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  • 1. Aaldering, L. J.
    et al.
    Poongavanam, V.
    Langkjær, N.
    Natarajan Arul, Murugan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Jørgensen, P. T.
    Wengel, J.
    Veedu, R. N.
    Development of an Efficient G-Quadruplex-Stabilised Thrombin-Binding Aptamer Containing a Three-Carbon Spacer Molecule2017In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 18, no 8, p. 755-763Article in journal (Refereed)
    Abstract [en]

    The thrombin-binding aptamer (TBA), which shows anticoagulant properties, is one of the most studied G-quadruplex-forming aptamers. In this study, we investigated the impact of different chemical modifications such as a three-carbon spacer (spacer-C3), unlocked nucleic acid (UNA) and 3′-amino-modified UNA (amino-UNA) on the structural dynamics and stability of TBA. All three modifications were incorporated at three different loop positions (T3, T7, T12) of the TBA G-quadruplex structure to result in a series of TBA variants and their stability was studied by thermal denaturation; folding was studied by circular dichroism spectroscopy and thrombin clotting time. The results showed that spacer-C3 introduction at the T7 loop position (TBA-SP7) significantly improved stability and thrombin clotting time while maintaining a similar binding affinity as TBA to thrombin. Detailed molecular modelling experiments provided novel insights into the experimental observations, further supporting the efficacy of TBA-SP7. The results of this study could provide valuable information for future designs of TBA analogues with superior thrombin inhibition properties. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  • 2. Abelein, Axel
    et al.
    Lang, Lisa
    Lendel, Christofer
    Gräslund, Astrid
    Danielsson, Jens
    Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly.2012In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, no 22, p. 3991-3995, article id S0014-5793(12)00757-0Article in journal (Refereed)
    Abstract [en]

    Small organic molecules, like Congo red and lacmoid, have been shown to modulate the self-assembly of the amyloid β peptide (Aβ). Here, we show that Aβ forms NMR invisible non-toxic co-aggregates together with lacmoid as well as Congo red. We find that the interaction involves two distinct kinetic processes and at every given time point only a small fraction of Aβ is in the co-aggregate. These weak transient interactions kinetically redirect the aggregation prone Aβ from self-assembling into amyloid fibrils. These findings suggest that even such weak binders might be effective as therapeutics against pathogenic protein aggregation.

  • 3. Abi-Rached, Laurent
    et al.
    Jobin, Matthew J.
    Kulkarni, Subhash
    McWhinnie, Alasdair
    Dalva, Klara
    Gragert, Loren
    Babrzadeh, Farbod
    Stanford University, United States .
    Gharizadeh, Baback
    Luo, Ma
    Plummer, Francis A.
    Kimani, Joshua
    Carrington, Mary
    Middleton, Derek
    Rajalingam, Raja
    Beksac, Meral
    Marsh, Steven G. E.
    Maiers, Martin
    Guethlein, Lisbeth A.
    Tavoularis, Sofia
    Little, Ann-Margaret
    Green, Richard E.
    Norman, Paul J.
    Parham, Peter
    The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans2011In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 334, no 6052, p. 89-94Article in journal (Refereed)
    Abstract [en]

    Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic human leukocyte antigen (HLA) class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems.

  • 4. Abrahamsson, T. R.
    et al.
    Jakobsson, H. E.
    Andersson, Anders F.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Björkstén, B.
    Engstrand, Lars
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jenmalm, M. C.
    Low gut microbiota diversity in early infancy precedes asthma at school age2014In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 44, no 6, p. 842-850Article in journal (Refereed)
    Abstract [en]

    Background Low total diversity of the gut microbiota during the first year of life is associated with allergic diseases in infancy, but little is known how early microbial diversity is related to allergic disease later in school age. Objective To assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to the prevalence of different allergic diseases in school age, such as asthma, allergic rhinoconjunctivitis (ARC) and eczema. Methods The microbial diversity and composition was analysed with barcoded 16S rDNA 454 pyrosequencing in stool samples at 1week, 1month and 12months of age in 47 infants which were subsequently assessed for allergic disease and skin prick test reactivity at 7years of age (ClinicalTrials.gov ID NCT01285830). Results Children developing asthma (n=8) had a lower diversity of the total microbiota than non-asthmatic children at 1week (P=0.04) and 1month (P=0.003) of age, whereas allergic rhinoconjunctivitis (n=13), eczema (n=12) and positive skin prick reactivity (n=14) at 7years of age did not associate with the gut microbiota diversity. Neither was asthma associated with the microbiota composition later in infancy (at 12months). Children having IgE-associated eczema in infancy and subsequently developing asthma had lower microbial diversity than those that did not. There were no significant differences, however, in relative abundance of bacterial phyla and genera between children with or without allergic disease. Conclusion and Clinical Relevance Low total diversity of the gut microbiota during the first month of life was associated with asthma but not ARC in children at 7years of age. Measures affecting microbial colonization of the infant during the first month of life may impact asthma development in childhood.

  • 5. Abrahamsson, Thomas R.
    et al.
    Jakobsson, Hedvig E.
    Andersson, Anders F.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Björksten, Bengt
    Engstrand, Lars
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jenmalm, Maria C.
    Gut microbiota diversity and atopic disease: Does breast-feeding play a role? Reply2013In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 131, no 1, p. 248-249Article in journal (Other academic)
  • 6. Adhikari, P. R.
    et al.
    Upadhyaya, B. B.
    Meng, Chen
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Hollmén, J.
    Gene selection in time-series gene expression data2011In: 6th IAPR International Conference on Pattern Recognition in Bioinformatics, PRIB 2011, 2011, p. 145-156Conference paper (Refereed)
    Abstract [en]

    The dimensionality of biological data is often very high. Feature selection can be used to tackle the problem of high dimensionality. However, majority of the work in feature selection consists of supervised feature selection methods which require class labels. The problem further escalates when the data is time-series gene expression measurements that measure the effect of external stimuli on biological system. In this paper we propose an unsupervised method for gene selection from time-series gene expression data founded on statistical significance testing and swap randomization. We perform experiments with a publicly available mouse gene expression dataset and also a human gene expression dataset describing the exposure to asbestos. The results in both datasets show a considerable decrease in number of genes.

  • 7. Adori, Csaba
    et al.
    Barde, Swapnali
    Vas, Szilvia
    Ebner, Karl
    Su, Jie
    Svensson, Camilla
    Mathé, Aleksander A.
    Singewald, Nicolas
    Reinscheid, Rainer R.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kultima, Kim
    Bagdy, Gyorgy
    Hökfelt, Tomas
    Exploring the role of neuropeptide S in the regulation of arousal: a functional anatomical study2016In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, no 7, p. 3521-3546Article in journal (Refereed)
    Abstract [en]

    Neuropeptide S (NPS) is a regulatory peptide expressed by limited number of neurons in the brainstem. The simultaneous anxiolytic and arousal-promoting effect of NPS suggests an involvement in mood control and vigilance, making the NPS-NPS receptor system an interesting potential drug target. Here we examined, in detail, the distribution of NPS-immunoreactive (IR) fiber arborizations in brain regions of rat known to be involved in the regulation of sleep and arousal. Such nerve terminals were frequently apposed to GABAergic/galaninergic neurons in the ventro-lateral preoptic area (VLPO) and to tyrosine hydroxylase-IR neurons in all hypothalamic/thalamic dopamine cell groups. Then we applied the single platform-on-water (mainly REM) sleep deprivation method to study the functional role of NPS in the regulation of arousal. Of the three pontine NPS cell clusters, the NPS transcript levels were increased only in the peri-coerulear group in sleep-deprived animals, but not in stress controls. The density of NPS-IR fibers was significantly decreased in the median preoptic nucleus-VLPO region after the sleep deprivation, while radioimmunoassay and mass spectrometry measurements showed a parallel increase of NPS in the anterior hypothalamus. The expression of the NPS receptor was, however, not altered in the VLPO-region. The present results suggest a selective activation of one of the three NPS-expressing neuron clusters as well as release of NPS in distinct forebrain regions after sleep deprivation. Taken together, our results emphasize a role of the peri-coerulear cluster in the modulation of arousal, and the importance of preoptic area for the action of NPS on arousal and sleep.

  • 8. Aebersold, Ruedi
    et al.
    Agar, Jeffrey N.
    Amster, I. Jonathan
    Baker, Mark S.
    Bertozzi, Carolyn R.
    Boja, Emily S.
    Costello, Catherine E.
    Cravatt, Benjamin F.
    Fenselau, Catherine
    Garcia, Benjamin A.
    Ge, Ying
    Gunawardena, Jeremy
    Hendrickson, Ronald C.
    Hergenrother, Paul J.
    Huber, Christian G.
    Ivanov, Alexander R.
    Jensen, Ole N.
    Jewett, Michael C.
    Kelleher, Neil L.
    Kiessling, Laura L.
    Krogan, Nevan J.
    Larsen, Martin R.
    Loo, Joseph A.
    Loo, Rachel R. Ogorzalek
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
    MacCoss, Michael J.
    Mallick, Parag
    Mootha, Vamsi K.
    Mrksich, Milan
    Muir, Tom W.
    Patrie, Steven M.
    Pesavento, James J.
    Pitteri, Sharon J.
    Rodriguez, Henry
    Saghatelian, Alan
    Sandoval, Wendy
    Schluter, Hartmut
    Sechi, Salvatore
    Slavoff, Sarah A.
    Smith, Lloyd M.
    Snyder, Michael P.
    Thomas, Paul M.
    Uhlen, Mathias
    Van Eyk, Jennifer E.
    Vidal, Marc
    Walt, David R.
    White, Forest M.
    Williams, Evan R.
    Wohlschlager, Therese
    Wysocki, Vicki H.
    Yates, Nathan A.
    Young, Nicolas L.
    Zhang, Bing
    How many human proteoforms are there?2018In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 14, no 3, p. 206-214Article in journal (Refereed)
    Abstract [en]

    Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One of the most fundamental queries is the extent to which the combinations of DNA-, RNA-and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, "How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype.

  • 9.
    Agaton, Charlotta
    et al.
    KTH, Superseded Departments, Biotechnology.
    Uhlén, Mathias
    KTH, Superseded Departments, Biotechnology.
    Hober, Sophia
    KTH, Superseded Departments, Biotechnology.
    Genome-based proteomics2004In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 25, no 9, p. 1280-1288Article in journal (Refereed)
    Abstract [en]

    Protein-protein interactions play crucial roles in various biological pathways and functions. Therefore, the characterization of protein levels and also the network of interactions within an organism would contribute considerably to the understanding of life. The availability of the human genome sequence has created a range of new possibilities for biomedical research. A crucial challenge is to utilize the genetic information for better understanding of protein distribution and function in normal as well as in pathological biological processes. In this review, we have focused on different platforms used for systematic genome-based proteome analyses. These technologies are in many ways complementary and should be seen as various ways to elucidate different functions of the proteome.

  • 10.
    Agerstrand, Marlene
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Kuester, A.
    Bachmann, J.
    Breitholtz, M.
    Ebert, I.
    Rechenberg, B.
    Ruden, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Reporting and evaluation criteria as means towards a transparent use of ecotoxicity data for environmental risk assessment of pharmaceuticals2011In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 159, no 10, p. 2487-2492Article in journal (Refereed)
    Abstract [en]

    Ecotoxicity data with high reliability and relevance are needed to guarantee the scientific quality of environmental risk assessments of pharmaceuticals. The main advantages of a more structured approach to data evaluation include increased transparency and predictability of the risk assessment process, and the possibility to use non-standard data. In this collaboration, between the research project MistraPharma and the German Federal Environment Agency, a new set of reporting and evaluation criteria is presented and discussed. The new criteria are based on the approaches in the literature and the OECD reporting requirements, and have been further developed to include both reliability and relevance of test data. Intended users are risk assessors and researchers performing ecotoxicological experiments, but the criteria can also be used for education purposes and in the peer-review process for scientific papers. This approach intends to bridge the gap between the regulator and the scientist's needs and way of work.

  • 11.
    Agliari, Elena
    et al.
    Dipartimento di Fisica, Universita` degli Studi di Parma, viale G. Usberti 7, 43100 Parma, Italy.
    Barra, Adriano
    Del Ferraro, Gino
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Guerra, Francesco
    Tantari, Daniele
    Anergy in self-directed B lymphocytes: A statistical mechanics perspective2013In: Journal of Theoretical Biology, ISSN 0022-5193, E-ISSN 1095-8541, Vol. 375, p. 21-31Article in journal (Refereed)
    Abstract [en]

    Self-directed lymphocytes may evade clonal deletion at ontogenesis but still remain harmless due to a mechanism called clonal anergy. For B-lymphocytes, two major explanations for anergy developed over the last decades: according to Varela theory, anergy stems from a proper orchestration of the whole B-repertoire, such that self-reactive clones, due to intensive feed-back from other clones, display strong inertia when mounting a response. Conversely, according to the model of cognate response, self-reacting cells are not stimulated by helper lymphocytes and the absence of such signaling yields anergy. Through statistical mechanics we show that helpers do not prompt activation of a sub-group of B-cells: remarkably, the latter are just those broadly interacting in the idiotypic network. Hence Varela theory can finally be reabsorbed into the prevailing framework of the cognate response model. Further, we show how the B-repertoire architecture may emerge, where highly connected clones are self-directed as a natural consequence of ontogenetic learning. 

  • 12. Agnarsdottir, Margret
    et al.
    Sooman, Linda
    Bolander, Asa
    Stromberg, Sara
    Rexhepaj, Elton
    Bergqvist, Michael
    Ponten, Fredrik
    Gallagher, William
    Lennartsson, Johan
    Ekman, Simon
    Uhlen, Mathias
    KTH, School of Biotechnology (BIO), Proteomics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Hedstrand, Hakan
    SOX10 expression in superficial spreading and nodular malignant melanomas2010In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 20, no 6, p. 468-478Article in journal (Refereed)
    Abstract [en]

    SOX10 is a transcription factor expressed in nerve cells and melanocytes. The aim of this study was to investigate the protein expression pattern of SOX10 in malignant melanoma tumors and to analyze whether the results correlated with clinical parameters and the proliferation marker Ki-67. Furthermore, proliferation and migration were analyzed in three different cell lines employing SOX10 small interfering RNA-mediated silencing. Expression patterns were determined in 106 primary tumors and 39 metastases in addition to 16 normal skin samples and six benign nevi employing immunohistochemistry and tissue microarrays. The immunohistochemical staining was evaluated manually and with an automated algorithm. SOX10 was strongly expressed in the benign tissues, but for the malignant tumors superficial spreading melanomas stained stronger than nodular malignant melanomas (P = 0.008). The staining intensity was also inversely correlated with T-stage (Spearman's rho = -0.261, P = 0.008). Overall survival and time to recurrence were significantly correlated with SOX10 intensity, but not in multivariate analysis including T-stage. With the automated algorithm there was an inverse correlation between the SOX10 staining intensity and the proliferation marker, Ki-67 (rho = -0.173, P = 0.02) and a significant difference in the intensity signal between the benign tissues, the primary tumors and the metastases where the metastases stained the weakest (P <= 0.001). SOX10 downregulation resulted in variable effects on proliferation and migration rates in the melanoma cell lines. In conclusion, the SOX10 intensity level differed depending on the tissue studied and SOX10 might have a role in survival. No conclusion regarding the role of SOX10 for in-vitro proliferation and migration could be drawn. Melanoma Res 20:468-478

  • 13. Agostinho, A.
    et al.
    Kouznetsova, A.
    Hernández-Hernández, A.
    Bernhem, Kristoffer
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Höög, C.
    Sexual dimorphism in the width of the mouse synaptonemal complex2018In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 131, no 5, article id jcs212548Article in journal (Refereed)
    Abstract [en]

    Sexual dimorphism has been used to describe morphological differences between the sexes, but can be extended to any biologically related process that varies between males and females. The synaptonemal complex (SC) is a tripartite structure that connects homologous chromosomes in meiosis. Here, aided by superresolution microscopy techniques, we show that the SC is subject to sexual dimorphism, in mouse germ cells. We have identified a significantly narrower SC in oocytes and have established that this difference does not arise from a different organization of the lateral elements nor from a different isoform of transverse filament protein SYCP1. Instead, we provide evidence for the existence of a narrower central element and a different integration site for the C-termini of SYCP1, in females. In addition to these female-specific features, we speculate that post-translation modifications affecting the SYCP1 coiled-coil region could render a more compact conformation, thus contributing to the narrower SC observed in females.

  • 14. Agostinho, Ana
    et al.
    Manneberg, Otto
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    van Schendel, Robin
    Hernandez-Hernandez, Abrahan
    Kouznetsova, Anna
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Höög, Christer
    High density of REC8 constrains sister chromatid axes and prevents illegitimate synaptonemal complex formation2016In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 17, no 6, p. 901-913Article in journal (Refereed)
    Abstract [en]

    During meiosis, cohesin complexes mediate sister chromatid cohesion (SCC), synaptonemal complex (SC) assembly and synapsis. Here, using super-resolution microscopy, we imaged sister chromatid axes in mouse meiocytes that have normal or reduced levels of cohesin complexes, assessing the relationship between localization of cohesin complexes, SCC and SC formation. We show that REC8 foci are separated from each other by a distance smaller than 15% of the total chromosome axis length in wild-type meiocytes. Reduced levels of cohesin complexes result in a local separation of sister chromatid axial elements (LSAEs), as well as illegitimate SC formation at these sites. REC8 but not RAD21 or RAD21L cohesin complexes flank sites of LSAEs, whereas RAD21 and RAD21L appear predominantly along the separated sister-chromatid axes. Based on these observations and a quantitative distribution analysis of REC8 along sister chromatid axes, we propose that the high density of randomly distributed REC8 cohesin complexes promotes SCC and prevents illegitimate SC formation.

  • 15. Ahmadian, Afshin
    et al.
    Pettersson, Erik
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Method for amplification2005Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    The invention refers to a method for multiplex amplification of at least one specific nucleic acid locus, comprising the steps of: providing at least one oligonucleotide probe pair that is designed so that the first and second probe of the pair anneal to a specific nucleic acid locus on a target molecule, in which pair the first probe has an extendable 3'-end, and a second probe has a 5'-end that is directly or indirectly labelled with a phosphate group; providing a target molecule comprising at least one specific nucleic acid locus; allowing the probe pair to anneal to the target molecule; allowing the 3'-end of the first probe to extend by influence of polymerase by adding a set of three different dNTPs; ligating the 3'-end of the extended first probe to the 5'-end of the second probe. Hereby, a method is provided which allows a high specificity for simultaneous amplification of several loci. Further, the invention involves a kit for use in the method of the invention.

  • 16.
    Ahrenstedt, Lage
    KTH, School of Biotechnology (BIO).
    Surface modification of cellulose materials: from wood pulps to artificial blood vessels2007Licentiate thesis, comprehensive summary (Other scientific)
    Abstract [en]

    This thesis describes the improvement of two radically different cellulose materials, paper and artificial blood vessels, constructed from two diverse cellulose sources, wood pulp and Acetobacter xylinum. The improvement of both materials was possible due to the natural affinity of the hemicellulose xyloglucan for cellulose.

    Chemical and mechanical pulps were treated with xyloglucan in the wet-end prior to hand sheet formation or by spray application of dry hand sheets, loading a comparable amount of xyloglucan. The tensile strength increases for the wet-end treatment and spray application were 28% and 71% respectively for bleached soft wood, compared to untreated sheets (20.7 Nm/g). The corresponding strength increases for hand sheets made of thermo-mechanical pulp were 6% and 13% respectively compared to untreated sheets (42.4 Nm/g). The tendency for chemical pulp to be superior to mechanical pulp with respect to strength increase was valid even for tear strength and Scott-Bond. These results suggest, in agreement with other studies, that adhesion of xyloglucan to wood fibres is dependent on their degree of surface lignification.

    Also, a method was developed to increase the blood compatibility of artificial blood vessels constructed of bacterial cellulose. Xyloglucan was covalently linked to the endothelial cell adhesion motif (Arg-Gly-Asp). To obtain this, new solid-phase coupling chemistry was developed. Xyloglucan oligosaccharides (XGO) were transformed into XGO-succinamic acid via the corresponding XGO--NH2 derivative prior to coupling with the N-terminus of the solid-phase synthesised Gly-Arg-Gly-Asp-Ser peptide. The resin-bound glyco-peptide was then cleaved and enzymatically re-incorporated into high molecular weight xyloglucan. The glyco-peptide was further adsorbed onto bacterial cellulose scaffolds, increasing the adhesion and proliferation of endothelial cells and therefore blood compatibility.

  • 17.
    Akander, Amanda
    KTH, School of Biotechnology (BIO).
    Massive parallell DNA-sequencing - future methods to obtain a human genome in 15 minutes2014Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 18.
    Akhras, Michael S.
    KTH, School of Biotechnology (BIO).
    Nucleic Acid Based Pathogen Diagnostics2008Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    Pathogenic organisms are transmitted to the host organism through all possible connected pathways, and cause a myriad of diseases states. Commonly occurring curable infectious diseases still impose the greatest health impacts on a worldwide perspective. The Bill & Melinda Gates Foundation partnered with RAND Corporation to form the Global Health Diagnostics Forum, with the goal of establishing and interpreting mathematical models for what effects a newly introduced point-of-care pathogen diagnostic would have in developing countries. The results were astonishing, with potentially millions of lives to be saved on an annual basis.

    Golden standard for diagnostics of pathogenic bacteria has long been cultureable medias. Environmental biologists have estimated that less than 1% of all bacteria are cultureable. Genomic-based approaches offer the potential to identify all microbes from all the biological kingdoms. Nucleic acid based pathogen diagnostics has evolved significantly over the past decades. Novel technologies offer increased potential in sensitivity, specificity, decreased costs and parallel sample management. However, most methods are confined to core laboratory facilities. To construct an ultimate nucleic acid based diagnostic for use in areas of need, potential frontline techniques need to be identified and combined.

    The research focus of this doctoral thesis work has been to develop and apply nucleic acid based methods for pathogen diagnostics. Methods and assays were applied to the two distinct systems i) screening for antibiotic resistance mutations in the bacterial pathogen Neisseria gonorrhoeae, and ii) genotype determination of the cancer causative Human Papillomavirus (HPV). The first part of the study included development of rapid, direct and multiplex Pyrosequencing nucleic acid screenings. With improved methodology in the sample preparation process, we could detect an existence of multiple co-infecting HPV genotypes at greater sensitivities than previously described, when using the same type of methodology. The second part of the study focused on multiplex nucleic acid amplification strategies using Molecular Inversion Probes with end-step Pyrosequencing screening. The PathogenMip assay presents a complete detection schematic for virtually any known pathogenic organism. We also introduce the novel Connector Inversion Probe, a padlock probe capable of complete gap-fill reactions for multiplex nucleic acid amplifications.

  • 19.
    Akpe, Victor
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Photophysical and Chemical Approaches to Cellular Biophysics2008Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    The central theme in this thesis is reversibility. Two main attempts has been made to approach reversibility in cellular systems from both chemical and physical points of view. Reversibility of immunolabeling of proteins on the cell surface has been adressed by development of new fluorescent substances optimized for CALI (Chromophore-Assisted Laser Inactivation of protein). Aluminum phthalocyanine (AlPc) is here identified to be a good candidate for a new generation of fluorophores for efficient hydroxyl radical generation. It is shown that cells can be reversibly labeled with antibody-AlPc conjugates. In experiments on living cells the AlPcs were not only active as classic fluorophores but also as photocatalytic substances with destaining properties. Reversibility of cell immobilization is also reported, where cells cultured in microstructures were immobilized and 3D supported using hydrogels. Hydrogel formulation and application was optimized to achieve a system where both viability and ease of use was satisfied. Gel reversibility was actualized with pH and enzyme treatment. The developped method offers the possibility of stop flow culturing cells in controlled and reusable 3D environments.

  • 20.
    Akpe, Victor
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Nyokong, Tebello
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Photophysics and photochemistry of zinc, aluminium and tin octakis (benzylthio) phthalocyanines2008Report (Other academic)
  • 21.
    Akpe, Victor
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Vernet, Erik
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Characterization studies of aluminum phthalocyanine binding to antibodies from SKBR 3 cell line2008Report (Other academic)
  • 22.
    Al Saleem, Evan
    KTH, School of Biotechnology (BIO).
    Improving unnatural amino acid mutagensis efficiency and selectivity in mammalian cell2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Genetically encoded, site-specific incorporation of unnatural amino acids (UAA)into proteins through selective recoding of an amber stop codon provides apowerful route for expressing synthetic proteins in living cells. Recoding of theamber stop codon is achieved by introducing an amber suppressortRNA/synthetase pair orthogonal to the endogenous tRNA complement intocells. Methanosarcina is a methane producing archaea with the unusualcapability of suppressing the stop codon (specifically the amber codon). Bysuppressing the amber codon Methanosarcina facilitate the incorporation of thenon-canonical amino acid pyrrolysine (pyl). The suppressing mechanismoriginates from a evolutionary unique Pyrrolysyl-tRNA synthetase (PylRS) and itsmatching tRNApyl. The PylRS has been further evolved and modified to allowincorporation of a wide range of UAAs. Amber suppression is today used tocontrol and study protein function in living cells. By making a series of wellcontrolledexperiments with HEK293T cells we aimed to develop this techniqueinto a robust and general tool for mammalian cell biology. Specifically we weretesting the incorporation of the unnatural amino acid bicyclononyne (BCN) by aset of known PylRS mutants. Our results suggest the mutant aaRS PylRS “AF” isthe most robust and efficient synthetase for BCN. We have improved ambersuppression by determining which factors leads to a more efficient method andsimultaneously decreasing the cost of the method.

  • 23. Alava, Mikko
    et al.
    Ardelius, John
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Aurell, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Kaski, P.
    Krishnamurthy, S.
    Orponen, P.
    Seitz, S
    Circumspect descent prevails in solving random constraint satisfaction problems2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 40, p. 15253-15257Article in journal (Refereed)
    Abstract [en]

    We study the performance of stochastic local search algorithms for random instances of the K-satisfiability (K-SAT) problem. We present a stochastic local search algorithm, ChainSAT, which moves in the energy landscape of a problem instance by never going upwards in energy. ChainSAT is a focused algorithm in the sense that it focuses on variables occurring in unsatisfied clauses. We show by extensive numerical investigations that ChainSAT and other focused algorithms solve large K-SAT instances almost surely in linear time, up to high clause-to-variable ratios a; for example, for K = 4 we observe linear-time performance well beyond the recently postulated clustering and condensation transitions in the solution space. The performance of ChainSAT is a surprise given that by design the algorithm gets trapped into the first local energy minimum it encounters, yet no such minima are encountered. We also study the geometry of the solution space as accessed by stochastic local search algorithms.

  • 24.
    Albertsson, Ann-Christine
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Voepel, Jens
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Edlund, Ulrica
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Dahlman, Olof
    Soderqvist-Lindblad, Margaretha
    Design of Renewable Hydrogel Release Systems from Fiberboard Mill Wastewater2010In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 11, no 5, p. 1406-1411Article in journal (Refereed)
    Abstract [en]

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

  • 25.
    Alexeyenko, Andrey
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lee, Woojoo
    Pernemalm, Maria
    Guegan, Justin
    Dessen, Philippe
    Lazar, Vladimir
    Lehtio, Janne
    Pawitan, Yudi
    Network enrichment analysis: extension of gene-set enrichment analysis to gene networks2012In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 13, p. 226-Article in journal (Refereed)
    Abstract [en]

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

  • 26.
    Alexeyenko, Andrey
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nystedt, Björn
    Vezzi, Francesco
    Sherwood, Ellen
    Ye, Rosa
    Knudsen, Bjarne
    Simonsen, Martin
    Turner, Benjamin
    de Jong, Pieter
    Wu, Cheng-Cang
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Efficient de novo assembly of large and complex genomes by massively parallel sequencing of Fosmid pools2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, no 1, p. 439-Article in journal (Refereed)
    Abstract [en]

    Background: Sampling genomes with Fosmid vectors and sequencing of pooled Fosmid libraries on the Illumina platform for massive parallel sequencing is a novel and promising approach to optimizing the trade-off between sequencing costs and assembly quality. Results: In order to sequence the genome of Norway spruce, which is of great size and complexity, we developed and applied a new technology based on the massive production, sequencing, and assembly of Fosmid pools (FP). The spruce chromosomes were sampled with similar to 40,000 bp Fosmid inserts to obtain around two-fold genome coverage, in parallel with traditional whole genome shotgun sequencing (WGS) of haploid and diploid genomes. Compared to the WGS results, the contiguity and quality of the FP assemblies were high, and they allowed us to fill WGS gaps resulting from repeats, low coverage, and allelic differences. The FP contig sets were further merged with WGS data using a novel software package GAM-NGS. Conclusions: By exploiting FP technology, the first published assembly of a conifer genome was sequenced entirely with massively parallel sequencing. Here we provide a comprehensive report on the different features of the approach and the optimization of the process. We have made public the input data (FASTQ format) for the set of pools used in this study: ftp://congenie.org/congenie/Nystedt_2013/Assembly/ProcessedData/FosmidPools/.(alternatively accessible via http://congenie.org/downloads).The software used for running the assembly process is available at http://research.scilifelab.se/andrej_alexeyenko/downloads/fpools/.

  • 27.
    Alexeyenko, Andrey
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schmitt, Thomas
    Tjärnberg, Andreas
    Stockholm University, Science for Life Laboratory.
    Guala, Dmitri
    Stockholm University, Science for Life Laboratory.
    Frings, Oliver
    Stockholm University, Science for Life Laboratory.
    Sonnhammer, Erik L. L.
    Stockholm University, Science for Life Laboratory.
    Comparative interactomics with Funcoup 2.02012In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no D1, p. D821-D828Article in journal (Refereed)
    Abstract [en]

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

  • 28.
    Ali, Raja Hashim
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Arvestad, Lars
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Burnin estimation and convergence assessment in Bayesian phylogenetic inferenceManuscript (preprint) (Other academic)
    Abstract [en]

     Convergence assessment and burnin estimation are central concepts in Markov chain Monte Carlo algorithms. Studies on eects, statistical properties, and comparisons between dierent convergence assessment methods have been conducted during the past few decades. However, not much work has been done on the eect of convergence diagnostic on posterior distribution of tree parameters and which method should be used by researchers in Bayesian phylogenetics inference. In this study, we propose and evaluate two novel burnin estimation methods that estimate burnin using all parameters jointly. We also consider some other popular convergence diagnostics, evaluate them in light of parallel chains and quantify the eect of burnin estimates from various convergence diagnostics on the posterior distribution of trees. We motivate the use of convergence diagnostics to assess convergence and estimate burnin in Bayesian phylogenetics inference and found out that it is better to employ convergence diagnostics rather than remove a xed percentage as burnin. We concluded that the last burnin estimator using eective sample size appears to estimate burnin better than all other convergence diagnostics.

  • 29.
    Ali, Raja Hashim
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Bark, Mikael
    KTH, School of Information and Communication Technology (ICT).
    Miro, Jorge
    KTH, School of Information and Communication Technology (ICT).
    Muhammad, Sayyed Auwn
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Sjöstrand, Joel
    Stockholm University.
    Zubair, Syed Muhammad
    KTH, School of Electrical Engineering (EES), Communication Networks. University of Balochistan, Pakistan.
    Abbas, Raja Manzar
    Arvestad, Lars
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    VMCMC: a graphical and statistical analysis tool for Markov chain Monte Carlo tracesManuscript (preprint) (Other academic)
    Abstract [en]

    Motivation: MCMC-based methods are important for Bayesian inference of phylogeny and related parameters. Although being computationally expensive, MCMC yields estimates of posterior distributions that are useful for estimating parameter values and are easy to use in subsequent analysis. There are, however, sometimes practical diculties with MCMC, relating to convergence assessment and determining burn-in, especially in large-scale analyses. Currently, multiple software are required to perform, e.g., convergence, mixing and interactive exploration of both continuous and tree parameters.

    Results: We have written a software called VMCMC to simplify post-processing of MCMC traces with, for example, automatic burn-in estimation. VMCMC can also be used both as a GUI-based application, supporting interactive exploration, and as a command-line tool suitable for automated pipelines.

    Availability: VMCMC is available for Java SE 6+ under the New BSD License. Executable jar les, tutorial manual and source code can be downloaded from https://bitbucket.org/rhali/visualmcmc/.

  • 30.
    Ali, Raja Hashim
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Khan, Ammad Aslam
    Tracing the evolution of FERM domain of Kindlins2014In: Molecular Phylogenetics and Evolution, ISSN 1055-7903, E-ISSN 1095-9513, Vol. 80, p. 193-204Article in journal (Refereed)
    Abstract [en]

    Kindlin proteins represent a novel family of evolutionarily conserved FERM domain containing proteins (FDCPs) and are members of B4.1 superfamily. Kindlins consist of three conserved protein homologs in vertebrates: Kindlin-1, Kindlin-2 and Kindlin-3. All three homologs are associated with focal adhesions and are involved in Integrin activation. FERM domain of each Kindlin is bipartite and plays a key role in Integrin activation. A single ancestral Kindlin protein can be traced back to earliest metazoans, e.g., to Parazoa. This protein underwent multiple rounds of duplication in vertebrates, leading to the present Kindlin family. In this study, we trace phylogenetic and evolutionary history of Kindlin FERM domain with respect to FERM domain of other FDCPs. We show that FERM domain in Kindlin homologs is conserved among Kindlins but amount of conservation is less in comparison with FERM domain of other members in B4.1 superfamily. Furthermore, insertion of Pleckstrin Homology like domain in Kindlin FERM domain has important evolutionary and functional consequences. Important residues in Kindlins are traced and ranked according to their evolutionary significance. The structural and functional significance of high ranked residues is highlighted and validated by their known involvement in Kindlin associated diseases. In light of these findings, we hypothesize that FERM domain originated from a proto-Talin protein in unicellular or proto-multicellular organism and advent of multi-cellularity was accompanied by burst of FDCPs, which supported multi-cellularity functions required for complex organisms. This study helps in developing a better understanding of evolutionary history of FERM domain of FDCPs and the role of FERM domain in metazoan evolution.

  • 31.
    Ali, Raja Hashim
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Muhammad, Sayyed Auwn
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Arvestad, Lars
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    GenFamClust: An accurate, synteny-aware and reliable homology inference algorithm2016In: BMC EVOLUTIONARY BIOLOGY, ISSN 1471-2148, Vol. 16Article in journal (Other academic)
    Abstract [en]

    Background: Homology inference is pivotal to evolutionary biology and is primarily based on significant sequence similarity, which, in general, is a good indicator of homology. Algorithms have also been designed to utilize conservation in gene order as an indication of homologous regions. We have developed GenFamClust, a method based on quantification of both gene order conservation and sequence similarity. Results: In this study, we validate GenFamClust by comparing it to well known homology inference algorithms on a synthetic dataset. We applied several popular clustering algorithms on homologs inferred by GenFamClust and other algorithms on a metazoan dataset and studied the outcomes. Accuracy, similarity, dependence, and other characteristics were investigated for gene families yielded by the clustering algorithms. GenFamClust was also applied to genes from a set of complete fungal genomes and gene families were inferred using clustering. The resulting gene families were compared with a manually curated gold standard of pillars from the Yeast Gene Order Browser. We found that the gene-order component of GenFamClust is simple, yet biologically realistic, and captures local synteny information for homologs. Conclusions: The study shows that GenFamClust is a more accurate, informed, and comprehensive pipeline to infer homologs and gene families than other commonly used homology and gene-family inference methods.

  • 32.
    Aljadi, Zenib
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. Karolinska Institute, Sweden.
    Mansouri, Ladan
    Nopp, Anna
    Paulsson, Josefin M.
    Winqvist, Ola
    Russom, Aman
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Stahl, Marten
    Hylander, Britta
    Jacobson, Stefan H.
    Lundahl, Joachim
    Activation of Basophils Is a New and Sensitive Marker of Biocompatibility in Hemodialysis2014In: Artificial Organs, ISSN 0160-564X, E-ISSN 1525-1594, Vol. 38, no 11, p. 945-953Article in journal (Refereed)
    Abstract [en]

    The hemodialysis procedure involves contact between peripheral blood and the surface of dialyzer membranes, which may lead to alterations in the pathways of innate and adaptive immunity. We aimed to study the effect of blood-membrane interaction on human peripheral basophils and neutrophils in hemodialysis with high- and low-permeability polysulfone dialyzers. The surface expression of CD203c (basophil selection marker) and CD63 (activation marker) after activation by the bacterial peptide formyl-methionyl-leucyl-phenylalanine (fMLP) or anti-Fc epsilon receptor I (Fc epsilon RI) antibody and the absolute number of basophils was investigated before and after hemodialysis with each of the dialyzers. Moreover, the expression on neutrophils of CD11b, the CD11b active epitope, and CD88 was analyzed in the same groups of individuals. The expression of CD63 in basophils following activation by fMLP was significantly higher in the patient group compared with that in healthy controls, but no differences were observed after activation by anti-Fc epsilon RI. During the hemodialysis procedure, the low-flux membrane induced up-regulation of CD63 expression on basophils, while passage through the high-flux membrane did not significantly alter the responsiveness. In addition, the absolute number of basophils was unchanged after hemodialysis with either of the dialyzers and compared with healthy controls. We found no significant differences in the expression of the neutrophil activation markers (CD11b, the active epitope of CD11b, and CD88) comparing the two different dialyzers before and after dialysis and healthy controls. Together, these findings suggest that alterations in basophil activity may be a useful marker of membrane bioincompatibility in hemodialysis.

  • 33.
    Aljadi, Zenib
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. Karolinska Inst, Sweden.
    Nopp, Anna
    Winqvist, Ola
    Russom, Aman
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. Karolinska Inst, Sweden.
    Hylander, Britta
    Jacobson, Stefan H.
    Lundahl, Joachim
    Altered basophil function in patients with chronic kidney disease on hemodialysis2017In: Clinical Nephrology, ISSN 0301-0430, Vol. 88, no 2, p. 86-96Article in journal (Refereed)
    Abstract [en]

    Aims: Chronic kidney disease (CKD) leads to impairment of immune cell function. Given the potential role of basophils in the pathogenesis of CKD, we aimed to study the basophil responsiveness towards microbial antigen exposure, judged as adhesion molecule expression and degranulation, in CKD patients on hemodialysis. Materials and methods: We selected markers linked to two crucial biological phases: the transmigration and degranulation processes, respectively. For the transmigration process, we selected the adhesion molecules CD11b, active CD11b epitope, and CD62L and for the degranulation process CD203c (piecemeal degranulation marker), CD63 (degranulation marker), and CD300a (inhibitory marker of degranulation). We measured basophil responsiveness after stimulation of different activation pathways in basophils using lipopolysaccharide (LPS), peptidoglycan (PGN), formyl-methyinoyl-leucyl-phenylalanine (fMLP), and anti-FceRI-ab. Results: The expression of CD63 in basophils following activation by fMLP was significantly higher in the patient group compared to matched healthy controls, but no differences were observed after activation by anti-Fc.RI. CD300a expression was significantly higher in patients following activation by fMLP and anti-Fc.RI, and the active epitope CD11b expression was significantly higher in patients after LPS activation. In addition, we found that CD62L was not shed from the cell surface after activation with LPS and fMLP. A slight downregulation was noted after activation with anti-Fc.RI in healthy controls. Conclusion: Together, these data demonstrate that basophil functions related to adhesion and degranulation are altered in CKD patients on hemodialysis, which indicates a potential role for the basophil in the pathogenesis of complications related to infections.

  • 34. Alkasalias, Twana
    et al.
    Alexeyenko, Andrey
    Hennig, Katharina
    Danielsson, Frida
    Lebbink, Robert Jan
    Fielden, Matthew
    Turunen, S. Pauliina
    Lehti, Kaisa
    Kashuba, Vladimir
    Madapura, Harsha S.
    Bozoky, Benedek
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Balland, Martial
    Guven, Hayrettin
    Klein, George
    Gad, Annica K. B.
    Pavlova, Tatiana
    RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 8, p. E1413-E1421Article in journal (Refereed)
    Abstract [en]

    Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins over-expressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of a-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.

  • 35.
    Al-Khalili, Lubna
    et al.
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    Gillner, Karin
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    Zhang, Ye
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    Åstrand, Carolina
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    Shokri, Atefeh
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    Hughes-Brittain, Nanaaya
    McKean, Robert
    Robb, Brendan
    Chotteau, Véronique
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    Characterization of Human CD133+Cells in Biocompatible Poly(l-lactic acid) Electrospun Nano-Fiber Scaffolds2016In: Journal of Biomaterials and Tissue Engineering, ISSN 2157-9083, E-ISSN 2157-9091, Vol. 6, no 12, p. 959-966Article in journal (Refereed)
    Abstract [en]

    CD133+ cells are potential myogenic progenitors for skeletal muscle regeneration to treat muscular dystrophies. The proliferation of human CD133+ stem cells was studied for 14 days in 3D biomimetic electrospun poly-L-lactic acid (PLLA) nano-fiber scaffolds. Additionally, the myogenic differentiation of the cells was studied during the last 7 days of the culture period. The cells were homogeneously distributed in the 3D scaffolds while colony formation and myotube formation occurred in 2D. After a lag phase due to lower initial cell attachment and an adaptation period, the cell growth rate in 3D was comparable to 2D after 7 and 14 days of culture. The expression of the stem cell (SC) marker PAX7 was 1.5-fold higher in 3D than 2D while the differentiation markers MyoG, Desmin and MyoD were only slightly changed (or remain unchanged) in 3D but strongly increased in 2D (12.6, 3.9, and 7.9-fold), and the myotube formation observed in 2D was absent in 3D. The marker expression during proliferation and differentiation, together with the absence of myotubes in 3D, indicates a better maintenance of stemness in 3D PLLA and stronger tendency for spontaneous differentiation in 2D culture. This makes 3D PLLA a promising biomaterial for the expansion of functional CD133+ cells.

  • 36. Al-Khalili Szigyarto, Cristina
    et al.
    Sibbons, P.
    Williams, G.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics.
    Metcalfe, S. M.
    The E3 Ligase Axotrophin/MARCH-7: Protein Expression Profiling of Human Tissues Reveals Links to Adult Stem Cells2010In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 58, no 4, p. 301-308Article in journal (Refereed)
    Abstract [en]

    Axotrophin/MARCH-7 was first identified in mouse embryonic stem cells as a neural stem cell gene. Using the axotrophin/MARCH-7 null mouse, we discovered profound effects on T lymphocyte responses, including 8-fold hyperproliferation and 5-fold excess release of the stem cell cytokine leukemia inhibitory factor (LIF). Our further discovery that axotrophin/MARCH-7 is required for targeted degradation of the LIF receptor subunit gp190 implies a direct role in the regulation of LIF signaling. Bioinformatics studies revealed a highly conserved RING-CH domain in common with the MARCH family of E3-ubiquitin ligases, and accordingly, axotrophin was renamed "MARCH-7." To probe protein expression of human axotrophin/MARCH-7, we prepared antibodies against different domains of the protein. Each antibody bound its specific target epitope with high affinity, and immunohistochemistry cross-validated target specificity. Forty-eight human tissue types were screened. Epithelial cells stained strongly, with trophoblasts having the greatest staining. In certain tissues, specific cell types were selectively positive, including neurons and neuronal progenitor cells in the hippocampus and cerebellum, endothelial sinusoids of the spleen, megakaryocytes in the bone marrow, crypt stem cells of the small intestine, and alveolar macrophages in the 7 lung. Approximately 20% of central nervous system neuropils were positive. Notably, axotrophin/MARCH-7 has an expression profile that is distinct from that of other MARCH family members. This manuscript contains online supplemental material at http://www.jhc. org. Please visit this article online to view these materials. (J Histochem Cytochem 58:301-308, 2010)

  • 37. Alkharusi, Amira
    et al.
    Yu, Shengze
    KTH, School of Biotechnology (BIO).
    Landazuri, Natalia
    Zadjali, Fahad
    Davodi, Belghis
    Nystrom, Thomas
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Protein Technology.
    Rahbar, Afsar
    Norstedt, Gunnar
    Stimulation of prolactin receptor induces STAT-5 phosphorylation and cellular invasion in glioblastoma multiforme2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 48, p. 79558-79569Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans and is characterized with poor outcome. In this study, we investigated components of prolactin (Prl) system in cell models of GBM and in histological tissue sections obtained from GBM patients. Expression of Prolactin receptor (PrlR) was detected at high levels in U251-MG, at low levels in U87-MG and barely detectable in U373 cell lines and in 66% of brain tumor tissues from 32 GBM patients by immunohistochemical technique. In addition, stimulation of U251-MG and U87-MG cells but not U373 with Prl resulted in increased STAT5 phosphorylation and only in U251-MG cells with increased cellular invasion. Furthermore, STAT5 phosphorylation and cellular invasion induced in Prl stimulated cells were significantly reduced by using a Prl receptor antagonist that consists of Prl with four amino acid replacements. We conclude that Prl receptor is expressed at different levels in the majority of GBM tumors and that blocking of PrlR in U251-MG cells significantly reduce cellular invasion.

  • 38. Allerbring, E. B.
    et al.
    Duru, A. D.
    Uchtenhagen, H.
    Madhurantakam, C.
    Tomek, M. B.
    Grimm, Sebastian
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Mazumdar, P. A.
    Friemann, R.
    Uhlin, M.
    Sandalova, T.
    Nygren, Per-Åke
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Achour, A.
    Unexpected T-cell recognition of an altered peptide ligand is driven by reversed thermodynamics2012In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 42, no 11, p. 2990-3000Article in journal (Refereed)
    Abstract [en]

    The molecular basis underlying T-cell recognition of MHC molecules presenting altered peptide ligands is still not well-established. A hierarchy of T-cell activation by MHC class I-restricted altered peptide ligands has been defined using the T-cell receptor P14 specific for H-2D b in complex with the immunodominant lymphocytic choriomeningitis virus peptide gp33 (KAVYNFATM). While substitution of tyrosine to phenylalanine (Y4F) or serine (Y4S) abolished recognition by P14, the TCR unexpectedly recognized H-2D b in complex with the alanine-substituted semiagonist Y4A, which displayed the most significant structural modification. The observed functional hierarchy gp33 &gt; Y4A &gt; Y4S = Y4F was neither due to higher stabilization capacity nor to differences in structural conformation. However, thermodynamic analysis demonstrated that while recognition of the full agonist H-2D b/gp33 was strictly enthalpy driven, recognition of the weak agonist H-2D b/Y4A was instead entropy driven with a large reduction in the favorable enthalpy term. The fourfold larger negative heat capacity derived for the interaction of P14 with H-2D b/gp33 compared with H-2D b/Y4A can possibly be explained by higher water entrapment at the TCR/MHC interface, which is also consistent with the measured opposite entropy contributions for the interactions of P14 with both MHCs. In conclusion, this study demonstrates that P14 makes use of different strategies to adapt to structural modifications in the MHC/peptide complex.

  • 39. Allerbring, Eva B.
    et al.
    Duru, Adil D.
    Chadderton, Jesseka
    Markov, Natalia
    Uchtenhagen, Hannes
    Popov, Alexander
    Madhurantakam, Chaithanya
    Sandalova, Tatyana
    Turner, Stephen J.
    Nygren, Per-Åke
    KTH, School of Biotechnology (BIO), Protein Technology.
    Achour, Adnane
    Structural and thermodynamic basis underlying in vivo reestablishment of T-cell recognition of a viral escape mutant2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 68, no 2, p. 151-151Article in journal (Other academic)
  • 40.
    Alm, Tove L.
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    The Affinity Binder Knockdown Initiative.2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 41.
    Alm, Tove L.
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    von Feilitzen, Kalle
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    ANTIBODYPEDIA: THE WIKI OF ANTIBODIES2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 42.
    Alm, Tove
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Introducing the Affinity Binder Knockdown Initiative-A public-private partnership for validation of affinity reagents2016In: EuPA Open Proteomics, ISSN 0014-2328, E-ISSN 2212-9685, Vol. 10, p. 56-58Article in journal (Refereed)
    Abstract [en]

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

  • 43.
    Alm, Tove
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    von Feilitzen, Kalle
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sivertsson, Åsa
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    A Chromosome-Centric Analysis of Antibodies Directed toward the Human Proteome Using Antibodypedia2014In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 3, p. 1669-1676Article in journal (Refereed)
    Abstract [en]

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

  • 44.
    Alm, Tove
    et al.
    KTH, School of Biotechnology (BIO), Proteomics.
    Yderland, Louise
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Nilvebrant, Johan
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Halldin, Anneli
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Hober, Sophia
    KTH, School of Biotechnology (BIO), Proteomics.
    A small bispecific protein selected for orthogonal affinity purification2010In: BIOTECHNOL J, ISSN 1860-6768, Vol. 5, no 6, p. 605-617Article in journal (Refereed)
    Abstract [en]

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

  • 45. Almandoz-Gil, Leire
    et al.
    Welander, Hedvig
    Ihse, Elisabet
    Khoonsari, Payam Emami
    Musunuri, Sravani
    Lendel, Christofer
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry.
    Sigvardson, Jessica
    Karlsson, Mikael
    Ingelsson, Martin
    Kultima, Kim
    Bergstrom, Joakim
    Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways2017In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, p. 421-431Article in journal (Refereed)
    Abstract [en]

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

  • 46.
    Almandoz-Gil, Leire
    et al.
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Welander, Hedvig
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Ihse, Elisabeth
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Khoonsari, Payam Emami
    Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
    Musunuri, Sravani
    Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry.
    Sigvardson, Jessica
    BioArctic AB, Warfvinges Vag 35, SE-11251 Stockholm, Sweden..
    Karlsson, Mikael
    Uppsala Univ, Dept Engn Sci, SE-75121 Uppsala, Sweden..
    Ingelsson, Martin
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Kultima, Kim
    Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
    Bergstrom, Joakim
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways (vol 110, pg 421, 2017)2018In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 117, p. 258-258Article in journal (Refereed)
  • 47.
    Almquist, Ann-Charlotte
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Fäldt, Jenny
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Yart, A.
    Chevet, Y.
    Sauvard, D.
    Lieutier, F.
    Borg-Karlson, Anna Karin
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Host selection in Tomicus piniperda L.: Composition of monoterpene hydrocarbons in relation to attack frequency in the shoot feeding phase2006In: Zeitschrift fur Naturforschung - Section C Journal of Biosciences, ISSN 0939-5075, Vol. 61, no 5-6, p. 439-444Article in journal (Refereed)
    Abstract [en]

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

  • 48.
    Alneberg, Johannes
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bioinformatic Methods in Metagenomics2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Microbial organisms are a vital part of our global ecosystem. Yet, our knowledge of them is still lacking. Direct sequencing of microbial communities, i.e. metagenomics, have enabled detailed studies of these microscopic organisms by inspection of their DNA sequences without the need to culture them. Furthermore, the development of modern high- throughput sequencing technologies have made this approach more powerful and cost-effective. Taken together, this has shifted the field of microbiology from previously being centered around microscopy and culturing studies, to largely consist of computational analyses of DNA sequences. One such computational analysis which is the main focus of this thesis, aims at reconstruction of the complete DNA sequence of an organism, i.e. its genome, directly from short metagenomic sequences.

    This thesis consists of an introduction to the subject followed by five papers. Paper I describes a large metagenomic data resource spanning the Baltic Sea microbial communities. This dataset is complemented with a web-interface allowing researchers to easily extract and visualize detailed information. Paper II introduces a bioinformatic method which is able to reconstruct genomes from metagenomic data. This method, which is termed CONCOCT, is applied on Baltic Sea metagenomics data in Paper III and Paper V. This enabled the reconstruction of a large number of genomes. Analysis of these genomes in Paper III led to the proposal of, and evidence for, a global brackish microbiome. Paper IV presents a comparison between genomes reconstructed from metagenomes with single-cell sequenced genomes. This further validated the technique presented in Paper II as it was found to produce larger and more complete genomes than single-cell sequencing.

  • 49.
    Alneberg, Johannes
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Bennke, Christin
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Beier, Sara
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Pinhassi, Jarone
    Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden.
    Jürgens, Klaus
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Ekman, Martin
    Department of Ecology, Environment and Plant Sciences, Stockholm University Science for Life Laboratory, Solna, Sweden.
    Ininbergs, Karolina
    Department of Ecology, Environment and Plant Sciences, Stockholm University Science for Life Laboratory, Solna, Sweden.
    Labrenz, Matthias
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Andersson, Anders F.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Recovering 2,032 Baltic Sea microbial genomes by optimized metagenomic binningManuscript (preprint) (Other academic)
    Abstract [en]

    Aquatic microorganism are key drivers of global biogeochemical cycles and form the basis of aquatic food webs. However, there is still much left to be learned about these organisms and their interaction within specific environments, such as the Baltic Sea. Crucial information for such an understanding can be found within the genome sequences of organisms within the microbial community.

    In this study, the previous set of Baltic Sea clusters, constructed by Hugert et al., is greatly expanded using a large set of metagenomic samples, spanning the environmental gradients of the Baltic Sea. In total, 124 samples were individually assembled and binned to obtain 2,032 Metagenome Assembled Genomes (MAGs), clustered into 353 prokaryotic and 14 eukaryotic species- level clusters. The prokaryotic genomes were widely distributed over the prokaryotic tree of life, representing 20 different phyla, while the eukaryotic genomes were mostly limited to the division of Chlorophyta. The large number of reconstructed genomes allowed us to identify key factors determining the quality of the genome reconstructions.

    The Baltic Sea is heavily influenced of human activities of which we might not see the full implications. The genomes reported within this study will greatly aid further studies in our strive for an understanding of the Baltic Sea microbial ecosystem.

  • 50.
    Alneberg, Johannes
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bjarnason, Brynjar Smári
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    de Bruijn, Ino
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Bioinformatics Infrastructure for Life Sciences (BILS), Sweden.
    Schirmer, Melanie
    Quick, Joshua
    Ijaz, Umer Z.
    Lahti, Leo
    Loman, Nicholas J.
    Andersson, Anders F.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Quince, Christopher
    Binning metagenomic contigs by coverage and composition2014In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 11, no 11, p. 1144-1146Article in journal (Refereed)
    Abstract [en]

    Shotgun sequencing enables the reconstruction of genomes from complex microbial communities, but because assembly does not reconstruct entire genomes, it is necessary to bin genome fragments. Here we present CONCOCT, a new algorithm that combines sequence composition and coverage across multiple samples, to automatically cluster contigs into genomes. We demonstrate high recall and precision on artificial as well as real human gut metagenome data sets.

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