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  • 1. Abraham, Mark
    et al.
    Apostolov, Rossen
    Barnoud, Jonathan
    Bauer, Paul
    Blau, Christian
    Bonvin, Alexandre M. J. J.
    Chavent, Matthieu
    Chodera, John
    Condic-Jurkic, Karmen
    Delemotte, Lucie
    Grubmueller, Helmut
    Howard, Rebecca J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jordan, E. Joseph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Ollila, O. H. Samuli
    Selent, Jana
    Smith, Daniel G. A.
    Stansfeld, Phillip J.
    Tiemann, Johanna K. S.
    Trellet, Mikael
    Woods, Christopher
    Zhmurov, Artem
    Sharing Data from Molecular Simulations2019In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 59, no 10, p. 4093-4099Article in journal (Refereed)
    Abstract [en]

    Given the need for modern researchers to produce open, reproducible scientific output, the lack of standards and best practices for sharing data and workflows used to produce and analyze molecular dynamics (MD) simulations has become an important issue in the field. There are now multiple well-established packages to perform molecular dynamics simulations, often highly tuned for exploiting specific classes of hardware, each with strong communities surrounding them, but with very limited interoperability/transferability options. Thus, the choice of the software package often dictates the workflow for both simulation production and analysis. The level of detail in documenting the workflows and analysis code varies greatly in published work, hindering reproducibility of the reported results and the ability for other researchers to build on these studies. An increasing number of researchers are motivated to make their data available, but many challenges remain in order to effectively share and reuse simulation data. To discuss these and other issues related to best practices in the field in general, we organized a workshop in November 2018 (https://bioexcel.eu/events/workshop-on-sharing-data-from-molecular-simulations/). Here, we present a brief overview of this workshop and topics discussed. We hope this effort will spark further conversation in the MD community to pave the way toward more open, interoperable, and reproducible outputs coming from research studies using MD simulations.

  • 2. Abrahamsson, Dimitri
    et al.
    Siddharth, Adi
    Young, Thomas M.
    Sirota, Marina
    Park, June-Soo
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Woodruff, Tracey J.
    In Silico Structure Predictions for Non-targeted Analysis: From Physicochemical Properties to Molecular Structures2022In: Journal of the American Society for Mass Spectrometry, ISSN 1044-0305, E-ISSN 1879-1123, Vol. 33, no 7, p. 1134-1147Article in journal (Refereed)
    Abstract [en]

    While important advances have been made in high-resolution mass spectrometry (HRMS) and its applications in non-targeted analysis (NTA), the number of identified compounds in biological and environmental samples often does not exceed 5% of the detected chemical features. Our aim was to develop a computational pipeline that leverages data from HRMS but also incorporates physicochemical properties (equilibrium partition ratios between organic solvents and water; Ksolvent–water) and can propose molecular structures for detected chemical features. As these physicochemical properties are often sufficiently different across isomers, when put together, they can form a unique profile for each isomer, which we describe as the “physicochemical fingerprint”. In our study, we used a comprehensive database of compounds that have been previously reported in human blood and collected their Ksolvent–water values for 129 partitioning systems. We used RDKit to calculate the number of RDKit fragments and the number of RDKit bits per molecule. We then developed and trained an artificial neural network, which used as an input the physicochemical fingerprint of a chemical feature and predicted the number and types of RDKit fragments and RDKit bits present in that structure. These were then used to search the database and propose chemical structures. The average success rate of predicting the right chemical structure ranged from 60 to 86% for the training set and from 48 to 81% for the testing set. These observations suggest that physicochemical fingerprints can assist in the identification of compounds with NTA and substantially improve the number of identified compounds.

  • 3. Abrishami, Vahid
    et al.
    Ilca, Serban L.
    Gomez-Blanco, Josue
    Rissanen, Ilona
    de La Rosa-Trevin, José Miguel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Reddy, Vijay S.
    Carazo, Jose-Maria
    Huiskonen, Juha T.
    Localized reconstruction in Scipion expedites the analysis of symmetry mismatches in cryo-EM data2021In: Progress in Biophysics and Molecular Biology, ISSN 0079-6107, E-ISSN 1873-1732, Vol. 160, p. 43-52Article, review/survey (Refereed)
    Abstract [en]

    Technological advances in transmission electron microscopes and detectors have turned cryogenic electron microscopy (cryo-EM) into an essential tool for structural biology. A commonly used cryo-EM data analysis method, single particle analysis, averages hundreds of thousands of low-dose images of individual macromolecular complexes to determine a density map of the complex. The presence of symmetry in the complex is beneficial since each projection image can be assigned to multiple views of the complex. However, data processing that applies symmetry can average out asymmetric features and consequently data analysis methods are required to resolve asymmetric structural features. Scipion is a cryo-EM image processing framework that integrates functions from different image processing packages as plugins. To extend its functionality for handling symmetry mismatches, we present here a Scipion plugin termed LocalRec implementing the localized reconstruction method. When tested on an adenovirus data set, the plugin enables resolving the symmetry-mismatched trimeric fibre bound to the five-fold vertices of the capsid. Furthermore, it improves the structure determination of the icosahedral capsid by dealing with the defocus gradient across the particle. LocalRec is expected to be widely applicable in a range of cryo-EM investigations of flexible and symmetry mismatched complexes.

  • 4. Acevedo, Nathalie
    et al.
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Katayama, Shintaro
    Bruhn, Sören
    Andersson, Anna
    Wikberg, Gustav
    Lundeberg, Lena
    Lindvall, Jessica M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Greco, Dario
    Kere, Juha
    Söderhäll, Cilla
    Scheynius, Annika
    Epigenetic alterations in skin homing CD4(+)CLA(+) T cells of atopic dermatitis patients2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 18020Article in journal (Refereed)
    Abstract [en]

    T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations -(CD4(+), -CD4(+)CD45RA(+) naive, -CD4(+)CLA(+), and -CD8(+)) from adult AD patients and healthy controls (HC). Skin homing -CD4(+)CLA(+) T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in -CD4(+)CLA(+) T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in -CD4(+)CLA(+) T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing -CD4(+)CLA(+) T cells and uncover putative molecules participating in AD pathways.

  • 5. Acevedo, Nathalie
    et al.
    Bornacelly, Adriana
    Mercado, Dilia
    Unneberg, Per
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    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 12016In: plos one, ISSN 1932-6203, Vol. 11, no 12, article id e0167453Article in journal (Refereed)
    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.

  • 6. Acevedo, Nathalie
    et al.
    Scala, Giovanni
    Kebede Merid, Simon
    Frumento, Paolo
    Bruhn, Sören
    Andersson, Anna
    Ogris, Christoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Helmholtz Center Munich, Germany.
    Bottai, Matteo
    Pershagen, Göran
    Koppelman, Gerard H.
    Melén, Erik
    Sonnhammer, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Alm, Johan
    Söderhäll, Cilla
    Kere, Juha
    Greco, Dario
    Scheynius, Annika
    DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life2021In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 2, article id 801Article in journal (Refereed)
    Abstract [en]

    DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak p <= 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.

  • 7. Ahmadi-Afzadi, Masoud
    et al.
    Orsel, Mathilde
    Pelletier, Sandra
    Bruneau, Maryline
    Proux-Wéra, Estelle
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, 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 apple2018In: Plant growth regulation (Print), ISSN 0167-6903, E-ISSN 1573-5087, Vol. 85, no 3, p. 375-387Article in journal (Refereed)
    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.

  • 8.
    Ahmed, Engy
    et al.
    Stockholm University, Faculty of Science, Department of Geological Sciences. Stockholm University, 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 system2016In: Process Safety and Environmental Protection, ISSN 0957-5820, E-ISSN 1744-3598, Vol. 104, p. 1-10Article in journal (Refereed)
    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.

  • 9.
    Ahmed, Engy
    et al.
    Stockholm University, Faculty of Science, Department of Geological Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Parducci, Laura
    Unneberg, Per
    Ågren, Rasmus
    Schenk, Frederik
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Rattray, Jayne E.
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Han, Lu
    Muschitiello, Francesco
    Stockholm University, Faculty of Science, Department of Geological Sciences. Columbia University, USA.
    Pedersen, Mikkel W.
    Smittenberg, Rienk H.
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Afrifa Yamoah, Kweku
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Slotte, Tanja
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wohlfarth, Barbara
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Archaeal community changes in Lateglacial lake sediments: Evidence from ancient DNA2018In: Quaternary Science Reviews, ISSN 0277-3791, E-ISSN 1873-457X, Vol. 181, p. 19-29Article in journal (Refereed)
    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.

  • 10. 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
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, 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 coils2017In: Journal of Magnetism and Magnetic Materials, ISSN 0304-8853, E-ISSN 1873-4766, Vol. 427, p. 14-18Article in journal (Refereed)
    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.

  • 11.
    Aibara, Shintaro
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Andréll, Juni
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Singh, Vivek
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Amunts, Alexey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Rapid Isolation of the Mitoribosome from HEK Cells2018In: Journal of Visualized Experiments, E-ISSN 1940-087X, no 140, article id e57877Article in journal (Refereed)
    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.

  • 12.
    Aibara, Shintaro
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Singh, Vivek
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Modelska, Angelika
    Amunts, Alexey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Structural basis of mitochondrial translation2020In: eLIFE, E-ISSN 2050-084X, Vol. 9, article id e58362Article in journal (Refereed)
    Abstract [en]

    Translation of mitochondrial messenger RNA (mt-mRNA) is performed by distinct mitoribosomes comprising at least 36 mitochondria-specific proteins. How these mitoribosomal proteins assist in the binding of mt-mRNA and to what extent they are involved in the translocation of transfer RNA (mt-tRNA) is unclear. To visualize the process of translation in human mitochondria, we report similar to 3.0 angstrom resolution structure of the human mitoribosome, including the L7/L12 stalk, and eight structures of its functional complexes with mt-mRNA, mt-tRNAs, recycling factor and additional trans factors. The study reveals a transacting protein module LRPPRC-SLIRP that delivers mt-mRNA to the mitoribosomal small subunit through a dedicated platform formed by the mitochondria-specific protein mS39. Mitoribosomal proteins of the large subunit mL40, mL48, and mL64 coordinate translocation of mt-tRNA. The comparison between those structures shows dynamic interactions between the mitoribosome and its ligands, suggesting a sequential mechanism of conformational changes.

  • 13.
    Akar, Roya
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Fink, Matthias J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Omnus, Deike J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Regulation of the general stress response sigma factor σT by Lon-mediated proteolysis2023In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 205, no 11Article in journal (Refereed)
    Abstract [en]

    The Lon protease is widely conserved in both prokaryotic and eukaryotic organisms and fulfills important regulatory functions. Nevertheless, the number of identified Lon substrates is limited in most organisms, and the precise role of Lon in regulating these proteins is poorly understood. Here, we describe the α-proteobacterial general stress response sigma factor σT as a novel Lon substrate in Caulobacter crescentus. Based on previously published quantitative proteomics data, we find σT to be a promising putative Lon substrate and confirm a direct role of Lon in degrading σT. We show that Lon contributes to the downregulation of σT abundance under optimal conditions and during recovery from sucrose-induced osmotic stress. Furthermore, the presence of the Lon activity regulator LarA enhances Lon-mediated degradation of σT in vitro and reduces σT levels in vivo indicating a role of LarA in modulating Lon-mediated degradation of σT. Together, our results highlight the importance of Lon during the recovery phase following stress exposure by adjusting the concentrations of critical regulators of stress responses.

  • 14. Alberro-Brage, Andres
    et al.
    Kryvenko, Vitalii
    Malainou, Christina
    Guenther, Stefan
    Morty, Rory E.
    Seeger, Werner
    Herold, Susanne
    Samakovlis, Christos
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Vadasz, Istvan
    Influenza virus decreases albumin uptake and megalin expression in alveolar epithelial cells2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1260973Article in journal (Refereed)
    Abstract [en]

    Introduction

    Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of plasma levels, causing severe impairment of gas exchange and promoting deleterious alveolar remodeling. Protein clearance from the alveolar space is at least in part facilitated by the multi-ligand receptor megalin through clathrin-mediated endocytosis.

    Methods

    To investigate whether IV infection impairs alveolar protein clearance, we examined albumin uptake and megalin expression in MLE-12 cells and alveolar epithelial cells (AEC) from murine precision-cut lung slices (PCLS) and in vivo, under IV infection conditions by flow cytometry and western blot. Transcriptional levels from AEC and broncho-alveolar lavage (BAL) cells were analyzed in an in-vivo mouse model by RNAseq.

    Results

    IV significantly downregulated albumin uptake, independently of activation of the TGF- β1/GSK3β axis that has been previously implicated in the regulation of megalin function. Decreased plasma membrane abundance, total protein levels, and mRNA expression of megalin were associated with this phenotype. In IV-infected mice, we identified a significant upregulation of matrix metalloproteinase (MMP)-14 in BAL fluid cells. Furthermore, the inhibition of this protease partially recovered total megalin levels and albumin uptake.

    Discussion

    Our results suggest that the previously described MMP-driven shedding mechanisms are potentially involved in downregulation of megalin cell surface abundance and clearance of excess alveolar protein. As lower alveolar edema protein concentrations are associated with better outcomes in respiratory failure, our findings highlight the therapeutic potential of a timely MMP inhibition in the treatment of IV-induced ARDS.

  • 15. Alcamán, M. Estrella
    et al.
    Alcorta, Jaime
    Bergman, Birgitta
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, 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 springs2017In: Systematic and Applied Microbiology, ISSN 0723-2020, E-ISSN 1618-0984, Vol. 40, no 2, p. 102-113Article in journal (Refereed)
    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.

  • 16. Alekseenko, Alisa
    et al.
    Barrett, Donal
    Pareja-Sanchez, Yerma
    Howard, Rebecca J.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Strandback, Emilia
    Ampah-Korsah, Henry
    Rovšnik, Urška
    Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, S-17121 Solna, Sweden.
    Zuniga-Veliz, Silvia
    Klenov, Alexander
    Malloo, Jayshna
    Ye, Shenglong
    Liu, Xiyang
    Reinius, Björn
    Elsässer, Simon J.
    Nyman, Tomas
    Sandh, Gustaf
    Yin, Xiushan
    Pelechano, Vicent
    Direct detection of SARS-CoV-2 using non-commercial RT-LAMP reagents on heat-inactivated samples2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 1820Article in journal (Refereed)
    Abstract [en]

    RT-LAMP detection of SARS-CoV-2 has been shown to be a valuable approach to scale up COVID-19 diagnostics and thus contribute to limiting the spread of the disease. Here we present the optimization of highly cost-effective in-house produced enzymes, and we benchmark their performance against commercial alternatives. We explore the compatibility between multiple DNA polymerases with high strand-displacement activity and thermostable reverse transcriptases required for RT-LAMP. We optimize reaction conditions and demonstrate their applicability using both synthetic RNA and clinical patient samples. Finally, we validate the optimized RT-LAMP assay for the detection of SARS-CoV-2 in unextracted heat-inactivated nasopharyngeal samples from 184 patients. We anticipate that optimized and affordable reagents for RT-LAMP will facilitate the expansion of SARS-CoV-2 testing globally, especially in sites and settings where the need for large scale testing cannot be met by commercial alternatives.

  • 17. Alexeyenko, Andrey
    et al.
    Nystedt, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sherwood, Ellen
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, 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 pools2014In: BMC Genomics, E-ISSN 1471-2164, Vol. 15, p. 439-Article in journal (Refereed)
    Abstract [en]

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

  • 18.
    Alexeyenko, Andrey
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Schmitt, Thomas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Tjärnberg, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Guala, Dmitri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Frings, Oliver
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sonnhammer, Erik L. L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Comparative interactomics with Funcoup 2.02012In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no D1, p. D821-D828Article in journal (Refereed)
    Abstract [en]

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

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  • 19. Ali, Raja H.
    et al.
    Bark, Mikael
    Miró, Jorge
    Muhammad, Sayyed A.
    Sjöstrand, Joel
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Centre, Sweden.
    Zubair, Syed M.
    Abbas, Raja M.
    Arvestad, Lars
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Centre, Sweden.
    VMCMC: a graphical and statistical analysis tool for Markov chain Monte Carlo traces2017In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 18, article id 97Article in journal (Refereed)
    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/.

  • 20. Ali, Raja H.
    et al.
    Muhammad, Sayyed A.
    Arvestad, Lars
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Centre, Sweden.
    GenFamClust: an accurate, synteny-aware and reliable homology inference algorithm2016In: BMC Evolutionary Biology, E-ISSN 1471-2148, Vol. 16, article id 120Article in journal (Refereed)
    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.

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

    Background

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

    Results

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

    Conclusions

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

  • 22. Allen, Lisa Zeigler
    et al.
    McCrow, John P.
    Ininbergs, Karolina
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Dupont, Christopher L.
    Badger, Jonathan H.
    Hoffman, Jeffery M.
    Ekman, Martin
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Allen, Andrew E.
    Bergman, Birgitta
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Venter, J. Craig
    The Baltic Sea Virome: Diversity and Transcriptional Activity of DNA and RNA Viruses2017In: mSystems, E-ISSN 2379-5077, Vol. 2, no 1, article id UNSP e00125-16Article in journal (Refereed)
    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.

  • 23. Allison, Timothy M.
    et al.
    Degiacomi, Matteo T.
    Marklund, Erik G.
    Jovine, Luca
    Elofsson, Arne
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Benesch, Justin L. P.
    Landreh, Michael
    Complementing machine learning-based structure predictions with native mass spectrometry2022In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 31, no 6, article id e4333Article in journal (Refereed)
    Abstract [en]

    The advent of machine learning-based structure prediction algorithms such as AlphaFold2 (AF2) and RoseTTa Fold have moved the generation of accurate structural models for the entire cellular protein machinery into the reach of the scientific community. However, structure predictions of protein complexes are based on user-provided input and may require experimental validation. Mass spectrometry (MS) is a versatile, time-effective tool that provides information on post-translational modifications, ligand interactions, conformational changes, and higher-order oligomerization. Using three protein systems, we show that native MS experiments can uncover structural features of ligand interactions, homology models, and point mutations that are undetectable by AF2 alone. We conclude that machine learning can be complemented with MS to yield more accurate structural models on a small and large scale.

  • 24. Almagro Armenteros, José Juan
    et al.
    Tsirigos, Konstantinos D.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, 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
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nielsen, Henrik
    SignalP 5.0 improves signal peptide predictions using deep neural networks2019In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 37, no 4, p. 420-423Article in journal (Refereed)
    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.

  • 25.
    Almamoun, Radwa
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Pierozan, Paula
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Karlsson, Oskar
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Mechanistic screening of reproductive toxicity in a 3D testicular co-culture shows significant impairments following exposure to low dibutyl phthalate concentrationsManuscript (preprint) (Other academic)
  • 26.
    Almamoun, Radwa
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Pierozan, Paula
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Manoharan, Lokeshwaran
    Karlsson, Oskar
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Altered gut microbiota community structure and correlated immune system changes in dibutyl phthalate exposed mice2023In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 262, article id 115321Article in journal (Refereed)
    Abstract [en]

    Di-n-butyl phthalate (DBP) is a ubiquitous environmental contaminant linked with various adverse health effects, including immune system dysfunction. Gut microbial dysbiosis can contribute to a wide range of pathogenesis, particularly immune disease. Here, we investigated the impact of DBP on the gut microbiome and examined correlations with immune system changes after five weeks oral exposure (10 or 100 mg/kg/day) in adult male mice. The fecal microbiome composition was characterized using 16S rRNA sequencing. DBP-treated mice displayed a significantly distinct microbial community composition, indicated by Bray-Curtis distance. Numerous amplicon sequence variants (ASVs) at the genus level were altered. Compared to the vehicle control group, the 10 mg/kg/day DBP group had 63 more abundant and 65 less abundant ASVs, while 60 ASVs were increased and 76 ASVs were decreased in the 100 mg/kg/day DBP group. Both DBP treatment groups showed higher abundances of ASVs assigned to Desulfovibrio (Proteobacteria phylum) and Enterorhabdus genera, while ASVs belonging to Parabacteroides, Lachnospiraceae UCG-006 and Lachnoclostridium were less common compared to the control group. Interestingly, an ASV belonging to Rumniniclostridium 6, which was less abundant in DBP-treated mice, demonstrated a negative correlation with the increased number of non-classical monocytes observed in the blood of DBP-treated animals. In addition, an ASV from Lachnospiraceae UCG-001, which was more abundant in the DBP-treated animals, showed a positive correlation with the non-classical monocyte increase. This study shows that DBP exposure greatly modifies the gut bacterial microbiome and indicates a potential contribution of microbial dysbiosis to DBP-induced immune system impairment, illustrating the importance of investigating how interactions between exposome components can affect health.

  • 27.
    Almamoun, Radwa
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Pierozan, Paula
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Sundh, John
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Karlsson, Oskar
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Shotgun metagenomic analysis of gut microbiota in dibutyl phthalate exposed miceManuscript (preprint) (Other academic)
  • 28. Almeida, Pedro
    et al.
    Proux-Wéra, Estelle
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Churcher, Allison
    Soler, Lucile
    Dainat, Jacques
    Pucholt, Pascal
    Nordlund, Jessica
    Martin, Tom
    Rönnberg-Wästljung, Ann-Christin
    Nystedt, Björn
    Berlin, Sofia
    Mank, Judith E.
    Genome assembly of the basket willow, Salix viminalis, reveals earliest stages of sex chromosome expansion2020In: BMC Biology, E-ISSN 1741-7007, Vol. 18, no 1, article id 78Article in journal (Refereed)
    Abstract [en]

    Background: Sex chromosomes have evolved independently multiple times in eukaryotes and are therefore considered a prime example of convergent genome evolution. Sex chromosomes are known to emerge after recombination is halted between a homologous pair of chromosomes, and this leads to a range of non-adaptive modifications causing gradual degeneration and gene loss on the sex-limited chromosome. However, the proximal causes of recombination suppression and the pace at which degeneration subsequently occurs remain unclear.

    Results: Here, we use long- and short-read single-molecule sequencing approaches to assemble and annotate a draft genome of the basket willow, Salix viminalis, a species with a female heterogametic system at the earliest stages of sex chromosome emergence. Our single-molecule approach allowed us to phase the emerging Z and W haplotypes in a female, and we detected very low levels of Z/W single-nucleotide divergence in the non-recombining region. Linked-read sequencing of the same female and an additional male (ZZ) revealed the presence of two evolutionary strata supported by both divergence between the Z and W haplotypes and by haplotype phylogenetic trees. Gene order is still largely conserved between the Z and W homologs, although the W-linked region contains genes involved in cytokinin signaling regulation that are not syntenic with the Z homolog. Furthermore, we find no support across multiple lines of evidence for inversions, which have long been assumed to halt recombination between the sex chromosomes.

    Conclusions: Our data suggest that selection against recombination is a more gradual process at the earliest stages of sex chromosome formation than would be expected from an inversion and may result instead from the accumulation of transposable elements. Our results present a cohesive understanding of the earliest genomic consequences of recombination suppression as well as valuable insights into the initial stages of sex chromosome formation and regulation of sex differentiation.

  • 29. Alneberg, Johannes
    et al.
    Sundh, John
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, 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 Sea2018In: Scientific Data, E-ISSN 2052-4463, Vol. 5, article id 180146Article in journal (Refereed)
    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] .

  • 30. 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
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Dessimoz, Christophe
    Standardized benchmarking in the quest for orthologs2016In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 13, no 5, p. 425-+Article in journal (Refereed)
    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.

  • 31. Altenhoff, Adrian M.
    et al.
    Garrayo-Ventas, Javier
    Cosentino, Salvatore
    Emms, David
    Glover, Natasha M.
    Hernández-Plaza, Ana
    Nevers, Yannis
    Sundesha, Vicky
    Szklarczyk, Damian
    Fernández, José M.
    Codó, Laia
    Li Gelpi, Josep
    Huerta-Cepas, Jaime
    Iwasaki, Wataru
    Kelly, Steven
    Lecompte, Odile
    Muffato, Matthieu
    Martin, Maria J.
    Capella-Gutierrez, Salvador
    Thomas, Paul D.
    Sonnhammer, Erik
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dessimoz, Christophe
    The Quest for Orthologs benchmark service and consensus calls in 20202020In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 48, no W1, p. W538-W545Article in journal (Refereed)
    Abstract [en]

    The identification of orthologs-genes in different species which descended from the same gene in their last common ancestor-is a prerequisite for many analyses in comparative genomics and molecular evolution. Numerous algorithms and resources have been conceived to address this problem, but benchmarking and interpreting them is fraught with difficulties (need to compare them on a common input dataset, absence of ground truth, computational cost of calling orthologs). To address this, the Quest for Orthologs consortium maintains a reference set of proteomes and provides a web server for continuous orthology benchmarking (http://orthology.benchmarkservice.org). Furthermore, consensus ortholog calls derived from public benchmark submissions are provided on the Alliance of Genome Resources website, the joint portal of NIH-funded model organism databases.

  • 32. Ambikan, Anoop T.
    et al.
    Svensson-Akusjärvi, Sara
    Krishnan, Shuba
    Sperk, Maike
    Nowak, Piotr
    Vesterbacka, Jan
    Sönnerborg, Anders
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Neogi, Ujjwal
    Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV infection2022In: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, no 9, article id e202201405Article in journal (Refereed)
    Abstract [en]

    Genome-scale metabolic models (GSMMs) can provide novel insights into metabolic reprogramming during disease progression and therapeutic interventions. We developed a context-specific system-level GSMM of people living with HIV (PLWH) using global RNA sequencing data from PBMCs with suppressive viremia either by natural (elite controllers, PLWHEC) or drug-induced (PLWHART) control. This GSMM was compared with HIV-negative controls (HC) to provide a comprehensive systems-level metabo-transcriptomic characterization. Transcriptomic analysis identified up-regulation of oxidative phosphorylation as a characteristic of PLWHART, differentiating them from PLWHEC with dysregulated complexes I, III, and IV. The flux balance analysis identified altered flux in several intermediates of glycolysis including pyruvate, a-ketoglutarate, and glutamate, among others, in PLWHART. The in vitro pharmacological inhibition of OXPHOS complexes in a latent lymphocytic cell model (J-Lat 10.6) suggested a role for complex IV in latency reversal and immunosenescence. Furthermore, inhibition of complexes I/III/IV induced apoptosis, collectively indicating their contribution to reservoir dynamics.

  • 33. Ambikan, Anoop T.
    et al.
    Yang, Hong
    Krishnan, Shuba
    Svensson Akusjarvi, Sara
    Gupta, Soham
    Lourda, Magda
    Sperk, Maike
    Arif, Muhammad
    Zhang, Chenq
    Nordqvist, Hampus
    Ponnan, Sivasankaran Munusamy
    Sonnerborg, Anders
    Treutiger, Carl Johan
    O'Mahony, Liam
    Mardinoglu, Adil
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Neogi, Ujjwal
    Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity2022In: Cell systems, ISSN 2405-4712, Vol. 13, no 8, p. 665-681Article in journal (Refereed)
    Abstract [en]

    The clinical outcome and disease severity in coronavirus disease 2019 (COVID-19) are heterogeneous, and the progression or fatality of the disease cannot be explained by a single factor like age or comorbidities. In this study, we used system-wide network-based system biology analysis using whole blood RNA sequencing, immunophenotyping by flow cytometry, plasma metabolomics, and single-cell-type metabolo-mics of monocytes to identify the potential determinants of COVID-19 severity at personalized and group levels. Digital cell quantification and immunophenotyping of the mononuclear phagocytes indicated a sub-stantial role in coordinating the immune cells that mediate COVID-19 severity. Stratum-specific and person-alized genome-scale metabolic modeling indicated monocarboxylate transporter family genes (e.g., SLC16A6), nucleoside transporter genes (e.g., SLC29A1), and metabolites such as a-ketoglutarate, succi-nate, malate, and butyrate could play a crucial role in COVID-19 severity. Metabolic perturbations targeting the central metabolic pathway (TCA cycle) can be an alternate treatment strategy in severe COVID-19.

  • 34. Ameur, Adam
    et al.
    Che, Huiwen
    Martin, Marcel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Bunikis, Ignas
    Dahlberg, Johan
    Höijer, Ida
    Häggqvist, Susana
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, 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 Data2018In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 9, no 10, article id 486Article in journal (Refereed)
    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.

  • 35. Ameur, Adam
    et al.
    Dahlberg, Johan
    Olason, Pall
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). National Genomics Infrastructure, Science for Life Laboratory, Sweden.
    Karlsson, Robert
    Martin, Marcel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Viklund, Johan
    Kähäri, Andreas Kusalananda
    Lundin, Pär
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Che, Huiwen
    Thutkawkorapin, Jessada
    Eisfeldt, Jesper
    Lampa, Samuel
    Dahlberg, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hagberg, Jonas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jareborg, Niclas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, 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 population2017In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, no 11, p. 1253-1260Article in journal (Refereed)
    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.

  • 36.
    Amunts, Alexey
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The revolution evolution2022In: Nature Plants, ISSN 2055-0278, Vol. 8, no 1, p. 14-17Article in journal (Other academic)
  • 37. An, Rong
    et al.
    Wu, Nanhua
    Gao, Qingwei
    Dong, Yihui
    Laaksonen, Aatto
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry. Luleå University of Technology, Sweden; ‘‘Petru Poni” Institute of Macromolecular Chemistry, Romania; Nanjing Tech University, China.
    Shah, Faiz Ullah
    Ji, Xiaoyan
    Fuchs, Harald
    Integrative studies of ionic liquid interface layers: bridging experiments, theoretical models and simulations2024In: Nanoscale Horizons, ISSN 2055-6764, E-ISSN 2055-6756Article, review/survey (Refereed)
    Abstract [en]

    Ionic liquids (ILs) are a class of salts existing in the liquid state below 100 degrees C, possessing low volatility, high thermal stability as well as many highly attractive solvent and electrochemical capabilities, etc., making them highly tunable for a great variety of applications, such as lubricants, electrolytes, and soft functional materials. In many applications, ILs are first either physi- or chemisorbed on a solid surface to successively create more functional materials. The functions of ILs at solid surfaces can differ considerably from those of bulk ILs, mainly due to distinct interfacial layers with tunable structures resulting in new ionic liquid interface layer properties and enhanced performance. Due to an almost infinite number of possible combinations among the cations and anions to form ILs, the diversity of various solid surfaces, as well as different external conditions and stimuli, a detailed molecular-level understanding of their structure-property relationship is of utmost significance for a judicious design of IL-solid interfaces with appropriate properties for task-specific applications. Many experimental techniques, such as atomic force microscopy, surface force apparatus, and so on, have been used for studying the ion structuring of the IL interface layer. Molecular Dynamics simulations have been widely used to investigate the microscopic behavior of the IL interface layer. To interpret and clarify the IL structure and dynamics as well as to predict their properties, it is always beneficial to combine both experiments and simulations as close as possible. In another theoretical model development to bridge the structure and properties of the IL interface layer with performance, thermodynamic prediction & property modeling has been demonstrated as an effective tool to add the properties and function of the studied nanomaterials. Herein, we present recent findings from applying the multiscale triangle experiment-simulation-thermodynamic modeling in the studies of ion structuring of ILs in the vicinity of solid surfaces, as well as how it qualitatively and quantitatively correlates to the overall ILs properties, performance, and function. We introduce the most common techniques behind experiment-simulation-thermodynamic modeling and how they are applied for studying the IL interface layer structuring, and we highlight the possibilities of the IL interface layer structuring in applications such as lubrication and energy storage. Integrative experiment-simulation-thermodynamic modeling is highly demanded for qualitatively and quantitatively correlating the ionic liquids interface layer structuring to the overall properties, performance, and function.

  • 38.
    An, Yueqing
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Braga, Mariana P.
    Garcia, Sarahi L.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Grudzinska-Sterno, Magdalena
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Hambäck, Peter A.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Host Phylogeny Structures the Gut Bacterial Community Within Galerucella Leaf Beetles2023In: Microbial Ecology, ISSN 0095-3628, E-ISSN 1432-184X, Vol. 86, no 4, p. 2477-2487Article in journal (Refereed)
    Abstract [en]

    Gut microbes play important roles for their hosts. Previous studies suggest that host-microbial systems can form long-term associations over evolutionary time and the dynamic changes of the intestinal system may represent major driving forces and contribute to insect dietary diversification and speciation. Our study system includes a set of six closely related leaf beetle species (Galerucella spp.) and our study aims to separate the roles of host phylogeny and ecology in determining the gut microbial community and to identify eventual relationship between host insects and gut bacteria. We collected adult beetles from their respective host plants and quantified their microbial community using 16S rRNA sequencing. The results showed that the gut bacteria community composition was structured by host beetle phylogeny, where more or less host-specific gut bacteria interact with the different Galerucella species. For example, the endosymbiotic bacteria Wolbachia was found almost exclusively in G. nymphaea and G. sagittariae. Diversity indicators also suggested that α- and β-diversities of gut bacteria communities varied among host beetle species. Overall, our results suggest a phylogenetically controlled co-occurrence pattern between the six closely related Galerucella beetles and their gut bacteria, indicating the potential of co-evolutionary processes occurring between hosts and their gut bacterial communities. 

  • 39.
    Andersson, Annika
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kudva, Renuka
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Magoulopoulou, Anastasia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lejarre, Quentin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lara, Patricia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Xu, Peibo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Goel, Suchi
    Pissi, Jennifer
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ru, Xing
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hessa, Tara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wahlgren, Mats
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet, Sweden.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tellgren-Roth, Åsa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Membrane integration and topology of RIFIN and STEVOR proteins of the Plasmodium falciparum parasite2020In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 287, no 13, p. 2744-2762Article in journal (Refereed)
    Abstract [en]

    The malarial parasite Plasmodium exports its own proteins to the cell surfaces of red blood cells (RBCs) during infection. Examples of exported proteins include members of the repetitive interspersed family (RIFIN) and subtelomeric variable open reading frame (STEVOR) family of proteins from Plasmodium falciparum. The presence of these parasite-derived proteins on surfaces of infected RBCs triggers the adhesion of infected cells to uninfected cells (rosetting) and to the vascular endothelium potentially obstructing blood flow. While there is a fair amount of information on the localization of these proteins on the cell surfaces of RBCs, less is known about how they can be exported to the membrane and the topologies they can adopt during the process. The first step of export is plausibly the cotranslational insertion of proteins into the endoplasmic reticulum (ER) of the parasite, and here, we investigate the insertion of three RIFIN and two STEVOR proteins into the ER membrane. We employ a well-established experimental system that uses N-linked glycosylation of sites within the protein as a measure to assess the extent of membrane insertion and the topology it assumes when inserted into the ER membrane. Our results indicate that for all the proteins tested, transmembranes (TMs) 1 and 3 integrate into the membrane, so that the protein assumes an overall topology of Ncyt-Ccyt. We also show that the segment predicted to be TM2 for each of the proteins likely does not reside in the membrane, but is translocated to the lumen.

  • 40. Angleby, Helen
    et al.
    Oskarsson, Mattias
    Pang, Junfeng
    Zhang, Ya-ping
    Leitner, Thomas
    Braham, Caitlyn
    Arvestad, Lars
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lundeberg, Joakim
    Webb, Kristen M.
    Savolainen, Peter
    Forensic Informativity of similar to 3000bp of Coding Sequence of Domestic Dog mtDNA2014In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 59, no 4, p. 898-908Article in journal (Refereed)
    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.

  • 41. Anh, Nhi
    et al.
    Taylan, Fulya
    Zachariadis, Vasilios
    Ivanov Öfverholm, Ingegerd
    Lindstrand, Anna
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lötstedt, Britta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nordenskjöld, Magnus
    Nordgren, Ann
    Nilsson, Daniel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Barbany, Gisela
    High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 3, article id e0193928Article in journal (Refereed)
    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.

  • 42. 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
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Antonio Marchal, Juan
    Oliver, Jose
    Hackenberg, Michael
    sRNAbench and sRNAtoolbox 2019: intuitive fast small RNA profiling and differential expression2019In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no W1, p. W530-W535Article in journal (Refereed)
    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.

  • 43. Appelberg, Sofia
    et al.
    Gupta, Soham
    Svensson Akusjärvi, Sara
    Ambikan, Anoop T.
    Mikaeloff, Flora
    Saccon, Elisa
    Végvári, Ákos
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sperk, Maike
    Ståhlberg, Marie
    Krishnan, Shuba
    Singh, Kamal
    Penninger, Josef M.
    Mirazimi, Ali
    Neogi, Ujjwal
    Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells2020In: Emerging Microbes & Infections, E-ISSN 2222-1751, Vol. 9, no 1, p. 1748-1760Article in journal (Refereed)
    Abstract [en]

    How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected Huh7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients.

  • 44. Arif, Muhammad
    et al.
    Klevstig, Martina
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Doran, Stephen
    Turkez, Hasan
    Uhlén, Mathias
    Clausen, Maryam
    Wikström, Johannes
    Etal, Damla
    Zhang, Cheng
    Levin, Malin
    Mardinoglu, Adil
    Boren, Jan
    Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction2021In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e66921Article in journal (Refereed)
    Abstract [en]

    Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genomewide transcriptomic analysis on tissue samples obtained 6- and 24 hr post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in two independent MI cohorts. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues.

  • 45. Armenteros, Jose Juan Almagro
    et al.
    Salvatore, Marco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Emanuelsson, Olof
    Winther, Ole
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nielsen, Henrik
    Detecting sequence signals in targeting peptides using deep learning2019In: Life Science Alliance, E-ISSN 2575-1077, Vol. 2, no 5, article id UNSP e201900429Article in journal (Refereed)
    Abstract [en]

    In bioinformatics, machine learning methods have been used to predict features embedded in the sequences. In contrast to what is generally assumed, machine learning approaches can also provide new insights into the underlying biology. Here, we demonstrate this by presenting TargetP 2.0, a novel state-of-the-art method to identify N-terminal sorting signals, which direct proteins to the secretory pathway, mitochondria, and chloroplasts or other plastids. By examining the strongest signals from the attention layer in the network, we find that the second residue in the protein, that is, the one following the initial methionine, has a strong influence on the classification. We observe that two-thirds of chloroplast and thylakoid transit peptides have an alanine in position 2, compared with 20% in other plant proteins. We also note that in fungi and single-celled eukaryotes, less than 30% of the targeting peptides have an amino acid that allows the removal of the N-terminal methionine compared with 60% for the proteins without targeting peptide. The importance of this feature for predictions has not been highlighted before.

  • 46. Arnqvist, Göran
    et al.
    Westerberg, Ivar
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Uppsala University, Sweden.
    Galbraith, James
    Sayadi, Ahmed
    Scofield, Douglas G.
    Olsen, Remi-André
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Immonen, Elina
    Bonath, Franziska
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ewels, Philip
    Suh, Alexander
    A chromosome-level assembly of the seed beetle Callosobruchus maculatus genome with annotation of its repetitive elements2024In: G3: Genes, Genomes, Genetics, E-ISSN 2160-1836, Vol. 14, no 2, article id jkad266Article in journal (Refereed)
    Abstract [en]

    Callosobruchus maculatus is a major agricultural pest of legume crops worldwide and an established model system in ecology and evolution. Yet, current molecular biological resources for this species are limited. Here, we employ Hi-C sequencing to generate a greatly improved genome assembly and we annotate its repetitive elements in a dedicated in-depth effort where we manually curate and classify the most abundant unclassified repeat subfamilies. We present a scaffolded chromosome-level assembly, which is 1.01 Gb in total length with 86% being contained within the 9 autosomes and the X chromosome. Repetitive sequences accounted for 70% of the total assembly. DNA transposons covered 18% of the genome, with the most abundant superfamily being Tc1-Mariner (9.75% of the genome). This new chromosome-level genome assembly of C. maculatus will enable future genetic and evolutionary studies not only of this important species but of beetles more generally. 

  • 47.
    Arvestad, Lars
    Stockholm University, Faculty of Science, Department of Mathematics. Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-science Research Centre, Sweden.
    alv: a console-based viewer for molecular sequence alignments2018In: Journal of Open Source Software, E-ISSN 2475-9066, Vol. 3, no 31, article id 955Article in journal (Refereed)
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  • 48. Asp, Michaela
    et al.
    Giacomello, Stefania
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Larsson, Ludvig
    Wu, Chenglin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Fürth, Daniel
    Qian, Xiaoyan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wärdell, Eva
    Custodio, Joaquin
    Reimegård, Johan
    Salmén, Fredrik
    Österholm, Cecilia
    Ståhl, Patrik L.
    Sundström, Erik
    Åkesson, Elisabet
    Bergmann, Olaf
    Bienko, Magda
    Månsson-Broberg, Agneta
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sylvén, Christer
    Lundeberg, Joakim
    A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart2019In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 179, no 7, p. 1647-1660Article in journal (Refereed)
    Abstract [en]

    The process of cardiac morphogenesis in humans is incompletely understood. Its full characterization requires a deep exploration of the organ-wide orchestration of gene expression with a single-cell spatial resolution. Here, we present a molecular approach that reveals the comprehensive transcriptional landscape of cell types populating the embryonic heart at three developmental stages and that maps cell-type-specific gene expression to specific anatomical domains. Spatial transcriptomics identified unique gene profiles that correspond to distinct anatomical regions in each developmental stage. Human embryonic cardiac cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of embryonic cardiac gene expression. In situ sequencing was then used to refine these results and create a spatial subcellular map for the three developmental phases. Finally, we generated a publicly available web resource of the human developing heart to facilitate future studies on human cardiogenesis.

  • 49. Atzori, Alessio
    et al.
    Liggi, Sonia
    Laaksonen, Aatto
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK). Stockholm University, Science for Life Laboratory (SciLifeLab). University of Cagliari, Italy.
    Porcu, Massimiliano
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK). Università di Cagliari, Italy.
    Lyubartsev, Alexander P.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Saba, Giuseppe
    Mocci, Francesca
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK). Stockholm University, Science for Life Laboratory (SciLifeLab). Università di Cagliari, Italy.
    Base sequence specificity of counterion binding to DNA: what can MD simulations tell us?2016In: Canadian journal of chemistry (Print), ISSN 0008-4042, E-ISSN 1480-3291, Vol. 94, no 12, p. 1181-1188Article in journal (Refereed)
    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.

  • 50.
    Axberg Pålsson, Sandra
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sekar, Vaishnovi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kutter, Claudia
    Friedländer, Marc R.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Spetz, Anna-Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Inhibition of Respiratory Syncytial Virus Infection by Small Non-Coding RNA Fragments2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 11, article id 5990Article in journal (Refereed)
    Abstract [en]

    Respiratory syncytial virus (RSV) causes acute lower respiratory tract infection in infants, immunocompromised individuals and the elderly. As the only current specific treatment options for RSV are monoclonal antibodies, there is a need for efficacious antiviral treatments against RSV to be developed. We have previously shown that a group of synthetic non-coding single-stranded DNA oligonucleotides with lengths of 25-40 nucleotides can inhibit RSV infection in vitro and in vivo. Based on this, herein, we investigate whether naturally occurring single-stranded small non-coding RNA (sncRNA) fragments present in the airways have antiviral effects against RSV infection. From publicly available sequencing data, we selected sncRNA fragments such as YRNAs, tRNAs and rRNAs present in human bronchoalveolar lavage fluid (BALF) from healthy individuals. We utilized a GFP-expressing RSV to show that pre-treatment with the selected sncRNA fragments inhibited RSV infection in A549 cells in vitro. Furthermore, by using a flow cytometry-based binding assay, we demonstrate that these naturally occurring sncRNAs fragments inhibit viral infection most likely by binding to the RSV entry receptor nucleolin and thereby preventing the virus from binding to host cells, either directly or via steric hindrance. This finding highlights a new function of sncRNAs and displays the possibility of using naturally occurring sncRNAs as treatments against RSV.

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