is a clear sigmoidal relationship between the CC bond lengths and the amount of p-electron (de)localization at these bonds, however, this relationship is lost for bond distorted geometries. In the latter cases, we specifically examined benzene in D3h symmetric “1,3,5-cyclohexatriene” structures and triphenylene in eight different structures. From the distorted benzenes and triphenylenes it becomes clear that there is a distinct tendency for the p-electron network to retain delocalization (aromaticity). The ELFp analysis thus reveals an antidistortive rather than a distortive behavior of the p-electrons in these investigated compounds.

  • 145.
    Zuberovic, Aida
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Hanrieder, Jörg
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Wetterhall, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Proteome profiling of human cerebrospinal fluid: exploring the potential of capillary electrophoresis with surface modified capillaries for analysis of complex biological samples.2008In: European journal of mass spectrometry, ISSN 1469-0667, E-ISSN 1751-6838, Vol. 14, no 4, p. 249-260Article in journal (Refereed)
    Abstract [en]

    A bottom-up proteomic approach, based on capillary electrophoresis (CE) in combination with matrix- assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-ToF/ToF MS), was used to analyze immunoaffinity depleted human cerebrospinal fluid (CSF) and compare it with a non-depleted sample. After enzymatic digestion and desalting, the tryptic peptides were separated by CE using PolyE-323 modified capillaries and fractionated off-line onto MALDI target plates for further analysis by MALDI-MS and MS/MS. The protein profile of the depleted sample was compared with non depleted CSF. Overall, 85 proteins were identified with 95% significance in both samples. The significance scores for proposed biomarkers, such as amyloid-like protein 1 precursor, could be increased up to 12 times after the depletion. Other proteins, often suggested to be related to neurodegenerative diseases, like amyloid beta A4 protein precursor, superoxide dismutase and apolipoprotein E precursor could only be found in the depleted CSF samples. The effect of a derivatization of tryptic peptides with 2- methoxy-4,5-dihydro-1H-imidazole reagent for protein identification with MS was also employed to increase the number of identified proteins and the sequence coverages. The results presented in this study illustrate the benefit of combining a sample pre-fractionation step and a label's ability to enhance the ionization efficiency with the potential of CE using PolyE-323 modified capillaries in the analysis of complex samples. The straight-forward approach that provides speed and simplicity resulting in high-resolution separations and low sample consumption represents an easily applicable separation technique that can serve as a complement to other currently existing analytical approaches needed in modern proteomic analysis of clinically relevant samples.

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