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  • 1. Ali, Raja Hashim
    et al.
    Muhammad, Sayyed Auwn
    Khan, Mehmood Alam
    Arvestad, Lars
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center, Sweden .
    Quantitative synteny scoring improves homology inference and partitioning of gene families2013In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 14, no Suppl,15, p. S12-Article in journal (Refereed)
    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.

  • 2.
    Alikhani, Nyosha
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The Mitochondrial Peptidasome, PreP, relation to Alzheimer Disease2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

  • 3.
    Andreo, Pedro
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Wulff, Joerg
    Burns, David T.
    Palmans, Hugo
    Consistency in reference radiotherapy dosimetry: resolution of an apparent conundrum when Co-60 is the reference quality for charged-particle and photon beams2013In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 58, no 19, p. 6593-6621Article in journal (Refereed)
    Abstract [en]

    Substantial changes in ion chamber perturbation correction factors in Co-60 gamma-rays, suggested by recent Monte Carlo (MC) calculations, would cause a decrease of about 1.5% in the reference dosimetry of all types of charged particles (electrons, protons and heavier ions) based on calculated k(Q) values. It has gone largely unnoticed that the ratio of calibration coefficients N-D,N-w,N-Co60 and N-K,N-air,N-Co60 yields an experimental value of F-ch,F-Co60 = (s(w-air) pch)(Co60) through N-D,N-air,N-Co60. Coefficients provided by the IAEA and traceable to the BIPM for 91 NE-2571 chambers result in an average F-ch,F-Co60 which is compared with published (and new) MC simulations and with the value in IAEA TRS-398. It is shown that TRS-398 agrees within 0.12% with the experimental F-ch,F-Co60. The 1.5% difference resulting from MC calculations (1.1% for the new simulations) cannot be justified using current fundamental data and BIPM standards if consistency in the entire dosimetry chain is sought. For photons, MC k(Q) factors are compared with TRS-398. Using the same uncertainty for W-air, the two sets of data overlap considerably. Experimental k(Q) values from standards laboratories lie between the two sets of calculated values, showing no preference for one set over the other. Observed chamber-to-chamber differences, that include the effect of waterproof sleeves (also seen for Co-60), justify the recommendation in TRS-398 for k(Q) values specifically measured for the user chamber. Current developments on I-values for the stopping powers of water and graphite are presented. A weighted average I-water = 78 +/- 2 eV is obtained from published experimental and DRF-based values; this would decrease sw-air for all types of radiotherapy beams between 0.3% and 0.6%, and would consequently decrease the MC derived F-ch,F-Co60. The implications of a recent proposal for I-graphite = 81 eV are analysed, resulting in a potential decrease of 0.7% in N-K,N-air,N-Co60 which would raise the experimental F-ch,F-Co60; this would result in an increase of about 0.8% in the current TRS-398 value when referred to the BIPM standards. MC derived F-ch,F-Co60 using new stopping powers would then agree at a level of 0.1% with the experimental value, confirming the need for consistency in the dosimetry chain data. Should world average standards be used as reference, the figures would become +0.4% for TRS-398 and -0.3% for the MC calculation. F-ch,F-Q calculated for megavoltage photons using new stopping powers would decrease by between 0.2% and 0.5%. When they enter as a ratios in k(Q), differences with MC values based on current key data would be within 0.2% but their discrepancy with k(Q) experimental photon values remains unresolved. For protons the new data would require an increase in W-air,W-Q of about 0.6%, as this is inferred from a combination of calorimetry and ionometry. This consistent scenario would leave unchanged the current TRS-398 k(Q) (NE-2571) data for protons, as well as for ions heavier than protons unless new independent W-air,W-Q values become available. Also in these advanced radiotherapy modalities, the need for maintaining data consistency in an analysis that unavoidably must include the complete dosimetry chain is demonstrated.

  • 4.
    Baars, Louise
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Protein targeting, translocation and insertion in Escherichia coli: Proteomic analysis of substrate-pathway relationships2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

  • 5.
    Bajinskis, Ainars
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Natarajan, Adayapalam T.
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    DNA double strand breaks induced by the indirect effect of radiation are more efficiently repaired by non-homologous end joining compared to homologous recombination repair2013In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 756, no 1-2, p. 21-29Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the relative involvement of three major DNA repair pathways, i.e., non-homologous end joining (NHEJ), homologous recombination (HRR) and base excision (BER) in repair of DNA lesions of different complexity induced by low- or high-LET radiation with emphasis on the contribution of the indirect effect of radiation for these radiation qualities. A panel of DNA repair-deficient CHO cell lines was irradiated by Cs-137 gamma-rays or radon progeny alpha-particles. Irradiation was also performed in the presence of 2 M DMSO to reduce the indirect effect of radiation and the complexity of the DNA damage formed. Clonogenic survival and micronucleus assays were used to estimate efficiencies of the different repair pathways for DNA damages produced by direct and indirect effects. Removal of the indirect effect of low-LET radiation by DMSO increased clonogenic survival and decreased MN formation for all cell lines investigated. A direct contribution of the indirect effect of radiation to DNA base damage was suggested by the significant protection by DMSO seen for the BER deficient cell line. Lesions formed by the indirect effect are more readily repaired by the NHEJ pathway than by HRR after irradiation with gamma-rays or alpha-particles as evaluated by cell survival and the yields of MN. The results obtained with BER- and NHEJ-deficient cells suggest that the indirect effect of radiation contributes significantly to the formation of repair substrates for these pathways.

  • 6.
    Bakali, Amin
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Herman, Maria Dolores
    Johnson, Kenneth A.
    Kelly, Amélie A.
    Wieslander, Åke
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hallberg, B. M.
    Nordlund, Pär
    Crystal structure of YegS, a homologue to the mammalian diacylglycerol kinases, reveals a novel regulatory metal binding site2007In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 282, no 27, p. 19644-19652Article in journal (Refereed)
    Abstract [en]

    The human lipid kinase family controls cell proliferation, differentiation, and tumorigenesis and includes diacylglycerol kinases, sphingosine kinases, and ceramide kinases. YegS is an Escherichia coli protein with significant sequence homology to the catalytic domain of the human lipid kinases. We have solved the crystal structure of YegS and shown that it is a lipid kinase with phosphatidylglycerol kinase activity. The crystal structure reveals a two-domain protein with significant structural similarity to a family of NAD kinases. The active site is located in the interdomain cleft formed by four conserved sequence motifs. Surprisingly, the structure reveals a novel metal binding site composed of residues conserved in most lipid kinases.

  • 7. Ball, Frank
    et al.
    Britton, Tom
    Stockholm University, Faculty of Science, Department of Mathematics.
    Sirl, David
    Household epidemic models with varying infection response2011In: Journal of Mathematical Biology, ISSN 0303-6812, E-ISSN 1432-1416, Vol. 63, no 2, p. 309-337Article in journal (Refereed)
    Abstract [en]

    This paper is concerned with SIR (susceptible -> infected -> removed) household epidemic models in which the infection response may be either mild or severe, with the type of response also affecting the infectiousness of an individual. Two different models are analysed. In the first model, the infection status of an individual is predetermined, perhaps due to partial immunity, and in the second, the infection status of an individual depends on the infection status of its infector and on whether the individual was infected by a within- or between-household contact. The first scenario may be modelled using a multitype household epidemic model, and the second scenario by a model we denote by the infector-dependent-severity household epidemic model. Large population results of the two models are derived, with the focus being on the distribution of the total numbers of mild and severe cases in a typical household, of any given size, in the event that the epidemic becomes established. The aim of the paper is to investigate whether it is possible to determine which of the two underlying explanations is causing the varying response when given final size household outbreak data containing mild and severe cases. We conduct numerical studies which show that, given data on sufficiently many households, it is generally possible to discriminate between the two models by comparing the Kullback-Leibler divergence for the two fitted models to these data.

  • 8.
    Baumgarten, Thomas
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Schlegel, Susan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wagner, Samuel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Löw, Mirjam
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Eriksson, Jonas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bonde, Ida
    Herrgård, Markus J.
    Heipieper, Hermann J.
    Nørholm, Morten H. H.
    Slotboom, Dirk Jan
    de Gier, Jan-Willem
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Isolation and characterization of the E. coli membrane protein production strain Mutant56(DE3)2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 45089Article in journal (Refereed)
    Abstract [en]

    Membrane protein production is usually toxic to E. coli. However, using genetic screens strains can be isolated in which the toxicity of membrane protein production is reduced, thereby improving production yields. Best known examples are the C41(DE3) and C43(DE3) strains, which are both derived from the T7 RNA polymerase (P)-based BL21(DE3) protein production strain. In C41(DE3) and C43(DE3) mutations lowering t7rnap expression levels result in strongly reduced T7 RNAP accumulation levels. As a consequence membrane protein production stress is alleviated in the C41(DE3) and C43(DE3) strains, thereby increasing membrane protein yields. Here, we isolated Mutant56(DE3) from BL21(DE3) using a genetic screen designed to isolate BL21(DE3)-derived strains with mutations alleviating membrane protein production stress other than the ones in C41(DE3) and C43(DE3). The defining mutation of Mutant56(DE3) changes one amino acid in its T7 RNAP, which weakens the binding of the T7 RNAP to the T7 promoter governing target gene expression rather than lowering T7 RNAP levels. For most membrane proteins tested yields in Mutant56(DE3) were considerably higher than in C41(DE3) and C43(DE3). Thus, the isolation of Mutant56(DE3) shows that the evolution of BL21(DE3) can be promoted towards further enhanced membrane protein production.

  • 9.
    Berglund, Anna-Karin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dual Targeting of Proteins to Mitochondria and Chloroplasts2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The vast majority of mitochondrial and chloroplastic proteins are nuclear encoded, synthesized in the cytosol and imported into the respective organelle using an N-terminal extension, the targeting peptide (TP). After import into the organelle, the TP is cleaved off and degraded by the Presequence protease (PreP). The import process is thought to be highly specific, however there is a group of proteins that are localised to both mitochondria and chloroplasts, using an ambiguous, dual targeting peptide (dTP). The aim of this thesis was to investigate targeting properties of dTPs. Analysis of the amino acid content of all currently known dually targeted proteins revealed that the dTPs are enriched in hydroxylated, hydrophobic and positively charged residues, lacking acidic residues, whereas the content of serine, arginine and proline is intermediary in comparison to the mitochondrial and chloroplastic TPs. dTPs do not form amphiphilic a-helices, characteristic of the mitochondrial TPs, but the helical structure can be induced in membrane mimetic environment, as revealed by spectroscopic studies of a dTP of an aminoacyl- tRNA-synthetase (aaRS). In vitro and in vivo import experiments of fusion constructs containing N-terminal truncations of seven aaRS-dTPs coupled to green fluorescent protein (GFP) demonstrated different organisation of targeting determinants showing that the N-terminal portion of dTPs was crucial for import into both organelles or at least one organelle for different constructs. In addition, studies of targeting capacity of the TPs of PreP homologues from plant, mammal and yeast (AtPreP, hPreP and Mop112) showed species dependent intra-mitochondrial localisation of the coupled GFP and demonstrated functional complementation of an intermembrane space located Mop112 with a matrix located AtPreP. The studies presented here contribute to understanding of the intracellular and intra-mitochondrial sorting process of proteins in the eukaryotic cell.

  • 10. Bestas, Burcu
    et al.
    Moreno, Pedro M. D.
    Blomberg, K. Emelie M.
    Mohammad, Dara K.
    Saleh, Amer F.
    Sutlu, Tolga
    Nordin, Joel Z.
    Guterstam, Peter
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gustafsson, Manuela O.
    Kharazi, Shabnam
    Piatosa, Barbara
    Roberts, Thomas C.
    Behlke, Mark A.
    Wood, Matthew J. A.
    Gait, Michael J.
    Lundin, Karin E.
    EL Andaloussi, Samir
    Mansson, Robert
    Berglof, Anna
    Wengel, Jesper
    Smith, C. I. Edvard
    Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 9, p. 4067-4081Article in journal (Refereed)
    Abstract [en]

    X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTKtranscripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.

  • 11.
    Bhushan, Shashi
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kuhn, Claus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berglund, Anna-Karin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Roth, Christian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The role of the N-terminal domain of chloroplast targeting peptides in organellar protein import and miss-sorting2006In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, no 16, p. 3966-3972Article in journal (Refereed)
    Abstract [en]

    We have analysed 385 mitochondrial and 567 chloroplastic signal sequences of proteins found in the organellar proteomes of Arabidopsis thaliana. Despite overall similarities, the first 16 residues of transit peptides differ remarkably. To test the hypothesis that the N-terminally truncated transit peptides would redirect chloroplastic precursor proteins to mitochondria, we studied import of the N-terminal deletion mutants of ELIP, PetC and Lhcb2.1. The results show that the deletion mutants were neither imported into chloroplasts nor miss-targeted to mitochondria in vitro and in vivo, showing that the entire transit peptide is necessary for correct targeting as well as miss-sorting.

  • 12.
    Bhushan, Shashi
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pavlov, Pavel F
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Rudhe, Charlotta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    In vitro and in vivo methods to study protein import into plant mitochondria.2007In: Methods Mol Biol, ISSN 1064-3745, Vol. 390, p. 131-50Article in journal (Refereed)
    Abstract [en]

    Plant mitochondria contain about 1000 proteins, 90-99% of which in different plant species are nuclear encoded, synthesized on cytosolic polyribosomes, and imported into the organelle. Most of the nuclear-encoded proteins are synthesized as precursors containing an N-terminal extension called a presequence or targeting peptide that directs the protein to the mitochondria. Here we describe in vitro and in vivo methods to study mitochondrial protein import in plants. In vitro synthesized precursor proteins can be imported in vitro into isolated mitochondria (single organelle import). However, missorting of chloroplast precursors in vitro into isolated mitochondria has been observed. A novel dual import system for simultaneous import of proteins into isolated mitochondria and chloroplasts followed by reisolation of the organelles is superior over the single import system as it abolishes the mistargeting. Precursor proteins can also be imported into the mitochondria in vivo using an intact cellular system. In vivo approaches include import of transiently expressed fusion constructs containing a presequence or a full-length precursor protein fused to a reporter gene, most commonly the green fluorescence protein (GFP) in protoplasts or in an Agrobacterium-mediated system in intact tobacco leaves.

  • 13. Bjorklund, Geir
    et al.
    Stejskal, Vera
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Urbina, Mauricio A.
    Dadar, Maryam
    Chirumbolo, Salvatore
    Mutter, Joachim
    Metals and Parkinson's Disease: Mechanisms and Biochemical Processes2018In: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 25, no 19, p. 2198-2214Article, review/survey (Refereed)
    Abstract [en]

    Genetic background accounts for only 5 to 10% of the reported cases of Parkinson's disease (PD), while the remaining cases are of unknown etiology. It is believed that environmental factors may be involved in the causality of a large proportion of PD cases. Several PD genes are activated by xenobiotic exposure, and a link between pesticide exposure and PD has been demonstrated. Many epidemiological studies have shown an association between PD and exposure to metals such as mercury, lead, manganese, copper, iron, aluminum, bismuth, thallium, and zinc. This review explores the biological effects, the pathogenetic processes, genetic susceptibilities to metals as well as examining future strategies for PD treatment, such as chelation therapy.

  • 14.
    Björkander, Sophia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hell, Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Johansson, Maria A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mata Forsberg, Manuel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lasaviciute, Gintare
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Roos, Stefan
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Staphylococcus aureus-derived factors induce IL-10, IFN-gamma and IL-17A-expressing FOXP3(+)CD161(+) T-helper cells in a partly monocyte-dependent manner2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 22083Article in journal (Refereed)
    Abstract [en]

    Staphylococcus aureus (S. aureus) is a human pathogen as well as a frequent colonizer of skin and mucosa. This bacterium potently activates conventional T-cells through superantigens and it is suggested to induce T-cell cytokine-production as well as to promote a regulatory phenotype in T-cells in order to avoid clearance. This study aimed to investigate how S. aureus impacts the production of regulatory and pro-inflammatory cytokines and the expression of CD161 and HELIOS by peripheral CD4(+)FOXP3(+) T-cells. Stimulation of PBMC with S. aureus 161:2-cell free supernatant (CFS) induced expression of IL-10, IFN-gamma and IL-17A in FOXP3(+) cells. Further, CD161 and HELIOS separated the FOXP3(+) cells into four distinct populations regarding cytokine-expression. Monocyte-depletion decreased S. aureus 161:2-induced activation of FOXP3(+) cells while pre-stimulation of purified monocytes with S. aureus 161:2-CFS and subsequent co-culture with autologous monocyte-depleted PBMC was sufficient to mediate activation of FOXP3(+) cells. Together, these data show that S. aureus potently induces FOXP3(+) cells and promotes a diverse phenotype with expression of regulatory and pro-inflammatory cytokines connected to increased CD161-expression. This could indicate potent regulation or a contribution of FOXP3(+) cells to inflammation and repression of immune-suppression upon encounter with S. aureus.

  • 15.
    Björklund, Asa K
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hedin, Linnea
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Quantitative assessment of the structural bias in protein-protein interaction assays.2008In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 8, no 22, p. 4657-46667Article in journal (Refereed)
    Abstract [en]

    With recent publications of several large-scale protein-protein interaction (PPI) studies, the realization of the full yeast interaction network is getting closer. Here, we have analysed several yeast protein interaction datasets to understand their strengths and weaknesses. In particular, we investigate the effect of experimental biases on some of the protein properties suggested to be enriched in highly connected proteins. Finally, we use support vector machines (SVM) to assess the contribution of these properties to protein interactivity. We find that protein abundance is the most important factor for detecting interactions in tandem affinity purifications (TAP), while it is of less importance for Yeast Two Hybrid (Y2H) screens. Consequently, sequence conservation and/or essentiality of hubs may be related to their high abundance. Further, proteins with disordered structure are over-represented in Y2H screens and in one, but not the other, large-scale TAP assay. Hence, disordered regions may be important both in transient interactions and interactions in complexes. Finally, a few domain families seem to be responsible for a large part of all interactions. Most importantly, we show that there are method-specific biases in PPI experiments. Thus, care should be taken before drawing strong conclusions based on a single dataset.

  • 16.
    Björklund, Åsa K.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Expansion of Protein Domain Repeats2006In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 2, no 8, p. 959-970Article in journal (Refereed)
    Abstract [en]

    Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not well-understood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e. g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.

  • 17. Brownstein, Catherine A.
    et al.
    Beggs, Alan H.
    Homer, Nils
    Merriman, Barry
    Yu, Timothy W.
    Flannery, Katherine C.
    DeChene, Elizabeth T.
    Towne, Meghan C.
    Savage, Sarah K.
    Price, Emily N.
    Holm, Ingrid A.
    Luquette, Lovelace J.
    Lyon, Elaine
    Majzoub, Joseph
    Neupert, Peter
    McCallie, David, Jr.
    Szolovits, Peter
    Willard, Huntington F.
    Mendelsohn, Nancy J.
    Temme, Renee
    Finkel, Richard S.
    Yum, Sabrina W.
    Medne, Livija
    Sunyaev, Shamil R.
    Adzhubey, Ivan
    Cassa, Christopher A.
    de Bakker, Paul I. W.
    Duzkale, Hatice
    Dworzynski, Piotr
    Fairbrother, William
    Francioli, Laurent
    Funke, Birgit H.
    Giovanni, Monica A.
    Handsaker, Robert E.
    Lage, Kasper
    Lebo, Matthew S.
    Lek, Monkol
    Leshchiner, Ignaty
    MacArthur, Daniel G.
    McLaughlin, Heather M.
    Murray, Michael F.
    Pers, Tune H.
    Polak, Paz P.
    Raychaudhuri, Soumya
    Rehm, Heidi L.
    Soemedi, Rachel
    Stitziel, Nathan O.
    Vestecka, Sara
    Supper, Jochen
    Gugenmus, Claudia
    Klocke, Bernward
    Hahn, Alexander
    Schubach, Max
    Menzel, Mortiz
    Biskup, Saskia
    Freisinger, Peter
    Deng, Mario
    Braun, Martin
    Perner, Sven
    Smith, Richard J. H.
    Andorf, Janeen L.
    Huang, Jian
    Ryckman, Kelli
    Sheffield, Val C.
    Stone, Edwin M.
    Bair, Thomas
    Black-Ziegelbein, E. Ann
    Braun, Terry A.
    Darbro, Benjamin
    DeLuca, Adam P.
    Kolbe, Diana L.
    Scheetz, Todd E.
    Shearer, Aiden E.
    Sompallae, Rama
    Wang, Kai
    Bassuk, Alexander G.
    Edens, Erik
    Mathews, Katherine
    Moore, Steven A.
    Shchelochkov, Oleg A.
    Trapane, Pamela
    Bossler, Aaron
    Campbell, Colleen A.
    Heusel, Jonathan W.
    Kwitek, Anne
    Maga, Tara
    Panzer, Karin
    Wassink, Thomas
    Van Daele, Douglas
    Azaiez, Hela
    Booth, Kevin
    Meyer, Nic
    Segal, Michael M.
    Williams, Marc S.
    Tromp, Gerard
    White, Peter
    Corsmeier, Donald
    Fitzgerald-Butt, Sara
    Herman, Gail
    Lamb-Thrush, Devon
    McBride, Kim L.
    Newsom, David
    Pierson, Christopher R.
    Rakowsky, Alexander T.
    Maver, Ales
    Lovrecic, Luca
    Palandacic, Anja
    Peterlin, Borut
    Torkamani, Ali
    Wedell, Anna
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Alexeyenko, Andrey
    Lindvall, Jessica M.
    Magnusson, Mans
    Nilsson, Daniel
    Stranneheim, Henrik
    Taylan, Fulya
    Gilissen, Christian
    Hoischen, Alexander
    van Bon, Bregje
    Yntema, Helger
    Nelen, Marcel
    Zhang, Weidong
    Sager, Jason
    Zhang, Lu
    Blair, Kathryn
    Kural, Deniz
    Cariaso, Michael
    Lennon, Greg G.
    Javed, Asif
    Agrawal, Saloni
    Ng, Pauline C.
    Sandhu, Komal S.
    Krishna, Shuba
    Veeramachaneni, Vamsi
    Isakov, Ofer
    Halperin, Eran
    Friedman, Eitan
    Shomron, Noam
    Glusman, Gustavo
    Roach, Jared C.
    Caballero, Juan
    Cox, Hannah C.
    Mauldin, Denise
    Ament, Seth A.
    Rowen, Lee
    Richards, Daniel R.
    San Lucas, F. Anthony
    Gonzalez-Garay, Manuel L.
    Caskey, C. Thomas
    Bai, Yu
    Huang, Ying
    Fang, Fang
    Zhang, Yan
    Wang, Zhengyuan
    Barrera, Jorge
    Garcia-Lobo, Juan M.
    Gonzalez-Lamuno, Domingo
    Llorca, Javier
    Rodriguez, Maria C.
    Varela, Ignacio
    Reese, Martin G.
    De la Vega, Francisco M.
    Kiruluta, Edward
    Cargill, Michele
    Hart, Reece K.
    Sorenson, Jon M.
    Lyon, Gholson J.
    Stevenson, David A.
    Bray, Bruce E.
    Moore, Barry M.
    Eilbeck, Karen
    Yandell, Mark
    Zhao, Hongyu
    Hou, Lin
    Chen, Xiaowei
    Yan, Xiting
    Chen, Mengjie
    Li, Cong
    Yang, Can
    Gunel, Murat
    Li, Peining
    Kong, Yong
    Alexander, Austin C.
    Albertyn, Zayed I.
    Boycott, Kym M.
    Bulman, Dennis E.
    Gordon, Paul M. K.
    Innes, A. Micheil
    Knoppers, Bartha M.
    Majewski, Jacek
    Marshall, Christian R.
    Parboosingh, Jillian S.
    Sawyer, Sarah L.
    Samuels, Mark E.
    Schwartzentruber, Jeremy
    Kohane, Isaac S.
    Margulies, David M.
    An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge2014In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, no 3, article id R53Article in journal (Refereed)
    Abstract [en]

    Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

  • 18.
    Brändén, Magnus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Electron and proton transfer in cytochrome c oxidase2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This doctoral thesis describes results from studies on the mechanisms by which the enzyme cytochrome c oxidase catalyses the reduction of oxygen to water. Cytochrome c oxidase is the last integral enzyme complex of the socalled respiratory chain in the mitochondrial inner membrane (plasma membrane of bacteria). The reaction catalysed by cytochrome c oxidase produces a charge separation across the membrane by two separate mechanisms. The protons and the electrons needed to reduce oxygen to water are supplied from different sides of the membrane, and the energy released in this reaction is used by cytochrome c oxidase to pump protons against the electro-chemical gradient across the membrane. Another integral enzyme, ATP-synthase, utilises this gradient for synthesis of ATP, which in turn is used in many of the energyrequiring processes of a cell. Cytochrome c oxidase holds four redox-active metal centres that mediate electron transfer to, and reduction of the O2-molecule. One part of the thesis concerns the rates of electron transfer as well as the redox equilibrium between the metal sites (papers II and IV).

    Since the oxygen chemistry takes place in the membrane-spanning part of the enzyme it is equipped with two proton-transfer pathways that lead from the bulk solution to the active site. A second part of the thesis concerns the location of the entry-point of one of these pathways as well as the role of this pathway during the catalytic cycle (papers I and III).

    The third part of the thesis concerns the mechanism by which the enzymecouples the O2-chemistry to proton pumping (paper V).

  • 19.
    Bäckman, Hans G
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pessoa, João
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Eneqvist, Therese
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Binding of divalent cations is essential for the activity of the organellar peptidasome in Arabidopsis thaliana, AtPreP.2009In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 583, no 17, p. 2727-33Article in journal (Refereed)
    Abstract [en]

    The dual-targeted mitochondrial and chloroplastic zinc metallooligopeptidase from Arabidopsis, AtPreP, functions as a peptidasome that degrades targeting peptides and other small unstructured peptides. In addition to Zn located in the catalytic site, AtPreP also contains two Mg-binding sites. We have investigated the role of Mg-binding using AtPreP variants, in which one or both sites were rendered unable to bind Mg(2+). Our results show that metal binding besides that of the active site is crucial for AtPreP proteolysis, particularly the inner site appears essential for normal proteolytic function. This is also supported by its evolutionary conservation among all plant species of PreP.

  • 20. Carter, Victoria
    et al.
    Underhill, Ann
    Baber, Ibrahima
    Sylla, Lakamy
    Baby, Mounirou
    Larget-Thiery, Isabelle
    Zettor, Agnès
    Bourgouin, Catherine
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Faye, Ingrid
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Otvos, Laszlo
    Wade, John D.
    Coulibaly, Mamadou B.
    Traore, Sekou F.
    Tripet, Frederic
    Eggleston, Paul
    Hurd, Hilary
    Killer bee molecules: antimicrobial peptides as effector molecules to target sporogonic stages of Plasmodium2013In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 9, no 11, article id e1003790Article in journal (Refereed)
    Abstract [en]

    A new generation of strategies is evolving that aim to block malaria transmission by employing genetically modified vectors or mosquito pathogens or symbionts that express anti-parasite molecules. Whilst transgenic technologies have advanced rapidly, there is still a paucity of effector molecules with potent anti-malaria activity whose expression does not cause detrimental effects on mosquito fitness. Our objective was to examine a wide range of antimicrobial peptides (AMPs) for their toxic effects on Plasmodium and anopheline mosquitoes. Specifically targeting early sporogonic stages, we initially screened AMPs for toxicity against a mosquito cell line and P. berghei ookinetes. Promising candidate AMPs were fed to mosquitoes to monitor adverse fitness effects, and their efficacy in blocking rodent malaria infection in Anopheles stephensi was assessed. This was followed by tests to determine their activity against P. falciparum in An. gambiae, initially using laboratory cultures to infect mosquitoes, then culminating in preliminary assays in the field using gametocytes and mosquitoes collected from the same area in Mali, West Africa. From a range of 33 molecules, six AMPs able to block Plasmodium development were identified: Anoplin, Duramycin, Mastoparan X, Melittin, TP10 and Vida3. With the exception of Anoplin and Mastoparan X, these AMPs were also toxic to an An. gambiae cell line at a concentration of 25 µM. However, when tested in mosquito blood feeds, they did not reduce mosquito longevity or egg production at concentrations of 50 µM. Peptides effective against cultured ookinetes were less effective when tested in vivo and differences in efficacy against P. berghei and P. falciparum were seen. From the range of molecules tested, the majority of effective AMPs were derived from bee/wasp venoms.

  • 21.
    Chiruvella, Kishore K.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rajaei, Naghmeh
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonna, Venkateswara Rao
    Hofer, Anders
    Åström, Stefan U.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Biochemical Characterization of Kat1: a Domesticated hAT-Transposase that Induces DNA Hairpin Formation and MAT-Switching2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 21671Article in journal (Refereed)
    Abstract [en]

    Kluyveromyces lactis hAT-transposase 1 (Kat1) generates hairpin-capped DNA double strand breaks leading to MAT-switching (MATa to MAT alpha). Using purified Kat1, we demonstrate the importance of terminal inverted repeats and subterminal repeats for its endonuclease activity. Kat1 promoted joining of the transposon end into a target DNA molecule in vitro, a biochemical feature that ties Kat1 to transposases. Gas-phase Electrophoretic Mobility Macromolecule analysis revealed that Kat1 can form hexamers when complexed with DNA. Kat1 point mutants were generated in conserved positions to explore structure-function relationships. Mutants of predicted catalytic residues abolished both DNA cleavage and strand-transfer. Interestingly, W576A predicted to be impaired for hairpin formation, was active for DNA cleavage and supported wild type levels of mating-type switching. In contrast, the conserved CXXH motif was critical for hairpin formation because Kat1 C402A/H405A completely blocked hairpinning and switching, but still generated nicks in the DNA. Mutations in the BED zinc-finger domain (C130A/C133A) resulted in an unspecific nuclease activity, presumably due to nonspecific DNA interaction. Kat1 mutants that were defective for cleavage in vitro were also defective for mating-type switching. Collectively, this study reveals Kat1 sharing extensive biochemical similarities with cut and paste transposons despite being domesticated and evolutionary diverged from active transposons.

  • 22. Clausson, Carl-Magnus
    et al.
    Arngården, Linda
    Ishaq, Omer
    Klaesson, Axel
    Kühnemund, Malte
    Grannas, Karin
    Koos, Björn
    Qian, Xiaoyan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ranefall, Petter
    Krzywkowski, Tomasz
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Brismar, Hjalmar
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wählby, Carolina
    Söderberg, Ola
    Compaction of rolling circle amplification products increases signal integrity and signal-to-noise ratio2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 12317Article in journal (Refereed)
    Abstract [en]

    Rolling circle amplification (RCA) for generation of distinct fluorescent signals in situ relies upon the self-collapsing properties of single-stranded DNA in commonly used RCA-based methods. By introducing a cross-hybridizing DNA oligonucleotide during rolling circle amplification, we demonstrate that the fluorophore-labeled RCA products (RCPs) become smaller. The reduced size of RCPs increases the local concentration of fluorophores and as a result, the signal intensity increases together with the signal-to-noise ratio. Furthermore, we have found that RCPs sometimes tend to disintegrate and may be recorded as several RCPs, a trait that is prevented with our cross-hybridizing DNA oligonucleotide. These effects generated by compaction of RCPs improve accuracy of visual as well as automated in situ analysis for RCA based methods, such as proximity ligation assays (PLA) and padlock probes.

  • 23. Czub, Joanna
    et al.
    Banas, Dariusz
    Braziewicz, Janusz
    Buraczewska, Iwona
    Jaskola, Marian
    Kazmierczak, Urszula
    Korman, Andrzej
    Lankoff, Anna
    Lisowska, Halina
    Szeflinski, Zygmunt
    Wojewodzka, Maria
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Jan Kochanowski University, Poland.
    Biological effects of mixed-ion beams. Part 1: Effect of irradiation of the CHO-K1 cells with a mixed-ion beam containing the carbon and oxygen ions2018In: Applied Radiation and Isotopes, ISSN 0969-8043, E-ISSN 1872-9800, Vol. 139, p. 304-309Article in journal (Refereed)
    Abstract [en]

    Carbon and oxygen ions were accelerated simultaneously to estimate the effect of irradiation of living cells with the two different ions. This mixed ion beam was used to irradiate the CHO-K1 cells, and a survival test was performed. The type of the effect of the mixed ion beam on the cells was determined with the isobologram method, whereby survival curves for irradiations with individual ion beams were also used. An additive effect of irradiation with the two ions was found.

  • 24. Darsalia, Vladimer
    et al.
    Mansouri, Shiva
    Ortsater, Henrik
    Olverling, Anna
    Nozadze, Nino
    Kappe, Camilla
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Tracy, Linda M.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Grankvist, Nina
    Sjöholm, Åke
    Patrone, Cesare
    Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats2012In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 122, no 9-10, p. 473-483Article in journal (Refereed)
    Abstract [en]

    Diabetes is a strong risk factor for premature and severe stroke. The GLP-IR (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto-Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 mu g/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2-4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-IR agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.

  • 25.
    Dian, Cyril
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Adaptive Responses by Transcriptional Regulators to small molecules in Prokaryotes: Structural studies of two bacterial one-component signal transduction systems DntR and HpNikR2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prokaryotes are continually exposed to variations in their environment. Survival in unstable milieu requires a wide range of transcriptional regulators (TRs) that respond to specific environmental and cellular signals by modulating gene expression and provide an appropriate physiological response to external stimuli. These adaptive responses to environmental signals are mostly mediated by TRs from one of two families: the single or the two component signal transduction systems (1CSTS; 2CSTS). In this thesis the structural analysis of two 1CSTS – DntR and NikR − are presented. One study was carried out to try to develop a bacterial biosensor for synthetic dinitrotulenes compounds, the other to characterise the Ni-sensing mechanism that contributes to the acid adaptation of the human pathogen Helicobacter pylori. DntR belongs to the LysR family and the crystal structures obtained have allowed the proposal a model of the interaction of DntR with salicylate inducer as well as giving insights into the signal propagation mechanism in LysR-type transcription factors (paper I). DntR mutant crystal structures combined with the modelling of DntR-2,4-dnt interactions led to the design of a DntR mutant that has a limited response to 2,4-dnt in a whole cell biosensor system (paper 2). Crystal structures of apo-NikR from H. pylori (HpNikR) and of Ni-bound intermediary states of the protein were obtained. The latter have helped in unravelling the Ni incorporation and selectivity mechanisms of NikRs and have shown a strong cooperativity between conformational changes in the Ni binding domain with movements of the DNA binding domain (paper 3). Biochemical studies and comparisons of the HpNikR crystal structures with those of NikR homologues strongly suggest that HpNikR has evolved different surface properties (paper 4) and a new mode of DNA binding.

  • 26. Dzintars, Eric
    et al.
    Stathakis, Sotirios
    Mavroidis, Panayiotis
    Stockholm University, Faculty of Science, Department of Physics.
    Sadeghi, Amir
    Papanikolaou, Nikos
    Performance of independent dose calculation in helical tomotherapy: implementation of the mcsim code2012In: Australasian Physical & Engineering Sciences in Medicine, ISSN 0158-9938, Vol. 35, no 4, p. 423-438Article in journal (Refereed)
    Abstract [en]

    Currently, a software-based second check dose calculation for helical tomotherapy (HT) is not available. The goal of this study is to evaluate the dose calculation accuracy of the in-house software using EGS4/MCSIM Monte Carlo environment against the treatment planning system calculations. In-house software was used to convert HT treatment plan information into a non-helical format. The MCSIM dose calculation code was evaluated by comparing point dose calculations and dose profiles against those from the HT treatment plan. Fifteen patients, representing five treatment sites, were used in this comparison. Point dose calculations between the HT treatment planning system and the EGS4/MCSIM Monte Carlo environment had percent difference values below 5 % for the majority of this study. Vertical and horizontal planar profiles also had percent difference values below 5 % for the majority of this study. Down sampling was seen to improve speed without much loss of accuracy. EGS4/MCSIM Monte Carlo environment showed good agreement with point dose measurements, compared to the HT treatment plans. Vertical and horizontal profiles also showed good agreement. Significant time saving may be obtained by down-sampling beam projections. The dose calculation accuracy of the in-house software using the MCSIM code against the treatment planning system calculations was evaluated. By comparing point doses and dose profiles, the EGS4/MCSIM Monte Carlo environment was seen to provide an accurate independent dose calculation.

  • 27. Edger, Patrick P.
    et al.
    Heidel-Fischer, Hanna M.
    Bekaert, Michael
    Rota, Jadranka
    Gloeckner, Gernot
    Platts, Adrian E.
    Heckel, David G.
    Der, Joshua P.
    Wafula, Eric K.
    Tang, Michelle
    Hofberger, Johannes A.
    Smithson, Ann
    Hall, Jocelyn C.
    Blanchette, Matthieu
    Bureau, Thomas E.
    Wright, Stephen I.
    dePamphilis, Claude W.
    Schranz, M. Eric
    Barker, Michael S.
    Conant, Gavin C.
    Wahlberg, Niklas
    Vogel, Heiko
    Pires, J. Chris
    Wheat, Christopher W.
    Stockholm University, Faculty of Science, Department of Zoology.
    The butterfly plant arms-race escalated by gene and genome duplications2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 27, p. 8362-8366Article in journal (Refereed)
    Abstract [en]

    Coevolutionary interactions are thought to have spurred the evolution of key innovations and driven the diversification of much of life on Earth. However, the genetic and evolutionary basis of the innovations that facilitate such interactions remains poorly understood. We examined the coevolutionary interactions between plants (Brassicales) and butterflies (Pieridae), and uncovered evidence for an escalating evolutionary arms-race. Although gradual changes in trait complexity appear to have been facilitated by allelic turnover, key innovations are associated with gene and genome duplications. Furthermore, we show that the origins of both chemical defenses and of molecular counter adaptations were associated with shifts in diversification rates during the arms-race. These findings provide an important connection between the origins of biodiversity, coevolution, and the role of gene and genome duplications as a substrate for novel traits.

  • 28.
    Eriksson, Olaspers Sara
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Geörg, Miriam
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sjölinder, Hong
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sillard, Rannar
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindberg, Staffan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Identification of Cell-Penetrating Peptides That Are Bactericidal to Neisseria meningitidis and Prevent Inflammatory Responses upon Infection2013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 8, p. 3704-3712Article in journal (Refereed)
    Abstract [en]

    Meningococcal disease is characterized by a fast progression and a high mortality rate. Cell-penetrating peptides (CPPs), developed as vectors for cargo delivery into eukaryotic cells, share structural features with antimicrobial peptides. A screen identified two CPPs, transportan-10 (TP10) and model amphipathic peptide (MAP), with bactericidal action against Neisseria meningitidis. Both peptides were active in human whole blood at micromolar concentrations, while hemolysis remained negligible. Additionally, TP10 exhibited significant antibacterial activity in vivo. Uptake of SYTOX green into live meningococci was observed within minutes after TP10 treatment, suggesting that TP10 may act by membrane permeabilization. Apart from its bactericidal activity, TP10 suppressed inflammatory cytokine release from macrophages infected with N. meningitidis as well as from macrophages stimulated with enterobacterial and meningococcal lipopolysaccharide (LPS). Finally, incubation with TP10 reduced the binding of LPS to macrophages. This novel endotoxin-inhibiting property of TP10, together with its antimicrobial activity in vivo, indicates the possibility to design peptide-based therapies for infectious diseases.

  • 29.
    Eriksson, Olivia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Brinne, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Zhou, Yishao
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Björkegren, Johan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tegnér, Jesper
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Deconstructing the core dynamics from a complex time-lagged regulatory biological circuit2009In: IET systems biology, ISSN 1751-8849, Vol. 3, no 2, p. 113-129Article in journal (Refereed)
    Abstract [en]

    Complex regulatory dynamics is ubiquitous in molecular networks composed of genes and proteins. Recent progress in computational biology and its application to molecular data generate a growing number of complex networks. Yet, it has been difficult to understand the governing principles of these networks beyond graphical analysis or extensive numerical simulations. Here the authors exploit several simplifying biological circumstances which thereby enable to directly detect the underlying dynamical regularities driving periodic oscillations in a dynamical nonlinear computational model of a protein-protein network. System analysis is performed using the cell cycle, a mathematically well-described complex regulatory circuit driven by external signals. By introducing an explicit time delay and using a -tearing-and-zooming- approach the authors reduce the system to a piecewise linear system with two variables that capture the dynamics of this complex network. A key step in the analysis is the identification of functional subsystems by identifying the relations between state-variables within the model. These functional subsystems are referred to as dynamical modules operating as sensitive switches in the original complex model. By using reduced mathematical representations of the subsystems the authors derive explicit conditions on how the cell cycle dynamics depends on system parameters, and can, for the first time, analyse and prove global conditions for system stability. The approach which includes utilising biological simplifying conditions, identification of dynamical modules and mathematical reduction of the model complexity may be applicable to other well-characterised biological regulatory circuits.

  • 30.
    Esbjörner, Elin K.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Oglęcka, Kamila
    Lincoln, Per
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nordén, Bengt
    Membrane binding of pH-sensitive Influenza fusion peptides. Positioning, configuration and induced leakage in lipid vesicles models2007In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 47, p. 13490-13504Article in journal (Refereed)
    Abstract [en]

    pH-sensitive HA2 fusion peptides from influenza virus hemagglutinin have potential as endosomal escape-inducing components in peptide-based drug delivery. Polarized light spectroscopy and tryptophan fluorescence were used to assess the conformation, orientation, effect on lipid order, and binding kinetics of wild-type peptide HA 1-23) and a glutamic acid-enriched analogue (INF7) in large unilamellar POPC or POPC/POPG (4:1) lipid vesicles (LUVs). pH-sensitive membrane leakage was established for INF7 but not HA2(1-23) using an entrapped-dye assay. A correlation is indicated between leakage and a low degree of lipid chain order (assessed by linear dichroism, LD, of the membrane orientation probe retinoic acid). Both peptides display poor alignment in zwitterionic POPC LUVs compared to POPC/POPG (4:1) LUVs, and it was found that peptide-lipid interactions display slow kinetics (hours), resulting in reduced lipid order and increased tryptophan shielding. At pH 7.4, INF7 displays tryptophan emission and LD features indicative of a surface-orientated peptide, suggesting that its N-terminal glutamic acid residues prevent deep penetration into the hydrocarbon core. At pH 5.0, INF7 displays weaker LD signals, indicating poor orientation, possibly due to aggregation. By contrast, the orientation of the HA2(1-23) peptide backbone supports previously reported oblique insertion (∼60-65° relative to the membrane normal), and aromatic side-chain orientations are consistent with an interfacial (pH-independent) location of the C-terminus. We propose that a conformational change upon reduction of pH is limited to minor rearrangements of the peptide "hinge region" around Trp14 and repositioning of this residue

  • 31.
    Ezzat, Kariem
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Cell-penetrating peptides; chemical modification, mechanism of uptake and formulation development2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Gene therapy holds the promise of revolutionizing the way we treat diseases. By using recombinant DNA and oligonucleotides (ONs), gene functions can be restored, altered or silenced according to the therapeutic need. However, gene therapy approaches require the delivery of large and charged nucleic acid-based molecules to their intracellular targets across the plasma membrane, which is inherently impermeable to such molecules. In this thesis, two chemically modified cell-penetrating peptides (CPPs) that have superior delivery properties for several nucleic acid-based therapeutics are developed. These CPPs can spontaneously form nanoparticles upon non-covalent complexation with the nucleic acid cargo, and the formed nanoparticles mediate efficient cellular transfection. In paper I, we show that an N-terminally stearic acid-modified version of transportan-10 (PF3) can efficiently transfect different cell types with plasmid DNA and mediates efficient gene delivery in-vivo when administrated intra muscularly (i.m.) or intradermaly (i.d.). In paper II, a new peptide with ornithine modification, PF14, is shown to efficiently deliver splice-switching oligonucleotides (SSOs) in different cell models including mdx mouse myotubes; a cell culture model of Duchenne’s muscular dystrophy (DMD). Additionally, we describe a method for incorporating the PF14-SSO nanoparticles into a solid formulation that is active and stable even when stored at elevated temperatures for several weeks. In paper III, we demonstrate the involvement of class-A scavenger receptor subtypes (SCARA3 & SCARA5) in the uptake of PF14-SSO nanoparticles, which possess negative surface charge, and suggest for the first time that some CPP-based systems function through scavenger receptors. In paper IV, the ability of PF14 to deliver siRNA to different cell lines is shown and their stability in simulated gastric acidic conditions is highlighted.

    Taken together, these results demonstrate that certain chemical modifications can drastically enhance the activity and stability of CPPs for delivering nucleic acids after spontaneous nanoparticle formation upon non-covalent complexation. Moreover, we show that CPP-based nanoparticles can be formulated into convenient and stable solid formulations that can be suitable for several therapeutic applications. Importantly, the involvement of scavenger receptors in the uptake of such nanoparticles is presented, which could yield novel possibilities to understand and improve the transfection by CPPs and other gene therapy nanoparticles.

  • 32.
    Ezzat, Kariem
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Zaghloul, Eman M.
    EL Andaloussi, Samir
    Lehto, Taavi
    Hilal, Ramy
    Magdy, Tarek
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Smith, Edvard C. I.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Solid formulation of cell-penetrating peptide nanoparticles with siRNA and their stability in simulated gastric conditions2012In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 162, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Cell-penetrating peptides (CPPs) are short cationic peptides that have been extensively studied as drug delivery vehicles for proteins, nucleic acids and nanoparticles. However, the formulation of CPP-based therapeutics into different pharmaceutical formulations and their stability in relevant biological environments have not been given the same attention. Here, we show that a newly developed CPP, PepFect 14 (PF14), forms non-covalent nanocomplexes with short interfering RNA (siRNA), which are able to elicit efficient RNA-interference (RNAi) response in different cell-lines. RNAi effect was obtained at low siRNA doses with a unique kinetic profile. Furthermore, we utilized the solid dispersion technique to formulate PF14/siRNA nanocomplexes into solid formulations that were as active as the freshly prepared nanocomplexes in solution. Importantly, the freshly prepared nanocomplexes and solid formulations were stable after incubation with simulated gastric fluid having a pH of 1.2 and containing proteolytic enzymes. These results demonstrate the activity of PF14 in delivering and protecting siRNA in different pharmaceutical forms and biological environments.

  • 33. Faxén, Kristina
    et al.
    Brzezinski, Peter
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The inside pH determines rates of electron and proton transfer in vesicle-reconstituted cytochrome c oxidase.2007In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1767, no 5, p. 381-386Article in journal (Refereed)
    Abstract [en]

    Cytochrome c oxidase is the terminal enzyme in the respiratory chains of mitochondria and many bacteria where it translocates protons across a membrane thereby maintaining an electrochemical proton gradient. Results from earlier studies on detergent-solubilized cytochrome c oxidase have shown that individual reaction steps associated with proton pumping display pH-dependent kinetics. Here, we investigated the effect of pH on the kinetics of these reaction steps with membrane-reconstituted cytochrome c oxidase such that the pH was adjusted to different values on the inside and outside of the membrane. The results show that the pH on the inside of the membrane fully determines the kinetics of internal electron transfers that are linked to proton pumping. Thus, even though proton release is rate limiting for these reaction steps (Salomonsson et al., Proc. Natl. Acad. Sci. USA, 2005, 102, 17624), the transition kinetics is insensitive to the outside pH (in the range 6–9.5).

  • 34. Ferreira, Brigida C.
    et al.
    Lopes, Maria do Carmo
    Mateus, Josefina
    Capela, Miguel
    Mavroidis, Panayiotis
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    Radiobiological evaluation of forward and inverse IMRT using different fractionations for head and neck tumours2010In: RADIAT ONCOL, ISSN 1748-717X, Vol. 5, p. 57-Article in journal (Refereed)
    Abstract [en]

    Purpose: To quantify the radiobiological advantages obtained by an Improved Forward Planning technique (IFP) and two IMRT techniques using different fractionation schemes for the irradiation of head and neck tumours. The conventional radiation therapy technique (CONVT) was used here as a benchmark. Methods: Seven patients with head and neck tumours were selected for this retrospective planning study. The PTV1 included the primary tumour, PTV2 the high risk lymph nodes and PTV3 the low risk lymph nodes. Except for the conventional technique where a maximum dose of 64.8 Gy was prescribed to the PTV1, 70.2 Gy, 59.4 Gy and 50.4 Gy were prescribed respectively to PTV1, PTV2 and PTV3. Except for IMRT2, all techniques were delivered by three sequential phases. The IFP technique used five to seven directions with a total of 15 to 21 beams. The IMRT techniques used five to nine directions and around 80 segments. The first, IMRT1, was prescribed with the conventional fractionation scheme of 1.8 Gy per fraction delivered in 39 fractions by three treatment phases. The second, IMRT2, simultaneously irradiated the PTV2 and PTV3 with 59.4 Gy and 50.4 Gy in 28 fractions, respectively, while the PTV1 was boosted with six subsequent fractions of 1.8 Gy. Tissue response was calculated using the relative seriality model and the Poisson Linear-Quadratic-Time model to simulate repopulation in the primary tumour. Results: The average probability of total tumour control increased from 38% with CONVT to 80% with IFP, to 85% with IMRT1 and 89% with IMRT2. The shorter treatment time and larger dose per fraction obtained with IMRT2 resulted in an 11% increase in the probability of control in the PTV1 with respect to IFP and 7% relatively to IMRT1 (p < 0.05). The average probability of total patient complications was reduced from 80% with CONVT to 61% with IFP and 31% with IMRT. The corresponding probability of complications in the ipsilateral parotid was 63%, 42% and 20%; in the contralateral parotid it was 50%, 20% and 9%; in the oral cavity it was 2%, 15% and 4% and in the mandible it was 1%, 5% and 3%, respectively. Conclusions: A significant improvement in treatment outcome was obtained with IMRT compared to conventional radiation therapy. The practical and biological advantages of IMRT2, employing a shorter treatment time, may outweigh the small differences obtained in the organs at risk between the two IMRT techniques. This technique is therefore presently being used in the clinic for selected patients with head and neck tumours. A significant improvement in the quality of the dose distribution was obtained with IFP compared to CONVT. Thus, this beam arrangement is used in the clinical routine as an alternative to IMRT.

  • 35. Freimann, Krista
    et al.
    Arukuusk, Piret
    Kurrikoff, Kaido
    Pärnaste, Ly
    Raid, Raivo
    Piirsoo, Andres
    Pooga, Margus
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Formulation of Stable and Homogeneous Cell-Penetrating Peptide NF55 Nanoparticles for Efficient Gene Delivery In Vivo2018In: Molecular Therapy - Nucleic Acids, ISSN 2162-2531, E-ISSN 2162-2531, Vol. 10, p. 28-35Article in journal (Refereed)
    Abstract [en]

    Although advances in genomics and experimental gene therapy have opened new possibilities for treating otherwise incurable diseases, the transduction of nucleic acids into the cells and delivery in vivo remain challenging. The high molecular weight and anionic nature of nucleic acids require their packing into nanoparticles for the delivery. The efficacy of nanoparticle drugs necessitates the high bioactivity of constituents, but their distribution in organisms is mostly governed by the physical properties of nanoparticles, and therefore, generation of stable particles with strictly defined characteristics is highly essential. Using previously designed efficient cell-penetrating peptide NF55, we searched for strategies enabling control over the nanoparticle formation and properties to further improve transfection efficacy. The size of the NF55/pDNA nanoparticles correlates with the concentration of its constituents at the beginning of assembly, but characteristics of nanoparticles measured by DLS do not reliably predict the applicability of particles in in vivo studies. We introduce a new formulation approach called cryo-concentration, where we acquired stable and homogeneous nanoparticles for administration in vivo. The cryo-concentrated NF55/pDNA nanoparticles exhibit several advantages over standard formulation: They have long shelf-life and do not aggregate after reconstitution, have excellent stability against enzymatic degradation, and show significantly higher bioactivity in vivo.

  • 36.
    Garcia Lobato Tavares, Raquel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Host cell responses to Helicobacter pylori secreted factors2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The infection of the human gastric mucosa by the bacterium Helicobacter pylori can lead to the development of gastritis, gastroduodenal ulcers, and cancer. The factors that determine disease development in a small percentage of infected individuals are still not fully understood.

    In this thesis, we aimed to identify and functionally characterize novel virulence factors of H. pylori and to understand their effect on host cell responses.

    In Paper I, we found that JHP0290, an uncharacterized secreted protein of H. pylori, induced macrophage apoptosis concomitant to the release of pro-inflammatory cytokine TNF via the regulation of the Src family of kinases and ERK MAPK pathways. In paper II, we demonstrated that JHP0290 exhibits both proliferative and anti-apoptotic activity, together with a faster progression of the cell cycle in gastric epithelial cells. During these responses, ERK MAPK and NF-κB pathways were activated. Paper III revealed a pro-apoptotic effect of another H. pylori-secreted protein HP1286 in macrophages via the TNF-independent and ERK-dependent pathways. No apoptosis was observed in HP1286-treated T cells or HL60 neutrophil-like cells, suggesting cell-type specific effect of HP1286. In Paper IV, we observed the pro-inflammatory activity of H. pylori secreted protein HP1173 in macrophages. The protein was found to induce TNF, IL-1β, and IL-8 in macrophages through MAPKs, NF-κB, and AP-1 signaling pathways. Furthermore, differential expression and release of JHP0290, HP1286, and HP1173 homologues was observed among H. pylori strains (papers II, III, IV). 

    Due to their ability to regulate multiple host cell responses, proteins JHP0290, HP1286, and HP1173 could play an important role in bacterial pathogenesis.

     

  • 37.
    Garcia-Bennett, Alfonso E.
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Konig, Niclas
    Abrahamsson, Ninnie
    Kozhevnikova, Mariya
    Zhou, Chunfang
    Trolle, Carl
    Pankratova, Stanislava
    Berezin, Vladimir
    Kozlova, Elena N.
    In vitro generation of motor neuron precursors from mouse embryonic stem cells using mesoporous nanoparticles2014In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, no 16, p. 2457-2466Article in journal (Refereed)
    Abstract [en]

    Aim: Stem cell-derived motor neurons (MNs) are utilized to develop replacement strategies for spinal cord disorders. Differentiation of embryonic stem cells into MN precursors involves factors and their repeated administration. We investigated if delivery of factors loaded into mesoporous nanoparticles could be effective for stem cell differentiation in vitro. Materials & methods: We used a mouse embryonic stem cell line expressing green fluorescent protein under the promoter for the MN-specific gene Hb9 to visualize the level of MN differentiation. The differentiation of stem cells was evaluated by expression of MN-specific transcription factors monitored by quantitative real-time PCR reactions and immunocytochemistry. Results: Mesoporous nanoparticles have strong affiliation to the embryoid bodies, penetrate inside the embryoid bodies and come in contact with differentiating cells. Conclusion: Repeated administration of soluble factors into a culture medium can be avoided due to a sustained release effect using mesoporous silica.

  • 38.
    Gilderson, Gwen
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Transmembrane proton transfer in biological systems: an investigation of bacterial and archaeal haem-copper oxidases2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Haem-copper oxidases are membrane-bound protein complexes that catalyse the reduction of dioxygen to water in the respiratory chain. These enzyme complexes are molecular machines that couple the free energy released from this reaction to pump protons across the membrane. Pumped protons as well as protons used for dioxygen reduction to water are taken up from the inside of the membrane, which contributes to maintaining an electrochemical gradient across the membrane. This gradient is used for other energy-requiring processes in the cell, among them the formation of ATP.

    This thesis focuses on the proton coupled reactions and the timing of the proton pumping events.

    Specific pathways provide rapid transfer of protons through haem-copper oxidases. Since the intermediates formed during reduction of dioxygen must rapidly and continuously be supplied with protons, the proton uptake from the outside bulk solution must be maintained at a high rate. One part of this thesis concerns the effect of altering the surrounding of the entrance of one of the proton pathways on the proton-uptake rates.

    The directionality of proton transfer through the membrane must be controlled by the enzyme to prevent the dissipation of the electrochemical gradient. A specific pump element within one of the proton pathways has been proposed to control this directionality. A part of this thesis addresses the proposed pump element.

    The timing of proton pumping, monitored using a pH sensitive dye present in the outside bulk solution, was investigated in oxidase incorporated into closed artificial membranes. The results show that proton release occurs on a millisecond-time scale. Since the results from other studies were interpreted to indicate also faster proton pumping events, it is speculated that the membrane surface plays an important role in the delay of the proton release to the bulk solution.

  • 39.
    Glaser, Elzbieta
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, Stefan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bhushan, Shashi
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Two novel mitochondrial and chloroplastic targeting-peptide-degrading peptidasomes in A. thaliana, AtPreP1 and AtPreP2.2006In: Biol Chem, ISSN 1431-6730, Vol. 387, no 10-11, p. 1441-7Article in journal (Refereed)
    Abstract [en]

    Two novel metalloendopeptidases in Arabidopsis thaliana, AtPreP1 and AtPreP2, are responsible for the degradation of targeting peptides in mitochondria and chloroplasts. Both AtPreP1 and AtPreP2 contain ambiguous targeting peptides and are dually targeted to both organelles. The proteases also have the capacity to degrade unstructured peptides of up to 65 amino acid residues, but not small proteins. The catalysis occurs in a huge catalytic chamber revealed by the crystal structure of AtPreP1 at 2.1 A. The enzymes show a preference for basic and small uncharged amino acids or serines at the cleavage sites. Despite similarities in cleavage specificities, cleavage-site recognition differs for both proteases and is context- and structure-dependent. The AtPreP1 and AtPreP2 genes are differentially expressed in Arabidopsis.

  • 40. Gordon, Amy R.
    et al.
    Karshikoff, Bianka
    Kimball, Bruce A.
    Lundström, Johan N.
    Soop, Anne
    Sorjonen, Kimmo
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, John
    Olsson, Mats J.
    The scent of disease2015In: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 40, no 3, p. 254-254Article in journal (Refereed)
    Abstract [en]

    Ability to detect diseases in conspecifics would be advantageous for the individual. In line with this, rodents avoid body odors of infected individuals. Two studies (Olsson et al. 20014; in prep.) indicated that this is possible by way of human smell and human observers. T-shirts from donors (worn for 4 hours) that had received an injection of endotoxin [0.8ng lipopolysaccharide (LPS) / kg body weight], which causes systemic inflammation, smelled more unpleasant, intense, and sick than shirts from donors that had received a placebo (Saline) injection. GC/MS analysis of the shirts suggested that the change of body odor was not due to a general increase of odorous compounds in the “sick shirts” compared to “placebo shirts” but rather to a qualitative change. Study 2 (ongoing) further investigated the nature of this perception. In a first experiment, we compared the body odor of 30 endotoxin (0.6ng LPS / kg body weight) and 21 placebo (Saline) donors. Again, body odors were sampled during 4 hours using T-shirts. Observers then smelled the shirts and rated intensity, pleasantness, and disgust. In a second experiment, urine from these donors were collected and was investigated in the same way with subjective ratings. Altogether the data suggest that systemic inflammation makes body odors more aversive within a few hours.

  • 41.
    Gurmu, Daniel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Structural Studies of Microbial Proteins - From Escherichia coli and Herpesviruses2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Structure biology concerns the study of the molecular structures of biological macromolecules, such as proteins, and how these relate to the function. Protein structures are also of importance in structure-based drug design. In this thesis, the work has been carried out in two different projects. The first project concerns structural studies of proteins from the bacterium Escherichia coli and the second of proteins from five different herpesviruses.

     The E. coli project resulted in the structural characterization of three proteins: CaiB, RibD, and YhaK. CaiB is a type-III CoA transferase involved in the metabolism of carnitine. Its molecular structure revealed a spectacular fold where two monomers were interlaced forming an interlocked dimer. RibD, a bi-functional enzyme, catalyzes two consecutive reactions during riboflavin biosynthesis. In an attempt to characterize the mechanism of action of the N-terminal reductase domain, the structure of RibD was also determined in two binary complexes with the oxidized cofactor, NADP+, and with the substrate analogue ribose-5-phosphate. YhaK is a protein of unknown function normally found in low abundance in the cytosol of E. coli and was previously annotated to be a member of the Pirin family. However, some structural features seem to distinguish YhaK from these other Pirin proteins and we showed that YhaK might be regulated by reactive oxygen species.

     The Herpesvirus project resulted in the structural determination of two proteins, the SOX protein and ORF60 from Kaposi’s sarcoma associated herpesvirus (KSHV). SOX, a bi-functional shutoff and exonuclease protein, is involved in the maturation and packaging of the viral genome into the viral capsid and in the host shutoff of cellular proteins at the mRNA level. The SOX structure was also used for modeling DNA binding. The crystallization and preliminary structural studies of ORF60, the small R2 subunit of the ribonucleotide reductase (RNR) from KSHV is also discussed.

  • 42.
    Gyllberg, Hanna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Löfgren Söderberg, Kajsa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Almeida, Ana
    Bedecs, Katarina
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Altered membrane distribution and increased Fyn activity in scrapie-infected neuronal cellsManuscript (preprint) (Other academic)
    Abstract [en]

    The suggested cause of Prion diseases is conversion of the cellular prion protein (PrPC) into aberrant scrapie prion protein (PrPSc) isoform triggered by the latter. PrPC is localized to membrane rafts, subdomains which are implicated in conversion. In this report we have analyzed the expression, plasma membrane distribution and activity of the raft associative Src family kinase member Fyn, in scrapie-infected neuronal cell lines. As a result of prion infection, the specific tyrosine kinase activity of Fyn is increased, although the protein level of Fyn kinase is reduced. This results in an increased overall tyrosine phosphorylation in the infected cells. Interestingly, prion infection also induced a membrane redistribution of Fyn from non-raft to raft-membrane subdomains, following the distribution of PrPSc, as shown by immunoblotting of flotation-fractions after density gradient centrifugation of Triton X-100 extracted cell extracts. This indicates a persistent Fyn activation, possibly due to clustering of intracellular Fyn kinases as a result of PrPSc association to membrane rafts. An increased Fyn kinase activity followed by a dramatic increase in tyrosine phosphorylation may cause and/or contribute to synaptic disorganization and loss which are fundamental features of prion disease.

  • 43.
    Haglund, Ellinor
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindberg, Magnus O.
    Oliveberg, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Changes of protein folding pathways by circular permutation. Overlapping nuclei promote global cooperativity.2008In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 41, p. 27904-27915Article in journal (Refereed)
    Abstract [en]

    The evolved properties of proteins are not limited to structure and stability but also include their propensity to undergo local conformational changes. The latter, dynamic property is related to structural cooperativity and is controlled by the folding-energy landscape. Here we demonstrate that the structural cooperativity of the ribosomal protein S6 is optimized by geometric overlap of two competing folding nuclei: they both include the central beta-strand 1. In this way, folding of one nucleus catalyzes the formation of the other, contributing to make the folding transition more concerted overall. The experimental evidence is provided by an extended set of circular permutations of S6 that allows quantitative analysis of pathway plasticity at the level of individual side chains. Because similar overlap between competing nuclei also has been discerned in other proteins, we hypothesize that the coupling of several small nuclei into extended "supernuclei" represents a general principle for propagating folding cooperativity across large structural distances.

  • 44. Hansson Petersen, Camilla A.
    et al.
    Alikhani, Nyosha
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Behbahani, Homira
    Wiehager, Birgitta
    Pavlov, Pavel F
    Alafuzoff, Irina
    Leinonen, Ville
    Ito, Akira
    Winblad, Bengt
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ankarcrona, Maria
    The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 35, p. 13145-13150Article in journal (Refereed)
    Abstract [en]

    The amyloid beta-peptide (Abeta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Abeta and accumulation of Abeta has been detected in mitochondria. Because Abeta is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial Abeta uptake. Our results from rat mitochondria show that Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed Abeta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Abeta to mitochondrial cristae. A similar distribution pattern of Abeta in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for Abeta in mitochondria and demonstrate both in vitro and in vivo that Abeta is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied Abeta can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of Abeta, a peptide considered to be of major significance in Alzheimer's disease.

  • 45.
    Heddad, Mounia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Light stress proteins from Arabidopsis thaliana: identification, characterisation and expression2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Plants are major players in the vital process of photosynthesis that takes place in organelles called chloroplasts. Plant's immobility makes them victims of the tremendous fluctuations in light intensity and quality that often lead to inhibition of their physiological functions. In order to maintain the photosynthetic processes under light stress conditions, plants have developed several protective mechanisms. In this thesis, one such protective strategy operating in the chloroplasts, namely the accumulation of light stress proteins from the Elip (early light-induced proteins) family of Arabidopsis thaliana is presented. Elips in higher plants are nuclear-encoded proteins located in the thylakoid membranes and related to the chlorophyll a/b-binding proteins of photosystem I and II. A photoprotective function either by binding of released free chlorophylls and thus preventing the formation of free radicals or by thermal dissipation of excess energy was proposed for Elip family members. Using genomic resources available for A. thaliana, two members of the classical three-helix Elips, a new class of two-helix stress-enhanced proteins (called Sep) and a Elip-like one-helix protein (called Ohp 2) were identified and characterised at the molecular level. We demonstrated that both light and retrograde signalling are involved in the regulation of these proteins and that this regulation occurrs independently at transcript and protein levels. We showed that while Elips and Seps are located in photosystem II, Ohp 2 was found in photosystem I, thus providing evidence for a novel protective mechanism present in this photosystem. This work further demonstrates the involvement of chlorophyll a in the posttranslational regulation of Elip expression, thus supporting the proposed photoprotective function of these proteins. Finally, the distribution of the Elip family members through oxygenic photosynthetic organisms from the prokaryotic cyanobacteria, all throughout primitive algae and finally to higher plants was analysed and a novel model for the evolution of Elips and chlorophyll a/b-binding proteins in higher plants and green algae is proposed.

  • 46.
    Hedin, Linnea E.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Öjemalm, Karin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bernsel, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hennerdal, Aron
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Illergård, Kristoffer
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Enquist, Karl
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kauko, Anni
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cristobal, Susana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lerch-Bader, Mirjam
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Membrane Insertion of Marginally Hydrophobic Transmembrane Helices Depends on Sequence Context2010In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 396, no 1, p. 221-229Article in journal (Refereed)
    Abstract [en]

    In mammalian cells, most integral membrane proteins are initially inserted into the endoplasmic reticulum membrane by the so-called Sec61 translocon. However, recent predictions suggest that many transmembrane helices (TMHs) in multispanning membrane proteins are not sufficiently hydrophobic to be recognized as such by the translocon. In this study, we have screened 16 marginally hydrophobic TMHs from membrane proteins of known three-dimensional structure. Indeed, most of these TMHs do not insert efficiently into the endoplasmic reticulum membrane by themselves. To test if loops or TMHs immediately upstream or downstream of a marginally hydrophobic helix might influence the insertion efficiency, insertion of marginally hydrophobic helices was also studied in the presence of their neighboring loops and helices. The results show that flanking loops and nearest-neighbor TMHs are sufficient to ensure the insertion of many marginally hydrophobic helices. However, for at least two of the marginally hydrophobic helices, the local interactions are not enough, indicating that post-insertional rearrangements are involved in the folding of these proteins.

  • 47. Hedskog, Louise
    et al.
    Pinho, Catarina Moreira
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Filadi, Riccardo
    Rönnbäck, Annica
    Hertwig, Laura
    Wiehager, Birgitta
    Larssen, Pia
    Gellhaar, Sandra
    Sandebring, Anna
    Westerlund, Marie
    Graff, Caroline
    Winblad, Bengt
    Galter, Dagmar
    Behbahani, Homira
    Pizzo, Paola
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ankarcrona, Maria
    Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 19, p. 7916-7921Article in journal (Refereed)
    Abstract [en]

    It is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer's disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation. The effect of AD pathogenesis on the ER-mitochondria interplay in the brain has so far remained unknown. Here, we studied ER-mitochondria contacts in human AD brain and related AD mouse and neuronal cell models. We found uniform distribution of MAM in neurons. Phosphofurin acidic cluster sorting protein-2 and sigma 1 receptor, two MAM-associated proteins, were shown to be essential for neuronal survival, because siRNA knockdown resulted in degeneration. Up-regulated MAM-associated proteins were found in the AD brain and amyloid precursor protein (APP)(Swe/Lon) mouse model, in which up-regulation was observed before the appearance of plaques. By studying an ER-mitochondria bridging complex, inositol-1,4,5-triphosphate receptor-voltage-dependent anion channel, we revealed that nanomolar concentrations of amyloid beta-peptide increased inositol-1,4,5-triphosphate receptor and voltage-dependent anion channel protein expression and elevated the number of ER-mitochondria contact points and mitochondrial calcium concentrations. Our data suggest an important role of ER-mitochondria contacts and cross-talk in AD pathology.

  • 48. Hu, Yue O. O.
    et al.
    Ndegwa, Nelson
    Alneberg, Johannes
    Johansson, Sebastian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Logue, Jurg Brendan
    Huss, Mikael
    Käller, Max
    Lundeberg, Joakim
    Fagerberg, Jens
    Andersson, Anders F.
    Stationary and portable sequencing-based approaches for tracing wastewater contamination in urban stormwater systems2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 11907Article in journal (Refereed)
    Abstract [en]

    Urban sewer systems consist of wastewater and stormwater sewers, of which only wastewater is processed before being discharged. Occasionally, misconnections or damages in the network occur, resulting in untreated wastewater entering natural water bodies via the stormwater system. Cultivation of faecal indicator bacteria (e.g. Escherichia coli; E. coli) is the current standard for tracing wastewater contamination. This method is cheap but has limited specificity and mobility. Here, we compared the E. coli culturing approach with two sequencing-based methodologies (Illumina MiSeq 16S rRNA gene amplicon sequencing and Oxford Nanopore MinION shotgun metagenomic sequencing), analysing 73 stormwater samples collected in Stockholm. High correlations were obtained between E. coli culturing counts and frequencies of human gut microbiome amplicon sequences, indicating E. coli is indeed a good indicator of faecal contamination. However, the amplicon data further holds information on contamination source or alternatively how much time has elapsed since the faecal matter has entered the system. Shotgun metagenomic sequencing on a subset of the samples using a portable real-time sequencer, MinION, correlated well with the amplicon sequencing data. This study demonstrates the use of DNA sequencing to detect human faecal contamination in stormwater systems and the potential of tracing faecal contamination directly in the field.

  • 49.
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Radical generation and stabilisation in ribonucleotide reductase R22003Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Diiron carboxylate proteins contain a cofactor that consists of two iron atoms coordinated by carboxylate and histidine ligands. These proteins perform a multitude of chemical reactions in the cell that generally involve activation of molecular oxygen at the diiron site.

    Ribonucleotide reductase is the only enzyme that performs de novo synthesis of all four deoxyribonucleotides, the building blocks of DNA. The R2 protein of Class-I ribonucleotide reductase, which is a diiron carboxylate protein, utilises the high-valent iron-oxygen species generated at the diiron site to produce a stable tyrosyl radical required for enzymatic activity.

    In this work, X-ray crystallography and EPR are used to study the R2 protein from Escherichia coli with the goal of understanding its mechanism of oxygen activation, radical generation and radical stabilisation. Based on these studies a detailed structural mechanism is proposed, which might be common to several oxygen activating diiron carboxylate proteins. The orientation of the active radical species in R2 has also been determined. In addition, these results provide a rationale for the unusual stability of the radical.

    Crystal structures of R2 proteins from two other species, Corynebacterium ammoniagenes and Chlamydia trachomatis, have also been solved.

    The C. ammoniagenes protein has been reported to be manganese-dependent. The results presented here, however, support dependence of iron and not manganese.

    Sequence alignments indicate that the chlamydial R2s lack the, otherwise conserved, radical harbouring tyrosine. This is confirmed by the structure, which also reveals other unique features in the diiron site. Hypotheses regarding the function of the protein and the reason for the differences are presented.

  • 50.
    Höhna, Sebastian
    Stockholm University, Faculty of Science, Department of Mathematics.
    Fast simulation of reconstructed phylogenies under global time-dependent birth-death processes2013In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 29, no 11, p. 1367-1374Article in journal (Refereed)
    Abstract [en]

    Motivation: Diversification rates and patterns may be inferred from reconstructed phylogenies. Both the time-dependent and the diversity-dependent birthdeath process can produce the same observed patterns of diversity over time. To develop and test new models describing the macro-evolutionary process of diversification, generic and fast algorithms to simulate under these models are necessary. Simulations are not only important for testing and developing models but play an influential role in the assessment of model fit.

    Results: In the present article, I consider as the model a global time-dependent birthdeath process where each species has the same rates but rates may vary over time. For this model, I derive the likelihood of the speciation times from a reconstructed phylogenetic tree and show that each speciation event is independent and identically distributed. This fact can be used to simulate efficiently reconstructed phylogenetic trees when conditioning on the number of species, the time of the process or both. I show the usability of the simulation by approximating the posterior predictive distribution of a birthdeath process with decreasing diversification rates applied on a published bird phylogeny (family Cettiidae).

    Availability: The methods described in this manuscript are implemented in the R package TESS, available from the repository CRAN (http://cran.r-project.org/web/packages/TESS/).

123 1 - 50 of 132
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