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  • 1051.
    Zhao, Jingjing
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Xu, Hongyi
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Lebrette, Hugo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Carroni, Marta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Taberman, Helena
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Zou, Xiaodong
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    A simple pressure-assisted method for MicroED specimen preparation2021In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 5036Article in journal (Refereed)
    Abstract [en]

    Micro-crystal electron diffraction (MicroED) has shown great potential for structure determination of macromolecular crystals too small for X-ray diffraction. However, specimen preparation remains a major bottleneck. Here, we report a simple method for preparing MicroED specimens, named Preassis, in which excess liquid is removed through an EM grid with the assistance of pressure. We show the ice thicknesses can be controlled by tuning the pressure in combination with EM grids with appropriate carbon hole sizes. Importantly, Preassis can handle a wide range of protein crystals grown in various buffer conditions including those with high viscosity, as well as samples with low crystal concentrations. Preassis is a simple and universal method for MicroED specimen preparation, and will significantly broaden the applications of MicroED.

  • 1052. Zhao, Yansong
    et al.
    Lin, Chen
    Wu, Pengcheng
    Chen, Xiaoyuan
    Zhao, Yuancun
    Li, Yupeng
    Chen, Lu
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ke, Rongqin
    Single Cell RNA Expression Analysis Using Flow Cytometry Based on Specific Probe Ligation and Rolling Circle Amplification2020In: ACS Sensors, E-ISSN 2379-3694, Vol. 5, no 10, p. 3031-3036Article in journal (Refereed)
    Abstract [en]

    Conventional flow cytometry has been widely used for high-throughput single-cell gene expression analysis using specific antibody staining. However, this is limited by the availability of high-quality antibodies. We developed a novel flow cytometry RNA detection technique termed RCA-Flow for single-cell RNA expression analysis. We showed that it is able to analyze not only mRNAs but also microRNAs and circular RNAs that are otherwise difficult to analyze by other flow cytometry techniques. The versatility for high-throughput analysis of different types of RNA molecules makes our method possess great potential for both biomedical and clinical applications.

  • 1053. Zheleznyakova, Galina Yurevna
    et al.
    Piket, Eliane
    Needhamsen, Maria
    Hagemann-Jensen, Michael
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Han, Yanan
    James, Tojo
    Khademi, Mohsen
    Al Nimer, Faiez
    Scicluna, Patrick
    Huang, Jesse
    Kockum, Ingrid
    Faridani, Omid R.
    Olsson, Tomas
    Piehl, Fredrik
    Jagodic, Maja
    Small noncoding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology2021In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 17, article id e2011574118Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system (CNS). Small non-coding RNAs (sncRNAs) and, in particular, microRNAs (miRNAs) have frequently been associated with MS. Here, we performed a comprehensive analysis of all classes of sncRNAs in matching samples of peripheral blood mononuclear cells (PBMCs), plasma, cerebrospinal fluid (CSF) cells, and cell-free CSF from relapsing-remitting (RRMS, n = 12 in relapse and n = 11 in remission) patients, secondary progressive (SPMS, n = 6) MS patients, and noninflammatory and inflammatory neurological disease controls (NINDC, n = 11; INDC, n = 5). We show widespread changes in miRNAs and sncRNA-derived fragments of small nuclear, nucleolar, and transfer RNAs. In CSF cells, 133 out of 133 and 115 out of 117 differentially expressed sncRNAs were increased in RRMS relapse compared to remission and RRMS compared to NINDC, respectively. In contrast, 65 out of 67 differentially expressed PBMC sncRNAs were decreased in RRMS compared to NINDC. The striking contrast between the periphery and CNS suggests that sncRNA-mediated mechanisms, including alternative splicing, RNA degradation, and mRNA translation, regulate the transcriptome of pathogenic cells primarily in the CNS target organ.

  • 1054.
    Zhivkoplias, Erik K.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Vavulov, Oleg
    Hillerton, Thomas
    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).
    Generation of Realistic Gene Regulatory Networks by Enriching for Feed-Forward Loops2022In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 13, article id 815692Article in journal (Refereed)
    Abstract [en]

    The regulatory relationships between genes and proteins in a cell form a gene regulatory network (GRN) that controls the cellular response to changes in the environment. A number of inference methods to reverse engineer the original GRN from large-scale expression data have recently been developed. However, the absence of ground-truth GRNs when evaluating the performance makes realistic simulations of GRNs necessary. One aspect of this is that local network motif analysis of real GRNs indicates that the feed-forward loop (FFL) is significantly enriched. To simulate this properly, we developed a novel motif-based preferential attachment algorithm, FFLatt, which outperformed the popular GeneNetWeaver network generation tool in reproducing the FFL motif occurrence observed in literature-based biological GRNs. It also preserves important topological properties such as scale-free topology, sparsity, and average in/out-degree per node. We conclude that FFLatt is well-suited as a network generation module for a benchmarking framework with the aim to provide fair and robust performance evaluation of GRN inference methods.

  • 1055. Zhu, Baoyi
    et al.
    Ekman, Mari
    Svensson, Daniel
    Lindvall, Jessica M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Lund University, Sweden.
    Nilsson, Bengt-Olof
    Uvelius, Bengt
    Swärd, Karl
    Array profiling reveals contribution of Cthrc1 to growth of the denervated rat urinary bladder2018In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 314, no 5, p. f893-f905Article in journal (Refereed)
    Abstract [en]

    Bladder denervation and bladder outlet obstruction are urological conditions that cause bladder growth. Transcriptomic surveys in outlet obstruction have identified differentially expressed genes, but similar studies following denervation have not been done. This was addressed using a rat model in which the pelvic ganglia were cryo-ablated followed by bladder microarray analyses. At 10 days following denervation, bladder weight had increased 5.6-fold, and 2,890 mRNAs and 135 micro-RNAs (miRNAs) were differentially expressed. Comparison with array data from obstructed bladders demonstrated overlap between the conditions, and 10% of mRNAs changed significantly and in the same direction. Many mRNAs, including collagen triple helix repeat containing 1 (Cthrc1), Prc1, Plod2, and Dkk3, and miRNAs, such as miR-212 and miR-29. resided in the shared signature. Discordantly regulated transcripts in the two models were rare, making up for <0.07% of all changes, and the gene products in this category localized to the urothelium of normal bladders. These transcripts may potentially be used to diagnose sensory denervation. Western blotting demonstrated directionally consistent changes at the protein level, with increases of, e.g., Cthrc1, Prc1, Plod2, and Dkk3. We chose Cthrc1 for further studies and found that Cthrcl was induced in the smooth muscle cell (SMC) layer following denervation. TGF-beta 1 stimulation and miR-30d-5p inhibition increased Cthrc1 in bladder SMCs, and knockdown and overexpression of Cthrc1 reduced and increased SMC proliferation. This work defines common and distinguishing features of bladder denervation and obstruction and suggests a role for Cthrc1 in bladder growth following denervation.

  • 1056. Zhu, Shaotong
    et al.
    Sridhar, Akshay
    Teng, Jinfeng
    Howard, Rebecca J.
    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.
    Hibbs, Ryan E.
    Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 4582Article in journal (Refereed)
    Abstract [en]

    γ-Aminobutyric acid type A (GABAA) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABAA) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABAA receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the α/γ subunit interface and two transmembrane sites at β/α interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABAA receptor allosteric modulators acting through a common site can have diverging activities.

  • 1057.
    Zhu, Wensi
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Shenoy, Aditi
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kundrotas, Petras
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). The University of Kansas, Lawrence, United States.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Evaluation of AlphaFold-Multimer prediction on multi-chain protein complexes2023In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 39, no 7, article id btad424Article in journal (Refereed)
    Abstract [en]

    Motivation: Despite near-experimental accuracy on single-chain predictions, there is still scope for improvement among multimeric predictions. Methods like AlphaFold-Multimer and FoldDock can accurately model dimers. However, how well these methods fare on larger complexes is still unclear. Further, evaluation methods of the quality of multimeric complexes are not well established.

    Results: We analysed the performance of AlphaFold-Multimer on a homology-reduced dataset of homo- and heteromeric protein complexes. We highlight the differences between the pairwise and multi-interface evaluation of chains within a multimer. We describe why certain complexes perform well on one metric (e.g. TM-score) but poorly on another (e.g. DockQ). We propose a new score, Predicted DockQ version 2 (pDockQ2), to estimate the quality of each interface in a multimer. Finally, we modelled protein complexes (from CORUM) and identified two highly confident structures that do not have sequence homology to any existing structures.

    Availability and implementation: All scripts, models, and data used to perform the analysis in this study are freely available at https://gitlab.com/ElofssonLab/afm-benchmark.

  • 1058. Zhu, Yafeng
    et al.
    Engström, Pär G.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Tellgren-Roth, Christian
    Baudo, Charles D.
    Kennell, John C.
    Sun, Sheng
    Billmyre, R. Blake
    Schröder, Markus S.
    Andersson, Anna
    Holm, Tina
    Sigurgeirsson, Benjamin
    Wu, Guangxi
    Sankaranarayanan, Sundar Ram
    Siddharthan, Rahul
    Sanyal, Kaustuv
    Lundeberg, Joakim
    Nystedt, Björn
    Boekhout, Teun
    Dawson, Thomas L.
    Heitman, Joseph
    Scheynius, Annika
    Lehtiö, Janne
    Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 5, p. 2629-2643Article in journal (Refereed)
    Abstract [en]

    Complete and accurate genome assembly and annotation is a crucial foundation for comparative and functional genomics. Despite this, few complete eukaryotic genomes are available, and genome annotation remains a major challenge. Here, we present a complete genome assembly of the skin commensal yeast Malassezia sympodialis and demonstrate how proteogenomics can substantially improve gene an-notation. Through long-read DNA sequencing, we obtained a gap-free genome assembly for M. sympodi-alis (ATCC 42132), comprising eight nuclear and one mitochondrial chromosome. We also sequenced and assembled four M. sympodialis clinical isolates, and showed their value for understanding Malassezia reproduction by confirming four alternative allele combinations at the two mating-type loci. Importantly, we demonstrated how proteomics data could be readily integrated with transcriptomics data in standard annotation tools. This increased the number of annotated protein-coding genes by 14% (from 3612 to 4113), compared to using transcriptomics evidence alone. Manual curation further increased the number of protein-coding genes by 9% (to 4493). All of these genes have RNA-seq evidence and 87% were confirmed by proteomics. The M. sympodialis genome assembly and annotation presented here is at a quality yet achieved only for a few eukaryotic organisms, and constitutes an important reference for future host-microbe interaction studies.

  • 1059. Zhu, Yafeng
    et al.
    Orre, Lukas M.
    Johansson, Henrik J.
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Boekel, Jorrit
    Vesterlund, Mattias
    Fernandez-Woodbridge, Alejandro
    Branca, Rui M. M.
    Lehtiö, Janne
    Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow2018In: Nature Communications, E-ISSN 2041-1723, Vol. 9, article id 903Article in journal (Refereed)
    Abstract [en]

    Proteogenomics enable the discovery of novel peptides (from unannotated genomic protein-coding loci) and single amino acid variant peptides (derived from single-nucleotide polymorphisms and mutations). Increasing the reliability of these identifications is crucial to ensure their usefulness for genome annotation and potential application as neoantigens in cancer immunotherapy. We here present integrated proteogenomics analysis workflow (IPAW), which combines peptide discovery, curation, and validation. IPAW includes the SpectrumAI tool for automated inspection of MS/MS spectra, eliminating false identifications of single-residue substitution peptides. We employ IPAW to analyze two proteomics data sets acquired from A431 cells and five normal human tissues using extended (pH range, 3-10) high-resolution isoelectric focusing (HiRIEF) pre-fractionation and TMT-based peptide quantitation. The IPAW results provide evidence for the translation of pseudogenes, lncRNAs, short ORFs, alternative ORFs, N-terminal extensions, and intronic sequences. Moreover, our quantitative analysis indicates that protein production from certain pseudogenes and lncRNAs is tissue specific.

  • 1060.
    Zhuang, Yuxuan
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Howard, Rebecca J.
    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).
    Symmetry-Adapted Markov State Models of Closing, Opening, and Desensitizing in α7 nicotinic acetylcholine receptorsManuscript (preprint) (Other academic)
    Abstract [en]

    The α7 nicotinic acetylcholine receptors (nAChRs) are homopentameric ligand-gated ion channels gated by the neurotransmitter acetylcholine. These receptors play a crucial role in controlling electrical signaling within the nervous system by facilitating the passage of cations across the membrane. Recent studies have resolved and functionally annotated closed, open, and desensitized states of α7 nAChRs, providing insight into ion permeation and lipid modulation effects. However, the process by which α7 nAChRs transition between states remains unclear. To better understand gating and lipid modulation, we generated two ensembles of molecular dynamics simulations of the apo form of α7 nAChRs, with or without cholesterol. Using symmetry-adapted Markov state modeling, we developed a five-state gating model. As expected for the unliganded condition, the channel predominantly resides in its closed state. The kinetics of the transition from open to one non-conductive intermediate (flipped) state corresponded to an experimentally-measured opening duration of 0.1 ms. The addition of cholesterol led to the stabilization of the desensitized state, and strengthened the coupling between various states. These results establish plausible asymmetric transition pathways between functionally important states, and define lipid modulation effects in the conformational cycle in α7 nAChRs, as well as providing an ensemble of structural models that could be utilized for future rational lipidic drug design.

  • 1061.
    Zhuang, Yuxuan
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Noviello, Colleen M.
    Hibbs, Ryan E.
    Howard, Rebecca J.
    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.
    Differential interactions of resting, activated, and desensitized states of the α7 nicotinic acetylcholine receptor with lipidic modulators2022In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 43, article id e2208081119Article in journal (Refereed)
    Abstract [en]

    The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that modulates neuronal excitability, largely by allowing Ca2+ permeation. Agonist binding promotes transition from a resting state to an activated state, and then rapidly to a desensitized state. Recently, cryogenic electron microscopy (cryo-EM) structures of the human α7 receptor in nanodiscs were reported in multiple conformations. These were selectively stabilized by inhibitory, activating, or potentiating compounds. However, the functional annotation of these structures and their differential interactions with unresolved lipids and ligands remain incomplete. Here, we characterized their ion permeation, membrane interactions, and ligand binding using computational electrophysiology, free-energy calculations, and coarse-grained molecular dynamics. In contrast to nonconductive structures in apparent resting and desensitized states, the structure determined in the presence of the potentiator PNU-120596 was consistent with an activated state permeable to Ca2+. Transition to this state was associated with compression and rearrangement of the membrane, particularly in the vicinity of the peripheral MX helix. An intersubunit transmembrane site was implicated in selective binding of either PNU-120596 in the activated state or cholesterol in the desensitized state. This substantiates functional assignment of all three lipid-embedded α7-receptor structures with ion-permeation simulations. It also proposes testable models of their state-dependent interactions with lipophilic ligands, including a mechanism for allosteric modulation at the transmembrane subunit interface.

  • 1062.
    Zignol, Francesco
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Faculty of Science, The Bolin Centre for Climate Research (together with KTH & SMHI).
    Kjellström, Erik
    Stockholm University, Faculty of Science, Department of Meteorology . Stockholm University, Faculty of Science, The Bolin Centre for Climate Research (together with KTH & SMHI). Swedish Meteorological and Hydrological Institute, Sweden.
    Hylander, Kristoffer
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Faculty of Science, The Bolin Centre for Climate Research (together with KTH & SMHI).
    Nurihun, Biruk Ayalew
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Faculty of Science, The Bolin Centre for Climate Research (together with KTH & SMHI).
    Zewdie, Beyene
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Faculty of Science, The Bolin Centre for Climate Research (together with KTH & SMHI).
    Rodríguez-Gijón, Alejandro
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab). Science for Life Laboratory, Sweden.
    Tack, Ayco J. M.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Faculty of Science, The Bolin Centre for Climate Research (together with KTH & SMHI).
    The understory microclimate in agroforestry now and in the future-a case study of Arabica coffee in its native range2023In: Agricultural and Forest Meteorology, ISSN 0168-1923, E-ISSN 1873-2240, Vol. 340, article id 109586Article in journal (Refereed)
    Abstract [en]

    Climate change is having a major impact on crop production and food security worldwide, and particularly so for smallholder farmers. As agroforestry is common with smallholder farmers, it is important to not only model the macroclimate, but also the microclimate that crops experience below the canopies. However, there are few highresolution spatiotemporal climate projections for forest understories, because of constraints related to the lack of i) development of models for downscaling global climate projections, ii) high-resolution gridded datasets of environmental factors influencing microclimate, and iii) spatially replicated in-situ microclimate measurements. We focused on a landscape in southwestern Ethiopia where Arabica coffee originated, and, in the present day, is commonly grown as a shade crop. We first examined the relative contribution of in-situ field measurements vs. GIS-derived estimates of vegetation and topographic features in explaining in-situ microclimate. Second, we used a statistical downscaling approach to obtain past and future microclimate maps at 30-meter spatial resolution for the part of the landscape that is covered by trees. Predictive models using in-situ variables performed equal to models with GIS variables, indicating that remote sensing data might substitute for in-situ field measurements. Vegetation and topographic features were both important in explaining microclimatic variation. Our spatiotemporal projections of the microclimate indicate that coffee farming might have to relocate to higher altitudes due to increasing temperatures, that vegetation might buffer the macroclimate at middle altitudes to some extent, and that decreasing trends in relative humidity at the beginning of the wet season might become problematic for coffee production. Taken together, our findings demonstrate that we can rely on remote sensing data to create microclimate maps in landscapes where in-situ field measurements are challenging, and we suggest how these microclimate projections can be used as a tool to promote climate-resilient agriculture at the local and landscape levels.

  • 1063. Zivanov, Jasenko
    et al.
    Nakane, Takanori
    Forsberg, Björn O.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kimanius, Dari
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hagen, Wim J. H.
    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.
    Scheres, Sjors H. W.
    New tools for automated high-resolution cryo-EM structure determination in RELION-32018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e42166Article in journal (Refereed)
    Abstract [en]

    Here, we describe the third major release of RELION. CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations. Reference-free autopicking with Laplacian-of-Gaussian filtering and execution of jobs from python allows non-interactive processing during acquisition, including 2D-classification, de novo model generation and 3D-classification. Per-particle refinement of CTF parameters and correction of estimated beam tilt provides higher resolution reconstructions when particles are at different heights in the ice, and/or coma-free alignment has not been optimal. Ewald sphere curvature correction improves resolution for large particles. We illustrate these developments with publicly available data sets: together with a Bayesian approach to beam-induced motion correction it leads to resolution improvements of 0.2-0.7 angstrom compared to previous RELION versions.

  • 1064. Zolotarov, Grygoriy
    et al.
    Fromm, Bastian
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). UiT The Arctic University of Norway, Norway.
    Legnini, Ivano
    Ayoub, Salah
    Polese, Gianluca
    Maselli, Valeria
    Chabot, Peter J.
    Vinther, Jakob
    Styfhals, Ruth
    Seuntjens, Eve
    Di Cosmo, Anna
    Peterson, Kevin J.
    Rajewsky, Nikolaus
    MicroRNAs are deeply linked to the emergence of the complex octopus brain2022In: Science Advances, E-ISSN 2375-2548, Vol. 8, no 47, article id eadd9938Article in journal (Refereed)
    Abstract [en]

    Soft-bodied cephalopods such as octopuses are exceptionally intelligent invertebrates with a highly complex nervous system that evolved independently from vertebrates. Because of elevated RNA editing in their nervous tissues, we hypothesized that RNA regulation may play a major role in the cognitive success of this group. We thus profiled messenger RNAs and small RNAs in three cephalopod species including 18 tissues of the Octopus vulgaris. We show that the major RNA innovation of soft-bodied cephalopods is an expansion of the microRNA (miRNA) gene repertoire. These evolutionarily novel miRNAs were primarily expressed in adult neuronal tissues and during the development and had conserved and thus likely functional target sites. The only comparable miRNA expansions happened, notably, in vertebrates. Thus, we propose that miRNAs are intimately linked to the evolution of complex animal brains. 

  • 1065. Zovko, Ana
    et al.
    Novak, Metka
    Hååg, Petra
    Kovalerchick, Dimitry
    Holmlund, Teresa
    Färnegårdh, Katarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ilan, Micha
    Carmeli, Shmuel
    Lewensohn, Rolf
    Viktorsson, Kristina
    Compounds from the marine sponge Cribrochalina vasculum offer a way to target IGF-1R mediated signaling in tumor cells2016In: Oncotarget, E-ISSN 1949-2553, Vol. 7, no 31, p. 50258-50276Article in journal (Refereed)
    Abstract [en]

    In this work two acetylene alcohols, compound 1 and compound 2, which were isolated and identified from the sponge Cribrochalina vasculum, and which showed antitumor effects were further studied with respect to targets and action mechanisms. Gene expression analyses suggested insulin like growth factor receptor (IGF-1R) signaling to be instrumental in controlling anti-tumor efficacy of these compounds in non-small cell lung cancer (NSCLC). Indeed compounds 1 and 2 inhibited phosphorylation of IGF-1R beta as well as reduced its target signaling molecules IRS-1 and PDK1 allowing inhibition of pro-survival signaling. In silico docking indicated that compound 1 binds to the kinase domain of IGF-1R at the same binding site as the well known tyrosine kinase inhibitor AG1024. Indeed, cellular thermal shift assay (CETSA) confirmed that C. vasculum compound 1 binds to IGF-1R but not to the membrane localized tyrosine kinase receptor EGFR. Importantly, we demonstrate that compound 1 causes IGF-1R beta but not Insulin Receptor degradation specifically in tumor cells with no effects seen in normal diploid fibroblasts. Thus, these compounds hold potential as novel therapeutic agents targeting IGF-1R signaling for anti-tumor treatment.

  • 1066. Zuo, Fanglei
    et al.
    Abolhassani, Hassan
    Du, Likun
    Piralla, Antonio
    Bertoglio, Federico
    de Campos-Mata, Leire
    Wan, Hui
    Schubert, Maren
    Cassaniti, Irene
    Wang, Yating
    Camilla Sammartino, Josè
    Sun, Rui
    Vlachiotis, Stelios
    Bergami, Federica
    Kumagai-Braesch, Makiko
    Andréll, Juni
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Zhang, Zhaoxia
    Xue, Yintong
    Wenzel, Esther Veronika
    Calzolai, Luigi
    Varani, Luca
    Rezaei, Nima
    Chavoshzadeh, Zahra
    Baldanti, Fausto
    Hust, Michael
    Hammarström, Lennart
    Marcotte, Harold
    Pan-Hammarström, Qiang
    Heterologous immunization with inactivated vaccine followed by mRNA-booster elicits strong immunity against SARS-CoV-2 Omicron variant2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 2670Article in journal (Refereed)
    Abstract [en]

    The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.

  • 1067.
    Öjemalm, Karin
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Calado Botelho, Salomé
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Stüdle, Chiara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Quantitative Analysis of SecYEG-Mediated Insertion of Transmembrane alpha-Helices into the Bacterial Inner Membrane2013In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 425, no 15, p. 2813-2822Article in journal (Refereed)
    Abstract [en]

    Most integral membrane proteins, both in prokaryotic and eukaryotic cells, are co-translationally inserted into the membrane via Sec-type translocons: the SecYEG complex in prokaryotes and the Sec61 complex in eukaryotes. The contributions of individual amino acids to the overall free energy of membrane insertion of single transmembrane alpha-helices have been measured for Sec61-mediated insertion into the endoplasmic reticulum (ER) membrane (Nature 450:1026-1030) but have not been systematically determined for SecYEG-mediated insertion into the bacterial inner membrane. We now report such measurements, carried out in Escherichia coli. Overall, there is a good correlation between the results found for the mammalian ER and the E. coli inner membrane, but the hydrophobicity threshold for SecYEG-mediated insertion is distinctly lower than that for Sec61-mediated insertion.

  • 1068.
    Öjemalm, Karin
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Halling, Katrin K.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Orientational Preferences of Neighboring Helices Can Drive ER Insertion of a Marginally Hydrophobic Transmembrane Helix2012In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 45, no 4, p. 529-540Article in journal (Refereed)
    Abstract [en]

    alpha-helical integral membrane proteins critically depend on the correct insertion of their transmembrane alpha helices into the lipid bilayer for proper folding, yet a surprisingly large fraction of the transmembrane alpha helices in multispanning integral membrane proteins are not sufficiently hydrophobic to insert into the target membrane by themselves. How can such marginally hydrophobic segments nevertheless form transmembrane helices in the folded structure? Here, we show that a transmembrane helix with a strong orientational preference (N-cyt-C-lum or N-lum-C-cyt) can both increase and decrease the hydrophobicity threshold for membrane insertion of a neighboring, marginally hydrophobic helix. This effect helps explain the missing hydrophobicity in polytopic membrane proteins.

  • 1069.
    Öjemalm, Karin
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Higuchi, Takashi
    Jiang, Yang
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    White, Stephen H.
    Suga, Hiroaki
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Apolar surface area determines the efficiency of translocon-mediated membrane-protein integration into the endoplasmic reticulum2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 31, p. E359-E364Article in journal (Refereed)
    Abstract [en]

    Integral membrane proteins are integrated cotranslationally into the membrane of the endoplasmic reticulum in a process mediated by the Sec61 translocon. Transmembrane α-helices in a translocating polypeptide chain gain access to the surrounding membrane through a lateral gate in the wall of the translocon channel [van den Berg B, et al. (2004) Nature427:36–44; Zimmer J, et al. (2008) Nature455:936–943; Egea PF, Stroud RM (2010)Proc Natl Acad Sci USA 107:17182–17187]. To clarify the nature of the membrane-integration process, we have measured the insertion efficiency into the endoplasmic reticulum membrane of model hydrophobic segments containing nonproteinogenic aliphatic and aromatic amino acids. We find that an amino acid’s contribution to the apparent free energy of membrane-insertion is directly proportional to the nonpolar accessible surface area of its side chain, as expected for thermodynamic partitioning between aqueous and nonpolar phases. But unlike bulk-phase partitioning, characterized by a nonpolar solvation parameter of 23 cal∕ðmol · Å2Þ, the solvation parameter for transfer from translocon to bilayer is 6 –10 cal∕ðmol · Å2Þ, pointing to important differences between translocon-guided partitioning and simple water-to-membrane partitioning. Our results provide compelling evidence for a termodynamic partitioning model and insights into the physical properties of the translocon.

  • 1070.
    Öjemalm, Karin
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Higuchi, Takashi
    Lara, Patricia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Suga, Hiroaki
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Energetics of side-chain snorkeling in transmembrane helices probed by nonproteinogenic amino acids2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 38, p. 10559-10564Article in journal (Refereed)
    Abstract [en]

    Cotranslational translocon-mediated insertion of membrane proteins into the endoplasmic reticulum is a key process in membrane protein biogenesis. Although the mechanism is understood in outline, quantitative data on the energetics of the process is scarce. Here, we have measured the effect on membrane integration efficiency of nonproteinogenic analogs of the positively charged amino acids arginine and lysine incorporated into model transmembrane segments. We provide estimates of the influence on the apparent free energy of membrane integration (Delta G(app)) of snorkeling of charged amino acids toward the lipid-water interface, and of charge neutralization. We further determine the effect of fluorine atoms and backbone hydrogen bonds (H-bonds) on Delta G(app). These results help establish a quantitative basis for our understanding of membrane protein assembly in eukaryotic cells.

  • 1071. Österberg, Frederik W.
    et al.
    Rizzi, Giovanni
    Donolato, Marco
    Bejhed, Rebecca S.
    Mezger, Anja
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Strömberg, Mattias
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Strømme, Maria
    Svedlindh, Peter
    Hansen, Mikkel F.
    On-Chip Detection of Rolling Circle Amplified DNA Molecules from Bacillus Globigii Spores and Vibrio Cholerae2014In: Small, ISSN 1613-6810, E-ISSN 1613-6829, Vol. 10, no 14, p. 2877-2882Article in journal (Refereed)
    Abstract [en]

    For the first time DNA coils formed by rolling circle amplification are quantified on-chip by Brownian relaxation measurements on magnetic nanobeads using a magnetoresistive sensor. No external magnetic fields are required besides the magnetic field arising from the current through the sensor, which makes the setup very compact. Limits of detection down to 500 Bacillus globigii spores and 2 pM of Vibrio cholerae are demonstrated, which are on the same order of magnitude or lower than those achieved previously using a commercial macro-scale AC susceptometer. The chip-based readout is an important step towards the realization of field tests based on rolling circle amplification molecular analyses.

  • 1072.
    Österlund, Nicklas
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Vosselman, Thibault
    Leppert, Axel
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jörnvall, Hans
    Ilag, Leopold L.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Marklund, Erik G.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Johansson, Jan
    Sahin, Cagla
    Landreh, Michael
    Mass Spectrometry and Machine Learning Reveal Determinants of Client Recognition by Antiamyloid Chaperones2022In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 21, no 10, article id 100413Article in journal (Refereed)
    Abstract [en]

    The assembly of proteins and peptides into amyloid fibrils is causally linked to serious disorders such as Alzheimer’s disease. Multiple proteins have been shown to prevent amyloid formation in vitro and in vivo, ranging from highly specific chaperone–client pairs to completely nonspecific binding of aggregation-prone peptides. The underlying interactions remain elusive. Here, we turn to the machine learning–based structure prediction algorithm AlphaFold2 to obtain models for the nonspecific interactions of β-lactoglobulin, transthyretin, or thioredoxin 80 with the model amyloid peptide amyloid β and the highly specific complex between the BRICHOS chaperone domain of C-terminal region of lung surfactant protein C and its polyvaline target. Using a combination of native mass spectrometry (MS) and ion mobility MS, we show that nonspecific chaperoning is driven predominantly by hydrophobic interactions of amyloid β with hydrophobic surfaces in β-lactoglobulin, transthyretin, and thioredoxin 80, and in part regulated by oligomer stability. For C-terminal region of lung surfactant protein C, native MS and hydrogen–deuterium exchange MS reveal that a disordered region recognizes the polyvaline target by forming a complementary β-strand. Hence, we show that AlphaFold2 and MS can yield atomistic models of hard-to-capture protein interactions that reveal different chaperoning mechanisms based on separate ligand properties and may provide possible clues for specific therapeutic intervention.

  • 1073.
    Östlund, Gabriel
    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). Swedish e-Science Research Centre, Sweden.
    Avoiding pitfalls in gene (co)expression meta-analysis2014In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 103, no 1, p. 21-30Article in journal (Refereed)
    Abstract [en]

    Differential gene expression analysis between healthy and diseased groups is a widely used approach to understand the molecular underpinnings of disease. A wide variety of experimental and bioinformatics techniques are available for this type of analysis, yet their impact on the reliability of the results has not been systematically studied. We performed a large scale comparative analysis of clinical expression data, using several background corrections and differential expression metrics. The agreement between studies was analyzed for study pairs of same cancer type, of different cancer types, and between cancer and non-cancer studies. We also replicated the analysis using differential coexpression. We found that agreement of differential expression is primarily dictated by the microarray platform, while differential coexpression requires large sample sizes. Two studies using different differential expression metrics may show no agreement, even if they agree strongly using the same metric. Our analysis provides practical recommendations for gene (co)expression analysis.

19202122 1051 - 1073 of 1073
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