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  • 51. Flentie, Kelly
    et al.
    Harrison, Gregory A.
    Tükenmez, Hasan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Livny, Jonathan
    Good, James A. D.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sarkar, Souvik
    Zhu, Dennis X.
    Kinsella, Rachel L.
    Weiss, Leslie A.
    Solomon, Samantha D.
    Schene, Miranda E.
    Hansen, Mette R.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cairns, Andrew G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Kulén, Martina
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wixe, Torbjörn
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Lindgren, Anders E. G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
    Bengtsson, Christoffer
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Krishnan, K. Syam
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hultgren, Scott J.
    Larsson, Christer
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Stallings, Christina L.
    Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 21, p. 10510-10517Article in journal (Refereed)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

  • 52. Forbes, Bruce C
    et al.
    Stammler, Florian
    Kumpula, Timo
    Meschtyb, Nina
    Pajunen, Anu
    Kaarlejärvi, Elina
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    High resilience in the Yamal-Nenets social–ecological system, West Siberian Arctic, Russia2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 52, p. 22041-22048Article in journal (Refereed)
    Abstract [en]

    Tundra ecosystems are vulnerable to hydrocarbon development, in part because small-scale, low-intensity disturbances can affect vegetation, permafrost soils, and wildlife out of proportion to their spatial extent. Scaling up to include human residents, tightly integrated arctic social-ecological systems (SESs) are believed similarly susceptible to industrial impacts and climate change. In contrast to northern Alaska and Canada, most terrestrial and aquatic components of West Siberian oil and gas fields are seasonally exploited by migratory herders, hunters, fishers, and domesticated reindeer (Rangifer tarandus L.). Despite anthropogenic fragmentation and transformation of a large proportion of the environment, recent socioeconomic upheaval, and pronounced climate warming, we find the Yamal-Nenets SES highly resilient according to a few key measures. We detail the remarkable extent to which the system has successfully reorganized in response to recent shocks and evaluate the limits of the system's capacity to respond. Our analytical approach combines quantitative methods with participant observation to understand the overall effects of rapid land use and climate change at the level of the entire Yamal system, detect thresholds crossed using surrogates, and identify potential traps. Institutional constraints and drivers were as important as the documented ecological changes. Particularly crucial to success is the unfettered movement of people and animals in space and time, which allows them to alternately avoid or exploit a wide range of natural and anthropogenic habitats. However, expansion of infrastructure, concomitant terrestrial and freshwater ecosystem degradation, climate change, and a massive influx of workers underway present a looming threat to future resilience.

  • 53. Fuchino, Katsuya
    et al.
    Bagchi, Sonchita
    Cantlay, Stuart
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wu, Di
    Bergman, Jessica
    Kamali-Moghaddam, Masood
    Flardh, Klas
    Ausmees, Nora
    Dynamic gradients of an intermediate filament-like cytoskeleton are recruited by a polarity landmark during apical growth2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 21, p. E1889-E1897Article in journal (Refereed)
    Abstract [en]

    Intermediate filament (IF)-like cytoskeleton emerges as a versatile tool for cellular organization in all kingdoms of life, underscoring the importance of mechanistically understanding its diverse manifestations. We showed previously that, in Streptomyces (a bacterium with a mycelial lifestyle similar to that of filamentous fungi, including extreme cell and growth polarity), the IF protein FilP confers rigidity to the hyphae by an unknown mechanism. Here, we provide a possible explanation for the IF-like function of FilP by demonstrating its ability to self-assemble into a cis-interconnected regular network in vitro and its localization into structures consistent with a cytoskeletal network in vivo. Furthermore, we reveal that a spatially restricted interaction between FilP and DivIVA, the main component of the Streptomyces polarisome complex, leads to formation of apical gradients of FilP in hyphae undergoing active tip extension. We propose that the coupling between the mechanism driving polar growth and the assembly of an IF cytoskeleton provides each new hypha with an additional stress-bearing structure at its tip, where the nascent cell wall is inevitably more flexible and compliant while it is being assembled and matured. Our data suggest that recruitment of cytoskeleton around a cell polarity landmark is a broadly conserved strategy in tip-growing cells.

  • 54. Fuchs, I
    et al.
    Philippar, K
    Ljung, K
    Sandberg, G
    Hedrich, R
    Blue light regulates an auxin-induced K+-channel gene in the maize coleoptile2003In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, no 20, p. 11795-11800Article in journal (Refereed)
    Abstract [en]

    Auxin redistribution along gravistimulated maize coleoptiles causes differential expression of the auxin-induced K+-channel gene ZMK1 (Zea mays K+ channel 1) and precedes the curvature response. To evaluate the role of ZMK1 during phototropism, we here investigated blue light-stimulated coleoptiles. Four hours of blue light stimulation resulted in phototropic bending (23degrees). Rotation on a clinostat, at nominally "zero" gravity, and simultaneous stimulation with unidirectional blue light, however, resulted in up to 510 bending toward the light. Differential ZMK1 transcription reached a maximum after 90 min of blue light stimulation under gravity, whereas ZMK1 expression remained asymmetric for at least 180 min in photostimulated coleoptiles on a clinostat. We therefore conclude that the stronger phototropic bending under nominally "zero" gravity results from prolonged differential expression of ZMK1. Under both conditions, asymmetric expression of ZMK1 could be superimposed on the lateral auxin gradient across the coleoptile tip, whereas the gene for the blue light receptor phototropin 1 (PHOT1), expressed in the tip only, was not differentially regulated in response to blue light. The activation of the two different receptors eliciting the photo- and gravitropic response of the coleoptile thus feeds into a common signaling pathway, resulting in auxin redistribution in the coleoptile tip and finally in differential transcription of ZMK1. In the process of signal integration, gravity transduction restricts the magnitude of the blue light-inducible ZMK1 gradient. The spatial and temporal distribution of ZMK1 transcripts and thus differential K+ uptake in both flanks of the coleoptile seem to limit the stimulus-induced bending of this sensory organ.

  • 55. Garrett, Douglas D.
    et al.
    Nagel, Irene E.
    Preuschhof, Claudia
    Burzynska, Agnieszka Z.
    Marchner, Janina
    Wiegert, Steffen
    Jungehuelsing, Gerhard J.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Villringer, Arno
    Li, Shu-Chen
    Heekeren, Hauke R.
    Baeckman, Lars
    Lindenberger, Ulman
    Amphetamine modulates brain signal variability and working memory in younger and older adults2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 24, p. 7593-7598Article in journal (Refereed)
    Abstract [en]

    Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI-based blood oxygen level-dependent (BOLD) signal variability (SDBOLD) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SDBOLD levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SDBOLD and reaction time means (RTmean) and SDs (RTSD). Older adults who received AMPH in the first session tended to improve in RTmean and RTSD when SDBOLD was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SDBOLD decreased (for RTmean) or no effect at all (for RTSD). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state-and practice-dependent neurochemical basis of human brain dynamics.

  • 56.
    Gendre, Delphine
    et al.
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences.
    Oh, Jaesung
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences.
    Boutté, Yohann
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences.
    Best, Jacob G
    Samuels, Lacey
    Nilsson, Robert
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences.
    Uemura, Tomohiro
    Marchant, Alan
    Bennett, Malcolm J
    Grebe, Markus
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Bhalerao, Rishikesh P
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences.
    Conserved Arabidopsis ECHIDNA protein mediates trans-Golgi-network trafficking and cell elongation2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 19, p. 8048-8053Article in journal (Refereed)
    Abstract [en]

    Multiple steps of plant growth and development rely on rapid cell elongation during which secretory and endocytic trafficking via the trans-Golgi network (TGN) plays a central role. Here, we identify the ECHIDNA (ECH) protein from Arabidopsis thaliana as a TGN-localized component crucial for TGN function. ECH partially complements loss of budding yeast TVP23 function and a Populus ECH complements the Arabidopsis ech mutant, suggesting functional conservation of the genes. Compared with wild-type, the Arabidopsis ech mutant exhibits severely perturbed cell elongation as well as defects in TGN structure and function, manifested by the reduced association between Golgi bodies and TGN as well as mislocalization of several TGN-localized proteins including vacuolar H(+)-ATPase subunit a1 (VHA-a1). Strikingly, ech is defective in secretory trafficking, whereas endocytosis appears unaffected in the mutant. Some aspects of the ech mutant phenotype can be phenocopied by treatment with a specific inhibitor of vacuolar H(+)-ATPases, concanamycin A, indicating that mislocalization of VHA-a1 may account for part of the defects in ech. Hence, ECH is an evolutionarily conserved component of the TGN with a central role in TGN structure and function.

  • 57.
    Goldsteins, Gundars
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Persson, Håkan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Karin
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Edvinsson, Åsa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Saraiva, Maria João
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants1999In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 96, no 6, p. 3108-3113Article in journal (Refereed)
    Abstract [en]

    The structural requirements for generation of amyloid from the plasma protein transthyretin (TTR) are not known, although it is assumed that TTR is partly misfolded in amyloid. In a search for structural determinants important for amyloid formation, we generated a TTR mutant with high potential to form amyloid. We demonstrated that the mutant represents an intermediate in a series of conformational changes leading to amyloid. Two monoclonal antibodies were generated against this mutant; each displayed affinity to ex vivo TTR and TTR mutants with amyloidogenic folding but not to wild-type TTR or mutants exhibiting the wild-type fold. Two cryptic epitopes were mapped to a domain of TTR, where most mutations associated with amyloidosis occur and which we propose is displaced at the initial phase of amyloid formation, opening up new surfaces necessary for autoaggregation of TTR monomers. The results provide direct biochemical evidence for structural changes in an amyloidogenic intermediate of TTR.

  • 58. Gros-Louis, Francois
    et al.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Dupre, Nicolas
    Urushitani, Makoto
    Dion, Patrick
    Souchon, Frederique
    D'Amour, Monique
    Camu, William
    Meininger, Vincent
    Bouchard, Jean-Pierre
    Rouleau, Guy A
    Julien, Jean-Pierre
    Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 51, p. 21777-21782Article in journal (Refereed)
    Abstract [en]

    Recently, chromogranins were reported to interact specifically with mutant forms of superoxide dismutase that are linked to amyotrophic lateral sclerosis (ALS). This interaction led us to analyze the frequencies of sequence variants of the CHGB gene in ALS patients and matched controls from three different countries. Of particular interest was the finding of the P413L CHGB variant present in 10% of ALS patients (n = 705) as compared to 4.5% in controls (n = 751), conferring a 2.2-fold greater relative risk to develop the disease (P < 0.0001). This effect was mainly contributed by the samples of French origin that yielded a frequency of the P413L variation at 17% in ALS (n = 289) and 5% in controls (n = 448), conferring a 3.3-fold greater risk to develop ALS. Furthermore, the P413L CHGB variant is associated with an earlier age of onset by almost a decade in both sporadic ALS and familial ALS cases. Genetic variation influencing age of onset in ALS had not previously been reported. Expression of fusion CHGB-EGFP constructs in SHSY-5Y cells revealed that the P413L variation can cause defective sorting of CHGB into secretory granules. The finding that CHGB may act as a susceptibility gene and modifier of onset in ALS is consistent with the emerging view that dysfunction of the secretory pathway may contribute to increased vulnerability of motor neurons.

  • 59.
    Guo, Betty P
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Teneberg, Susann
    Münch, Robert
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Terunuma, Daiyo
    Hatano, Ken
    Matsuoka, Koji
    Angström, Jonas
    Borén, Thomas
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Relapsing fever Borrelia binds to neolacto glycans and mediates rosetting of human erythrocytes.2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 46, p. 19280-19285Article in journal (Refereed)
    Abstract [en]

    A hallmark of acute relapsing fever borreliosis is severe bacteremia. Some Borrelia species, such as B. duttonii and B. crocidurae, associate with erythrocytes and induce aggregation recognized as erythrocyte rosetting. Erythrocyte rosettes contribute to disease severity by increased tissue invasiveness (such as invasion of CNS and encephalitis), hemorrhaging, and reduced blood flow in affected microcapillaries. Here we report that relapsing fever Borrelia binds to neolacto (Galbeta4GlcNAcbeta3Galbeta4Glcbeta1)-carrying glycoconjugates that are present on human erythrocytes. This interaction is of low affinity but is compensated for by the multivalency of neo-lacto-oligosaccharides on the erythrocyte cell surface. Hence, the protein-carbohydrate interaction is dependent on multivalent neolacto-glycans to mediate binding.

  • 60. Haglund, Ellinor
    et al.
    Lind, Jesper
    Öman, Tommy
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Öhman, Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mäler, Lena
    Oliveberg, Mikael
    The HD-exchange motions of ribosomal protein S6 are insensitive to reversal of the protein-folding pathway2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 51, p. 21619-21624Article in journal (Refereed)
    Abstract [en]

    An increasing number of protein structures are found to encompass multiple folding nuclei, allowing their structures to be formed by several competing pathways. A typical example is the ribosomal protein S6, which comprises two folding nuclei (sigma1 and sigma2) defining two competing pathways in the folding energy landscape: sigma1 --> sigma2 and sigma2 --> sigma1. The balance between the two pathways, and thus the order of folding events, is easily controlled by circular permutation. In this study, we make use of this ability to manipulate the folding pathway to demonstrate that the dynamic motions of the S6 structure are independent of how the protein folds. The HD-exchange protection factors remain the same upon complete reversal of the folding order. The phenomenon arises because the HD-exchange motions and the high-energy excitations controlling the folding pathway occur at separated free-energy levels: the Boltzmann distribution of unproductive unfolding attempts samples all unfolding channels in parallel, even those that end up in excessively high barriers. Accordingly, the findings provide a simple rationale for how to interpret native-state dynamics without the need to invoke fluctuations off the normal unfolding reaction coordinate.

  • 61.
    Hall, Michael
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Begum, Afshan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Lindberg, Mikael J.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sauer, Uwe H.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Structural basis for glutathione-mediated activation of the virulence regulatory protein PrfA in Listeria2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 51, p. 14733-14738Article in journal (Refereed)
    Abstract [en]

    Infection by the human bacterial pathogen Listeria monocytogenes is mainly controlled by the positive regulatory factor A (PrfA), a member of the Crp/Fnr family of transcriptional activators. Published data suggest that PrfA requires the binding of a cofactor for full activity, and it was recently proposed that glutathione (GSH) could fulfill this function. Here we report the crystal structures of PrfA in complex with GSH and in complex with GSH and its cognate DNA, the hly operator PrfA box motif. These structures reveal the structural basis for a GSH-mediated allosteric mode of activation of PrfA in the cytosol of the host cell. The crystal structure of PrfAWT in complex only with DNA confirms that PrfAWT can adopt a DNA binding-compatible structure without binding the GSH activator molecule. By binding to PrfA in the cytosol of the host cell, GSH induces the correct fold of the HTH motifs, thus priming the PrfA protein for DNA interaction.

  • 62.
    Hallberg, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Polozkov, Gennady
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hu, Guo-Zhen
    Beve, Jenny
    Gustafsson, Claes M.
    Ronne, Hans
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Site-specific Srb10-dependent phosphorylation of the yeast Mediator subunit Med2 regulates gene expression from the 2-microm plasmid2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 10, p. 3370-3375Article in journal (Refereed)
    Abstract [en]

    The yeast Mediator complex is required for transcriptional regulation both in vivo and in vitro, and its function is conserved in all eukaryotes. Mediator interacts with both transcriptional activators and RNA polymerase II, but little is known about the mechanisms by which it operates at the molecular level. Here, we show that the cyclin-dependent kinase Srb10 interacts with, and phosphorylates, the Med2 subunit of Mediator both in vivo and in vitro. A point mutation of the single phosphorylation site in Med2 results in a strongly reduced expression of the REP1, REP2, FLP1, and RAF1 genes, which are all located on the endogenous 2-microm plasmid. Combined with previous studies on the effects of SRB10/SRB11 deletions, our data suggest that posttranslational modifications of Mediator subunits are important for regulation of gene expression.

  • 63. Hambäck, Peter A
    et al.
    Summerville, Keith S
    Steffan-Dewenter, Ingolf
    Krauss, Jochen
    Englund, Göran
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Crist, Thomas O
    Habitat specialization, body size, and family identity explain lepidopteran density-area relationships in a cross-continental comparison.2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 20, p. 8368-73Article in journal (Refereed)
    Abstract [en]

    Habitat fragmentation may strongly affect species density, species interactions, and the rate of ecosystem processes. It is therefore important to understand the observed variability among species responses to fragmentation and the underlying mechanisms. In this study, we compare density-area relationships (DARs) for 344 lepidopteran species belonging to 22 families (butterflies and moths). This analysis suggested that the DAR(slope) is generally positive for moths and negative for butterflies. The differences are suggested to occur because moths are largely olfactory searchers, whereas most butterflies are visual searchers. The analysis also suggests that DARs vary as a function of habitat specialization and body size. In butterflies, generalist species had a more negative DAR(slope) than specialist species because of a lower patch size threshold. In moths, the differences in DAR(slope) between forest and open habitat species were large for small species but absent for large species. This difference is argued to occur because the DAR(slope) in large species mainly reflects their search mode, which does not necessarily vary between moth groups, whereas the slope in small species reflects population growth rates.

  • 64.
    Hauser, Jannek
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sveshnikova, Natalia
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wallenius, Anders
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Baradaran, Sanna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Saarikettu, Juha
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 4, p. 1267-1272Article in journal (Refereed)
    Abstract [en]

    Upon encountering antigens, B-lymphocytes can adapt to produce a highly specific and potent antibody response. Somatic hypermutation, which introduces point mutations in the variable regions of antibody genes, can increase the affinity for antigen, and antibody effector functions can be altered by class switch recombination (CSR), which changes the expressed constant region exons. Activation-induced cytidine deaminase (AID) is the mutagenic antibody diversification enzyme that is essential for both somatic hypermutation and CSR. The mutagenic AID enzyme has to be tightly controlled. Here, we show that engagement of the membrane-bound antibodies of the B-cell receptor (BCR), which signals that good antibody affinity has been reached, inhibits AID gene expression and that calcium (Ca(2+)) signaling is essential for this inhibition. Moreover, we show that overexpression of the Ca(2+) sensor protein calmodulin inhibits AID gene expression, and that the transcription factor E2A is required for regulation of the AID gene by the BCR. E2A mutated in the binding site for calmodulin, and thus showing calmodulin-resistant DNA binding, makes AID expression resistant to the inhibition through BCR activation. Thus, BCR activation inhibits AID gene expression through Ca(2+)/calmodulin inhibition of E2A.

  • 65. Heskel, Mary A.
    et al.
    Atkin, Owen K.
    O'Sullivan, Odhran S.
    Reich, Peter
    Tjoelker, Mark G.
    Weerasinghe, Lasantha K.
    Penillard, Aurore
    Egerton, John J. G.
    Creek, Danielle
    Bloomfield, Keith J.
    Xiang, Jen
    Sinca, Felipe
    Stangl, Zsofia R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Martinez-de la Torre, Alberto
    Griffin, Kevin L.
    Huntingford, Chris
    Hurry, Vaughan
    Meir, Patrick
    Turnbull, Matthew H.
    Reply to Adams et al.: Empirical versus process-based approaches to modeling temperature responses of leaf respiration2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 41, p. E5996-E5997Article in journal (Refereed)
  • 66. Heskel, Mary A.
    et al.
    O'Sullivan, Odhran S.
    Reich, Peter B.
    Tjoelker, Mark G.
    Weerasinghe, Lasantha K.
    Penillard, Aurore
    Egerton, John J. G.
    Creek, Danielle
    Bloomfield, Keith J.
    Xiang, Jen
    Sinca, Felipe
    Stangl, Zsofia R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Martinez-de la Torre, Alberto
    Griffin, Kevin L.
    Huntingford, Chris
    Hurry, Vaughan
    Meir, Patrick
    Turnbull, Matthew H.
    Atkin, Owen K.
    Convergence in the temperature response of leaf respiration across biomes and plant functional types2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 14, p. 3832-3837Article in journal (Refereed)
    Abstract [en]

    Plant respiration constitutes a massive carbon flux to the atmosphere, and a major control on the evolution of the global carbon cycle. It therefore has the potential to modulate levels of climate change due to the human burning of fossil fuels. Neither current physiological nor terrestrial biosphere models adequately describe its short-term temperature response, and even minor differences in the shape of the response curve can significantly impact estimates of ecosystem carbon release and/or storage. Given this, it is critical to establish whether there are predictable patterns in the shape of the respiration-temperature response curve, and thus in the intrinsic temperature sensitivity of respiration across the globe. Analyzing measurements in a comprehensive database for 231 species spanning 7 biomes, we demonstrate that temperature-dependent increases in leaf respiration do not follow a commonly used exponential function. Instead, we find a decelerating function as leaves warm, reflecting a declining sensitivity to higher temperatures that is remarkably uniform across all biomes and plant functional types. Such convergence in the temperature sensitivity of leaf respiration suggests that there are universally applicable controls on the temperature response of plant energy metabolism, such that a single new function can predict the temperature dependence of leaf respiration for global vegetation. This simple function enables straightforward description of plant respiration in the land-surface components of coupled earth system models. Our cross-biome analyses shows significant implications for such fluxes in cold climates, generally projecting lower values compared with previous estimates.

  • 67. Hoernke, Maria
    et al.
    Mohan, Jagan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kahra, Dana
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Westenhoff, Sebastian
    Schwieger, Christian
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    EHD2 restrains dynamics of caveolae by an ATP-dependent, membrane-bound, open conformation2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 22, p. E4360-E4369Article in journal (Refereed)
    Abstract [en]

    The EH-domain-containing protein 2 (EHD2) is a dynamin-related ATPase that confines caveolae to the cell surface by restricting the scission and subsequent endocytosis of these membrane pits. For this, EHD2 is thought to first bind to the membrane, then to oligomerize, and finally to detach, in a stringently regulated mechanistic cycle. It is still unclear how ATP is used in this process and whether membrane binding is coupled to conformational changes in the protein. Here, we show that the regulatory N-terminal residues and the EH domain keep the EHD2 dimer in an autoinhibited conformation in solution. By significantly advancing the use of infrared reflection-absorption spectroscopy, we demonstrate that EHD2 adopts an open conformation by tilting the helical domains upon membrane binding. We show that ATP binding enables partial insertion of EHD2 into the membrane, where G-domain-mediated oligomerization occurs. ATP hydrolysis is related to detachment of EHD2 from the membrane. Finally, we demonstrate that the regulation of EHD2 oligomerization in a membrane-bound state is crucial to restrict caveolae dynamics in cells.

  • 68. Holmberg, Rebecka
    et al.
    Refai, Essam
    Höög, Anders
    Crooke, Rosanne M
    Graham, Mark
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Berggren, Per-Olof
    Juntti-Berggren, Lisa
    Lowering apolipoprotein CIII delays onset of type 1 diabetes2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 26, p. 10685-10689Article in journal (Refereed)
    Abstract [en]

    Serum levels of apolipoprotein CIII (apoCIII) are increased in type 1 diabetic patients, and when β cells are exposed to these diabetic sera, apoptosis occurs, an effect abolished by an antibody against apoCIII. We have investigated the BB rat, an animal model that develops a human-like type 1 diabetes, and found that apoCIII was also increased in sera from prediabetic rats. This increase in apoCIII promoted β-cell death. The endogenous levels of apoCIII were reduced by treating prediabetic animals with an antisense against this apolipoprotein, resulting in a significantly delayed onset of diabetes. ApoCIII thus serves as a diabetogenic factor, and intervention with this apolipoprotein in the prediabetic state can arrest disease progression. These findings suggest apoCIII as a target for the treatment of type 1 diabetes.

  • 69. Homouz, Dirar
    et al.
    Perham, Michael
    Samiotakis, Antonios
    Cheung, Margaret S
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Crowded, cell-like environment induces shape changes in aspherical protein2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 33, p. 11754-11759Article in journal (Refereed)
    Abstract [en]

    How the crowded environment inside cells affects the structures of proteins with aspherical shapes is a vital question because many proteins and protein–protein complexes in vivo adopt anisotropic shapes. Here we address this question by combining computational and experimental studies of a football-shaped protein (i.e., Borrelia burgdorferi VlsE) in crowded, cell-like conditions. The results show that macromolecular crowding affects protein-folding dynamics as well as overall protein shape. In crowded milieus, distinct conformational changes in VlsE are accompanied by secondary structure alterations that lead to exposure of a hidden antigenic region. Our work demonstrates the malleability of “native” proteins and implies that crowding-induced shape changes may be important for protein function and malfunction in vivo.

  • 70. Jain, Neha
    et al.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nagamatsu, Kanna
    Evans, Margery L.
    Li, Xinyi
    McMichael, Brennan
    Ivanova, Magdalena I.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Buxbaum, Joel N.
    Chapman, Matthew R.
    Inhibition of curli assembly and Escherichia coli biofilm formation by the human systemic amyloid precursor transthyretin2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 46, p. 12184-12189Article in journal (Refereed)
    Abstract [en]

    During biofilm formation, Escherichia coli and other Enterobacteriaceae produce an extracellular matrix consisting of curli amyloid fibers and cellulose. The precursor of curli fibers is the amyloidogenic protein CsgA. The human systemic amyloid precursor protein transthyretin (TTR) is known to inhibit amyloid-β (Aβ) aggregation in vitro and suppress the Alzheimer’s-like phenotypes in a transgenic mouse model of Aβ deposition. We hypothesized that TTR might have broad antiamyloid activity because the biophysical properties of amyloids are largely conserved across species and kingdoms. Here, we report that both human WT tetrameric TTR (WT-TTR) and its engineered nontetramer-forming monomer (M-TTR, F87M/L110M) inhibit CsgA amyloid formation in vitro, with M-TTR being the more efficient inhibitor. Preincubation of WT-TTR with small molecules that occupy the T4 binding site eliminated the inhibitory capacity of the tetramer; however, they did not significantly compromise the ability of M-TTR to inhibit CsgA amyloidogenesis. TTR also inhibited amyloid-dependent biofilm formation in two different bacterial species with no apparent bactericidal or bacteriostatic effects. These discoveries suggest that TTR is an effective antibiofilm agent that could potentiate antibiotic efficacy in infections associated with significant biofilm formation.

  • 71.
    Johansson, Marcus J O
    et al.
    University of Massachusetts Medical School, Department of Molecular Genetics and Microbiology,.
    He, Feng
    University of Massachusetts Medical School, Department of Molecular Genetics and Microbiology,.
    Spatrick, Phyllis
    University of Massachusetts Medical School, Department of Molecular Genetics and Microbiology,.
    Li, Chunfang
    University of Massachusetts Medical School, Department of Molecular Genetics and Microbiology,.
    Jacobson, Allan
    University of Massachusetts Medical School, Department of Molecular Genetics and Microbiology,.
    Association of yeast Upf1p with direct substrates of the NMD pathway.2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 52, p. 20872-7Article in journal (Refereed)
    Abstract [en]

    Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades transcripts containing premature translation termination codons. Gene expression profiling experiments have shown that inactivation of the NMD pathway leads to the accumulation of both aberrant, nonsense-containing mRNAs, and many apparently wild-type transcripts. Such increases in transcript steady-state levels could arise from direct changes in the respective mRNA half-lives, or indirectly, as a consequence of the stabilization of transcripts encoding specific regulatory proteins. Here, we distinguished direct from indirect substrates by virtue of their association with the Saccharomyces cerevisiae Upf1 protein. Analyses of this dataset, and its comparison to the sets of transcripts that respectively increase or decrease in abundance when NMD is either inactivated or reactivated, indicate that the number of direct NMD substrates is larger than previously thought and that low abundance, alternatively transcribed mRNAs, i.e., mRNAs whose 5' ends are derived from previously unannotated 5' flanking sequences, comprise a significant class of direct substrates. Using thiamine metabolism as an example, we also show that apparent NMD-regulated cellular pathways may actually reflect the detection of low-abundance alternative transcripts under conditions where a pathway is repressed.

  • 72.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Elo, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sironen, Reijo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Goldring, Mary
    Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
    Eriksson, John
    †Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Sistonen, Lea
    †Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hsp70 accumulation in chondrocytic cells exposed to high continuous hydrostatic pressure coincides with mRNA stabilization rather than transcriptional activation.1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 5, p. 2319-2324, article id 9482883Article in journal (Refereed)
    Abstract [en]

    In response to various stress stimuli, heat shock genes are induced to express heat shock proteins (Hsps). Previous studies have revealed that expression of heat shock genes is regulated both at transcriptional and posttranscriptional level, and the rapid transcriptional induction of heat shock genes involves activation of the specific transcription factor, heat shock factor 1 (HSF1). Furthermore, the transcriptional induction can vary in intensity and kinetics in a signal- and cell-type-dependent manner. In this study, we demonstrate that mechanical loading in the form of hydrostatic pressure increases heat shock gene expression in human chondrocyte-like cells. The response to continuous high hydrostatic pressure was characterized by elevated mRNA and protein levels of Hsp70, without activation of HSF1 and transcriptional induction of hsp70 gene. The increased expression of Hsp70 was mediated through stabilization of hsp70 mRNA molecules. Interestingly, in contrast to static pressurization, cyclic hydrostatic loading did not result in the induction of heat shock genes. Our findings show that hsp70 gene expression is regulated posttranscriptionally without transcriptional induction in chondrocyte-like cells upon exposure to high continuous hydrostatic pressure. We suggest that the posttranscriptional regulation in the form of hsp70 mRNA stabilization provides an additional mode of heat shock gene regulation that is likely to be of significant importance in certain forms of stress.

  • 73. Kapoor, Amit
    et al.
    Simmonds, Peter
    Gerold, Gisa
    Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065.
    Qaisar, Natasha
    Jain, Komal
    Henriquez, Jose A
    Firth, Cadhla
    Hirschberg, David L
    Rice, Charles M
    Shields, Shelly
    Lipkin, W Ian
    Characterization of a canine homolog of hepatitis C virus2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 28, p. 11608-11613Article in journal (Refereed)
    Abstract [en]

    An estimated 3% of the world's population is chronically infected with hepatitis C virus (HCV). Although HCV was discovered more than 20 y ago, its origin remains obscure largely because no closely related animal virus homolog has been identified; furthermore, efforts to understand HCV pathogenesis have been hampered by the absence of animal models other than chimpanzees for human disease. Here we report the identification in domestic dogs of a nonprimate hepacivirus. Comparative phylogenetic analysis of the canine hepacivirus (CHV) confirmed it to be the most genetically similar animal virus homolog of HCV. Bayesian Markov chains Monte Carlo and associated time to most recent common ancestor analyses suggest a mean recent divergence time of CHV and HCV clades within the past 500-1,000 y, well after the domestication of canines. The discovery of CHV may provide new insights into the origin and evolution of HCV and a tractable model system with which to probe the pathogenesis, prevention, and treatment of diseases caused by hepacivirus infection.

  • 74. Kern, Jan
    et al.
    Alonso-Mori, Roberto
    Hellmich, Julia
    Tran, Rosalie
    Hattne, Johan
    Laksmono, Hartawan
    Glöckner, Carina
    Echols, Nathaniel
    Sierra, Raymond G
    Sellberg, Jonas
    Lassalle-Kaiser, Benedikt
    Gildea, Richard J
    Glatzel, Pieter
    Grosse-Kunstleve, Ralf W
    Latimer, Matthew J
    McQueen, Trevor A
    Difiore, Dörte
    Fry, Alan R
    Messerschmidt, Marc
    Miahnahri, Alan
    Schafer, Donald W
    Seibert, M Marvin
    Sokaras, Dimosthenis
    Weng, Tsu-Chien
    Zwart, Petrus H
    White, William E
    Adams, Paul D
    Bogan, Michael J
    Boutet, Sébastien
    Williams, Garth J
    Messinger, Johannes
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sauter, Nicholas K
    Zouni, Athina
    Bergmann, Uwe
    Yano, Junko
    Yachandra, Vittal K
    Room temperature femtosecond X-ray diffraction of photosystem II microcrystals2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 25, p. 9721-9726Article in journal (Refereed)
    Abstract [en]

    Most of the dioxygen on earth is generated by the oxidation of water by photosystem II (PS II) using light from the sun. This light-driven, four-photon reaction is catalyzed by the Mn(4)CaO(5) cluster located at the lumenal side of PS II. Various X-ray studies have been carried out at cryogenic temperatures to understand the intermediate steps involved in the water oxidation mechanism. However, the necessity for collecting data at room temperature, especially for studying the transient steps during the O-O bond formation, requires the development of new methodologies. In this paper we report room temperature X-ray diffraction data of PS II microcrystals obtained using ultrashort (< 50 fs) 9 keV X-ray pulses from a hard X-ray free electron laser, namely the Linac Coherent Light Source. The results presented here demonstrate that the "probe before destroy" approach using an X-ray free electron laser works even for the highly-sensitive Mn(4)CaO(5) cluster in PS II at room temperature. We show that these data are comparable to those obtained in synchrotron radiation studies as seen by the similarities in the overall structure of the helices, the protein subunits and the location of the various cofactors. This work is, therefore, an important step toward future studies for resolving the structure of the Mn(4)CaO(5) cluster without any damage at room temperature, and of the reaction intermediates of PS II during O-O bond formation.

  • 75. Keunen, Olivier
    et al.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Oudin, Anaïs
    Sanzey, Morgane
    Rahim, Siti A Abdul
    Fack, Fred
    Thorsen, Frits
    Taxt, Torfinn
    Bartos, Michal
    Jirik, Radovan
    Miletic, Hrvoje
    Wang, Jian
    Stieber, Daniel
    Stuhr, Linda
    Moen, Ingrid
    Brekke Rygh, Cecilie
    Bjerkvig, Rolf
    Niclou, Simone P
    Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 9, p. 3749-3754Article in journal (Refereed)
    Abstract [en]

    Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.

  • 76. Kim, Jimi
    et al.
    Lei, Yunping
    Guo, Jin
    Kim, Sung-Eun
    Wlodarczyk, Bogdan J.
    Cabrera, Robert M.
    Lin, Ying Linda
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zhang, Ting
    Ren, Aiguo
    Wang, Linlin
    Yuan, Zhengwei
    Zheng, Yu-Fang
    Wang, Hong-Yan
    Finnell, Richard H.
    Formate rescues neural tube defects caused by mutations in Slc25a322018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 18, p. 4690-4695Article in journal (Refereed)
    Abstract [en]

    Periconceptional folic acid (FA) supplementation significantly reduces the prevalence of neural tube defects (NTDs). Unfortunately, some NTDs are FA resistant, and as such, NTDs remain a global public health concern. Previous studies have identified SLC25A32 as a mitochondrial folate transporter (MFT), which is capable of transferring tetrahydrofolate (THF) from cellular cytoplasm to the mitochondria in vitro. Herein, we show that gene trap inactivation of Slc25a32 (Mft) in mice induces NTDs that are folate (5-methyltetrahydrofolate, 5-mTHF) resistant yet are preventable by formate supplementation. Slc25a32gt/gt embryos die in utero with 100% penetrant cranial NTDs. 5-mTHF supplementation failed to promote normal neural tube closure (NTC) in mutant embryos, while formate supplementation enabled the majority (78%) of knockout embryos to complete NTC. A parallel genetic study in human subjects with NTDs identified biallelic loss of function SLC25A32 variants in a cranial NTD case. These data demonstrate that the loss of functional Slc25a32 results in cranial NTDs in mice and has also been observed in a human NTD patient.

  • 77.
    Koroidov, Sergey
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Shevela, Dmitriy
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Shutova, Tatyana
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Samuelsson, Göran
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Messinger, Johannes
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mobile hydrogen carbonate acts as proton acceptor in photosynthetic water oxidation2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 11, no 17, p. 6299-6304Article in journal (Refereed)
    Abstract [en]

    Cyanobacteria, algae and plants oxidize water to the O2 we breathe, and consume CO2 during the synthesis of biomass. Although these vital processes are functionally and structurally well separated in photosynthetic organisms, there is a long-debated role for CO2/HCO3 in water oxidation. Using membrane-inlet mass spectrometry we demonstrate that HCO3 acts as a mobile proton acceptor that helps to transport the protons produced inside of photosystem II by water-oxidation out into the chloroplast's lumen, resulting in a light-driven production of O2 and CO2. Depletion of HCO3 from the media leads, in the absence of added buffers, to a reversible down-regulation of O2 production by about 20%. These findings add a previously unidentified component to the regulatory network of oxygenic photosynthesis, and conclude the more than 50-y-long quest for the function of CO2/ HCO3 in photosynthetic water oxidation.

  • 78.
    Kovermann, Michael
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. University of Konstanz, Department of Chemistry, Constance, Germany.
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sauer, Uwe H.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wolf-Watz, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Structural basis for ligand binding to an enzyme by a conformational selection pathway2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 24, p. 6298-6303Article in journal (Refereed)
    Abstract [en]

    Proteins can bind target molecules through either induced fit or conformational selection pathways. In the conformational selection model, a protein samples a scarcely populated high-energy state that resembles a target-bound conformation. In enzymatic catalysis, such high-energy states have been identified as crucial entities for activity and the dynamic interconversion between ground states and high-energy states can constitute the rate-limiting step for catalytic turnover. The transient nature of these states has precluded direct observation of their properties. Here, we present a molecular description of a high-energy enzyme state in a conformational selection pathway by an experimental strategy centered on NMR spectroscopy, protein engineering, and X-ray crystallography. Through the introduction of a disulfide bond, we succeeded in arresting the enzyme adenylate kinase in a closed high-energy conformation that is on-pathway for catalysis. A 1.9-angstrom X-ray structure of the arrested enzyme in complex with a transition state analog shows that catalytic side-chains are properly aligned for catalysis. We discovered that the structural sampling of the substrate free enzyme corresponds to the complete amplitude that is associated with formation of the closed and catalytically active state. In addition, we found that the trapped high-energy state displayed improved ligand binding affinity, compared with the wild-type enzyme, demonstrating that substrate binding to the high-energy state is not occluded by steric hindrance. Finally, we show that quenching of fast time scale motions observed upon ligand binding to adenylate kinase is dominated by enzyme-substrate interactions and not by intramolecular interactions resulting from the conformational change.

  • 79. Kristensen, Kristian K.
    et al.
    Midtgaard, Søren Roi
    Mysling, Simon
    Kovrov, Oleg
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hansen, Lars Bo
    Skar-Gislinge, Nicholas
    Beigneux, Anne P.
    Kragelund, Birthe B.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Young, Stephen G.
    Jørgensen, Thomas J. D.
    Fong, Loren G.
    Ploug, Michael
    A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 26, p. E6020-E6029Article in journal (Refereed)
    Abstract [en]

    The intravascular processing of triglyceride-rich lipoproteins depends on lipoprotein lipase (LPL) and GPIHBP1, a membrane protein of endothelial cells that binds LPL within the subendothelial spaces and shuttles it to the capillary lumen. In the absence of GPIHBP1, LPL remains mislocalized within the subendothelial spaces, causing severe hypertriglyceridemia (chylomicronemia). The N-terminal domain of GPIHBP1, an intrinsically disordered region (IDR) rich in acidic residues, is important for stabilizing LPL's catalytic domain against spontaneous and ANGPTL4-catalyzed unfolding. Here, we define several important properties of GPIHBP1's IDR. First, a conserved tyrosine in the middle of the IDR is posttranslationally modified by O-sulfation; this modification increases both the affinity of GPIHBP1-LPL interactions and the ability of GPIHBP1 to protect LPL against. ANGPTL4-catalyzed unfolding. Second, the acidic IDR of GPIHBP1 increases the probability of a GPIHBP1-LPL encounter via electrostatic steering, increasing the association rate constant (k(on)) for LPL binding by >250-fold. Third, we show that LPL accumulates near capillary endothelial cells even in the absence of GPIHBP1. In wild-type mice, we expect that the accumulation of LPL in close proximity to capillaries would increase interactions with GPIHBP1. Fourth, we found that GPIHBP1's IDR is not a key factor in the pathogenicity of chylomicronemia in patients with the GPIHBP1 autoimmune syndrome. Finally, based on biophysical studies, we propose that the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1's ability to preserve LPL structure and activity.

  • 80.
    Kurucz, Eva
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Zettervall, Carl-Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Sinka, Rita
    Vilmos, Peter
    Pivarcsi, Andor
    Ekengren, Sophia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hegedüs, Zoltán
    Ando, Istvan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hemese, a hemocyte-specific transmembrane protein, affects the cellular immune response in Drosophila.2003In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, no 5, p. 2622-7Article in journal (Refereed)
    Abstract [en]

    We have identified a previously undescribed transmembrane protein, Hemese, from Drosophila melanogaster blood cells (hemocytes), by using a monoclonal pan-hemocyte antibody. Heavy glycosylation is suggested by the heterogeneous size distribution, ranging between 37 and 70 kDa. Hemese expression is restricted to the cell surfaces of hemocytes of all classes, and to the hematopoietic organs. The sequence of the corresponding gene, Hemese (He), predicts a glycophorin-like protein of 15 kDa, excluding an N-terminal signal peptide, with a single hydrophobic transmembrane region. The extracellular region consists mainly of Ser/Thr-rich sequence of low complexity, with several potential O-glycosylation sites. Hemese contains phosphotyrosine and the cytoplasmic region has potential phosphorylation sites, suggesting an involvement in signal transduction. Depletion of Hemese by RNA interference has no obvious effect under normal conditions, but the cellular response to parasitic wasps is much enhanced. This finding indicates that Hemese plays a modulatory role in the activation or recruitment of the hemocytes.

  • 81. Lai, Dazhi
    et al.
    Wan, Mimi
    Wu, Jie
    Preston-Hurlburt, Paula
    Kushwaha, Ritu
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Imbalzano, Anthony N
    Chi, Tian
    Induction of TLR4-target genes entails calcium/calmodulin-dependent regulation of chromatin remodeling.2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 4, p. 1169-1174Article in journal (Refereed)
    Abstract [en]

    Upon toll-like receptor 4 (TLR4) signaling in macrophages, the mammalian Swi/Snf-like BAF chromatin remodeling complex is recruited to many TLR4 target genes where it remodels their chromatin to promote transcription. Here, we show that, surprisingly, recruitment is not sufficient for chromatin remodeling; a second event, dependent on calcium/calmodulin (CaM), is additionally required. Calcium/CaM directly binds the HMG domain of the BAF57 subunit within the BAF complex. Calcium/CaM antagonists, including a CaM-binding peptide derived from BAF57, abolish BAF-dependent remodeling and gene expression without compromising BAF recruitment. BAF57 RNAi and BAF57 dominant negative mutants defective in CaM binding similarly impair the induction of BAF target genes. Our data implicate calcium/CaM in TLR4 signaling, and reveal a previously undescribed, recruitment-independent mode of regulation of the BAF complex that is probably achieved through a direct CaM-BAF interaction.

  • 82. Lang, Lisa
    et al.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Danielsson, Jens
    Oliveberg, Mikael
    SOD1 aggregation in ALS mice shows simplistic test tube behavior2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 32, p. 9878-9883Article in journal (Refereed)
    Abstract [en]

    A longstanding challenge in studies of neurodegenerative disease has been that the pathologic protein aggregates in live tissue are not amenable to structural and kinetic analysis by conventional methods. The situation is put in focus by the current progress in demarcating protein aggregation in vitro, exposing new mechanistic details that are now calling for quantitative in vivo comparison. In this study, we bridge this gap by presenting a direct comparison of the aggregation kinetics of the ALS-associated protein superoxide dismutase 1 (SOD1) in vitro and in transgenic mice. The results based on tissue sampling by quantitative antibody assays show that the SOD1 fibrillation kinetics in vitro mirror with remarkable accuracy the spinal cord aggregate buildup and disease progression in transgenic mice. This similarity between in vitro and in vivo data suggests that, despite the complexity of live tissue, SOD1 aggregation follows robust and simplistic rules, providing new mechanistic insights into the ALS pathology and organism-level manifestation of protein aggregation phenomena in general.

  • 83.
    Larsson, Jan
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Svensson, Malin J
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Mäkitalo, Maria
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Painting of fourth in genus Drosophila suggests autosome-specific gene regulation2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 26, p. 9728-9733Article in journal (Refereed)
    Abstract [en]

    Painting of fourth (POF) is a chromosome-specific protein in Drosophila and represents the first example of an autosome-specific protein. POF binds to chromosome 4 in Drosophila melanogaster, initiating at the proximal region, followed by a spreading dependent on chromosome 4-specific sequences or structures. Chromosome-specific gene regulation is known thus far only as a mechanism to equalize the transcriptional activity of the single male X chromosome with that of the two female X chromosomes. In Drosophila, a complex including the male-specific lethal proteins, "paints" the male X chromosome, mediating its hypertranscription, explained to some extent by the acetylation of lysine 16 on histone H4. Here, we show that Pof is essential for viability in both sexes and for female fertility. POF binding to an autosome, the F element, is conserved in genus Drosophila, indicating functional conservation of the autosome specificity. In three of nine studied species, POF binds to the male X chromosome. When bound to the male X, it also colocalizes with the dosage compensation protein male-specific lethal 3, suggesting a relationship to dosage compensation. The chromosome specificity is determined at the species level and not by the amino acid sequence. We argue that POF is involved in a chromosome-specific regulatory function.

  • 84.
    Lenman, Annasara
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Liaci, A. Manuel
    Liu, Yan
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Frank, Martin
    Blaum, Bärbel S.
    Chai, Wengang
    Podgorski, Iva I.
    Harrach, Balázs
    Benko, Mária
    Feizi, Ten
    Stehle, Thilo
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Polysialic acid is a cellular receptor for human adenovirus 522018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 18, p. E4264-E4273Article in journal (Refereed)
    Abstract [en]

    Human adenovirus 52 (HAdV-52) is one of only three known HAdVs equipped with both a long and a short fiber protein. While the long fiber binds to the coxsackie and adenovirus receptor, the function of the short fiber in the virus life cycle is poorly understood. Here, we show, by glycan microarray analysis and cellular studies, that the short fiber knob (SFK) of HAdV-52 recognizes long chains of α-2,8-linked polysialic acid (polySia), a large posttranslational modification of selected carrier proteins, and that HAdV-52 can use polySia as a receptor on target cells. X-ray crystallography, NMR, molecular dynamics simulation, and structure-guided mutagenesis of the SFK reveal that the nonreducing, terminal sialic acid of polySia engages the protein with direct contacts, and that specificity for polySia is achieved through subtle, transient electrostatic interactions with additional sialic acid residues. In this study, we present a previously unrecognized role for polySia as a cellular receptor for a human viral pathogen. Our detailed analysis of the determinants of specificity for this interaction has general implications for protein-carbohydrate interactions, particularly concerning highly charged glycan structures, and provides interesting dimensions on the biology and evolution of members of Human mastadenovirus G.

  • 85. Leonardsson, G
    et al.
    Peng, X R
    Liu, K
    Nordström, L
    Carmeliet, P
    Mulligan, R
    Collen, D
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ovulation efficiency is reduced in mice that lack plasminogen activator gene function: functional redundancy among physiological plasminogen activators.1995In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 92, no 26, p. 12446-50Article in journal (Refereed)
    Abstract [en]

    Several lines of indirect evidence suggest that plasminogen activation plays a crucial role in degradation of the follicular wall during ovulation. However, single-deficient mice lacking tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), or PA inhibitor type 1(PAI-1) gene function were recently found to have normal reproduction, although mice with a combined deficiency of tPA and uPA were significantly less fertile. To investigate whether the reduced fertility of mice lacking PA gene function is due to a reduced ovulation mechanism, we have determined the ovulation efficiency in 25-day-old mice during gonadotropin-induced ovulation. Our results reveal that ovulation efficiency is normal in mice with a single deficiency of tPA or uPA but reduced by 26% in mice lacking both physiological PAs. This result suggests that plasminogen activation plays a role in ovulatory response, although neither tPA nor uPA individually or in combination is obligatory for ovulation. The loss of an individual PA seems to be functionally complemented by the remaining PA but this compensation does not appear to involve any compensatory up-regulation. Our data imply that a functionally redundant mechanism for plasmin formation operates during gonadotropin-induced ovulation and that PAs together with other proteases generate the proteolytic activity required for follicular wall degradation.

  • 86. Leuzinger, Sebastian
    et al.
    Bigler, Christof
    Wolf, Annett
    Umeå University. Swiss Fed Inst Technol, Inst Terr Ecosyst, Dept Environm Sci, CH-8092 Zurich, Switzerland.
    Koerner, Christian
    Poor methodology for predicting large-scale tree die-off2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 38Article in journal (Refereed)
  • 87. Li, Ping
    et al.
    Wind, Julia J
    Shi, Xiaoliang
    Zhang, Honglei
    Hanson, Johannes
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Smeekens, Sjef C
    Teng, Sheng
    Fructose sensitivity is suppressed in Arabidopsis by the transcription factor ANAC089 lacking the membrane-bound domain2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 8, p. 3436-3441Article in journal (Refereed)
    Abstract [en]

    In living organisms sugars not only provide energy and carbon skeletons but also act as evolutionarily conserved signaling molecules. The three major soluble sugars in plants are sucrose, glucose, and fructose. Information on plant glucose and sucrose signaling is available, but to date no fructose-specific signaling pathway has been reported. In this study, sugar repression of seedling development was used to study fructose sensitivity in the Landsberg erecta (Ler)/Cape Verde Islands (Cvi) recombinant inbred line population, and eight fructose-sensing quantitative trait loci (QTLs) (FSQ1-8) were mapped. Among them, FSQ6 was confirmed to be a fructose-specific QTL by analyzing near-isogenic lines in which Cvi genomic fragments were introgressed in the Ler background. These results indicate the existence of a fructose-specific signaling pathway in Arabidopsis. Further analysis demonstrated that the FSQ6-associated fructose-signaling pathway functions independently of the hexokinase1 (HXK1) glucose sensor. Remarkably, fructose-specific FSQ6 downstream signaling interacts with abscisic acid (ABA)- and ethylene-signaling pathways, similar to HXK1-dependent glucose signaling. The Cvi allele of FSQ6 acts as a suppressor of fructose signaling. The FSQ6 gene was identified using map-based cloning approach, and FSQ6 was shown to encode the transcription factor gene Arabidopsis NAC (petunia No apical meristem and Arabidopsis transcription activation factor 1, 2 and Cup-shaped cotyledon 2) domain containing protein 89 (ANAC089). The Cvi allele of FSQ6/ANAC089 is a gain-of-function allele caused by a premature stop in the third exon of the gene. The truncated Cvi FSQ6/ANAC089 protein lacks a membrane association domain that is present in ANAC089 proteins from other Arabidopsis accessions. As a result, Cvi FSQ6/ANAC089 is constitutively active as a transcription factor in the nucleus.

  • 88. Li, Y
    et al.
    Bjorklund, Stefan
    Jiang, Y W
    Kim, Y J
    Lane, W S
    Stillman, D J
    Kornberg, R D
    Yeast global transcriptional regulators Sin4 and Rgr1 are components of mediator complex/RNA polymerase II holoenzyme.1995In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 92, no 24, p. 10864-8Article in journal (Refereed)
    Abstract [en]

    Sin4 and Rgr1 proteins, previously shown by genetic studies to play both positive and negative roles in the transcriptional regulation of many genes, are identified here as components of mediator and RNA polymerase II holoenzyme complexes. Results with Sin4 deletion and Rgr1 truncation strains indicate the association of these proteins in a subcomplex comprising Sin4, Rgr1, Gal11, and a 50-kDa polypeptide. Taken together with the previous genetic evidence, our findings point to a role of the mediator in repression as well as in transcriptional activation.

  • 89. Lin, Yao-Cheng
    et al.
    Wang, Jing
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Centre for Integrative Genetics (CIGENE), Department of Animal and Aquacultural Sciences, Faculty of Biosciences, Norwegian University of Life Sciences, Ås, Norway.
    Delhomme, Nicolas
    Schiffthaler, Bastian
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Sundström, Görel
    Zuccolo, Andrea
    Nystedt, Björn
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    de la Torre, Amanda
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). School of Forestry, Northern Arizona University, Flagstaff, AZ.
    Cossu, Rosa M.
    Hoeppner, Marc P.
    Lantz, Henrik
    Scofield, Douglas G.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Ecology and Genetics: Evolutionary Biology, Uppsala University, Sweden; Uppsala Multidisciplinary Center for Advanced Computational Science, Uppsala University, Sweden.
    Zamani, Neda
    Johansson, Anna
    Mannapperuma, Chanaka
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Robinson, Kathryn M.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Mähler, Niklas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Leitch, Ilia J.
    Pellicer, Jaume
    Park, Eung-Jun
    Van Montagu, Marc
    Van de Peer, Yves
    Grabherr, Manfred
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Ingvarsson, Pär K.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Plant Biology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Street, Nathaniel R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Functional and evolutionary genomic inferences in Populus through genome and population sequencing of American and European aspen2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 46, p. E10970-E10978Article in journal (Refereed)
    Abstract [en]

    The Populus genus is one of the major plant model systems, but genomic resources have thus far primarily been available for poplar species, and primarily Populus trichocarpa (Torr. & Gray), which was the first tree with a whole-genome assembly. To further advance evolutionary and functional genomic analyses in Populus, we produced genome assemblies and population genetics resources of two aspen species, Populus tremula L. and Populus tremuloides Michx. The two aspen species have distributions spanning the Northern Hemisphere, where they are keystone species supporting a wide variety of dependent communities and produce a diverse array of secondary metabolites. Our analyses show that the two aspens share a similar genome structure and a highly conserved gene content with P. trichocarpa but display substantially higher levels of heterozygosity. Based on population resequencing data, we observed widespread positive and negative selection acting on both coding and noncoding regions. Furthermore, patterns of genetic diversity and molecular evolution in aspen are influenced by a number of features, such as expression level, coexpression network connectivity, and regulatory variation. To maximize the community utility of these resources, we have integrated all presented data within the PopGenIE web resource (PopGenIE.org).

  • 90. Lind, Peter A
    et al.
    Andersson, Dan I
    Whole-genome mutational biases in bacteria.2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 46Article in journal (Refereed)
    Abstract [en]

    A fundamental biological question is what forces shape the guanine plus cytosine (GC) content of genomes. We studied the specificity and rate of different mutational biases in real time in the bacterium Salmonella typhimurium under conditions of strongly reduced selection and in the absence of the major DNA repair systems involved in repairing common spontaneous mutations caused by oxidized and deaminated DNA bases. The mutational spectrum was determined by whole-genome sequencing of two S. typhimurium mutants that were serially passaged for 5,000 generations. Analysis of 943 identified base pair substitutions showed that 91% were GC-to-TA transversions and 7% were GC-to-AT transitions, commonly associated with 8-oxoG- and deamination-induced damages, respectively. Other types of base pair substitutions constituted the remaining 2% of the mutations. With regard to mutational biases, there was a significant increase in C-to-T transitions on the nontranscribed strand, and for highly expressed genes, C/G-to-T mutations were more common than expected; however, no significant mutational bias with regard to leading and lagging strands of replication or chromosome position were found. These results suggest that, based on the experimentally determined mutational rates and specificities, a bacterial genome lacking the relevant DNA repair systems could, as a consequence of these underlying mutational biases, very rapidly reduce its GC content.

  • 91.
    Lu, Xin
    et al.
    Karolinska Institute.
    Bengtsson, Linus
    Karolinska Institute.
    Holme, Petter
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Predictability of population displacement after the 2010 Haiti earthquake2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 29, p. 11576-11581Article in journal (Refereed)
    Abstract [en]

    Most severe disasters cause large population movements. These movements make it difficult for relief organizations to efficiently reach people in need. Understanding and predicting the locations of affected people during disasters is key to effective humanitarian relief operations and to long-term societal reconstruction. We collaborated with the largest mobile phone operator in Haiti (Digicel) and analyzed the movements of 1.9 million mobile phone users during the period from 42 d before, to 341 d after the devastating Haiti earthquake of January 12, 2010. Nineteen days after the earthquake, population movements had caused the population of the capital Port-au-Prince to decrease by an estimated 23%. Both the travel distances and size of people’s movement trajectories grew after the earthquake. These findings, in combination with the disorder that was present after the disaster, suggest that people’s movements would have become less predictable. Instead, the predictability of people’s trajectories remained high and even increased slightly during the three-month period after the earthquake. Moreover, the destinations of people who left the capital during the first three weeks after the earthquake was highly correlated with their mobility patterns during normal times, and specifically with the locations in which people had significant social bonds. For the people who left Port-au-Prince, the duration of their stay outside the city, as well as the time for their return, all followed a skewed, fat-tailed distribution. The findings suggest that population movements during disasters may be significantly more predictable than previously thought.

  • 92. Lund, B
    et al.
    Edlund, T
    Lindenmaier, W
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Collins, J
    Lundgren, E
    von Gabain, A
    Novel cluster of alpha-interferon gene sequences in a placental cosmid DNA library.1984In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 81, no 8, p. 2435-9Article in journal (Refereed)
    Abstract [en]

    A human cosmid library was constructed and probed with a human alpha interferon (IFN-alpha) cDNA clone. One clone giving a strong hybridizing signal was isolated and characterized. The cosmid DNA insert represents a section of the human genome containing three regions of IFN-alpha-like sequences. The DNA was characterized with restriction endonuclease mapping, thereby allowing comparison to similar linkage groups reported recently and determination of homologous regions on the known physical map. The three IFN-alpha-like sequences were analyzed by a partial sequence analysis. Mapping and sequence data establish this section as a not-yet-described cluster of IFN-alpha sequences in the human genome; however, a part of the section matches to some degree to a previously described genomic region. The region described here could represent genetic polymorphism or a duplicated segment.

  • 93.
    Lécrivain, Anne-Laure
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Max Planck Unit for the Science of Pathogens, Berlin, Germany; Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Le Rhun, Anaïs
    Max Planck Unit for the Science of Pathogens, Berlin, Germany; Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Renault, Thibaud T.
    Max Planck Unit for the Science of Pathogens, Berlin, Germany; Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany; nstitute for Biology, Humboldt University, Berlin, Germany .
    Ahmed-Begrich, Rina
    Max Planck Unit for the Science of Pathogens, Berlin, Germany; Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Hahnke, Karin
    Max Planck Unit for the Science of Pathogens, Berlin, Germany; Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Charpentier, Emmanuelle
    Max Planck Unit for the Science of Pathogens, Berlin, Germany; Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany; nstitute for Biology, Humboldt University, Berlin, Germany.
    In vivo 3′-to-5′ exoribonuclease targetomes of Streptococcus pyogenes2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 46, p. 11814-11819Article in journal (Refereed)
    Abstract [en]

    mRNA decay plays an essential role in the control of gene expression in bacteria. Exoribonucleases (exoRNases), which trim transcripts starting from the 5′ or 3′ end, are particularly important to fully degrade unwanted transcripts and renew the pool of nucleotides available in the cell. While recent techniques have allowed genome-wide identification of ribonuclease (RNase) targets in bacteria in vivo, none of the 3′-to-5′ exoRNase targetomes (i.e., global processing sites) have been studied so far. Here, we report the targetomes of YhaM, polynucleotide phosphorylase (PNPase), and RNase R of the human pathogen Streptococcus pyogenes. We determined that YhaM is an unspecific enzyme that trims a few nucleotides and targets the majority of transcript ends, generated either by transcription termination or by endonucleolytic activity. The molecular determinants for YhaM-limited processivity are yet to be deciphered. We showed that PNPase clears the cell from mRNA decay fragments produced by endoribonucleases (endoRNases) and is the major 3′-to-5′ exoRNase for RNA turnover in S. pyogenes. In particular, PNPase is responsible for the degradation of regulatory elements from 5′ untranslated regions. However, we observed little RNase R activity in standard culture conditions. Overall, our study sheds light on the very distinct features of S. pyogenes 3′-to-5′ exoRNases.

  • 94. Malaker, Stacy A.
    et al.
    Pedram, Kayvon
    Ferracane, Michael J.
    Bensing, Barbara A.
    Krishnan, Venkatesh
    Pett, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Leibniz-Institut für Analytische Wissenschaften (ISAS), 44227 Dortmund, Germany.
    Yu, Jin
    Woods, Elliot C.
    Kramer, Jessica R.
    Westerlind, Ulrika
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Leibniz-Institut für Analytische Wissenschaften (ISAS), 44227 Dortmund, Germany.
    Dorigo, Oliver
    Bertozzi, Carolyn R.
    The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no (15), p. 7278-7287Article in journal (Refereed)
    Abstract [en]

    Mucin-domain glycoproteins are found in nearly every tissue of the human body, and are important in biological processes ranging from embryogenesis to cancer. Because there are few tools to study mucin domains, their biological functions at the molecular scale remain unclear. Here, we help address a hurdle to the study of mucin-domain glycoproteins by characterizing a bacterial protease with selectivity for mucins. This mucinase selectively removes native mucins from cell surfaces and cuts them into fragments amenable to analysis.Mucin domains are densely O-glycosylated modular protein domains that are found in a wide variety of cell surface and secreted proteins. Mucin-domain glycoproteins are known to be key players in a host of human diseases, especially cancer, wherein mucin expression and glycosylation patterns are altered. Mucin biology has been difficult to study at the molecular level, in part, because methods to manipulate and structurally characterize mucin domains are lacking. Here, we demonstrate that secreted protease of C1 esterase inhibitor (StcE), a bacterial protease from Escherichia coli, cleaves mucin domains by recognizing a discrete peptide- and glycan-based motif. We exploited StcE’s unique properties to improve sequence coverage, glycosite mapping, and glycoform analysis of recombinant human mucins by mass spectrometry. We also found that StcE digests cancer-associated mucins from cultured cells and from ascites fluid derived from patients with ovarian cancer. Finally, using StcE, we discovered that sialic acid-binding Ig-type lectin-7 (Siglec-7), a glycoimmune checkpoint receptor, selectively binds sialomucins as biological ligands, whereas the related receptor Siglec-9 does not. Mucin-selective proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of mucin domain structure and function.

  • 95.
    Maurya, Devendra Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Alenius, Mattias
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hedgehog signaling regulates ciliary localization of mouse odorant receptors2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 44, p. E9386-E9394Article in journal (Refereed)
    Abstract [en]

    The ciliary localization of odorant receptors (ORs) is evolutionary conserved and essential for olfactory transduction. However, how the transport of ORs is regulated in mammalian olfactory sensory neurons is poorly understood. Here we demonstrate that odorant responsiveness and OR transport is regulated by the Hedgehog pathway. OR transport is inhibited by conditional gene inactivation of the Hedgehog signal mediator Smoothened (Smo) as well as by systemic administration of the Smo inhibitor vismodegib, a clinically used anticancer drug reported to distort smell perception in patients. The ciliary phenotype of Smo inhibition is haploinsufficient, cell autonomous, and correlates with the accumulation of OR-containing putative transport vesicles in the cytosol. The Smo-dependent OR transport route works in parallel with a low basal transport of vesicle containing both ORs and other olfactory transduction components. These findings both define a physio logical function of Hedgehog signaling in olfaction and provide an important evolutionary link between olfaction and the requirement of a ciliary compartment for Hedgehog signaling.

  • 96. Mellin, JR
    et al.
    Tiensuu, Teresa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Becavin, Christophe
    Gouin, Edith
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cossart, Pascale
    A riboswitch-regulated antisense RNA in Listeria monocytogenes2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 32, p. 13132-13137Article in journal (Refereed)
  • 97. Melo, Arthur Alves
    et al.
    Hegde, Balachandra G.
    Shah, Claudio
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Isas, J. Mario
    Kunz, Severine
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Langen, Ralf
    Daumke, Oliver
    Structural insights into the activation mechanism of dynamin-like EHD ATPases2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 22, p. 5629-5634Article in journal (Refereed)
    Abstract [en]

    Eps15 (epidermal growth factor receptor pathway substrate 15)homology domain containing proteins (EHDs) comprise a family of dynamin-related mechano-chemical ATPases involved in cellular membrane trafficking. Previous studies have revealed the structure of the EHD2 dimer, but the molecular mechanisms of membrane recruitment and assembly have remained obscure. Here, we determined the crystal structure of an amino-terminally truncated EHD4 dimer. Compared with the EHD2 structure, the helical domains are 50 degrees rotated relative to the GTPase domain. Using electron paramagnetic spin resonance (EPR), we show that this rotation aligns the two membrane-binding regions in the helical domain toward the lipid bilayer, allowing membrane interaction. A loop rearrangement in GTPase domain creates a new interface for oligomer formation. Our results suggest that the EHD4 structure represents the active EHD conformation, whereas the EHD2 structure is autoinhibited, and reveal a complex series of domain rearrangements accompanying activation. A comparison with other peripheral membrane proteins elucidates common and specific features of this activation mechanism.

  • 98.
    Mertz, Tony M
    et al.
    Omaha, Nebraska, USA.
    Sharma, Sushma
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Shcherbakova, Polina V
    Omaha, Nebraska, USA.
    Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 19, p. E2467-E2476Article in journal (Refereed)
    Abstract [en]

    Defects in DNA polymerases δ (Polδ) and ε (Polε) cause hereditary colorectal cancer and have been implicated in the etiology of some sporadic colorectal and endometrial tumors. We previously reported that the yeast pol3-R696W allele mimicking a human cancer-associated variant, POLD1-R689W, causes a catastrophic increase in spontaneous mutagenesis. Here, we describe the mechanism of this extraordinary mutator effect. We found that the mutation rate increased synergistically when the R696W mutation was combined with defects in Polδ proofreading or mismatch repair, indicating that pathways correcting DNA replication errors are not compromised in pol3-R696W mutants. DNA synthesis by purified Polδ-R696W was error-prone, but not to the extent that could account for the unprecedented mutator phenotype of pol3-R696W strains. In a search for cellular factors that augment the mutagenic potential of Polδ-R696W, we discovered that pol3-R696W causes S-phase checkpoint-dependent elevation of dNTP pools. Abrogating this elevation by strategic mutations in dNTP metabolism genes eliminated the mutator effect of pol3-R696W, whereas restoration of high intracellular dNTP levels restored the mutator phenotype. Further, the use of dNTP concentrations present in pol3-R696W cells for in vitro DNA synthesis greatly decreased the fidelity of Polδ-R696W and produced a mutation spectrum strikingly similar to the spectrum observed in vivo. The results support a model in which (i) faulty synthesis by Polδ-R696W leads to a checkpoint-dependent increase in dNTP levels and (ii) this increase mediates the hypermutator effect of Polδ-R696W by facilitating the extension of mismatched primer termini it creates and by promoting further errors that continue to fuel the mutagenic pathway.

  • 99.
    Meyer-Jacob, Carsten
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Tolu, Julie
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Bigler, Christian
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Yang, Handong
    Environmental Change Research Centre, University College London, London WC1E 6BT, United Kingdom.
    Bindler, Richard
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Early land use and centennial scale changes in lake-water organic carbon prior to contemporary monitoring2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 21, p. 6579-6584Article in journal (Refereed)
    Abstract [en]

    Organic carbon concentrations have increased in surface waters across parts of Europe and North America during the past decades, but the main drivers causing this phenomenon are still debated. A lack of observations beyond the last few decades inhibits a better mechanistic understanding of this process and thus a reliable prediction of future changes. Here we present past lake-water organic carbon trends inferred from sediment records across central Sweden that allow us to assess the observed increase on a centennial to millennial time scale. Our data show the recent increase in lake-water carbon but also that this increase was preceded by a landscape-wide, long-term decrease beginning already A. D. 1450-1600. Geochemical and biological proxies reveal that these dynamics coincided with an intensification of human catchment disturbance that decreased over the past century. Catchment disturbance was driven by the expansion and later cessation of widespread summer forest grazing and farming across central Scandinavia. Our findings demonstrate that early land use strongly affected past organic carbon dynamics and suggest that the influence of historical landscape utilization on contemporary changes in lake-water carbon levels has thus far been underestimated. We propose that past changes in land use are also a strong contributing factor in ongoing organic carbon trends in other regions that underwent similar comprehensive changes due to early cultivation and grazing over centuries to millennia.

  • 100. Michel, F Marc
    et al.
    Barrón, Vidal
    Torrent, José
    Morales, María P
    Serna, Carlos J
    Boily, Jean-François
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Liu, Qingsong
    Ambrosini, Andrea
    Cismasu, A Cristina
    Brown, Gordon E
    Ordered ferrimagnetic form of ferrihydrite reveals links among structure, composition, and magnetism2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 7, p. 2787-92Article in journal (Refereed)
    Abstract [en]

    The natural nanomineral ferrihydrite is an important component of many environmental and soil systems and has been implicated as the inorganic core of ferritin in biological systems. Knowledge of its basic structure, composition, and extent of structural disorder is essential for understanding its reactivity, stability, and magnetic behavior, as well as changes in these properties during aging. Here we investigate compositional, structural, and magnetic changes that occur upon aging of "2-line" ferrihydrite in the presence of adsorbed citrate at elevated temperature. Whereas aging under these conditions ultimately results in the formation of hematite, analysis of the atomic pair distribution function and complementary physicochemical and magnetic data indicate formation of an intermediate ferrihydrite phase of larger particle size with few defects, more structural relaxation and electron spin ordering, and pronounced ferrimagnetism relative to its disordered ferrihydrite precursor. Our results represent an important conceptual advance in understanding the nature of structural disorder in ferrihydrite and its relation to the magnetic structure and also serve to validate a controversial, recently proposed structural model for this phase. In addition, the pathway we identify for forming ferrimagnetic ferrihydrite potentially explains the magnetic enhancement that typically precedes formation of hematite in aerobic soil and weathering environments. Such magnetic enhancement has been attributed to the formation of poorly understood, nano-sized ferrimagnets from a ferrihydrite precursor. Whereas elevated temperatures drive the transformation on timescales feasible for laboratory studies, our results also suggest that ferrimagnetic ferrihydrite could form naturally at ambient temperature given sufficient time.

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