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  • 1. Alcamán, M. Estrella
    et al.
    Alcorta, Jaime
    Bergman, Birgitta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Vásquez, Mónica
    Polz, Martin
    Díez, Beatriz
    Physiological and gene expression responses to nitrogen regimes and temperatures in Mastigocladus sp strain CHP1, a predominant thermotolerant cyanobacterium of hot springs2017Ingår i: Systematic and Applied Microbiology, ISSN 0723-2020, E-ISSN 1618-0984, Vol. 40, nr 2, s. 102-113Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyanobacteria are widely distributed primary producers with significant implications for the global biogeochemical cycles of carbon and nitrogen. Diazotrophic cyanobacteria of subsection V (Order Stigonematales) are particularly ubiquitous in photoautotrophic microbial mats of hot springs. The Stigonematal cyanobacterium strain CHPI isolated from the Porcelana hot spring (Chile) was one of the major contributors of the new nitrogen through nitrogen fixation. Further morphological and genetic characterization verified that the strain CHP1 belongs to Stigonematales, and it formed a separate Glade together with other thermophiles of the genera Fischerella and Mastigocladus. Strain CHP1 fixed maximum N-2 in the light, independent of the temperature range. At 50 degrees C niJH gene transcripts showed high expression during the light period, whereas the nifH gene expression at 45 degrees C was arrhythmic. The strain displayed a high affinity for nitrate and a low tolerance for high ammonium concentrations, whereas the narB and glnA genes showed higher expression in light and at the beginning of the dark phase. It is proposed that Mastigocladus sp. strain CHPI would represent a good model for the study of subsection V thermophilic cyanobacteria, and for understanding the adaptations of these photoautotrophic organisms inhabiting microbial mats in hot springs globally.

  • 2. Ali, Raja H.
    et al.
    Bark, Mikael
    Miró, Jorge
    Muhammad, Sayyed A.
    Sjöstrand, Joel
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Centre, Sweden.
    Zubair, Syed M.
    Abbas, Raja M.
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Centre, Sweden.
    VMCMC: a graphical and statistical analysis tool for Markov chain Monte Carlo traces2017Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 18, artikel-id 97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: 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 difficulties 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.

    Conclusions: VMCMC is a free software available under the New BSD License. Executable jar files, tutorial manual and source code can be downloaded from https://bitbucket. org/rhali/visualmcmc/.

  • 3.
    Baumgarten, Thomas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ytterberg, A. Jimmy
    Zubarev, Roman A.
    de Gier, Jan-Willem
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Optimizing Recombinant Protein Production in the Escherichia coli Periplasm Alleviates Stress2018Ingår i: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 84, nr 12, artikel-id e00270Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In Escherichia coli, many recombinant proteins are produced in the periplasm. To direct these proteins to this compartment, they are equipped with an N-terminal signal sequence so that they can traverse the cytoplasmic membrane via the protein-conducting Sec translocon. Recently, using the single-chain variable antibody fragment BL1, we have shown that harmonizing the target gene expression intensity with the Sec translocon capacity can be used to improve the production yields of a recombinant protein in the periplasm. Here, we have studied the consequences of improving the production of BL1 in the periplasm by using a proteomics approach. When the target gene expression intensity is not harmonized with the Sec translocon capacity, the impaired translocation of secretory proteins, protein misfolding/aggregation in the cytoplasm, and an inefficient energy metabolism result in poor growth and low protein production yields. The harmonization of the target gene expression intensity with the Sec translocon capacity results in normal growth, enhanced protein production yields, and, surprisingly, a composition of the proteome that is-besides the produced target-the same as that of cells with an empty expression vector. Thus, the single-chain variable antibody fragment BL1 can be efficiently produced in the periplasm without causing any notable detrimental effects to the production host. Finally, we show that under the optimized conditions, a small fraction of the target protein is released into the extracellular milieu via outer membrane vesicles. We envisage that our observations can be used to design strategies to further improve the production of secretory recombinant proteins in E. coli.

    IMPORTANCE The bacterium Escherichia coli is widely used to produce recombinant proteins. Usually, trial-and-error-based screening approaches are used to identify conditions that lead to high recombinant protein production yields. Here, for the production of an antibody fragment in the periplasm of E. coli, we show that an optimization of its production is accompanied by the alleviation of stress. This indicates that the monitoring of stress responses could be used to facilitate enhanced recombinant protein production yields.

  • 4.
    Bergqvist, Cecilia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Jafferali, Mohammed Hakim
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Gudise, Santhosh
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Markus, Robert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Hallberg, Einar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    An inner nuclear membrane protein induces rapid differentiation of human induced pluripotent stem cells2017Ingår i: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 23, s. 33-38Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ability of iPSCs (induced pluripotent stem cells) to generate any cell type in the body makes them valuable tools for cell replacement therapies. However, differentiation of iPSCs can be demanding, slowand variable. During differentiation chromatin is re-organized and silent dense heterochromatin becomes tethered to the nuclear periphery by processes involving the nuclear lamina and proteins of the INM(inner nuclearmembrane). The INM protein, Samp1 (Spindle AssociatedMembrane Protein 1) interacts with Lamin A/C and the INMprotein Emerin, which has a chromatin binding LEM(Lap2-Emerin-Man1)-domain. In this paperweinvestigate if Samp1 can play a role in the differentiation of iPSCs. Samp1 levels increased as differentiating iPSCs started to express Lamin A/C. Interestingly, even under pluripotent culturing conditions, ectopic expression of Samp1 induced a rapid differentiation of iPSCs, ofwhich some expressed the neuronal marker beta III-tubulin already after 6 days. This suggests that Samp1 is involved in early differentiation of iPSCs and could potentially be explored as a tool to promote progression of the differentiation process.

  • 5.
    Bonaglia, Stefano
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Rämö, Robert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Marzocchi, Ugo
    Le Bouille, Léonie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Leermakers, Martine
    Nascimento, Francisco J. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Gunnarsson, Jonas S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Capping with activated carbon reduces nutrient fluxes, denitrification and meiofauna in contaminated sediments2019Ingår i: Water Research, ISSN 0043-1354, E-ISSN 1879-2448, Vol. 148, s. 515-525Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sediment capping with activated carbon (AC) is an effective technique used in remediation of contaminated sediments, but the ecological effects on benthic microbial activity and meiofauna communities have been largely neglected. This study presents results from a 4-week experiment investigating the influence of two powdered AC materials (bituminous coal-based and coconut shell-derived) and one control material (clay) on biogeochemical processes and meiofauna in contaminated sediments. Capping with AC induced a 62‒63% decrease in denitrification and a 66‒87 % decrease in dissimilatory nitrate reduction to ammonium (DNRA). Sediment porewater pH increased from 7.1 to 9.0 and 9.7 after addition of bituminous AC and biomass-derived AC, respectively. High pH (>8) persisted for at least two weeks in the bituminous AC and for at least 24 days in the coconut based AC, while capping with clay had no effect on pH. We observed a strong impact (nitrate fluxes being halved in presence of AC) on nitrification activity as nitrifiers are sensitive to high pH. This partly explains the significant decrease in nitrate reduction rates since denitrification was almost entirely coupled to nitrification. Total benthic metabolism estimated by sediment oxygen uptake was reduced by 30 and 43 % in presence of bituminous coal-based AC and coconut shell-derived AC, respectively. Meiofauna abundances decreased by 60‒62 % in the AC treatments. Taken together, these observations suggest that AC amendments deplete natural organic carbon, intended as food, to heterotrophic benthic communities. Phosphate efflux was 91 % lower in presence of bituminous AC compared to untreated sediment probably due to its content of aluminum (Al) oxides, which have high affinity for phosphate. This study demonstrates that capping with powdered AC produces significant effects on benthic biogeochemical fluxes, microbial processes and meiofauna abundances, which are likely due to an increase in porewater pH and to the sequestration of natural, sedimentary organic matter by AC particles.

  • 6. Bylund, Jonas
    What's The Problem With Non-conventional Technology?: The Stockholm Local Investment Programme and the Eco-cycling Districts2003Ingår i: Time to turn down energy demand / [ed] Sophie Attali, Eliane Métreau, Mélisande Prône, Kenya Tillerson, Stockholm: European Council for an Energy-Efficient Economy - ECEEE , 2003, s. 853-861Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    This paper analyses barriers towards implementation of non-conventional energy and resource efficient technology in the context of urban development. It gives tentative conclusions based on an ongoing Ph.D. dissertation project. The case is the measures the city of Stockholm launched with the help of a Swedish Governmental subsidy program – the Local Investment Program (LIP). The LIP runs from 1998 to 2003 and is intended to help municipalities nationwide adapt to the demands of an ecologically sustainable society. Measures that uses new, or in the terminology of this paper, non-conventional technology are explicitly supported in the program. Stockholm was granted 67 million Euro to subsidize different projects, among them the eco-cycling districts of Hammarby Sjöstad, Östberga and Skärholmen. Experiences reported by the municipal LIP co-ordinators nationwide are that only half of all the programs are realized as intended in the applications. As the project is work in progress this paper will try to answer the following questions: Why are some projects successful and others not? Why are sustainability-measures in these projects not carried out completely? Which agents and mediators do help or hinder the subsidies to become a realized and working technology in the city? What is the problem with non-conventional technology really? What parts does politics, policy and administrative practices as well as ‘rational’ economical behaviours play? Some old obstacles, but are new solutions dependent on unorthodox practice or simply more money? Knowledge on these issues is (still) important for subsequent policies and programs on energy and resource efficiency.

  • 7. Carinelli, S.
    et al.
    Kühnemund, M.
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Pividori, M. I.
    Yoctomole electrochemical genosensing of Ebola virus cDNA by rolling circle and circle to circle amplification2017Ingår i: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 93, s. 65-71Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This work addresses the design of an Ebola diagnostic test involving a simple, rapid, specific and highly sensitive procedure based on isothermal amplification on magnetic particles with electrochemical readout. Ebola padlock probes were designed to detect a specific L-gene sequence present in the five most common Ebola species. Ebola cDNA was amplified by rolling circle amplification (RCA) on magnetic particles. Further re-amplification was performed by circle-to-circle amplification (C2CA) and the products were detected in a double-tagging approach using a biotinylated capture probe for immobilization on magnetic particles and a readout probe for electrochemical detection by square-wave voltammetry on commercial screen-printed electrodes. The electrochemical genosensor was able to detect as low as 200 ymol, corresponding to 120 cDNA molecules of L-gene Ebola virus with a limit of detection of 33 cDNA molecules. The isothermal double-amplification procedure by C2CA combined with the electrochemical readout and the magnetic actuation enables the high sensitivity, resulting in a rapid, inexpensive, robust and user-friendly sensing strategy that offers a promising approach for the primary care in low resource settings, especially in less developed countries.

  • 8.
    Dahlin, Paul
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Royal Institute of Technology (KTH), Sweden.
    Müller, Marion C.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Royal Institute of Technology (KTH), Sweden.
    Ekengren, Sophia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Royal Institute of Technology (KTH), Sweden.
    McKee, Lauren S.
    Bulone, Vincent
    The Impact of Steroidal Glycoalkaloids on the Physiology of Phytophthora infestans, the Causative Agent of Potato Late Blight2017Ingår i: Molecular Plant-Microbe Interactions, ISSN 0894-0282, E-ISSN 1943-7706, Vol. 30, nr 7, s. 531-542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Steroidal glycoalkaloids (SGAs) are plant secondary metabolites known to be toxic to animals and humans and that have putative roles in defense against pests. The proposed mechanisms of SGA toxicity are sterol-mediated disruption of membranes and inhibition of cholinesterase activity in neurons. It has been suggested that phytopathogenic microorganisms can overcome SGA toxicity by enzymatic deglycosylation of SGAs. Here, we have explored SGA-mediated toxicity toward the invasive oomycete Phytophthora infestans, the causative agent of the late blight disease in potato and tomato, as well as the potential for SGA deglycosylation by this species. Our growth studies indicate that solanidine, the nonglycosylated precursor of the potato SGAs a-chaconine and a-solanine, has a greater physiological impact than its glycosylated forms. All of these compounds were incorporated into the mycelium, but only solanidine could strongly inhibit the growth of P. infestans in liquid culture. Genes encoding several glycoside hydrolases with potential activity on SGAs were identified in the genome of P. infestans and were shown to be expressed. However, we found no indication that deglycosylation of SGAs takes place. We present additional evidence for apparent host-specific adaptation to potato SGAs and assess all results in terms of future pathogen management strategies.

  • 9.
    Daniel, Chammiran
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Widmark, Albin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Rigardt, Ditte
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Öhman, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Editing inducer elements increases A-to-I editing efficiency in the mammalian transcriptome2017Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 18, artikel-id 195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Adenosine to inosine (A-to-I) RNA editing has been shown to be an essential event that plays a significant role in neuronal function, as well as innate immunity, in mammals. It requires a structure that is largely double-stranded for catalysis but little is known about what determines editing efficiency and specificity in vivo. We have previously shown that some editing sites require adjacent long stem loop structures acting as editing inducer elements (EIEs) for efficient editing. Results: The glutamate receptor subunit A2 is edited at the Q/R site in almost 100% of all transcripts. We show that efficient editing at the Q/R site requires an EIE in the downstream intron, separated by an internal loop. Also, other efficiently edited sites are flanked by conserved, highly structured EIEs and we propose that this is a general requisite for efficient editing, while sites with low levels of editing lack EIEs. This phenomenon is not limited to mRNA, as non-coding primary miRNAs also use EIEs to recruit ADAR to specific sites. Conclusions: We propose a model where two regions of dsRNA are required for efficient editing: first, an RNA stem that recruits ADAR and increases the local concentration of the enzyme, then a shorter, less stable duplex that is ideal for efficient and specific catalysis. This discovery changes the way we define and determine a substrate for A-to-I editing. This will be important in the discovery of novel editing sites, as well as explaining cases of altered editing in relation to disease.

  • 10. Dash-Wagh, Suvarna
    et al.
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ulfendahl, Mats
    PepFect6 Mediated SiRNA Delivery into Organotypic Cultures2016Ingår i: SiRNA Delivery Methods: Methods and Protocols / [ed] K. Shum, J. Rossi, TOTOWA: HUMANA PRESS INC , 2016, Vol. 1364, s. 27-35Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Gene silencing by small interfering RNA (SiRNA) is an attractive therapeutic approach for pathological disorders that targets a specific gene. However, its applications are limited, as naked RNA is rapidly degraded by RNases and is inadequately internalized by the target cells in the body. Several viral and non-viral vectors have been described to improve the delivery of SiRNAs both in cultured cells as well as in vivo. Increasing evidence suggests that cell-penetrating peptides (CPPs) are an efficient, non-cytotoxic tool for intracellular delivery of SiRNA. Recently, a new peptide, PepFect6 (PF6), based system has been described for efficient SiRNA delivery in various cell types. PF6 is an amphipathic stearyl-TP10 peptide carrying a pH titratable trifluoromethylquinoline moiety that facilitate endosomal release. PF6 forms stable non-covalent complexes with SiRNA. Upon internalization, the complexes rapidly escape the endosomal compartment, resulting in robust RNA interference (RNAi) responses. This chapter describes a protocol to use the PF6-nanoparticle technology for SiRNA delivery into organotypic cultures of the inner ear i.e., cochlea. We also highlight different critical points in the peptide/SiRNA complex preparation, transfection and in analyzing the efficacy of PF6-SiRNA associated RNAi response.

  • 11. Dimou, Niki L.
    et al.
    Tsirigos, Konstantinos D.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center, Sweden.
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center, Sweden.
    Bagos, Pantelis G.
    GWAR: robust analysis and meta-analysis of genome-wide association studies2017Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 33, nr 10, s. 1521-1527Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: In the context of genome-wide association studies (GWAS), there is a variety of statistical techniques in order to conduct the analysis, but, in most cases, the underlying genetic model is usually unknown. Under these circumstances, the classical Cochran-Armitage trend test (CATT) is suboptimal. Robust procedures that maximize the power and preserve the nominal type I error rate are preferable. Moreover, performing a meta-analysis using robust procedures is of great interest and has never been addressed in the past. The primary goal of this work is to implement several robust methods for analysis and meta-analysis in the statistical package Stata and subsequently to make the software available to the scientific community. Results: The CATT under a recessive, additive and dominant model of inheritance as well as robust methods based on the Maximum Efficiency Robust Test statistic, the MAX statistic and the MIN2 were implemented in Stata. Concerning MAX and MIN2, we calculated their asymptotic null distributions relying on numerical integration resulting in a great gain in computational time without losing accuracy. All the aforementioned approaches were employed in a fixed or a random effects meta-analysis setting using summary data with weights equal to the reciprocal of the combined cases and controls. Overall, this is the first complete effort to implement procedures for analysis and meta-analysis in GWAS using Stata.

  • 12. Drake, Henrik
    et al.
    Åström, Mats E.
    Heim, Christine
    Broman, Curt
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper.
    Åström, Jan
    Whitehouse, Martin
    Ivarsson, Magnus
    Siljeström, Sandra
    Sjövall, Peter
    Extreme C-13 depletion of carbonates formed during oxidation of biogenic methane in fractured granite2015Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 7020Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Precipitation of exceptionally C-13-depleted authigenic carbonate is a result of, and thus a tracer for, sulphate-dependent anaerobic methane oxidation, particularly in marine sediments. Although these carbonates typically are less depleted in C-13 than in the source methane, because of incorporation of C also from other sources, they are far more depleted in C-13 (delta C-13 as light as - 69% V-PDB) than in carbonates formed where no methane is involved. Here we show that oxidation of biogenic methane in carbon-poor deep groundwater in fractured granitoid rocks has resulted in fracture-wall precipitation of the most extremely C-13-depleted carbonates ever reported, delta C-13 down to - 125% V-PDB. A microbial consortium of sulphate reducers and methane oxidizers has been involved, as revealed by biomarker signatures in the carbonates and S-isotope compositions of co-genetic sulphide. Methane formed at shallow depths has been oxidized at several hundred metres depth at the transition to a deep-seated sulphate-rich saline water. This process is so far an unrecognized terrestrial sink of methane.

  • 13. Duchemin, Wandrille
    et al.
    Gence, Guillaume
    Chifolleau, Anne-Muriel Arigon
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Matematiska institutionen. Swedish e-Science Research Centre (SeRC), Sweden.
    Bansal, Mukul S.
    Berry, Vincent
    Boussau, Bastien
    Chevenet, Francois
    Comte, Nicolas
    Davin, Adrian A.
    Dessimoz, Christophe
    Dylus, David
    Hasic, Damir
    Mallo, Diego
    Planel, Remi
    Posada, David
    Scornavacca, Celine
    Szollosi, Gergely
    Zhang, Louxin
    Tannier, Eric
    Daubin, Vincent
    RecPhyloXML: a format for reconciled gene trees2018Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 34, nr 21, s. 3646-3652Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: A reconciliation is an annotation of the nodes of a gene tree with evolutionary events-for example, speciation, gene duplication, transfer, loss, etc. -along with a mapping onto a species tree. Many algorithms and software produce or use reconciliations but often using different reconciliation formats, regarding the type of events considered or whether the species tree is dated or not. This complicates the comparison and communication between different programs. Results: Here, we gather a consortium of software developers in gene tree species tree reconciliation to propose and endorse a format that aims to promote an integrative-albeit flexible-specification of phylogenetic reconciliations. This format, named recPhyloXML, is accompanied by several tools such as a reconciled tree visualizer and conversion utilities.

  • 14. Eberlein, Christian
    et al.
    Baumgarten, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Starke, Stephan
    Heipieper, Hermann J.
    Immediate response mechanisms of Gram-negative solvent-tolerant bacteria to cope with environmental stress: cis-trans isomerization of unsaturated fatty acids and outer membrane vesicle secretion2018Ingår i: Applied Microbiology and Biotechnology, ISSN 0175-7598, E-ISSN 1432-0614, Vol. 102, nr 6, s. 2583-2593Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Bacteria have evolved an array of adaptive mechanisms enabling them to survive and grow in the presence of different environmental stresses. These mechanisms include either modifications of the membrane or changes in the overall energy status, cell morphology, and cell surface properties. Long-term adaptations are dependent on transcriptional regulation, the induction of anabolic pathways, and cell growth. However, to survive sudden environmental changes, bacterial short-term responses are essential to keep the cells alive after the occurrence of an environmental stress factor such as heat shock or the presence of toxic organic solvents. Thus far, two main short-term responses are known. On the one hand, a fast isomerization of cis into trans unsaturated fatty leads to a quick rigidification of the cell membrane, a mechanism known in some genera of Gram-negative bacteria. On the other hand, a fast, effective, and ubiquitously present countermeasure is the release of outer membrane vesicles (OMVs) from the cell surface leading to a rapid increase in cell surface hydrophobicity and finally to the formation of cell aggregates and biofilms. These immediate response mechanisms just allow the bacteria to stay physiologically active and to employ long-term responses to assure viability upon changing environmental conditions. Here, we provide insight into the two aforementioned rapid adaptive mechanisms affecting ultimately the cell envelope of Gram-negative bacteria.

  • 15.
    Eriksson, Olivia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden; Swedish e-Science Research Centre (SeRC), Sweden.
    Jauhiainen, Alexandra
    Sasane, Sara Maad
    Kramer, Andrei
    Nair, Anu G.
    Sartorius, Carolina
    Hellgren Kotaleski, Jeanette
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden; Swedish e-Science Research Centre (SeRC), Sweden.
    Uncertainty quantification, propagation and characterization by Bayesian analysis combined with global sensitivity analysis applied to dynamical intracellular pathway models2019Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, nr 2, s. 284-292Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: Dynamical models describing intracellular phenomena are increasing in size and complexity as more information is obtained from experiments. These models are often over-parameterized with respect to the quantitative data used for parameter estimation, resulting in uncertainty in the individual parameter estimates as well as in the predictions made from the model. Here we combine Bayesian analysis with global sensitivity analysis (GSA) in order to give better informed predictions; to point out weaker parts of the model that are important targets for further experiments, as well as to give guidance on parameters that are essential in distinguishing different qualitative output behaviours.

    Results: We used approximate Bayesian computation (ABC) to estimate the model parameters from experimental data, as well as to quantify the uncertainty in this estimation (inverse uncertainty quantification), resulting in a posterior distribution for the parameters. This parameter uncertainty was next propagated to a corresponding uncertainty in the predictions (forward uncertainty propagation), and a GSA was performed on the predictions using the posterior distribution as the possible values for the parameters. This methodology was applied on a relatively large model relevant for synaptic plasticity, using experimental data from several sources. We could hereby point out those parameters that by themselves have the largest contribution to the uncertainty of the prediction as well as identify parameters important to separate between qualitatively different predictions. This approach is useful both for experimental design as well as model building.

  • 16.
    Ewels, Philip
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Magnusson, Måns
    Lundin, Sverker
    Käller, Max
    MultiQC: summarize analysis results for multiple tools and samples in a single report2016Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, nr 19, s. 3047-3048Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: Fast and accurate quality control is essential for studies involving next-generation sequencing data. Whilst numerous tools exist to quantify QC metrics, there is no common approach to flexibly integrate these across tools and large sample sets. Assessing analysis results across an entire project can be time consuming and error prone; batch effects and outlier samples can easily be missed in the early stages of analysis.

    Results: We present MultiQC, a tool to create a single report visualising output from multiple tools across many samples, enabling global trends and biases to be quickly identified. MultiQC can plot data from many common bioinformatics tools and is built to allow easy extension and customization.

  • 17. Garg, Shilpa
    et al.
    Martin, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Marschall, Tobias
    Read-based phasing of related individuals2016Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, nr 12, s. 234-242Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: Read-based phasing deduces the haplotypes of an individual from sequencing reads that cover multiple variants, while genetic phasing takes only genotypes as input and applies the rules of Mendelian inheritance to infer haplotypes within a pedigree of individuals. Combining both into an approach that uses these two independent sources of information-reads and pedigree-has the potential to deliver results better than each individually. Results: We provide a theoretical framework combining read-based phasing with genetic haplotyping, and describe a fixed-parameter algorithm and its implementation for finding an optimal solution. We show that leveraging reads of related individuals jointly in this way yields more phased variants and at a higher accuracy than when phased separately, both in simulated and real data. Coverages as low as 2 x for each member of a trio yield haplotypes that are as accurate as when analyzed separately at 15 x coverage per individual.

  • 18. Gómez-Navarro, Natalia
    et al.
    Jordán-Pla, Antonio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Universitat de València, Spain.
    Estruch, Francisco
    Pérez-Ortín, José E.
    Defects in the NC2 repressor affect both canonical and non-coding RNA polymerase II transcription initiation in yeast2016Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The formation of the pre-initiation complex in eukaryotic genes is a key step in transcription initiation. The TATA-binding protein (TBP) is a universal component of all pre-initiation complexes for all kinds of RNA polymerase II (RNA pol II) genes, including those with a TATA or a TATA-like element, both those that encode proteins and those that transcribe non-coding RNAs. Mot1 and the negative cofactor 2 (NC2) complex are regulators of TBP, and it has been shown that depletion of these factors in yeast leads to defects in the control of transcription initiation that alter cryptic transcription levels in selected yeast loci. Results: In order to cast light on the molecular functions of NC2, we performed genome-wide studies in conditional mutants in yeast NC2 essential subunits Ydr1 and Bur6. Our analyses show a generally increased level of cryptic transcription in all kinds of genes upon depletion of NC2 subunits, and that each kind of gene (canonical or ncRNAs, TATA or TATA-like) shows some differences in the cryptic transcription pattern for each NC2 mutant. Conclusions: We conclude that NC2 plays a general role in transcription initiation in RNA polymerase II genes that is related with its known TBP interchange function from free to promoter bound states. Therefore, loss of the NC2 function provokes increases in cryptic transcription throughout the yeast genome. Our results also suggest functional differences between NC2 subunits Ydr1 and Bur6.

  • 19. Hagey, Daniel W.
    et al.
    Zaouter, Cecile
    Combeau, Gaelle
    Andersson Lendahl, Monika
    Andersson, Olov
    Huss, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Muhr, Jonas
    Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells2016Ingår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 26, nr 7, s. 908-917Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spatially distinct gene expression profiles in neural stem cells (NSCs) are a prerequisite to the formation of neuronal diversity, but how these arise from the regulatory interactions between chromatin accessibility and transcription factor activity has remained unclear. Here, we demonstrate that, despite their distinct gene expression profiles, NSCs of the mouse cortex and spinal cord share the majority of their DNase I hypersensitive sites (DHSs). Regardless of this similarity, domain-specific gene expression is highly correlated with the relative accessibility of associated DHSs, as determined by sequence read density. Notably, the binding pattern of the general NSC transcription factor SOX2 is also largely cell type specific and coincides with an enrichment of LHX2 motifs in the cortex and HOXA9 motifs in the spinal cord. Interestingly, in a zebrafish reporter gene system, these motifs were critical determinants of patterned gene expression along the rostral-caudal axis. Our findings establish a predictive model for patterned NSC gene expression, whereby domain-specific expression of LHX2 and HOX proteins act on their target motifs within commonly accessible cis-regulatory regions to specify SOX2 binding. In turn, this binding correlates strongly with these DHSs relative accessibility-a robust predictor of neighboring gene expression.

  • 20.
    Haider, Christian
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). University of Applied Sciences Upper Austria, Austria.
    Kavic, Marina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). University of Applied Sciences Upper Austria, Austria.
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    TreeDom: a graphical web tool for analysing domain architecture evolution2016Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, nr 15, s. 2384-2385Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present TreeDom, a web tool for graphically analysing the evolutionary history of domains in multi-domain proteins. Individual domains on the same protein chain may have distinct evolutionary histories, which is important to grasp in order to understand protein function. For instance, it may be important to know whether a domain was duplicated recently or long ago, to know the origin of inserted domains, or to know the pattern of domain loss within a protein family. TreeDom uses the Pfam database as the source of domain annotations, and displays these on a sequence tree. An advantage of TreeDom is that the user can limit the analysis to N sequences that are most similar to a query, or provide a list of sequence IDs to include. Using the Pfam alignment of the selected sequences, a tree is built and displayed together with the domain architecture of each sequence.

  • 21.
    Hernández-Neuta, Iván
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Pereiro, Iago
    Ahlford, Annika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ferraro, Davide
    Zhang, Qiongdi
    Viovy, Jean-Louis
    Descroix, Stéphanie
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Microfluidic magnetic fluidized bed for DNA analysis in continuous flow mode2018Ingår i: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 102, s. 531-539Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Magnetic solid phase substrates for biomolecule manipulation have become a valuable tool for simplification and automation of molecular biology protocols. However, the handling of magnetic particles inside microfluidic chips for miniaturized assays is often challenging due to inefficient mixing, aggregation, and the advanced instrumentation required for effective actuation. Here, we describe the use of a microfluidic magnetic fluidized bed approach that enables dynamic, highly efficient and simplified magnetic bead actuation for DNA analysis in a continuous flow platform with minimal technical requirements. We evaluate the performance of this approach by testing the efficiency of individual steps of a DNA assay based on padlock probes and rolling circle amplification. This assay comprises common nucleic acid analysis principles, such as hybridization, ligation, amplification and restriction digestion. We obtained efficiencies of up to 90% for these reactions with high throughput processing up to 120 mu L of DNA dilution at flow rates ranging from 1 to 5 mu L/min without compromising performance. The fluidized bed was 20-50% more efficient than a commercially available solution for microfluidic manipulation of magnetic beads. Moreover, to demonstrate the potential of this approach for integration into micro-total analysis systems, we optimized the production of a low-cost polymer based microarray and tested its analytical performance for integrated single-molecule digital read-out. Finally, we provide the proof-of-concept for a single-chamber microfluidic chip that combines the fluidized bed with the polymer microarray for a highly simplified and integrated magnetic bead-based DNA analyzer, with potential applications in diagnostics.

  • 22.
    Höhna, Sebastian
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Matematiska institutionen. University of California, USA.
    May, Michael R.
    Moore, Brian R.
    TESS: an R package for efficiently simulating phylogenetic trees and performing Bayesian inference of lineage diversification rates2016Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, nr 5, s. 789-791Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many fundamental questions in evolutionary biology entail estimating rates of lineage diversification (speciation-extinction) that are modeled using birth-death branching processes. We leverage recent advances in branching-process theory to develop a flexible Bayesian framework for specifying diversification models-where rates are constant, vary continuously, or change episodically through time-and implement numerical methods to estimate parameters of these models from molecular phylogenies, even when species sampling is incomplete. We enable both statistical inference and efficient simulation under these models. We also provide robust methods for comparing the relative and absolute fit of competing branching-process models to a given tree, thereby providing rigorous tests of biological hypotheses regarding patterns and processes of lineage diversification.

  • 23.
    Johnson, Francis X.
    et al.
    Stockholms universitet, Stockholm Resilience Centre, Stockholm Environment Institute.
    Seebaluck, Vikram
    Bioenergy for sustainable development and international competitiveness: the role of sugar cane in Africa2012Samlingsverk (redaktörskap) (Övrigt vetenskapligt)
  • 24. Jong, Wouter S. P.
    et al.
    ten Hagen-Jongman, Corinne M.
    Vikström, David
    Dontje, Wendy
    Abdallah, Abdallah M.
    de Gier, Jan-Willem
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Bitter, Wilbert
    Luirink, Joen
    Mutagenesis-Based Characterization and Improvement of a Novel Inclusion Body Tag2020Ingår i: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 7, artikel-id 442Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Whereas, bacterial inclusion bodies (IBs) for long were regarded as undesirable aggregates emerging during recombinant protein production, they currently receive attention as promising nanoparticulate biomaterials with diverse applications in biotechnology and biomedicine. We previously identified ssTorA, a signal sequence that normally directs protein export via the Tat pathway in E. coli, as a tag that induces the accumulation of fused proteins into IBs under overexpression conditions. Here, we used targeted mutagenesis to identify features and motifs being either critical or dispensable for IB formation. We found that IB formation is neither related to the function of ssTorA as a Tat-signal sequence nor is it a general feature of this family of signal sequences. IB formation was inhibited by co-overexpression of ssTorA binding chaperones TorD and DnaK and by amino acid substitutions that affect the propensity of ssTorA to form an alpha-helix. Systematic deletion experiments identified a minimal region of ssTorA required for IB formation in the center of the signal sequence. Unbiased genetic screening of a library of randomly mutagenized ssTorA sequences for reduced aggregation properties allowed us to pinpoint residues that are critical to sustain insoluble expression. Together, the data point to possible mechanisms for the aggregation of ssTorA fusions. Additionally, they led to the design of a tag with superior IB-formation properties compared to the original ssTorA sequence.

  • 25. Jong, Wouter S. P.
    et al.
    Vikström, David
    Houben, Diane
    van den Berg van Saparoea, H. Bart
    de Gier, Jan-Willem
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Luirink, Joen
    Application of an E. coli signal sequence as a versatile inclusion body tag2017Ingår i: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 16, artikel-id 50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Heterologous protein production in Escherichia coli often suffers from bottlenecks such as proteolytic degradation, complex purification procedures and toxicity towards the expression host. Production of proteins in an insoluble form in inclusion bodies (IBs) can alleviate these problems. Unfortunately, the propensity of heterologous proteins to form IBs is variable and difficult to predict. Hence, fusing the target protein to an aggregation prone polypeptide or IB-tag is a useful strategy to produce difficult-to-express proteins in an insoluble form. Results: When screening for signal sequences that mediate optimal targeting of heterologous proteins to the periplasmic space of E. coli, we observed that fusion to the 39 amino acid signal sequence of E. coli TorA (ssTorA) did not promote targeting but rather directed high-level expression of the human proteins hEGF, Pla2 and IL-3 in IBs. Further analysis revealed that ssTorA even mediated IB formation of the highly soluble endogenous E. coli proteins TrxA and MBP. The ssTorA also induced aggregation when fused to the C-terminus of target proteins and appeared functional as IB-tag in E. coli K-12 as well as B strains. An additive effect on IB-formation was observed upon fusion of multiple ssTorA sequences in tandem, provoking almost complete aggregation of TrxA and MBP. The ssTorA-moiety was successfully used to produce the intrinsically unstable hEGF and the toxic fusion partner SymE, demonstrating its applicability as an IB-tag for difficult-to-express and toxic proteins. Conclusions: We present proof-of-concept for the use of ssTorA as a small, versatile tag for robust E. coli-based expression of heterologous proteins in IBs.

  • 26.
    Jordán-Pla, Antonio
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Yu, Simei
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Waldholm, Johan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Källman, Thomas
    Östlund Farrants, Ann-Kristin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Visa, Neus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    SWI/SNF regulates half of its targets without the need of ATP-driven nucleosome remodeling by Brahma2018Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 19, artikel-id 367Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Brahma (BRM) is the only catalytic subunit of the SVVI/SNF chromatin-remodeling complex of Drosophila melanogaster. The function of SWI/SNF in transcription has long been attributed to its ability to remodel nucleosomes, which requires the ATPase activity of BRM. However, recent studies have provided evidence for a non-catalytic function of BRM in the transcriptional regulation of a few specific genes.

    Results: Here we have used RNA-seq and ChIP-seq to identify the BRM target genes in 52 cells, and we have used a catalytically inactive BRM mutant (K804R) that is unable to hydrolyze ATP to investigate the magnitude of the non-catalytic function of BRM in transcription regulation. We show that 49% of the BRM target genes in 52 cells are regulated through mechanisms that do not require BRM to have an ATPase activity. We also show that the catalytic and non-catalytic mechanisms of SVVI/SNF regulation operate on two subsets of genes that differ in promoter architecture and are linked to different biological processes.

    Conclusions: This study shows that the non-catalytic role of SWI/SNF in transcription regulation is far more prevalent than previously anticipated and that the genes that are regulated by SVVI/SNF through ATPase-dependent and ATPase-independent mechanisms have specialized roles in different cellular and developmental processes.

  • 27.
    Kang, Wenjing
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Eldfjell, Yrin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fromm, Bastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Estivill, Xavier
    Biryukova, Inna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Friedländer, Marc R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    miRTrace reveals the organismal origins of microRNA sequencing data2018Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 19, artikel-id 213Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present here miRTrace, the first algorithm to trace microRNA sequencing data back to their taxonomic origins. This is a challenge with profound implications for forensics, parasitology, food control, and research settings where cross-contamination can compromise results. miRTrace accurately (> 99%) assigns real and simulated data to 14 important animal and plant groups, sensitively detects parasitic infection in mammals, and discovers the primate origin of single cells. Applying our algorithm to over 700 public datasets, we find evidence that over 7% are cross-contaminated and present a novel solution to clean these computationally, even after sequencing has occurred.

  • 28. Khan, Mehmood Alam
    et al.
    Mahmudi, Owais
    Ullah, Ikram
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Centre, Sweden.
    Lagergren, Jens
    Probabilistic inference of lateral gene transfer events2016Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 17, nr Suppl 14, artikel-id 431Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Lateral gene transfer (LGT) is an evolutionary process that has an important role in biology. It challenges the traditional binary tree-like evolution of species and is attracting increasing attention of the molecular biologists due to its involvement in antibiotic resistance. A number of attempts have been made to model LGT in the presence of gene duplication and loss, but reliably placing LGT events in the species tree has remained a challenge.

    Results: In this paper, we propose probabilistic methods that samples reconciliations of the gene tree with a dated species tree and computes maximum a posteriori probabilities. The MCMC-based method uses the probabilistic model DLTRS, that integrates LGT, gene duplication, gene loss, and sequence evolution under a relaxed molecular clock for substitution rates. We can estimate posterior distributions on gene trees and, in contrast to previous work, the actual placement of potential LGT, which can be used to, e.g., identify highways of LGT.

    Conclusions: Based on a simulation study, we conclude that the method is able to infer the true LGT events on gene tree and reconcile it to the correct edges on the species tree in most cases. Applied to two biological datasets, containing gene families from Cyanobacteria and Molicutes, we find potential LGTs highways that corroborate other studies as well as previously undetected examples.

  • 29.
    Kucerova, Lucie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kubrak, Olga I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Bengtsson, Jonas M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Strnad, Hynek
    Nylin, Sören
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Slowed aging during reproductive dormancy is reflected in genome-wide transcriptome changes in Drosophila melanogaster2016Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, artikel-id 50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In models extensively used in studies of aging and extended lifespan, such as C. elegans and Drosophila, adult senescence is regulated by gene networks that are likely to be similar to ones that underlie lifespan extension during dormancy. These include the evolutionarily conserved insulin/IGF, TOR and germ line-signaling pathways. Dormancy, also known as dauer stage in the larval worm or adult diapause in the fly, is triggered by adverse environmental conditions, and results in drastically extended lifespan with negligible senescence. It is furthermore characterized by increased stress resistance and somatic maintenance, developmental arrest and reallocated energy resources. In the fly Drosophila melanogaster adult reproductive diapause is additionally manifested in arrested ovary development, improved immune defense and altered metabolism. However, the molecular mechanisms behind this adaptive lifespan extension are not well understood. Results: A genome wide analysis of transcript changes in diapausing D. melanogaster revealed a differential regulation of more than 4600 genes. Gene ontology (GO) and KEGG pathway analysis reveal that many of these genes are part of signaling pathways that regulate metabolism, stress responses, detoxification, immunity, protein synthesis and processes during aging. More specifically, gene readouts and detailed mapping of the pathways indicate downregulation of insulin-IGF (IIS), target of rapamycin (TOR) and MAP kinase signaling, whereas Toll-dependent immune signaling, Jun-N-terminal kinase (JNK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are upregulated during diapause. Furthermore, we detected transcriptional regulation of a large number of genes specifically associated with aging and longevity. Conclusions: We find that many affected genes and signal pathways are shared between dormancy, aging and lifespan extension, including IIS, TOR, JAK/STAT and JNK. A substantial fraction of the genes affected by diapause have also been found to alter their expression in response to starvation and cold exposure in D. melanogaster, and the pathways overlap those reported in GO analysis of other invertebrates in dormancy or even hibernating mammals. Our study, thus, shows that D. melanogaster is a genetically tractable model for dormancy in other organisms and effects of dormancy on aging and lifespan.

  • 30.
    Kuipers, Grietje
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Xbrane Biopharma AB, Sweden.
    Karyolaimos, Alexandros
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Zhang, Zhe
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ismail, Nurzian
    Trinco, Gianluca
    Vikström, David
    Slotboom, Dirk Jan
    de Gier, Jan-Willem
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The tunable pReX expression vector enables optimizing the T7-based production of membrane and secretory proteins in E. coli2017Ingår i: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 16, artikel-id 226Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: To optimize the production of membrane and secretory proteins in Escherichia coli, it is critical to harmonize the expression rates of the genes encoding these proteins with the capacity of their biogenesis machineries. Therefore, we engineered the Lemo21(DE3) strain, which is derived from the T7 RNA polymerase-based BL21(DE3) protein production strain. In Lemo21(DE3), the T7 RNA polymerase activity can be modulated by the controlled co-production of its natural inhibitor T7 lysozyme. This setup enables to precisely tune target gene expression rates in Lemo21(DE3). The t7lys gene is expressed from the pLemo plasmid using the titratable rhamnose promoter. A disadvantage of the Lemo21(DE3) setup is that the system is based on two plasmids, a T7 expression vector and pLemo. The aim of this study was to simplify the Lemo21(DE3) setup by incorporating the key elements of pLemo in a standard T7-based expression vector.

    Results: By incorporating the gene encoding the T7 lysozyme under control of the rhamnose promoter in a standard T7-based expression vector, pReX was created (ReX stands for Regulated gene eXpression). For two model membrane proteins and a model secretory protein we show that the optimized production yields obtained with the pReX expression vector in BL21(DE3) are similar to the ones obtained with Lemo21(DE3) using a standard T7 expression vector. For another secretory protein, a c-type cytochrome, we show that pReX, in contrast to Lemo21(DE3), enables the use of a helper plasmid that is required for the maturation and hence the production of this heme c protein.

    Conclusions: Here, we created pReX, a T7-based expression vector that contains the gene encoding the T7 lysozyme under control of the rhamnose promoter. pReX enables regulated T7-based target gene expression using only one plasmid. We show that with pReX the production of membrane and secretory proteins can be readily optimized. Importantly, pReX facilitates the use of helper plasmids. Furthermore, the use of pReX is not restricted to BL21(DE3), but it can in principle be used in any T7 RNAP-based strain. Thus, pReX is a versatile alternative to Lemo21(DE3).

  • 31. Kupferschmidt, Natalia
    et al.
    Xia, Xin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Labrador, Roberto H.
    Atluri, Rambabu
    Ballell, Lluis
    Garcia-Bennett, Alfonso E.
    In vivo oral toxicological evaluation of mesoporous silica particles2013Ingår i: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 8, nr 1, s. 57-64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Mesoporous silica particles are highly promising nanomaterials for biomedical applications. They can be used to improve bioavailability, solubility and drug stability and to protect drugs from the acidic conditions of the stomach, leading to increased drug effectiveness. Their biocompatibility in vivo has recieved little attention, in particular regarding oral administration. Aim: To study the oral tolerance of micron-sized nanoporous folic acid-templated material-1 (cylindrical, 2D hexagonal pore structure) and nanometer-sized anionic-surfactant-templated mesoporous silica material-6 (cylindrical, 3D cubic pore structure) mesoporous silica particles in Sprague Dawley rats. Materials & methods: A dose stepwise procedure or range finding test was followed by a consequent confirmatory test. The confirmatory test included daily administrations of 2000 and 1200 mg/kg doses for nanoporous folic acid-templated material-1 and anionic-surfactant-templated mesoporous silica material-6, respectively. Results: The maximum tolerated dose for anionic-surfactant-templated mesoporous silica material-6 was not reached. Similar results were observed for nanometer-sized anionic-surfactant-templated mesoporous silica material-1 in most of the animals, although adverse effects were observed in some animals that are most probably due to the administration by oral gavage of the formulated particles. Conclusion: The results are promising for the use of mesoporous silica materials as drug-delivery systems in oral administration.

  • 32. Lindskog, Cecilia
    et al.
    Linne, Jerker
    Fagerberg, Linn
    Hallström, Björn M.
    Sundberg, Carl Johan
    Lindholm, Malene
    Huss, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Kampf, Caroline
    Choi, Howard
    Liem, David A.
    Ping, Peipei
    Varemo, Leif
    Mardinoglu, Adil
    Nielsen, Jens
    Larsson, Erik
    Ponten, Fredrik
    Uhlen, Mathias
    The human cardiac and skeletal muscle proteomes defined by transcriptomics and antibody-based profiling2015Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, artikel-id 475Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: To understand cardiac and skeletal muscle function, it is important to define and explore their molecular constituents and also to identify similarities and differences in the gene expression in these two different striated muscle tissues. Here, we have investigated the genes and proteins with elevated expression in cardiac and skeletal muscle in relation to all other major human tissues and organs using a global transcriptomics analysis complemented with antibody-based profiling to localize the corresponding proteins on a single cell level. Results: Our study identified a comprehensive list of genes expressed in cardiac and skeletal muscle. The genes with elevated expression were further stratified according to their global expression pattern across the human body as well as their precise localization in the muscle tissues. The functions of the proteins encoded by the elevated genes are well in line with the physiological functions of cardiac and skeletal muscle, such as contraction, ion transport, regulation of membrane potential and actomyosin structure organization. A large fraction of the transcripts in both cardiac and skeletal muscle correspond to mitochondrial proteins involved in energy metabolism, which demonstrates the extreme specialization of these muscle tissues to provide energy for contraction. Conclusions: Our results provide a comprehensive list of genes and proteins elevated in striated muscles. A number of proteins not previously characterized in cardiac and skeletal muscle were identified and localized to specific cellular subcompartments. These proteins represent an interesting starting point for further functional analysis of their role in muscle biology and disease.

  • 33. Lopes, Viviana R.
    et al.
    Loitto, Vesa
    Audinot, Jean-Nicolas
    Bayat, Narges
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gutleb, Arno C.
    Cristobal, Susana
    Dose-dependent autophagic effect of titanium dioxide nanoparticles in human HaCaT cells at non-cytotoxic levels2016Ingår i: Journal of Nanobiotechnology, ISSN 1477-3155, E-ISSN 1477-3155, Vol. 14, artikel-id 22Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Interactions between nanoparticles and cells are now the focus of a fast-growing area of research. Though many nanoparticles interact with cells without any acute toxic responses, metal oxide nanoparticles including those composed of titanium dioxide (TiO2-NPs) may disrupt the intracellular process of macroautophagy. Autophagy plays a key role in human health and disease, particularly in cancer and neurodegenerative diseases. We herein investigated the in vitro biological effects of TiO2-NPs (18 nm) on autophagy in human keratinocytes (HaCaT) cells at non-cytotoxic levels. Results: TiO2-NPs were characterized by transmission electron microscopy (TEM) and dynamic light scattering techniques. Cellular uptake, as evaluated by TEM and NanoSIMS revealed that NPs internalization led to the formation of autophagosomes. TiO2-NPs treatment did not reduce cell viability of HaCaT cells nor increased oxidative stress. Cellular autophagy was additionally evaluated by confocal microscopy using eGFP-LC3 keratinocytes, western blotting of autophagy marker LC3I/II, immunodetection of p62 and NBR1 proteins, and gene expression of LC3II, p62, NBR1, beclin1 and ATG5 by RT-qPCR. We also confirmed the formation and accumulation of autophagosomes in NPs treated cells with LC3-II upregulation. Based on the lack of degradation of p62 and NBR1 proteins, autophagosomes accumulation at a high dose (25.0 mu g/ml) is due to blockage while a low dose (0.16 mu g/ml) promoted autophagy. Cellular viability was not affected in either case. Conclusions: The uptake of TiO2-NPs led to a dose-dependent increase in autophagic effect under non-cytotoxic conditions. Our results suggest dose-dependent autophagic effect over time as a cellular response to TiO2-NPs. Most importantly, these findings suggest that simple toxicity data are not enough to understand the full impact of TiO2-NPs and their effects on cellular pathways or function.

  • 34. Mahmudi, Owais
    et al.
    Sennblad, Bengt
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA).
    Nowick, Katja
    Lagergren, Jens
    Gene-pseudogene evolution: a probabilistic approach2015Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, artikel-id S12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Over the last decade, methods have been developed for the reconstruction of gene trees that take into account the species tree. Many of these methods have been based on the probabilistic duplication-loss model, which describes how a gene-tree evolves over a species-tree with respect to duplication and losses, as well as extension of this model, e.g., the DLRS (Duplication, Loss, Rate and Sequence evolution) model that also includes sequence evolution under relaxed molecular clock. A disjoint, almost as recent, and very important line of research has been focused on non protein-coding, but yet, functional DNA. For instance, DNA sequences being pseudogenes in the sense that they are not translated, may still be transcribed and the thereby produced RNA may be functional. We extend the DLRS model by including pseudogenization events and devise an MCMC framework for analyzing extended gene families consisting of genes and pseudogenes with respect to this model, i.e., reconstructing gene-trees and identifying pseudogenization events in the reconstructed gene-trees. By applying the MCMC framework to biologically realistic synthetic data, we show that gene-trees as well as pseudogenization points can be inferred well. We also apply our MCMC framework to extended gene families belonging to the Olfactory Receptor and Zinc Finger superfamilies. The analysis indicate that both these super families contains very old pseudogenes, perhaps so old that it is reasonable to suspect that some are functional. In our analysis, the sub families of the Olfactory Receptors contains only lineage specific pseudogenes, while the sub families of the Zinc Fingers contains pseudogene lineages common to several species.

  • 35.
    Masser, Anna E.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kandasamy, Ganapathi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Andréasson, Claes
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Luciferase NanoLuc as a reporter for gene expression and protein levels in Saccharomyces cerevisiae2016Ingår i: Yeast, ISSN 0749-503X, E-ISSN 1097-0061, Vol. 33, nr 5, s. 191-200Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Reporter proteins are essential tools in the study of biological processes and are employed to monitor changes in gene expression and protein levels. Luciferases are reporter proteins that enable rapid and highly sensitive detection with an outstanding dynamic range. Here we evaluated the usefulness of the 19 kDa luciferase NanoLuc (Nluc), derived from the deep sea shrimp Oplophorus gracilirostris, as a reporter protein in yeast. Cassettes with codon-optimized genes expressing yeast Nluc (yNluc) or its destabilized derivative yNlucPEST have been assembled in the context of the dominant drug resistance marker kanMX. The reporter proteins do not impair the growth of yeast cells and exhibit half-lives of 40 and 5 min, respectively. The commercial substrate Nano-Glo (R) is compatible with detection of yNluc bioluminescence in < 50 cells. Using the unstable yNlucPEST to report on the rapid and transient expression of a heat-shock promoter (PCYC1-HSE), we found a close match between the intensity of the bioluminescent signal and mRNA levels during both induction and decay. We demonstrated that the bioluminescence of yNluc fused to the C-terminus of a temperature-sensitive protein reports on its protein levels. In conclusion, yNluc and yNlucPEST are valuable new reporter proteins suitable for experiments with yeast using standard commercial substrate.

  • 36. McGinn, Steven
    et al.
    Bauer, David
    Brefort, Thomas
    Dong, Liqin
    EI-Sagheer, Afaf
    Elsharawy, Abdou
    Evans, Geraint
    Falk-Sorqvist, Elin
    Forster, Michael
    Fredriksson, Simon
    Freeman, Peter
    Freitag, Camilla
    Fritzsche, Joachim
    Gibson, Spencer
    Gullberg, Mats
    Gut, Marta
    Heath, Simon
    Heath-Brun, Isabelle
    Heron, Andrew J.
    Hohlbein, Johannes
    Ke, Rongqin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Lancaster, Owen
    Le Reste, Ludovic
    Maglia, Giovanni
    Marie, Rodolphe
    Mauger, Florence
    Mertes, Florian
    Mignardi, Marco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Moens, Lotte
    Oostmeijer, Jelle
    Out, Ruud
    Nyvold Pedersen, Jonas
    Persson, Fredrik
    Picaud, Vincent
    Rotem, Dvir
    Schracke, Nadine
    Sengenes, Jennifer
    Stähler, Peer F.
    Stade, Björn
    Stoddart, David
    Teng, Xia
    Veal, Colin D.
    Zahra, Nathalie
    Bayley, Hagan
    Beier, Markus
    Brown, Tom
    Dekker, Cees
    Ekström, Björn
    Flyvbjerg, Henrik
    Franke, Andre
    Guenther, Simone
    Kapanidis, Achillefs N.
    Kaye, Jane
    Kristensen, Anders
    Lehrach, Hans
    Mangion, Jonathan
    Sauer, Sascha
    Schyns, Emile
    Tost, Jörg
    van Helvoort, Joop M. L. M.
    van der Zaag, Pieter J.
    Tegenfeldt, Jonas O.
    Brookes, Anthony J.
    Mir, Kalim
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Willcocks, James P.
    Gut, Ivo G.
    New technologies for DNA analysis - a review of the READNA Project2016Ingår i: New Biotechnology, ISSN 1871-6784, E-ISSN 1876-4347, Vol. 33, nr 3, s. 311-330Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received funding from the European Commission for 4 1/2 years. The objectives of the project revolved around technological developments in nucleic acid analysis. The project partners have discovered, created and developed a huge body of insights into nucleic acid analysis, ranging from improvements and implementation of current technologies to the most promising sequencing technologies that constitute a 3rd and 4th generation of sequencing methods with nanopores and in situ sequencing, respectively.

  • 37.
    Mezger, Anja
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Kuhnemund, Malte
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Herthnek, David
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Highly specific DNA detection employing ligation on suspension bead array readout2015Ingår i: New Biotechnology, ISSN 1871-6784, E-ISSN 1876-4347, Vol. 32, nr 5, s. 504-510Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We show for the first time that monomerized rolling circle amplification (RCA) products can be directly detected with the Luminex suspension bead array readout without the need of PCR amplification. Furthermore, using monomerized RCA products to guide ligation of the detection oligonucleotide (DO) to barcode sequences on the magnetic Luminex beads, combined with efficient washing and increased measurement temperature, yields a higher signal to noise ratio. As a proof-of-principle, we demonstrate detection of pathogenic DNA sequences with high reproducibility, sensitivity and a dynamic range over four orders of magnitude. Using padlock probes in combination with bead suspension arrays opens up the possibility for highly multiplexed DNA targeting and readout.

  • 38.
    Michel, Mirco
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Skwark, Marcin J.
    Menéndez Hurtado, David
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ekeberg, Magnus
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Predicting accurate contacts in thousands of Pfam domain families using PconsC32017Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 33, nr 18, s. 2859-2866Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: A few years ago it was shown that by using a maximum entropy approach to describe couplings between columns in a multiple sequence alignment it is possible to significantly increase the accuracy of residue contact predictions. For very large protein families with more than 1000 effective sequences the accuracy is sufficient to produce accurate models of proteins as well as complexes. Today, for about half of all Pfam domain families no structure is known, but unfortunately most of these families have at most a few hundred members, i.e. are too small for such contact prediction methods. Results: To extend accurate contact predictions to the thousands of smaller protein families we present PconsC3, a fast and improved method for protein contact predictions that can be used for families with even 100 effective sequence members. PconsC3 outperforms direct coupling analysis (DCA) methods significantly independent on family size, secondary structure content, contact range, or the number of selected contacts. Availability and implementation: PconsC3 is available as a web server and downloadable version at http://c3.pcons.net. The downloadable version is free for all to use and licensed under the GNU General Public License, version 2. At this site contact predictions for most Pfam families are also available. We do estimate that more than 4000 contact maps for Pfam families of unknown structure have more than 50% of the top-ranked contacts predicted correctly. Contact: arne@bioinfo.se Supplementary information: Supplementary data are available at Bioinformatics online.

  • 39. Mukherjee, Oindrilla
    et al.
    Singh, Birendra
    Bayrak, Burcu
    Jonsson, Ann-Beth
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Morgelin, Matthias
    Riesbeck, Kristian
    A fusion protein derived from Moraxella catarrhalis and Neisseria meningitidis aimed for immune modulation of human B cells2015Ingår i: Human Vaccines & Immunotherapeutics, ISSN 2164-5515, E-ISSN 2164-554X, Vol. 11, nr 9, s. 2223-2227Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Moraxella IgD-binding protein (MID) is a well characterized trimeric autotransporter that specifically targets the IgD of B cells. We fused the membrane anchor of the meningococcal autotransporter NhhA with the IgD-binding region of MID (aa 962-1200) to create a chimeric protein designated as NID. The aim was to use this specific targeting to provide a better vaccine candidate against meningococci, in particular serogroup B by enhancing the immunogenicity of NhhA. NID was thereafter recombinantly expressed in E. coli. The NID-expressing E. coli bound to peripheral B lymphocytes that resulted in cellular activation. Furthermore, we also successfully expressed NID on outer membrane vesicles, nanoparticles that are commonly used in meningococcal vaccines. This study thus highlights the applicability of the menigococcal-Moraxella fusion protein NID to be used for specific targeting of vaccine components to the IgD B cell receptor.

  • 40.
    Musdal, Yaman
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Govindarajan, Sridhar
    Mannervik, Bengt
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Exploring sequence-function space of a poplar glutathione transferase using designed information-rich gene variants2017Ingår i: Protein Engineering Design & Selection, ISSN 1741-0126, E-ISSN 1741-0134, Vol. 30, nr 8, s. 543-549Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exploring the vicinity around a locus of a protein in sequence space may identify homologs with enhanced properties, which could become valuable in biotechnical and other applications. A rational approach to this pursuit is the use of 'infologs', i.e. synthetic sequences with specific substitutions capturing maximal sequence information derived from the evolutionary history of the protein family. Ninety-five such infolog genes of poplar glutathione transferase were synthesized and expressed in Escherichia coli, and the catalytic activities of the proteins determined with alternative substrates. Sequence-activity relationships derived from the infologs were used to design a second set of 47 infologs in which 90% of the members exceeded wild-type properties. Two mutants, C2 (V55I/E95D/D108E/A160V) and G5 (F13L/C70A/G122E), were further functionally characterized. The activities of the infologs with the alternative substrates 1-chloro-2,4-dinitrobenzene and phenethyl isothiocyanate, subject to different chemistries, were positively correlated, indicating that the examined mutations were affecting the overall catalytic competence without major shift in substrate discrimination. By contrast, the enhanced protein expressivity observed in many of the mutants were not similarly correlated with the activities. In conclusion, small libraries of well-defined infologs can be used to systematically explore sequence space to optimize proteins in multidimensional functional space.

  • 41. Nakonieczna, A.
    et al.
    Cooper, Callum J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Gryko, R.
    Bacteriophages and bacteriophage-derived endolysins as potential therapeutics to combat Gram-positive spore forming bacteria2015Ingår i: Journal of Applied Microbiology, ISSN 1364-5072, E-ISSN 1365-2672, Vol. 119, nr 3, s. 620-631Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Since their discovery in 1915, bacteriophages have been routinely used within Eastern Europe to treat a variety of bacterial infections. Although initially ignored by the West due to the success of antibiotics, increasing levels and diversity of antibiotic resistance is driving a renaissance for bacteriophage-derived therapy, which is in part due to the highly specific nature of bacteriophages as well as their relative abundance. This review focuses on the bacteriophages and derived lysins of relevant Gram-positive spore formers within the Bacillus cereus group and Clostridium genus that could have applications within the medical, food and environmental sectors.

  • 42.
    Nguyen, Thanh Van
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Wibberg, Daniel
    Battenberg, Kai
    Blom, Jochen
    Vanden Heuvel, Brian
    Berry, Alison M.
    Kalinowski, Jörn
    Pawlowski, Katharina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    An assemblage of Frankia Cluster II strains from California contains the canonical nod genes and also the sulfotransferase gene nodH2016Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, artikel-id 796Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The ability to establish root nodule symbioses is restricted to four different plant orders. Soil actinobacteria of the genus Frankia can establish a symbiotic relationship with a diverse group of plants within eight different families from three different orders, the Cucurbitales, Fagales and Rosales. Phylogenetically, Frankia strains can be divided into four clusters, three of which (I, II, III) contain symbiotic strains. Members of Cluster II nodulate the broadest range of host plants with species from four families from two different orders, growing on six continents. Two Cluster II genomes were sequenced thus far, both from Asia.

    Results: In this paper we present the first Frankia cluster II genome from North America (California), Dg2, which represents a metagenome of two major and one minor strains. A phylogenetic analysis of the core genomes of 16 Frankia strains shows that Cluster II the ancestral group in the genus, also ancestral to the non-symbiotic Cluster IV. Dg2 contains the canonical nod genes nodABC for the production of lipochitooligosaccharide Nod factors, but also two copies of the sulfotransferase gene nodH. In rhizobial systems, sulfation of Nod factors affects their host specificity and their stability.

    Conclusions: A comparison with the nod gene region of the previously sequenced Dg1 genome from a Cluster II strain from Pakistan shows that the common ancestor of both strains should have contained nodABC and nodH. Phylogenetically, Dg2 NodH proteins are sister to rhizobial NodH proteins. A glnA-based phylogenetic analysis of all Cluster II strains sampled thus far supports the hypothesis that Cluster II Frankia strains came to North America with Datisca glomerata following the Madrean-Tethyan pattern.

  • 43. Pazos Obregón, Flavio
    et al.
    Soto, Pablo
    Lavín, José Luis
    Cortázar, Ana Rosa
    Barrio, Rosa
    Aransay, Ana María
    Cantera, Rafael
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen. IIBCE, Uruguay.
    Cluster Locator, online analysis and visualization of gene clustering2018Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 34, nr 19, s. 3377-3379Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genes sharing functions, expression patterns or quantitative traits are not randomly distributed along eukaryotic genomes. In order to study the distribution of genes that share a given feature, we present Cluster Locator, an online analysis and visualization tool. Cluster Locator determines the number, size and position of all the clusters formed by the protein-coding genes on a list according to a given maximum gap, the percentage of gene clustering of the list and its statistical significance. The output includes a visual representation of the distribution of genes and gene clusters along the reference genome.

  • 44. Pelto-Piri, Veikko
    et al.
    Engström, Karin
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Barn- och ungdomsvetenskapliga institutionen.
    Engström, Ingemar
    Paternalism, autonomy and reciprocity: ethical perspectives in encounters with patients in psychiatric in-patient care.2013Ingår i: BMC Medical Ethics, ISSN 1472-6939, Vol. 14, nr 1, s. 49-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Psychiatric staff members have the power to decide the options that frame encounters with patients. Intentional as well as unintentional framing can have a crucial impact on patients' opportunities to be heard and participate in the process. We identified three dominant ethical perspectives in the normative medical ethics literature concerning how doctors and other staff members should frame interactions in relation to patients; paternalism, autonomy and reciprocity. The aim of this study was to describe and analyse statements describing real work situations and ethical reflections made by staff members in relation to three central perspectives in medical ethics; paternalism, autonomy and reciprocity.

    METHODS: All staff members involved with patients in seven adult psychiatric and six child and adolescent psychiatric clinics were given the opportunity to freely describe ethical considerations in their work by keeping an ethical diary over the course of one week and 173 persons handed in their diaries. Qualitative theory-guided content analysis was used to provide a description of staff encounters with patients and in what way these encounters were consistent with, or contrary to, the three perspectives.

    RESULTS: The majority of the statements could be attributed to the perspective of paternalism and several to autonomy. Only a few statements could be attributed to reciprocity, most of which concerned staff members acting contrary to the perspective. The result is presented as three perspectives containing eight values.Paternalism; 1) promoting and restoring the health of the patient, 2) providing good care and 3) assuming responsibility.Autonomy; 1) respecting the patient's right to self-determination and information, 2) respecting the patient's integrity and 3) protecting human rights.Reciprocity; 1) involving patients in the planning and implementation of their care and 2) building trust between staff and patients.

    CONCLUSIONS: Paternalism clearly appeared to be the dominant perspective among the participants, but there was also awareness of patients' right to autonomy. Despite a normative trend towards reciprocity in psychiatry throughout the Western world, identifying it proved difficult in this study. This should be borne in mind by clinics when considering the need for ethical education, training and supervision.

  • 45.
    Pesquet, Edouard
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Wagner, Armin
    Grabber, John H.
    Cell culture systems: invaluable tools to investigate lignin formation and cell wall properties2019Ingår i: Current Opinion in Biotechnology, ISSN 0958-1669, E-ISSN 1879-0429, Vol. 56, s. 215-222Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Although the use of cell culture systems in Plant Biology and Biotechnology has been limited compared to other areas of Life Sciences, plant cell cultures capable of lignifying on demand have proven invaluable in unravelling the lignification process and its impact on biomass utilization. Inducible cell cultures have enabled researchers to decipher multiple levels of cellular control used in and between plant cells to define the spatiotemporal deposition, composition, structure, and quantity of lignin. Artificially lignified cell cultures have also been used to determine the effects of lignin composition on the susceptibility of cell walls to chemical treatments, and digestion by rumen microflora or fungal enzymes. Plant cell cultures have enabled the fast-tracking of lignin-related research and provided insights into the lignification processes that could not have been easily obtained by using whole plants as model systems.

  • 46. Pimchan, T.
    et al.
    Cooper, Callum J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Eumkeb, G.
    Nilsson, Anders S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    In vitro activity of a combination of bacteriophages and antimicrobial plant extracts2018Ingår i: Letters in Applied Microbiology, ISSN 0266-8254, E-ISSN 1472-765X, Vol. 66, nr 3, s. 182-187Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The continuing threat of antimicrobial resistance presents a considerable challenge to researchers to develop novel strategies ensuring that bacterial infections remain treatable. Many plant extracts have been shown to have antibacterial properties and could potentially be combined with other antibacterial agents to create more effective formulations. In this study, the antibacterial activity of three plant extracts and virulent bacteriophages have been assessed as individual components and in combination. When assessed with a modified suspension test, these plant extracts also exhibit antiviral activity at bacterial inhibitory concentrations. Hence, to investigate any potential additive effects between the extracts and virulent phages, the extracts were tested at subantiviral concentrations. Phages alone and in combination with plant extracts significantly reduced (< 0·05) the bacterial concentration compared to untreated and extract treated controls up to 6 h (2–3log10), but this reduction did not extend to 24 h. In most cases, the phage and extract combinations did not significantly reduce bacterial content compared to phages alone. Additionally, there was little impact on the ability of the phages to reproduce within their bacterial hosts. To our knowledge, this study represents the first of its kind, in which antimicrobial plant extracts have been combined with virulent phages and has highlighted the necessity for plant extracts to be functionally characterized prior to the design of combinatorial therapies.

    Significance and Impact of Study

    This preliminary study provides insights into the potential combination of bacteriophages and antimicrobial plant bulk extracts to target bacterial pathogens. It is to our knowledge the first time in which virulent bacteriophages have been combined with antimicrobial plant extracts.

  • 47.
    Plummer, Ryan
    et al.
    Stockholms universitet, Stockholm Resilience Centre.
    de Loe, Rob
    Armitage, Derek
    A systematic review of water vulnerability assessment tools2012Ingår i: Water resources management, ISSN 0920-4741, E-ISSN 1573-1650, Vol. 26, nr 15, s. 4327-4346Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The important relationship between health and water necessitates consideration of water vulnerability. Water vulnerability is contingent upon biophysical and social drivers operating at multiple scales, and is difficult to assess. This paper offers a systematic review of 50 water vulnerability assessment tools. We identify and synthesise the contents of these assessment tools (710 indicators) into five dimensions and 22 sub-dimensions and consider the extent to which they reflect environmental and social aspects. The findings are discussed in light of a holistic approach to water resources management, and specifically Integrated Water Resources Management (IWRM). Significant opportunities exist to enhance the efficacy of water vulnerability assessment tools by incorporating indicators and operational measures for social considerations (e.g., adaptation, institutions, governance) that are developed outside the context of water.

  • 48. Pujolar, J. M.
    et al.
    Dalén, L.
    Olsen, Remi-André
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Hansen, M. M.
    Madsen, J.
    First de novo whole genome sequencing and assembly of the pink-footed goose2018Ingår i: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 110, nr 2, s. 75-79Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Annotated genomes can provide new perspectives on the biology of species. We present the first de novo whole genome sequencing for the pink-footed goose. In order to obtain a high-quality de novo assembly the strategy used was to combine one short insert paired-end library with two mate-pair libraries. The pink-footed goose genome was assembled de novo using three different assemblers and an assembly evaluation was subsequently performed in order to choose the best assembler. For our data, ALLPATHS-LG performed the best, since the assembly produced covers most of the genome, while introducing the fewest errors. A total of 26,134 genes were annotated, with bird species accounting for virtually all BLAST hits. We also estimated the substitution rate in the pink-footed goose, which can be of use in future demographic studies, by using a comparative approach with the genome of the chicken, the mallard and the swan goose. A substitution rate of 1.38 x 10(-7) per nucleotide per generation was obtained when comparing the genomes of the two closely-related goose species (the pink-footed and the swan goose). Altogether, we provide a valuable tool for future genomic studies aiming at particular genes and regions of the pink-footed goose genome as well as other bird species.

  • 49. Rivera-Monroy, Victor H.
    et al.
    Twilley, Robert R.
    Ernesto Mancera-Pineda, J.
    Madden, Christopher J.
    Alcantara-Eguren, Ariel
    Moser, E. Barry
    Jonsson, Bror F.
    Stockholms universitet, Naturvetenskapliga fakulteten, Meteorologiska institutionen (MISU).
    Castaneda-Moya, Edward
    Casas-Monroy, Oscar
    Reyes-Forero, Paola
    Restrepo, Jorge
    Salinity and Chlorophyll a as Performance Measures to Rehabilitate a Mangrove-Dominated Deltaic Coastal Region: the Cienaga Grande de Santa Marta-Pajarales Lagoon Complex, Colombia2011Ingår i: Estuaries and Coasts, ISSN 1559-2723, E-ISSN 1559-2731, Vol. 34, nr 1, s. 1-19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Salinity, water temperature, and chlorophyll a (chl-a) biomass were used as performance measures in the period 1999-2001 to evaluate the effect of a hydrological rehabilitation project in the Cienaga Grande de Santa Marta (CGSM)-Pajarales lagoon complex, Colombia where freshwater diversions were initiated in 1995 and completed in 1998. The objective of this study was to evaluate how diversions of freshwater into previously hypersaline (>80) environments changed the spatial and temporal distribution of environmental characteristics. Following the diversion, 19 surveys and transects using a flow-through system were surveyed in the CGSM-Pajarales complex to continuously measure selected water quality parameters. Geostatistical analysis indicates that hydrology and salinity regimes and water circulation patterns in the CGSM lagoon are largely controlled by freshwater discharge from the Fundacion, Aracataca, and Sevilla Rivers. Residence times in the CGSM lagoon were similar before (15.5+/-3.8 days) and after (14.2+/-2.0 days) the rehabilitation project and indicated that the system is flushed regularly. In contrast, chl-a biomass was highly variable in the CGSM-Pajarales lagoon complex and not related to discharge patterns. Mean annual chl-a biomass (44-250 mu g L(-1)) following the diversion project was similar to values recorded since the 1980s and still remains among the highest reported in coastal systems around the world owing to its unique hydrology regulated by the Magdalena River and Sierra Nevada de Santa Marta watersheds and the high teleconnection to the El Nino Southern Oscillation (ENSO). Our results confirm that the reduction in salinity in the CGSM lagoon and Pajarales complex during 1999-2000 was largely driven by high precipitation (2500 mm) induced by the ENSO-La Nina rather than by the freshwater diversions.

  • 50.
    Román, Mikael
    et al.
    Stockholms universitet, Stockholm Resilience Centre, Stockholm Environment Institute.
    Hoffmaister, Juan P.
    Stockholms universitet, Stockholm Resilience Centre, Stockholm Environment Institute.
    Climate and development: the potential for climate cobenefits in the Mozambican rice sector2012Ingår i: Climate and Development, ISSN 1756-5529, E-ISSN 1756-5537, Vol. 4, nr 3, s. 219-233Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This article discusses the opportunities and pitfalls of linking a future Sustainable Development – Policies and Measures (SD-PAM) mechanism to Mozambican rice policies. It concludes that there are various ways in which the ambition to increase the production of rice can also reduce greenhouse gas (GHG) emissions. Moreover, the analysis suggests that an SD-PAM mechanism may be instrumental in supporting this type of co-benefits. This implies that the pursuit of development policies as a precursor for climate mitigation is valid also for the agricultural sector and, similarly, least developed countries (LDCs) may have a role to play. Three traits of the LDC setting will influence the design of a future SD-PAM mechanism. One is the way contextual factors influence individual policy programmes. Another is the need for capacity building in its broader sense, which then emerges as another leverage mechanism in addition to funding, credits and technology transfer. Finally, it requires the recognition that GHG mitigation in LDCs is not about reducing emissions in an absolute sense but, rather, a question of changing development paths and thereby avoiding future GHG emissions

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