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  • 1.
    Abdel-Rehim, Mohamed
    Karlstads universitet, Fakulteten för teknik- och naturvetenskap, Avdelningen för kemi och biomedicinsk vetenskap. AstraZeneca R&D Sodertalje, Global DMPK, SE-15185 Sodertalje, Sweden.;Stockholm Univ, Dept Analyt Chem, SE-10691 Stockholm, Sweden.;Karlstad Univ, Dept Chem & Biomed Sci, Fac Sci & Technol, SE-65188 Karlstad, Sweden..
    Microextraction by packed sorbent (MEPS): A tutorial2011Inngår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 701, nr 2, 119-128 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This tutorial provides an overview on a new technique for sample preparation, microextraction by packed sorbent (MEPS). Not only the automation process by MEPS is the advantage but also the much smaller volumes of the samples, solvents and dead volumes in the system. Other significant advantages such as the speed and the simplicity of the sample preparation process are provided. In this tutorial the main concepts of MEPS will be elucidated. Different practical aspects in MEPS are addressed. The factors affecting MEPS performance will be discussed. The application of MEPS in clinical and pre-clinical studies for quantification of drugs and metabolites in blood, plasma and urine will be provided. A comparison between MEPS and other extraction techniques such as SPE, LLE, SPME and SBSE will be discussed. (C) 2011 Elsevier B.V. All rights reserved.

  • 2.
    Abdel-Rehim, Mohamed
    Karlstads universitet, Fakulteten för teknik- och naturvetenskap, Avdelningen för kemi och biomedicinsk vetenskap. AstraZeneca R&D Sodertalje, Global DMPK, Sodertalje, Sweden.;Karlstad Univ, Fac Sci & Technol, Dept Chem & Biomed Sci, Karlstad, Sweden..
    On-Line Whole Blood Analysis Using Microextraction by Packed Sorbent and LC-MS-MS2011Inngår i: LC GC North America, ISSN 1527-5949, E-ISSN 1939-1889, Vol. 29, nr 7, 612-618 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Microextraction by packed sorbent (MEPS) is a new technique for sample preparation that can be connected on-line with liquid chromatography (LC) or gas chromatography (GC) systems without any modifications. This article describes the use of MEPS in clinical and preclinical studies to quantify different drugs in whole blood samples. MEPS was used to determine cyclophosphamide in mouse blood from preclinical g studies using 20 mu L of blood samples. The interday accuracies and 0 precisions ranged from 107-109% and from 2.0-7.0%, respectively. The determination of four immunosuppressive drugs in human blood by MEPS and liquid chromatography-mass spectrometry (LC-MS) is described. The method showed a good selectivity and sensitivity. The calibration curves for everolimus, sirolimus, and tacrolimus ranged from 0.5 to 50 ng/mL and for cyclosporine from 3.0 to 1500 ng/mL. Intraday precisions for the studied immunosuppressive drugs were 2.0-11.7% and interday precision ranged from 5.1 to 13.7% (CV).

  • 3. Acero Sanchez, Josep Ll.
    et al.
    Joda, Hamdi
    Henry, Olivier Y. F.
    Solnestam, Beata W.
    Kvastad, Linda
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sahlén, Pelin
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Laddach, Nadja
    Ramakrishnan, Dheeraj
    Riley, Ian
    Schwind, Carmen
    Latta, Daniel
    O'Sullivan, Ciara K.
    Electrochemical Genetic Profiling of Single Cancer Cells2017Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 89, nr 6, 3378-3385 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent understandings in the development and spread of cancer have led to the realization of novel single cell analysis platforms focused on circulating tumor cells (CTCs). A simple, rapid, and inexpensive analytical platform capable of providing genetic information on these rare cells is highly desirable to support clinicians and researchers alike to either support the selection or adjustment of therapy or provide fundamental insights into cell function and cancer progression mechanisms. We report on the genetic profiling of single cancer cells, exploiting a combination of multiplex ligation-dependent probe amplification (MLPA) and electrochemical detection. Cells were isolated using laser capture and lysed, and the mRNA was extracted and transcribed into DNA. Seven markers were amplified by MLPA, which allows for the simultaneous amplification of multiple targets with a single primer pair, using MLPA probes containing unique barcode sequences. Capture probes complementary to each of these barcode sequences were immobilized on a printed circuit board (PCB) manufactured electrode array and exposed to single-stranded MLPA products and subsequently to a single stranded DNA reporter probe bearing a HRP molecule, followed by substrate addition and fast electrochemical pulse amperometric detection. We present asimple, rapid, flexible, and inexpensive approach for the simultaneous quantification of multiple breast cancer related mRNA markers, with single tumor cell sensitivity.

  • 4. Addario, Barbara
    et al.
    Sandblad, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Persson, Karina
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Backman, Lars
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Characterisation of Schizosaccharomyces pombe alpha-actinin2016Inngår i: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 4, e1858Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The actin cytoskeleton plays a fundamental role in eukaryotic cells. Its reorganization is regulated by a plethora of actin-modulating proteins, such as a-actinin. In higher organisms, alpha-actinin is characterized by the presence of three distinct structural domains: an N-terminal actin-binding domain and a C-terminal region with EF-hand motif separated by a central rod domain with four spectrin repeats. Sequence analysis has revealed that the central rod domain of alpha-actinin from the fission yeast Schizosaccharomyces pombe consists of only two spectrin repeats. To obtain a firmer understanding of the structure and function of this unconventional alpha-actinin, we have cloned and characterized each structural domain. Our results show that this alpha-actinin isoform is capable of forming dimers and that the rod domain is required for this. However, its actin-binding and cross-linking activity appears less efficient compared to conventional alpha-actinins. The solved crystal structure of the actin-binding domain indicates that the closed state is stabilised by hydrogen bonds and a salt bridge not present in other a-actinins, which may reduce the affinity for actin.

  • 5.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Flohr, Gilian
    Hogeschool Leiden, Zernikedreef 11,2333 CK Leiden, The Netherlands.
    Gorre, Nagaraju
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shen, Yan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Yang, Hairu
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lan, Zijian
    University of Louisville Health Sciences Center, Louisville, Kentucky, USA.
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles2009Inngår i: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 15, nr 12, 765-770 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To maintain the length of reproductive life in a woman, it is essential that most of her ovarian primordial follicles are maintained in a quiescent state to provide a continuous supply of oocytes. However, our understanding of the molecular mechanisms that control the quiescence and activation of primordial follicles is still in its infancy. In this study, we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 (Tsc2), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the dormancy of primordial follicles. In mutant mice lacking the Tsc2 gene in oocytes, the pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in oocytes. This results in depletion of follicles in early adulthood, causing premature ovarian failure (POF). Our results suggest that the Tsc1-Tsc2 complex mediated suppression of mTORC1 activity is indispensable for maintenance of the dormancy of primordial follicles, thus preserving the follicular pool, and that mTORC1 activity in oocytes promotes follicular activation. Our results also indicate that deregulation of Tsc/mTOR signaling in oocytes may cause pathological conditions of the ovary such as infertility and POF.

  • 6.
    Adrian-Kalchhauser, Irene
    et al.
    Univ Basel, Program Man Soc Environm, Dept Environm Sci, Vesalgasse 1, CH-4051 Basel, Switzerland..
    Svensson, Ola
    Univ Gothenburg, Dept Biol & Environm Sci, Medicinaregatan 18A, S-41390 Gothenburg, Sweden.;Univ Gothenburg, Linnaeus Ctr Marine Evolutionary Biol, POB 46040530, Gothenburg, Sweden..
    Kutschera, Verena E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Rosenblad, Magnus Alm
    Univ Gothenburg, Linnaeus Ctr Marine Evolutionary Biol, POB 46040530, Gothenburg, Sweden.;Univ Gothenburg, Dept Marine Sci, NBIS Bioinformat Infrastruct Life Sci, Medicinaregatan 9C, S-41390 Gothenburg, Sweden..
    Pippel, Martin
    Heidelberg Inst Theoret Studies, Schloss Wolfsbrunnenweg 35, D-69118 Heidelberg, Germany..
    Winkler, Sylke
    Max Planck Inst Mol Cell Biol & Genet, Pfotenhauerstr 108, D-01307 Dresden, Germany..
    Schloissnig, Siegfried
    Heidelberg Inst Theoret Studies, Schloss Wolfsbrunnenweg 35, D-69118 Heidelberg, Germany..
    Blomberg, Anders
    Univ Gothenburg, Linnaeus Ctr Marine Evolutionary Biol, POB 46040530, Gothenburg, Sweden.;Univ Gothenburg, Dept Marine Sci, Medicinaregatan 9C, S-41390 Gothenburg, Sweden..
    Burkhardt-Holm, Patricia
    Univ Basel, Program Man Soc Environm, Dept Environm Sci, Vesalgasse 1, CH-4051 Basel, Switzerland.;Univ Alberta, Dept Biol Sci, 11455 Saskatchewan Dr, Edmonton, AB, Canada..
    The mitochondrial genome sequences of the round goby and the sand goby reveal patterns of recent evolution in gobiid fish2017Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, 177Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Vertebrate mitochondrial genomes are optimized for fast replication and low cost of RNA expression. Accordingly, they are devoid of introns, are transcribed as polycistrons and contain very little intergenic sequences. Usually, vertebrate mitochondrial genomes measure between 16.5 and 17 kilobases ( kb). Results: During genome sequencing projects for two novel vertebrate models, the invasive round goby and the sand goby, we found that the sand goby genome is exceptionally small (16.4 kb), while the mitochondrial genome of the round goby is much larger than expected for a vertebrate. It is 19 kb in size and is thus one of the largest fish and even vertebrate mitochondrial genomes known to date. The expansion is attributable to a sequence insertion downstream of the putative transcriptional start site. This insertion carries traces of repeats from the control region, but is mostly novel. To get more information about this phenomenon, we gathered all available mitochondrial genomes of Gobiidae and of nine gobioid species, performed phylogenetic analyses, analysed gene arrangements, and compared gobiid mitochondrial genome sizes, ecological information and other species characteristics with respect to the mitochondrial phylogeny. This allowed us amongst others to identify a unique arrangement of tRNAs among Ponto-Caspian gobies. Conclusions: Our results indicate that the round goby mitochondrial genome may contain novel features. Since mitochondrial genome organisation is tightly linked to energy metabolism, these features may be linked to its invasion success. Also, the unique tRNA arrangement among Ponto- Caspian gobies may be helpful in studying the evolution of this highly adaptive and invasive species group. Finally, we find that the phylogeny of gobiids can be further refined by the use of longer stretches of linked DNA sequence.

  • 7.
    Aguilo, Francesca
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
    Zakirova, Zuchra
    Nolan, Katie
    Wagner, Ryan
    Sharma, Rajal
    Hogan, Megan
    Wei, Chengguo
    Sun, Yifei
    Walsh, Martin J.
    Kelley, Kevin
    Zhang, Weijia
    Ozelius, Laurie J.
    Gonzalez-Alegre, Pedro
    Zwaka, Thomas P.
    Ehrlich, Michelle E.
    THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation2017Inngår i: Stem Cell Reports, ISSN 2213-6711, Vol. 9, nr 1, 92-107 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression.

  • 8.
    Ahmad, Irfan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Rouf, Syed Fazle
    Sun, Lei
    Cimdins, Annika
    Shafeeq, Sulman
    Le Guyon, Soazig
    Schottkowski, Marco
    Rhen, Mikael
    Romling, Ute
    BcsZ inhibits biofilm phenotypes and promotes virulence by blocking cellulose production in Salmonella enterica serovar Typhimurium2016Inngår i: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 15, 177Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Cellulose, a 1,4 beta-glucan polysaccharide, is produced by a variety of organisms including bacteria. Although the production of cellulose has a high biological, ecological and economical impact, regulatory mechanisms of cellulose biosynthesis are mostly unknown. Family eight cellulases are regularly associated with cellulose biosynthesis operons in bacteria; however, their function is poorly characterized. In this study, we analysed the role of the cellulase BcsZ encoded by the bcsABZC cellulose biosynthesis operon of Salmonella enterica serovar Typhimurium (S. Typhimurium) in biofilm related behavior. We also investigated the involvement of BcsZ in pathogenesis of S. Typhimurium including a murine typhoid fever infection model. Result: In S. Typhimurium, cellulase BcsZ with a putative periplasmic location negatively regulates cellulose biosynthesis. Moreover, as assessed with a non-polar mutant, BcsZ affects cellulose-associated phenotypes such as the rdar biofilm morphotype, cell clumping, biofilm formation, pellicle formation and flagella-dependent motility. Strikingly, although upregulation of cellulose biosynthesis was not observed on agar plate medium at 37 degrees C, BcsZ is required for efficient pathogen-host interaction. Key virulence phenotypes of S. Typhimurium such as invasion of epithelial cells and proliferation in macrophages were positively regulated by BcsZ. Further on, a bcsZ mutant was outcompeted by the wild type in organ colonization in the murine typhoid fever infection model. Selected phenotypes were relieved upon deletion of the cellulose synthase BcsA and/or the central biofilm activator CsgD. Conclusion: Although the protein scaffold has an additional physiological role, our findings indicate that the catalytic activity of BcsZ effectively downregulates CsgD activated cellulose biosynthesis. Repression of cellulose production by BcsZ subsequently enables Salmonella to efficiently colonize the host.

  • 9.
    Ahrenstedt, Lage
    et al.
    KTH, Skolan för bioteknologi (BIO). KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Olksanen, Antti
    VTT Technical Research Centre of Finland.
    Salmien, Kristian
    VTT Technical Research Centre of Finland.
    Brumer, Harry
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap. KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Paper dry strength improvement by xyloglucan addition: Wet-end application, spray coating and synergism with borate2008Inngår i: Holzforschung, ISSN 0018-3830, Vol. 62, nr 1, 8-14 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The polysaccharide xyloglucan as a wet-end additive improves paper properties. In the present study, paper strength improvement was analysed for dry handsheets made from chemical, mechanical and recycled pulps coated with xyloglucan in a spray application. Results are compared with sheets made from the same pulps treated with xyloglucan in the wet-end. Kraft pulp handsheets of bleached hardwood and softwood showed significant improvements of tensile, tear and Z-strength by xyloglucan spray treatment versus wet-end application, whereas handsheets of de-inked and thermomechanical pulp were improved only slightly. In both wet-end and spray applications, the effect of xyloglucan addition was intimately related to the presence of non-cellulosic components on the fibre surface. Further strength improvements were obtained for chemical pulps by addition of borax to the spray solution, which were likely to be due to the formation of borate-mediated xyloglucan cross-links. Spray coating of xyloglucan, with or without borax, thus represents a potential new application of this polysaccharide to increase paper dry strength.

  • 10.
    Aisenbrey, Christopher
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Byström, Roberth
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Oliveberg, Mikael
    Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
    Gröbner, Gerhard
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    SOD1 associates to membranes in its folded apo-stateManuskript (Annet (populærvitenskap, debatt, mm))
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease accompanied by misfolding and intracellular deposition of superoxide dismutase 1 (SOD1). Although the molecular details behind this misfolding process are yet poorly understood, increasing evidence suggest that SOD1 is most susceptible to misfolding in its metal-free and relatively unstable apo-state. Here, we addressed the question, if misfolding and aggregation of SOD1 involves erroneous interactions with membranes as has been implicated for the Aβ peptide in Alzheimers disease. To examine this possibility we subjected various apo SOD1 variants to the presence of different membrane systems. The results reveal that wild type apoSOD1 but to less extent destabilized ALS mutations interact with charged vesicles under physiologically relevant conditions, thereby acquiring pronounced helical structural features. As the data further show, the protein binds to the membranes by an electrostatically driven mechanism, which requires a folded apo-state conformation and a negative membrane surface potential. Unfolded SOD1 molecules show no appreciable affinity to the membrane surfaces yielding a correlation between increased stability, i. e. occupancy of folded molecules and extend of membrane association. Since this trend opposes the correlation between decreased SOD1 stability and progression of neural damage, the results suggest that membrane association is not part of the ALS mechanism. An explanation could be that the observed membrane association of apo SOD1 is reversible and does not ‘bleed out’ in irreversible aggregation as observed for other precursors of protein-misfolding diseases.

  • 11.
    Ajalloueian, F.
    et al.
    Isfahan Univ Technol, Dept Text Engn, Ctr Excellence Appl Nanotechnol, Esfahan, Iran..
    Fransson, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Tavanai, H.
    Isfahan Univ Technol, Dept Text Engn, Ctr Excellence Appl Nanotechnol, Esfahan, Iran..
    Hilborn, Jöns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Magnusson, Peetra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala Univ, Dept Immunol Genet & Pathol IGP, Uppsala, Sweden..
    Arpanaei, A.
    Natl Inst Genet Engn & Biotechnol, Dept Ind & Environm Biotechnol, Tehran, Iran..
    Comparing PLGA and PLGA/Chitosan Nanofibers Seeded by Msc: A Cell-scaffold Interaction Study2015Inngår i: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, S406-S407 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 12.
    Ajalloueian, F.
    et al.
    Tech Univ Denmark, Copenhagen, Denmark..
    Hilborn, Jöns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Fossum, M.
    Karolinska Inst, Stockholm, Sweden..
    Chronakis, I. S.
    Tech Univ Denmark, Copenhagen, Denmark..
    Integrated Micro/Nanofibrous PLGA-Collagen Scaffold: an Optimized Method for Plastic Compression of Collagen into PLGA Microfibers2015Inngår i: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, S347-S347 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 13. Akoachere, Monique
    et al.
    Iozef, Rimma
    Rahlfs, Stefan
    Deponte, Marcel
    Mannervik, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi. Institutionen för biokemi och organisk kemi, Biokemi.
    Creighton, Donald J
    Schirmer, Heiner
    Becker, Katja
    Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison with their human counterparts.2005Inngår i: Biol Chem, ISSN 1431-6730, Vol. 386, nr 1, 41-52 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The glyoxalase system consisting of glyoxalase I (GloI) and glyoxalase II (GloII) constitutes a glutathione-dependent intracellular pathway converting toxic 2-oxoaldehydes, such as methylglyoxal, to the corresponding 2-hydroxyacids. Here we describe a complete glyoxalase system in the malarial parasite Plasmodium falciparum. The biochemical, kinetic and structural properties of cytosolic GloI (cGloI) and two GloIIs (cytosolic GloII named cGloII, and tGloII preceded by a targeting sequence) were directly compared with the respective isofunctional host enzymes. cGloI and cGloII exhibit lower K(m) values and higher catalytic efficiencies (k(cat)/K(m) ) than the human counterparts, pointing to the importance of the system in malarial parasites. A Tyr185Phe mutant of cGloII shows a 2.5-fold increase in K(m) , proving the contribution of Tyr185 to substrate binding. Molecular models suggest very similar active sites/metal binding sites of parasite and host cell enzymes. However, a fourth protein, which has highest similarities to GloI, was found to be unique for malarial parasites; it is likely to act in the apicoplast, and has as yet undefined substrate specificity. Various S-(N-hydroxy-N-arylcarbamoyl)glutathiones tested as P. falciparum Glo inhibitors were active in the lower nanomolar range. The Glo system of Plasmodium will be further evaluated as a target for the development of antimalarial drugs.

  • 14.
    Akula, Srinivas
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Kemisk biologi.
    Thorpe, Michael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Kemisk biologi.
    Boinapally, Vamsi
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Kemisk biologi.
    Hellman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Kemisk biologi.
    Granule Associated Serine Proteases of Hematopoietic Cells - An Analysis of Their Appearance and Diversification during Vertebrate Evolution2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 11, e0143091Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Serine proteases are among the most abundant granule constituents of several hematopoietic cell lineages including mast cells, neutrophils, cytotoxic T cells and NK cells. These proteases are stored in their active form in the cytoplasmic granules and in mammals are encoded from four different chromosomal loci: the chymase locus, the met-ase locus, the T cell tryptase and the mast cell tryptase locus. In order to study their appearance during vertebrate evolution we have performed a bioinformatic analysis of related genes and gene loci from a large panel of metazoan animals from sea urchins to placental mammals for three of these loci: the chymase, met-ase and granzyme A/K loci. Genes related to mammalian granzymes A and K were the most well conserved and could be traced as far back to cartilaginous fish. Here, the granzyme A and K genes were found in essentially the same chromosomal location from sharks to humans. However in sharks, no genes clearly identifiable as members of the chymase or met-ase loci were found. A selection of these genes seemed to appear with bony fish, but sometimes in other loci. Genes related to mammalian met-ase locus genes were found in bony fish. Here, the most well conserved member was complement factor D. However, genes distantly related to the neutrophil proteases were also identified in this locus in several bony fish species, indicating that this locus is also old and appeared at the base of bony fish. In fish, a few of the chymase locus-related genes were found in a locus with bordering genes other than the mammalian chymase locus and some were found in the fish met-ase locus. This indicates that a convergent evolution rather than divergent evolution has resulted in chymase locus-related genes in bony fish.

  • 15. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Bergman, Åke
    Andersson, Patrik L
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, 164-173 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and gamma H2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 mu M of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 mu M). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and gamma H2AX. CYP1A1 mRNA induction was seen at 1 h, and gamma H2AX at 3 h. The anti-oxidant N-Acetyl-L-Cysteine (NAC) completely prevented, and 17 beta-estradiol amplified the gamma H2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.

  • 16.
    Alberti, Esteban
    et al.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Garcia, Rocio
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Fraga, JL
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Serrano, T.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Hernandez, E.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Macías, R.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Martinez, L.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Castillo, L.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    de la Cuétara, K.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba.
    Prolonged Survival and expression of neural markers by bone marrow-derived stem cells transplanted into brain lesions2009Inngår i: Medical Science Monitor, ISSN 1234-1010, Vol. 15, nr 2, BR47-BR54 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Bone marrow-derived stem cell transplantation is a potentially viable therapeutic option for the treatment of neurodegenerative disease. MATERIAL/METHODS: We have isolated bone marrow stem cells by standard method. We then evaluated the survival of rats' bone marrow mononuclear cells implanted in rats' brain. The cells were extracted from rats' femurs, and marked for monitoring purposes by adenoviral transduction with Green Fluorescent Protein (GFP). Labeled cells were implanted within the area of rats' striatum lesions that were induced a month earlier employing quinolinic acid-based method. The implants were phenotyped by monitoring CD34; CD38; CD45 and CD90 expression. Bone marrow stromal cells were extracted from rats' femurs and cultivated until monolayer bone marrow stromal cells were obtained. The ability of bone marrow stromal cells to express NGF and GDNF was evaluated by RT-PCR. RESULTS: Implanted cells survived for at least one month after transplantation and dispersed from the area of injection towards corpus callosum and brain cortex. Interestingly, passaged rat bone marrow stromal cells expressed NGF and GDNF mRNA. CONCLUSIONS: The bone marrow cells could be successfully transplanted to the brain either for the purpose of trans-differentiation, or for the expression of desired growth factors.

  • 17. Albèr, C.
    et al.
    Brandner, B. D.
    Björklund, S.
    Billsten, P.
    Corkery, Robert
    KTH, Skolan för kemivetenskap (CHE), Kemi, Tillämpad fysikalisk kemi.
    Engblom, J.
    Effects of water gradients and use of urea on skin ultrastructure evaluated by confocal Raman microspectroscopy2013Inngår i: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1828, nr 11, 2470-2478 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The rather thin outermost layer of the mammalian skin, stratum corneum (SC), is a complex biomembrane which separates the water rich inside of the body from the dry outside. The skin surface can be exposed to rather extreme variations in ambient conditions (e.g. water activity, temperature and pH), with potential effects on the barrier function. Increased understanding of how the barrier is affected by such changes is highly relevant for regulation of transdermal uptake of exogenous chemicals. In the present study we investigate the effect of hydration and the use of a well-known humectant, urea, on skin barrier ultrastructure by means of confocal Raman microspectroscopy. We also perform dynamic vapor sorption (DVS) microbalance measurements to examine the water uptake capacity of SC pretreated with urea. Based on novel Raman images, constructed from 2D spectral maps, we can distinguish large water inclusions within the skin membrane exceeding the size of fully hydrated corneocytes. We show that these inclusions contain water with spectral properties similar to that of bulk water. The results furthermore show that the ambient water activity has an important impact on the formation of these water inclusions as well as on the hydration profile across the membrane. Urea significantly increases the water uptake when present in skin, as compared to skin without urea, and it promotes formation of larger water inclusions in the tissue. The results confirm that urea can be used as a humectant to increase skin hydration.

  • 18. Alcocer, Marcos
    et al.
    Rundqvist, Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Larsson, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ber e 1 protein: the versatile major allergen from Brazil nut seeds.2012Inngår i: Biotechnology letters, ISSN 0141-5492, E-ISSN 1573-6776, Vol. 34, nr 4, 597-610 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Due mainly to its extremely high content of sulphur amino acids, Ber e 1 protein, the major allergen from Brazil nut, has attracted much scientific and press attention. Ber e 1 was the main target protein in early biotechnology transgenic work, in early processing studies of plant storage proteins, in plant vacuolar targeting studies and as the main protein in early nutritional supplementation experiments. Ber e 1 was also one of the first food allergens to be unintentionally transferred from one plant to another and was involved in the first reported case of systemic allergic reaction caused by a food allergen transferred in semen. In this review, many of the Ber e 1 unique biotechnological and structural functions are discussed with a particular emphasis on its use as model protein for studies of intrinsic allergenicity of food proteins.

  • 19.
    Alexander, Helen K.
    et al.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Booy, Evan P.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Xiao, Wenyan
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Ezzati, Peyman
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Baust, Heinrich
    Department of Radiooncology, University of Erlangen, Erlangen, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Selected technologies to control genes and their products for experimental and clinical purposes2007Inngår i: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 55, nr 3, 139-149 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    "On-demand" regulation of gene expression is a powerful tool to elucidate the functions of proteins and biologically-active RNAs. We describe here three different approaches to the regulation of expression or activity of genes or proteins. Promoter-based regulation of gene expression was among the most rapidly developing techniques in the 1980s and 1990s. Here we provide basic information and also some characteristics of the metallothionein-promoter-based system, the tet-off system, Muristerone-A-regulated expression through the ecdysone response element, RheoSwitch (R), coumermycin/novobiocin-regulated gene expression, chemical dimerizer-based promoter activation systems, the "Dual Drug Control" system, "constitutive androstane receptor"-based regulation of gene expression, and RU486/mifepristone-driven regulation of promoter activity. A large part of the review concentrates on the principles and usage of various RNA interference techniques (RNAi: siRNA, shRNA, and miRNA-based methods). Finally, the last part of the review deals with historically the oldest, but still widely used, methods of temperature-dependent regulation of enzymatic activity or protein stability (temperature-sensitive mutants). Due to space limitations we do not describe in detail but just mention the tet-regulated systems and also fusion-protein-based regulation of protein activity, such as estrogen-receptor fusion proteins. The information provided below is aimed to assist researchers in choosing the most appropriate method for the planned development of experimental systems with regulated expression or activity of studied proteins.

  • 20.
    Alfredsson-Timmins, Jenny
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Kristell, Carolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Henningson, Frida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Lyckman, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Bjerling, Pernilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe2009Inngår i: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 118, nr 1, 99-112 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There are several documented events of changes in subnuclear localization during gene activation. However, there are conflicting data on whether the nuclear periphery is a compartment for gene repression or activation, and whether genes are moved to the pores at the nuclear membrane (NM) or not during gene activation. Nitrogen starvation of fission yeast serves as a good model system for studying gene induction since it causes fast regulation of hundreds of genes. In this study the subnuclear localization of two gene clusters repressed by nitrogen was investigated. During normal growth conditions the gene clusters localized to the nuclear periphery at the opposite side of the nucleus as compared to the spindle pole body (SPB). This constrained localization was dependent on the histone deacetylase Clr3, known to transcriptionally repress genes in these clusters. Already 20 minutes after nitrogen depletion drastic changes in subnuclear localization of the two loci were observed, away from the NM towards the nuclear interior. At least for one of the clusters the movement was clearly transcription dependent. Data presented here illustrates how interconnected events of gene activation and nuclear reorganization are, as well as provides a suggestion of how nuclear organization might be maintained.

  • 21. Ali, Raja Hashim
    et al.
    Muhammad, Sayyed Auwn
    Khan, Mehmood Alam
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center, Sweden .
    Quantitative synteny scoring improves homology inference and partitioning of gene families2013Inngår i: BMC Bioinformatics, ISSN 1471-2105, Vol. 14, nr Suppl,15, S12- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Clustering sequences into families has long been an important step in characterization of genes and proteins. There are many algorithms developed for this purpose, most of which are based on either direct similarity between gene pairs or some sort of network structure, where weights on edges of constructed graphs are based on similarity. However, conserved synteny is an important signal that can help distinguish homology and it has not been utilized to its fullest potential.

    Results

    Here, we present GenFamClust, a pipeline that combines the network properties of sequence similarity and synteny to assess homology relationship and merge known homologs into groups of gene families. GenFamClust identifies homologs in a more informed and accurate manner as compared to similarity based approaches. We tested our method against the Neighborhood Correlation method on two diverse datasets consisting of fully sequenced genomes of eukaryotes and synthetic data.

    Conclusions

    The results obtained from both datasets confirm that synteny helps determine homology and GenFamClust improves on Neighborhood Correlation method. The accuracy as well as the definition of synteny scores is the most valuable contribution of GenFamClust.

  • 22.
    Alikhani, Nyosha
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The Mitochondrial Peptidasome, PreP, relation to Alzheimer Disease2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Amyloid-β (Aβ) is the toxic peptide implicated in the pathogenesis of Alzheimer Disease (AD). Accumulation of Aβ has been shown in brain mitochondria from AD patients and AD mice models. The occurrence of Aβ in the mitochondrial matrix leads to free radical generation and apoptosis in neurons.

    In our studies, Aβ was found in brain mitochondria of living patients with plaque pathology. Extracellular Aβ was taken up by neuroblastoma cells and was found in the mitochondria. Moreover, we showed that Aβ40 and Aβ42 are transported into mitochondria via the Translocase of the Outer Membrane, the TOM machinery.

    We have identified the mitochondrial Aβ-degrading protease hPreP, in human brain mitochondrial matrix. PreP is a metalloprotease, originally identified as presequence protease, but was also shown to degrade other unstructured peptides including Aβ. Immunoinactivation of PreP in human brain mitochondria revealed PreP to be the protease responsible for Aβ degradation in mitochondria.

    Also, we have investigated if genetic variation in the gene encoding hPreP is associated with AD by genotyping 19 single nucleotide polymorphisms (SNPs) in the Swedish population. The study did not show a genetic association between any of the genotyped SNPs and the risk to AD. However, the biochemical analysis of four SNPs selected on the basis of their location within a structural homology model of hPreP revealed a decreased activity compared to wildtype.

    Interestingly, the activity of PreP in human brain mitochondrial matrix in AD individuals was significantly lower compared to non-dement aged-matched controls. These findings were also confirmed in brain mitochondrial matrix of AD mouse models. These results suggest that a decreased PreP activity may contribute to Aβ aggregation and accumulation inside mitochondria leading to neuronal death in AD. In summary, our findings show that the degradation of Aβ by hPreP may be of importance in the pathology of AD.

  • 23.
    Alrifaiy, Ahmed
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Ramser, Kerstin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    How to integrate a micropipette into a closed microfluidic system: absorption spectra of an optically trapped erythrocyte2011Inngår i: Biomedical Optics Express, ISSN 2156-7085, E-ISSN 2156-7085, Vol. 2, nr 8, 2299-2306 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We present a new concept of integrating a micropipette within a closed microfluidic system equipped with optical tweezers and a UV-Vis spectrometer. A single red blood cell (RBC) was optically trapped and steered in three dimensions towards a micropipette that was integrated in the microfluidic system. Different oxygenation states of the RBC, triggered by altering the oxygen content in the microchannels through a pump system, were optically monitored by a UV-Vis spectrometer. The built setup is aimed to act as a multifunctional system where the biochemical content and the electrophysiological reaction of a single cell can be monitored simultaneously. The system can be used for other applications like single cell sorting, in vitro fertilization or electrophysiological experiments with precise environmental control of the gas-, and chemical content. 

  • 24. Alvarez, Francisco J.
    et al.
    Ryman, Kicki
    Hooijmaijers, Cornelis
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Bulone, Vincent
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Ljungdahl, Per O.
    Diverse Nitrogen Sources in Seminal Fluid Act in Synergy To Induce Filamentous Growth of Candida albicans2015Inngår i: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 81, nr 8, 2770-2780 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pathogenic fungus Candida albicans is the leading cause of vulvovaginal candidiasis (VVC). VVC represents a major quality- of-life issue for women during their reproductive years, a stage of life where the vaginal epithelium is subject to periodic hormonally induced changes associated with menstruation and concomitant exposure to serum as well as potential intermittent contact with seminal fluid. Seminal fluid potently triggers Candida albicans to switch from yeastlike to filamentous modes of growth, a developmental response tightly linked to virulence. Conversely, vaginal fluid inhibits filamentation. Here, we used artificial formulations of seminal and vaginal fluids that faithfully mimic genuine fluids to assess the contribution of individual components within these fluids to filamentation. The high levels of albumin, amino acids, and N-acetylglucosamine in seminal fluid act synergistically as potent inducers of filamentous growth, even at atmospheric levels of CO2 and reduced temperatures (30 degrees C). Using a simplified in vitro model that mimics the natural introduction of seminal fluid into the vulvovaginal environment, a pulse of artificial seminal fluid (ASF) was found to exert an enduring potential to overcome the inhibitory efficacy of artificial vaginal fluid (AVF) on filamentation. These findings suggest that a transient but substantial change in the nutrient levels within the vulvovaginal environment during unprotected coitus can induce resident C. albicans cells to engage developmental programs associated with virulent growth.

  • 25.
    Alvarez, Laura
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Espaillat, Akbar
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Hermoso, Juan A.
    de Pedro, Miguel A.
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Peptidoglycan Remodeling by the Coordinated Action of Multispecific Enzymes2014Inngår i: Microbial Drug Resistance, ISSN 1076-6294, E-ISSN 1931-8448, Vol. 20, nr 3, 190-198 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The peptidoglycan (PG) cell wall constitutes the main defense barrier of bacteria against environmental insults and acts as communication interface. The biochemistry of this macromolecule has been well characterized throughout the years but recent discoveries have unveiled its chemical plasticity under environmental stresses. Non-canonical D-amino acids (NCDAA) are produced and released to the extracellular media by diverse bacteria. Such molecules govern cell wall adaptation to challenging environments through their incorporation into the polymer, a widespread capability among bacteria that reveals the inherent catalytic plasticity of the enzymes involved in the cell wall metabolism. Here, we analyze the recent structural and biochemical characterization of Bsr, a new family of broad spectrum racemases able to generate a wide range of NCDAA. We also discuss the necessity of a coordinated action of PG multispecific enzymes to generate adequate levels of modification in the murein sacculus. Finally, we also highlight how this catalytic plasticity of NCDAA-incorporating enzymes has allowed the development of new revolutionary methodologies for the study of PG modes of growth and in vivo dynamics.

  • 26.
    Anderl, Ines
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Laboratory of Genetic Immunology, BioMediTech, University of Tampere, Tampere, Finland.
    Hultmark, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Laboratory of Genetic Immunology, BioMediTech, University of Tampere, Tampere, Finland.
    New ways to make a blood cell2015Inngår i: eLIFE, E-ISSN 2050-084X, Vol. 4, e06877Artikkel i tidsskrift (Annet vitenskapelig)
  • 27.
    Anderson, Judy E.
    et al.
    Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Child's Health (MICH), University of Manitoba, Winnipeg, Canada.
    Hansen, Lise Lotte
    Institute of Human Genetics, University of Aarhus, Denmark.
    Mooren, Frank C.
    Department of Sports Medicine, Institute of Sport Sciences, University Giessen, Germany.
    Post, Markus
    Department of Sports Medicine, Institute of Sport Sciences, University Giessen, Germany.
    Hug, Hubert
    DSM Nutritional Products Ltd, Research & Development, Kaiseraugst, Switzerland.
    Zuse, Anne
    Manitoba Institute of Cell Biology (MICB), CancerCare Manitoba, 675 McDermot Ave. Rm. ON6010, Winnipeg, Man. R3E 0V9, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Methods and biomarkers for the diagnosis and prognosis of cancer and other diseases: Towards personalized medicine2006Inngår i: Drug resistance updates, ISSN 1368-7646, E-ISSN 1532-2084, Vol. 9, nr 4-5, 198-210 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The rapid development of new diagnostic procedures, the mapping of the human genome, progress in mapping genetic polymorphisms, and recent advances in nucleic acid- and protein chip technologies are driving the development of personalized therapies. This breakthrough in medicine is expected to be achieved largely due to the implementation of "lab-on-the-chip" technology capable of performing hundreds, even thousands of biochemical, cellular and genetic tests on a single sample of blood or other body fluid. Focusing on a few disease-specific examples, this review discusses selected technologies and their combinations likely to be incorporated in the "lab-on-the-chip" and to provide rapid and versatile information about specific diseases entities. Focusing on breast cancer and after an overview of single-nucleofide polymorphism (SNP)-screening methodologies, we discuss the diagnostic and prognostic importance of SNPs. Next, using Duchenne muscular dystrophy (DMD) as an example, we provide a brief overview of powerful and innovative integration of traditional immuno-histochemistry techniques with advanced biophysical methods such as NMR-spectroscopy or Fourier-transformed infrared (FT-IR) spectroscopy. A brief overview of the challenges and opportunities provided by protein and aptamer microarrays follows. We conclude by highlighting novel and promising biochemical markers for the development of personalized treatment of cancer and other diseases: serum cytochrome c, cytokeratin-18 and -19 and their proteolytic fragments for the detection and quantitation of malignant tumor mass, tumor cell turn-over, inflammatory processes during hepatitis and Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis and apoptotic/necrotic cancer cell death. (c) 2006 Elsevier Ltd. All rights reserved.

  • 28.
    Andersson, Christopher
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Gripenland, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Johansson, Jörgen
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Using the chicken embryo to assess virulence of Listeria monocytogenes and to model other microbial infections2015Inngår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 10, nr 8, 1155-1164 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Microbial infections are a global health problem, particularly as microbes are continually developing resistance to antimicrobial treatments. An effective and reliable method for testing the virulence of different microbial pathogens is therefore a useful research tool. This protocol describes how the chicken embryo can be used as a trustworthy, inexpensive, ethically desirable and quickly accessible model to assess the virulence of the human bacterial pathogen Listeria monocytogenes, which can also be extended to other microbial pathogens. We provide a step-by-step protocol and figures and videos detailing the method, including egg handling, infection strategies, pathogenicity screening and isolation of infected organs. From the start of incubation of the fertilized eggs, the protocol takes <4 weeks to complete, with the infection part taking only 3 d. We discuss the appropriate controls to use and potential adjustments needed for adapting the protocol for other microbial pathogens.

  • 29.
    Andersson, Dan I
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Shrinking Bacterial Genomes: Former skeptics recognize that the genomes of microbial parasites and symbionts are subject to dynamic downsizing2008Inngår i: Microbe, ISSN 1558-7452, Vol. 3, nr 3, 124-130 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 30.
    Andersson, Dan I.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hughes, Diarmaid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Gene amplification and adaptive evolution in bacteria2009Inngår i: Annual Review of Genetics, ISSN 0066-4197, E-ISSN 1545-2948, Vol. 43, 167-195 s.Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Gene duplication-amplification (GDA) processes are highly relevant biologically because they generate extensive and reversible genetic variation on which adaptive evolution can act. Whenever cellular growth is restricted, escape from these growth restrictions often occurs by GDA events that resolve the selective problem. In addition, GDA may facilitate subsequent genetic change by allowing a population to grow and increase in number, thereby increasing the probability for subsequent adaptive mutations to occur in the amplified genes or in unrelated genes. Mathematical modeling of the effect of GDA on the rate of adaptive evolution shows that GDA will facilitate adaptation, especially when the supply of mutations in the population is rate-limiting. GDA can form via several mechanisms, both RecA-dependent and RecA-independent, including rolling-circle amplification and nonequal crossing over between sister chromatids. Due to the high intrinsic instability and fitness costs associated with GDAs, they are generally transient in nature, and consequently their evolutionary and medical importance is often underestimated.

  • 31.
    Andersson, Eva-Lotta
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Bläckberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Fält, Helen
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Bile salt-stimulated lipase and pancreatic lipase-related protein 2: key enzymes for lipid digestion in the newborn examined using the Caco-2 cell line2011Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 52, nr 11, 1949-1956 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In rodents, bile salt-stimulated lipase (BSSL) and pancreatic lipase-related protein 2 (PLRP2) are the dominant lipases expressed in the exocrine pancreas in early life, when milk is the main food. The aim of the present study was to evaluate if BSSL and PLRP2 are also key enzymes in neonatal intestinal fat digestion. Using Caco-2 cells as a model for the small intestinal epithelium, purified human enzymes were incubated in the apical chamber with substrates and bile salt concentrations resembling the milieu of the small intestine of newborn infants. BSSL and PLRP2 hydrolyzed triglycerides (TG) to free fatty acids (FA) and glycerol. The cells took up the FA, which were reesterfied to TG. Together, BSSL and PLRP2 have a synergistic effect, increasing cellular uptake 4-fold compared to the sum of each lipase alone. A synergistic effect was also observed with retinyl ester as a substrate. PLRP2 hydrolyzed cholesteryl ester but not as efficiently as BSSL, and the two had an additive rather than synergistic effect. We conclude the key enzymes in intestinal fat digestion are different in newborns than later in life. Further studies are needed to fully understand this difference and its implication for designing optimal neonatal nutrition.

  • 32.
    Andersson, Karl
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Characterization of Biomolecular Interactions Using a Multivariate Approach2004Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis presents a novel bioinformatic methodology denoted the bio-chemometric approach. The methodology is designed for generation of detailed descriptions and predictions of biomolecular interactions. It is based on multivariate analysis of the sensitivity of a biomolecular interaction to multiple minor changes in the experimental conditions. In this work, either the chemical environment where the interaction takes place, or the molecular structure of one of the interacting molecules, was varied. The sensitivity of the interaction to the performed variations was presented as a vector called the sensitivity fingerprint. The bio-chemometric approach was tested on several biomolecular interactions. Useful descriptions of the interactions were obtained by measuring binding kinetics for each interaction in 12-20 different buffers and correlating buffer composition to binding kinetics. The obtained chemical sensitivity fingerprints were reproducible, significantly different and showed a weak correlation to binding site properties for the tested interactions. The results indicate that the fingerprints contained useful information about the binding site. The predictive ability of the bio-chemometric approach was tested on two different biomolecular interactions where one of the binding partners was slightly modified into multiple analogues by amino acid exchanges. In one example, interactions of 18 peptide analogues with an antibody gave data that could be used for accurate prediction of the dissociation rates of novel analogues. Reliable predictions of binding kinetics and affinity were also obtained for single domain camel antibody analogues binding to a protein antigen. By using the three-dimensional structure of camel antibodies and data obtained using the bio-chemometric approach, even the importance of non-exchanged amino acids for the binding could be estimated. The bio-chemometric approach can potentially improve the development of peptides and proteins for therapeutic and diagnostic use. It is suggested to be valid for general use in biochemistry.

  • 33.
    Andrae, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Gouveia, Leonor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Gallini, Radiosa
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Fredriksson, Linda
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Nilsson, Ingrid
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Johansson, Bengt R.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Electron Microscopy Unit, S-40530 Gothenburg, Sweden..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex2016Inngår i: BIOLOGY OPEN, ISSN 2046-6390, Vol. 5, nr 4, 461-474 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Platelet-derived growth factor-C (PDGF-C) is one of three known ligands for the tyrosine kinase receptor PDGFR alpha. Analysis of Pdgfc null mice has demonstrated roles for PDGF-C in palate closure and the formation of cerebral ventricles, but redundancy with other PDGFR alpha ligands might obscure additional functions. In search of further developmental roles for PDGF-C, we generated mice that were double mutants for Pdgfc(-/-) and Pdgfra(GFP/+). These mice display a range of severe phenotypes including spina bifida, lung emphysema, abnormal meninges and neuronal over-migration in the cerebral cortex. We focused our analysis on the central nervous system (CNS), where PDGF-C was identified as a critical factor for the formation of meninges and assembly of the glia limitans basement membrane. We also present expression data on Pdgfa, Pdgfc and Pdgfra in the cerebral cortex and microarray data on cerebral meninges.

  • 34. Andre, Kadri
    et al.
    Kampman, Olli
    Illi, Ari
    Viikki, Merja
    Setala-Soikkeli, Eija
    Mononen, Nina
    Lehtimaki, Terho
    Haraldsson, Susann
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Koivisto, Pasi A.
    Leinonen, Esa
    SERT and NET polymorphisms, temperament and antidepressant response2015Inngår i: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 69, nr 7, 531-538 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The genetic variations in norepinephrine transporter (NET) and serotonin transporter (SERT) genes have been associated with personality traits, several psychiatric disorders and the efficacy of antidepressant treatment. Aims: We investigated the separate effects and possible interactions between NET T-182C (rs2242446) and SERT 5-HTTLPR (rs4795541) polymorphisms on selective serotonin reuptake inhibitors (SSRI) treatment response and temperamental traits assessed by the Temperament and Character Inventory (TCI) in a clinical sample of subjects with major depressive disorder (MDD). Methods: Our sample of 97 patients with major depression completed the 107-item TCI temperament questionnaire (version IX) at the initial assessment of the study and after 6 weeks of follow-up. All subjects received selective SSRI medications. Temperament dimension scores at baseline (1) and endpoint (2) during antidepressant treatment were analyzed between NET and SERT genotypes. Results: SS-genotype of 5-HTTLPR was associated with higher baseline Persistence scores than SL- or LL-genotype. A corresponding but weaker association was found at endpoint. No differences were found between 5-HTTLPR genotypes and other temperament dimensions and 5-HTTLPR genotypes had no effect on treatment response. Conclusions: Our results suggest that the SS-genotype of 5-HTTLPR is associated with Persistence scores in patients with MDD. Higher Persistence could be viewed as a negative trait when recovering from stress and its association with short and "weaker" S-allele may be related to less efficient serotonin neurotransmission, possibly resulting in less effective coping strategies on a behavioral level.

  • 35. Antoni, Gunnar
    et al.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Hall, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Molecular Imaging of Transporters with Positron Emission Tomography2009Inngår i: Transporters as Targets for Drugs, Berlin: Springer, 2009, Vol. 4, 155-186 s.Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Positron emission tomography (PET) visualization of brain components in vivo is a rapidly growing field. Molecular imaging with PET is also increasingly used in drug development, especially for the determination of drug receptor interaction for CNS-active drugs. This gives the opportunity to relate clinical efficacy to per cent receptor occupancy of a drug on a certain targeted receptor and to relate drug pharmacokinetics in plasma to interaction with target protein. In the present review we will focus on the study of transporters, such as the monoamine transporters, the P-glycoprotein (Pgp) transporter, the vesicular monoamine transporter type 2, and the glucose transporter using PET radioligands. Neurotransmitter transporters are presynaptically located and in vivo imaging using PET can therefore be used for the determination of the density of afferent neurons. Several promising PET ligands for the noradrenaline transporter (NET) have been labeled and evaluated in vivo including in man, but a really useful PET ligand for NET still remains to be identified. The most promising tracer to date is (S,S)-[18F]FMeNER-D2. The in vivo visualization of the dopamine transporter (DAT) may give clues in the evaluation of conditions related to dopamine, such as Parkinson's disease and drug abuse. The first PET radioligands based on cocaine were not selective, but more recently several selective tracers such as [11C]PE2I have been characterized and shown to be suitable as PET radioligands. Although there are a large number of serotonin transporter inhibitors used today as SSRIs, it was not until very recently, when [11C]McN5652 was synthesized, that this transporter was studied using PET. New candidates as PET radioligands for the SERT have subsequently been developed and [11C]DASB and [11C]MADAM and their analogues are today the most promising ligands. The existing radioligands for Pgp transporters seem to be suitable tools for the study of both peripheral and central drug–Pgp interactions, although [11C]verapamil and [18F]fluoropaclitaxel are probably restricted to use in studies of the blood–brain barrier. The vesicular monoamine transporter 2 (VMAT2) is another interesting target for diagnostic imaging and [11C]DTBZ is a promising tracer. The noninvasive imaging of transporter density as a function of disease progression or availability following interaction with blocking drugs is highlighted, including the impact on both development of new therapies and the process of developing new drugs. Although CNS-related work focusing on psychiatric disorders is the main focus of this review, other applications of PET ligands, such as diagnosis of cancer, diabetes research, and drug interactions with efflux systems, are also discussed. The use of PET especially in terms of tracer development is briefly described. Finally, it can be concluded that there is an urgent need for new, selective radioligands for the study of the transporter systems in the human brain using PET.

  • 36. Arab, Khelifa
    et al.
    Park, Yoon Jung
    Lindroth, Anders M.
    Schaefer, Andrea
    Oakes, Christopher
    Weichenhan, Dieter
    Lukanova, Annekatrin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Risch, Angela
    Meister, Michael
    Dienemann, Hendrik
    Dyckhoff, Gerhard
    Herold-Mende, Christel
    Grummt, Ingrid
    Niehrs, Christof
    Plass, Christoph
    Long Noncoding RNA TARID Directs Demethylation and Activation of the Tumor Suppressor TCF21 via GADD45A2014Inngår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 55, nr 4, 604-614 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.

  • 37. Arenz, Stefan
    et al.
    Abdelshahid, Maha
    Sohmen, Daniel
    Payoe, Roshani
    Starosta, Agata L.
    Berninghausen, Otto
    Hauryliuk, Vasili
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). University of Tartu, Institute of Technology, Tartu, Estonia.
    Beckmann, Roland
    Wilson, Daniel N.
    The stringent factor RelA adopts an open conformation on the ribosome to stimulate ppGpp synthesis2016Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, nr 13, 6471-6481 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Under stress conditions, such as nutrient starvation, deacylated tRNAs bound within the ribosomal A-site are recognized by the stringent factor RelA, which converts ATP and GTP/GDP to (p)ppGpp. The signaling molecules (p) ppGpp globally rewire the cellular transcriptional program and general metabolism, leading to stress adaptation. Despite the additional importance of the stringent response for regulation of bacterial virulence, antibiotic resistance and persistence, structural insight into how the ribosome and deacylated-tRNA stimulate RelA-mediated (p)ppGpp has been lacking. Here, we present a cryo-EM structure of RelA in complex with the Escherichia coli 70S ribosome with an average resolution of 3.7 angstrom and local resolution of 4 to > 10 angstrom for RelA. The structure reveals that RelA adopts a unique 'open' conformation, where the C-terminal domain (CTD) is intertwined around an A/T-like tRNA within the intersubunit cavity of the ribosome and the N-terminal domain (NTD) extends into the solvent. We propose that the open conformation of RelA on the ribosome relieves the autoinhibitory effect of the CTD on the NTD, thus leading to stimulation of (p)ppGpp synthesis by RelA.

  • 38.
    Armulik, Annika
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Studies on the transmembrane signaling of β1 integrins2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Integrins are heterodimeric cell surface receptors, composed of an α and a β subunit, mainly binding for extracellular matrix proteins. lntegrin subunit β1 can combine with at least 12 a subunits and thus form the biggest subfamily within the integrin family. In this thesis, functional properties of the splice variant β1Β, and the effects of several mutations in the cytoplasmic tail of integrin subunit β1Α were studied. In addition, the border between the transmembrane and cytoplasmic domains of several integrin subunits was determined.

    The β1Β splice variant has been reported to have a dominant negative effect on functions of β1Α integrins. In this study, it was studied if the expression of β1Β had similar negative effects on the αvβ3 integrin functions since the β3 subunit is structurally similar to β1Α. The β1Β subunit was expressed in an integrin β1-deficient cell line and it was found that the presence of β1Β does not interfere with adhesion or signaling of endogenous αvβ3

    The border between the cytoplasmic domain and the C-terminal end of the transmembrane domain of integrin α and β subunits has been unclear. This question was experimentally addressed for integrin subunits β1, β2, α2 and α5. It was found that integrin subunits contain a positively charged lysine, which is embedded in the membrane in the absence of interacting proteins.

    The functional importance of the lysine in integrin transmembrane domains was investigated by mutating this amino acid to leucine in β1Α. The mutation affected cell spreading and tyrosine phosphorylation of the adapter protein CAS. The activation of focal adhesion kinase and tyrosine phosphorylation of paxillin was not affected. Furthermore, the mutation of two tyrosines to phenylalanines in the β1Α cytoplasmic tail was found to reduce the capability of β1Α integrins to mediate cell spreading and migration. Activation of focal adhesion kinase in response to the later β1Α mutant was shown to be impaired as well as tyrosine phosphorylation of adapter proteins paxillin and tensin whereas overall tyrosine phosphorylation of CAS was unaffected. These data suggests the presence of focal adhesion kinase-dependent and -independent pathways for tyrosine phosphorylation of CAS after integrin β1Α-mediated adhesion.

  • 39.
    Ashri, Nadia Y.
    et al.
    Najd Consulting Hosp, Riyadh, Saudi Arabia..
    Abdel-Rehim, Mohamed
    Karlstads universitet, Fakulteten för teknik- och naturvetenskap, Avdelningen för kemi och biomedicinsk vetenskap. AstraZeneca R&D Sodertalje, Clin Pharmacol, SE-15185 Sodertalje, Sweden.;AstraZeneca R&D Sodertalje, DMPK, SE-15185 Sodertalje, Sweden.;Karlstad Univ, Dept Chem & Biomed Sci, SE-65188 Karlstad, Sweden.;Stockholm Univ, Dept Analyt Chem, SE-10691 Stockholm, Sweden..
    Sample treatment based on extraction techniques in biological matrices2011Inngår i: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 3, nr 17, 2003-2018 s.Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The importance of sample preparation methods as the first stage in bioanalysis is described. In this article, the sample preparation concept and strategies will be discussed, along with the requirements for good sample preparation. The most widely used sample preparation methods in the pharmaceutical industry are presented; for example, the need for same-day rotation of results from large numbers of biological samples in pharmaceutical industry makes high throughput bioanalysis more essential. In this article, high-throughput sample preparation techniques are presented; examples are given of the extraction and concentration of analytes from biological matrices, including protein precipitation, solid-phase extraction, liquid-liquid extraction and microextraction-related techniques. Finally, the potential role of selective extraction methods, including molecular imprinted phases, is considered.

  • 40.
    Asif, Sana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Ekdahl, Kristina N
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Fromell, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Gustafson, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Barnkirurgi.
    Barbu, Andreea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Le Bland, Katarina
    Nilsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Teramura, Yuji
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes2016Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 35, 194-205 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival.

  • 41.
    Asper, M.
    et al.
    Charles River Biopharmaceut Serv GmbH, D-51105 Cologne, Germany..
    Hanrieder, T.
    Charles River Biopharmaceut Serv GmbH, D-51105 Cologne, Germany..
    Quellmalz, Arne
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Mihranyan, Albert
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Removal of xenotropic murine leukemia virus by nanocellulose based filter paper2015Inngår i: Biologicals (Print), ISSN 1045-1056, E-ISSN 1095-8320, Vol. 43, nr 6, 452-456 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The removal of xenotrpic murine leukemia virus (xMuLV) by size-exclusion filter paper composed of 100% naturally derived cellulose was validated. The filter paper was produced using cellulose nanofibers derived from Cladophora sp. algae. The filter paper was characterized using atomic force microscopy, scanning electron microscopy, helium pycnometry, and model tracer (100 nm latex beads and 50 nm gold nanoparticles) retention tests. Following the filtration of xMuLV spiked solutions, LRV >= 5.25 log(10) TCID50 was observed, as limited by the virus titre in the feed solution and sensitivity of the tissue infectivity test. The results of the validation study suggest that the nanocellulose filter paper is useful for removal of endogenous rodent retroviruses and retrovirus-like particles during the production of recombinant proteins.

  • 42.
    Assadi, Ghazaleh
    et al.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden .
    Vesterlund, Liselotte
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Bonfiglio, Ferdinando
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Mazzurana, Luca
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Cordeddu, Lina
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Schepis, Danika
    Rheumatology unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden .
    Mjösberg, Jenny
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden .
    Ruhrmann, Sabrina
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fabbri, Alessia
    Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy .
    Vukojevic, Vladana
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Percipalle, Piergiorgio
    Biology Program, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Salomons, Florian A.
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Laurencikiene, Jurga
    Lipid laboratory, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Törkvist, Leif
    Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden .
    Halfvarson, Jonas
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Gastroenterology.
    D'Amato, Mauro
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioDonostia Health Research Institute, San Sebastian and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain .
    Functional Analyses of the Crohn's Disease Risk Gene LACC12016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 12, e0168276Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Genetic variation in the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene has been shown to affect the risk of Crohn's disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression.

    Methods: We implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function.

    Results: FAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems.

    Conclusion: FAMIN is a peroxisome-associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated.

  • 43. Assi, Nada
    et al.
    Fages, Anne
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Stepien, Magdalena
    Duarte-Salles, Talita
    Byrnes, Graham
    Boumaza, Houda
    Knueppel, Sven
    Kuehn, Tilman
    Palli, Domenico
    Bamia, Christina
    Boshuizen, Hendriek
    Bonet, Catalina
    Overvad, Kim
    Johansson, Mattias
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Travis, Ruth
    Gunter, Marc J.
    Lund, Eiliv
    Dossus, Laure
    Elena-Herrmann, Benedicte
    Riboli, Elio
    Jenab, Mazda
    Viallon, Vivian
    Ferrari, Pietro
    A statistical framework to model the meeting-in-the-middle principle using metabolomic data: application to hepatocellular carcinoma in the EPIC study2015Inngår i: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 30, nr 6, 743-753 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metabolomics is a potentially powerful tool for identification of biomarkers associated with lifestyle exposures and risk of various diseases. This is the rationale of the 'meeting-in-the-middle' concept, for which an analytical framework was developed in this study. In a nested case-control study on hepatocellular carcinoma (HCC) within the European Prospective Investigation into Cancer and nutrition (EPIC), serum H-1 nuclear magnetic resonance (NMR) spectra (800 MHz) were acquired for 114 cases and 222 matched controls. Through partial least square (PLS) analysis, 21 lifestyle variables (the 'predictors', including information on diet, anthropometry and clinical characteristics) were linked to a set of 285 metabolic variables (the 'responses'). The three resulting scores were related to HCC risk by means of conditional logistic regressions. The first PLS factor was not associated with HCC risk. The second PLS metabolomic factor was positively associated with tyrosine and glucose, and was related to a significantly increased HCC risk with OR = 1.11 (95% CI: 1.02, 1.22, P = 0.02) for a 1SD change in the responses score, and a similar association was found for the corresponding lifestyle component of the factor. The third PLS lifestyle factor was associated with lifetime alcohol consumption, hepatitis and smoking, and had negative loadings on vegetables intake. Its metabolomic counterpart displayed positive loadings on ethanol, glutamate and phenylalanine. These factors were positively and statistically significantly associated with HCC risk, with 1.37 (1.05, 1.79, P = 0.02) and 1.22 (1.04, 1.44, P = 0.01), respectively. Evidence of mediation was found in both the second and third PLS factors, where the metabolomic signals mediated the relation between the lifestyle component and HCC outcome. This study devised a way to bridge lifestyle variables to HCC risk through NMR metabolomics data. This implementation of the 'meeting-in-the-middle' approach finds natural applications in settings characterised by high-dimensional data, increasingly frequent in the omics generation.

  • 44.
    Atikuzzaman, Mohammad
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Sanz, Libia
    Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
    Pla, Davinia
    Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
    Alvarez-Rodriguez, Manuel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Rubér, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Wright, Dominic
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Calvete, Juan J.
    Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Selection for higher fertility reflects in the seminal fluid proteome of modern domestic chicken2017Inngår i: Comparative Biochemistry and Physiology - Part D: Genomics and Proteomics, ISSN 1744-117X, E-ISSN 1878-0407, Vol. 21, 27-40 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The high egg-laying capacity of the modern domestic chicken (i.e. White Leghorn, WL) has arisen from the low egg-laying ancestor Red Junglefowl (RJF) via continuous trait selection and breeding. To investigate whether this long-term selection impacted the seminal fluid (SF)-proteome, 2DE electrophoresis-based proteomic analyses and immunoassays were conducted to map SF-proteins/cytokines in RJF, WL and a 9th generation Advanced Intercross Line (AIL) of RJF/WL-L13, including individual SF (n = 4, from each RJF, WL and AIL groups) and pools of the SF from 15 males of each group, analyzed by 2DE to determine their degree of intra-group (AIL, WL, and RJF) variability using Principal Component Analysis (PCA); respectively an inter-breed comparative analysis of intergroup fold change of specific SF protein spots intensity between breeds. The PCA clearly highlighted a clear intra-group similarity among individual roosters as well as a clear inter-group variability (e.g. between RJF, WL and AIL) validating the use of pools to minimize confounding individual variation. Protein expression varied considerably for processes related to sperm motility, nutrition, transport and survival in the female, including signaling towards immunomodulation. The major conserved SF-proteins were serum albumin and ovotransferrin. Aspartate aminotransferase, annexin A5, arginosuccinate synthase, glutathione S-transferase 2 and l-lactate dehydrogenase-A were RJF-specific. Glyceraldehyde-3-phosphate dehydrogenase appeared specific to the WL-SF while angiotensin-converting enzyme, γ-enolase, coagulation factor IX, fibrinogen α-chain, hemoglobin subunit α-D, lysozyme C, phosphoglycerate kinase, Src-substrate protein p85, tubulins and thioredoxin were AIL-specific. The RJF-SF contained fewer immune system process proteins and lower amounts of the anti-inflammatory/immunomodulatory TGF-β2 compared to WL and AIL, which had low levels- or lacked pro-inflammatory CXCL10 compared to RJF. The seminal fluid proteome differs between ancestor and modern chicken, with a clear enrichment of proteins and peptides related to immune-modulation for sperm survival in the female and fertility.

    Fulltekst tilgjengelig fra 2017-11-03 13:41
  • 45. Augestad, Ingrid Lovise
    et al.
    Nyman, Axel Karl Gottfrid
    Costa, Alex Ignatius
    Barnett, Susan Carol
    Sandvig, Axel
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Haberg, Asta Kristine
    Sandvig, Ioanna
    Effects of Neural Stem Cell and Olfactory Ensheathing Cell Co-transplants on Tissue Remodelling After Transient Focal Cerebral Ischemia in the Adult Rat2017Inngår i: Neurochemical Research, ISSN 0364-3190, E-ISSN 1573-6903, Vol. 42, nr 6, 1599-1609 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Effective transplant-mediated repair of ischemic brain lesions entails extensive tissue remodeling, especially in the ischemic core. Neural stem cells (NSCs) are promising reparative candidates for stroke induced lesions, however, their survival and integration with the host-tissue post-transplantation is poor. In this study, we address this challenge by testing whether co-grafting of NSCs with olfactory ensheathing cells (OECs), a special type of glia with proven neuroprotective, immunomodulatory, and angiogenic effects, can promote graft survival and host tissue remodelling. Transient focal cerebral ischemia was induced in adult rats by a 60-min middle cerebral artery occlusion (MCAo) followed by reperfusion. Ischemic lesions were verified by neurological testing and magnetic resonance imaging. Transplantation into the globus pallidus of NSCs alone or in combination with OECs was performed at two weeks post-MCAo, followed by histological analyses at three weeks post-transplantation. We found evidence of extensive vascular remodelling in the ischemic core as well as evidence of NSC motility away from the graft and into the infarct border in severely lesioned animals co-grafted with OECs. These findings support a possible role of OECs as part of an in situ tissue engineering paradigm for transplant mediated repair of ischemic brain lesions.

  • 46.
    Axner, Ove
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Andersson, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Björnham, Oscar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Castelain, Mickaël
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Klinth, Jeanna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Koutris, Efstratios
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Schedin, Staffan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Assessing bacterial adhesion on an individual adhesin and single pili level using optical tweezers 2011Inngår i: Bacterial adhesion: chemistry, biology and physics / [ed] D. Line and A. Goldman, Berlin: Springer Berlin/Heidelberg, 2011, 301-313 s.Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Optical tweezers (OT) are a technique that, by focused laser light, can both manipulate micrometer sized objects and measure minute forces (in the pN range) in biological systems. The technique is therefore suitable for assessment of bacterial adhesion on an individual adhesin-receptor and single attachment organelle (pili) level. This chapter summarizes the use of OT for assessment of adhesion mechanisms of both non-piliated and piliated bacteria. The latter include the important helix-like pili expressed by uropathogenic Escherichia coli (UPEC), which have shown to have unique and intricate biomechanical properties. It is conjectured that the large flexibility of this type of pili allows for a redistribution of an external shear force among several pili, thereby extending the adhesion lifetime of bacteria. Systems with helix-like adhesion organelles may therefore act as dynamic biomechanical machineries, enhancing the ability of bacteria to withstand high shear forces originating from rinsing flows such as in the urinary tract. This implies that pili constitute an important virulence factor and a possible target for future anti-microbial drugs.

  • 47. Azuaje, Jhonny
    et al.
    Carbajales, Carlos
    Gonzalez-Gomez, Manuel
    Coelho, Alberto
    Caamano, Olga
    Gutierrez-de-Teran, Hugo
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Sotelo, Eddy
    Pyrazin-2(1H)-ones as a novel class of selective A3 adenosine receptor antagonists2015Inngår i: Future Medicinal Chemistry, ISSN 1756-8919, E-ISSN 1756-8927, Vol. 7, nr 11, 1373-1380 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: A(3)AR antagonists are promising drug candidates as neuroprotective agents as well as for the treatment of inflammation or glaucoma. The most widely known A(3)AR antagonists are derived from polyheteroaromatic scaffolds, which usually show poor pharmacokinetic properties. Accordingly, the identification of structurally simple A(3)AR antagonists by the exploration of novel diversity spaces is a challenging goal. Results: A convergent and efficient Ugi-based multicomponent approach enabled the discovery of pyrazin-2(1H)-ones as a novel class of A(3)AR antagonists. A combined experimental/computational strategy accelerated the establishment of the most salient features of the structure-activity and structure-selectivity relationships in this series. Conclusion: The optimization process provided pyrazin-2(1H)-ones with improved affinity and a plausible hypothesis regarding their binding modes was proposed.

  • 48.
    Baars, Louise
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Protein targeting, translocation and insertion in Escherichia coli: Proteomic analysis of substrate-pathway relationships2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Approximately 10% of the open reading frames in the genome of the Gram-negative bacterium E. coli encodes secretory proteins, and 20% encodes integral inner membrane proteins (IMPs). These proteins are sorted to their correct cellular compartments (the periplasm and the outer and inner membranes) by specialized targeting and translocation/insertion systems. So far, a very limited set of model proteins have been used to study proteins sorting requirements in E. coli. The main objective of all the papers presented in this thesis was to determine the targeting and translocation/insertion requirements of more E. coli proteins. In papers I and II, this was done using focused approaches. Selected model proteins (lipoproteins and putative outer membrane proteins) were expressed from plasmids and their targeting and translocation were analysed in vitro by crosslinking experiments and/or in vivo by pulse-chase analysis in different E. coli mutant strains. In papers III a comparative sub-proteome analysis was carried out to define the role of the cytoplasmic chaperone SecB in protein targeting. In paper IV, a similar approach was used to study how protein translocation and insertion is affected upon depletion of the essential Sec-translocon component SecE. The ‘global’ approach used in paper III and IV allowed us to study protein targeting and translocation/insertion requirements on a proteome level. This led to the identification of several novel SecB substrates and a large number of potential Sec-translocon independent IMPs.

  • 49. Backly, R. E.
    et al.
    Todeschi, M. R.
    Varghese, Oommen
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Hilborn, Jöns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Cancedda, R.
    Mastrogiacomo, M.
    Host cell recruitment patterns by BMP-2 releasing hyaluronic acid gels in a mouse subcutaneous model2014Inngår i: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 8, 65-65 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 50.
    Baeza, Gabriela
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    X-ray Crystallographic Structure of theMurine Norovirus protease at 1.66 Å Resolutionand Functional Studies of the β-ribbon2011Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    In humans, noroviruses (NVs) cause acute epidemic and viral gastroenteritis. NVs do not only infect humans; viruseshave also been found in pigs, cows, sheep, mice and dogs. The focus in this project has been on the murine norovirus(MNV). MNV is a member of the viral family Caliciviridae and it consists of a single-stranded, positive sense RNAgenome. The genome includes three open reading frames (ORFs), ORF1 encodes for a polyprotein that consists of theprecursor to the 6-7 non-structural (NS) proteins. The polyprotein is cleaved by the NS6 protease. The NS6 isresponsible for all the cleaving in ORF1 and that makes it an attractive target for antiviral drugs. The NS6 proteinstructure has been determined at 1.66 Å resolution using X-ray diffraction techniques. Surprisingly, the electrondensity map revealed density for a peptide bound in the active site. The peptide had a length of 7 residues andoriginated from the C-terminus of another chain in an adjacent asymmetric unit. The active site triad was composed ofthe conserved residues; histidine 30, aspargine 54 and cysteine 139, however in the structure the cysteine 139 ismutated to an alanine to inactivate the protease. Activity assays were performed to probe the importance of the residuein position 109 in the β-ribbon located close to the active site. The three full-length constructs with the mutations;I109A, I109S and I109T were found to have less activity than the full-length wt (1-183). A truncated protease, lacking9 residues in the C-terminus, also had less activity. This indicates that the terminal residues are also important foractivity.

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