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  • 301. Gossen, Jonas
    et al.
    Albani, Simone
    Hanke, Anton
    Joseph, Benjamin P.
    Bergh, Cathrine
    Kuzikov, Maria
    Costanzi, Elisa
    Manelfi, Candida
    Storici, Paola
    Gribbon, Philip
    Beccari, Andrea R.
    Talarico, Carmine
    Spyrakis, Francesca
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Zaliani, Andrea
    Carloni, Paolo
    Wade, Rebecca C.
    Musiani, Francesco
    Kokh, Daria B.
    Rossetti, Giulia
    A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics2021In: Acs pharmacology and translational science, ISSN 2575-9108, Vol. 4, no 3, p. 1079-1095Article in journal (Refereed)
    Abstract [en]

    The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of similar to 30 000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing similar to 200 virtual screenings of compound libraries on selected protein structures, we redefine the protein's druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites.

  • 302.
    Gowda, Naveen Kumar Chandappa
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Masser, Anna E.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kang, Wenjing
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Friedländer, Marc R.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cytosolic splice isoform of Hsp70 nucleotide exchange factor Fes1 is required for the degradation of misfolded proteins in yeast2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27, no 8, p. 1210-1219Article in journal (Refereed)
    Abstract [en]

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

  • 303. Grahn, Oskar
    et al.
    Holmgren, Klas
    Hong, Mun-Gwan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sund, Malin
    Rutegard, Martin
    Mutation of the cyclooxygenase 2 gene promoter and anastomotic leakage in colorectal cancer patients: retrospective cohort study2024In: BJS Open, E-ISSN 2474-9842, Vol. 8, no 1, article id zrae004Article in journal (Refereed)
    Abstract [en]

    Anastomotic leakage after surgery for colorectal cancer is a serious complication, causing an increased morbidity rate and mortality rate1,2.

    There is a debate and conflicting evidence on whether non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of leak3,4. NSAIDs act by inhibiting cyclooxygenase (COX) enzymes, which can be subdivided into isoenzymes COX-1 and COX-2. In a seminal study by Reisinger et al.5, knocking out the COX-2 gene resulted in an increase of colonic anastomotic leaks in mice. In a complementary cohort of colorectal cancer patients5, an increased frequency of anastomotic leaks was demonstrated among those homozygous for the COX-2 gene promoter mutation −765G > C (also known as rs20417). This finding could potentially be translated into clinical use following external validation.

    Biological effects might not only be present among those homozygous for the minor allele of −765C/C. For example, the heterozygous state of −765G/C has been associated with a decreased postoperative inflammatory response6.

    The present study aimed to evaluate the prevalence of the polymorphism 765G > C in a Swedish cohort of colorectal cancer patients, and its association with postoperative peritoneal infection.

  • 304.
    Granholm, Viktor
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kim, Sangtae
    Navarro, José C. F.
    Sjölund, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Smith, Richard D.
    Käll, Lukas
    Fast and Accurate Database Searches with MS-GF plus Percolator:  2014In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 2, p. 890-897Article in journal (Refereed)
    Abstract [en]

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

  • 305.
    Granholm, Viktor
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Navarro, Jose Fernandez
    Noble, William Stafford
    Käll, Lukas
    Determining the calibration of confidence estimation procedures for unique peptides in shotgun proteomics2013In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 80, p. 123-131Article in journal (Refereed)
    Abstract [en]

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

  • 306.
    Granholm, Viktor
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Noble, William Stafford
    Käll, Lukas
    A cross-validation scheme for machine learning algorithms in shotgun proteomics2012In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 13, p. S3-Article in journal (Refereed)
    Abstract [en]

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

  • 307. Green, Alanna C.
    et al.
    Marttila, Petra
    Kiweler, Nicole
    Chalkiadaki, Christina
    Wiita, Elisée
    Cookson, Victoria
    Lesur, Antoine
    Eiden, Kim
    Bernardin, François
    Vallin, Karl S. A.
    Borhade, Sanjay
    Long, Maeve
    Ghahe, Elahe Kamali
    Jiménez-Alonso, Julio J.
    Jemth, Ann-Sofie
    Loseva, Olga
    Mortusewicz, Oliver
    Meyers, Marianne
    Viry, Elodie
    Johansson, Annika I.
    Hodek, Ondřej
    Homan, Evert
    Bonagas, Nadilly
    Ramos, Louise
    Sandberg, Lars
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Frödin, Morten
    Moussay, Etienne
    Slipicevic, Ana
    Letellier, Elisabeth
    Paggetti, Jérôme
    Storgaard Sørensen, Claus
    Helleday, Thomas
    Henriksson, Martin
    Meiser, Johannes
    Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells2023In: Nature Metabolism, E-ISSN 2522-5812, Vol. 5, no 4, p. 642-659Article in journal (Refereed)
    Abstract [en]

    Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a ‘folate trap’. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

  • 308. Grohs, Melody N.
    et al.
    Reynolds, Jess E.
    Liu, Jiaying
    Martin, Jonathan W.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Pollock, Tyler
    Lebe, Catherine
    Dewey, Deborah
    Kaplan, Bonnie J.
    Field, Catherine J.
    Bell, Rhonda C.
    Bernier, Francois P.
    Cantell, Marja
    Casey, Linda M.
    Eliasziw, Misha
    Farmer, Anna
    Gagnon, Lisa
    Giesbrecht, Gerald F.
    Goonewardene, Laksiri
    Johnston, David W.
    Kooistra, Libbe
    Letoumeau, Nicole
    Manca, Donna P.
    McCargar, Linda J.
    O'Beirne, Maeve
    Pop, Victor J.
    Singhal, Nalini
    Prenatal maternal and childhood bisphenol a exposure and brain structure and behavior of young children2019In: Environmental Health, E-ISSN 1476-069X, Vol. 18, no 1, article id 85Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 309. Grottesi, Alessandro
    et al.
    Bešker, Neva
    Emerson, Andrew
    Manelfi, Candida
    Beccari, Andrea R.
    Frigerio, Francesco
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Cerchia, Carmen
    Talarico, Carmine
    Computational Studies of SARS-CoV-2 3CLpro: Insights from MD Simulations2020In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 21, no 15, article id 5346Article in journal (Refereed)
    Abstract [en]

    Given the enormous social and health impact of the pandemic triggered by severe acute respiratory syndrome 2 (SARS-CoV-2), the scientific community made a huge effort to provide an immediate response to the challenges posed by Coronavirus disease 2019 (COVID-19). One of the most important proteins of the virus is an enzyme, called 3CLpro or main protease, already identified as an important pharmacological target also in SARS and Middle East respiratory syndrome virus (MERS) viruses. This protein triggers the production of a whole series of enzymes necessary for the virus to carry out its replicating and infectious activities. Therefore, it is crucial to gain a deeper understanding of 3CLpro structure and function in order to effectively target this enzyme. All-atoms molecular dynamics (MD) simulations were performed to examine the different conformational behaviors of the monomeric and dimeric form of SARS-CoV-2 3CLpro apo structure, as revealed by microsecond time scale MD simulations. Our results also shed light on the conformational dynamics of the loop regions at the entry of the catalytic site. Studying, at atomic level, the characteristics of the active site and obtaining information on how the protein can interact with its substrates will allow the design of molecules able to block the enzymatic function crucial for the virus.

  • 310.
    Grujčić, Vesna
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Saarenpää, Sami
    Sundh, John
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sennblad, Bengt
    Norgren, Benjamin
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Latz, Meike
    Giacomello, Stefania
    Foster, Rachel Ann
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Andersson, Anders F.
    Towards high-throughput parallel imaging and single-cell transcriptomics of microbial eukaryotic plankton2024In: PLOS ONE, E-ISSN 1932-6203, Vol. 19, no 1, article id e0296672Article in journal (Refereed)
    Abstract [en]

    Single-cell transcriptomics has the potential to provide novel insights into poorly studied microbial eukaryotes. Although several such technologies are available and benchmarked on mammalian cells, few have been tested on protists. Here, we applied a microarray single-cell sequencing (MASC-seq) technology, that generates microscope images of cells in parallel with capturing their transcriptomes, on three species representing important plankton groups with different cell structures; the ciliate Tetrahymena thermophila, the diatom Phaeodactylum tricornutum, and the dinoflagellate Heterocapsa sp. Both the cell fixation and permeabilization steps were adjusted. For the ciliate and dinoflagellate, the number of transcripts of microarray spots with single cells were significantly higher than for background spots, and the overall expression patterns were correlated with that of bulk RNA, while for the much smaller diatom cells, it was not possible to separate single-cell transcripts from background. The MASC-seq method holds promise for investigating "microbial dark matter”, although further optimizations are necessary to increase the signal-to-noise ratio.

  • 311. Grundberg, Ida
    et al.
    Kiflemariam, Sara
    Mignardi, Marco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Imgenberg-Kreuz, Juliana
    Edlund, Karolina
    Micke, Patrick
    Sundström, Magnus
    Sjöblom, Tobias
    Botling, Johan
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    In situ mutation detection and visualization of intratumor heterogeneity for cancer research and diagnostics2013In: Oncotarget, E-ISSN 1949-2553, Vol. 4, no 12, p. 2407-2418Article in journal (Refereed)
    Abstract [en]

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

  • 312. Grunewald, Johan
    et al.
    Kaiser, Ylva
    Ostadkarampour, Mahyar
    Rivera, Natalia V.
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lötstedt, Britta
    Olsen, Remi-André
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sylwan, Lina
    Lundin, Sverker
    Käller, Max
    Sandalova, Tatiana
    Ahlgren, Kerstin M.
    Wahlström, Jan
    Achour, Adnane
    Ronninger, Marcus
    Eklund, Anders
    T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis2016In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 47, no 3, p. 898-909Article in journal (Refereed)
    Abstract [en]

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

  • 313. Grønberg, Christina
    et al.
    Sitsel, Oleg
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Gourdon, Pontus
    Andersson, Magnus
    Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 111, no 11, p. 2417-2429Article in journal (Refereed)
    Abstract [en]

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

  • 314. Grüning, Björn A.
    et al.
    Lampa, Samuel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Vaudel, Marc
    Blankenberg, Daniel
    Software engineering for scientific big data analysis2019In: GigaScience, E-ISSN 2047-217X, Vol. 8, no 5, article id giz054Article, review/survey (Refereed)
    Abstract [en]

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

  • 315.
    Guala, Dimitri
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Bernhem, Kristoffer
    Ait Blal, Hammou
    Lundberg, Emma
    Brismar, Hjalmar
    Sonnhammer, Erik L. L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Experimental validation of predicted cancer genes using FRETManuscript (preprint) (Other academic)
  • 316.
    Guala, Dimitri
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Bernhem, Kristoffer
    Blal, Hammou Ait
    Jans, Daniel
    Lundberg, Emma
    Brismar, Hjalmar
    Sonnhammer, Erik L. L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Experimental validation of predicted cancer genes using FRET2018In: Methods and applications in fluorescence, ISSN 2050-6120, Vol. 6, no 3, article id 035007Article in journal (Refereed)
    Abstract [en]

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

  • 317.
    Guala, Dimitri
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sonnhammer, Erik L. L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    A large-scale benchmark of gene prioritization methods2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 46598Article in journal (Refereed)
    Abstract [en]

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

  • 318.
    Guala, Dimitri
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Merck AB, Sweden.
    Sonnhammer, Erik L. L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Network Crosstalk as a Basis for Drug Repurposing2022In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 13, article id 792090Article in journal (Refereed)
    Abstract [en]

    The need for systematic drug repurposing has seen a steady increase over the past decade and may be particularly valuable to quickly remedy unexpected pandemics. The abundance of functional interaction data has allowed mapping of substantial parts of the human interactome modeled using functional association networks, favoring network-based drug repurposing. Network crosstalk-based approaches have never been tested for drug repurposing despite their success in the related and more mature field of pathway enrichment analysis. We have, therefore, evaluated the top performing crosstalk-based approaches for drug repurposing. Additionally, the volume of new interaction data as well as more sophisticated network integration approaches compelled us to construct a new benchmark for performance assessment of network-based drug repurposing tools, which we used to compare network crosstalk-based methods with a state-of-the-art technique. We find that network crosstalk-based drug repurposing is able to rival the state-of-the-art method and in some cases outperform it.

  • 319.
    Gubanova, Evgenia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Issaeva, Natalia
    Gokturk, Camilla
    Djureinovic, Tatjana
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Helleday, Thomas
    SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways2013In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 12, no 24, p. 3770-3780Article in journal (Refereed)
    Abstract [en]

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

  • 320.
    Gulati, Ashutosh
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Perez Boerema, Annemarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Meier, Pascal Florian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Matsuoka, Rei
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Structure and mechanism of the K+/H+ exchanger KefC2022Manuscript (preprint) (Other academic)
  • 321. Gunnarsdottir, Frida Björk
    et al.
    Bendahl, Pär-Ola
    Johansson, Alexandra
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Rydén, Lisa
    Bergenfelz, Caroline
    Larsson, Anna-Maria
    Serum immuno-oncology markers carry independent prognostic information in patients with newly diagnosed metastatic breast cancer, from a prospective observational study2023In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 25, article id 29Article in journal (Refereed)
    Abstract [en]

    Background Metastatic breast cancer (MBC) is a challenging disease, and despite new therapies, prognosis is still poor for a majority of patients. There is a clinical need for improved prognostication where immuno-oncology markers can provide important information. The aim of this study was to evaluate serum immuno-oncology markers in MBC patients and their respective relevance for prediction of survival.

    Patients and methods We investigated a broad panel of 92 immuno-oncology proteins in serum from 136 MBC patients included in a prospective observational study (NCT01322893) with long-term follow-up. Serum samples were collected before start of systemic therapy and analyzed using multiplex proximity extension assay (Olink Target 96 Immuno-Oncology panel). Multiple machine learning techniques were used to identify serum markers with highest importance for prediction of overall and progression-free survival (OS and PFS), and associations to survival were further evaluated using Cox regression analyses. False discovery rate was then used to adjust for multiple comparisons.

    Results Using random forest and random survival forest analyses, we identified the top nine and ten variables of highest predictive importance for OS and PFS, respectively. Cox regression analyses revealed significant associations (P < 0.005) of higher serum levels of IL-8, IL-10 and CAIX with worse OS in multivariable analyses, adjusted for established clinical prognostic factors including circulating tumor cells (CTCs). Similarly, high serum levels of IL-8, IL-10, ADA and CASP8 significantly associated with worse PFS. Interestingly, high serum levels of FasL significantly associated with improved OS and PFS. In addition, CSF-1, IL-6, MUC16, TFNSFR4 and CD244 showed suggestive evidence (P < 0.05) for an association to survival in multivariable analyses. After correction for multiple comparisons, IL-8 still showed strong evidence for correlation to survival.

    Conclusion To conclude, we found six serum immuno-oncology markers that were significantly associated with OS and/or PFS in MBC patients, independently of other established prognostic factors including CTCs. Furthermore, an additional five serum immuno-oncology markers provided suggestive evidence for an independent association to survival. These findings highlight the relevance of immuno-oncology serum markers in MBC patients and support their usefulness for improved prognostication.

  • 322. Guo, Maoxiang
    et al.
    Hernández-Neuta, Iván
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Madaboosi, Narayanan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    van der Wijngaart, Wouter
    Efficient DNA-assisted synthesis of trans-membrane gold nanowires2018In: microsystems and nanoengineering, ISSN 2055-7434, Vol. 4, article id UNSP 17084Article in journal (Refereed)
    Abstract [en]

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

  • 323. Gurwitz, Kim T.
    et al.
    Gaur, Prakash Singh
    Bellis, Louisa J.
    Larcombe, Lee
    Alloza, Eva
    Balint, Balint Laszlo
    Botzki, Alexander
    Dimec, Jure
    del Angel, Victoria Dominguez
    Fernandes, Pedro L.
    Korpelainen, Eija
    Krause, Roland
    Kuzak, Mateusz
    Le Pera, Loredana
    Leskošek, Brane
    Lindvall, Jessica M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Marek, Diana
    Martinez, Paula A.
    Muyldermans, Tuur
    Nygård, Ståle
    Palagi, Patricia M.
    Peterson, Hedi
    Psomopoulos, Fotis
    Spiwok, Vojtech
    van Gelder, Celia W. G.
    Via, Allegra
    Vidak, Marko
    Wibberg, Daniel
    Morgan, Sarah L.
    Rustici, Gabriella
    A framework to assess the quality and impact of bioinformatics training across ELIXIR2020In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 16, no 7, article id e1007976Article in journal (Refereed)
    Abstract [en]

    ELIXIR is a pan-European intergovernmental organisation for life science that aims to coordinate bioinformatics resources in a single infrastructure across Europe; bioinformatics training is central to its strategy, which aims to develop a training community that spans all ELIXIR member states. In an evidence-based approach for strengthening bioinformatics training programmes across Europe, the ELIXIR Training Platform, led by the ELIXIR EXCELERATE Quality and Impact Assessment Subtask in collaboration with the ELIXIR Training Coordinators Group, has implemented an assessment strategy to measure quality and impact of its entire training portfolio. Here, we present ELIXIR’s framework for assessing training quality and impact, which includes the following: specifying assessment aims, determining what data to collect in order to address these aims, and our strategy for centralised data collection to allow for ELIXIR-wide analyses. In addition, we present an overview of the ELIXIR training data collected over the past 4 years. We highlight the importance of a coordinated and consistent data collection approach and the relevance of defining specific metrics and answer scales for consortium-wide analyses as well as for comparison of data across iterations of the same course.

  • 324. Gustafsson, Nina M. S.
    et al.
    Färnegårdh, Katarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab). Kancera AB, Sweden.
    Bonagas, Nadilly
    Ninou, Anna Huguet
    Groth, Petra
    Wiita, Elisee
    Jönsson, Mattias
    Hallberg, Kenth
    Lehto, Jemina
    Pennisi, Rosa
    Martinsson, Jessica
    Norström, Carina
    Hollers, Jessica
    Schultz, Johan
    Andersson, Martin
    Markova, Natalia
    Marttila, Petra
    Kim, Baek
    Norin, Martin
    Olin, Thomas
    Helleday, Thomas
    Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination2018In: Nature Communications, E-ISSN 2041-1723, Vol. 9, article id 3872Article in journal (Refereed)
    Abstract [en]

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

  • 325.
    Gustafsson, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jemth, Ann-Sofie
    Gustafsson, Nina M. S.
    Färnegårdh, Katarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Loseva, Olga
    Wiita, Elisée
    Bonagas, Nadilly
    Dahllund, Leif
    Llona-Minguez, Sabin
    Häggblad, Maria
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Henriksson, Martin
    Andersson, Yasmin
    Homan, Evert
    Helleday, Thomas
    Stenmark, Pal
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 4, p. 937-948Article in journal (Refereed)
    Abstract [en]

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

  • 326.
    Gutiérrez-Valencia, Juanita
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Fracassetti, Marco
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Berdan, Emma L.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Bunikis, Ignas
    Soler, Lucile
    Dainat, Jacques
    Kutschera, Verena E.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Losvik, Aleksandra
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Désamoré, Aurélie
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hughes, P. William
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Foroozani, Alireza
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Laenen, Benjamin
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Pesquet, Edouard
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Abdelaziz, Mohamed
    Pettersson, Olga Vinnere
    Nystedt, Björn
    Brennan, Adrian C.
    Arroyo, Juan
    Slotte, Tanja
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Genomic analyses of the Linum distyly supergene reveal convergent evolution at the molecular level2022In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 32, no 20, p. 4360-4371, 4371.e1-4371.e6Article in journal (Refereed)
    Abstract [en]

    Supergenes govern multi-trait-balanced polymorphisms in a wide range of systems; however, our understanding of their origins and evolution remains incomplete. The reciprocal placement of stigmas and anthers in pin and thrum floral morphs of distylous species constitutes an iconic example of a balanced polymorphism governed by a supergene, the distyly S-locus. Recent studies have shown that the Primula and Turnera distyly supergenes are both hemizygous in thrums, but it remains unknown whether hemizygosity is pervasive among distyly S-loci. As hemizygosity has major consequences for supergene evolution and loss, clarifying whether this genetic architecture is shared among distylous species is critical. Here, we have characterized the genetic architecture and evolution of the distyly supergene in Linum by generating a chromosome-level genome assembly of Linum tenue, followed by the identification of the S-locus using population genomic data. We show that hemizygosity and thrum-specific expression of S-linked genes, including a pistil-expressed candidate gene for style length, are major features of the Linum S-locus. Structural variation is likely instrumental for recombination suppression, and although the non-recombining dominant haplotype has accumulated transposable elements, S-linked genes are not under relaxed purifying selection. Our findings reveal remarkable convergence in the genetic architecture and evolution of independently derived distyly supergenes, provide a counterexample to classic inversion-based supergenes, and shed new light on the origin and maintenance of an iconic floral polymorphism.

  • 327.
    Gutiérrez-Valencia, Juanita
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Fracassetti, Marco
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Horvath, Robert
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Laenen, Benjamin
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Désamore, Aurélie
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Drouzas, Andreas D.
    Friberg, Magne
    Kolář, Filip
    Slotte, Tanja
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Genomic Signatures of Sexual Selection on Pollen-Expressed Genes in Arabis alpina2022In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 39, no 1, article id msab349Article in journal (Refereed)
    Abstract [en]

    Fertilization in angiosperms involves the germination of pollen on the stigma, followed by the extrusion of a pollen tube that elongates through the style and delivers two sperm cells to the embryo sac. Sexual selection could occur throughout this process when male gametophytes compete for fertilization. The strength of sexual selection during pollen competition should be affected by the number of genotypes deposited on the stigma. As increased self-fertilization reduces the number of mating partners, and the genetic diversity and heterozygosity of populations, it should thereby reduce the intensity of sexual selection during pollen competition. Despite the prevalence of mating system shifts, few studies have directly compared the molecular signatures of sexual selection during pollen competition in populations with different mating systems. Here we analyzed whole-genome sequences from natural populations of Arabis alpina, a species showing mating system variation across its distribution, to test whether shifts from cross- to self-fertilization result in molecular signatures consistent with sexual selection on genes involved in pollen competition. We found evidence for efficient purifying selection on genes expressed in vegetative pollen, and overall weaker selection on sperm-expressed genes. This pattern was robust when controlling for gene expression level and specificity. In agreement with the expectation that sexual selection intensifies under cross-fertilization, we found that the efficacy of purifying selection on male gametophyte-expressed genes was significantly stronger in genetically more diverse and outbred populations. Our results show that intra-sexual competition shapes the evolution of pollen-expressed genes, and that its strength fades with increasing self-fertilization rates.

  • 328.
    Gutiérrez-Valencia, Juanita
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hughes, P. William
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Berdan, Emma L.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Slotte, Tanja
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    The Genomic Architecture and Evolutionary Fates of Supergenes2021In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 13, no 5, article id evab057Article, review/survey (Refereed)
    Abstract [en]

    Supergenes are genomic regions containing sets of tightly linked loci that control multi-trait phenotypic polymorphisms under balancing selection. Recent advances in genomics have uncovered significant variation in both the genomic architecture as well as the mode of origin of supergenes across diverse organismal systems. Although the role of genomic architecture for the origin of supergenes has been much discussed, differences in the genomic architecture also subsequently affect the evolutionary trajectory of supergenes and the rate of degeneration of supergene haplotypes. In this review, we synthesize recent genomic work and historical models of supergene evolution, highlighting how the genomic architecture of supergenes affects their evolutionary fate. We discuss how recent findings on classic supergenes involved in governing ant colony social form, mimicry in butterflies, and heterostyly in flowering plants relate to theoretical expectations. Furthermore, we use forward simulations to demonstrate that differences in genomic architecture affect the degeneration of supergenes. Finally, we discuss implications of the evolution of supergene haplotypes for the long-term fate of balanced polymorphisms governed by supergenes.

  • 329.
    Gyllborg, Daniel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mattsson Langseth, Christoffer
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Qian, Xiaoyan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Choi, Eunkyoung
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Marco Salas, Sergio
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hilscher, Markus M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lein, Ed S.
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hybridization-based in situ sequencing (HybISS) for spatially resolved transcriptomics in human and mouse brain tissue2020In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 48, no 19, article id e112Article in journal (Refereed)
    Abstract [en]

    Visualization of the transcriptome in situ has proven to be a valuable tool in exploring single-cell RNA-sequencing data, providing an additional spatial dimension to investigate multiplexed gene expression, cell types, disease architecture or even data driven discoveries. In situ sequencing (ISS) method based on padlock probes and rolling circle amplification has been used to spatially resolve gene transcripts in tissue sections of various origins. Here, we describe the next iteration of ISS, HybISS, hybridization-based in situ sequencing. Modifications in probe design allows for a new barcoding system via sequence-by-hybridization chemistry for improved spatial detection of RNA transcripts. Due to the amplification of probes, amplicons can be visualized with standard epifluorescence microscopes for high-throughput efficiency and the new sequencing chemistry removes limitations bound by sequence-by-ligation chemistry of ISS. HybISS design allows for increased flexibility and multiplexing, increased signal-to-noise, all without compromising throughput efficiency of imaging large fields of view. Moreover, the current protocol is demonstrated to work on human brain tissue samples, a source that has proven to be difficult to work with image-based spatial analysis techniques. Overall, HybISS technology works as a targeted amplification detection method for improved spatial transcriptomic visualization, and importantly, with an ease of implementation.

  • 330. Gómez de la Torre, Teresa Zardán
    et al.
    Herthnek, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Strømme, Maria
    A Magnetic Nanobead-Based Read-Out Procedure for Rapid Detection of DNA Molecules2017In: Journal of Nanoscience and Nanotechnology, ISSN 1533-4880, E-ISSN 1533-4899, Vol. 17, no 4, p. 2861-2864Article in journal (Refereed)
    Abstract [en]

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

  • 331. Gómez-Blanco, J.
    et al.
    de la Rosa-Trevín, José Miguel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Marabini, R.
    del Cano, L.
    Jimenez, A.
    Martinez, M.
    Melero, R.
    Majtner, T.
    Maluenda, D.
    Mota, J.
    Rancel, Y.
    Ramirez-Aportela, E.
    Vilas, J. L.
    Carroni, Marta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Fleischmann, Stefan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Ashton, A. W.
    Basham, M.
    Clare, D. K.
    Savage, K.
    Siebert, C. A.
    Sharov, G. G.
    Sorzano, C. O. S.
    Conesa, P.
    Carazo, J. M.
    Using Scipion for stream image processing at Cryo-EM facilities2018In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 204, no 3, p. 457-463Article in journal (Refereed)
    Abstract [en]

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

  • 332. Günther, Torsten
    et al.
    Malmström, Helena
    Svensson, Emma M.
    Omrak, Ayça
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies.
    Sánchez-Quinto, Federico
    Kılınç, Gülşah M.
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. Uppsala University, Sweden; Middle East Technical University, Turkey.
    Krzewińska, Maja
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies.
    Eriksson, Gunilla
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies.
    Fraser, Magdalena
    Edlund, Hanna
    Munters, Arielle R.
    Coutinho, Alexandra
    Simões, Luciana G.
    Vicente, Mario
    Sjölander, Anders
    Jansen Sellevold, Berit
    Jørgensen, Roger
    Claes, Peter
    Shriver, Mark D.
    Valdiosera, Cristina
    Netea, Mihai G.
    Apel, Jan
    Lidén, Kerstin
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies.
    Skar, Birgitte
    Storå, Jan
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies.
    Götherström, Anders
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jakobsson, Mattias
    Population genomics of Mesolithic Scandinavia: Investigating early postglacial migration routes and high-latitude adaptation2018In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 16, no 1, article id e2003703Article in journal (Refereed)
    Abstract [en]

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

  • 333. Hagey, Daniel W.
    et al.
    Zaouter, Cecile
    Combeau, Gaelle
    Andersson Lendahl, Monika
    Andersson, Olov
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Muhr, Jonas
    Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells2016In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 26, no 7, p. 908-917Article in journal (Refereed)
    Abstract [en]

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

  • 334. Hagström, Åke
    et al.
    Zweifel, Ulla Li
    Sundh, John
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Osbeck, Christofer M. G.
    Bunse, Carina
    Sjöstedt, Johanna
    Müller-Karulis, Bärbel
    Stockholm University, Faculty of Science, Stockholm University Baltic Sea Centre.
    Pinhassi, Jarone
    Composition and Seasonality of Membrane Transporters in Marine Picoplankton2021In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 12, article id 714732Article in journal (Refereed)
    Abstract [en]

    In this study, we examined transporter genes in metagenomic and metatranscriptomic data from a time-series survey in the temperate marine environment of the Baltic Sea. We analyzed the abundance and taxonomic distribution of transporters in the 3μm–0.2μm size fraction comprising prokaryotes and some picoeukaryotes. The presence of specific transporter traits was shown to be guiding the succession of these microorganisms. A limited number of taxa were associated with the dominant transporter proteins that were identified for the nine key substrate categories for microbial growth. Throughout the year, the microbial taxa at the level of order showed highly similar patterns in terms of transporter traits. The distribution of transporters stayed the same, irrespective of the abundance of each taxon. This would suggest that the distribution pattern of transporters depends on the bacterial groups being dominant at a given time of the year. Also, we find notable numbers of secretion proteins that may allow marine bacteria to infect and kill prey organisms thus releasing nutrients. Finally, we demonstrate that transporter proteins may provide clues to the relative importance of biogeochemical processes, and we suggest that virtual transporter functionalities may become important components in future population dynamics models.

  • 335.
    Haider, Christian
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Applied Sciences Upper Austria, Austria.
    Kavic, Marina
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Applied Sciences Upper Austria, Austria.
    Sonnhammer, Erik L. L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    TreeDom: a graphical web tool for analysing domain architecture evolution2016In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, no 15, p. 2384-2385Article in journal (Refereed)
    Abstract [en]

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

  • 336.
    Hallgren, Joel
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Koonce, Kira
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Felletti, Michele
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mortier, Julien
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Turco, Eloisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Phosphate starvation decouples cell differentiation from DNA replication control in the dimorphic bacterium Caulobacter crescentus2023In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 19, no 11, article id e1010882Article in journal (Refereed)
    Abstract [en]

    Upon nutrient depletion, bacteria stop proliferating and undergo physiological and morphological changes to ensure their survival. Yet, how these processes are coordinated in response to distinct starvation conditions is poorly understood. Here we compare the cellular responses of Caulobacter crescentus to carbon (C), nitrogen (N) and phosphorus (P) starvation conditions. We find that DNA replication initiation and abundance of the replication initiator DnaA are, under all three starvation conditions, regulated by a common mechanism involving the inhibition of DnaA translation. By contrast, cell differentiation from a motile swarmer cell to a sessile stalked cell is regulated differently under the three starvation conditions. During C and N starvation, production of the signaling molecules (p)ppGpp is required to arrest cell development in the motile swarmer stage. By contrast, our data suggest that low (p)ppGpp levels under P starvation allow P-starved swarmer cells to differentiate into sessile stalked cells. Further, we show that limited DnaA availability, and consequently absence of DNA replication initiation, is the main reason that prevents P-starved stalked cells from completing the cell cycle. Together, our findings demonstrate that Ccrescentus decouples cell differentiation from DNA replication initiation under certain starvation conditions, two otherwise intimately coupled processes. We hypothesize that arresting the developmental program either as motile swarmer cells or as sessile stalked cells improves the chances of survival of Ccrescentus during the different starvation conditions.

  • 337. Haloi, Nandan
    et al.
    Huang, Shan
    Nichols, Aaron L.
    Fine, Eve J.
    Friesenhahn, Nicholas J.
    Marotta, Christopher B.
    Dougherty, Dennis A.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Howard, Rebecca J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mayo, Stephen L.
    Lester, Henry A.
    Interactive computational and experimental approaches improve the sensitivity of periplasmic binding protein-based nicotine biosensors for measurements in biofluids2024In: Protein Engineering Design & Selection, ISSN 1741-0126, E-ISSN 1741-0134, Vol. 37, article id gzae003Article in journal (Refereed)
    Abstract [en]

    We developed fluorescent protein sensors for nicotine with improved sensitivity. For iNicSnFR12 at pH 7.4, the proportionality constant for ∆F/F0vs [nicotine] (δ-slope, 2.7 μM−1) is 6.1-fold higher than the previously reported iNicSnFR3a. The activated state of iNicSnFR12 has a fluorescence quantum yield of at least 0.6. We measured similar dose-response relations for the nicotine-induced absorbance increase and fluorescence increase, suggesting that the absorbance increase leads to the fluorescence increase via the previously described nicotine-induced conformational change, the ‘candle snuffer’ mechanism. Molecular dynamics (MD) simulations identified a binding pose for nicotine, previously indeterminate from experimental data. MD simulations also showed that Helix 4 of the periplasmic binding protein (PBP) domain appears tilted in iNicSnFR12 relative to iNicSnFR3a, likely altering allosteric network(s) that link the ligand binding site to the fluorophore. In thermal melt experiments, nicotine stabilized the PBP of the tested iNicSnFR variants. iNicSnFR12 resolved nicotine in diluted mouse and human serum at 100 nM, the peak [nicotine] that occurs during smoking or vaping, and possibly at the decreasing levels during intervals between sessions. NicSnFR12 was also partially activated by unidentified endogenous ligand(s) in biofluids. Improved iNicSnFR12 variants could become the molecular sensors in continuous nicotine monitors for animal and human biofluids.

  • 338. Hammarström, Lars G. J.
    et al.
    Harmel, Robert K.
    Granath, Mikael
    Ringom, Rune
    Gravenfors, Ylva
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Färnegårdh, Katarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Svensson, Per H.
    Wennman, David
    Lundin, Göran
    Roddis, Ylva
    Kitambi, Satish S.
    Bernlind, Alexandra
    Lehmann, Fredrik
    Ernfors, Patrik
    The Oncolytic Efficacy and in Vivo Pharmacokinetics of [2-(4-Chlorophenyl)quinolin-4-yl](piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 18, p. 8577-8592Article in journal (Refereed)
    Abstract [en]

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

  • 339. Haniffa, Muzlifah
    et al.
    Taylor, Deanne
    Linnarsson, Sten
    Aronow, Bruce J.
    Bader, Gary D.
    Barker, Roger A.
    Camara, Pablo G.
    Camp, J. Gray
    Chedotal, Alain
    Copp, Andrew
    Etchevers, Heather C.
    Giacobini, Paolo
    Gottgens, Berthold
    Guo, Guoji
    Hupalowska, Ania
    James, Kylie R.
    Kirby, Emily
    Kriegstein, Arnold
    Lundeberg, Joakim
    Marioni, John C.
    Meyer, Kerstin B.
    Niakan, Kathy K.
    Nilsson, Mats
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Olabi, Bayanne
    Pe'er, Dana
    Regev, Aviv
    Rood, Jennifer
    Rozenblatt-Rosen, Orit
    Satija, Rahul
    Teichmann, Sarah A.
    Treutlein, Barbara
    Vento-Tormo, Roser
    Webb, Simone
    A roadmap for the Human Developmental Cell Atlas2021In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 597, no 7875, p. 196-205Article in journal (Refereed)
    Abstract [en]

    This Perspective outlines the Human Developmental Cell Atlas initiative, which uses state-of-the-art technologies to map and model human development across gestation, and discusses the early milestones that have been achieved. The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development.

  • 340. Hansen, Eline P.
    et al.
    Fromm, Bastian
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Oslo University Hospital, Norway.
    Andersen, Sidsel D.
    Marcilla, Antonio
    Andersen, Kasper L.
    Borup, Anne
    Williams, Andrew R.
    Jex, Aaron R.
    Gasser, Robin B.
    Young, Neil D.
    Hall, Ross S.
    Stensballe, Allan
    Ovchinnikov, Vladimir
    Yan, Yan
    Fredholm, Merete
    Thamsborg, Stig M.
    Nejsum, Peter
    Exploration of extracellular vesicles from Ascaris suum provides evidence of parasite-host cross talk2019In: Journal of Extracellular Vesicles, E-ISSN 2001-3078, Vol. 8, no 1, article id 1578116Article in journal (Refereed)
    Abstract [en]

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

  • 341. Harner, Tom
    et al.
    Rauert, Cassandra
    Muir, Derek
    Schuster, Jasmin K.
    Hsu, Yu-Mei
    Zhang, Leiming
    Marson, George
    Watson, John G.
    Ahad, Jason
    Cho, Sunny
    Jariyasopit, Narumol
    Kirk, Jane
    Korosi, Jennifer
    Landis, Matthew S.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Alberta, Canada.
    Zhang, Yifeng
    Fernie, Kim
    Wentworth, Gregory R.
    Wnorowski, Andrzej
    Dabek, Ewa
    Charland, Jean-Pierre
    Pauli, Bruce
    Wania, Frank
    Galarneau, Elisabeth
    Cheng, Irene
    Makar, Paul
    Whaley, Cynthia
    Chow, Judith C.
    Wang, Xiaoliang
    Air synthesis review: polycyclic aromatic compounds in the oil sands region2018In: Environmental Reviews, ISSN 1181-8700, E-ISSN 1208-6053, Vol. 26, no 4, p. 430-468Article, review/survey (Refereed)
    Abstract [en]

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

  • 342. Hasmats, Johanna
    et al.
    Gréen, Henrik
    Orear, Cedric
    Validire, Pierre
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Käller, Max
    Lundeberg, Joakim
    Assessment of Whole Genome Amplification for Sequence Capture and Massively Parallel Sequencing2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 1, article id e84785Article in journal (Refereed)
    Abstract [en]

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

  • 343.
    Hasselgren, Malin
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Dussex, Nicolas
    Stockholm University, Faculty of Science, Department of Zoology. Swedish Museum of Natural History, Sweden.
    von Seth, Johanna
    Stockholm University, Faculty of Science, Department of Zoology. Swedish Museum of Natural History, Sweden.
    Angerbjörn, Anders
    Stockholm University, Faculty of Science, Department of Zoology.
    Olsen, Remi-André
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dalén, Love
    Norén, Karin
    Stockholm University, Faculty of Science, Department of Zoology.
    Genomic and fitness consequences of inbreeding in an endangered carnivore2021In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 30, no 12, p. 2790-2799Article in journal (Refereed)
    Abstract [en]

    Reduced fitness through genetic drift and inbreeding is a major threat to small and isolated populations. Although previous studies have generally used genetically verified pedigrees to document effects of inbreeding and gene flow, these often fail to capture the whole inbreeding history of the species. By assembling a draft arctic fox (Vulpes lagopus) genome and resequencing complete genomes of 23 additional foxes born before and after a well-documented immigration event in Scandinavia, we here look into the genomic consequences of inbreeding and genetic rescue. We found a difference in genome-wide diversity, with 18% higher heterozygosity and 81% lower F-ROH in immigrant F1 compared to native individuals. However, more distant descendants of immigrants (F2, F3) did not show the same pattern. We also found that foxes with lower inbreeding had higher probability to survive their first year of life. Our results demonstrate the important link between genetic variation and fitness as well as the transient nature of genetic rescue. Moreover, our results have implications in conservation biology as they demonstrate that inbreeding depression can effectively be detected in the wild by a genomic approach.

  • 344. Hasselrot, Tyra
    et al.
    Franzén Boger, Mathias
    Kaldhusdal, Vilde
    Åhlberg, Alexandra
    Omollo, Kenneth
    Lajoie, Julie
    Kimani, Joshua
    Tjernlund, Annelie
    Fowke, Keith R.
    Czarnewski, Paulo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Broliden, Kristina
    Vaginal candida infection is associated with host molecular signatures of neutrophil activation in the adjacent ectocervical mucosa in Kenyan sex workers2024In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 91, no 2, article id e13814Article in journal (Refereed)
    Abstract [en]

    Problem: Overgrowth of candida species in the human vaginal mucosa causes inflammation, which could render the mucosal barrier more susceptible to HIV infection. Here, we investigated whether this condition also affects the ectocervical mucosa, a potential site of HIV entry, in women at high risk of HIV infection.

    Method of study: Retrospective medical data and ectocervical tissue samples were obtained from a cohort of Kenyan sex workers. Among 108 women, seven had signs of vaginal candida infection by wet smear microscopy and/or the presence of characteristic discharge. Women lacking these two criteria served as controls. Host transcriptomic profiling and quantitative in situ image analysis of epithelial barrier markers and CD4+ cell distribution were performed.

    Results: The candida group had 162 differentially expressed genes out of 15 435 genes as compared with the control group. Among these 162 genes, 147 were upregulated and 15 were downregulated. Gene expression pathway analysis indicated associations with an upregulated inflammatory response, defined primarily by markers of neutrophil activation. Transcription factor analysis revealed upregulation of pathways related to RELA/REL/NFKB1JUN and STAT1 in the candida group. In situ image analysis of ectocervical tissue samples showed no differences between groups in terms of epithelial height, expression of epithelial junction proteins (E-cadherin, claudin-1, zonula occludens 1, and desmoglein-1), or epithelial CD4+ cell distribution.

    Conclusions: Vaginal candida infection was associated with inflammation and neutrophil infiltration, but not with severe epithelial disruption or CD4+ cell infiltration, in the ectocervical mucosa.

  • 345. Hatorangan, Marcelinus R.
    et al.
    Laenen, Benjamin
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Steige, Kim A.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Slotte, Tanja
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kohler, Claudia
    Rapid Evolution of Genomic Imprinting in Two Species of the Brassicaceae2016In: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 28, no 8, p. 1815-1827Article in journal (Refereed)
    Abstract [en]

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

  • 346. Hatos, Andras
    et al.
    Hajdu-Soltesz, Borbala
    Monzon, Alexander M.
    Palopoli, Nicolas
    Alvarez, Lucia
    Aykac-Fas, Burcu
    Bassot, Claudio
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Benitez, Guillermo
    Bevilacqua, Martina
    Chasapi, Anastasia
    Chemes, Lucia
    Davey, Norman E.
    Davidovic, Radoslav
    Dunker, A. Keith
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Gobeill, Julien
    Gonzalez Foutel, Nicolas S.
    Sudha, Govindarajan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Guharoy, Mainak
    Horvath, Tamas
    Iglesias, Valentin
    Kajava, Andrey
    Kovacs, Orsolya P.
    Lamb, John
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lambrughi, Matteo
    Lazar, Tamas
    Leclercq, Jeremy Y.
    Leonardi, Emanuela
    Macedo-Ribeiro, Sandra
    Macossay-Castillo, Mauricio
    Maiani, Emiliano
    Manso, Jose A.
    Marino-Buslje, Cristina
    Martinez-Perez, Elizabeth
    Meszaros, Balint
    Micetic, Ivan
    Minervini, Giovanni
    Murvai, Nikoletta
    Necci, Marco
    Ouzounis, Christos A.
    Pajkos, Matyas
    Paladin, Lisanna
    Pancsa, Rita
    Papaleo, Elena
    Parisi, Gustavo
    Pasche, Emilie
    Barbosa Pereira, Pedro J.
    Promponas, Vasilis J.
    Pujols, Jordi
    Quaglia, Federica
    Ruch, Patrick
    Salvatore, Marco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Schad, Eva
    Szabo, Beata
    Szaniszlo, Tamas
    Tamana, Stella
    Tantos, Agnes
    Veljkovic, Nevena
    Ventura, Salvador
    Vranken, Wim
    Dosztanyi, Zsuzsanna
    Tompa, Peter
    Tosatto, Silvio C. E.
    Piovesan, Damiano
    DisProt: intrinsic protein disorder annotation in 20202020In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 48, no D1, p. D269-D276Article in journal (Refereed)
    Abstract [en]

    The Database of Protein Disorder (DisProt, URL:https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the 'dark' proteome.

  • 347.
    Hayat, Sikander
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ranking models of transmembrane beta-barrel proteins using Z-coordinate predictions2012In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 28, no 12, p. i90-I96Article in journal (Refereed)
    Abstract [en]

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

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  • 348. Hayat, Sikander
    et al.
    Peters, Christoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Shu, Nanjiang
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Tsirigos, Konstantinos D.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Inclusion of dyad-repeat pattern improves topology prediction of transmembrane beta-barrel proteins2016In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, no 10, p. 1571-1573Article in journal (Refereed)
    Abstract [en]

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

  • 349. Hayat, Sikander
    et al.
    Sander, Chris
    Marks, Debora S.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    All-atom 3D structure prediction of transmembrane beta-barrel proteins from sequences2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 17, p. 5413-5418Article in journal (Refereed)
    Abstract [en]

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

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  • 350. Haytural, Hazal
    et al.
    Benfeitas, Rui
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Schedin-Weiss, Sophia
    Bereczki, Erika
    Rezeli, Melinda
    Unwin, Richard D.
    Wang, Xusheng
    Dammer, Eric B.
    Johnson, Erik C. B.
    Seyfried, Nicholas T.
    Winblad, Bengt
    Tijms, Betty M.
    Visser, Pieter Jelle
    Frykman, Susanne
    Tjernberg, Lars O.
    Insights into the changes in the proteome of Alzheimer disease elucidated by a meta-analysis2021In: Scientific Data, E-ISSN 2052-4463, Vol. 8, no 1, article id 312Article in journal (Refereed)
    Abstract [en]

    Mass spectrometry (MS)-based proteomics is a powerful tool to explore pathogenic changes of a disease in an unbiased manner and has been used extensively in Alzheimer disease (AD) research. Here, by performing a meta-analysis of high-quality proteomic studies, we address which pathological changes are observed consistently and therefore most likely are of great importance for AD pathogenesis. We retrieved datasets, comprising a total of 21,588 distinct proteins identified across 857 postmortem human samples, from ten studies using labeled or label-free MS approaches. Our meta-analysis findings showed significant alterations of 757 and 1,195 proteins in AD in the labeled and label-free datasets, respectively. Only 33 proteins, some of which were associated with synaptic signaling, had the same directional change across the individual studies. However, despite alterations in individual proteins being different between the labeled and the label-free datasets, several pathways related to synaptic signaling, oxidative phosphorylation, immune response and extracellular matrix were commonly dysregulated in AD. These pathways represent robust changes in the human AD brain and warrant further investigation.

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