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  • 51.
    Akkuratov, Evgeny E.
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab. St Petersburg State Univ, Inst Translat Biomed, St Petersburg, Russia.
    Gelfand, Mikhail S.
    Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Moscow, Russia.;Russian Acad Sci, Inst Informat Transmiss Problems, Moscow, Russia.;Natl Res Univ, Higher Sch Econ, Fac Comp Sci, Moscow, Russia.;MM Lomonosov Moscow State Univ, Dept Bioengn & Bioinformat, Moscow, Russia..
    Khrameeva, Ekaterina E.
    Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Moscow, Russia.;Russian Acad Sci, Inst Informat Transmiss Problems, Moscow, Russia..
    Neanderthal and Denisovan ancestry in Papuans: A functional study2018Inngår i: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 16, nr 2, artikkel-id 1840011Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sequencing of complete nuclear genomes of Neanderthal and Denisovan stimulated studies about their relationship with modern humans demonstrating, in particular, that DNA alleles from both Neanderthal and Denisovan genomes are present in genomes of modern humans. The Papuan genome is a unique object because it contains both Neanderthal and Denisovan alleles. Here, we have shown that the Papuan genomes contain different gene functional groups inherited from each of the ancient people. The Papuan genomes demonstrate a relative prevalence of Neanderthal alleles in genes responsible for the regulation of transcription and neurogenesis. The enrichment of specific functional groups with Denisovan alleles is less pronounced; these groups are responsible for bone and tissue remodeling. This analysis shows that introgression of alleles from Neanderthals and Denisovans to Papuans occurred independently and retention of these alleles may carry specific adaptive advantages.

  • 52.
    Aksoy, N. H.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi. Aksaray Univ, Dept Biochem, Aksaray, Turkey..
    Mannervik, B.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Inhibitory effects of ethacrynic acid on glutathione S-transferase A1-1 from Callithrix jacchus2015Inngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 282, s. 348-348Artikkel i tidsskrift (Annet vitenskapelig)
  • 53.
    Alam, Athar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Golovliov, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Javed, Eram
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Kumar, Rajender
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Dissociation between the critical role of ClpB of Francisella tularensis for the heat shock response and the DnaK interaction and its important role for efficient type VI secretion and bacterial virulence2020Inngår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 16, nr 4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Author summary Type VI secretion systems (T6SSs) are essential virulence determinants of many Gram-negative pathogens, including Francisella tularensis. This highly virulent bacterium encodes an atypical T6SS lacking ClpV, the ATPase crucial for prototypic T6SS sheath disassembly. It, however, possesses ClpB, a protein critical for heat shock survival via its interaction with DnaK. Since ClpB possesses ATPase activity, it has been hypothesized to provide a compensatory function for the absence of ClpV, a hypothesis supported by the recent findings from us and others. Here, we investigated how F. tularensis ClpB controls T6S. In silico modelling of the ClpB-DnaK complex identified key interactions that were experimentally verified. For example, mutating one of the DnaK-interacting residues rendered the bacterium exquisitely susceptible to heat shock, but had no effect on T6S and virulence. In contrast, removing the N-terminal of ClpB only had a slight effect on the heat shock response, but strongly compromised both T6S and virulence. Intriguingly, the Escherichia coli ClpB could fully complement the function of F. tularensis ClpB. The data demonstrate that the two critical roles of ClpB, mediating heat shock survival and effective T6S, are dissociated and that the N-terminal is crucial for T6S and virulence.

    Fulltekst (pdf)
    fulltext
  • 54.
    Alanentalo, Tomas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Optical projection tomography based 3D-spatial and quantitative assessments of the diabetic pancreas2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The gastrointestinal tract comprises a number of digestive organs including the stomach and pancreas. The stomach is involved in the digestion and short term storage of food while the pancreas is a mixed endocrine and exocrine gland which provides the body with hormones and enzymes essential for nutritional utilisation. The pancreas consists of three different cell lineages, acinar, ductal and endocrine cells. The endocrine cells, organised in the islets of Langerhans, are scattered throughout the exocrine parenchyma and regulate blood glucose levels by production of hormones such as glucagon and insulin.

    The Nkx family of homeodomain proteins controls numerous processes during development. Previous studies have identified two members belonging to the Nkx6 subfamily of Nkx proteins, Nkx6.1 and Nkx6.2. We have described the cloning and embryonic expression pattern of Nkx6.3. All three members of the Nkx6 gene family were shown to be expressed in partially overlapping domains during the development of the gastrointestinal tract and the central nervous system. Nkx6.2 was also identified as a transient marker for pancreatic exocrine cells.

    Analysing gene expression patterns and morphological features in tissues and organs is often performed by stereologic sampling which is a labour-intensive two dimensional approach that rely on certain assumptions when calculating e.g. β-cell mass and islet number in the pancreas. By combined improvements in immunohistochemical protocols, computational processing and tomographic scanning, we have developed a methodology based on optical projection tomography (OPT) allowing for 3D visualisation and quantification of specifically labelled objects within intact adult mouse organs. In the pancreas, this technique allows for spatial and quantitative measurements of total islet number and β-cell mass. We have further developed a protocol allowing for high resolution regional analyses based on global OPT assessments of the pancreatic constitution. This methodology is likely to facilitate detailed cellular and molecular analysis of user defined regions of interest in the pancreas, at the same time providing information on the overall disease state of the gland.

    Type 1 diabetes mellitus (T1D) can occur at any age and is characterized by the marked inability of the pancreas to secrete insulin due to an autoimmune destruction of the insulin producing β-cells. Information on the key cellular and molecular events underlying the recruitment of lymphocytes, their infiltration of the islets of Langerhans and consequent β-cell destruction is essential for understanding the pathogenesis of T1D. Using the developed methodology we have recorded the spatial and quantitative distribution of islet β-cells and infiltrating lymphocytes in the non obese diabetic (NOD) mouse model for T1D. This study shows that the smaller islets, which are predominantly organised in the periphery of the organ, are the first to disappear during the progression of T1D. The larger islets appear more resistant and our data suggest that a compensatory proliferative process is going on side by side with the autoimmune-induced β-cell destruction. Further, the formation of structures resembling tertiary lymphoid organs (TLOs) in areas apparently unaffected by insulitis suggests that local factors may provide cues for the homing of these lymphocytes back to the pancreas.

    Fulltekst (pdf)
    FULLTEXT01
  • 55.
    Al-Bayati, Omar
    Högskolan i Skövde, Institutionen för biovetenskap. Baghdad university.
    Optimizing the Fluorescence In situ hybridization technique for a more rapid inspection of Sepsis causative pathogens by employing DNA probes2014Independent thesis Advanced level (degree of Master (One Year)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Abstract

    Sepsis is a serious clinical condition that is characterized by a systemic inflammatory response syndrome resulting from a known or suspected infection. The major clinical symptoms involve an abnormal WBC count, elevated body temperature, respiration and pulse rate. Reported cases with high mortality rate range between 13 - 20 million. In order to treat Sepsis, the detection of bacteria in blood culture is extremely crucial. Treating patients with broad spectrum antibiotics is usually related to adverse effects, drug resistance, increased mortality, and high cost. In the past decades, researches had detected that E. coli and S. aureus are the major role players that cause sepsis. These microbes are molecularly tested by methods like MALDI TOF, FISH and Microarrays.  

    In this analysis, DNA fluorescence in situ hybridization (FISH) assessment for the identification of S. aureus, one of the most frequent blood pathogens, was optimized in the labs of Högskolan i Skövde. As a result, the growth of S. aureus was observed very carefully, optimizing the FISH procedure for gram positive bacteria was done and the sensitivity, stability and specificity of the DNA probe were examined under variant conditions like the continuous decrease in the bacteria cells number and utilizing a mixture of different types of bacteria cells. 

    Fulltekst (pdf)
    Omar Al-Bayati thesis project
  • 56. Al-Behadili, Ali
    et al.
    Uhler, Jay P.
    Berglund, Anna-Karin
    Peter, Bradley
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Reyes, Aurelio
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zeviani, Massimo
    Falkenberg, Maria
    A two-nuclease pathway involving RNase H1 is required for primer removal at human mitochondrial OriL2018Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, nr 18, s. 9471-9483Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of Ribonuclease H1 (RNase H1) during primer removal and ligation at the mitochondrial origin of light-strand DNA synthesis (OriL) is a key, yet poorly understood, step in mitochondrial DNA maintenance. Here, we reconstitute the replication cycle of L-strand synthesis in vitro using recombinant mitochondrial proteins and model OriL substrates. The process begins with initiation of DNA replication at OriL and ends with primer removal and ligation. We find that RNase H1 partially removes the primer, leaving behind the last one to three ribonucleotides. These 5′-end ribonucleotides disturb ligation, a conclusion which is supported by analysis of RNase H1-deficient patient cells. A second nuclease is therefore required to remove the last ribonucleotides and we demonstrate that Flap endonuclease 1 (FEN1) can execute this function in vitro. Removal of RNA primers at OriL thus depends on a two-nuclease model, which in addition to RNase H1 requires FEN1 or a FEN1-like activity. These findings define the role of RNase H1 at OriL and help to explain the pathogenic consequences of disease causing mutations in RNase H1.

    Fulltekst (pdf)
    fulltext
  • 57.
    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, E-ISSN 1643-3750, Vol. 15, nr 2, s. BR47-BR54Artikkel 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.

    Fulltekst (pdf)
    fulltext
  • 58.
    Albertsson, Ann-Christine
    et al.
    KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknologi.
    Edlund, Ulrica
    KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknologi.
    Wood hydrolysates: From fractions to products2015Inngår i: Abstracts of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 249Artikkel i tidsskrift (Annet vitenskapelig)
  • 59.
    Albertsson, Ann-Christine
    et al.
    KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknik.
    Voepel, Jens
    KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknik.
    Edlund, Ulrica
    KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknik.
    Dahlman, Olof
    Soderqvist-Lindblad, Margaretha
    Design of Renewable Hydrogel Release Systems from Fiberboard Mill Wastewater2010Inngår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 11, nr 5, s. 1406-1411Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A new route for the design of renewable hydrogels is presented. The soluble waste from masonite production was isolated, fractionized, and upgraded. The resulting hemicellulose rich fraction was alkenyl-functionalized and used in the preparation of covalently cross-linked hydrogels capable of sustained release of incorporated agents. Said hydrogels showed a Fickian diffusion-based release of incorporated bovine serum albumin. Also, a method for the coating of seeds with hydrogel was developed. The sustained release of incorporated growth retardant agents from the hydrogel coating on rape seeds was shown to enable the temporary inhibition of germination.

  • 60.
    Alderborn, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Sundström, Jens
    Soeria-Atmadja, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sandberg, Martin
    Andersson, H. Christer
    Hammerling, Ulf
    Genetically modified plants for non-food or non-feed purposes: straightforward screening for their appearance in food and feed2010Inngår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 48, nr 2, s. 453-464Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetically modified (GM) plants aimed at producing food/feed are part of regular agriculture in many areas of the World. Commodity plants have also found application as bioreactors, designated non-food/non-feed GM (NFGM) plants, thereby making raw material for further refinement to industrial, diagnostic or pharmaceutical preparations. Many among them may pose health challenge to consumers or livestock animals, if occurring in food/feed. NFGM plants are typically released into the environment, but are grown under special oversight and any among several containment practices, none of which provide full protection against accidental dispersal. Adventitious admixture with food or feed can occur either through distributional mismanagement or as a consequence of gene flow to plant relatives. To facilitate NFGM surveillance we propose a new mandatory tagging of essentially all such plants, prior to cultivation or marketing in the European Union. The suggested tag--Plant-Made Industrial or Pharmaceutical Products Tag (PMIP-T)--is envisaged to occur as a transgenic silent DNA identifier in host plants and designed to enable technically simple identification and characterisation of any NFGM. Implementation of PMIP-T would permit inexpensive, reliable and high-throughput screening for NFGM specifically. The paper outlines key NFGM prospects and challenges as well as the PMIP-T concept.

  • 61.
    Aleckovic, Ehlimana
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Andersson, Linnea
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Chamoun, Sherley
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Einarsson, Ellen
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Ekstedt, Ebba
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Eriksen, Emma
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Madan-Andersson, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Method Development for Determining the Stability of Heat Stable Proteins Combined with Biophysical Characterization of Human Calmodulin and the Disease Associated Variant D130G2016Independent thesis Basic level (degree of Bachelor), 10,5 poäng / 16 hpOppgave
    Abstract [en]

    Calmodulin is a highly conserved calcium ion binding protein expressed in all eukaryotic species. The 149 amino acid residues in the primary structure are organized in seven α helices with the highly flexible central α helix connecting the two non-cooperative domains of calmodulin. Each domain contains two EF-hand motifs to which calcium ions bind in a cooperative manner, hence the binding of four calcium ions saturate one calmodulin molecule. In the cardiovascular area calmodulin is involved in the activation of cardiac muscle contraction, and mutations that arise in the genetic sequence of the protein often have severe consequences. One such consequential mutation that can arise brings about the replacement of the highly conserved aspartic acid with glycine at position 130 in the amino acid sequence. In this research, the thermal and chemical stability within the C domain of the D130G variant of human calmodulin was investigated using a new method only requiring circular dichroism spectroscopic measurements. Affinity studies within the C domain of the D130G variant of human calmodulin were performed using fluorescence spectroscopy, and the ligands chosen for this purpose were trifluoperazine and p- HTMI. All analytical experiments were performed with the C domain of wild type human calmodulin as a reference. From the new method, it was concluded that the C domain of the D130G variant of human calmodulin has a slightly decreased stability in terms of Tm and Cm values compared to the C domain of wild type human calmodulin. The affinity analyses indicated that neither trifluoperazine nor p-HTMI discriminates between the C domain of the D130G variant of human calmodulin and the C domain of wild type human calmodulin in terms of dissociation constants. The pivotal outcome from this research is that the new method is applicable for determination of the stability parameters Tm and Cm of heat stable proteins. 

    Fulltekst (pdf)
    fulltext
  • 62. Alekeyenko, Artyom A.
    et al.
    Ho, Joshua W. K.
    Peng, Shouyong
    Gelbart, Marnie
    Tolstorukov, Michael Y.
    Plachetka, Annette
    Kharchenko, Peter V.
    Jung, Youngsook L.
    Gorchakov, Andrey A.
    Larschan, Erica
    Gu, Tingting
    Minoda, Aki
    Riddle, Nicole C.
    Schwartz, Yuri B.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Elgin, Sarah C. R.
    Karpen, Gary H.
    Pirrotta, Vincenzo
    Kuroda, Mitzi I.
    Park, Peter J.
    Sequence-Specific Targeting of Dosage Compensation in Drosophila Favors an Active Chromatin Context2012Inngår i: PLoS Genetics, ISSN 1553-7390, Vol. 8, nr 4, s. e1002646-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Drosophila MSL complex mediates dosage compensation by increasing transcription of the single X chromosome in males approximately two-fold. This is accomplished through recognition of the X chromosome and subsequent acetylation of histone H4K16 on X-linked genes. Initial binding to the X is thought to occur at "entry sites" that contain a consensus sequence motif ("MSL recognition element" or MRE). However, this motif is only similar to 2 fold enriched on X, and only a fraction of the motifs on X are initially targeted. Here we ask whether chromatin context could distinguish between utilized and non-utilized copies of the motif, by comparing their relative enrichment for histone modifications and chromosomal proteins mapped in the modENCODE project. Through a comparative analysis of the chromatin features in male S2 cells (which contain MSL complex) and female Kc cells (which lack the complex), we find that the presence of active chromatin modifications, together with an elevated local GC content in the surrounding sequences, has strong predictive value for functional MSL entry sites, independent of MSL binding. We tested these sites for function in Kc cells by RNAi knockdown of Sxl, resulting in induction of MSL complex. We show that ectopic MSL expression in Kc cells leads to H4K16 acetylation around these sites and a relative increase in X chromosome transcription. Collectively, our results support a model in which a pre-existing active chromatin environment, coincident with H3K36me3, contributes to MSL entry site selection. The consequences of MSL targeting of the male X chromosome include increase in nucleosome lability, enrichment for H4K16 acetylation and JIL-1 kinase, and depletion of linker histone H1 on active X-linked genes. Our analysis can serve as a model for identifying chromatin and local sequence features that may contribute to selection of functional protein binding sites in the genome.

    Fulltekst (pdf)
    fulltext
  • 63.
    Alenius, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå University.
    Bohm, Staffan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Identification of a novel neural cell adhesion molecule-related gene with a potential role in selective axonal projection1997Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 272, nr 42, s. 26083-26086Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We describe here the cloning of mouse complementary DNAs encoding a novel protein, Rb-8 neural cell adhesion molecule (RNCAM), with a predicted extracellular region of five immunoglobulin Ca-type domains followed by two fibronectin type III domains, Alternative splicing is likely to generate two RNCAM isoforms, which are differently attached to the cell membrane, These structural features and overall sequence identity identify this protein as a novel member of a cell adhesion molecule subgroup together with vertebrate neural cell adhesion molecule, Aplysia cell adhesion molecule, and Drosophila fasciclin II, In insects, fasciclin II is present on a restricted subset of embryonic central nervous system axons where it controls selective axon fasciculation. Intriguingly, RNCAM likewise is expressed in subsets of olfactory and vomeronasal neurons with topographically defined axonal projections, The spatial expression RNCAM corresponds precisely to that of certain odorant receptor expression zones of the olfactory epithelium. These expression patterns thus render RNCAM the first described cell adhesion molecule with a potential regulatory role in formation of selective axonal projections important for olfactory sensory information coding.

  • 64.
    Alexander, Helen K.
    et al.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Booy, Evan P.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. 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
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba,.
    Los, Marek Jan
    Department of Human Anatomy and Cell Science, University of 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, Vol. 55, nr 3, s. 139-149Artikkel, forskningsoversikt (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.

  • 65.
    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, s. 139-149Artikkel 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.

    Fulltekst (pdf)
    fulltext
  • 66.
    Alexandre, Campos
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Apraiz, Itzaso
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    da Fonseca, Rute R
    The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Shotgun analysis of the marine mussel Mytilus edulis hemolymph proteome and mapping the innate immunity elements.2015Inngår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 15, nr 23-24, s. 4021-4029Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The marine mussel innate immunity provides protection to pathogen invasion and inflammation.In this regard, the mussel hemolymph takes a main role in the animal innate response.Despite the importance of this body fluid in determining the physiological condition of theanimal, little is known about the molecular mechanisms underlying the cellular and humoralresponses. In this work, we have applied aMS (nano-LC-MS/MS) strategy integrating genomicand transcriptomic data with the aim to: (i) identify the main protein functional groups thatcharacterize hemolymph and (ii) to map the elements of innate immunity in the marine musselMytilus edulis hemolymph proteome. After sample analysis and first protein identificationbased onMS/MS data comparison, proteins with unknown functions were annotated with blastusing public database (nrNCBI) information. Overall 595 hemolymph proteins were identifiedwith high confidence and annotated. These proteins encompass primary cellular metabolicprocesses: energy production and metabolism of biomolecules, as well as processes related tooxidative stress defence, xenobiotic detoxification, drug metabolism, and immune response.A group of proteins was identified with putative immune effector, receptor, and signalingfunctions in M. edulis. Data are available via ProteomeXchange with identifier PXD001951(http://proteomecentral.proteomexchange.org/dataset/PXD001951).

    Fulltekst (pdf)
    fulltext
  • 67.
    Alexeyenko, Andrey
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lee, Woojoo
    Pernemalm, Maria
    Guegan, Justin
    Dessen, Philippe
    Lazar, Vladimir
    Lehtio, Janne
    Pawitan, Yudi
    Network enrichment analysis: extension of gene-set enrichment analysis to gene networks2012Inngår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 13, s. 226-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Gene-set enrichment analyses (GEA or GSEA) are commonly used for biological characterization of an experimental gene-set. This is done by finding known functional categories, such as pathways or Gene Ontology terms, that are over-represented in the experimental set; the assessment is based on an overlap statistic. Rich biological information in terms of gene interaction network is now widely available, but this topological information is not used by GEA, so there is a need for methods that exploit this type of information in high-throughput data analysis. Results: We developed a method of network enrichment analysis (NEA) that extends the overlap statistic in GEA to network links between genes in the experimental set and those in the functional categories. For the crucial step in statistical inference, we developed a fast network randomization algorithm in order to obtain the distribution of any network statistic under the null hypothesis of no association between an experimental gene-set and a functional category. We illustrate the NEA method using gene and protein expression data from a lung cancer study. Conclusions: The results indicate that the NEA method is more powerful than the traditional GEA, primarily because the relationships between gene sets were more strongly captured by network connectivity rather than by simple overlaps.

  • 68.
    Alexeyenko, Andrey
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Schmitt, Thomas
    Tjärnberg, Andreas
    Stockholm University, Science for Life Laboratory.
    Guala, Dmitri
    Stockholm University, Science for Life Laboratory.
    Frings, Oliver
    Stockholm University, Science for Life Laboratory.
    Sonnhammer, Erik L. L.
    Stockholm University, Science for Life Laboratory.
    Comparative interactomics with Funcoup 2.02012Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, nr D1, s. D821-D828Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    FunCoup (http://FunCoup.sbc.su.se) is a database that maintains and visualizes global gene/protein networks of functional coupling that have been constructed by Bayesian integration of diverse high-throughput data. FunCoup achieves high coverage by orthology-based integration of data sources from different model organisms and from different platforms. We here present release 2.0 in which the data sources have been updated and the methodology has been refined. It contains a new data type Genetic Interaction, and three new species: chicken, dog and zebra fish. As FunCoup extensively transfers functional coupling information between species, the new input datasets have considerably improved both coverage and quality of the networks. The number of high-confidence network links has increased dramatically. For instance, the human network has more than eight times as many links above confidence 0.5 as the previous release. FunCoup provides facilities for analysing the conservation of subnetworks in multiple species. We here explain how to do comparative interactomics on the FunCoup website.

  • 69.
    Alexis, Laura
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    Alftrén, Ida
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    Elvmarker, Josefin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    Mach, Klara-Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    Nyman, Rebecca
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    DETEKTERA MERA!: - En studie av LigandTracer® och andra vanliga detektionstekniker för interaktion inom antikroppsutveckling2013Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Ridgeview Instruments AB är ett företag, med säte i Uppsala, som bland annat utvecklar mjukvara för detektionsanalys och detektionsinstrumenten LigandTracer®. Instrumenten detekterar cellinteraktioner i realtid och tillhandahåller information om hur interaktion mellan undersökt ligand och receptor sker. LigandTracer® används bland annat vid cancerstudier och affinitetsstudier av antikroppsinbindning till antigener på celler.

     

    LigandTracer® och teknologin bakom den har studerats för att hitta de främsta styrkorna samt utvecklingsområden i jämförelse med andra detektionstekniker. Dessa tekniker är surface plasmon resonance, BioLayer Interferometry, quartz crystal microbalance samt surface acoustic wave. Främsta styrkan hos detektion med LigandTracer® är att stor mängd data som beskriver interaktionerna erhålls. Information av denna typ är viktig för att få en helhetsbild av cellers ytprotein. Därför kan instrumenten exempelvis användas som kvalitetssäkrande steg i antikroppsprocessen. LigandTracer® kan även användas för studier av hela celler och vävnader. Utöver detta finns styrkor som minimerar det laborativa arbetet, så som tvättar i prepareringssteg. Detta gör att både tid och reagens sparas.

     

    En utvecklingsmöjlighet för LigandTracer® är egenskapen att kunna detektera fler antikroppar och cellinjer samtidigt. Då mjukvaran TraceDrawer™ är ett viktigt tillbehör för utvärderingen av detektionen, skulle utveckling med avseende på celldynamiken och receptorernas rörelsemönster kunna förbättra instrumenten ytterligare.

    Fulltekst (pdf)
    Detektera mera!
  • 70.
    Alfirevic, Ana
    et al.
    University of Liverpool, UK.
    Gonzalez-Galarza, Faviel
    University of Liverpool, UK.
    Bell, Catherine
    University of Liverpool, UK.
    Martinsson, Klara
    University of Liverpool, UK.
    Platt, Vivien
    University of Liverpool, UK.
    Bretland, Giovanna
    University of Liverpool, UK.
    Evely, Jane
    University of Liverpool, UK.
    Lichtenfels, Maike
    University of Liverpool, UK.
    Cederbrant, Karin
    Safety Assessment, AstraZeneca, Gartuna, Södertälje, Sweden.
    French, Neil
    University of Liverpool, UK.
    Naisbitt, Dean
    University of Liverpool, UK.
    Park, B Kevin
    University of Liverpool, UK.
    Jones, Andrew R
    University of Liverpool, UK.
    Pirmohamed, Munir
    University of Liverpool, UK.
    In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers2012Inngår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 4, nr 6, artikkel-id 51Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Recently, genome-wide association studies have identified a number of human leukocyte antigen (HLA) alleles associated with DILI; however, the cellular and chemical mechanisms are not fully understood.

    METHODS: To study these mechanisms, we established an HLA-typed cell archive from 400 healthy volunteers. In addition, we utilized HLA genotype data from more than four million individuals from publicly accessible repositories such as the Allele Frequency Net Database, Major Histocompatibility Complex Database and Immune Epitope Database to study the HLA alleles associated with DILI. We utilized novel in silico strategies to examine HLA haplotype relationships among the alleles associated with DILI by using bioinformatics tools such as NetMHCpan, PyPop, GraphViz, PHYLIP and TreeView.

    RESULTS: We demonstrated that many of the alleles that have been associated with liver injury induced by structurally diverse drugs (flucloxacillin, co-amoxiclav, ximelagatran, lapatinib, lumiracoxib) reside on common HLA haplotypes, which were present in populations of diverse ethnicity.

    CONCLUSIONS: Our bioinformatic analysis indicates that there may be a connection between the different HLA alleles associated with DILI caused by therapeutically and structurally different drugs, possibly through peptide binding of one of the HLA alleles that defines the causal haplotype. Further functional work, together with next-generation sequencing techniques, will be needed to define the causal alleles associated with DILI.

    Fulltekst (pdf)
    fulltext
  • 71.
    Alfredsson Timmins, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Functional organisation of the cell nucleus in the fission yeast, Schizosaccharomyces pombe2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In eukaryotes the genome adopts a non-random spatial organisation, which is important for gene regulation. However, very little is known about the driving forces behind nuclear organisation. In the simple model eukaryote fission yeast, Schizosaccharomyces pombe, it has been known for a long time that transcriptionally repressed heterochromatin localise to the nuclear membrane (NM); the centromeres attaches to spindle pole body (SPB), while the telomeres are positioned at the NM on the opposite side of the nucleus compared to the SPB. Studies presented in this thesis aimed at advancing our knowledge of nuclear organisation in Schizosaccharomyces pombe.

    We show that the heterochromatic mating-type region localises to the NM in the vicinity of the SPB. This positioning was completely dependent on Clr4, a histone methyl transferase crucial for the formation of heterochromatin. Additional factors important for localisation were also identified: the chromo domain protein Swi6, and the two boundary elements IR-L and IR-R surrounding this locus. We further identify two other chromo domain proteins; Chp1 and Chp2, as crucial factors for correct subnuclear localisation of this region. From these results we suggest that the boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

    Gene regulation can affect the subnuclear localisation of genes. Using nitrogen starvation in S. pombe as a model for gene induction we determined the subnuclear localisation of two gene clusters repressed by nitrogen: Chr1 and Tel1. When repressed these loci localise to the NM, and this positioning is dependent on the histone deacetylase Clr3. During induction the gene clusters moved towards the nuclear interior in a transcription dependent manner.

    The knowledge gained from work presented in this thesis, regarding nuclear organisation in the S. pombe model system, can hopefully aid to a better understanding of human nuclear organisation.

    Fulltekst (pdf)
    FULLTEXT01
  • 72.
    Al-Furoukh, Natalie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ianni, Alessandro
    Nolte, Hendrik
    Hölper, Soraya
    Krüger, Marcus
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Braun, Thomas
    ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells2015Inngår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1853, nr 10, s. 2580-2591Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Proteostasis is crucial for life and maintained by cellular chaperones and proteases. One major mitochondrial protease is the ClpXP complex, which is comprised of a catalytic ClpX subunit and a proteolytic ClpP subunit. Based on two separate observations, we hypothesized that ClpX may play a leading role in the cellular function of ClpXP. Therefore, we analyzed the effect of ClpX overexpression on a myoblast proteome by quantitative proteomics. ClpX overexpression results in the upregulation of markers of the mitochondria( proteostasis pathway, known as the "mitochondrial unfolded protein response" (UPRmt). Although this pathway is described in detail in Caenorhabditis elegans, it is not clear whether it is conserved in mammals. Therefore, we compared features of the classical nematode UPRmt with our mammalian ClpX-triggered UPRmt dataset. We show that they share the same retrograde mitochondria-to-nucleus signaling pathway that involves the key UPRmt transcription factor CHOP (also known as Ddit3, CEBPZ or GADD153). In conclusion, our data confirm the existence of a mammalian UPRmt that has great similarity to the C elegans pathway. Furthermore, our results illustrate that ClpX overexpression is a good and simple model to study the underlying mechanisms of the UPRmt in mammalian cells.

  • 73.
    Ali, Muhammad
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Ivarsson, Ylva
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    High-throughput discovery of functional disordered regions2018Inngår i: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 14, nr 5, artikkel-id e8377Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Partially or fully intrinsically disordered proteins are widespread in eukaryotic proteomes and play important biological functions. With the recognition that well defined protein structure is not a fundamental requirement for function come novel challenges, such as assigning function to disordered regions. In their recent work, Babu and colleagues (Ravarani etal,) took on this challenge by developing IDR-Screen, a robust high-throughput approach for identifying functions of disordered regions.

  • 74. 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, E-ISSN 1471-2105, Vol. 14, nr Suppl,15, s. S12-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.

  • 75.
    Alikhani, Nyosha
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ankarcrona, Maria
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mitochondria and Alzheimer's disease: amyloid-beta peptide uptake and degradation by the presequence protease, hPreP2009Inngår i: Journal of Bioenergetics and Biomembranes, ISSN 0145-479X, E-ISSN 1573-6881, Vol. 41, nr 5, s. 447-451Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several lines of evidence suggest mitochondrial dysfunction as a possible underlying mechanism of Alzheimer's disease (AD). Accumulation of the amyloid-beta peptide (Abeta), a neurotoxic peptide implicated in the pathogenesis of AD, has been detected in brain mitochondria of AD patients and AD transgenic mouse models. In vitro evidence suggests that the Abeta causes mitochondrial dysfunction e.g. oxidative stress, mitochondrial fragmentation and decreased activity of cytochrome c oxidase and TCA cycle enzymes. Here we review the link between mitochondrial dysfunctions and AD. In particular we focus on the mechanism for Abeta uptake by mitochondria and on the recently identified Abeta degrading protease in human brain mitochondria.

  • 76.
    Alikhani, Nyosha
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Berglund, Anna-Karin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Engmann, Tanja
    Pavlov, Pavel
    Langer, Thomas
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Matrix localized AtPreP complements intermembrane space located homologue, MOP112, in Saccaromyces cerevisiaeManuskript (Annet vitenskapelig)
  • 77.
    Alikhani, Nyosha
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Berglund, Anna-Karin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Engmann, Tanja
    Spånning, Erika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Voegtle, F. -Nora
    Pavlov, Pavel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Meisinger, Chris
    Langer, Thomas
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Targeting Capacity and Conservation of PreP Homologues Localization in Mitochondria of Different Species2011Inngår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 410, nr 3, s. 400-410Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondrial presequences and other unstructured peptides are degraded inside mitochondria by presequence proteases (PrePs) identified in Arabidopsis thaliana (AtPreP), humans (hPreP), and yeast (Cym1/Mop112). The presequences of A. thaliana and human PreP are predicted to consist of 85 and 29 amino acids, respectively, whereas the Saccharomyces cerevisiae Cym1/Mop112 presequence contains only 7 residues. These differences may explain the reported targeting of homologous proteins to different mitochondrial subcompartments. Here we have investigated the targeting capacity of the PreP homologues' presequences. We have produced fusion constructs containing N-terminal portions of AtPreP(1-125), hPreP(1-69), and Cym1(1-40) coupled to green fluorescent protein (GFP) and studied their import into isolated plant, mammalian, and yeast mitochondria, followed by mitochondrial subfractionation. Whereas the AtPreP presequence has the capacity to target GFP into the mitochondrial matrix of all three species, the hPreP presequence only targets GFP to the matrix of mammalian and yeast mitochondria. The Cym1/Mop112 presequence has an overall much weaker targeting capacity and only ensures mitochondrial sorting in its host species yeast. Revisiting the submitochondrial localization of Cym1 revealed that endogenous Cym1/Mop112 is localized to the matrix space, as has been previously reported for the plant and human homologues. Moreover, complementation studies in yeast show that native AtPreP restores the growth phenotype of yeast cells lacking Cym1, demonstrating functional conservation.

  • 78.
    Alikhani, Nyosha
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Guo, Lan
    Pinho, Catarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Yan, Shi Du
    Decreased proteolytic activity of the PreP peptidasome in Alzheimer disease brain mitochondria and transgenic modelsManuskript (Annet vitenskapelig)
  • 79.
    Alikhani, Nyosha
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Guo, Lan
    Yan, Shiqiang
    Du, Heng
    Pinho, Catarina Moreira
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Chen, John Xi
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Yan, Shirley ShiDu
    Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria2011Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 27, nr 1, s. 75-87Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD.

  • 80. Alizadehheidari, Mohammadreza
    et al.
    Werner, Erik
    Noble, Charleston
    Reiter-Schad, Michaela
    Nyberg, Lena K.
    Fritzsche, Joachim
    Mehlig, Bernhard
    Tegenfeldt, Jonas O.
    Ambjornsson, Tobias
    Persson, Fredrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Westerlund, Fredrik
    Nanoconfined Circular and Linear DNA: Equilibrium Conformations and Unfolding Kinetics2015Inngår i: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 48, nr 3, s. 871-878Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studies of circular DNA confined to nanofluidic channels are relevant both from a fundamental polymer-physics perspective and due to the importance of circular DNA molecules in vivo. We here observe the unfolding of confined DNA from the circular to linear configuration as a light-induced double-strand break occurs, characterize the dynamics, and compare the equilibrium conformational statistics of linear and circular configurations. This is important because it allows us to determine to what extent existing statistical theories describe the extension of confined circular DNA. We find that the ratio of the extensions of confined linear and circular DNA configurations increases as the buffer concentration decreases. The experimental results fall between theoretical predictions for the extended de Gennes regime at weaker confinement and the Odijk regime at stronger confinement. We show that it is possible to directly distinguish between circular and linear DNA molecules by measuring the emission intensity from the DNA. Finally, we determine the rate of unfolding and show that this rate is larger for more confined DNA, possibly reflecting the corresponding larger difference in entropy between the circular and linear configurations.

  • 81.
    Alkemar, Gunnar
    et al.
    Södertörns högskola, Avdelning Naturvetenskap. Stockholm Universtiy.
    Nygård, Odd
    Södertörns högskola, Avdelning Naturvetenskap.
    A possible tertiary rRNA interaction between expansion segments ES3 and ES6 in eukaryotic 40S ribosomal subunits2003Inngår i: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 9, nr 1, s. 20-24Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Eukaryotic 16S-like ribosomal RNAs contain 12 so-called expansion segments, i.e., sequences not included in the RNA secondary structure core common to eubacteria, archaea, and eukarya. Two of these expansion segments, ES3 and ES6, are juxtaposed in the recent three-dimensional model of the eukaryotic 40S ribosomal subunit. We have analyzed ES3 and ES6 sequences from more than 2900 discrete eukaryotic species, for possible sequence complementarity between the two expansion segments. The data show that ES3 and ES6 could interact by forming a helix consisting of seven to nine contiguous base pairs in almost all analyzed species. We, therefore, suggest that ES3 and ES6 form a direct RNA-RNA contact in the ribosome.

  • 82.
    Alkemar, Gunnar
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper. Stockholm University.
    Nygård, Odd
    Södertörns högskola, Institutionen för livsvetenskaper.
    Probing the secondary structure of expansion segment ES6 in 18S ribosomal RNA2006Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 45, nr 26, s. 8067-8078Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Expansion segment ES6 in 18S ribosomal RNA is, unlike many other expansion segments, present in all eukaryotes. The available data suggest that ES6 is located on the surface of the small ribosomal subunit. Here we have analyzed the secondary structure of the complete ES6 sequence in intact ribosomes from three eukaryotes, wheat, yeast, and mouse, representing different eukaryotic kingdoms. The availability of the ES6 sequence for modification and cleavage by structure sensitive chemicals and enzymatic reagents was analyzed by primer extension and gel electrophoresis on an ABI 377 automated DNA sequencer. The experimental results were used to restrict the number of possible secondary structure models of ES6 generated by the folding software MFOLD. The modification data obtained from the three experimental organisms were very similar despite the sequence variation. Consequently, similar secondary structure models were obtained for the ES6 sequence in wheat, yeast, and mouse ribosomes. A comparison of sequence data from more than 6000 eukaryotes showed that similar structural elements could also be formed in other organisms. The comparative analysis also showed that the extent of compensatory base changes in the suggested helices was low. The in situ structure analysis was complemented by a secondary structure analysis of wheat ES6 transcribed and folded in vitro. The obtained modification data indicate that the secondary structure of the in vitro transcribed sequence differs from that observed in the intact ribosome. These results suggest that chaperones, ribosomal proteins, and/or tertiary rRNA interactions could be involved in the in vivo folding of ES6.

  • 83.
    Alkemar, Gunnar
    et al.
    Södertörns högskola, Institutionen för kemi, biologi, geografi och miljövetenskap. Stockholm University.
    Nygård, Odd
    Södertörns högskola, Institutionen för kemi, biologi, geografi och miljövetenskap.
    Secondary structure of two regions in expansion segments ES3 and ES6 with the potential of forming a tertiary interaction in eukaryotic 40S ribosomal subunits2004Inngår i: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 10, nr 3, s. 403-411Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The 18S rRNA of the small eukaryotic ribosomal subunit contains several expansion segments. Electron microscopy data indicate that two of the largest expansion segments are juxtaposed in intact 40S subunits, and data from phylogenetic sequence comparisons indicate that these two expansion segments contain complementary sequences that could form a direct tertiary interaction on the ribosome. We have investigated the secondary structure of the two expansion segments in the region around the putative tertiary interaction. Ribosomes from yeast, wheat, and mouse-three organisms representing separate eukaryotic kingdoms-were isolated, and the structure of ES3 and part of the ES6 region were analyzed using the single-strand-specific chemical reagents CMCT and DMS and the double-strand-specific ribonuclease V1. The modification patterns were analyzed by primer extension and gel electrophoresis on an ABI 377 automated DNA sequencer. The investigated sequences were relatively exposed to chemical and enzymatic modification. This is in line with their indicated location on the surface at the solvent side of the subunit. The complementary ES3 and ES6 sequences were clearly inaccessible to single-strand modification, but available for cleavage by double-strand-specific RNase V1. The results are compatible with a direct helical interaction between bases in ES3 and ES6. Almost identical results were obtained with ribosomes from the three organisms investigated.

  • 84. Allahverdiyeva, Yagut
    et al.
    Mamedov, Fikret
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström.
    Mäenpää, Pirkko
    Vass, Imre
    Aro, Eva-Mari
    Modulation of photosynthetic electron transport in the absence of terminal electron acceptors: characterization of the rbcL deletion mutant of tobacco2005Inngår i: Biochimica et Biophysica Acta (BBA) - Bioenergetics, ISSN 0005-2728, Vol. 1709, nr 1, s. 69-83Artikkel i tidsskrift (Fagfellevurdert)
  • 85. Allas, Ular
    et al.
    Toom, Lauri
    Selyutina, Anastasia
    Maeorg, Uno
    Medina, Ricardo
    Merits, Andres
    Rinken, Ago
    Hauryliuk, Vasili
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). University of Tartu, Institute of Technology, Nooruse 1, Tartu 50411, Estonia.
    Kaldalu, Niilo
    Tenson, Tanel
    Antibacterial activity of the nitrovinylfuran G1 (Furvina) and its conversion products2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 36844Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    2-Bromo-5-(2-bromo-2-nitrovinyl) furan (G1 or Furvina) is an antimicrobial with a direct reactivity against thiol groups. It is active against Gram-positive and Gram-negative bacteria, yeasts and filamentous fungi. By reacting with thiol groups it causes direct damage to proteins but, as a result, is very short-living and interconverts into an array of reaction products. Our aim was to characterize thiol reactivity of G1 and its conversion products and establish how much of antimicrobial and cytotoxic effects are due to the primary activity of G1 and how much can be attributed to its reaction products. Stability of G1 in growth media as well as its conversion in the presence of thiols was characterized. The structures of G1 decomposition products were determined using NMR and mass-spectroscopy. Concentration-and time-dependent killing curves showed that G1 is bacteriostatic for Escherichia coli at the concentration of 16 mu g/ml and bactericidal at 32 mu g/ml. However, G1 is inefficient against non-growing E. coli. Addition of cysteine to medium reduces the antimicrobial potency of G1. Nevertheless, the reaction products of G1 and cysteine enabled prolonged antimicrobial action of the drug. Therefore, the activity of 2-bromo-5-(2-bromo-2-nitrovinyl) furan is a sum of its immediate reactivity and the antibacterial effects of the conversion products.

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  • 86. Allendorf, Fred W.
    et al.
    Berry, Oliver
    Ryman, Nils
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    So long to genetic diversity, and thanks for all the fish2014Inngår i: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 23, nr 1, s. 23-25Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    The world faces a global fishing crisis. Wild marine fisheries comprise nearly 15% of all animal protein in the human diet, but, according to the U.N. Food and Agriculture Organization, nearly 60% of all commercially important marine fish stocks are overexploited, recovering, or depleted (FAO 2012; Fig. 1). Some authors have suggested that the large population sizes of harvested marine fish make even collapsed populations resistant to the loss of genetic variation by genetic drift (e. g. Beverton 1990). In contrast, others have argued that the loss of alleles because of overfishing may actually be more dramatic in large populations than in small ones (Ryman et al. 1995). In this issue, Pinsky & Palumbi (2014) report that overfished populations have approximately 2% lower heterozygosity and 12% lower allelic richness than populations that are not overfished. They also performed simulations which suggest that their estimates likely underestimate the actual loss of rare alleles by a factor of three or four. This important paper shows that the harvesting of marine fish can have genetic effects that threaten the long-term sustainability of this valuable resource.

  • 87. Allerbring, Eva B.
    et al.
    Duru, Adil D.
    Chadderton, Jesseka
    Markov, Natalia
    Uchtenhagen, Hannes
    Popov, Alexander
    Madhurantakam, Chaithanya
    Sandalova, Tatyana
    Turner, Stephen J.
    Nygren, Per-Åke
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Achour, Adnane
    Structural and thermodynamic basis underlying in vivo reestablishment of T-cell recognition of a viral escape mutant2015Inngår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 68, nr 2, s. 151-151Artikkel i tidsskrift (Annet vitenskapelig)
  • 88.
    Alling, Vanja
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för tillämpad miljövetenskap (ITM).
    Humborg, Christoph
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för tillämpad miljövetenskap (ITM).
    Mörth, Carl-Magnus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper.
    Rahm, Lars
    Polehne, Falk
    Tracing terrestrial organic matter by delta34S and delta13C signatures in a subarctic estuary2008Inngår i: Limnology and Oceanography, ISSN 0024-3590, E-ISSN 1939-5590, Vol. 53, nr 6, s. 2594-2602Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A key issue to understanding the transformations of terrestrial organic carbon in the ocean is to disentangle the latter from marine-produced organic matter. We applied a multiple stable isotope approach using 34S and 13C isotope signatures from estuarine dissolved organic matter (DOM), enabling us to constrain the contribution of terrestrial-derived DOM in an estuarine gradient of the northern Baltic Sea. The stable isotope signatures for dissolved organic sulfur (34SDOS) have twice the range between terrestrial and marine end members compared to the stable isotope signatures for dissolved organic carbon (13CDOC); hence, the share of terrestrial DOM in the total estuarine DOM can be calculated more precisely. DOM samples from the water column were collected using ultrafiltration on board the German RV Maria S Merian during a winter cruise, in the Bothnian Bay, Bothnian Sea, and Baltic proper. We calculated the terrestrial fraction of the estuarine DOC (DOCter) from both 13CDOC and 34SDOS signatures and applying fixed C: S ratios for riverine and marine end members to convert S isotope signatures into DOC concentrations. The 34SDOS signature of the riverine end member was +7.02‰, and the mean signatures from Bothnian Bay, Bothnian Sea, and Baltic proper were +10.27, +12.51, and +13.67‰, respectively, showing an increasing marine signal southwards (34SDOS marine end member 5 18.1‰). These signatures indicate that 87‰, 75‰, and 67‰, respectively, of the water column DOC is of terrestrial origin (DOCter) in these basins. Comparing the fractions of DOCter in each basin—that are still based on few winter values only—with the annual river input of DOC, it appears that the turnover time for DOCter in the Gulf of Bothnia is much shorter than the hydraulic turnover time, suggesting that high-latitude estuaries might be efficient sinks for DOCter.

  • 89.
    Alling, Vanja
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för tillämpad miljövetenskap (ITM).
    Sanchez-Garcia, Laura
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för tillämpad miljövetenskap (ITM).
    Porcelli, Don
    Pugach, Sveta
    Vonk, Jorien E.
    van Dongen, Bart
    Mörth, Carl-Magnus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper. Stockholms universitet, Stockholm Resilience Centre.
    Anderson, Leif G.
    Sokolov, Alexander
    Stockholms universitet, Stockholm Resilience Centre.
    Andersson, Per
    Humborg, Christoph
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för tillämpad miljövetenskap (ITM). Stockholms universitet, Stockholm Resilience Centre.
    Semiletov, Igor
    Gustafsson, Örjan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för tillämpad miljövetenskap (ITM).
    Non-conservative behavior of dissolved organic carbon across the Laptev and East Siberian Seas2010Inngår i: Global Biogeochemical Cycles, ISSN 0886-6236, E-ISSN 1944-9224, Vol. 24, s. GB4033-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Climate change is expected to have a strong effect on the Eastern Siberian Arctic Shelf (ESAS) region, which includes 40% of the Arctic shelves and comprises the Laptev and East Siberian seas. The largest organic carbon pool, the dissolved organic carbon (DOC), may change significantly due to changes in both riverine inputs and transformation rates; however, the present DOC inventories and transformation patterns are poorly understood. Using samples from the International Siberian Shelf Study 2008, this study examines for the first time DOC removal in Arctic shelf waters with residence times that range from months to years. Removals of up to 10%–20% were found in the Lena River estuary, consistent with earlier studies in this area, where surface waters were shown to have a residence time of approximately 2 months. In contrast, the DOC concentrations showed a strong nonconservative pattern in areas with freshwater residence times of several years. The average losses of DOC were estimated to be 30%–50% during mixing along the shelf, corresponding to a first-order removal rate constant of 0.3 yr−1. These data provide the first observational evidence for losses of DOC in the Arctic shelf seas, and the calculated DOC deficit reflects DOC losses that are higher than recent model estimates for the region. Overall, a large proportion of riverine DOC is removed from the surface waters across the Arctic shelves. Such significant losses must be included in models of the carbon cycle for the Arctic Ocean, especially since the breakdown of terrestrial DOC to CO2 in Arctic shelf seas may constitute a positive feedback mechanism for Arctic climate warming. These data also provide a baseline for considering the effects of future changes in carbon fluxes, as the vast northern carbon-rich permafrost areas draining into the Arctic are affected by global warming.

  • 90.
    Alm, Tove
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Introducing the Affinity Binder Knockdown Initiative-A public-private partnership for validation of affinity reagents2016Inngår i: EuPA Open Proteomics, ISSN 0014-2328, E-ISSN 2212-9685, Vol. 10, s. 56-58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The newly launched Affinity Binder Knockdown Initiative encourages antibody suppliers and users to join this public-private partnership, which uses crowdsourcing to collect characterization data on antibodies. Researchers are asked to share validation data from experiments where gene-editing techniques (such as siRNA or CRISPR) have been used to verify antibody binding. The initiative is launched under the aegis of Antibodypedia, a database designed to allow comparisons and scoring of publicly available antibodies towards human protein targets. What is known about an antibody is the foundation of the scoring and ranking system in Antibodypedia.

  • 91.
    Alm, Tove
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    von Feilitzen, Kalle
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sivertsson, Åsa
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    A Chromosome-Centric Analysis of Antibodies Directed toward the Human Proteome Using Antibodypedia2014Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, nr 3, s. 1669-1676Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Antibodies are crucial for the study of human proteins and have been defined as one of the three pillars in the human chromosome-centric Human Proteome Project (CHPP). In this article the chromosome-centric structure has been used to analyze the availability of antibodies as judged by the presence within the portal Antibodypedia, a database designed to allow comparisons and scoring of publicly available antibodies toward human protein targets. This public database displays antibody data from more than one million antibodies toward human protein targets. A summary of the content in this knowledge resource reveals that there exist more than 10 antibodies to over 70% of all the putative human genes, evenly distributed over the 24 human chromosomes. The analysis also shows that at present, less than 10% of the putative human protein-coding genes (n = 1882) predicted from the genome sequence lack antibodies, suggesting that focused efforts from the antibody-based and mass spectrometry-based proteomic communities should be encouraged to pursue the analysis of these missing proteins. We show that Antibodypedia may be used to track the development of available and validated antibodies to the individual chromosomes, and thus the database is an attractive tool to identify proteins with no or few antibodies yet generated.

  • 92.
    Alm, Tove
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Yderland, Louise
    KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Nilvebrant, Johan
    KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Halldin, Anneli
    KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Hober, Sophia
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    A small bispecific protein selected for orthogonal affinity purification2010Inngår i: BIOTECHNOL J, ISSN 1860-6768, Vol. 5, nr 6, s. 605-617Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A novel protein domain with dual affinity has been created by randomization and selection. The small alkali-stabilized albumin-binding domain (ABD(star)), used as scaffold to construct the library, has affinity to human serum albumin (HSA) and is constituted of 46 amino acids of which 11 were randomized. To achieve a dual binder, the binding site of the inherent HSA affinity was untouched and the randomization was made on the opposite side of the molecule. Despite its small size and randomization of almost a quarter of its amino acids, a bifunctional molecule, ABDz1, with ability to bind to both HSA and the Z(2) domain/protein A was successfully selected using phage display. Moreover, the newly selected variant showed improved affinity for HSA compared to the parental molecule. This novel protein domain has been characterized regarding secondary structure and affinity to the two different ligands. The possibility for affinity purification on two different matrices has been investigated using the two ligands, the HSA matrix and the protein A-based, MabSelect SuRe matrix, and the new protein domain was purified to homogeneity. Furthermore, gene fusions between the new domain and three different target proteins with different characteristics were made. To take advantage of both affinities, a purification strategy referred to as orthogonal affinity purification using two different matrices was created. Successful purification of all three versions was efficiently carried out using this strategy.

  • 93.
    Almandoz Gil, Leire
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Characterization of Physiological and Pathological Alpha-Synuclein: Implications for Parkinson’s Disease and Related Disorders2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies and Lewy neurites, intraneuronal inclusions found in the brains of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) patients (synucleinopathies). Alpha-synuclein is a presynaptic protein, which is most commonly an unfolded monomer in its physiological state. However, under pathological conditions it can start to misfold and enter an aggregation pathway that will lead to the formation of oligomers of increasing size and finally insoluble fibrils. The oligomers have been hypothesized to be the most neurotoxic species, but studies of their properties have been hindered by their heterogeneity and kinetic instability. The overall aim of this thesis was to characterize and compare physiological and pathological forms of alpha-synuclein from different sources: recombinant monomers, oligomers formed in vitro through exposure to oxidative stress related reactive aldehydes, aggregates from a synucleinopathy mouse model and from synucleinopathy patients.

    In paper I we studied the effect of low molar excess of two lipid peroxidation products, 4-oxo-2-nonenal (ONE) and 4-hydroxy-2-nonenal (HNE), on the oligomerization of alpha-synuclein. Through biophysical methods we observed that, although both aldehydes bound to alpha-synuclein directly, ONE produced SDS-stable oligomers more rapidly than HNE. Moreover, ONE induced oligomerization at both acidic and neutral pH, while HNE only formed oligomers at neutral pH.

    In paper II we mapped the surface exposed epitopes of in vitro and in vivo generated alpha-synuclein species by using immunoglobulin Y antibodies raised against short linear peptides covering most of the alpha-synuclein sequence. Monomers were found to react with most antibodies, while the latter part of the N-terminus and mid-region of HNE oligomers and fibrils was found to be occluded in oligomers and fibrils. Through immunohistochemistry we compared alpha-synuclein aggregates in brain tissue from patients with synucleinopathies as well as from a mouse model expressing A30P human alpha-synuclein. Although the exposed epitopes were found to be similar overall, subtle differences were detected in the C-terminus.

    An additional aim of this thesis was to characterize synaptic aggregates of alpha-synuclein. In paper III we obtained synaptosomal preparations of the A30P mouse model and found that a subset of the alpha-synuclein present in the synaptosomes was proteinase K resistant and therefore aggregated. Further biochemical analyses showed that the aggregated alpha-synuclein mainly was of human, i.e. transgenic, origin and that Ser 129 was not phosphorylated, which otherwise is a common post translational modification of alpha-synuclein in Lewy bodies.

    It has been suggested that alpha-synuclein plays a role in neurotransmitter release by binding to the SNARE protein VAMP-2 and thereby chaperoning the SNARE complex assembly. In paper IV we used proximity ligation assay to visualize the co-localization of alpha-synuclein and the SNARE proteins in primary neurons from non-transgenic and A30P transgenic mice.

    In conclusion, in this thesis we have characterized a variety of alpha-synuclein species and shed light on the diversity of alpha-synuclein aggregates. Additionally, we have characterized synaptic species of alpha-synuclein and analyzed the co-localization between alpha-synuclein and SNARE proteins in neurons.

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  • 94.
    Almandoz-Gil, Leire
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Welander, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Khoonsari, Payam Emami
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Musunuri, Sravani
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lendel, Christofer
    KTH Royal Inst Technol, Dept Chem, Stockholm, Sweden.
    Sigvardson, Jessica
    BioArctic AB, Stockholm, Sweden.
    Karlsson, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Corrigendum to “Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways” [Free Rad. Biol. Med. (2017) 421–431]2018Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 117, s. 258-258Artikkel i tidsskrift (Fagfellevurdert)
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  • 95.
    Almandoz-Gil, Leire
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Welander, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Khoonsari, Payam Emami
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Musunuri, Sravani
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lendel, Christofer
    KTH, Royal Institute of Technology, Sweden.
    Sigvardson, Jessica
    BioArctic AB, Sweden.
    Karlsson, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways2017Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, s. 421-431Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.

    Fulltekst (pdf)
    fulltext
  • 96.
    Almaqwashi, Ali A.
    et al.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA.;King Abdulaziz Univ, Dept Phys, Rabigh 21911, Saudi Arabia..
    Andersson, Johanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC. Chalmers, Dept Chem & Chem Engn, SE-41296 Gothenburg, Sweden..
    Lincoln, Per
    Chalmers, Dept Chem & Chem Engn, SE-41296 Gothenburg, Sweden..
    Rouzina, Ioulia
    Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA..
    Westerlund, Fredrik
    Chalmers, Dept Biol & Biol Engn, SE-41296 Gothenburg, Sweden..
    Williams, Mark C.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
    DNA intercalation optimized by two-step molecular lock mechanism2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 37993Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The diverse properties of DNA intercalators, varying in affinity and kinetics over several orders of magnitude, provide a wide range of applications for DNA-ligand assemblies. Unconventional intercalation mechanisms may exhibit high affinity and slow kinetics, properties desired for potential therapeutics. We used single-molecule force spectroscopy to probe the free energy landscape for an unconventional intercalator that binds DNA through a novel two-step mechanism in which the intermediate and final states bind DNA through the same mono-intercalating moiety. During this process, DNA undergoes significant structural rearrangements, first lengthening before relaxing to a shorter DNA-ligand complex in the intermediate state to form a molecular lock. To reach the final bound state, the molecular length must increase again as the ligand threads between disrupted DNA base pairs. This unusual binding mechanism results in an unprecedented optimized combination of high DNA binding affinity and slow kinetics, suggesting a new paradigm for rational design of DNA intercalators.

    Fulltekst (pdf)
    fulltext
  • 97. Al-Minawi, Ali Z.
    et al.
    Lee, Yin-Fai
    Håkansson, Daniel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Johansson, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Lundin, Cecilia
    Saleh-Gohari, Nasrollah
    Schultz, Niklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Jenssen, Dag
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Bryant, Helen E.
    Meuth, Mark
    Hinz, John M.
    Helleday, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    The ERCC1/XPF endonuclease is required for completion of homologous recombination at DNA replication forks stalled by inter-strand cross-links2009Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, nr 19, s. 6400-6413Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Both the ERCC1-XPF complex and the proteins involved in homoIogous recombination (HR) have critical roles in inter-strand cross-link (ICL) repair. Here, we report that mitomycin C-induced lesions inhibit replication fork elongation. Furthermore, mitomycin C-induced DNA double-strand breaks (DSBs) are the result of the collapse of ICL-stalled replication forks. These are not formed through replication run off, as we show that mitomycin C or cisplatin-induced DNA lesions are not incised by global genome nucleotide excision repair (GGR). We also suggest that ICL-lesion repair is initiated either by replication or transcription, as the GGR does not incise ICL-lesions. Furthermore, we report that RAD51 foci are induced by cisplatin or mitomycin C independently of ERCC1, but that mitomycin C-induced HR measured in a reporter construct is impaired in ERCC1-defective cells. These data suggest that ERCC1-XPF plays a role in completion of HR in ICL repair. We also find no additional sensitivity to cisplatin by siRNA co-depletion of XRCC3 and ERCC1, showing that the two proteins act on the same pathway to promote survival.

  • 98.
    Al-Minawi, Ali Z
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Saleh-Gohari, Nasrollah
    Helleday, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    The ERCC1/XPF endonuclease is required for efficient single-strand annealing and gene conversion in mammalian cells2008Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 36, nr 1, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mammalian ERCC1-XPF endonuclease has a suggested role in the repair of DNA double-strand breaks (DSB) by single-strand annealing (SSA). Here, we investigated the role of ERCC1 in homologous recombination in mammalian cells, and confirm a role of ERCC1 in SSA. Interestingly, we also report an unexpected role for ERCC1 in gene conversion. This provides support that gene conversion in mammalian somatic cells is carried out through synthesis-dependent strand annealing, rather than through a double Holliday Junction mechanism. Moreover, we find low frequencies of SSA and gene conversion in G1-arrested cells, suggesting that SSA is not a frequent DSB repair pathway in G1-arrested mammalian cells, even in the presence of perfect repeats. Furthermore, we find that SSA is not influenced by inhibition of CDK2 (using Roscovitine), ATM (using Caffeine and KU55933), Chk1 (using CEP-3891) or DNA-PK (using NU7026).

  • 99.
    Almquist, Ann-Charlotte
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi.
    Fäldt, Jenny
    KTH, Skolan för kemivetenskap (CHE), Kemi.
    Yart, A.
    Chevet, Y.
    Sauvard, D.
    Lieutier, F.
    Borg-Karlson, Anna Karin
    KTH, Skolan för kemivetenskap (CHE), Kemi.
    Host selection in Tomicus piniperda L.: Composition of monoterpene hydrocarbons in relation to attack frequency in the shoot feeding phase2006Inngår i: Zeitschrift fur Naturforschung - Section C Journal of Biosciences, ISSN 0939-5075, Vol. 61, nr 5-6, s. 439-444Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to investigate the host selection capacity of the pine shoot beetle, Tomicus piniperda, in the shoot-feeding phase and analyze the chiral and non-chiral host volatiles by means of GC-MS and 2D-GC in five Pinus species originating from France (Pinus sylvestris, P. halepensis, P. nigra laricio, P. pinaster maritima, P. pinaster mesogeensis). Dominating monoterpenes were (-)-α-pinene, (+)-α-pinene, (-)-β-pinene and (+)-3-carene. The amounts of the enantiomers varied considerably within and among the species. In a principal component analysis-plot, based on the absolute amounts of 18 monoterpene hydrocarbons, separation of the pine species into two groups was obtained. P. halepensis and P. sylvestris were grouped according to the amount of (+)-α-pinene and (+)-3-carene, while P. nigra laricio, P. pinaster maritima and P. pinaster mesogeensis were grouped according to (-)-α-pinene and (-)-β-pinene. P. nigra laricio was the species most attacked and P. halepensis the one least attacked by T. piniperda.

  • 100.
    Almstedt, Karin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Protein Misfolding in Human Diseases2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    There are several diseases well known that are due to aberrant protein folding. These types of diseases can be divided into three main categories:

    1. Loss-of-function diseases
    2. Gain-of-toxic-function diseases
    3. Infectious misfolding diseases

     

    Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to inherited mutations. The rare disease marble brain disease (MBD) also known as carbonic anhydrase II deficiency syndrome (CADS) can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. We have over the past 10-15 years studied the folding, misfolding and aggregation of the enzyme human carbonic anhydrase II. In summary our HCA II folding studies have shown that the protein folds via an intermediate of molten-globule type, which lacks enzyme activity and the molten globule state of HCA II is prone to aggregation. One mutation associated with MBD entails the His107Tyr (H107Y) substitution. We have demonstrated that the H107Y mutation is a remarkably destabilizing mutation influencing the folding behavior of HCA II. A mutational survey of position H107 and a neighboring conserved position E117 has been performed entailing the mutants H107A, H107F, H107N, E117A and the double mutants H107A/E117A and H107N/E117A. All mutants were severely destabilized versus GuHCl and heat denaturation. Thermal denaturation and GuHCl phase diagram and ANS analyses showed that the mutants shifted HCA II towards populating ensembles of intermediates of molten globule type under physiological conditions. The enormously destabilizing effects of the H107Y mutation is not due to loss of specific interactions of H107 with residue E117, instead it is caused by long range sterical destabilizing effects of the bulky tyrosine residue. We also showed that the folding equilibrium can be shifted towards the native state by binding of the small-molecule drug acetazolamide, and we present a small molecule inhibitor assessment with select sulfonamide inhibitors of varying potency to investigate the effectiveness of these molecules to inhibit the misfolding of HCA II H107Y. We also demonstrate that high concentration of the activator compound L-His increases the enzyme activity of the mutant but without stabilizing the folded protein.

     

    The infectious misfolding diseases is the smallest group of misfolding diseases. The only protein known to have the ability to be infectious is the prion protein. The human prion diseases Kuru, Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob are characterized by depositions of amyloid plaque from misfolded prion protein (HuPrP) in various regions of the brain depending on disease. Amyloidogenesis of HuPrP is hence strongly correlated with prion disease.

    Our results show that amyloid formation of recHuPrP90-231 can be achieved starting from the native protein under gentle conditions without addition of denaturant or altered pH. The process is efficiently catalyzed by addition of preformed recHuPrP90-231 amyloid seeds. It is plausible that amyloid seeding reflect the mechanism of transmissibility of prion diseases. Elucidating the mechanism of PrP amyloidogenesis is therefore of interest for strategic prevention of prion infection.

    Fulltekst (pdf)
    Protein Misfolding in Human Diseases
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