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  • 1. Acevedo, Nathalie
    et al.
    Bornacelly, Adriana
    Mercado, Dilia
    Unneberg, Per
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mittermann, Irene
    Valenta, Rudolf
    Kennedy, Malcolm
    Scheynius, Annika
    Caraballo, Luis
    Genetic Variants in CHIA and CHI3L1 Are Associated with the IgE Response to the Ascaris Resistance Marker ABA-1 and the Birch Pollen Allergen Bet v 12016Ingår i: plos one, ISSN 1932-6203, Vol. 11, nr 12, artikel-id e0167453Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Helminth infections and allergic diseases are associated with IgE hyperresponsiveness but the genetics of this phenotype remain to be defined. Susceptibility to Ascaris lumbricoides infection and antibody levels to this helminth are associated with polymorphisms in locus 13q33-34. We aimed to explore this and other genomic regions to identify genetic variants associated with the IgE responsiveness in humans. Forty-eight subjects from Cartagena, Colombia, with extreme values of specific IgE to Ascaris and ABA-1, a resistance marker of this nematode, were selected for targeted resequencing. Burden analyses were done comparing extreme groups for IgE values. One-hundred one SNPs were genotyped in 1258 individuals of two well-characterized populations from Colombia and Sweden. Two low-frequency coding variants in the gene encoding the Acidic Mammalian Chitinase (CHIA rs79500525, rs139812869, tagged by rs10494133) were found enriched in high IgE responders to ABA-1 and confirmed by genetic association analyses. The SNP rs4950928 in the Chitinase 3 Like 1 gene (CHI3L1) was associated with high IgE to ABA-1 in Colombians and with high IgE to Bet v 1 in the Swedish population. CHIA rs10494133 and ABDH13 rs3783118 were associated with IgE responses to Ascaris. SNPs in the Tumor Necrosis Factor Superfamily Member 13b gene (TNFSF13B) encoding the cytokine B cell activating Factor were associated with high levels of total IgE in both populations. This is the first report on the association between low-frequency and common variants in the chitinases- related genes CHIA and CHI3L1 with the intensity of specific IgE to ABA-1 in a population naturally exposed to Ascaris and with Bet v 1 in a Swedish population. Our results add new information about the genetic influences of human IgE responsiveness; since the genes encode for enzymes involved in the immune response to parasitic infections, they could be helpful for understanding helminth immunity and allergic responses. We also confirmed that TNFSF13B has an important and conserved role in the regulation of total IgE levels, which supports potential evolutionary links between helminth immunity and allergic response.

  • 2. Ahmadi-Afzadi, Masoud
    et al.
    Orsel, Mathilde
    Pelletier, Sandra
    Bruneau, Maryline
    Proux-Wéra, Estelle
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish University of Agricultural Sciences, Sweden.
    Nybom, Hilde
    Renou, Jean-Pierre
    Genome-wide expression analysis suggests a role for jasmonates in the resistance to blue mold in apple2018Ingår i: Plant growth regulation (Print), ISSN 0167-6903, E-ISSN 1573-5087, Vol. 85, nr 3, s. 375-387Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Blue mold, caused by the necrotrophic fungal pathogen Penicillium expansum, causes serious postharvest losses in apple, and threatens human health through production of the potent mycotoxin patulin. Recent studies indicate a quantitative control of resistance against this disease in apple cultivars. A whole genome apple microarray covering 60k transcripts was used to identify gene(s) that appear to be differentially regulated between resistant and susceptible cultivars in P. expansum-infected fruits. A number of potential candidates was encountered among defense- and oxidative stress-related genes, cell wall modification and lignification genes, and genes related to localization and transport. Induction of one cell wall-related gene and three genes involved in the 'down-stream' flavonoid biosynthesis pathway, demonstrates the fundamental role of the cell wall as an important barrier, and suggests that fruit flavonoids are involved in the resistance to blue mold. Moreover, exogenous application of the plant hormone methyl jasmonate (MeJA) reduced the symptoms resulting from inoculating apples with P. expansum. This is the first report linking MeJA and activation of cell wall and flavonoid pathway genes to resistance against blue mold in a study comparing different cultivars of domesticated apple. Our results provide an initial categorization of genes that are potentially involved in the resistance mechanism, and should be useful for developing tools for gene marker-assisted breeding of apple cultivars with an improved resistance to blue mold.

  • 3.
    Ahmed, Engy
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Abdulla, Hesham M.
    Mohamed, Amy H.
    El-Bassuony, Ahmed D.
    Remediation and recycling of chromium from tannery wastewater using combined chemical-biological treatment system2016Ingår i: Process Safety and Environmental Protection, ISSN 0957-5820, E-ISSN 1744-3598, Vol. 104, s. 1-10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tannery wastewater containing chromium (Cr) is one of the most serious problems in leather industry. In order to develop an effective and eco-friendly treatment technology, a combined chemical-biological treatment system was performed for Cr remediation and recycling. The aim of the present study is to design a laboratory scale system using chemical precipitation of Cr(III) combined with biological removal of Cr(VI) from tannery wastewater, and to investigate the possibility of recycling the recovered Cr(III) in the tanning industry. Chemical precipitation of Cr(III) was carried out using lime and cement dust. The actinomycete strain Kitasatosporia sp. was used in microcosm studies for Cr(VI) bioremoval. Moreover, parameters such as type of porous medium, inoculum size, flow rate and culture conditions were investigated. The precipitated Cr(III) that was recovered from the chemical precipitation stage was recycled in the leather tanning industry. Our findings indicate that the maximum Cr(III) precipitation (98%) was achieved using 2 g/100 mL of lime and 2 h of settling rate. On the other hand, microcosm columns using sand that was inoculated with induced culture (OD600 = 2.43) and flow rate (2 mL/min) gave the maximum recovery (99%) of Cr(VI). The experimental Cr(III) was successfully recycled in the tanning process and the experimental leathers showed comparable properties as same as the leathers tanned with commercial Cr(III). Thus, we concluded that using combined chemical-biological treatment system for Cr remediation from tanning wastewater together with recycling process for the recovered Cr(III) is a promising strategy for economic and environmental friendly tanning industry.

  • 4.
    Ahmed, Engy
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Parducci, Laura
    Unneberg, Per
    Ågren, Rasmus
    Schenk, Frederik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper.
    Rattray, Jayne E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper.
    Han, Lu
    Muschitiello, Francesco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper. Columbia University, USA.
    Pedersen, Mikkel W.
    Smittenberg, Rienk H.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper.
    Afrifa Yamoah, Kweku
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper.
    Slotte, Tanja
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Wohlfarth, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper.
    Archaeal community changes in Lateglacial lake sediments: Evidence from ancient DNA2018Ingår i: Quaternary Science Reviews, ISSN 0277-3791, E-ISSN 1873-457X, Vol. 181, s. 19-29Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Lateglacial/early Holocene sediments from the ancient lake at Hasseldala Port, southern Sweden provide an important archive for the environmental and climatic shifts at the end of the last ice age and the transition into the present Interglacial. The existing multi-proxy data set highlights the complex interplay of physical and ecological changes in response to climatic shifts and lake status changes. Yet, it remains unclear how microorganisms, such as Archaea, which do not leave microscopic features in the sedimentary record, were affected by these climatic shifts. Here we present the metagenomic data set of Hasseldala Port with a special focus on the abundance and biodiversity of Archaea. This allows reconstructing for the first time the temporal succession of major Archaea groups between 13.9 and 10.8 ka BP by using ancient environmental DNA metagenomics and fossil archaeal cell membrane lipids. We then evaluate to which extent these findings reflect physical changes of the lake system, due to changes in lake-water summer temperature and seasonal lake-ice cover. We show that variations in archaeal composition and diversity were related to a variety of factors (e.g., changes in lake water temperature, duration of lake ice cover, rapid sediment infilling), which influenced bottom water conditions and the sediment-water interface. Methanogenic Archaea dominated during the Allerod and Younger Dryas pollen zones, when the ancient lake was likely stratified and anoxic for large parts of the year. The increase in archaeal diversity at the Younger Dryas/Holocene transition is explained by sediment infilling and formation of a mire/peatbog.

  • 5. Ahrentorp, Fredrik
    et al.
    Blomgren, Jakob
    Jonasson, Christian
    Sarwe, Anna
    Sepehri, Sobhan
    Eriksson, Emil
    Kalaboukhov, Alexei
    Jesorka, Aldo
    Winkler, Dag
    Schneiderman, Justin F.
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Albert, Jan
    Gómez de la Torre, Teresa Zardán
    Strømme, Maria
    Johansson, Christer
    Sensitive magnetic biodetection using magnetic multi-core nanoparticles and RCA coils2017Ingår i: Journal of Magnetism and Magnetic Materials, ISSN 0304-8853, E-ISSN 1873-4766, Vol. 427, s. 14-18Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We use functionalized iron oxide magnetic multi-core particles of 100 nm in size (hydrodynamic particle diameter) and AC susceptometry (ACS) methods to measure the binding reactions between the magnetic nanoparticles (MNPs) and bio-analyte products produced from DNA segments using the rolling circle amplification (RCA) method. We use sensitive induction detection techniques in order to measure the ACS response. The DNA is amplified via RCA to generate RCA coils with a specific size that is dependent on the amplification time. After about 75 min of amplification we obtain an average RCA coil diameter of about 1 mu m. We determine a theoretical limit of detection (LOD) in the range of 11 attomole (corresponding to an analyte concentration of 55 fM for a sample volume of 200 mu L) from the ACS dynamic response after the MNPs have bound to the RCA coils and the measured ACS readout noise. We also discuss further possible improvements of the LOD.

  • 6.
    Aibara, Shintaro
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Andréll, Juni
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Singh, Vivek
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Amunts, Alexey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Rapid Isolation of the Mitoribosome from HEK Cells2018Ingår i: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, nr 140, artikel-id e57877Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human mitochondria possess a dedicated set of ribosomes (mitoribosomes) that translate 13 essential protein components of the oxidative phosphorylation complexes encoded by the mitochondria! genome. Since all proteins synthesized by human mitoribosomes are integral membrane proteins, human mitoribosomes are tethered to the mitochondrial inner membrane during translation. Compared to the cytosolic ribosome the mitoribosome has a sedimentation coefficient of 55S, half the rRNA content, no 5S rRNA and 36 additional proteins. Therefore, a higher protein-to-RNA ratio and an atypical structure make the human mitoribosome substantially distinct from its cytosolic counterpart. Despite the central importance of the mitoribosome to life, no protocols were available to purify the intact complex from human cell lines. Traditionally, mitoribosomes were isolated from mitochondria-rich animal tissues that required kilograms of starting material. We reasoned that mitochondria in dividing HEK293-derived human cells grown in nutrient-rich expression medium would have an active mitochondrial translation, and, therefore, could be a suitable source of material for the structural and biochemical studies of the mitoribosome. To investigate its structure, we developed a protocol for large-scale purification of intact mitoribosomes from HEK cells. Herein, we introduce nitrogen cavitation method as a faster, less labor-intensive and more efficient alternative to traditional mechanical shear-based methods for cell lysis. This resulted in preparations of the mitoribosome that allowed for its structural determination to high resolution, revealing the composition of the intact human mitoribosome and its assembly intermediates. Here, we follow up on this work and present an optimized and more cost-effective method requiring only similar to 10(10) cultured HEK cells. The method can be employed to purify human mitoribosomal translating complexes, mutants, quality control assemblies and mitoribosomal subunits intermediates. The purification can be linearly scaled up tenfold if needed, and also applied to other types of cells.

  • 7. 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.

  • 8. Alexeyenko, Andrey
    et al.
    Nystedt, Björn
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Vezzi, Francesco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Sherwood, Ellen
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ye, Rosa
    Knudsen, Bjarne
    Simonsen, Martin
    Turner, Benjamin
    de Jong, Pieter
    Wu, Cheng-Cang
    Lundeberg, Joakim
    Efficient de novo assembly of large and complex genomes by massively parallel sequencing of Fosmid pools2014Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, s. 439-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 9.
    Alexeyenko, Andrey
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Schmitt, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Tjärnberg, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Guala, Dmitri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Frings, Oliver
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Comparative interactomics with Funcoup 2.02012Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, nr D1, s. D821-D828Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 10. 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/.

  • 11. Ali, Raja H.
    et al.
    Muhammad, Sayyed A.
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Centre, Sweden.
    GenFamClust: an accurate, synteny-aware and reliable homology inference algorithm2016Ingår i: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 16, artikel-id 120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 12. Ali, Raja Hashim
    et al.
    Muhammad, Sayyed Auwn
    Khan, Mehmood Alam
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center, Sweden .
    Quantitative synteny scoring improves homology inference and partitioning of gene families2013Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 14, nr Suppl,15, s. S12-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

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

    Results

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

    Conclusions

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

  • 13. Allen, Lisa Zeigler
    et al.
    McCrow, John P.
    Ininbergs, Karolina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Dupont, Christopher L.
    Badger, Jonathan H.
    Hoffman, Jeffery M.
    Ekman, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Allen, Andrew E.
    Bergman, Birgitta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Venter, J. Craig
    The Baltic Sea Virome: Diversity and Transcriptional Activity of DNA and RNA Viruses2017Ingår i: mSystems, ISSN 2379-5077, Vol. 2, nr 1, artikel-id UNSP e00125-16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Metagenomic and metatranscriptomic data were generated from size-fractionated samples from 11 sites within the Baltic Sea and adjacent marine waters of Kattegat and freshwater Lake Tornetrask in order to investigate the diversity, distribution, and transcriptional activity of virioplankton. Such a transect, spanning a salinity gradient from freshwater to the open sea, facilitated a broad genome-enabled investigation of natural as well as impacted aspects of Baltic Sea viral communities. Taxonomic signatures representative of phages within the widely distributed order Caudovirales were identified with enrichments in lesser-known families such as Podoviridae and Siphoviridae. The distribution of phage reported to infect diverse and ubiquitous heterotrophic bacteria (SAR11 clades) and cyanobacteria (Synechococcus sp.) displayed population-level shifts in diversity. Samples from higher-salinity conditions (>14 practical salinity units [PSU]) had increased abundances of viruses for picoeukaryotes, i.e., Ostreococcus. These data, combined with host diversity estimates, suggest viral modulation of diversity on the whole-community scale, as well as in specific prokaryotic and eukaryotic lineages. RNA libraries revealed single-stranded DNA (ssDNA) and RNA viral populations throughout the Baltic Sea, with ssDNA phage highly represented in Lake Tornetrask. Further, our data suggest relatively high transcriptional activity of fish viruses within diverse families known to have broad host ranges, such as Nodoviridae (RNA), Iridoviridae (DNA), and predicted zoonotic viruses that can cause ecological and economic damage as well as impact human health. IMPORTANCE Inferred virus-host relationships, community structures of ubiquitous ecologically relevant groups, and identification of transcriptionally active populations have been achieved with our Baltic Sea study. Further, these data, highlighting the transcriptional activity of viruses, represent one of the more powerful uses of omics concerning ecosystem health. The use of omics-related data to assess ecosystem health holds great promise for rapid and relatively inexpensive determination of perturbations and risk, explicitly with regard to viral assemblages, as no single marker gene is suitable for widespread taxonomic coverage.

  • 14. Almagro Armenteros, José Juan
    et al.
    Tsirigos, Konstantinos D.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Technical University of Denmark, Denmark; Max Planck Institute for Molecular Genetics, Germany.
    Kaae Sonderby, Casper
    Nordahl Petersen, Thomas
    Winther, Ole
    Brunak, Søren
    von Heijne, Gunnar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Nielsen, Henrik
    SignalP 5.0 improves signal peptide predictions using deep neural networks2019Ingår i: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 37, nr 4, s. 420-423Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Signal peptides (SPs) are short amino acid sequences in the amino terminus of many newly synthesized proteins that target proteins into, or across, membranes. Bioinformatic tools can predict SPs from amino acid sequences, but most cannot distinguish between various types of signal peptides. We present a deep neural network-based approach that improves SP prediction across all domains of life and distinguishes between three types of prokaryotic SPs.

  • 15. Alneberg, Johannes
    et al.
    Sundh, John
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Bennke, Christin
    Beier, Sara
    Lundin, Daniel
    Hugerth, Luisa W.
    Pinhassi, Jarone
    Kisand, Veljo
    Riemann, Lasse
    Jürgens, Klaus
    Labrenz, Matthias
    Andersson, Anders F.
    BARM and BalticMicrobeDB, a reference metagenome and interface to meta-omic data for the Baltic Sea2018Ingår i: Scientific Data, E-ISSN 2052-4463, Vol. 5, artikel-id 180146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Baltic Sea is one of the world's largest brackish water bodies and is characterised by pronounced physicochemical gradients where microbes are the main biogeochemical catalysts. Meta-omic methods provide rich information on the composition of, and activities within, microbial ecosystems, but are computationally heavy to perform. We here present the Baltic Sea Reference Metagenome (BARM), complete with annotated genes to facilitate further studies with much less computational effort. The assembly is constructed using 2.6 billion metagenomic reads from 81 water samples, spanning both spatial and temporal dimensions, and contains 6.8 million genes that have been annotated for function and taxonomy. The assembly is useful as a reference, facilitating taxonomic and functional annotation of additional samples by simply mapping their reads against the assembly. This capability is demonstrated by the successful mapping and annotation of 24 external samples. In addition, we present a public web interface, BalticMicrobeDB, for interactive exploratory analysis of the dataset. [GRAPHICS] .

  • 16. Altenhoff, Adrian M.
    et al.
    Boeckmann, Brigitte
    Capella-Gutierrez, Salvador
    Dalquen, Daniel A.
    DeLuca, Todd
    Forslund, Kristoffer
    Huerta-Cepas, Jaime
    Linard, Benjamin
    Pereira, Cecile
    Pryszcz, Leszek P.
    Schreiber, Fabian
    da Silva, Alan Sousa
    Szklarczyk, Damian
    Train, Clement-Marie
    Bork, Peer
    Lecompte, Odile
    von Mering, Christian
    Xenarios, Ioannis
    Sjölander, Kimmen
    Juhl Jensen, Lars
    Martin, Maria J.
    Muffato, Matthieu
    Gabaldon, Toni
    Lewis, Suzanna E.
    Thomas, Paul D.
    Sonnhammer, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Dessimoz, Christophe
    Standardized benchmarking in the quest for orthologs2016Ingår i: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 13, nr 5, s. 425-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Achieving high accuracy in orthology inference is essential for many comparative, evolutionary and functional genomic analyses, yet the true evolutionary history of genes is generally unknown and orthologs are used for very different applications across phyla, requiring different precision-recall trade-offs. As a result, it is difficult to assess the performance of orthology inference methods. Here, we present a community effort to establish standards and an automated web-based service to facilitate orthology benchmarking. Using this service, we characterize 15 well-established inference methods and resources on a battery of 20 different benchmarks. Standardized benchmarking provides a way for users to identify the most effective methods for the problem at hand, sets a minimum requirement for new tools and resources, and guides the development of more accurate orthology inference methods.

  • 17. Ameur, Adam
    et al.
    Che, Huiwen
    Martin, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Bunikis, Ignas
    Dahlberg, Johan
    Höijer, Ida
    Häggqvist, Susana
    Vezzi, Francesco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Nordlund, Jessica
    Olason, Pall
    Feuk, Lars
    Gyllensten, Ulf
    De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data2018Ingår i: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 9, nr 10, artikel-id 486Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The current human reference sequence (GRCh38) is a foundation for large-scale sequencing projects. However, recent studies have suggested that GRCh38 may be incomplete and give a suboptimal representation of specific population groups. Here, we performed a de novo assembly of two Swedish genomes that revealed over 10 Mb of sequences absent from the human GRCh38 reference in each individual. Around 6 Mb of these novel sequences (NS) are shared with a Chinese personal genome. The NS are highly repetitive, have an elevated GC-content, and are primarily located in centromeric or telomeric regions. Up to 1 Mb of NS can be assigned to chromosome Y, and large segments are also missing from GRCh38 at chromosomes 14, 17, and 21. Inclusion of NS into the GRCh38 reference radically improves the alignment and variant calling from short-read whole-genome sequencing data at several genomic loci. A re-analysis of a Swedish population-scale sequencing project yields > 75,000 putative novel single nucleotide variants (SNVs) and removes > 10,000 false positive SNV calls per individual, some of which are located in protein coding regions. Our results highlight that the GRCh38 reference is not yet complete and demonstrate that personal genome assemblies from local populations can improve the analysis of short-read whole-genome sequencing data.

  • 18. Ameur, Adam
    et al.
    Dahlberg, Johan
    Olason, Pall
    Vezzi, Francesco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). National Genomics Infrastructure, Science for Life Laboratory, Sweden.
    Karlsson, Robert
    Martin, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Viklund, Johan
    Kähäri, Andreas Kusalananda
    Lundin, Pär
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Che, Huiwen
    Thutkawkorapin, Jessada
    Eisfeldt, Jesper
    Lampa, Samuel
    Dahlberg, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Hagberg, Jonas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Jareborg, Niclas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Liljedahl, Ulrika
    Jonasson, Inger
    Johansson, Åsa
    Feuk, Lars
    Lundeberg, Joakim
    Syvänen, Ann-Christine
    Lundin, Sverker
    Nilsson, Daniel
    Nystedt, Björn
    Magnusson, Patrik K. E.
    Gyllensten, Ulf
    SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population2017Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, nr 11, s. 1253-1260Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.

  • 19. Angleby, Helen
    et al.
    Oskarsson, Mattias
    Pang, Junfeng
    Zhang, Ya-ping
    Leitner, Thomas
    Braham, Caitlyn
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lundeberg, Joakim
    Webb, Kristen M.
    Savolainen, Peter
    Forensic Informativity of similar to 3000bp of Coding Sequence of Domestic Dog mtDNA2014Ingår i: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 59, nr 4, s. 898-908Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The discriminatory power of the noncoding control region (CR) of domestic dog mitochondrial DNA alone is relatively low. The extent to which the discriminatory power could be increased by analyzing additional highly variable coding regions of the mitochondrial genome (mtGenome) was therefore investigated. Genetic variability across the mtGenome was evaluated by phylogenetic analysis, and the three most variable similar to 1kb coding regions identified. We then sampled 100 Swedish dogs to represent breeds in accordance with their frequency in the Swedish population. A previously published dataset of 59 dog mtGenomes collected in the United States was also analyzed. Inclusion of the three coding regions increased the exclusion capacity considerably for the Swedish sample, from 0.920 for the CR alone to 0.964 for all four regions. The number of mtDNA types among all 159 dogs increased from 41 to 72, the four most frequent CR haplotypes being resolved into 22 different haplotypes.

  • 20. Anh, Nhi
    et al.
    Taylan, Fulya
    Zachariadis, Vasilios
    Ivanov Öfverholm, Ingegerd
    Lindstrand, Anna
    Vezzi, Francesco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lötstedt, Britta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Nordenskjöld, Magnus
    Nordgren, Ann
    Nilsson, Daniel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Barbany, Gisela
    High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 3, artikel-id e0193928Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome-wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements. Samples were selected based on cytogenetic and FISH results at leukemia diagnosis to include common rearrangements of prognostic relevance. Using MP-WGS and in-house bioinformatic analysis all sought rearrangements were successfully detected. In addition, unexpected complexity or additional, previously undetected rearrangements was unraveled in three samples. Finally, the MP-WGS analysis pinpointed the location of chromosome junctions at high resolution and we were able to identify the exact exons involved in the resulting fusion genes in all samples and the specific junction at the nucleotide level in half of the samples. The results show that our approach combines the screening character from karyotype analysis with the specificity and resolution of cytogenetic and molecular methods. As a result of the straightforward analysis and high-resolution detection of clinically relevant rearrangements, we conclude that MP-WGS is a feasible method for routine leukemia diagnostics of structural chromosomal rearrangements.

  • 21. Aparicio-Puerta, Ernesto
    et al.
    Lebron, Ricardo
    Rueda, Antonio
    Gomez-Martin, Cristina
    Giannoukakos, Stavros
    Jaspez, David
    Maria Medina, Jose
    Zubkovic, Andreja
    Jurak, Igor
    Fromm, Bastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Antonio Marchal, Juan
    Oliver, Jose
    Hackenberg, Michael
    sRNAbench and sRNAtoolbox 2019: intuitive fast small RNA profiling and differential expression2019Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, nr W1, s. W530-W535Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Since the original publication of sRNAtoolbox in 2015, small RNA research experienced notable advances in different directions. New protocols for small RNA sequencing have become available to address important issues such as adapter ligation bias, PCR amplification artefacts or to include internal controls such as spike-in sequences. New microRNA reference databases were developed with different foci, either prioritizing accuracy (low number of false positives) or completeness (low number of false negatives). Additionally, other small RNA molecules as well asmicroRNA sequence and length variants (isomiRs) have continued to gain importance. Finally, the number of microRNA sequencing studies deposited in GEO nearly triplicated from 2014 (280) to 2018 (764). These developments imply that fast and easy-to-use tools for expression profiling and subsequent downstream analysis of miRNAseq data are essential to many researchers. Key features in this sRNAtoolbox release include addition of all major RNA library preparation protocols to sRNAbench and improvements in sRNAde, a tool that summarizes several aspects of small RNA sequencing studies including the detection of consensus differential expression. A special emphasis was put on the user-friendliness of the tools, for instance sRNAbench now supports parallel launching of several jobs to improve reproducibility and user time efficiency.

  • 22.
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Matematiska institutionen. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-science Research Centre, Sweden.
    alv: a console-based viewer for molecular sequence alignments2018Ingår i: Journal of Open Source Software, ISSN 2475-9066, Vol. 3, nr 31, artikel-id 955Artikel i tidskrift (Refereegranskat)
  • 23. Atzori, Alessio
    et al.
    Liggi, Sonia
    Laaksonen, Aatto
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK). Stockholms universitet, Science for Life Laboratory (SciLifeLab). University of Cagliari, Italy.
    Porcu, Massimiliano
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK). Università di Cagliari, Italy.
    Lyubartsev, Alexander P.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Saba, Giuseppe
    Mocci, Francesca
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Università di Cagliari, Italy.
    Base sequence specificity of counterion binding to DNA: what can MD simulations tell us?2016Ingår i: Canadian journal of chemistry (Print), ISSN 0008-4042, E-ISSN 1480-3291, Vol. 94, nr 12, s. 1181-1188Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nucleic acids are highly charged biopolymers whose secondary structure is strongly dependent on electrostatic interactions. Solvent molecules and ions are also believed to play an important role in mediating and directing both sequence recognition and interactions with other molecules, such as proteins and a variety of ligands. Therefore, to fully understand the biological functions of DNA, it is necessary to understand the interactions with the surrounding counterions. It is well known that monovalent counterions can bind to the minor groove of DNA with consecutive sequences of four, or more, adenine and thymine (A-tracts) with relatively long residence times. However, much less is known about their binding to the backbone and to the major groove. In this work, we used molecular dynamics simulations to both investigate the interactions between the backbone and major groove of DNA and one of its physiological counterions (Na+) and evaluate the relationship between these interactions and the nucleotide sequence. Three dodecamers, namely CGAAAATTTTCG, CGCTCTAGAGCG, and CGCGAATTCGCG, were simulated using the Toukan-Rahman flexible SPC water model and Smith and Dang parameters for Na+, revealing a significant sequence dependence on the ion binding to both backbone and major groove. In the absence of experimental data on the atomistic details of the studied interactions, the reliability of the results was evaluated performing the simulations with additional sets of potential parameters for ions and solvent, namely the A. qvist or the Joung and Cheatham ion parameters and the TIP3P water model. This allowed us to evaluate the results by verifying which features are preserved independently from the parameters adopted.

  • 24. Ayoglu, Burcu
    et al.
    Birgersson, Elin
    Mezger, Anja
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Uhlén, Mathias
    Nilsson, Peter
    Schwenk, Jochen M.
    Multiplexed protein profiling by sequential affinity capture2016Ingår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 16, nr 8, s. 1251-1256Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antibody microarrays enable parallelized and miniaturized analysis of clinical samples, and have proven to provide novel insights for the analysis of different proteomes. However, there are concerns that the performance of such direct labeling and single antibody assays are prone to off-target binding due to the sample context. To improve selectivity and sensitivity while maintaining the possibility to conduct multiplexed protein profiling, we developed a multiplexed and semi-automated sequential capture assay. This novel bead-based procedure encompasses a first antigen capture, labeling of captured protein targets on magnetic particles, combinatorial target elution and a read-out by a secondary capture bead array. We demonstrate in a proof-of-concept setting that target detection via two sequential affinity interactions reduced off-target contribution, while lowered background and noise levels, improved correlation to clinical values compared to single binder assays. We also compared sensitivity levels with single binder and classical sandwich assays, explored the possibility for DNA-based signal amplification, and demonstrate the applicability of the dual capturebead-based antibody microarray for biomarker analysis. Hence, the described concept enhances the possibilities for antibody array assays to be utilized for protein profiling in body fluids and beyond.

  • 25. Babbitt, Patricia C.
    et al.
    Bagos, Pantelis G.
    Bairoch, Amos
    Bateman, Alex
    Chatonnet, Arnaud
    Chen, Mark Jinan
    Craik, David J.
    Finn, Robert D.
    Gloriam, David
    Haft, Daniel H.
    Henrissat, Bernard
    Holliday, Gemma L.
    Isberg, Vignir
    Kaas, Quentin
    Landsman, David
    Lenfant, Nicolas
    Manning, Gerard
    Nagano, Nozomi
    Srinivasan, Narayanaswamy
    O'Donovan, Claire
    Pruitt, Kim D.
    Sowdhamini, Ramanathan
    Rawlings, Neil D.
    Saier, Milton H.
    Sharman, Joanna L.
    Spedding, Michael
    Tsirigos, Konstantinos D.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Vastermark, Ake
    Vriend, Gerrit
    Creating a specialist protein resource network: a meeting report for the protein bioinformatics and community resources retreat2015Ingår i: Database: The Journal of Biological Databases and Curation, ISSN 1758-0463, E-ISSN 1758-0463, artikel-id bav063Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During 11-12 August 2014, a Protein Bioinformatics and Community Resources Retreat was held at the Wellcome Trust Genome Campus in Hinxton, UK. This meeting brought together the principal investigators of several specialized protein resources (such as CAZy, TCDB and MEROPS) as well as those from protein databases from the large Bioinformatics centres (including UniProt and RefSeq). The retreat was divided into five sessions: (1) key challenges, (2) the databases represented, (3) best practices for maintenance and curation, (4) information flow to and from large data centers and (5) communication and funding. An important outcome of this meeting was the creation of a Specialist Protein Resource Network that we believe will improve coordination of the activities of its member resources. We invite further protein database resources to join the network and continue the dialogue.

  • 26.
    Bachmann, Jörg A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Tedder, Andrew
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Laenen, Benjamin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Fracassetti, Marco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Désamore, Aurélie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lafon-Placette, Clement
    Steige, Kim A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Callot, Caroline
    Marande, William
    Neuffer, Barbara
    Bergès, Hélène
    Köhler, Claudia
    Castric, Vincent
    Slotte, Tanja
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Genetic basis and timing of a major mating system shift in Capsella2019Ingår i: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 224, nr 1, s. 505-517Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A crucial step in the transition from outcrossing to self-fertilization is the loss of genetic self-incompatibility (SI). In the Brassicaceae, SI involves the interaction of female and male specificity components, encoded by the genes SRK and SCR at the self-incompatibility locus (S-locus). Theory predicts that S-linked mutations, and especially dominant mutations in SCR, are likely to contribute to loss of SI. However, few studies have investigated the contribution of dominant mutations to loss of SI in wild plant species. Here, we investigate the genetic basis of loss of SI in the self-fertilizing crucifer species Capsella orientalis, by combining genetic mapping, long-read sequencing of complete S-haplotypes, gene expression analyses and controlled crosses. We show that loss of SI in C. orientalis occurred S-locus. We identify a fixed frameshift deletion in the male specificity gene SCR and confirm loss of male SI specificity. We further identify an S-linked small RNA that is predicted to cause dominance of self-compatibility. Our results agree with predictions on the contribution of dominant S-linked mutations to loss of SI, and thus provide new insights into the molecular basis of mating system transitions.

  • 27.
    Bachmann, Jörg A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Tedder, Andrew
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Laenen, Benjamin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Steige, Kim A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Slotte, Tanja
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Targeted Long-Read Sequencing of a Locus Under Long-Term Balancing Selection in Capsella2018Ingår i: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 8, nr 4, s. 1327-1333Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rapid advances in short-read DNA sequencing technologies have revolutionized population genomic studies, but there are genomic regions where this technology reaches its limits. Limitations mostly arise due to the difficulties in assembly or alignment to genomic regions of high sequence divergence and high repeat content, which are typical characteristics for loci under strong long-term balancing selection. Studying genetic diversity at such loci therefore remains challenging. Here, we investigate the feasibility and error rates associated with targeted long-read sequencing of a locus under balancing selection. For this purpose, we generated bacterial artificial chromosomes (BACs) containing the Brassicaceae S-locus, a region under strong negative frequency-dependent selection which has previously proven difficult to assemble in its entirety using short reads. We sequence S-locus BACs with single-molecule long-read sequencing technology and conduct de novo assembly of these S-locus haplotypes. By comparing repeated assemblies resulting from independent long-read sequencing runs on the same BAC clone we do not detect any structural errors, suggesting that reliable assemblies are generated, but we estimate an indel error rate of 5.7x10(-5). A similar error rate was estimated based on comparison of Illumina short-read sequences and BAC assemblies. Our results show that, until de novo assembly of multiple individuals using long-read sequencing becomes feasible, targeted long-read sequencing of loci under balancing selection is a viable option with low error rates for single nucleotide polymorphisms or structural variation. We further find that short-read sequencing is a valuable complement, allowing correction of the relatively high rate of indel errors that result from this approach.

  • 28. Baeza-Delgado, Carlos
    et al.
    von Heijne, Gunnar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Marti-Renom, Marc A.
    Mingarro, Ismael
    Biological insertion of computationally designed short transmembrane segments2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 23397Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The great majority of helical membrane proteins are inserted co-translationally into the ER membrane through a continuous ribosome-translocon channel. The efficiency of membrane insertion depends on transmembrane (TM) helix amino acid composition, the helix length and the position of the amino acids within the helix. In this work, we conducted a computational analysis of the composition and location of amino acids in transmembrane helices found in membrane proteins of known structure to obtain an extensive set of designed polypeptide segments with naturally occurring amino acid distributions. Then, using an in vitro translation system in the presence of biological membranes, we experimentally validated our predictions by analyzing its membrane integration capacity. Coupled with known strategies to control membrane protein topology, these findings may pave the way to de novo membrane protein design.

  • 29. Bano-Polo, Manuel
    et al.
    Martinez-Gill, Luis
    Wallner, Björn
    Nieva, Jose L.
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Mingarro, Ismael
    Charge Pair Interactions in Transmembrane Helices and Turn Propensity of the Connecting Sequence Promote Helical Hairpin Insertion2013Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 425, nr 4, s. 830-840Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    alpha-Helical hairpins, consisting of a pair of closely spaced transmembrane (TM) helices that are connected by a short interfacial turn, are the simplest structural motifs found in multi-spanning membrane proteins. In naturally occurring hairpins, the presence of polar residues is common and predicted to complicate membrane insertion. We postulate that the pre-packing process offsets any energetic cost of allocating polar and charged residues within the hydrophobic environment of biological membranes. Consistent with this idea, we provide here experimental evidence demonstrating that helical hairpin insertion into biological membranes can be driven by electrostatic interactions between closely separated, poorly hydrophobic sequences. Additionally, we observe that the integral hairpin can be stabilized by a short loop heavily populated by turn-promoting residues. We conclude that the combined effect of TM-TM electrostatic interactions and tight turns plays an important role in generating the functional architecture of membrane proteins and propose that helical hairpin motifs can be acquired within the context of the Sec61 translocon at the early stages of membrane protein biosynthesis. Taken together, these data further underline the potential complexities involved in accurately predicting TM domains from primary structures.

  • 30. Barisic, Ivan
    et al.
    Schoenthaler, Silvia
    Ke, Rongqin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Noehammer, Christa
    Wiesinger-Mayr, Herbert
    Multiplex detection of antibiotic resistance genes using padlock probes2013Ingår i: Diagnostic microbiology and infectious disease, ISSN 0732-8893, E-ISSN 1879-0070, Vol. 77, nr 2, s. 118-125Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The elucidation of resistance mechanisms is of central importance to providing and maintaining efficient medical treatment. However, molecular detection methods covering the complete set of resistance genes with a single test are still missing. Here, we present a novel 100-plex assay based on padlock probes in combination with a microarray that allows the simultaneous large-scale identification of highly diverse beta-lactamases. The specificity of the assay was performed using 70 clinical bacterial isolates, recovering 98% of the beta-lactamase nucleotide sequences present. Additionally, the sensitivity was evaluated with PCR products and genomic bacterial DNA, revealing a detection limit of 10(4) DNA copies per reaction when using PCR products as the template. Pre-amplification of genomic DNA in a 25-multiplex PCR further facilitated the detection of beta-lactamase genes in dilutions of 10(7) cells/mL. In summary, we present an efficient, highly specific, and highly sensitive multiplex detection method for any gene.

  • 31. Barrientos-Somarribas, Mauricio
    et al.
    Messina, David N.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Pou, Christian
    Lysholm, Fredrik
    Bjerkner, Annelie
    Allander, Tobias
    Andersson, Bjorn
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Discovering viral genomes in human metagenomic data by predicting unknown protein families2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Massive amounts of metagenomics data are currently being produced, and in all such projects a sizeable fraction of the resulting data shows no or little homology to known sequences. It is likely that this fraction contains novel viruses, but identification is challenging since they frequently lack homology to known viruses. To overcome this problem, we developed a strategy to detect ORFan protein families in shotgun metagenomics data, using similarity-based clustering and a set of filters to extract bona fide protein families. We applied this method to 17 virus-enriched libraries originating from human nasopharyngeal aspirates, serum, feces, and cerebrospinal fluid samples. This resulted in 32 predicted putative novel gene families. Some families showed detectable homology to sequences in metagenomics datasets and protein databases after reannotation. Notably, one predicted family matches an ORF from the highly variable Torque Teno virus (TTV). Furthermore, follow-up from a predicted ORFan resulted in the complete reconstruction of a novel circular genome. Its organisation suggests that it most likely corresponds to a novel bacteriophage in the microviridae family, hence it was named bacteriophage HFM.

  • 32. Barrio, Alvaro Martinez
    et al.
    Lamichhaney, Sangeet
    Fan, Guangyi
    Rafati, Nima
    Pettersson, Mats
    Zhang, He
    Dainat, Jacques
    Ekman, Diana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Hoppner, Marc
    Jern, Patric
    Martin, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Nystedt, Björn
    Liu, Xin
    Chen, Wenbin
    Liang, Xinming
    Shi, Chengcheng
    Fu, Yuanyuan
    Ma, Kailong
    Zhan, Xiao
    Feng, Chungang
    Gustafson, Ulla
    Rubin, Carl-Johan
    Almen, Markus Sallman
    Blass, Martina
    Casini, Michele
    Folkvord, Arild
    Laikre, Linda
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Ryman, Nils
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Lee, Simon Ming-Yuen
    Xu, Xun
    Andersson, Leif
    The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing2016Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 5, artikel-id e12081Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation.

  • 33.
    Basile, Walter
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Sachenkova, Oxana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Light, Sara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Linköping University, Sweden.
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Kungliga Tekniska Högskolan, Sweden.
    High GC content causes orphan proteins to be intrinsically disordered2017Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, nr 3, artikel-id e1005375Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    De novo creation of protein coding genes involves the formation of short ORFs from noncoding regions; some of these ORFs might then become fixed in the population These orphan proteins need to, at the bare minimum, not cause serious harm to the organism, meaning that they should for instance not aggregate. Therefore, although the creation of short ORFs could be truly random, the fixation should be subjected to some selective pressure. The selective forces acting on orphan proteins have been elusive, and contradictory results have been reported. In Drosophila young proteins are more disordered than ancient ones, while the opposite trend is present in yeast. To the best of our knowledge no valid explanation for this difference has been proposed. To solve this riddle we studied structural properties and age of proteins in 187 eukaryotic organisms. We find that, with the exception of length, there are only small differences in the properties between proteins of different ages. However, when we take the GC content into account we noted that it could explain the opposite trends observed for orphans in yeast (low GC) and Drosophila (high GC). GC content is correlated with codons coding for disorder promoting amino acids. This leads us to propose that intrinsic disorder is not a strong determining factor for fixation of orphan proteins. Instead these proteins largely resemble random proteins given a particular GC level. During evolution the properties of a protein change faster than the GC level causing the relationship between disorder and GC to gradually weaken.

  • 34.
    Basile, Walter
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Salvatore, Marco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Bassot, Claudio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center (SeRC), Sweden.
    Why do eukaryotic proteins contain more intrinsically disordered regions?2019Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, nr 7, artikel-id e1007186Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intrinsic disorder is more abundant in eukaryotic than prokaryotic proteins. Methods predicting intrinsic disorder are based on the amino acid sequence of a protein. Therefore, there must exist an underlying difference in the sequences between eukaryotic and prokaryotic proteins causing the (predicted) difference in intrinsic disorder. By comparing proteins, from complete eukaryotic and prokaryotic proteomes, we show that the difference in intrinsic disorder emerges from the linker regions connecting Pfam domains. Eukaryotic proteins have more extended linker regions, and in addition, the eukaryotic linkers are significantly more disordered, 38% vs. 12-16% disordered residues. Next, we examined the underlying reason for the increase in disorder in eukaryotic linkers, and we found that the changes in abundance of only three amino acids cause the increase. Eukaryotic proteins contain 8.6% serine; while prokaryotic proteins have 6.5%, eukaryotic proteins also contain 5.4% proline and 5.3% isoleucine compared with 4.0% proline and ≈ 7.5% isoleucine in the prokaryotes. All these three differences contribute to the increased disorder in eukaryotic proteins. It is tempting to speculate that the increase in serine frequencies in eukaryotes is related to regulation by kinases, but direct evidence for this is lacking. The differences are observed in all phyla, protein families, structural regions and type of protein but are most pronounced in disordered and linker regions. The observation that differences in the abundance of three amino acids cause the difference in disorder between eukaryotic and prokaryotic proteins raises the question: Are amino acid frequencies different in eukaryotic linkers because the linkers are more disordered or do the differences cause the increased disorder?

  • 35.
    Basile, Walter
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Salvatore, Marco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center (SeRC), Sweden.
    The classification of orphans is improved by combining searches in both proteomes and genomes2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The identification of de novo created genes is important as it provides a glimpse on the evolutionary processes of gene creation. Potential de novo created genes are identified by selecting genes that have no homologs outside a particular species, but for an accurate detection this identification needs to be correct.

    Genes without any homologs are often referred to as orphans; in addition to de novo created ones, fast evolving genes or genes lost in all related genomes might also be classified as orphans. The identification of orphans is dependent on: (i) a method to detect homologs and (ii) a database including genes from related genomes.

    Here, we set out to investigate how the detection of orphans is influenced by these two factors. Using Saccharomyces cerevisiae we identify that best strategy is to use a combination of searching annotated proteins and a six-frame translation of all ORFs from closely related genomes. Using this strategy we obtain a set of 54 orphans in Drosophila melanogaster and 38 in Drosophila pseudoobscura, significantly less than what is reported in some earlier studies.

  • 36. Beghini, Alessandro
    et al.
    Corlazzoli, Francesca
    Del Giacco, Luca
    Re, Matteo
    Lazzaroni, Francesca
    Brioschi, Matteo
    Valentini, Giorgio
    Ferrazzi, Fulvia
    Ghilardi, Anna
    Righi, Marco
    Turrini, Mauro
    Mignardi, Marco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Cesana, Clara
    Bronte, Vincenzo
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Morra, Enrica
    Cairoli, Roberto
    Regeneration-associated WNT Signaling Is Activated in Long-term Reconstituting AC133(bright) Acute Myeloid Leukemia Cells2012Ingår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 14, nr 12, s. 1236-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by two molecularly distinct self-renewing leukemic stem cell (LSC) populations most closely related to normal progenitors and organized as a hierarchy. A requirement for WNT/beta-catenin signaling in the pathogenesis of AML has recently been suggested by a mouse model. However, its relationship to a specific molecular function promoting retention of self-renewing leukemia-initiating cells (LICs) in human remains elusive. To identify transcriptional programs involved in the maintenance of a self-renewing state in LICs, we performed the expression profiling in normal (n = 10) and leukemic (n = 33) human long-term reconstituting AC133(+) cells, which represent an expanded cell population in most AML patients. This study reveals the ligand-dependent WNT pathway activation in AC133(bright) AML cells and shows a diffuse expression and release of WNT 10B, a hematopoietic stem cell regenerative-associated molecule. The establishment of a primary AC133(+) AML cell culture (A46) demonstrated that leukemia cells synthesize and secrete WNT ligands, increasing the levels of dephosphorylated beta-catenin in vivo. We tested the LSC functional activity in AC133(+) cells and found significant levels of engraftment upon transplantation of A46 cells into irradiated Rag2(-/-)gamma c(-/-) mice. Owing to the link between hematopoietic regeneration and developmental signaling, we transplanted A46 cells into developing zebrafish. This system revealed the formation of ectopic structures by activating dorsal organizer markers that act downstream of the WNT pathway. In conclusion, our findings suggest that AC133(bright) LSCs are promoted by misappropriating homeostatic WNT programs that control hematopoietic regeneration. Neoplasia (2012) 14, 1236-1248

  • 37. Bejhed, Rebecca S.
    et al.
    Strömme, Maria
    Svedlindh, Peter
    Ahlford, Annika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Strömberg, Mattias
    Magnetic nanobeads present during enzymatic amplification and labeling for a simplified DNA detection protocol based on AC susceptometry2015Ingår i: AIP Advances, ISSN 2158-3226, E-ISSN 2158-3226, Vol. 5, nr 12, artikel-id 127139Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Magnetic biosensors are promising candidates for low-cost point-of-care biodiagnostic devices. For optimal efficiency it is crucial to minimize the time and complexity of the assay protocol including target recognition, amplification, labeling and read-out. In this work, possibilities for protocol simplifications for a DNA biodetection principle relying on hybridization of magnetic nanobeads to rolling circle amplification (RCA) products are investigated. The target DNA is recognized through a padlock ligation assay resulting in DNA circles serving as templates for the RCA process. It is found that beads can be present during amplification without noticeably interfering with the enzyme used for RCA (phi29 polymerase). As a result, the bead-coil hybridization can be performed immediately after amplification in a one-step manner at elevated temperature within a few minutes prior to read-out in an AC susceptometer setup, i.e. a combined protocol approach. Moreover, by recording the phase angle xi = arctan(chi ''/chi'), where chi and chi '' are the in-phase and out-of-phase components of the AC susceptibility, respectively, at one single frequency the total assay time for the optimized combined protocol would be no more than 1.5 hours, often a relevant time frame for diagnosis of cancer and infectious disease. Also, applying the phase angle method normalization of AC susceptibility data is not needed. These findings are useful for the development of point-of-care biodiagnostic devices relying on bead-coil binding and magnetic AC susceptometry.

  • 38.
    Bendz, Maria
    et al.
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Skwark, Marcin
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Nilsson, Daniel
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Granholm, Viktor
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Cristobal, Susana
    Kall, Lukas
    Elofsson, Arne
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Membrane protein shaving with thermolysin can be used to evaluate topology predictors2013Ingår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 13, nr 9, s. 1467-1480Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Topology analysis of membrane proteins can be obtained by enzymatic shaving in combination with MS identification of peptides. Ideally, such analysis could provide quite detailed information about the membrane spanning regions. Here, we examine the ability of some shaving enzymes to provide large-scale analysis of membrane proteome topologies. To compare different shaving enzymes, we first analyzed the detected peptides from two over-expressed proteins. Second, we analyzed the peptides from non-over-expressed Escherichia coli membrane proteins with known structure to evaluate the shaving methods. Finally, the identified peptides were used to test the accuracy of a number of topology predictors. At the end we suggest that the usage of thermolysin, an enzyme working at the natural pH of the cell for membrane shaving, is superior because: (i) we detect a similar number of peptides and proteins using thermolysin and trypsin; (ii) thermolysin shaving can be run at a natural pH and (iii) the incubation time is quite short. (iv) Fewer detected peptides from thermolysin shaving originate from the transmembrane regions. Using thermolysin shaving we can also provide a clear separation between the best and the less accurate topology predictors, indicating that using data from shaving can provide valuable information when developing new topology predictors.

  • 39. Bengtsson-Palme, Johan
    et al.
    Angelin, Martin
    Huss, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Kjellqvist, Sanela
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Kristiansson, Erik
    Palmgren, Helena
    Larsson, D. G. Joakim
    Johansson, Anders
    The Human Gut Microbiome as a Transporter of Antibiotic Resistance Genes between Continents2015Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, nr 10, s. 6551-6560Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous studies of antibiotic resistance dissemination by travel have, by targeting only a select number of cultivable bacterial species, omitted most of the human microbiome. Here, we used explorative shotgun metagenomic sequencing to address the abundance of >300 antibiotic resistance genes in fecal specimens from 35 Swedish students taken before and after exchange programs on the Indian peninsula or in Central Africa. All specimens were additionally cultured for extended-spectrum beta-lactamase (ESBL)-producing enterobacteria, and the isolates obtained were genome sequenced. The overall taxonomic diversity and composition of the gut microbiome remained stable before and after travel, but there was an increasing abundance of Proteobacteria in 25/35 students. The relative abundance of antibiotic resistance genes increased, most prominently for genes encoding resistance to sulfonamide (2.6-fold increase), trimethoprim (7.7-fold), and beta-lactams (2.6-fold). Importantly, the increase observed occurred without any antibiotic intake. Of 18 students visiting the Indian peninsula, 12 acquired ESBL-producing Escherichia coli, while none returning from Africa were positive. Despite deep sequencing efforts, the sensitivity of metagenomics was not sufficient to detect acquisition of the low-abundant genes responsible for the observed ESBL phenotype. In conclusion, metagenomic sequencing of the intestinal microbiome of Swedish students returning from exchange programs in Central Africa or the Indian peninsula showed increased abundance of genes encoding resistance to widely used antibiotics.

  • 40.
    Berg, Carlo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Dupont, Chris L.
    Asplund-Samuelsson, Johannes
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Celepli, Narin A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Eiler, Alexander
    Allen, Andrew E.
    Ekman, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Bergman, Birgitta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ininbergs, Karolina
    Dissection of Microbial Community Functions during a Cyanobacterial Bloom in the Baltic Sea via Metatranscriptomics2018Ingår i: Frontiers in Marine Science, E-ISSN 2296-7745, artikel-id UNSP 55Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Marine and brackish surface waters are highly dynamic habitats that undergo repeated seasonal variations in microbial community composition and function throughout time. While succession of the various microbial groups has been well investigated, little is known about the underlying gene-expression of the microbial community. We investigated microbial interactions via metatranscriptomics over a spring to fall seasonal cycle in the brackish Baltic Sea surface waters, a temperate brackish water ecosystem periodically promoting massive cyanobacterial blooms, which have implications for primary production, nutrient cycling, and expansion of hypoxic zones. Network analysis of the gene expression of all microbes from 0.22 to 200 mu m in size and of the major taxonomic groups dissected the seasonal cycle into four components that comprised genes peaking during different periods of the bloom. Photoautotrophic nitrogen-fixing Cyanobacteria displayed the highest connectivity among the microbes, in contrast to chemoautotrophic ammonia-oxidizing Thaumarchaeota, while heterotrophs dominated connectivity among pre- and post-bloom peaking genes. The network was also composed of distinct functional connectivities, with an early season balance between carbon metabolism and ATP synthesis shifting to a dominance of ATP synthesis during the bloom, while carbon degradation, specifically through the glyoxylate shunt, characterized the post-bloom period, driven by Alphaproteobacteria as well as by Gammaproteobacteria of the SAR86 and SAR92 clusters. Our study stresses the exceptionally strong biotic driving force executed by cyanobacterial blooms on associated microbial communities in the Baltic Sea and highlights the impact cyanobacterial blooms have on functional microbial community composition.

  • 41.
    Berg, Carlo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Leibniz Institute for Baltic Sea Research Warnemünde (IOW), Germany.
    Vandieken, Verona
    Thamdrup, Bo
    Juergens, Klaus
    Significance of archaeal nitrification in hypoxic waters of the Baltic Sea2015Ingår i: The ISME Journal, ISSN 1751-7362, E-ISSN 1751-7370, Vol. 9, nr 6, s. 1319-1332Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ammonia-oxidizing archaea (AOA) of the phylum Thaumarchaeota are widespread, and their abundance in many terrestrial and aquatic ecosystems suggests a prominent role in nitrification. AOA also occur in high numbers in oxygen-deficient marine environments, such as the pelagic redox gradients of the central Baltic Sea; however, data on archaeal nitrification rates are scarce and little is known about the factors, for example sulfide, that regulate nitrification in this system. In the present work, we assessed the contribution of AOA to ammonia oxidation rates in Baltic deep basins and elucidated the impact of sulfide on this process. Rate measurements with N-15-labeled ammonium, CO2 dark fixation measurements and quantification of AOA by catalyzed reporter deposition-fluorescence in situ hybridization revealed that among the three investigated sites the highest potential nitrification rates (122-884 nmol l(-1) per day) were measured within gradients of decreasing oxygen, where thaumarchaeotal abundance was maximal (2.5-6.9 x 10(5) cells per ml) and CO2 fixation elevated. In the presence of the archaeal-specific inhibitor GC7, nitrification was reduced by 86-100%, confirming the assumed dominance of AOA in this process. In samples spiked with sulfide at concentrations similar to those of in situ conditions, nitrification activity was inhibited but persisted at reduced rates. This result together with the substantial nitrification potential detected in sulfidic waters suggests the tolerance of AOA to periodic mixing of anoxic and sulfidic waters. It begs the question of whether the globally distributed Thaumarchaeota respond similarly in other stratified water columns or whether the observed robustness against sulfide is a specific feature of the thaumarchaeotal subcluster present in the Baltic Deeps.

  • 42. Berglund, Emelie
    et al.
    Maaskola, Jonas
    Schultz, Niklas
    Friedrich, Stefanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Marklund, Maja
    Bergenstråhle, Joseph
    Tarish, Firas
    Tanoglidi, Anna
    Vickovic, Sanja
    Larsson, Ludvig
    Salmén, Fredrik
    Ogris, Christoph
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Wallenborg, Karolina
    Lagergren, Jens
    Ståhl, Patrik
    Sonnhammer, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Helleday, Thomas
    Lundeberg, Joakim
    Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 2419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.

  • 43. Bernet, Néstor Vazquez
    et al.
    Corcoran, Martin
    Hardt, Uta
    Kaduk, Mateusz
    Phad, Ganesh E.
    Martin, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Hedestam, Gunilla B. Karlsson
    High-Quality Library Preparation for NGS-Based Immunoglobulin Germline Gene Inference and Repertoire Expression Analysis2019Ingår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, artikel-id 660Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Next generation sequencing (NGS) of immunoglobulin (Ig) repertoires (Rep-seq) enables examination of the adaptive immune system at an unprecedented level. Applications include studies of expressed repertoires, gene usage, somatic hypermutation levels, Ig lineage tracing and identification of genetic variation within the Ig loci through inference methods. All these applications require starting libraries that allow the generation of sequence data with low error rate and optimal representation of the expressed repertoire. Here, we provide detailed protocols for the production of libraries suitable for human Ig germline gene inference and Ig repertoire studies. Various parameters used in the process were tested in order to demonstrate factors that are critical to obtain high quality libraries. We demonstrate an improved 5'RACE technique that reduces the length constraints of Illumina MiSeq based Rep-seq analysis but allows for the acquisition of sequences upstream of Ig V genes, useful for primer design. We then describe a 5' multiplex method for library preparation, which yields full length V(D)J sequences suitable for genotype identification and novel gene inference. We provide comprehensive sets of primers targeting IGHV, IGKV, and IGLV genes. Using the optimized protocol, we produced IgM, IgG, IgK, and IgL libraries and analyzed them using the germline inference tool IgDiscover to identify expressed germline V alleles. This process additionally uncovered three IGHV, one IGKV, and six IGLV novel alleles in a single individual, which are absent from the IMGT reference database, highlighting the need for further study of Ig genetic variation. The library generation protocols presented here enable a robust means of analyzing expressed Ig repertoires, identifying novel alleles and producing individualized germline gene databases from humans.

  • 44. Bhambri, Aksheev
    et al.
    Dhaunta, Neeraj
    Patel, Surendra Singh
    Hardikar, Mitali
    Bhatt, Abhishek
    Srikakulam, Nagesh
    Shridhar, Shruti
    Vellarikkal, Shamsudheen
    Pandey, Rajesh
    Jayarajan, Rijith
    Verma, Ankit
    Kumar, Vikram
    Gautam, Pradeep
    Khanna, Yukti
    Khan, Jameel Ahmed
    Fromm, Bastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Peterson, Kevin J.
    Scaria, Vinod
    Sivasubbu, Sridhar
    Pillai, Beena
    Large scale changes in the transcriptome of Eisenia fetida during regeneration2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 9, artikel-id e0204234Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Earthworms show a wide spectrum of regenerative potential with certain species like Eisenia fetida capable of regenerating more than two-thirds of their body while other closely related species, such as Paranais litoralis seem to have lost this ability. Earthworms belong to the phylum Annelida, in which the genomes of the marine oligochaete Capitella telata and the freshwater leech Helobdella robusta have been sequenced and studied. Herein, we report the transcriptomic changes in Eisenia fetida (Indian isolate) during regeneration. Following injury, E. fetida regenerates the posterior segments in a time spanning several weeks. We analyzed gene expression changes both in the newly regenerating cells and in the adjacent tissue, at early (15days post amputation), intermediate (20days post amputation) and late (30 days post amputation) by RNAseq based de novo assembly and comparison of transcriptomes. We also generated a draft genome sequence of this terrestrial red worm using short reads and mate-pair reads. An in-depth analysis of the miRNome of the worm showed that many miRNA gene families have undergone extensive duplications. Sox4, a master regulator of TGF-beta mediated epithelial-mesenchymal transition was induced in the newly regenerated tissue. Genes for several proteins such as sialidases and neurotrophins were identified amongst the differentially expressed transcripts. The regeneration of the ventral nerve cord was also accompanied by the induction of nerve growth factor and neurofilament genes. We identified 315 novel differentially expressed transcripts in the transcriptome, that have no homolog in any other species. Surprisingly, 82% of these novel differentially expressed transcripts showed poor potential for coding proteins, suggesting that novel ncRNAs may play a critical role in regeneration of earthworm.

  • 45. Bigalke, Janna M.
    et al.
    Aibara, Shintaro
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Roth, Robert
    Dahl, Göran
    Gordon, Euan
    Dorbéus, Sarah
    Amunts, Alexey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Sandmark, Jenny
    Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain2019Ingår i: Science Advances, E-ISSN 2375-2548, Vol. 5, nr 7, artikel-id eaau4202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Signaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details of receptor activation have remained elusive. We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFR alpha 2 and determined its structure at 5.7-angstrom resolution by cryo-EM. The proteins form an assembly through RET-GFR alpha 2 and RET-NRTN interfaces. Two key interaction points required for RET extracellular domain binding were observed: (i) the calcium-binding site in RET that contacts GFR alpha 2 domain 3 and (ii) the RET cysteine-rich domain interaction with NRTN. The structure highlights the importance of the RET cysteine-rich domain and allows proposition of a model to explain how complex formation leads to RET receptor dimerization and its activation. This provides a framework for targeting RET activity and for further exploration of mechanisms underlying neurological diseases.

  • 46. Binder, Zev A.
    et al.
    Haseley Thorne, Amy
    Bakas, Spyridon
    Wileyto, E. Paul
    Bilello, Michel
    Akbari, Hamed
    Rathore, Saima
    Ha, Sung Min
    Zhang, Logan
    Ferguson, Cole J.
    Dahiya, Sonika
    Bi, Wenya Linda
    Reardon, David A.
    Idbaih, Ahmed
    Felsberg, Joerg
    Hentschel, Bettina
    Weller, Michael
    Bagley, Stephen J.
    Morrissette, Jennifer J. D.
    Nasrallah, MacLean P.
    Ma, Jianhui
    Zanca, Ciro
    Scott, Andrew M.
    Orellana, Laura
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Davatzikos, Christos
    Furnari, Frank B.
    O'Rourke, Donald M.
    Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development2018Ingår i: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 34, nr 1, s. 163-177Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR(A289D/T/V)). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR(A289D/T/V) mutants, corroborated in mice bearing intracranial tumors expressing EGFR(A289V) and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR(A289V) tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR(A289V) mutation in glioblastoma, postulating EGFR(A289V) as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.

  • 47.
    Björkholm, Patrik
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ernst, Andreas M.
    Hacke, Moritz
    Wieland, Felix
    Bruegger, Britta
    von Heijne, Gunnar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Identification of novel sphingolipid-binding motifs in mammalian membrane proteins2014Ingår i: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1838, nr 8, s. 2066-2070Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Specific interactions between transmembrane proteins and sphingolipids is a poorly understood phenomenon, and only a couple of instances have been identified. The best characterized example is the sphingolipid-binding motif VXXTLXXIY found in the transmembrane helix of the vesicular transport protein p24. Here, we have used a simple motif-probability algorithm (MOPRO) to identify proteins that contain putative sphingolipid-binding motifs in a dataset comprising proteomes from mammalian organisms. From these motif-containing candidate proteins, four with different numbers of transmembrane helices were selected for experimental study: i) major histocompatibility complex II Q alpha chain subtype (DQA1), ii) GPI-attachment protein 1 (GAA1), iii) tetraspanin-7 TSN7, and iv), metabotropic glutamate receptor 2 (GRM2). These candidates were subjected to photo-affinity labeling using radiolabeled sphingolipids, confirming all four candidate proteins as sphingolipid-binding proteins. The sphingolipid-binding motifs are enriched in the 7TM family of G-protein coupled receptors, predominantly in transmembrane helix 6. The ability of the motif-containing candidate proteins to bind sphingolipids with high specificity opens new perspectives on their respective regulation and function.

  • 48. Boije, Henrik
    et al.
    Ring, Henrik
    Fard, Shahrzad Shirazi
    Grundberg, Ida
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Uppsala University .
    Hallbook, Finn
    Alternative Splicing of the Chromodomain Protein Morf4l1 Pre-mRNA Has Implications on Cell Differentiation in the Developing Chicken Retina2013Ingår i: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 51, nr 2, s. 615-628Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The proliferation, cell cycle exit and differentiation of progenitor cells are controlled by several different factors. The chromodomain protein mortality factor 4-like 1 (Morf4l1) has been ascribed a role in both proliferation and differentiation. Little attention has been given to the existence of alternative splice variants of the Morf4l1 mRNA, which encode two Morf41l isoforms: a short isoform (S-Morf4l1) with an intact chromodomain and a long isoform (L-Morf4l1) with an insertion in or in the vicinity of the chromodomain. The aim of this study was to investigate if this alternative splicing has a function during development. We analysed the temporal and spatial distribution of the two mRNAs and over-expressed both isoforms in the developing retina. The results showed that the S-Morf4l1 mRNA is developmentally regulated. Over-expression of S-Morf4l1 using a retrovirus vector produced a clear phenotype with an increase of early-born neurons: retinal ganglion cells, horizontal cells and cone photoreceptor cells. Over-expression of L-Morf4l1 did not produce any distinguishable phenotype. The over-expression of S-Morf4l1 but not L-Morf4l1 also increased apoptosis in the infected regions. Our results suggest that the two Morf4l1 isoforms have different functions during retinogenesis and that Morf4l1 functions are fine-tuned by developmentally regulated alternative splicing. The data also suggest that Morf4l1 contributes to the regulation of cell genesis in the retina.

  • 49.
    Bonath, Franziska
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Domingo-Prim, Judit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Tarbier, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Friedländer, Marc R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Visa, Neus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Next-generation sequencing reveals two populations of damage-induced small RNAs at endogenous DNA double-strand breaks2018Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, nr 22, s. 11869-11882Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent studies suggest that transcription takes place at DNA double-strand breaks (DSBs), that transcripts at DSBs are processed by Drosha and Dicer into damage-induced small RNAs (diRNAs), and that diRNAs are required for DNA repair. However, diRNAs have been mostly detected in reporter constructs or repetitive sequences, and their existence at endogenous loci has been questioned by recent reports. Using the homing endonuclease I-PpoI, we have investigated diRNA production in genetically unperturbed human and mouse cells. I-PpoI is an ideal tool to clarify the requirements for diRNA production because it induces DSBs in different types of loci: the repetitive 28S locus, unique genes and intergenic loci. We show by extensive sequencing that the rDNA locus produces substantial levels of diRNAs, whereas unique genic and intergenic loci do not. Further characterization of diRNAs emerging from the 28S locus reveals the existence of two diRNA subtypes. Surprisingly, Drosha and its partner DGCR8 are dispensable for diRNA production and only one diRNAs subtype depends on Dicer processing. Furthermore, we provide evidence that diRNAs are incorporated into Argonaute. Our findings provide direct evidence for diRNA production at endogenous loci in mammalian cells and give insights into RNA processing at DSBs.

  • 50.
    Bonath, Franziska
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Domingo-Prim, Judit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Tarbier, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Friedländer, Marc
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Visa, Neus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Next-generation sequencing reveals two populations of damage- induced small RNAs at endogenous DNA double-strand breaksIngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962Artikel i tidskrift (Refereegranskat)
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