Ändra sökning
Avgränsa sökresultatet
1234567 101 - 150 av 548
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Träffar per sida
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
Markera
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 101. Desamore, Aurelie
    et al.
    Patino, Jairo
    Mardulyn, Patrick
    Mcdaniel, Stuart F.
    Zanatta, Florian
    Laenen, Benjamin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). University of Liège, Belgium.
    Vanderpoorten, Alain
    High migration rates shape the postglacial history of amphi-Atlantic bryophytes2016Ingår i: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 25, nr 21, s. 5568-5584Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Paleontological evidence and current patterns of angiosperm species richness suggest that European biota experienced more severe bottlenecks than North American ones during the last glacial maximum. How well this pattern fits other plant species is less clear. Bryophytes offer a unique opportunity to contrast the impact of the last glacial maximum in North America and Europe because about 60% of the European bryoflora is shared with North America. Here, we use population genetic analyses based on approximate Bayesian computation on eight amphi-Atlantic species to test the hypothesis that North American populations were less impacted by the last glacial maximum, exhibiting higher levels of genetic diversity than European ones and ultimately serving as a refugium for the postglacial recolonization of Europe. In contrast with this hypothesis, the best-fit demographic model involved similar patterns of population size contractions, comparable levels of genetic diversity and balanced migration rates between European and North American populations. Our results thus suggest that bryophytes have experienced comparable demographic glacial histories on both sides of the Atlantic. Although a weak, but significant genetic structure was systematically recovered between European and North American populations, evidence for migration from and towards both continents suggests that amphi-Atlantic bryophyte population may function as a metapopulation network. Reconstructing the biogeographic history of either North American or European bryophyte populations therefore requires a large, trans-Atlantic geographic framework.

  • 102. Dickerson, Aisha S.
    et al.
    Ransome, Yusuf
    Karlsson, Oskar
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Human prenatal exposure to polychlorinated biphenyls (PCBs) and risk behaviors in adolescence2019Ingår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 129, s. 247-255Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) are chemicals used in a variety of products before they were widely banned due to toxic effects in humans and wildlife. Because of continued persistence and ubiquity of these contaminants, risk of exposure to people living in industrialized countries is still high. Experimental research show that developmental exposure to PCB may alter function of brain pleasure centers and potentially influence disinhibitory behaviors, including tobacco and alcohol use. Yet, the potential effects of developmental PCB exposure on adolescent substance use have not been studied in humans. We used the Child Health and Development Studies (CHDS), a prospective birth cohort study in the Oakland and East Bay areas of California, to investigate associations between prenatal exposure to PCB congeners (66, 74, 99, 118, 138, 153, 170, 180, 187, and 203) and later disinhibitory behaviors in adolescents, specifically alcohol consumption and smoking, in a randomly selected sample (n = 554). Total prenatal PCB exposure was not associated with disinhibitory behaviors, among adolescents. However, the adjusted odds ratio (aOR) for being a current smoker, was higher in subjects within the third quartile of maternal PCB 66 exposure compared to those below the median (aOR = 1.93; 95% CI 1.05, 3.55). The aOR for drinking > 2 alcoholic beverages per week, were also higher for adolescents within the third (aOR = 1.46; 95% CI 0.86, 2.47) and fourth quartile of PCB 66 exposure (aOR = 1.39; 95% CI 0.83, 2.35), but the differences did not reach statistical significance. These results suggest that this specific PCB congener may play a role inducing neurodevelopmental alterations that could potentially increase the risk of becoming a long-term user of tobacco and possibly alcohol. There were no notable differences between magnitude or direction of effect between boys and girls. Future replicate analyses with larger longitudinal samples and animal experimental studies of potential underlying mechanisms are warranted.

  • 103. Didion, John P.
    et al.
    Martin, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Collins, Francis S.
    Atropos: specific, sensitive, and speedy trimming of sequencing reads2017Ingår i: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 5, artikel-id e3720Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A key step in the transformation of raw sequencing reads into biological insights is the trimming of adapter sequences and low-quality bases. Read trimming has been shown to increase the quality and reliability while decreasing the computational requirements of downstream analyses. Many read trimming software tools are available; however, no tool simultaneously provides the accuracy, computational efficiency, and feature set required to handle the types and volumes of data generated in modern sequencing-based experiments. Here we introduce Atropos and show that it trims reads with high sensitivity and specificity while maintaining leadingedge speed. Compared to other state-of-the-art read trimming tools, Atropos achieves significant increases in trimming accuracy while remaining competitive in execution times. Furthermore, Atropos maintains high accuracy even when trimming data with elevated rates of sequencing errors. The accuracy, high performance, and broad feature set offered by Atropos makes it an appropriate choice for the pre-processing of Illumina, ABI SOLiD, and other current-generation short-read sequencing datasets. Atropos is open source and free software written in Python (3.3+) and available at https://github. com/jdidion/atropos.

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

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

  • 105.
    Domingo-Prim, Judit
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Endara-Coll, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bonath, Franziska
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Jimeno, Sonia
    Prados-Carvaja, Rosario
    Friedländer, Marc R.
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Huertas, Pablo
    Visa, Neus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 2135Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The exosome is a ribonucleolytic complex that plays important roles in RNA metabolism. Here we show that the exosome is necessary for the repair of DNA double-strand breaks (DSBs) in human cells and that RNA clearance is an essential step in homologous recombination. Transcription of DSB-flanking sequences results in the production of damage-induced long non-coding RNAs (dilncRNAs) that engage in DNA-RNA hybrid formation. Depletion of EXOSC10, an exosome catalytic subunit, leads to increased dilncRNA and DNA-RNA hybrid levels. Moreover, the targeting of the ssDNA-binding protein RPA to sites of DNA damage is impaired whereas DNA end resection is hyper-stimulated in EXOSC10-depleted cells. The DNA end resection deregulation is abolished by transcription inhibitors, and RNase H1 overexpression restores the RPA recruitment defect caused by EXOSC10 depletion, which suggests that RNA clearance of newly synthesized dilncRNAs is required for RPA recruitment, controlled DNA end resection and assembly of the homologous recombination machinery.

  • 106.
    Domingo-Prim, Judit
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Endara-Coll, Martín
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bonath, Franziska
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Jimeno, Sonia
    Friedländer, Marc
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Huertas, Pablo
    Visa, Neus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    EXOSC10 is required for RPA assembly and controlled DNA resection at DNA dobule-strand breaksManuskript (preprint) (Övrigt vetenskapligt)
  • 107. Donolato, Marco
    et al.
    Antunes, Paula
    Bejhed, Rebecca S.
    Gómez de la Torre, Teresa Zardán
    Österberg, Frederik W.
    Strömberg, Mattias
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Strømme, Maria
    Svedlindh, Peter
    Hansen, Mikkel F.
    Vavassori, Paolo
    Novel Readout Method for Molecular Diagnostic Assays Based on Optical Measurements of Magnetic Nanobead Dynamics2015Ingår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 87, nr 3, s. 1622-1629Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We demonstrate detection of DNA coils formed from a Vibrio cholerae DNA target at picomolar concentrations using a novel optomagnetic approach exploiting the dynamic behavior and optical anisotropy of magnetic nanobead (MNB) assemblies. We establish that the complex second harmonic optical transmission spectra of MNB suspensions measured upon application of a weak uniaxial AC magnetic field correlate well with the rotation dynamics of the individual MNBs. Adding a target analyte to the solution leads to the formation of permanent MNB clusters, namely, to the suppression of the dynamic MNB behavior. We prove that the optical transmission spectra are highly sensitive to the formation of permanent MNB clusters and, thereby to the target analyte concentration. As a specific clinically relevant diagnostic case, we detect DNA coils formed via padlock probe recognition and isothermal rolling circle amplification and benchmark against a commercial equipment. The results demonstrate the fast optomagnetic readout of rolling circle products from bacterial DNA utilizing the dynamic properties of MNBs in a miniaturized and low-cost platform requiring only a transparent window in the chip.

  • 108.
    Dou, Dan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hernández-Neuta, Iván
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Wang, Hao
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Östbye, Henrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Qian, Xiaoyan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Thiele, Swantje
    Resa-Infante, Patricia
    Mounogou Kouassi, Nancy
    Sender, Vicky
    Hentrich, Karina
    Mellroth, Peter
    Henriques-Normark, Birgitta
    Gabriel, Gülsah
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Daniels, Robert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Analysis of IAV Replication and Co-infection Dynamics by a Versatile RNA Viral Genome Labeling Method2017Ingår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, nr 1, s. 251-263Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome delivery to the proper cellular compartment for transcription and replication is a primary goal of viruses. However, methods for analyzing viral genome localization and differentiating genomes with high identity are lacking, making it difficult to investigate entry-related processes and co-examine heterogeneous RNA viral populations. Here, we present an RNA labeling approach for single-cell analysis of RNA viral replication and co-infection dynamics in situ, which uses the versatility of padlock probes. We applied this method to identify influenza A virus (IAV) infections in cells and lung tissue with single-nucleotide specificity and to classify entry and replication stages by gene segment localization. Extending the classification strategy to co-infections of IAVs with single-nucleotide variations, we found that the dependence on intracellular trafficking places a time restriction on secondary co-infections necessary for genome reassortment. Altogether, these data demonstrate how RNA viral genome labeling can help dissect entry and co-infections.

  • 109.
    Díez, Beatriz
    et al.
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Pontificia Universidad Católica de Chile, Chile; Center for Climate Change and Resilience Research (CR)2, Chile.
    Nylander, Johan A. A.
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Swedish Museum of Natural History, Sweden.
    Ininbergs, Karolina
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Dupont, Christopher L.
    Allen, Andrew E.
    Yooseph, Shibu
    Rusch, Douglas B.
    Bergman, Birgitta
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Metagenomic Analysis of the Indian Ocean Picocyanobacterial Community: Structure, Potential Function and Evolution2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 5, artikel-id e0155757Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Unicellular cyanobacteria are ubiquitous photoautotrophic microbes that contribute substantially to global primary production. Picocyanobacteria such as Synechococcus and Prochlorococcus depend on chlorophyll a-binding protein complexes to capture light energy. In addition, Synechococcus has accessory pigments organized into phycobilisomes, and Prochlorococcus contains chlorophyll b. Across a surface water transect spanning the sparsely studied tropical Indian Ocean, we examined Synechococcus and Prochlorococcus occurrence, taxonomy and habitat preference in an evolutionary context. Shotgun sequencing of size fractionated microbial communities from 0.1 mu m to 20 mu m and subsequent phylogenetic analysis indicated that cyanobacteria account for up to 15% of annotated reads, with the genera Prochlorococcus and Synechococcus comprising 90% of the cyanobacterial reads, even in the largest size fraction (3.0-20 mm). Phylogenetic analyses of cyanobacterial lightharvesting genes (chl-binding pcb/isiA, allophycocyanin (apcAB), phycocyanin (cpcAB) and phycoerythin (cpeAB)) mostly identified picocyanobacteria clades comprised of overlapping sequences obtained from Indian Ocean, Atlantic and/or Pacific Oceans samples. Habitat reconstructions coupled with phylogenetic analysis of the Indian Ocean samples suggested that large Synechococcus-like ancestors in coastal waters expanded their ecological niche towards open oligotrophic waters in the Indian Ocean through lineage diversification and associated streamlining of genomes (e.g. loss of phycobilisomes and acquisition of Chl b); resulting in contemporary small celled Prochlorococcus. Comparative metagenomic analysis with picocyanobacteria populations in other oceans suggests that this evolutionary scenario may be globally important.

  • 110. Einarsdottir, Elisabet
    et al.
    Svensson, Idor
    Darki, Fahimeh
    Peyrard-Janvid, Myriam
    Lindvall, Jessica M.
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Ameur, Adam
    Jacobsson, Christer
    Klingberg, Torkel
    Kere, Juha
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden; Folkhälsan Institute of Genetics, Finland; University of Helsinki, Finland.
    Matsson, Hans
    Mutation in CEP63 co-segregating with developmental dyslexia in a Swedish family2015Ingår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 134, nr 11-12, s. 1239-1248Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Developmental dyslexia is the most common learning disorder in children. Problems in reading and writing are likely due to a complex interaction of genetic and environmental factors, resulting in reduced power of studies of the genetic factors underlying developmental dyslexia. Our approach in the current study was to perform exome sequencing of affected and unaffected individuals within an extended pedigree with a familial form of developmental dyslexia. We identified a two-base mutation, causing a p.R229L amino acid substitution in the centrosomal protein 63 kDa (CEP63), co-segregating with developmental dyslexia in this pedigree. This mutation is novel, and predicted to be highly damaging for the function of the protein. 3D modelling suggested a distinct conformational change caused by the mutation. CEP63 is localised to the centrosome in eukaryotic cells and is required for maintaining normal centriole duplication and control of cell cycle progression. We found that a common polymorphism in the CEP63 gene had a significant association with brain white matter volume. The brain regions were partly overlapping with the previously reported region influenced by polymorphisms in the dyslexia susceptibility genes DYX1C1 and KIAA0319. We hypothesise that CEP63 is particularly important for brain development and might control the proliferation and migration of cells when those two events need to be highly coordinated.

  • 111. Eisfeldt, Jesper
    et al.
    Pettersson, Maria
    Vezzi, Francesco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Wincent, Josephine
    Käller, Max
    Gruselius, Joel
    Nilsson, Daniel
    Lundberg, Elisabeth Syk
    Carvalho, Claudia M. B.
    Lindstrand, Anna
    Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements2019Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, nr 2, artikel-id e1007858Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Complex chromosomal rearrangements (CCRs) are rearrangements involving more than two chromosomes or more than two breakpoints. Whole genome sequencing (WGS) allows for outstanding high resolution characterization on the nucleotide level in unique sequences of such rearrangements, but problems remain for mapping breakpoints in repetitive regions of the genome, which are known to be prone to rearrangements. Hence, multiple complementary WGS experiments are sometimes needed to solve the structures of CCRs. We have studied three individuals with CCRs: Case 1 and Case 2 presented with de novo karyotypically balanced, complex interchromosomal rearrangements (46,XX,t(2;8;15)(q35;q24.1;q22) and 46,XY,t(1;10;5)(q32;p12;q31)), and Case 3 presented with a de novo, extremely complex intrachromosomal rearrangement on chromosome 1. Molecular cytogenetic investigation revealed cryptic deletions in the breakpoints of chromosome 2 and 8 in Case 1, and on chromosome 10 in Case 2, explaining their clinical symptoms. In Case 3, 26 breakpoints were identified using WGS, disrupting five known disease genes. All rearrangements were subsequently analyzed using optical maps, linked-read WGS, and short-read WGS. In conclusion, we present a case series of three unique de novo CCRs where we by combining the results from the different technologies fully solved the structure of each rearrangement. The power in combining short-read WGS with long-molecule sequencing or optical mapping in these unique de novo CCRs in a clinical setting is demonstrated. Author summary Unexpected complexities are common findings in the breakpoints of karyotypically balanced complex chromosomal rearrangements (CCRs). Such findings are of clinical importance, as they may be the cause of mendelian phenotypes in the rearrangement carrier. Whole genome sequencing (WGS) allows for high resolution characterization of CCRs, but problems remain for mapping breakpoints located in repetitive regions of the genome, which are known to be prone to rearrangements. In our study, we use multiple complementary WGS experiments to solve the structures of three CCRs originally identified by karyotyping. In all cases, the genomic structure of the derivative chromosomes was resolved and a molecular genetic explanation of the clinical symptoms of the patients was obtained. Furthermore, we compare the performance, sensitivity and resolution of four different WGS techniques for solving these CCRs in a clinical diagnostic laboratory set.

  • 112. El-Gebali, Sara
    et al.
    Mistry, Jaina
    Bateman, Alex
    Eddy, Sean R.
    Luciani, Aurelien
    Potter, Simon C.
    Qureshi, Matloob
    Richardson, Lorna J.
    Salazar, Gustavo A.
    Smart, Alfredo
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Hirsh, Layla
    Paladin, Lisanna
    Piovesan, Damiano
    Tosatto, Silvio C. E.
    Finn, Robert D.
    The Pfam protein families database in 20192019Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, nr D1, s. D427-D432Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The last few years have witnessed significant changes in Pfam (https://pfam.xfam.org). The number of families has grown substantially to a total of 17,929 in release 32.0. New additions have been coupled with efforts to improve existing families, including refinement of domain boundaries, their classification into Pfam clans, as well as their functional annotation. We recently began to collaborate with the RepeatsDB resource to improve the definition of tandem repeat families within Pfam. We carried out a significant comparison to the structural classification database, namely the Evolutionary Classification of Protein Domains (ECOD) that led to the creation of 825 new families based on their set of uncharacterized families(EUFs). Furthermore, we also connected Pfam entries to the Sequence Ontology (SO) through mapping of the Pfam type definitions to SO terms. Since Pfam has many community contributors, we recently enabled the linking between authorship of all Pfam entries with the corresponding authors' ORCID identifiers. This effectively permits authors to claim credit for their Pfam curation and link them to their ORCID record.

  • 113. El-Heliebi, Amin
    et al.
    Hille, Claudia
    Laxman, Navya
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Svedlund, Jessica
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Haudum, Christoph
    Ercan, Erkan
    Kroneis, Thomas
    Chen, Shukun
    Smolle, Maria
    Rossmann, Christopher
    Krzywkowski, Tomasz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Ahlford, Annika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Devyser AB, Sweden.
    Darai, Evangelia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    von Amsberg, Gunhild
    Alsdorf, Winfried
    König, Frank
    Löhr, Matthias
    de Kruijff, Inge
    Riethdorf, Sabine
    Gorges, Tobias M.
    Pantel, Klaus
    Bauernhofer, Thomas
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Sedlmayr, Peter
    In Situ Detection and Quantification of AR-V7, AR-FL, PSA, and KRAS Point Mutations in Circulating Tumor Cells2018Ingår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, nr 3, s. 536-546Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Liquid biopsies can be used in castration-resistant prostate cancer (CRPC) to detect androgen receptor splice variant 7 (AR-V7), a splicing product of the androgen receptor. Patients with AR-V7-positive circulating tumor cells (CTCs) have greater benefit of taxane chemotherapy compared with novel hormonal therapies, indicating a treatment-selection biomarker. Likewise, in those with pancreatic cancer (PaCa), KRAS mutations act as prognostic biomarkers. Thus, there is an urgent need for technology investigating the expression and mutation status of CTCs. Here, we report an approach that adds AR-V7 or KRAS status to CTC enumeration, compatible with multiple CTC-isolation platforms.

    METHODS: We studied 3 independent CTC-isolation devices (CellCollector, Parsortix, CellSearch) for the evaluation of AR-V7 or KRAS status of CTCs with in situ padlock probe technology. Padlock probes allow highly specific detection and visualization of transcripts on a cellular level. We applied padlock probes for detecting AR-V7, androgen receptor full length (AR-FL), and prostate-specific antigen (PSA) in CRPC and KRAS wildtype (wt) and mutant (mut) transcripts in PaCa in CTCs from 46 patients.

    RESULTS: In situ analysis showed that 71% (22 of 31) of CRPC patients had detectable AR-V7 expression ranging from low to high expression [1-76 rolling circle products (RCPs)/CTC]. In PaCa patients, 40% (6 of 15) had KRAS mut expressing CTCs with 1 to 8 RCPs/CTC. In situ padlock probe analysis revealed CTCs with no detectable cytokeratin expression but positivity for AR-V7 or KRAS mut transcripts.

    CONCLUSIONS: Padlock probe technology enables quantification of AR-V7, AR-FL, PSA, and KRAS mut/wt transcripts in CTCs. The technology is easily applicable in routine laboratories and compatible with multiple CTC-isolation devices.

  • 114. El-Morsy, E. M.
    et al.
    Hassan, H. M.
    Ahmed, Engy
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för geologiska vetenskaper. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Biodegradative activities of fungal isolates from plastic contaminated soils2017Ingår i: Mycosphere, ISSN 2077-7000, E-ISSN 2077-7019, Vol. 8, nr 8, s. 1071-1087Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fungal strains were isolated from plastic contaminated soils in open dump sites located in different governorates in Egypt. The isolates showed various abilities in enzymes production that were related to soil origins and characteristics. For example, fungi isolated from El-Sharqia soil were able to produce protease, esterase, lipase followed by those isolated from Ismailia soil. Moreover, isolates with high esterase activity were identified as Monascus ruber, Monascus sanguineus and Monascus sp. The results showed that M. ruber could produce maximum esterase concentration followed by M. sanguineus. The same three Monascus species were selected to assess polyurethane biodegradation. Monascus sp. isolated from El-Sharqia was the most efficient isolate in degradation of polyurethane in the form of Impranil DLN. In addition, SEM micrographs and zeta potential measurements confirmed the adsorption and complex formation between the polyurethane and the hyphae of Monascus sp.

  • 115.
    Elofsson, Arne
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Joo, Keehyoung
    Keasar, Chen
    Lee, Jooyoung
    Maghrabi, Ali H. A.
    Manavalan, Balachandran
    McGuffin, Liam J.
    Menéndez Hurtado, David
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Mirabello, Claudio
    Pilstål, Robert
    Sidi, Tomer
    Uziela, Karolis
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Wallner, Björn
    Methods for estimation of model accuracy in CASP122018Ingår i: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 86, nr S1, s. 361-373Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Methods to reliably estimate the quality of 3D models of proteins are essential drivers for the wide adoption and serious acceptance of protein structure predictions by life scientists. In this article, the most successful groups in CASP12 describe their latest methods for estimates of model accuracy (EMA). We show that pure single model accuracy estimation methods have shown clear progress since CASP11; the 3 top methods (MESHI, ProQ3, SVMQA) all perform better than the top method of CASP11 (ProQ2). Although the pure single model accuracy estimation methods outperform quasi-single (ModFOLD6 variations) and consensus methods (Pcons, ModFOLDclust2, Pcomb-domain, and Wallner) in model selection, they are still not as good as those methods in absolute model quality estimation and predictions of local quality. Finally, we show that when using contact-based model quality measures (CAD, lDDT) the single model quality methods perform relatively better.

  • 116.
    Elvers, Ingegerd
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Hagenkort, Anna
    Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Johansson, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Djureinovic, Tatjana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Lagerqvist, Anne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Schultz, Niklas
    Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Stoimenov, Ivaylo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Erixon, Klaus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Helleday, Thomas
    Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    CHK1 activity is required for continuous replication fork elongation but not stabilization of post-replicative gaps after UV irradiation2012Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, nr 17, s. 8440-8448Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ultraviolet (UV)-induced DNA damage causes an efficient block of elongating replication forks. The checkpoint kinase, CHK1 has been shown to stabilize replication forks following hydroxyurea treatment. Therefore, we wanted to test if the increased UV sensitivity caused by the unspecific kinase inhibitor caffeine-inhibiting ATM and ATR amongst other kinases-is explained by inability to activate the CHK1 kinase to stabilize replicative structures. For this, we used cells deficient in polymerase eta (Pol eta), a translesion synthesis polymerase capable of properly bypassing the UV-induced cis-syn TT pyrimidine dimer, which blocks replication. These cells accumulate gaps behind progressing replication forks after UV exposure. We demonstrate that both caffeine and CHK1 inhibition, equally retards continuous replication fork elongation after UV treatment. Interestingly, we found more pronounced UV-sensitization by caffeine than with the CHK1 inhibitor in clonogenic survival experiments. Furthermore, we demonstrate an increased collapse of replicative structures after caffeine treatment, but not after CHK1 inhibition, in UV-irradiated cells. This demonstrates that CHK1 activity is not required for stabilization of gaps induced during replication of UV-damaged DNA. These data suggest that elongation and stabilization of replicative structures at UV-induced DNA damage are distinct mechanisms, and that CHK1 is only involved in replication elongation.

  • 117. Emanuelsson, Olof
    et al.
    Arvestad, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center, Sweden.
    Käll, Lukas
    Engagera och aktivera studenter med inspiration från konferenser: examination genom poster-presentation2014Ingår i: Proceedings 2014: 8:e Pedagogiska inspirationskonferensen 17 december 2014, Lund: Lund University , 2014Konferensbidrag (Refereegranskat)
    Abstract [sv]

    I en forskningsnära kurs om 7.5 hp på master-nivå inom bioinformatikämnet vid KTH består drygt halva kursen av ett projekt som genomförs i grupper om tre studenter. Varje projekt har en egen projektuppgift med inget eller marginellt överlapp med andra gruppers uppgifter. Projekten är så gott som uteslutande baserade på aktuella frågeställningar i lärarteamets egna forskningsgrupper eller deras närhet. Projektet redovisas dels genom en posterpresentation, dels med individuell webbaserad projektdagbok. Vid posterredovisningen, som omfattar tre timmar i slutet av tentamensperioden, är alla kursdeltagare med. Vi försöker i möjligaste mån efterlikna situationen där ett autentiskt forskningsresultat presenteras på en riktig konferens. Varje deltagare (student) förväntas alltså ta del av varje annan grupps poster, på samma sätt som sker vid de flesta vetenskapliga konferenser. Vi genomför en enklare kamratbedömning på posternivå, där varje student ska avge en kort och konfidentiell kommentar om var och en av övriga postrar. Kursens lärare bedömer förstås också postrarna. En av svårigheterna är att sätta individuella betyg. Här använder vi oss av individuella projektdagböcker, som ger vägledning till de olika individernas insatser inom projektet. Vi har provat detta under fyra kursomgångar med som mest sju projekt. Examinationsformen är rolig och motiverande både för studenterna och lärarna.

  • 118. Engström, Anna
    et al.
    Gómez de la Torre, Teresa Zardán
    Strømme, Maria
    Nilsson, Mats E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Herthnek, David
    Detection of Rifampicin Resistance in Mycobacterium tuberculosis by Padlock Probes and Magnetic Nanobead-Based Readout2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 4, artikel-id e62015Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Control of the global epidemic tuberculosis is severely hampered by the emergence of drug-resistant Mycobacterium tuberculosis strains. Molecular methods offer a more rapid means of characterizing resistant strains than phenotypic drug susceptibility testing. We have developed a molecular method for detection of rifampicin-resistant M. tuberculosis based on padlock probes and magnetic nanobeads. Padlock probes were designed to target the most common mutations associated with rifampicin resistance in M. tuberculosis, i.e. at codons 516, 526 and 531 in the gene rpoB. For detection of the wild type sequence at all three codons simultaneously, a padlock probe and two gap-fill oligonucleotides were used in a novel assay configuration, requiring three ligation events for circularization. The assay also includes a probe for identification of the M. tuberculosis complex. Circularized probes were amplified by rolling circle amplification. Amplification products were coupled to oligonucleotide-conjugated magnetic nanobeads and detected by measuring the frequency-dependent magnetic response of the beads using a portable AC susceptometer.

  • 119. Engström, Karin
    et al.
    Wojdacz, Tomasz K.
    Marabita, Francesco
    Ewels, Philip
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Kaller, Max
    Vezzi, Francesco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Prezza, Nicola
    Gruselius, Joel
    Vahter, Marie
    Broberg, Karin
    Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women2017Ingår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, nr 5, s. 2067-2078Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Arsenic, a carcinogen with immunotoxic effects, is a common contaminant of drinking water and certain food worldwide. We hypothesized that chronic arsenic exposure alters gene expression, potentially by altering DNA methylation of genes encoding central components of the immune system. We therefore analyzed the transcriptomes (by RNA sequencing) and methylomes (by target-enrichment next-generation sequencing) of primary CD4-positive T cells from matched groups of four women each in the Argentinean Andes, with fivefold differences in urinary arsenic concentrations (median concentrations of urinary arsenic in the lower- and high-arsenic groups: 65 and 276 mu g/l, respectively). Arsenic exposure was associated with genome-wide alterations of gene expression; principal component analysis indicated that the exposure explained 53% of the variance in gene expression among the top variable genes and 19% of 28,351 genes were differentially expressed (false discovery rate < 0.05) between the exposure groups. Key genes regulating the immune system, such as tumor necrosis factor alpha and interferon gamma, as well as genes related to the NF-kappa-beta complex, were significantly downregulated in the high-arsenic group. Arsenic exposure was associated with genome-wide DNA methylation; the high-arsenic group had 3% points higher genome-wide full methylation (> 80% methylation) than the lower-arsenic group. Differentially methylated regions that were hyper-methylated in the high-arsenic group showed enrichment for immune-related gene ontologies that constitute the basic functions of CD4-positive T cells, such as isotype switching and lymphocyte activation and differentiation. In conclusion, chronic arsenic exposure from drinking water was related to changes in the transcriptome and methylome of CD4-positive T cells, both genome wide and in specific genes, supporting the hypothesis that arsenic causes immunotoxicity by interfering with gene expression and regulation.

  • 120.
    Eriksson, Olivia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden; Swedish e-Science Research Centre (SeRC), Sweden.
    Jauhiainen, Alexandra
    Sasane, Sara Maad
    Kramer, Andrei
    Nair, Anu G.
    Sartorius, Carolina
    Hellgren Kotaleski, Jeanette
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden; Swedish e-Science Research Centre (SeRC), Sweden.
    Uncertainty quantification, propagation and characterization by Bayesian analysis combined with global sensitivity analysis applied to dynamical intracellular pathway models2019Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, nr 2, s. 284-292Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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

  • 121. Estrella Alcamán, María
    et al.
    Fernandez, Camila
    Delgado, Antonio
    Bergman, Birgitta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Diez, Beatriz
    The cyanobacterium Mastigocladus fulfills the nitrogen demand of a terrestrial hot spring microbial mat2015Ingår i: The ISME Journal, ISSN 1751-7362, E-ISSN 1751-7370, Vol. 9, nr 10, s. 2290-2303Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyanobacteria from Subsection V (Stigonematales) are important components of microbial mats in non-acidic terrestrial hot springs. Despite their diazotrophic nature (N-2 fixers), their impact on the nitrogen cycle in such extreme ecosystems remains unknown. Here, we surveyed the identity and activity of diazotrophic cyanobacteria in the neutral hot spring of Porcelana (Northern Patagonia, Chile) during 2009 and 2011-2013. We used 16S rRNA and the nifH gene to analyze the distribution and diversity of diazotrophic cyanobacteria. Our results demonstrate the dominance of the heterocystous genus Mastigocladus (Stigonematales) along the entire temperature gradient of the hot spring (69-38 degrees C). In situ nitrogenase activity (acetylene reduction), nitrogen fixation rates (cellular uptake of N-15(2)) and nifH transcription levels in the microbial mats showed that nitrogen fixation and nifH mRNA expression were light-dependent. Nitrogen fixation activities were detected at temperatures ranging from 58 degrees C to 46 degrees C, with maximum daily rates of 600 nmol C2H4 cm(-2) per day and 94.1 nmol N cm(-2) per day. These activity patterns strongly suggest a heterocystous cyanobacterial origin and reveal a correlation between nitrogenase activity and nifH gene expression during diurnal cycles in thermal microbial mats. N and C fixation in the mats contributed similar to 3 g Nm(-2) per year and 27 g Cm-2 per year, suggesting that these vital demands are fully met by the diazotrophic and photoautotrophic capacities of the cyanobacteria in the Porcelana hot spring.

  • 122. Evkaikina, Anastasiia I.
    et al.
    Berke, Lidija
    Romanova, Marina A.
    Proux-Wéra, Estelle
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish University of Agricultural Sciences, Sweden.
    Ivanova, Alexandra N.
    Rydin, Catarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Pawlowski, Katharina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och botanik.
    Voitsekhovskaja, Olga V.
    The Huperzia selago Shoot Tip Transcriptome Sheds New Light on the Evolution of Leaves2017Ingår i: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 9, nr 9, s. 2444-2460Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lycopodiophyta-consisting of three orders, Lycopodiales, Isoetales and Selaginellales, with different types of shoot apical meristems (SAMs)-form the earliest branch among the extant vascular plants. They represent a sister group to all other vascular plants, from which they differ in that their leaves are microphylls-that is, leaves with a single, unbranched vein, emerging from the protostele without a leaf gap-not megaphylls. All leaves represent determinate organs originating on the flanks of indeterminate SAMs. Thus, leaf formation requires the suppression of indeterminacy, that is, of KNOX transcription factors. In seed plants, this is mediated by different groups of transcription factors including ARP and YABBY. We generated a shoot tip transcriptome of Huperzia selago (Lycopodiales) to examine the genes involved in leaf formation. Our H. selago transcriptome does not contain any ARP homolog, although transcriptomes of Selaginella spp. do. Surprisingly, we discovered a YABBY homolog, although these transcription factors were assumed to have evolved only in seed plants. The existence of a YABBY homolog in H. selago suggests that YABBY evolved already in the common ancestor of the vascular plants, and subsequently was lost in some lineages like Selaginellales, whereas ARP may have been lost in Lycopodiales. The presence of YABBY in the common ancestor of vascular plants would also support the hypothesis that this common ancestor had a simplex SAM. Furthermore, a comparison of the expression patterns of ARP in shoot tips of Selaginella kraussiana (Harrison CJ, et al. 2005. Independent recruitment of a conserved developmental mechanism during leaf evolution. Nature 434(7032): 509-514.) and YABBY in shoot tips of H. selago implies that the development of microphylls, unlike megaphylls, does not seem to depend on the combined activities of ARP and YABBY. Altogether, our data show that Lycopodiophyta are a diverse group; so, in order to understand the role of Lycopodiophyta in evolution, representatives of Lycopodiales, Selaginellales, as well as of Isoetales, have to be examined.

  • 123.
    Ewels, Philip
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Magnusson, Måns
    Lundin, Sverker
    Käller, Max
    MultiQC: summarize analysis results for multiple tools and samples in a single report2016Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, nr 19, s. 3047-3048Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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

  • 124.
    Ewels, Philip
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Sikora, Thierry
    Serin, Virginie
    Ewels, Chris P.
    Lajaunie, Luc
    A Complete Overhaul of the Electron Energy-Loss Spectroscopy and X-Ray Absorption Spectroscopy Database: eelsdb.eu2016Ingår i: Microscopy and Microanalysis, ISSN 1431-9276, E-ISSN 1435-8115, Vol. 22, nr 3, s. 717-724Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The electron energy-loss spectroscopy (EELS) and X-ray absorption spectroscopy (XAS) database has been completely rewritten, with an improved design, user interface, and a number of new tools. The database is accessible at https://eelsdb.eu/ and can now be used without registration. The submission process has been streamlined to encourage spectrum submissions and the new design gives greater emphasis on contributors' original work by highlighting their papers. With numerous new filters and a powerful search function, it is now simple to explore the database of several hundred EELS and XAS spectra. Interactive plots allow spectra to be overlaid, facilitating online comparison. An application-programming interface has been created, allowing external tools and software to easily access the information held within the database. In addition to the database itself, users can post and manage job adverts and read the latest news and events regarding the EELS and XAS communities. In accordance with the ongoing drive toward open access data increasingly demanded by funding bodies, the database will facilitate open access data sharing of EELS and XAS spectra.

  • 125.
    Farias-Rico, Jose Arcadio
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ruud Selin, Frida
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Myronidi, Ioanna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Fruehauf, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    von Heijne, Gunnar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Effects of protein size, thermodynamic stability, and net charge on cotranslational folding on the ribosome2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 40, s. e9280-E9287Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During the last five decades, studies of protein folding in dilute buffer solutions have produced a rich picture of this complex process. In the cell, however, proteins can start to fold while still attached to the ribosome (cotranslational folding) and it is not yet clear how the ribosome affects the folding of protein domains of different sizes, thermodynamic stabilities, and net charges. Here, by using arrest peptides as force sensors and on-ribosome pulse proteolysis, we provide a comprehensive picture of how the distance from the peptidyl transferase center in the ribosome at which proteins fold correlates with protein size. Moreover, an analysis of a large collection of mutants of the Escherichia coli ribosomal protein 56 shows that the force exerted on the nascent chain by protein folding varies linearly with the thermodynamic stability of the folded state, and that the ribosome environment disfavors folding of domains of high net-negative charge.

  • 126.
    Farías-Rico, José Arcadio
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Goetz, Sara Kathrin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Marino, Jacopo
    von Heijne, Gunnar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Mutational analysis of protein folding inside the ribosome exit tunnel2017Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 591, nr 1, s. 155-163Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent work has demonstrated that cotranslational folding of proteins or protein domains in, or in the immediate vicinity of, the ribosome exit tunnel generates a pulling force on the nascent polypeptide chain that can be detected using a so-called translational arrest peptide (AP) engineered into the nascent chain as a force sensor. Here, we show that AP-based force measurements combined with systematic Ala and Trp scans of a zinc-finger domain that folds in the exit tunnel can be used to identify the residues that are critical for intraribosomal folding. Our results suggest a general approach to characterize the folded state(s) that may form as a protein domain moves progressively down the ribosome exit tunnel.

  • 127. Fasterius, Erik
    et al.
    Raso, Cinzia
    Kennedy, Susan
    Rauch, Nora
    Lundin, Pär
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Kolch, Walter
    Uhlen, Mathias
    Al-Khalili Szigyarto, Cristina
    A novel RNA sequencing data analysis method for cell line authentication2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 2, artikel-id e0171435Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have developed a novel analysis method that can interrogate the authenticity of biological samples used for generation of transcriptome profiles in public data repositories. The method uses RNA sequencing information to reveal mutations in expressed transcripts and subsequently confirms the identity of analysed cells by comparison with publicly available cell-specific mutational profiles. Cell lines constitute key model systems widely used within cancer research, but their identity needs to be confirmed in order to minimise the influence of cell contaminations and genetic drift on the analysis. Using both public and novel data, we demonstrate the use of RNA-sequencing data analysis for cell line authentication by examining the validity of COLO205, DLD1, HCT15, HCT116, HKE3, HT29 and RKO colorectal cancer cell lines. We successfully authenticate the studied cell lines and validate previous reports indicating that DLD1 and HCT15 are synonymous. We also show that the analysed HKE3 cells harbour an unexpected KRAS-G13D mutation and confirm that this cell line is a genuine KRAS dosage mutant, rather than a true isogenic derivative of HCT116 expressing only the wild type KRAS. This authentication method could be used to revisit the numerous cell line based RNA sequencing experiments available in public data repositories, analyse new experiments where whole genome sequencing is not available, as well as facilitate comparisons of data from different experiments, platforms and laboratories.

  • 128.
    Felletti, Michele
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Omnus, Deike J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Regulation of the replication initiator DnaA in Caulobacter crescentus2019Ingår i: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, ISSN 1874-9399, E-ISSN 1876-4320, Vol. 1862, nr 7, s. 697-705Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The decision to initiate DNA replication is a critical step in the cell cycle of all organisms. In nearly all bacteria, replication initiation requires the activity of the conserved replication initiation protein DnaA. Due to its central role in cell cycle progression, DnaA activity must be precisely regulated. This review summarizes the current state of DnaA regulation in the asymmetrically dividing alpha-proteobacterium Caulobacter crescentus, an important model for bacterial cell cycle studies. Mechanisms will be discussed that regulate DnaA activity and abundance under optimal conditions and in coordination with the asymmetric Caulobacter cell cycle. Furthermore, we highlight recent findings of how regulated DnaA synthesis and degradation collaborate to adjust DnaA abundance under stress conditions. The mechanisms described provide important examples of how DNA replication is regulated in an a-proteobacterium and thus represent an important starting point for the study of DNA replication in many other bacteria. This article is part of a Special Issue entitled: Dynamic gene expression, edited by Prof. Patrick Viollier.

  • 129. Ferreira, Pedro G.
    et al.
    Oti, Martin
    Barann, Matthias
    Wieland, Thomas
    Ezquina, Suzana
    Friedländer, Marc R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Rivas, Manuel A.
    Esteve-Codina, Anna
    Rosenstiel, Philip
    Strom, Tim M.
    Lappalainen, Tuuli
    Guigo, Roderic
    Sammeth, Michael
    Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 32406Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent advances in the cost-efficiency of sequencing technologies enabled the combined DNA-and RNA-sequencing of human individuals at the population-scale, making genome-wide investigations of the inter-individual genetic impact on gene expression viable. Employing mRNA-sequencing data from the Geuvadis Project and genome sequencing data from the 1000 Genomes Project we show that the computational analysis of DNA sequences around splice sites and poly-A signals is able to explain several observations in the phenotype data. In contrast to widespread assessments of statistically significant associations between DNA polymorphisms and quantitative traits, we developed a computational tool to pinpoint the molecular mechanisms by which genetic markers drive variation in RNA-processing, cataloguing and classifying alleles that change the affinity of core RNA elements to their recognizing factors. The in silico models we employ further suggest RNA editing can moonlight as a splicing-modulator, albeit less frequently than genomic sequence diversity. Beyond existing annotations, we demonstrate that the ultra-high resolution of RNA-Seq combined from 462 individuals also provides evidence for thousands of bona fide novel elements of RNA processing-alternative splice sites, introns, and cleavage sites-which are often rare and lowly expressed but in other characteristics similar to their annotated counterparts.

  • 130. Finn, Robert D.
    et al.
    Bateman, Alex
    Clements, Jody
    Coggill, Penelope
    Eberhardt, Ruth Y.
    Eddy, Sean R.
    Heger, Andreas
    Hetherington, Kirstie
    Holm, Liisa
    Mistry, Jaina
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Tate, John
    Punta, Marco
    Pfam: the protein families database2014Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, nr D1, s. d222-D230Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pfam, available via servers in the UK (http://pfam.sanger.ac.uk/) and the USA (http://pfam.janelia.org/), is a widely used database of protein families, containing 14 831 manually curated entries in the current release, version 27.0. Since the last update article 2 years ago, we have generated 1182 new families and maintained sequence coverage of the UniProt Knowledgebase (UniProtKB) at nearly 80%, despite a 50% increase in the size of the underlying sequence database. Since our 2012 article describing Pfam, we have also undertaken a comprehensive review of the features that are provided by Pfam over and above the basic family data. For each feature, we determined the relevance, computational burden, usage statistics and the functionality of the feature in a website context. As a consequence of this review, we have removed some features, enhanced others and developed new ones to meet the changing demands of computational biology. Here, we describe the changes to Pfam content. Notably, we now provide family alignments based on four different representative proteome sequence data sets and a new interactive DNA search interface. We also discuss the mapping between Pfam and known 3D structures.

  • 131.
    Fluman, Nir
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Tobiasson, Victor
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    von Heijne, Gunnar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Stable membrane orientations of small dual-topology membrane proteins2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 30, s. 7987-7992Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The topologies of alpha-helical membrane proteins are generally thought to be determined during their cotranslational insertion into the membrane. It is typically assumed that membrane topologies remain static after this process has ended. Recent findings, however, question this static view by suggesting that some parts of, or even the whole protein, can reorient in the membrane on a biologically relevant time scale. Here, we focus on antiparallel homo- or heterodimeric small multidrug resistance proteins and examine whether the individual monomers can undergo reversible topological inversion (flip flop) in the membrane until they are trapped in a fixed orientation by dimerization. By perturbing dimerization using various means, we show that the membrane orientation of a monomer is unaffected by the presence or absence of its dimerization partner. Thus, membrane-inserted monomers attain their final orientations independently of dimerization, suggesting that wholesale topological inversion is an unlikely event in vivo.

  • 132.
    Forsberg, Björn O.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Aibara, Shintaro
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Kimanius, Dari
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Paul, Bijoya
    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).
    Amunts, Alexey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Cryo-EM reconstruction of the chlororibosome to 3.2 angstrom resolution within 24 h2017Ingår i: IUCrJ, ISSN 0972-6918, E-ISSN 2052-2525, Vol. 4, s. 723-727Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The introduction of direct detectors and the automation of data collection in cryo-EM have led to a surge in data, creating new opportunities for advancing computational processing. In particular, on-the-fly workflows that connect data collection with three-dimensional reconstruction would be valuable for more efficient use of cryo-EM and its application as a sample-screening tool. Here, accelerated on-the-fly analysis is reported with optimized organization of the data-processing tools, image acquisition and particle alignment that make it possible to reconstruct the three-dimensional density of the 70S chlororibosome to 3.2 angstrom resolution within 24 h of tissue harvesting. It is also shown that it is possible to achieve even faster processing at comparable quality by imposing some limits to data use, as illustrated by a 3.7 angstrom resolution map that was obtained in only 80 min on a desktop computer. These on-the-fly methods can be employed as an assessment of data quality from small samples and extended to high-throughput approaches.

  • 133. Forslund, Kristoffer
    et al.
    Pereira, Cecile
    Capella-Gutierrez, Salvador
    Sousa da Silva, Alan
    Altenhoff, Adrian
    Huerta-Cepas, Jaime
    Muffato, Matthieu
    Patricio, Mateus
    Vandepoele, Klaas
    Ebersberger, Ingo
    Blake, Judith
    Fernandez Breis, Jesualdo Tomas
    Boeckmann, Brigitte
    Gabaldon, Toni
    Sonnhammer, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Dessimoz, Christophe
    Lewis, Suzanna
    Gearing up to handle the mosaic nature of life in the quest for orthologs2018Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 34, nr 2, s. 323-329Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Quest for Orthologs (QfO) is an open collaboration framework for experts in comparative phylogenomics and related research areas who have an interest in highly accurate orthology predictions and their applications. We here report highlights and discussion points from the QfO meeting 2015 held in Barcelona. Achievements in recent years have established a basis to support developments for improved orthology prediction and to explore new approaches. Central to the QfO effort is proper benchmarking of methods and services, as well as design of standardized datasets and standardized formats to allow sharing and comparison of results. Simultaneously, analysis pipelines have been improved, evaluated and adapted to handle large datasets. All this would not have occurred without the long-term collaboration of Consortium members. Meeting regularly to review and coordinate complementary activities from a broad spectrum of innovative researchers clearly benefits the community. Highlights of the meeting include addressing sources of and legitimacy of disagreements between orthology calls, the context dependency of orthology definitions, special challenges encountered when analyzing very anciently rooted orthologies, orthology in the light of whole-genome duplications, and the concept of orthologous versus paralogous relationships at different levels, including domain-level orthology. Furthermore, particular needs for different applications (e.g. plant genomics, ancient gene families and others) and the infrastructure for making orthology inferences available (e.g. interfaces with model organism databases) were discussed, with several ongoing efforts that are expected to be reported on during the upcoming 2017 QfO meeting.

  • 134. Fourati, Zaineb
    et al.
    Howard, Rebecca J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Heusser, Stephanie A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Hu, Haidai
    Ruza, Reinis R.
    Sauguet, Ludovic
    Lindahl, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Delarue, Marc
    Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels2018Ingår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 23, nr 4, s. 993-1004Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking[1] . The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore, or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

  • 135. Franco, Irene
    et al.
    Johansson, Anna
    Olsson, Karl
    Vrtačnik, Peter
    Lundin, Pär
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Helgadottir, Hafdis T.
    Larsson, Malin
    Revêchon, Gwladys
    Bosia, Carla
    Pagnani, Andrea
    Provero, Paolo
    Gustafsson, Thomas
    Fischer, Helene
    Eriksson, Maria
    Somatic mutagenesis in satellite cells associates with human skeletal muscle aging2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 800Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

  • 136.
    Friedrich, Stefanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Fusion transcript detection using spatial transcriptomicsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Fusion transcripts are involved in tumourigenesis and play a crucial role in tumour heterogeneity, tumour evolution and cancer treatment resistance. However, fusion transcripts have not been studied at high spatial resolution in tissue sections due to the lack of full-length transcripts with spatial information. New high-throughput technologies like spatial transcriptomics measure the transcriptome of tissue sections on almost single-cell level. While this technique does not allow for direct detection of fusion transcripts, we show that they can be inferred using the relative poly(A) tail abundance of the involved parental genes.

    We present a new method STfusion, which uses spatial transcriptomics to infer the presence and absence of poly(A) tails. A fusion transcript lacks a poly(A) tail for the 5´ gene and has an elevated number of poly(A) tails for the 3´ gene. Its expression level is defined by the upstream promoter of the 5´ gene. STfusion measures the difference between the observed and expected number of poly(A) tails with a novel C-score. 

    We verified the STfusion ability to predict fusion transcripts on HeLa cells with known fusions. STfusion and C-sore applied to clinical prostate cancer data revealed the spatial distribution of the cis-SAGe SLC45A3-ELK4 in 12 tissue sections with almost single-cell resolution. The cis-SAGe occured in the centre or periphery of inflamed, prostatic intraepithelial neoplastic, or cancerous areas, and occasionally in normal glands.

  • 137.
    Friedrich, Stefanie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Barbulescu, Remus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Helleday, Thomas
    Sonnhammer, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    MetaCNV - a consensus approach to infer accurate copy numbers from low coverage dataManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: The majority of copy number callers requires high read coverage data that is often achieved with elevated material input, which increases the heterogeneity of tissue samples. However, to gain insights into smaller areas within a tissue sample, e.g a cancerous area in a heterogeneous tissue sample, less material is used for sequencing, which results in lower read coverage. Therefore, more focus needs to be put on copy number calling that is sensitive enough for low coverage data. 

    Results: We present MetaCNV, a copy number caller that infers reliable copy numbers for human genomes with a consensus approach. MetaCNV specializes in low coverage data, but also performs well on normal and high coverage data. MetaCNV integrates the results of multiple copy number callers and infers absolute and unbiased copy numbers for the entire genome. MetaCNV is based on a meta-model that bypasses the weaknesses of current calling models while combining the strengths of existing approaches. Here we apply MetaCNV based on ReadDepth, SVDetect, and CNVnator to real and simulated datasets in order to demonstrate how the approach improves copy number calling. 

    Conclusions: MetaCNV, available at https://bitbucket.org/sonnhammergroup/metacnv, provides accurate copy number prediction on low coverage data and performs well on high coverage data.

  • 138.
    Frings, Oliver
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Alexeyenko, Andrey
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    MGclus: network clustering employing shared neighbors2013Ingår i: Molecular BioSystems, ISSN 1742-206X, Vol. 9, nr 7, s. 1670-1675Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Network analysis is an important tool for functional annotation of genes and proteins. A common approach to discern structure in a global network is to infer network clusters, or modules, and assume a functional coherence within each module, which may represent a complex or a pathway. It is however not trivial to define optimal modules. Although many methods have been proposed, it is unclear which methods perform best in general. It seems that most methods produce far from optimal results but in different ways. MGclus is a new algorithm designed to detect modules with a strongly interconnected neighborhood in large scale biological interaction networks. In our benchmarks we found MGclus to outperform other methods when applied to random graphs with varying degree of noise, and to perform equally or better when applied to biological protein interaction networks. MGclus is implemented in Java and utilizes the JGraphT graph library. It has an easy to use command-line interface and is available for download from http://sonnhammer.sbc.su.se/download/software/MGclus/.

  • 139.
    Frings, Oliver
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Augsten, Martin
    Tobin, Nicholas P.
    Carlson, Joseph
    Paulsson, Janna
    Pena, Cristina
    Olsson, Eleonor
    Veerla, Srinivas
    Bergh, Jonas
    Östman, Arne
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Swedish Escience Research Center, Sweden.
    Prognostic Significance in Breast Cancer of a Gene Signature Capturing Stromal PDGF Signaling2013Ingår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 182, nr 6, s. 2037-2047Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, we describe a novel gene expression signature of platelet-derived growth factor (PDGF) activated fibroblasts, which is able to identify breast cancers with a PDGF-stimulated fibroblast stroma and displays an independent and strong prognostic significance. Global gene expression was compared between PDGF-stimulated human fibroblasts and cultured resting fibroblasts. The most differentially expressed genes were reduced to a gene expression signature of 113 genes. The biological significance and prognostic capacity of this signature were investigated using four independent clinical breast cancer data sets. Concomitant high expression of PDGF beta receptor and its cognate Ligands is associated with a high PDGF signature score. This supports the notion that the signature detects tumors with PDGF-activated stroma. Subsequent analyses indicated significant associations between high PDGF signature score and clinical characteristics, including human epidermal growth factor receptor 2 positivity, estrogen receptor negativity, high tumor grade, and large tumor size. A high PDGF signature score is associated with shorter survival in univariate analysis. Furthermore, the high PDGF signature score acts as a significant marker of poor prognosis in multivariate survival analyses, including classic prognostic markers, Ki-67 status, a proliferation gene signature, or other recently described stroma-derived gene expression signatures.

  • 140.
    Frings, Oliver
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Augsten, Martin
    Tobin, Nicholas P.
    Carlson, Joseph
    Paulsson, Janna
    Pena, Cristina
    Olsson, Eleonor
    Veerla, Sunny
    Bergh, Jonas
    Östman, Arne
    Sonnhammer, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Prognostic significance in breast cancer of a gene signature capturing stromal PDGF signalingIngår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191Artikel i tidskrift (Refereegranskat)
  • 141.
    Frings, Oliver
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Mank, Judith E.
    Alexeyenko, Andrey
    Sonnhammer, Erik L. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Network Analysis of Functional Genomics Data: Application to Avian Sex-Biased Gene Expression2012Ingår i: Scientific World Journal, ISSN 1537-744X, E-ISSN 1537-744X, s. 130491-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gene expression analysis is often used to investigate the molecular and functional underpinnings of a phenotype. However, differential expression of individual genes is limited in that it does not consider how the genes interact with each other in networks. To address this shortcoming we propose a number of network-based analyses that give additional functional insights into the studied process. These were applied to a dataset of sex-specific gene expression in the chicken gonad and brain at different developmental stages. We first constructed a global chicken interaction network. Combining the network with the expression data showed that most sex-biased genes tend to have lower network connectivity, that is, act within local network environments, although some interesting exceptions were found. Genes of the same sex bias were generally more strongly connected with each other than expected. We further studied the fates of duplicated sex-biased genes and found that there is a significant trend to keep the same pattern of sex bias after duplication. We also identified sex-biased modules in the network, which reveal pathways or complexes involved in sex-specific processes. Altogether, this work integrates evolutionary genomics with systems biology in a novel way, offering new insights into the modular nature of sex-biased genes.

  • 142.
    Frånberg, Mattias
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Gertow, Karl
    Hamsten, Anders
    Lagergren, Jens
    Sennblad, Bengt
    Discovering Genetic Interactions in Large-Scale Association Studies by Stage-wise Likelihood Ratio Tests2015Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 9, artikel-id e1005502Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite the success of genome-wide association studies in medical genetics, the underlying genetics of many complex diseases remains enigmatic. One plausible reason for this could be the failure to account for the presence of genetic interactions in current analyses. Exhaustive investigations of interactions are typically infeasible because the vast number of possible interactions impose hard statistical and computational challenges. There is, therefore, a need for computationally efficient methods that build on models appropriately capturing interaction. We introduce a new methodology where we augment the interaction hypothesis with a set of simpler hypotheses that are tested, in order of their complexity, against a saturated alternative hypothesis representing interaction. This sequential testing provides an efficient way to reduce the number of non-interacting variant pairs before the final interaction test. We devise two different methods, one that relies on a priori estimated numbers of marginally associated variants to correct for multiple tests, and a second that does this adaptively. We show that our methodology in general has an improved statistical power in comparison to seven other methods, and, using the idea of closed testing, that it controls the family-wise error rate. We apply our methodology to genetic data from the PRO-CARDIS coronary artery disease case/control cohort and discover three distinct interactions. While analyses on simulated data suggest that the statistical power may suffice for an exhaustive search of all variant pairs in ideal cases, we explore strategies for a priori selecting subsets of variant pairs to test. Our new methodology facilitates identification of new disease-relevant interactions from existing and future genome-wide association data, which may involve genes with previously unknown association to the disease. Moreover, it enables construction of interaction networks that provide a systems biology view of complex diseases, serving as a basis for more comprehensive understanding of disease pathophysiology and its clinical consequences.

  • 143.
    Frånberg, Mattias
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Strawbridge, Rona J.
    Hamster, Anders
    de Faire, Ulf
    Lagergren, Jens
    Sennblad, Bengt
    Fast and general tests of genetic interaction for genome-wide association studies2017Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, nr 6, artikel-id e1005556Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A complex disease has, by definition, multiple genetic causes. In theory, these causes could be identified individually, but their identification will likely benefit from informed use of anticipated interactions between causes. In addition, characterizing and understanding interactions must be considered key to revealing the etiology of any complex disease. Large-scale collaborative efforts are now paving the way for comprehensive studies of interaction. As a consequence, there is a need for methods with a computational efficiency sufficient for modern data sets as well as for improvements of statistical accuracy and power. Another issue is that, currently, the relation between different methods for interaction inference is in many cases not transparent, complicating the comparison and interpretation of results between different interaction studies. In this paper we present computationally efficient tests of interaction for the complete family of generalized linear models (GLMs). The tests can be applied for inference of single or multiple interaction parameters, but we show, by simulation, that jointly testing the full set of interaction parameters yields superior power and control of false positive rate. Based on these tests we also describe how to combine results from multiple independent studies of interaction in a meta-analysis. We investigate the impact of several assumptions commonly made when modeling interactions. We also show that, across the important class of models with a full set of interaction parameters, jointly testing the interaction parameters yields identical results. Further, we apply our method to genetic data for cardiovascular disease. This allowed us to identify a putative interaction involved in Lp(a) plasma levels between two 'tag' variants in the LPA locus (p = 2.42 . 10(-09)) as well as replicate the interaction (p = 6.97 . 10(-07)). Finally, our meta-analysis method is used in a small (N = 16,181) study of interactions in myocardial infarction.

  • 144. Gad, Helge
    et al.
    Svensson, Linda M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Saleh, Aljona
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Berntsson, Ronnie P.-A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gustafsson, Robert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Johansson, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Djureinovic, Tatjana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Häggblad, Maria
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Martens, Ulf
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lundgren, Bo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Granelli, Ingrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Stenmark, Pål
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Helleday, Thomas
    MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool2014Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, nr 7495, s. 215-221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

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

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

  • 146. Gaulton, Kyle J.
    et al.
    Ferreira, Teresa
    Lee, Yeji
    Raimondo, Anne
    Maegi, Reedik
    Reschen, Michael E.
    Mahajan, Anubha
    Locke, Adam
    Rayner, N. William
    Robertson, Neil
    Scott, Robert A.
    Prokopenko, Inga
    Scott, Laura J.
    Green, Todd
    Sparso, Thomas
    Thuillier, Dorothee
    Yengo, Loic
    Grallert, Harald
    Wahl, Simone
    Frånberg, Mattias
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Strawbridge, Rona J.
    Kestler, Hans
    Chheda, Himanshu
    Eisele, Lewin
    Gustafsson, Stefan
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Qi, Lu
    Karssen, Lennart C.
    van Leeuwen, Elisabeth M.
    Willems, Sara M.
    Li, Man
    Chen, Han
    Fuchsberger, Christian
    Kwan, Phoenix
    Ma, Clement
    Linderman, Michael
    Lu, Yingchang
    Thomsen, Soren K.
    Rundle, Jana K.
    Beer, Nicola L.
    van de Bunt, Martijn
    Chalisey, Anil
    Kang, Hyun Min
    Voight, Benjamin F.
    Abecasis, Goncalo R.
    Almgren, Peter
    Baldassarre, Damiano
    Balkau, Beverley
    Benediktsson, Rafn
    Blueher, Matthias
    Boeing, Heiner
    Bonnycastle, Lori L.
    Bottinger, Erwin P.
    Burtt, Noel P.
    Carey, Jason
    Charpentier, Guillaume
    Chines, Peter S.
    Cornelis, Marilyn C.
    Couper, David J.
    Crenshaw, Andrew T.
    van Dam, Rob M.
    Doney, Alex S. F.
    Dorkhan, Mozhgan
    Edkins, Sarah
    Eriksson, Johan G.
    Esko, Tonu
    Eury, Elodie
    Fadista, Joao
    Flannick, Jason
    Fontanillas, Pierre
    Fox, Caroline
    Franks, Paul W.
    Gertow, Karl
    Gieger, Christian
    Gigante, Bruna
    Gottesman, Omri
    Grant, George B.
    Grarup, Niels
    Groves, Christopher J.
    Hassinen, Maija
    Have, Christian T.
    Herder, Christian
    Holmen, Oddgeir L.
    Hreidarsson, Astradur B.
    Humphries, Steve E.
    Hunter, David J.
    Jackson, Anne U.
    Jonsson, Anna
    Jorgensen, Marit E.
    Jorgensen, Torben
    Kao, Wen-Hong L.
    Kerrison, Nicola D.
    Kinnunen, Leena
    Klopp, Norman
    Kong, Augustine
    Kovacs, Peter
    Kraft, Peter
    Kravic, Jasmina
    Langford, Cordelia
    Leander, Karin
    Liang, Liming
    Lichtner, Peter
    Lindgren, Cecilia M.
    Lindholm, Eero
    Linneberg, Allan
    Liu, Ching-Ti
    Lobbens, Stephane
    Luan, Jian'an
    Lyssenko, Valeriya
    Mannisto, Satu
    McLeod, Olga
    Meyer, Julia
    Mihailov, Evelin
    Mirza, Ghazala
    Muehleisen, Thomas W.
    Mueller-Nurasyid, Martina
    Navarro, Carmen
    Noethen, Markus M.
    Oskolkov, Nikolay N.
    Owen, Katharine R.
    Palli, Domenico
    Pechlivanis, Sonali
    Peltonen, Leena
    Perry, John R. B.
    Platou, Carl G. P.
    Roden, Michael
    Ruderfer, Douglas
    Rybin, Denis
    van der Schouw, Yvonne T.
    Sennblad, Bengt
    Sigurdsson, Gunnar
    Stancakova, Alena
    Steinbach, Gerald
    Storm, Petter
    Strauch, Konstantin
    Stringham, Heather M.
    Sun, Qi
    Thorand, Barbara
    Tikkanen, Emmi
    Tonjes, Anke
    Trakalo, Joseph
    Tremoli, Elena
    Tuomi, Tiinamaija
    Wennauer, Roman
    Wiltshire, Steven
    Wood, Andrew R.
    Zeggini, Eleftheria
    Dunham, Ian
    Birney, Ewan
    Pasquali, Lorenzo
    Ferrer, Jorge
    Loos, Ruth J. F.
    Dupuis, Josee
    Florez, Jose C.
    Boerwinkle, Eric
    Pankow, James S.
    van Duijn, Cornelia
    Sijbrands, Eric
    Meigs, James B.
    Hu, Frank B.
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Lakka, Timo A.
    Rauramaa, Rainer
    Stumvoll, Michael
    Pedersen, Nancy L.
    Lind, Lars
    Keinanen-Kiukaanniemi, Sirkka M.
    Korpi-Hyovalti, Eeva
    Saaristo, Timo E.
    Saltevo, Juha
    Kuusisto, Johanna
    Laakso, Markku
    Metspalu, Andres
    Erbel, Raimund
    Joecke, Karl-Heinz
    Moebus, Susanne
    Ripatti, Samuli
    Salomaa, Veikko
    Ingelsson, Erik
    Boehm, Bernhard O.
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Koistinen, Heikki
    Tuomilehto, Jaakko
    Hveem, Kristian
    Njolstad, Inger
    Deloukas, Panagiotis
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    de Faire, Ulf
    Hamsten, Anders
    Illig, Thomas
    Peters, Annette
    Cauchi, Stephane
    Sladek, Rob
    Froguel, Philippe
    Hansen, Torben
    Pedersen, Oluf
    Morris, Andrew D.
    Palmer, Collin N. A.
    Kathiresan, Sekar
    Melander, Olle
    Nilsson, Peter M.
    Groop, Leif C.
    Barroso, Ines
    Langenberg, Claudia
    Wareham, Nicholas J.
    O'Callaghan, Christopher A.
    Gloyn, Anna L.
    Altshuler, David
    Boehnke, Michael
    Teslovich, Tanya M.
    McCarthy, Mark I.
    Morris, Andrew P.
    Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci2015Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, nr 12, s. 1415-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

  • 147. Geny, Sylvain
    et al.
    Moreno, Pedro M. D.
    Krzywkowski, Tomasz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Gissberg, Olof
    Andersen, Nicolai K.
    Isse, Abdirisaq J.
    El-Madani, Amro M.
    Lou, Chenguang
    Pabon, Y. Vladimir
    Anderson, Brooke A.
    Zaghloul, Eman M.
    Zain, Rula
    Hrdlicka, Patrick J.
    Jørgensen, Per T.
    Nilsson, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lundin, Karin E.
    Pedersen, Erik B.
    Wengel, Jesper
    Smith, C. I. Edvard
    Next-generation bis-locked nucleic acids with stacking linker and 2 '-glycylamino-LNA show enhanced DNA invasion into supercoiled duplexes2016Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, nr 5, s. 2007-2019Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Targeting and invading double-stranded DNA with synthetic oligonucleotides under physiological conditions remain a challenge. Bis-locked nucleic acids (bisLNAs) are clamp-forming oligonucleotides able to invade into supercoiled DNA via combined Hoogsteen and Watson-Crick binding. To improve the bisLNA design, we investigated its mechanism of binding. Our results suggest that bisLNAs bind via Hoogsteen-arm first, followed by Watson-Crick arm invasion, initiated at the tail. Based on this proposed hybridization mechanism, we designed next-generation bisLNAs with a novel linker able to stack to adjacent nucleobases, a new strategy previously not applied for any type of clamp-constructs. Although the Hoogsteen-arm limits the invasion, upon incorporation of the stacking linker, bisLNA invasion is significantly more efficient than for non-clamp, or nucleotide-linker containing LNA-constructs. Further improvements were obtained by substituting LNA with 2'-glycylamino-LNA, contributing a positive charge. For regular bisLNAs a 14-nt tail significantly enhances invasion. However, when two stacking linkers were incorporated, tail-less bisLNAs were able to efficiently invade. Finally, successful targeting of plasmids inside bacteria clearly demonstrates that strand invasion can take place in a biologically relevant context.

  • 148. Gertow, Joanna
    et al.
    Ng, Chang Zhi
    Branca, Rui Miguel Mamede
    Werngren, Olivera
    Du, Lei
    Kjellqvist, Sanela
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Hemmingsson, Peter
    Bruchfeld, Annette
    MacLaughlin, Helen
    Eriksson, Per
    Axelsson, Jonas
    Fisher, Rachel M.
    Altered Protein Composition of Subcutaneous Adipose Tissue in Chronic Kidney Disease2017Ingår i: Kidney International Reports, ISSN 2468-0249, Vol. 2, nr 6, s. 1208-1218Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Loss of renal function is associated with high mortality from cardiovascular disease (CVD). Patients with chronic kidney disease (CKD) have altered circulating adipokine and nonesterified fatty acid concentrations and insulin resistance, which are features of disturbed adipose tissue metabolism. Because dysfunctional adipose tissue contributes to the development of CVD, we hypothesize that adipose tissue dysfunctionality in patients with CKD could explain, at least in part, their high rates of CVD. Therefore we characterized adipose tissue from patients with CKD, in comparison to healthy controls, to search for signs of dysfunctionality. Methods: Biopsy samples of subcutaneous adipose tissue from 16 CKD patients and 11 healthy controls were analyzed for inflammation, fibrosis, and adipocyte size. Protein composition was assessed using 2dimensional gel proteomics combined with multivariate analysis. Results: Adipose tissue of CKD patients contained significantly more CD68-positive cells, but collagen content did not differ. Adipocyte size was significantly smaller in CKD patients. Proteomic analysis of adipose tissue revealed significant differences in the expression of certain proteins between the groups. Proteins whose expression differed the most were a-1-microglobulin/ bikunin precursor (AMBP, higher in CKD) and vimentin (lower in CKD). Vimentin is a lipid droplet-associated protein, and changes in its expression may impair fatty acid storage/mobilization in adipose tissue, whereas high levels of AMBP may reflect oxidative stress. Discussion: These findings demonstrate that adipose tissue of CKD patients shows signs of inflammation and disturbed functionality, thus potentially contributing to the unfavorable metabolic profile and increased risk of CVD in these patients.

  • 149. Gharpure, Anant
    et al.
    Teng, Jinfeng
    Zhuang, Yuxuan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Noviello, Colleen M.
    Walsh, Richard M.
    Cabuco, Rico
    Howard, Rebecca J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Zaveri, Nurulain T.
    Lindahl, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Hibbs, Ryan E.
    Agonist Selectivity and Ion Permeation in the alpha 3 beta 4 Ganglionic Nicotinic Receptor2019Ingår i: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 104, nr 3, s. 501-511Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The alpha 3 beta 4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the alpha 3 beta 4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the alpha 3 beta 4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.

  • 150.
    Giacomello, Stefania
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Lundeberg, Joakim
    Preparation of plant tissue to enable Spatial Transcriptomics profiling using barcoded microarrays2018Ingår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 13, nr 11, s. 2425-2446Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Elucidation of the complex processes involved in plant growth requires analysis of the spatial gene expression patterns in all affected tissues. This protocol extension is an adaptation of a protocol that describes how to use barcoded oligo-dT microarrays to evaluate spatial global gene expression profiles in mammalian tissue to enable it to be applied to plant material. Here, we explain the required adjustments for preparing and treating plant tissue sections on the array surface, specifically in regard to how to permeabilize and remove the tissue. Once the tissue has been removed, the cDNA-mRNA hybrid that is left on the slide is processed in the same way as cDNA obtained during experiments on mammalian tissue; thus the later stages of the protocol are not included here, and readers should follow the accompanying protocol for those. We have previously used our protocol to generate high-quality sequencing libraries for Arabidopsis thaliana inflorescence, Populus tremula developing and dormant leaf buds, and Picea abies female cones. However, we anticipate that the protocol can be adapted to other tissue types and species. The entire protocol for preparing samples and processing libraries can be completed in 3-4 d.

1234567 101 - 150 av 548
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf