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  • 151.
    Giacomello, Stefania
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Salmén, Fredrik
    Terebieniec, Barbara K.
    Vickovic, Sanja
    Fernandez Navarro, José
    Alexeyenko, Andrey
    Reimegård, Johan
    McKee, Lauren S.
    Mannapperuma, Chanaka
    Bulone, Vincent
    Ståhl, Patrik L.
    Sundström, Jens F.
    Street, Nathaniel R.
    Lundeberg, Joakim
    Spatially resolved transcriptome profiling in model plant species2017Ingår i: Nature Plants, ISSN 2055-026X, Vol. 3, nr 6, artikel-id 17061Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Understanding complex biological systems requires functional characterization of specialized tissue domains. However, existing strategies for generating and analysing high-throughput spatial expression profiles were developed for a limited range of organisms, primarily mammals. Here we present the first available approach to generate and study highresolution, spatially resolved functional profiles in a broad range of model plant systems. Our process includes highthroughput spatial transcriptome profiling followed by spatial gene and pathway analyses. We first demonstrate the feasibility of the technique by generating spatial transcriptome profiles from model angiosperms and gymnosperms microsections. In Arabidopsis thaliana we use the spatial data to identify differences in expression levels of 141 genes and 189 pathways in eight inflorescence tissue domains. Our combined approach of spatial transcriptomics and functional profiling offers a powerful new strategy that can be applied to a broad range of plant species, and is an approach that will be pivotal to answering fundamental questions in developmental and evolutionary biology.

  • 152. Gil-Lopez, Manuel J.
    et al.
    Segarra-Moragues, Jose G.
    Desamore, Aurelie
    Laenen, Benjamin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ojeda, Fernando
    Different historical backgrounds determine contrasting phylogeographical patterns in two co-distributed Erica species (Ericaceae) across the Strait of Gibraltar2017Ingår i: Botanical journal of the Linnean Society, ISSN 0024-4074, E-ISSN 1095-8339, Vol. 185, nr 3, s. 359-375Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Erica australis and Erica arborea are morphologically and ecologically similar heather species. Erica australis is restricted to the western Mediterranean Basin where it overlaps with the westernmost distribution of E. arborea. Here we investigate the role of the Strait of Gibraltar (SG) as a potential biogeographical barrier to dispersal and/or as glacial refugium in these two Erica spp. in the western Mediterranean (WMed) region with contrasting geographical origins and distributions. Samples were collected from 55 and 54 populations of E. australis and E. arborea, respectively. One individual each of 52 and 45 populations of E. australis and E. arborea, respectively, were sequenced for plastid DNA regions, and 1304 and 1214 individuals from 44 and 42 populations of E. australis and E. arborea, respectively, were genotyped using nuclear microsatellites (SSRs). Plastid DNA sequences were used to estimate divergence time of lineages and to construct haplotype networks. SSR data helped to infer population genetic diversity and fixation indices and genetic structure patterns through Bayesian analysis, analysis of molecular variance and isolation by distance. Plastid haplotype diversity of E. australis was higher in the SG than in the WMed area, whereas the opposite was found in E. arborea. SSRs revealed high genetic diversity within populations of both species and population genetic structure patterns were consistent with those retrieved from plastid DNA. The SG was identified as the likely area of origin and diversification for E. australis in the late Pliocene-Pleistocene, where it survived the Last Glacial Maximum (LGM) and expanded northwards into the western Iberian Peninsula. In contrast, two separate evolutionary lineages were found for E. arborea in the Iberian Peninsula. The SG and southern WMed areas represent the western Mediterranean expansion limit of an E. arborea lineage from East Africa/Arabia in the late Pliocene-Pleistocene, whereas the northern WMed populations were relicts from an older refugium that survived LGM in north-western Iberia. This study illustrates how geographical range and origin explain differences in the phylogeographical structure of co-distributed Mediterranean plants and highlights the role of the SG as a Pleistocene refugium and biogeographical crossroads in the Mediterranean.

  • 153. Gioti, Anastasia
    et al.
    Nystedt, Björn
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Li, Wenjun
    Xu, Jun
    Andersson, Anna
    Averette, Anna F.
    Muench, Karin
    Wang, Xuying
    Kappauf, Catharine
    Kingsbury, Joanne M.
    Kraak, Bart
    Walker, Louise A.
    Johansson, Henrik J.
    Holm, Tina
    Lehtio, Janne
    Stajich, Jason E.
    Mieczkowski, Piotr
    Kahmann, Regine
    Kennell, John C.
    Cardenas, Maria E.
    Lundeberg, Joakim
    Saunders, Charles W.
    Boekhout, Teun
    Dawson, Thomas L.
    Munro, Carol A.
    de Groot, Piet W. J.
    Butler, Geraldine
    Heitman, Joseph
    Scheynius, Annika
    Genomic Insights into the Atopic Eczema-Associated Skin Commensal Yeast Malassezia sympodialis2013Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 4, nr 1, s. e00572-12-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Malassezia commensal yeasts are associated with a number of skin disorders, such as atopic eczema/dermatitis and dandruff, and they also can cause systemic infections. Here we describe the 7.67-Mbp genome of Malassezia sympodialis, a species associated with atopic eczema, and contrast its genome repertoire with that of Malassezia globosa, associated with dandruff, as well as those of other closely related fungi. Ninety percent of the predicted M. sympodialis protein coding genes were experimentally verified by mass spectrometry at the protein level. We identified a relatively limited number of genes related to lipid biosynthesis, and both species lack the fatty acid synthase gene, in line with the known requirement of these yeasts to assimilate lipids from the host. Malassezia species do not appear to have many cell wall-localized glycosylphosphatidylinositol (GPI) proteins and lack other cell wall proteins previously identified in other fungi. This is surprising given that in other fungi these proteins have been shown to mediate interactions (e. g., adhesion and biofilm formation) with the host. The genome revealed a complex evolutionary history for an allergen of unknown function, Mala s 7, shown to be encoded by a member of an amplified gene family of secreted proteins. Based on genetic and biochemical studies with the basidiomycete human fungal pathogen Cryptococcus neoformans, we characterized the allergen Mala s 6 as the cytoplasmic cyclophilin A. We further present evidence that M. sympodialis may have the capacity to undergo sexual reproduction and present a model for a pseudobipolar mating system that allows limited recombination between two linked MAT loci. IMPORTANCE Malassezia commensal yeasts are associated with a number of skin disorders. The previously published genome of M. globosa provided some of the first insights into Malassezia biology and its involvement in dandruff. Here, we present the genome of M. sympodialis, frequently isolated from patients with atopic eczema and healthy individuals. We combined comparative genomics with sequencing and functional characterization of specific genes in a population of clinical isolates and in closely related model systems. Our analyses provide insights into the evolution of allergens related to atopic eczema and the evolutionary trajectory of the machinery for sexual reproduction and meiosis. We hypothesize that M. sympodialis may undergo sexual reproduction, which has important implications for the understanding of the life cycle and virulence potential of this medically important yeast. Our findings provide a foundation for the development of genetic and genomic tools to elucidate host-microbe interactions that occur on the skin and to identify potential therapeutic targets.

  • 154. Gliga, Anda R.
    et al.
    Di Bucchianico, Sebastiano
    Lindvall, Jessica
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Fadeel, Bengt
    Karlsson, Hanna L.
    RNA-sequencing reveals long-term effects of silver nanoparticles on human lung cells2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 6668Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite a considerable focus on the adverse effects of silver nanoparticles (AgNPs) in recent years, studies on the potential long-term effects of AgNPs are scarce. The aim of this study was to explore the effects of AgNPs following repeated low-dose, long-term exposure of human bronchial epithelial cells. To this end, the human BEAS-2B cell line was exposed to 1 mu g/mL AgNPs (10 nm) for 6 weeks followed by RNA-sequencing (RNA-Seq) as well as genome-wide DNA methylation analysis. The transcriptomics analysis showed that a substantial number of genes (1717) were differentially expressed following AgNP exposure whereas only marginal effects on DNA methylation were observed. Downstream analysis of the transcriptomics data identified several affected pathways including the 'fibrosis' and 'epithelial-mesenchymal transition' (EMT) pathway. Subsequently, functional validation studies were performed using AgNPs of two different sizes (10 nm and 75 nm). Both NPs increased collagen deposition, indicative of fibrosis, and induced EMT, as evidenced by an increased invasion index, anchorage independent cell growth, as well as cadherin switching. In conclusion, using a combination of RNA-Seq and functional assays, our study revealed that repeated low-dose, long-term exposure of human BEAS-2B cells to AgNPs is pro-fibrotic, induces EMT and cell transformation.

  • 155. Glover, Natasha
    et al.
    Dessimoz, Christophe
    Ebersberger, Ingo
    Forslund, Sofia K.
    Gabaldón, Toni
    Huerta-Cepas, Jaime
    Martin, Maria-Jesus
    Muffato, Matthieu
    Patricio, Mateus
    Pereira, Cécile
    da Silva, Alan Sousa
    Wang, Yan
    Sonnhammer, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Thomas, Paul D.
    Advances and Applications in the Quest for Orthologs2019Ingår i: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 36, nr 10, s. 2157-2164Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Gene families evolve by the processes of speciation (creating orthologs), gene duplication (paralogs), and horizontal gene transfer (xenologs), in addition to sequence divergence and gene loss. Orthologs in particular play an essential role in comparative genomics and phylogenomic analyses. With the continued sequencing of organisms across the tree of life, the data are available to reconstruct the unique evolutionary histories of tens of thousands of gene families. Accurate reconstruction of these histories, however, is a challenging computational problem, and the focus of the Quest for Orthologs Consortium. We review the recent advances and outstanding challenges in this field, as revealed at a symposium and meeting held at the University of Southern California in 2017. Key advances have been made both at the level of orthology algorithm development and with respect to coordination across the community of algorithm developers and orthology end-users. Applications spanned a broad range, including gene function prediction, phylostratigraphy, genome evolution, and phylogenomics. The meetings highlighted the increasing use of meta-analyses integrating results from multiple different algorithms, and discussed ongoing challenges in orthology inference as well as the next steps toward improvement and integration of orthology resources.

  • 156.
    Gowda, Naveen Kumar Chandappa
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Masser, Anna E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kang, Wenjing
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Friedländer, Marc R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Andréasson, Claes
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cytosolic splice isoform of Hsp70 nucleotide exchange factor Fes1 is required for the degradation of misfolded proteins in yeast2016Ingår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27, nr 8, s. 1210-1219Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cells maintain proteostasis by selectively recognizing and targeting misfolded proteins for degradation. In Saccharomyces cerevisiae, the Hsp70 nucleotide exchange factor Fes1 is essential for the degradation of chaperone-associated misfolded proteins by the ubiquitin-proteasome system. Here we show that the FES1 transcript undergoes unique 3' alternative splicing that results in two equally active isoforms with alternative C-termini, Fes1L and Fes1S. Fes1L is actively targeted to the nucleus and represents the first identified nuclear Hsp70 nucleotide exchange factor. In contrast, Fes1S localizes to the cytosol and is essential to maintain proteostasis. In the absence of Fes1S, the heat-shock response is constitutively induced at normally non-stressful conditions. Moreover, cells display severe growth defects when elevated temperatures, amino acid analogues or the ectopic expression of misfolded proteins, induce protein misfolding. Importantly, misfolded proteins are not targeted for degradation by the ubiquitin-proteasome system. These observations support the notion that cytosolic Fes1S maintains proteostasis by supporting the removal of toxic misfolded proteins by proteasomal degradation. This study provides key findings for the understanding of the organization of protein quality control mechanisms in the cytosol and nucleus.

  • 157.
    Granholm, Viktor
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Kim, Sangtae
    Navarro, José C. F.
    Sjölund, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Smith, Richard D.
    Käll, Lukas
    Fast and Accurate Database Searches with MS-GF plus Percolator:  2014Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, nr 2, s. 890-897Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One can interpret fragmentation spectra stemming from peptides in mass-spectrometry-based proteomics experiments using so-called database search engines. Frequently, one also runs post-processors such as Percolator to assess the confidence, infer unique peptides, and increase the number of identifications. A recent search engine, MS-GF+, has shown promising results, due to a new and efficient scoring algorithm. However, MS-GF+ provides few statistical estimates about the peptide-spectrum matches, hence limiting the biological interpretation. Here, we enabled Percolator processing for MS-GF+ output and observed an increased number of identified peptides for a wide variety of data sets. In addition, Percolator directly reports p values and false discovery rate estimates, such as q values and posterior error probabilities, for peptide-spectrum matches, peptides, and proteins, functions that are useful for the whole proteomics community.

  • 158.
    Granholm, Viktor
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Navarro, Jose Fernandez
    Noble, William Stafford
    Käll, Lukas
    Determining the calibration of confidence estimation procedures for unique peptides in shotgun proteomics2013Ingår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 80, s. 123-131Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The analysis of a shotgun proteomics experiment results in a list of peptide-spectrum matches (PSMs) in which each fragmentation spectrum has been matched to a peptide in a database. Subsequently, most protein inference algorithms rank peptides according to the best-scoring PSM for each peptide. However, there is disagreement in the scientific literature on the best method to assess the statistical significance of the resulting peptide identifications. Here, we use a previously described calibration protocol to evaluate the accuracy of three different peptide-level statistical confidence estimation procedures: the classical Fisher's method, and two complementary procedures that estimate significance, respectively, before and after selecting the top-scoring PSM for each spectrum. Our experiments show that the latter method, which is employed by MaxQuant and Percolator, produces the most accurate, well-calibrated results.

  • 159.
    Granholm, Viktor
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Noble, William Stafford
    Käll, Lukas
    A cross-validation scheme for machine learning algorithms in shotgun proteomics2012Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 13, s. S3-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peptides are routinely identified from mass spectrometry-based proteomics experiments by matching observed spectra to peptides derived from protein databases. The error rates of these identifications can be estimated by target-decoy analysis, which involves matching spectra to shuffled or reversed peptides. Besides estimating error rates, decoy searches can be used by semi-supervised machine learning algorithms to increase the number of confidently identified peptides. As for all machine learning algorithms, however, the results must be validated to avoid issues such as overfitting or biased learning, which would produce unreliable peptide identifications. Here, we discuss how the target-decoy method is employed in machine learning for shotgun proteomics, focusing on how the results can be validated by cross-validation, a frequently used validation scheme in machine learning. We also use simulated data to demonstrate the proposed cross-validation scheme's ability to detect overfitting.

  • 160. Grohs, Melody N.
    et al.
    Reynolds, Jess E.
    Liu, Jiaying
    Martin, Jonathan W.
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Pollock, Tyler
    Lebe, Catherine
    Dewey, Deborah
    Kaplan, Bonnie J.
    Field, Catherine J.
    Bell, Rhonda C.
    Bernier, Francois P.
    Cantell, Marja
    Casey, Linda M.
    Eliasziw, Misha
    Farmer, Anna
    Gagnon, Lisa
    Giesbrecht, Gerald F.
    Goonewardene, Laksiri
    Johnston, David W.
    Kooistra, Libbe
    Letoumeau, Nicole
    Manca, Donna P.
    McCargar, Linda J.
    O'Beirne, Maeve
    Pop, Victor J.
    Singhal, Nalini
    Prenatal maternal and childhood bisphenol a exposure and brain structure and behavior of young children2019Ingår i: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 18, nr 1, artikel-id 85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Bisphenol A (BPA) is commonly used in the manufacture of plastics and epoxy resins. In North America, over 90% of the population has detectable levels of urinary BPA. Human epidemiological studies have reported adverse behavioral outcomes with BPA exposure in children, however, corresponding effects on children's brain structure have not yet been investigated. The current study examined the association between prenatal maternal and childhood BPA exposure and white matter microstructure in children aged 2 to 5 years, and investigated whether brain structure mediated the association between BPA exposure and child behavior.

    Methods: Participants were 98 mother-child pairs who were recruited between January 2009 and December 2012. Total BPA concentrations in spot urine samples obtained from mothers in the second trimester of pregnancy and from children at 3-4 years of age were analyzed. Children participated in a diffusion magnetic resonance imaging (MRI) scan at age 2-5 years (3.7 +/- 0.8 years). Associations between prenatal maternal and childhood BPA and children's fractional anisotropy and mean diffusivity of 10 isolated white matter tracts were investigated, controlling for urinary creatinine, child sex, and age at the time of MRI. Post-hoc analyses examined if alterations in white matter mediated the relationship of BPA and children's scores on the Child Behavior Checklist (CBCL).

    Results: Prenatal maternal urinary BPA was significantly associated with child mean diffusivity in the splenium and right inferior longitudinal fasciculus. Splenium diffusivity mediated the relationship between maternal prenatal BPA levels and children's internalizing behavior (indirect effect: beta = 0.213, CI [0.0167, 0.564]). No significant associations were found between childhood BPA and white matter microstructure.

    Conclusions: This study provides preliminary evidence for the neural correlates of BPA exposure in humans. Our findings suggest that prenatal maternal exposure to BPA may lead to alterations in white matter microstructure in preschool aged children, and that such alterations mediate the relationship between early life exposure to BPA and internalizing problems.

  • 161. Grundberg, Ida
    et al.
    Kiflemariam, Sara
    Mignardi, Marco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Imgenberg-Kreuz, Juliana
    Edlund, Karolina
    Micke, Patrick
    Sundström, Magnus
    Sjöblom, Tobias
    Botling, Johan
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    In situ mutation detection and visualization of intratumor heterogeneity for cancer research and diagnostics2013Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 4, nr 12, s. 2407-2418Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Current assays for somatic mutation analysis are based on extracts from tissue sections that often contain morphologically heterogeneous neoplastic regions with variable contents of genetically normal stromal and inflammatory cells, obscuring the results of the assays. We have developed an RNA-based in situ mutation assay that targets oncogenic mutations in a multiplex fashion that resolves the heterogeneity of the tissue sample. Activating oncogenic mutations are targets for a new generation of cancer drugs. For anti-EGFR therapy prediction, we demonstrate reliable in situ detection of KRAS mutations in codon 12 and 13 in colon and lung cancers in three different types of routinely processed tissue materials. High-throughput screening of KRAS mutation status was successfully performed on a tissue microarray. Moreover, we show how the patterns of expressed mutated and wild-type alleles can be studied in situ in tumors with complex combinations of mutated EGFR, KRAS and TP53. This in situ method holds great promise as a tool to investigate the role of somatic mutations during tumor progression and for prediction of response to targeted therapy.

  • 162. Grunewald, Johan
    et al.
    Kaiser, Ylva
    Ostadkarampour, Mahyar
    Rivera, Natalia V.
    Vezzi, Francesco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lötstedt, Britta
    Olsen, Remi-André
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Sylwan, Lina
    Lundin, Sverker
    Käller, Max
    Sandalova, Tatiana
    Ahlgren, Kerstin M.
    Wahlström, Jan
    Achour, Adnane
    Ronninger, Marcus
    Eklund, Anders
    T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis2016Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 47, nr 3, s. 898-909Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In pulmonary sarcoidosis, CD4(+) T-cells expressing T-cell receptor V alpha 2.3 accumulate in the lungs of HLA-DRB1*03(+) patients. To investigate T-cell receptor-HLA-DRB1*03 interactions underlying recognition of hitherto unknown antigens, we performed detailed analyses of T-cell receptor expression on bronchoalveolar lavage fluid CD4(+) T-cells from sarcoidosis patients. Pulmonary sarcoidosis patients (n=43) underwent bronchoscopy with bronchoalveolar lavage. T-cell receptor alpha and beta chains of CD4(+) T-cells were analysed by flow cytometry, DNA-sequenced, and three-dimensional molecular models of T-cell receptor-HLA-DRB1*03 complexes generated. Simultaneous expression of V alpha 2.3 with the V beta 22 chain was identified in the lungs of all HLA-DRB1*03(+) patients. Accumulated V alpha 2.3/V beta 22-expressing T-cells were highly clonal, with identical or near-identical V alpha 2.3 chain sequences and inter-patient similarities in V beta 22 chain amino acid distribution. Molecular modelling revealed specific T-cell receptor-HLA-DRB1*03-peptide interactions, with a previously identified, sarcoidosis-associated vimentin peptide, (Vim)(429-443) DSLPLVDTHSKRTLL, matching both the HLA peptide-binding cleft and distinct T-cell receptor features perfectly. We demonstrate, for the first time, the accumulation of large clonal populations of specific V alpha 2.3/V beta 22 T-cell receptor-expressing CD4(+) T-cells in the lungs of HLA-DRB1*03(+) sarcoidosis patients. Several distinct contact points between V alpha 2.3/V beta 22 receptors and HLA-DRB1*03 molecules suggest presentation of prototypic vimentin-derived peptides.

  • 163. Grønberg, Christina
    et al.
    Sitsel, Oleg
    Lindahl, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Gourdon, Pontus
    Andersson, Magnus
    Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport2016Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 111, nr 11, s. 2417-2429Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cu+-specific P-type ATPase membrane protein transporters regulate cellular copper levels. The lack of crystal structures in Cu+-binding states has limited our understanding of how ion entry and binding are achieved. Here, we characterize the molecular basis of Cu+ entry using molecular-dynamics simulations, structural modeling, and in vitro and in vivo functional assays. Protein structural rearrangements resulting in the exposure of positive charges to bulk solvent rather than to lipid phosphates indicate a direct molecular role of the putative docking platform in Cu+ delivery. Mutational analyses and simulations in the presence and absence of Cu+ predict that the ion-entry path involves two ion-binding sites: one transient Met148-Cys382 site and one intramembranous site formed by trigonal coordination to Cys384, Asn689, and Met717. The results reconcile earlier biochemical and x-ray absorption data and provide a molecular understanding of ion entry in Cu+-transporting P-type ATPases.

  • 164. Grüning, Björn A.
    et al.
    Lampa, Samuel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Vaudel, Marc
    Blankenberg, Daniel
    Software engineering for scientific big data analysis2019Ingår i: GigaScience, ISSN 2047-217X, E-ISSN 2047-217X, Vol. 8, nr 5, artikel-id giz054Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The increasing complexity of data and analysis methods has created an environment where scientists, who may not have formal training, are finding themselves playing the impromptu role of software engineer. While several resources are available for introducing scientists to the basics of programming, researchers have been left with little guidance on approaches needed to advance to the next level for the development of robust, large-scale data analysis tools that are amenable to integration into workflow management systems, tools, and frameworks. The integration into such workflow systems necessitates additional requirements on computational tools, such as adherence to standard conventions for robustness, data input, output, logging, and flow control. Here we provide a set of 10 guidelines to steer the creation of command-line computational tools that are usable, reliable, extensible, and in line with standards of modern coding practices.

  • 165.
    Guala, Dimitri
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Bernhem, Kristoffer
    Ait Blal, Hammou
    Lundberg, Emma
    Brismar, Hjalmar
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Experimental validation of predicted cancer genes using FRETManuskript (preprint) (Övrigt vetenskapligt)
  • 166.
    Guala, Dimitri
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Bernhem, Kristoffer
    Blal, Hammou Ait
    Jans, Daniel
    Lundberg, Emma
    Brismar, Hjalmar
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Experimental validation of predicted cancer genes using FRET2018Ingår i: Methods and applications in fluorescence, ISSN 2050-6120, Vol. 6, nr 3, artikel-id 035007Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Huge amounts of data are generated in genome wide experiments, designed to investigate diseases with complex genetic causes. Follow up of all potential leads produced by such experiments is currently cost prohibitive and time consuming. Gene prioritization tools alleviate these constraints by directing further experimental efforts towards the most promising candidate targets. Recently a gene prioritization tool called MaxLink was shown to outperform other widely used state-of-the-art prioritization tools in a large scale in silico benchmark. An experimental validation of predictions made by MaxLink has however been lacking. In this study we used Fluorescence Resonance Energy Transfer, an established experimental technique for detection of protein-protein interactions, to validate potential cancer genes predicted by MaxLink. Our results provide confidence in the use of MaxLink for selection of new targets in the battle with polygenic diseases.

  • 167.
    Guala, Dimitri
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    A large-scale benchmark of gene prioritization methods2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 46598Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In order to maximize the use of results from high-throughput experimental studies, e.g. GWAS, for identification and diagnostics of new disease-associated genes, it is important to have properly analyzed and benchmarked gene prioritization tools. While prospective benchmarks are underpowered to provide statistically significant results in their attempt to differentiate the performance of gene prioritization tools, a strategy for retrospective benchmarking has been missing, and new tools usually only provide internal validations. The Gene Ontology (GO) contains genes clustered around annotation terms. This intrinsic property of GO can be utilized in construction of robust benchmarks, objective to the problem domain. We demonstrate how this can be achieved for network-based gene prioritization tools, utilizing the FunCoup network. We use cross-validation and a set of appropriate performance measures to compare state-of-the-art gene prioritization algorithms: three based on network diffusion, NetRank and two implementations of Random Walk with Restart, and MaxLink that utilizes network neighborhood. Our benchmark suite provides a systematic and objective way to compare the multitude of available and future gene prioritization tools, enabling researchers to select the best gene prioritization tool for the task at hand, and helping to guide the development of more accurate methods.

  • 168.
    Gubanova, Evgenia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Issaeva, Natalia
    Gokturk, Camilla
    Djureinovic, Tatjana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Helleday, Thomas
    SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways2013Ingår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 12, nr 24, s. 3770-3780Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The DNA damage response is coordinated by phosphatidylinositol 3-kinase-related kinases, ATM, ATR, and DNA-PK. SMG-1 is the least studied stress-responsive member of this family. Here, we show that SMG-1 regulates the G 1/S checkpoint through both a p53-dependent, and a p53-independent pathway. We identify Cdc25A as a new SMG-1 substrate, and show that cells depleted of SMG-1 exhibit prolonged Cdc25A stability, failing to inactivate CDK2 in response to radiation. Given an increased tumor growth following depletion of SMG-1, our data demonstrate a novel role for SMG-1 in regulating Cdc25A and suppressing oncogenic CDK2 driven proliferation, confirming SMG-1 as a tumor suppressor.

  • 169. Guo, Maoxiang
    et al.
    Hernández-Neuta, Iván
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Madaboosi, Narayanan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    van der Wijngaart, Wouter
    Efficient DNA-assisted synthesis of trans-membrane gold nanowires2018Ingår i: microsystems and nanoengineering, ISSN 2055-7434, Vol. 4, artikel-id UNSP 17084Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Whereas electric circuits and surface-based (bio) chemical sensors are mostly constructed in-plane due to ease of manufacturing, 3D microscale and nanoscale structures allow denser integration of electronic components and improved mass transport of the analyte to (bio) chemical sensor surfaces. This work reports the first out-of-plane metallic nanowire formation based on stretching of DNA through a porous membrane. We use rolling circle amplification (RCA) to generate long single-stranded DNA concatemers with one end anchored to the surface. The DNA strands are stretched through the pores in the membrane during liquid removal by forced convection. Because the liquid-air interface movement across the membrane occurs in every pore, DNA stretching across the membrane is highly efficient. The stretched DNA molecules are transformed into trans-membrane gold nanowires through gold nanoparticle hybridization and gold enhancement chemistry. A 50 fM oligonucleotide concentration, a value two orders of magnitude lower than previously reported for flat surface-based nanowire formation, was sufficient for nanowire formation. We observed nanowires in up to 2.7% of the membrane pores, leading to an across-membrane electrical conductivity reduction from open circuit to <20 Omega. The simple electrical read-out offers a high signal-to-noise ratio and can also be extended for use as a biosensor due to the high specificity and scope for multiplexing offered by RCA.

  • 170. Gustafsson, Nina M. S.
    et al.
    Färnegårdh, Katarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Kancera AB, Sweden.
    Bonagas, Nadilly
    Ninou, Anna Huguet
    Groth, Petra
    Wiita, Elisee
    Jönsson, Mattias
    Hallberg, Kenth
    Lehto, Jemina
    Pennisi, Rosa
    Martinsson, Jessica
    Norström, Carina
    Hollers, Jessica
    Schultz, Johan
    Andersson, Martin
    Markova, Natalia
    Marttila, Petra
    Kim, Baek
    Norin, Martin
    Olin, Thomas
    Helleday, Thomas
    Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 3872Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anticancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-gamma H2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.

  • 171.
    Gustafsson, Robert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jemth, Ann-Sofie
    Gustafsson, Nina M. S.
    Färnegårdh, Katarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Loseva, Olga
    Wiita, Elisée
    Bonagas, Nadilly
    Dahllund, Leif
    Llona-Minguez, Sabin
    Häggblad, Maria
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Henriksson, Martin
    Andersson, Yasmin
    Homan, Evert
    Helleday, Thomas
    Stenmark, Pal
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor2017Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, nr 4, s. 937-948Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD(+) and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment.

  • 172. Gómez de la Torre, Teresa Zardán
    et al.
    Herthnek, David
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Strømme, Maria
    A Magnetic Nanobead-Based Read-Out Procedure for Rapid Detection of DNA Molecules2017Ingår i: Journal of Nanoscience and Nanotechnology, ISSN 1533-4880, E-ISSN 1533-4899, Vol. 17, nr 4, s. 2861-2864Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The presented measurement and data analysis procedure reduces the read-out time for the volumeamplified magnetic nanobead detection assay from similar to 30 min to only 2 min, providing fast, sensitive detection of DNA molecules. The molecular detection and amplification protocol was verified using samples containing rolling circle-amplified DNA products formed from synthetic Vibrio cholerae target DNA, with a limit of detection of 5 pM. The developed read-out method could be used to rapidly identify pathogens in a variety of applications including target screening in hospitals with limited resources, in out-patient settings and in the field.

  • 173. Gómez-Blanco, J.
    et al.
    de la Rosa-Trevín, José Miguel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Marabini, R.
    del Cano, L.
    Jimenez, A.
    Martinez, M.
    Melero, R.
    Majtner, T.
    Maluenda, D.
    Mota, J.
    Rancel, Y.
    Ramirez-Aportela, E.
    Vilas, J. L.
    Carroni, Marta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Fleischmann, Stefan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Ashton, A. W.
    Basham, M.
    Clare, D. K.
    Savage, K.
    Siebert, C. A.
    Sharov, G. G.
    Sorzano, C. O. S.
    Conesa, P.
    Carazo, J. M.
    Using Scipion for stream image processing at Cryo-EM facilities2018Ingår i: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 204, nr 3, s. 457-463Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Three dimensional electron microscopy is becoming a very data-intensive field in which vast amounts of experimental images are acquired at high speed. To manage such large-scale projects, we had previously developed a modular workflow system called Scipion (de la Rosa-Trevfn et al., 2016). We present here a major extension of Scipion that allows processing of EM images while the data is being acquired. This approach helps to detect problems at early stages, saves computing time and provides users with a detailed evaluation of the data quality before the acquisition is finished. At present, Scipion has been deployed and is in production mode in seven Cryo-EM facilities throughout the world.

  • 174. Günther, Torsten
    et al.
    Malmström, Helena
    Svensson, Emma M.
    Omrak, Ayca
    Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur.
    Sánchez-Quinto, Federico
    Kılınç, Gülşah M.
    Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur. Uppsala University, Sweden; Middle East Technical University, Turkey.
    Krzewińska, Maja
    Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur.
    Eriksson, Gunilla
    Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur.
    Fraser, Magdalena
    Edlund, Hanna
    Munters, Arielle R.
    Coutinho, Alexandra
    Simões, Luciana G.
    Vicente, Mario
    Sjölander, Anders
    Jansen Sellevold, Berit
    Jørgensen, Roger
    Claes, Peter
    Shriver, Mark D.
    Valdiosera, Cristina
    Netea, Mihai G.
    Apel, Jan
    Lidén, Kerstin
    Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur.
    Skar, Birgitte
    Storå, Jan
    Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur.
    Götherström, Anders
    Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Jakobsson, Mattias
    Population genomics of Mesolithic Scandinavia: Investigating early postglacial migration routes and high-latitude adaptation2018Ingår i: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 16, nr 1, artikel-id e2003703Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Scandinavia was one of the last geographic areas in Europe to become habitable for humans after the Last Glacial Maximum (LGM). However, the routes and genetic composition of these postglacial migrants remain unclear. We sequenced the genomes, up to 57x coverage, of seven hunter-gatherers excavated across Scandinavia and dated from 9,500-6,000 years before present (BP). Surprisingly, among the Scandinavian Mesolithic individuals, the genetic data display an east-west genetic gradient that opposes the pattern seen in other parts of Mesolithic Europe. Our results suggest two different early postglacial migrations into Scandinavia: initially from the south, and later, from the northeast. The latter followed the ice-free Norwegian north Atlantic coast, along which novel and advanced pressure-blade stone-tool techniques may have spread. These two groups met and mixed in Scandinavia, creating a genetically diverse population, which shows patterns of genetic adaptation to high latitude environments. These potential adaptations include high frequencies of low pigmentation variants and a gene region associated with physical performance, which shows strong continuity into modern-day northern Europeans.

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

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

  • 176.
    Haider, Christian
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). University of Applied Sciences Upper Austria, Austria.
    Kavic, Marina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). University of Applied Sciences Upper Austria, Austria.
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    TreeDom: a graphical web tool for analysing domain architecture evolution2016Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, nr 15, s. 2384-2385Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 177. Hammarström, Lars G. J.
    et al.
    Harmel, Robert K.
    Granath, Mikael
    Ringom, Rune
    Gravenfors, Ylva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Färnegårdh, Katarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Svensson, Per H.
    Wennman, David
    Lundin, Göran
    Roddis, Ylva
    Kitambi, Satish S.
    Bernlind, Alexandra
    Lehmann, Fredrik
    Ernfors, Patrik
    The Oncolytic Efficacy and in Vivo Pharmacokinetics of [2-(4-Chlorophenyl)quinolin-4-yl](piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features2016Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, nr 18, s. 8577-8592Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.

  • 178. Hansen, Eline P.
    et al.
    Fromm, Bastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Oslo University Hospital, Norway.
    Andersen, Sidsel D.
    Marcilla, Antonio
    Andersen, Kasper L.
    Borup, Anne
    Williams, Andrew R.
    Jex, Aaron R.
    Gasser, Robin B.
    Young, Neil D.
    Hall, Ross S.
    Stensballe, Allan
    Ovchinnikov, Vladimir
    Yan, Yan
    Fredholm, Merete
    Thamsborg, Stig M.
    Nejsum, Peter
    Exploration of extracellular vesicles from Ascaris suum provides evidence of parasite-host cross talk2019Ingår i: Journal of Extracellular Vesicles, ISSN 2001-3078, E-ISSN 2001-3078, Vol. 8, nr 1, artikel-id 1578116Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The prevalent porcine helminth, Ascaris suum, compromises pig health and reduces farm productivity worldwide. The closely related human parasite, A. lumbricoides, infects more than 800 million people representing a disease burden of 1.31 million disability-adjusted life years. The infections are often chronic in nature, and the parasites have a profound ability to modulate their hosts' immune responses. This study provides the first in-depth characterisation of extracellular vesicles (EVs) from different developmental stages and body parts of A. suum and proposes the role of these vesicles in the host-parasite interplay. The release of EVs from the third- (L3) and fourth-stage (L4) larvae and adults was demonstrated by transmission electron microscopy (TEM), and sequencing of EV-derived RNA identified a number of microRNAs (miRNAs) and transcripts of potential host immune targets, such as IL-13, IL-25 and IL-33, were identified. Furthermore, proteomics of EVs identified several proteins with immunomodulatory properties and other proteins previously shown to be associated with parasite EVs. Taken together, these results suggest that A. suum EVs and their cargo may play a role in host-parasite interactions. This knowledge may pave the way to novel strategies for helminth infection control and knowledge of their immune modulatory potential.

  • 179. Harner, Tom
    et al.
    Rauert, Cassandra
    Muir, Derek
    Schuster, Jasmin K.
    Hsu, Yu-Mei
    Zhang, Leiming
    Marson, George
    Watson, John G.
    Ahad, Jason
    Cho, Sunny
    Jariyasopit, Narumol
    Kirk, Jane
    Korosi, Jennifer
    Landis, Matthew S.
    Martin, Jonathan W.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi. Stockholms universitet, Science for Life Laboratory (SciLifeLab). University of Alberta, Canada.
    Zhang, Yifeng
    Fernie, Kim
    Wentworth, Gregory R.
    Wnorowski, Andrzej
    Dabek, Ewa
    Charland, Jean-Pierre
    Pauli, Bruce
    Wania, Frank
    Galarneau, Elisabeth
    Cheng, Irene
    Makar, Paul
    Whaley, Cynthia
    Chow, Judith C.
    Wang, Xiaoliang
    Air synthesis review: polycyclic aromatic compounds in the oil sands region2018Ingår i: Environmental Reviews, ISSN 1181-8700, E-ISSN 1208-6053, Vol. 26, nr 4, s. 430-468Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    This air synthesis review presents the current state of knowledge on the sources, fates, and effects for polycyclic aromatic compounds (PACs) and related chemicals released to air in the oil sands region (OSR) in Alberta, Canada. Through the implementation of the Joint Canada-Alberta Oil Sands Monitoring Program in 2012 a vast amount of new information on PACs has been acquired through directed monitoring and research projects and reported to the scientific community and public. This new knowledge addresses questions related to cumulative effects and informs the sustainable management of the oil sands resource while helping to identify gaps in understanding and priorities for future work. As a result of this air synthesis review on PACs, the following topics have been identified as new science priorities: (i) improving emissions reporting to better account for fugitive mining emissions of PACs that includes a broader range of PACs beyond the conventional polycyclic aromatic hydrocarbons (PAHs) including, inter alia, alkylated-PAHs (alk-PAHs), dibenzothiophene (DBT), alk-DBTs, nitro-PAHs, oxy-PAHs including quinones and thia-and aza-arenes; (ii) improving information on the ambient concentrations, long-range transport, and atmospheric deposition of these broader classes of PACs and their release (with co-contaminants) from different types of mining activities; (iii) further optimizing electricity-free and cost-effective approaches for assessing PAC deposition (e.g., snow sampling, lichens, passive ambient sampling) spatially across the OSR and downwind regions; (iv) designing projects that integrate monitoring efforts with source attribution models and ecosystem health studies to improve understanding of sources, receptors, and effects; (v) further optimizing natural deposition archives (e.g., sediment, peat, tree rings) and advanced forensic techniques (e.g., isotope analysis, marker compounds) to provide better understanding of sources of PACs in the OSR over space and time; (vi) conducting process research to improve model capabilities for simulating atmospheric chemistry of PACs and assessing exposure to wildlife and humans; and (vii) developing tools and integrated strategies for assessing cumulative risk to wildlife and humans by accounting for the toxicity of the mixture of chemicals in air rather than on a single compound basis.

  • 180. Hasmats, Johanna
    et al.
    Gréen, Henrik
    Orear, Cedric
    Validire, Pierre
    Huss, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Käller, Max
    Lundeberg, Joakim
    Assessment of Whole Genome Amplification for Sequence Capture and Massively Parallel Sequencing2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 1, artikel-id e84785Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exome sequence capture and massively parallel sequencing can be combined to achieve inexpensive and rapid global analyses of the functional sections of the genome. The difficulties of working with relatively small quantities of genetic material, as may be necessary when sharing tumor biopsies between collaborators for instance, can be overcome using whole genome amplification. However, the potential drawbacks of using a whole genome amplification technology based on random primers in combination with sequence capture followed by massively parallel sequencing have not yet been examined in detail, especially in the context of mutation discovery in tumor material. In this work, we compare mutations detected in sequence data for unamplified DNA, whole genome amplified DNA, and RNA originating from the same tumor tissue samples from 16 patients diagnosed with non-small cell lung cancer. The results obtained provide a comprehensive overview of the merits of these techniques for mutation analysis. We evaluated the identified genetic variants, and found that most (74%) of them were observed in both the amplified and the unamplified sequence data. Eighty-nine percent of the variations found by WGA were shared with unamplified DNA. We demonstrate a strategy for avoiding allelic bias by including RNA-sequencing information.

  • 181. Hatorangan, Marcelinus R.
    et al.
    Laenen, Benjamin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Steige, Kim A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Slotte, Tanja
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Kohler, Claudia
    Rapid Evolution of Genomic Imprinting in Two Species of the Brassicaceae2016Ingår i: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 28, nr 8, s. 1815-1827Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genomic imprinting is an epigenetic phenomenon occurring in mammals and flowering plants that causes genes to adopt a parent-of-origin-specific mode of expression. While the imprinting status of genes is well conserved in mammals, clear estimates for the degree of conservation were lacking in plants. We therefore analyzed the genome-wide imprinting status of Capsella rubella, which shared a common recent ancestor with Arabidopsis thaliana similar to 10 to 14 million years ago. However, only similar to 14% of maternally expressed genes (MEGs) and similar to 29% of paternally expressed genes (PEGs) in C. rubella were commonly imprinted in both species, revealing that genomic imprinting is a rapidly evolving phenomenon in plants. Nevertheless, conserved PEGs exhibited signs of selection, suggesting that a subset of imprinted genes play an important functional role and are therefore maintained in plants. Like in Arabidopsis, PEGs in C. rubella are frequently associated with the presence of transposable elements that preferentially belong to helitron and MuDR families. Our data further reveal that MEGs and PEGs differ in their targeting by 24-nucleotide small RNAs and asymmetric DNA methylation, suggesting different mechanisms establishing DNA methylation at MEGs and PEGs.

  • 182.
    Hayat, Sikander
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ranking models of transmembrane beta-barrel proteins using Z-coordinate predictions2012Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 28, nr 12, s. i90-I96Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: Transmembrane beta-barrels exist in the outer membrane of gram-negative bacteria as well as in chloroplast and mitochondria. They are often involved in transport processes and are promising antimicrobial drug targets. Structures of only a few beta-barrel protein families are known. Therefore, a method that could automatically generate such models would be valuable. The symmetrical arrangement of the barrels suggests that an approach based on idealized geometries may be successful. Results: Here, we present tobmodel; a method for generating 3D models of beta-barrel transmembrane proteins. First, alternative topologies are obtained from the BOCTOPUS topology predictor. Thereafter, several 3D models are constructed by using different angles of the beta-sheets. Finally, the best model is selected based on agreement with a novel predictor, ZPRED3, which predicts the distance from the center of the membrane for each residue, i.e. the Z-coordinate. The Z-coordinate prediction has an average error of 1.61 A. Tobmodel predicts the correct topology for 75% of the proteins in the dataset which is a slight improvement over BOCTOPUS alone. More importantly, however, tobmodel provides a C alpha template with an average RMSD of 7.24 A from the native structure.

  • 183. Hayat, Sikander
    et al.
    Peters, Christoph
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Shu, Nanjiang
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Tsirigos, Konstantinos D.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Inclusion of dyad-repeat pattern improves topology prediction of transmembrane beta-barrel proteins2016Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, nr 10, s. 1571-1573Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Accurate topology prediction of transmembrane beta-barrels is still an open question. Here, we present BOCTOPUS2, an improved topology prediction method for transmembrane beta-barrels that can also identify the barrel domain, predict the topology and identify the orientation of residues in transmembrane beta-strands. The major novelty of BOCTOPUS2 is the use of the dyad-repeat pattern of lipid and pore facing residues observed in transmembrane beta-barrels. In a cross-validation test on a benchmark set of 42 proteins, BOCTOPUS2 predicts the correct topology in 69% of the proteins, an improvement of more than 10% over the best earlier method (BOCTOPUS) and in addition, it produces significantly fewer erroneous predictions on non-transmembrane beta-barrel proteins.

  • 184. Hayat, Sikander
    et al.
    Sander, Chris
    Marks, Debora S.
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    All-atom 3D structure prediction of transmembrane beta-barrel proteins from sequences2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 17, s. 5413-5418Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transmembrane beta-barrels (TMBs) carry out major functions in substrate transport and protein biogenesis but experimental determination of their 3D structure is challenging. Encouraged by successful de novo 3D structure prediction of globular and alpha-helical membrane proteins from sequence alignments alone, we developed an approach to predict the 3D structure of TMBs. The approach combines the maximum-entropy evolutionary coupling method for predicting residue contacts (EVfold) with a machine-learning approach (boctopus2) for predicting beta-strands in the barrel. In a blinded test for 19 TMB proteins of known structure that have a sufficient number of diverse homologous sequences available, this combined method (EVfold_bb) predicts hydrogen-bonded residue pairs between adjacent beta-strands at an accuracy of similar to 70%. This accuracy is sufficient for the generation of all-atom 3D models. In the transmembrane barrel region, the average 3D structure accuracy [template-modeling (TM) score] of top-ranked models is 0.54 (ranging from 0.36 to 0.85), with a higher (44%) number of residue pairs in correct strand-strand registration than in earlier methods (18%). Although the nonbarrel regions are predicted less accurately overall, the evolutionary couplings identify some highly constrained loop residues and, for FecA protein, the barrel including the structure of a plug domain can be accurately modeled (TM score = 0.68). Lower prediction accuracy tends to be associated with insufficient sequence information and we therefore expect increasing numbers of beta-barrel families to become accessible to accurate 3D structure prediction as the number of available sequences increases.

  • 185.
    Heinrich, Kristina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Leslie, David J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Morlock, Michaela
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Bertilsson, Stefan
    Jonas, Kristina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Molecular Basis and Ecological Relevance of Caulobacter Cell Filamentation in Freshwater Habitats2019Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 10, nr 4, artikel-id e01557-19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    All living cells are characterized by certain cell shapes and sizes. Many bacteria can change these properties depending on the growth conditions. The underlying mechanisms and the ecological relevance of changing cell shape and size remain unclear in most cases. One bacterium that undergoes extensive shape-shifting in response to changing growth conditions is the freshwater bacterium Caulobacter crescentus. When incubated for an extended time in stationary phase, a subpopulation of C. crescentus forms viable filamentous cells with a helical shape. Here, we demonstrated that this stationary-phase-induced filamentation results from downregulation of most critical cell cycle regulators and a consequent block of DNA replication and cell division while cell growth and metabolism continue. Our data indicate that this response is triggered by a combination of three stresses caused by prolonged growth in complex medium, namely, the depletion of phosphate, alkaline pH, and an excess of ammonium. We found that these conditions are experienced in the summer months during algal blooms near the surface in freshwater lakes, a natural habitat of C. crescentus, suggesting that filamentous growth is a common response of C. crescentus to its environment. Finally, we demonstrate that when grown in a biofilm, the filamentous cells can reach beyond the surface of the biofilm and potentially access nutrients or release progeny. Altogether, our work highlights the ability of bacteria to alter their morphology and suggests how this behavior might enable adaptation to changing environments.

  • 186.
    Heinrich, Kristina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Philipps University Marburg, Germany.
    Sobetzko, Patrick
    Jonas, Kristina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Philipps University Marburg, Germany.
    A Kinase-Phosphatase Switch Transduces Environmental Information into a Bacterial Cell Cycle Circuit2016Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, nr 12, artikel-id e1006522Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The bacterial cell cycle has been extensively studied under standard growth conditions. How it is modulated in response to environmental changes remains poorly understood. Here, we demonstrate that the freshwater bacterium Caulobacter crescentus blocks cell division and grows to filamentous cells in response to stress conditions affecting the cell membrane. Our data suggest that stress switches the membrane-bound cell cycle kinase CckA to its phosphatase mode, leading to the rapid dephosphorylation, inactivation and proteolysis of the master cell cycle regulator CtrA. The clearance of CtrA results in downregulation of division and morphogenesis genes and consequently a cell division block. Upon shift to non-stress conditions, cells quickly restart cell division and return to normal cell size. Our data indicate that the temporary inhibition of cell division through the regulated inactivation of CtrA constitutes a growth advantage under stress. Taken together, our work reveals a new mechanism that allows bacteria to alter their mode of proliferation in response to environmental cues by controlling the activity of a master cell cycle transcription factor. Furthermore, our results highlight the role of a bifunctional kinase in this process that integrates the cell cycle with environmental information.

  • 187. Helgadottir, Hafdis
    et al.
    Lundin, Pär
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Wallén Arzt, Emelie
    Lindström, Anna-Karin
    Graff, Caroline
    Eriksson, Maria
    Somatic mutation that affects transcription factor binding upstream of CD55 in the temporal cortex of a late-onset Alzheimer disease patient2019Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 28, nr 16, s. 2675-2685Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Familial cases suggest genetic components; however, monogenetic causes are few, and the vast majority of incidences have unknown cause. Sequencing efforts have focused on germline mutations, but improved technology has opened up for studies on somatic mutations in affected brain tissue samples. Here we use ultra-deep sequencing on brain and blood from early-onset AD (EOAD) and late-onset AD (LOAD) patients and non-AD individuals (n = 16). In total, 2.86 Mb of genomic regions, previously associated with AD, were targeted included 28 genes and upstream and downstream regulatory regions. Tailored downstream bioinformatics filtering identified 11 somatic single nucleotide variants in the temporal cortex in AD patients and none in the controls. One variant was validated to be present at 0.4% allele frequency in temporal cortex of a LOAD patient. This variant was predicted to affect transcription factor binding sites upstream of the CD55 gene, contributing to AD pathogenesis by affecting the complement system. Our results suggest that future studies targeting larger portions of the genome for somatic mutation analysis are important to obtain an increased understanding for the molecular basis of both EOAD and LOAD.

  • 188.
    Hernández-Neuta, Iván
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Neumann, Felix
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Brightmeyer, J.
    Tis, T. Ba
    Madaboosi, Narayanan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Wei, Q.
    Ozcan, A.
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Smartphone-based clinical diagnostics: towards democratization of evidence-based health care2019Ingår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, nr 1, s. 19-39Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Recent advancements in bioanalytical techniques have led to the development of novel and robust diagnostic approaches that hold promise for providing optimal patient treatment, guiding prevention programs and widening the scope of personalized medicine. However, these advanced diagnostic techniques are still complex, expensive and limited to centralized healthcare facilities or research laboratories. This significantly hinders the use of evidence-based diagnostics for resource-limited settings and the primary care, thus creating a gap between healthcare providers and patients, leaving these populations without access to precision and quality medicine. Smartphone-based imaging and sensing platforms are emerging as promising alternatives for bridging this gap and decentralizing diagnostic tests offering practical features such as portability, cost-effectiveness and connectivity. Moreover, towards simplifying and automating bioanalytical techniques, biosensors and lab-on-a-chip technologies have become essential to interface and integrate these assays, bringing together the high precision and sensitivity of diagnostic techniques with the connectivity and computational power of smartphones. Here, we provide an overview of the emerging field of clinical smartphone diagnostics and its contributing technologies, as well as their wide range of areas of application, which span from haematology to digital pathology and rapid infectious disease diagnostics.

  • 189.
    Hernández-Neuta, Iván
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Pereiro, Iago
    Ahlford, Annika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ferraro, Davide
    Zhang, Qiongdi
    Viovy, Jean-Louis
    Descroix, Stéphanie
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Microfluidic magnetic fluidized bed for DNA analysis in continuous flow mode2018Ingår i: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 102, s. 531-539Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 190.
    Hernández-Neuta, Iván
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Pereiro, Iago
    Ahlford, Annika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ferraro, Davide
    Zhang, Qiongdi
    Viovy, Jean-Louis
    Descroix, Stéphanie
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Microfluidic magnetic fluidized bed for DNA analysis in continuous flow modeManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

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

  • 191.
    Heusser, Stephanie A.
    et al.
    Swiss Federal Institute of Technology, Switzerland.
    Howard, Rebecca J.
    Borghese, Cecilia M.
    Cullins, Madeline A.
    Broemstrup, Torben
    Lee, Ui S.
    Lindahl, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Carlsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Harris, R. Adron
    Functional Validation of Virtual Screening for Novel Agents with General Anesthetic Action at Ligand-Gated Ion Channelss2013Ingår i: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 84, nr 5, s. 670-678Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    GABA(A) receptors play a crucial role in the actions of general anesthetics. The recently published crystal structure of the general anesthetic propofol bound to Gloeobacter violaceus ligand-gated ion channel (GLIC), a bacterial homolog of GABA(A) receptors, provided an opportunity to explore structure-based ligand discovery for pentameric ligand-gated ion channels (pLGICs). We used molecular docking of 153,000 commercially available compounds to identify molecules that interact with the propofol binding site in GLIC. In total, 29 compounds were selected for functional testing on recombinant GLIC, and 16 of these compounds modulated GLIC function. Active compounds were also tested on recombinant GABA(A) receptors, and point mutations around the presumed binding pocket were introduced into GLIC and GABA(A) receptors to test for binding specificity. The potency of active compounds was only weakly correlated with properties such as lipophilicity or molecular weight. One compound was found to mimic the actions of propofol on GLIC and GABA(A), and to be sensitive to mutations that reduce the action of propofol in both receptors. Mutant receptors also provided insight about the position of the binding sites and the relevance of the receptor's conformation for anesthetic actions. Overall, the findings support the feasibility of the use of virtual screening to discover allosteric modulators of pLGICs, and suggest that GLIC is a valid model system to identify novel GABA(A) receptor ligands.

  • 192.
    Heusser, Stephanie A
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lycksell, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wang, Xueqing
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Howard, Rebecca J
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Propofol potentiation in the pentameric ion channel GLIC is mediated by a deep membrane-facing cavityManuskript (preprint) (Övrigt vetenskapligt)
  • 193.
    Heusser, Stephanie A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lycksell, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Wang, Xueqing
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Mc Comas, Sarah E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Howard, Rebecca J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 42, s. 10672-10677Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to similar to 30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.

  • 194.
    Heusser, Stephanie A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Yoluk, Özge
    Klement, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Riederer, Erika A.
    Lindahl, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Howard, Rebecca J.
    Functional characterization of neurotransmitter activation and modulation in a nematode model ligand-gated ion channel2016Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 138, nr 2, s. 243-253Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The superfamily of pentameric ligand-gated ion channels includes neurotransmitter receptors that mediate fast synaptic transmission in vertebrates, and are targets for drugs including alcohols, anesthetics, benzodiazepines, and anticonvulsants. However, the mechanisms of ion channel opening, gating, and modulation in these receptors leave many open questions, despite their pharmacological importance. Subtle conformational changes in both the extracellular and transmembrane domains are likely to influence channel opening, but have been difficult to characterize given the limited structural data available for human membrane proteins. Recent crystal structures of a modified Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in multiple states offer an appealing model system for structure-function studies. However, the pharmacology of the crystallographic GluCl construct is not well established. To establish the functional relevance of this system, we used two-electrode voltage-clamp electrophysiology in Xenopus oocytes to characterize activation of crystallographic and native-like GluCl constructs by L-glutamate and ivermectin. We also tested modulation by ethanol and other anesthetic agents, and used site-directed mutagenesis to explore the role of a region of Loop F which was implicated in ligand gating by molecular dynamics simulations. Our findings indicate that the crystallographic construct functionally models concentration-dependent agonism and allosteric modulation of pharmacologically relevant receptors. Specific substitutions at residue Leu174 in loop F altered direct L-glutamate activation, consistent with computational evidence for this region's role in ligand binding. These insights demonstrate conservation of activation and modulation properties in this receptor family, and establish a framework for GluCl as a model system, including new possibilities for drug discovery. In this study, we elucidate the validity of a modified glutamate-gated chloride channel (GluCl(cryst)) as a structurally accessible model for GABA(A) receptors. In contrast to native-like controls, GluCl(cryst) exhibits classical activation by its neurotransmitter ligand L-glutamate. The modified channel is also sensitive to allosteric modulators associated with human GABA(A) receptors, and to site-directed mutations predicted to alter channel opening.

  • 195. Holst, Mikkel Roland
    et al.
    Vidal-Quadras, Maite
    Larsson, Elin
    Song, Jie
    Hubert, Madlen
    Blomberg, Jeanette
    Lundborg, Magnus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Landström, Maréne
    Lundmark, Richard
    Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion2017Ingår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, nr 8, s. 1893-1905Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cellular blebbing, caused by local alterations in cellsurface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrinindependent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension- mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol- interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

  • 196.
    Horvath, Robert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Laenen, Benjamin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Takuno, Shohei
    Slotte, Tanja
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Single-cell expression noise and gene-body methylation in Arabidopsis thaliana2019Ingår i: Heredity, ISSN 0018-067X, E-ISSN 1365-2540, Vol. 123, nr 2, s. 81-91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gene-body methylation (gbM) refers to an increased level of methylated cytosines specifically in a CG sequence context within genes. gbM is found in plant genes with intermediate expression level, which evolve slowly, and is often broadly conserved across millions of years of evolution. Intriguingly however, some plants lack gbM, and thus it remains unclear whether gbM has a function. In animals, there is support for a role of gbM in reducing erroneous transcription and transcription noise, but so far most studies in plants have tested for an effect of gbM on expression level, not noise. Here, we therefore tested whether gbM was associated with reduced expression noise in Arabidopsis thaliana, using single-cell transcriptome sequencing data from root quiescent centre cells. We find that gbM genes have lower expression noise levels than unmethylated genes. However, an analysis of covariance revealed that, if other genomic features are taken into account, this association disappears. Nonetheless, gbM genes were more consistently expressed across single-cell samples, supporting previous inference that gbM genes are constitutively expressed. Finally, we observed that fewer RNAseq reads map to introns of gbM genes than to introns of unmethylated genes, which indicates that gbM might be involved in reducing erroneous transcription by reducing intron retention.

  • 197.
    Horvath, Robert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Slotte, Tanja
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    The Role of Small RNA-Based Epigenetic Silencing for Purifying Selection on Transposable Elements in Capsella grandiflora2017Ingår i: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 9, nr 10, s. 2911-2920Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To avoid negative effects of transposable element (TE) proliferation, plants epigenetically silence TEs using a number of mechanisms, including RNA-directed DNA methylation. These epigenetic modifications can extend outside the boundaries of TE insertions and lead to silencing of nearby genes, resulting in a trade-off between TE silencing and interference with nearby gene regulation. Therefore, purifying selection is expected to remove silenced TE insertions near genes more efficiently and prevent their accumulation within a population. To explore how effects of TE silencing on gene regulation shapes purifying selection on TEs, we analyzed whole genome sequencing data from 166 individuals of a large population of the outcrossing species Capsella grandiflora. We found that most TEs are rare, and in chromosome arms, silenced TEs are exposed to stronger purifying selection than those that are not silenced by 24-nucleotide small RNAs, especially with increasing proximity to genes. An age-of-allele test of neutrality on a subset of TEs supports our inference of purifying selection on silenced TEs, suggesting that our results are robust to varying transposition rates. Our results provide new insights into the processes affecting the accumulation of TEs in an outcrossing species and support the view that epigenetic silencing of TEs results in a trade-off between preventing TE proliferation and interference with nearby gene regulation. We also suggest that in the centromeric and pericentromeric regions, the negative aspects of epigenetic TE silencing are missing.

  • 198. Hou, Yan
    et al.
    Nowak, Michael D.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). University of Oslo, Norway.
    Mirre, Virginia
    Bjora, Charlotte S.
    Brochmann, Christian
    Popp, Magnus
    Thousands of RAD-seq Loci Fully Resolve the Phylogeny of the Highly Disjunct Arctic-Alpine Genus Diapensia (Diapensiaceae)2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 10, artikel-id e0140175Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Restriction-site associated DNA sequencing (RAD-seq) has recently become an important method to generate genome-widemolecular data for species delimitation, phylogeography, and population genetic studies. However, very few empirical studies have so far tested its applicability in phylogenetic reconstruction. The alpine-arctic genus Diapensia was selected to study the origin of the disjunction between the Arctic and the Himalayan-Hengduan Mountains (HHM). However, a previous phylogenetic analysis based on one nuclear and four plastid DNA regions failed to resolve the oldest divergences in Diapensia as well as the relationship between the two HHM species. Here we reconstruct a fully resolved phylogeny of Diapensia and address the conflict between the currently accepted taxonomy and the gene trees in the HHM species using RAD-seq. Based on a data set containing 2,650 loci selected to maximize the number of parsimony informative sites and allowing for a high level of missing data (51%), the phylogeny of Diapensia was fully resolved and each of the four species was reciprocally monophyletic. Whereas the arctic D. lapponica was inferred as sister to the HHM clade in the previous study, the RAD-seq data resolved the two arctic species as sisters to the HHM clade. Similar relationships were inferred from a differently filtered data set with far fewer loci (114) and lessmissing data (21%), but with lower support and with one of the two HHM species as non-monophyletic. Bayesian concordance analysis and Patterson's D-statistic tests suggested that admixture has occurred between the two HHM species.

  • 199.
    Howard, Rebecca J.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Carnevale, Vincenzo
    Delemotte, Lucie
    Hellmich, Ute A.
    Rothberg, Brad S.
    Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport2018Ingår i: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1860, nr 4, s. 927-942Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Ion translocation across biological barriers is a fundamental requirement for life. In many cases, controlling this process for example with neuroactive drugs demands an understanding of rapid and reversible structural changes in membrane-embedded proteins, including ion channels and transporters. Classical approaches to electrophysiology and structural biology have provided valuable insights into several such proteins over macroscopic, often discontinuous scales of space and time. Integrating these observations into meaningful mechanistic models now relies increasingly on computational methods, particularly molecular dynamics simulations, while surfacing important challenges in data management and conceptual alignment. Here, we seek to provide contemporary context, concrete examples, and a look to the future for bridging disciplinary gaps in biological ion transport. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin Mcllwain.

  • 200. Hu, Hailong
    et al.
    Li, Zhong
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Xie, Shangxin
    A Bi-LSTM Based Ensemble Algorithm for Prediction of Protein Secondary Structure2019Ingår i: Applied Sciences, E-ISSN 2076-3417, Vol. 9, nr 17, artikel-id 3538Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The prediction of protein secondary structure continues to be an active area of research in bioinformatics. In this paper, a Bi-LSTM based ensemble model is developed for the prediction of protein secondary structure. The ensemble model with dual loss function consists of five sub-models, which are finally joined by a Bi-LSTM layer. In contrast to existing ensemble methods, which generally train each sub-model and then join them as a whole, this ensemble model and sub-models can be trained simultaneously and the performance of each model can be observed and compared during the training process. Three independent test sets (e.g., data1199, 513 protein Cuff & Barton set (CB513) and 203 proteins from Critical Appraisals Skills Programme (CASP203)) are employed to test the method. On average, the ensemble model achieved 84.3% in Q(3) accuracy and 81.9% in segment overlap measure (SOV) score by using 10-fold cross validation. There is an improvement of up to 1% over some state-of-the-art prediction methods of protein secondary structure.

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