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  • 1.
    Abdollahi Sani, Negar
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Robertsson, Mats
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Cooper, Philip
    De La Rue Plc, Overton, Hampshire, UK .
    Wang, Xin
    Acreo AB, Norrköping, Sweden.
    Svensson, Magnus
    Acreo AB, Norrköping, Sweden.
    Andersson Ersman, Peter
    Acreo AB, Norrköping, Sweden.
    Norberg, Petronella
    Acreo AB, Norrköping, Sweden.
    Nilsson, Marie
    Acreo AB, Norrköping, Sweden.
    Nilsson, David
    Acreo AB, Norrköping, Sweden.
    Liu, Xianjie
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry. Linköping University, The Institute of Technology.
    Hesselbom, Hjalmar
    Hesselbom Innovation and Development HB, Huddinge, Sweden .
    Akesso, Laurent
    De La Rue Plc, Overton, Hampshire, UK .
    Fahlman, Mats
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry. Linköping University, The Institute of Technology.
    Crispin, Xavier
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Engquist, Isak
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology. Acreo AB, Norrköping, Sweden.
    Gustafsson, Goran
    Acreo AB, Norrköping, Sweden.
    All-printed diode operating at 1.6 GHz2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 33, p. 11943-11948Article in journal (Refereed)
    Abstract [en]

    Printed electronics are considered for wireless electronic tags and sensors within the future Internet-of-things (IoT) concept. As a consequence of the low charge carrier mobility of present printable organic and inorganic semiconductors, the operational frequency of printed rectifiers is not high enough to enable direct communication and powering between mobile phones and printed e-tags. Here, we report an all-printed diode operating up to 1.6 GHz. The device, based on two stacked layers of Si and NbSi2 particles, is manufactured on a flexible substrate at low temperature and in ambient atmosphere. The high charge carrier mobility of the Si microparticles allows device operation to occur in the charge injection-limited regime. The asymmetry of the oxide layers in the resulting device stack leads to rectification of tunneling current. Printed diodes were combined with antennas and electrochromic displays to form an all-printed e-tag. The harvested signal from a Global System for Mobile Communications mobile phone was used to update the display. Our findings demonstrate a new communication pathway for printed electronics within IoT applications.

  • 2.
    Abelein, Axel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Zinc as chaperone-mimicking agent for retardation of amyloid beta peptide fibril formation2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 17, p. 5407-5412Article in journal (Refereed)
    Abstract [en]

    Metal ions have emerged to play a key role in the aggregation process of amyloid beta (A beta) peptide that is closely related to the pathogenesis of Alzheimer's disease. A detailed understanding of the underlying mechanistic process of peptide-metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic A beta-Zn2+ binding features as well as how Zn2+ modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn2+ effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc A beta(40) aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn2+, the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn2+ transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn2+ ion, forming a marginally stable, short-lived folded A beta(40) species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded A beta(40)-Zn2+ complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for A beta(40).

  • 3. Abraham, Nabil M.
    et al.
    Liu, Lei
    Jutras, Brandon Lyon
    Yadav, Akhilesh K.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Narasimhan, Sukanya
    Gopalakrishnan, Vissagan
    Ansari, Juliana M.
    Jefferson, Kimberly K.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Jacobs-Wagner, Christine
    Fikrig, Erol
    Pathogen-mediated manipulation of arthropod microbiota to promote infection2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 5, p. E781-E790Article in journal (Refereed)
    Abstract [en]

    Arthropods transmit diverse infectious agents; however, the ways microbes influence their vector to enhance colonization are poorly understood. Ixodes scapularis ticks harbor numerous human pathogens, including Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis. We now demonstrate that A. phagocytophilum modifies the I. scapularis microbiota to more efficiently infect the tick. A. phagocytophilum induces ticks to express Ixodes scapularis antifreeze glycoprotein (iafgp), which encodes a protein with several properties, including the ability to alter bacterial biofilm formation. IAFGP thereby perturbs the tick gut microbiota, which influences the integrity of the peritrophic matrix and gut barrier-critical obstacles for Anaplasma colonization. Mechanistically, IAFGP binds the terminal D-alanine residue of the pentapeptide chain of bacterial peptidoglycan, resulting in altered permeability and the capacity of bacteria to form biofilms. These data elucidate the molecular mechanisms by which a human pathogen appropriates an arthropod antibacterial protein to alter the gut microbiota and more effectively colonize the vector.

  • 4.
    Acerbi, Alberto
    et al.
    Department of Psychology, University of Bologna.
    Enquist, Magnus
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution. Stockholm University, Faculty of Science, Department of Zoology, Department of Ethology.
    Ghirlanda, Stefano
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution.
    Cultural evolution and individual development of openness and conservatism2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 45, p. 18931-18935Article in journal (Refereed)
    Abstract [en]

    We present a model of cultural evolution in which an individual's propensity to engage in social learning is affected by social learning itself. We assume that individuals observe cultural traits displayed by others and decide whether to copy them based on their overall preference for the displayed traits. Preferences, too, can be transmitted between individuals. Our results show that such cultural dynamics tends to produce conservative individuals, i.e., individuals who are reluctant to copy new traits. Openness to new information, however, can be maintained when individuals need significant time to acquire the cultural traits that make them effective cultural models. We show that a gradual enculturation of young individuals by many models and a larger cultural repertoire to be acquired are favorable circumstances for the long-term maintenance of openness in individuals and groups. Our results agree with data about lifetime personality change, showing that openness to new information decreases with age. Our results show that cultural remodeling of cultural transmission is a powerful force in cultural evolution, i.e., that cultural evolution can change its own dynamics

  • 5. Achen, M G
    et al.
    Jeltsch, M
    Kukk, E
    Mäkinen, T
    Vitali, A
    Wilks, A F
    Alitalo, K
    Stacker, S A
    Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 2Article in journal (Refereed)
    Abstract [en]

    We have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.

  • 6. Adamczyk, Andrew J.
    et al.
    Cao, Jie
    Kamerlin, Shina C. Lynn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Warshel, Arieh
    Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 34, p. 14115-14120Article in journal (Refereed)
    Abstract [en]

    The proposal that enzymatic catalysis is due to conformational fluctuations has been previously promoted by means of indirect considerations. However, recent works have focused on cases where the relevant motions have components toward distinct conformational regions, whose population could be manipulated by mutations. In particular, a recent work has claimed to provide direct experimental evidence for a dynamical contribution to catalysis in dihydrofolate reductase, where blocking a relevant conformational coordinate was related to the suppression of the motion toward the occluded conformation. The present work utilizes computer simulations to elucidate the true molecular basis for the experimentally observed effect. We start by reproducing the trend in the measured change in catalysis upon mutations (which was assumed to arise as a result of a "dynamical knockout" caused by the mutations). This analysis is performed by calculating the change in the corresponding activation barriers without the need to invoke dynamical effects. We then generate the catalytic landscape of the enzyme and demonstrate that motions in the conformational space do not help drive catalysis. We also discuss the role of flexibility and conformational dynamics in catalysis, once again demonstrating that their role is negligible and that the largest contribution to catalysis arises from electrostatic preorganization. Finally, we point out that the changes in the reaction potential surface modify the reorganization free energy (which includes entropic effects), and such changes in the surface also alter the corresponding motion. However, this motion is never the reason for catalysis, but rather simply a reflection of the shape of the reaction potential surface.

  • 7. Agerberth, B
    et al.
    Gunne, H
    Odeberg, Jacob
    KTH, Superseded Departments, Biotechnology.
    Kogner, P
    Boman, H G
    Gudmundsson, G H
    FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis.1995In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 92, no 1, p. 195-9Article in journal (Refereed)
    Abstract [en]

    PR-39, a proline/arginine-rich peptide antibiotic, has been purified from pig intestine and later shown to originate in the bone marrow. Intending to isolate a clone for a human counterpart to PR-39, we synthesized a PCR probe derived from the PR-39 gene. However, when this probe was used to screen a human bone marrow cDNA library, eight clones were obtained with information for another putative human peptide antibiotic, designated FALL-39 after the first four residues. FALL-39 is a 39-residue peptide lacking cysteine and tryptophan. All human peptide antibiotics previously isolated (or predicted) belong to the defensin family and contain three disulfide bridges. The clone for prepro-FALL-39 encodes a cathelin-like precursor protein with 170 amino acid residues. We have postulated a dibasic processing site for the mature FALL-39 and chemically synthesized the putative peptide. In basal medium E, synthetic FALL-39 was highly active against Escherichia coli and Bacillus megaterium. Residues 13-34 in FALL-39 can be predicted to form a perfect amphiphatic helix, and CD spectra showed that medium E induced 30% helix formation in FALL-39. RNA blot analyses disclosed that the gene for FALL-39 is expressed mainly in human bone marrow and testis.

  • 8. Ahn, Young O.
    et al.
    Mahinthichaichan, Paween
    Lee, Hyun Ju
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ouyang, Hanlin
    Kaluka, Daniel
    Yeh, Syun-Ru
    Arjona, Davinia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Rousseau, Denis L.
    Tajkhorshid, Emad
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gennis, Robert B.
    Conformational coupling between the active site and residues within the K-C-channel of the Vibrio cholerae cbb(3)-type (C-family) oxygen reductase2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 42, p. E4419-E4428Article in journal (Refereed)
    Abstract [en]

    The respiratory chains of nearly all aerobic organisms are terminated by proton-pumping heme-copper oxygen reductases (HCOs). Previous studies have established that C-family HCOs contain a single channel for uptake from the bacterial cytoplasm of all chemical and pumped protons, and that the entrance of the K-C-channel is a conserved glutamate in subunit III. However, the majority of the K-C-channel is within subunit I, and the pathway from this conserved glutamate to subunit I is not evident. In the present study, molecular dynamics simulations were used to characterize a chain of water molecules leading from the cytoplasmic solution, passing the conserved glutamate in subunit III and extending into subunit I. Formation of the water chain, which controls the delivery of protons to the K-C-channel, was found to depend on the conformation of Y241(Vc), located in subunit I at the interface with subunit III. Mutations of Y241(Vc) (to A/F/H/S) in the Vibrio cholerae cbb(3) eliminate catalytic activity, but also cause perturbations that propagate over a 28-angstrom distance to the active site heme b(3). The data suggest a linkage between residues lining the KC-channel and the active site of the enzyme, possibly mediated by transmembrane helix alpha 7, which contains both Y241(Vc) and the active site crosslinked Y255(Vc), as well as two Cu-B histidine ligands. Other mutations of residues within or near helix alpha 7 also perturb the active site, indicating that this helix is involved in modulation of the active site of the enzyme.

  • 9. Aizman, O.
    et al.
    Uhlen, P.
    Lal, M.
    Brismar, Hjalmar
    Aperia, A.
    Ouabain, a steroid hormone that signals with slow calcium oscillations2001In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 98, no 23, p. 13420-13424Article in journal (Refereed)
    Abstract [en]

    The plant-derived steroid, digoxin, a specific inhibitor of Na,K-ATPase, has been used for centuries in the treatment of heart disease. Recent studies demonstrate the presence of a digoxin analog, ouabain, in mammalian tissue, but its biological role has not been elucidated. Here, we show in renal epithelial cells that ouabain, in doses causing only partial Na,K-ATPase inhibition, acts as a biological inducer of regular, low-frequency intracellular calcium ([Ca2+](i)) oscillations that elicit activation of the transcription factor, NF-KB. Partial inhibition of Na,K-ATPase using low extracellular K+ and depolarization of cells did not have these effects. Incubation of cells in Ca2+-free media, inhibition of voltage-gated calcium channels, inositol triphosphate receptor antagonism, and redistribution of actin to a thick layer adjacent to the plasma membrane abolished [Ca2+](i) oscillations, indicating that they were caused by a concerted action of inositol triphosphate receptors and capacitative calcium entry via plasma membrane channels. Blockade of ouabain-induced [C-a2+](i) oscillations prevented activation of NF-kappaB. The results demonstrate a new mechanism for steroid signaling via plasma membrane receptors and underline a novel role for the steroid hormone, ouabain, as a physiological inducer of [Ca2+](i) oscillations involved in transcriptional regulation in mammalian cells.

  • 10. Akopyan, Karen
    et al.
    Edgren, Tomas
    Wang-Edgren, Helen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rosqvist, Roland
    Fahlgren, Anna
    Wolf-Watz, Hans
    Fallman, Maria
    Translocation of surface-localized effectors in type III secretion2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 4, p. 1639-1644Article in journal (Refereed)
    Abstract [en]

    Pathogenic Yersinia species suppress the host immune response by using a plasmid-encoded type III secretion system (T3SS) to trans- locate virulence proteins into the cytosol of the target cells. T3SS- dependent protein translocation is believed to occur in one step from the bacterial cytosol to the target-cell cytoplasm through a conduit created by the T3SS upon target cell contact. Here, we report that T3SS substrates on the surface of Yersinia pseudotuberculosis are translocated into target cells. Upon host cell contact, purified YopH coated on Y. pseudotuberculosis was specifically and rapidly trans- located across the target-cell membrane, which led to a physiological response in the infected cell. In addition, translocation of externally added YopH required a functional T3SS and a specific translocation domain in the effector protein. Efficient, T3SS-dependent transloca- tion of purified YopH added in vitro was also observed when using coated Salmonella typhimurium strains, which implies that T3SS- mediated translocation of extracellular effector proteins is conserved among T3SS-dependent pathogens. Our results demonstrate that polarized T3SS-dependent translocation of proteins can be achieved through an intermediate extracellular step that can be reconstituted in vitro. These results indicate that translocation can occur by a differ- ent mechanism from the assumed single-step conduit model.

  • 11.
    Akopyan, Karen
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Edgren, Tomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wang-Edgren, Helen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Fällman, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Translocation of surface-localized effectors in type III secretion2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 4, p. 1639-1644Article in journal (Refereed)
    Abstract [en]

    Pathogenic Yersinia species suppress the host immune response by using a plasmid-encoded type III secretion system (T3SS) to translocate virulence proteins into the cytosol of the target cells. T3SS-dependent protein translocation is believed to occur in one step from the bacterial cytosol to the target-cell cytoplasm through a conduit created by the T3SS upon target cell contact. Here, we report that T3SS substrates on the surface of Yersinia pseudotuberculosis are translocated into target cells. Upon host cell contact, purified YopH coated on Y. pseudotuberculosis was specifically and rapidly translocated across the target-cell membrane, which led to a physiological response in the infected cell. In addition, translocation of externally added YopH required a functional T3SS and a specific translocation domain in the effector protein. Efficient, T3SS-dependent translocation of purified YopH added in vitro was also observed when using coated Salmonella typhimurium strains, which implies that T3SS-mediated translocation of extracellular effector proteins is conserved among T3SS-dependent pathogens. Our results demonstrate that polarized T3SS-dependent translocation of proteins can be achieved through an intermediate extracellular step that can be reconstituted in vitro. These results indicate that translocation can occur by a different mechanism from the assumed single-step conduit model.

  • 12. Alava, Mikko
    et al.
    Ardelius, John
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Aurell, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Kaski, P.
    Krishnamurthy, S.
    Orponen, P.
    Seitz, S
    Circumspect descent prevails in solving random constraint satisfaction problems2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 40, p. 15253-15257Article in journal (Refereed)
    Abstract [en]

    We study the performance of stochastic local search algorithms for random instances of the K-satisfiability (K-SAT) problem. We present a stochastic local search algorithm, ChainSAT, which moves in the energy landscape of a problem instance by never going upwards in energy. ChainSAT is a focused algorithm in the sense that it focuses on variables occurring in unsatisfied clauses. We show by extensive numerical investigations that ChainSAT and other focused algorithms solve large K-SAT instances almost surely in linear time, up to high clause-to-variable ratios a; for example, for K = 4 we observe linear-time performance well beyond the recently postulated clustering and condensation transitions in the solution space. The performance of ChainSAT is a surprise given that by design the algorithm gets trapped into the first local energy minimum it encounters, yet no such minima are encountered. We also study the geometry of the solution space as accessed by stochastic local search algorithms.

  • 13.
    Alavioon, Ghazal
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Hotzy, Cosima
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Nakhro, Khriezhanuo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Rudolf, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Scofield, Douglas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Zajitschek, Susanne
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Spanish Natl Res Council, Donana Biol Stn, Seville 41092, Spain.
    Maklakov, Alex A
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Univ East Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England.
    Immler, Simone
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Univ East Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England.
    Haploid selection within a single ejaculate increases offspring fitness2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, no 30, p. 8053-8058Article in journal (Refereed)
    Abstract [en]

    An inescapable consequence of sex in eukaryotes is the evolution of a biphasic life cycle with alternating diploid and haploid phases. The occurrence of selection during the haploid phase can have far-reaching consequences for fundamental evolutionary processes including the rate of adaptation, the extent of inbreeding depression, and the load of deleterious mutations, as well as for applied research into fertilization technology. Although haploid selection is well established in plants, current dogma assumes that in animals, intact fertile sperm within a single ejaculate are equivalent at siring viable offspring. Using the zebrafish Danio rerio, we show that selection on phenotypic variation among intact fertile sperm within an ejaculate affects offspring fitness. Longer-lived sperm sired embryos with increased survival and a reduced number of apoptotic cells, and adult male offspring exhibited higher fitness. The effect on embryo viability was carried over into the second generation without further selection and was equally strong in both sexes. Sperm pools selected by motile phenotypes differed genetically at numerous sites throughout the genome. Our findings clearly link within-ejaculate variation in sperm phenotype to offspring fitness and sperm genotype in a vertebrate and have major implications for adaptive evolution.

  • 14. Alberts, Susan C.
    et al.
    Altmann, Jeanne
    Brockman, Diane K.
    Cords, Marina
    Fedigan, Linda M.
    Pusey, Anne
    Stoinski, Tara S.
    Strier, Karen B.
    Morris, William F.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Bronikowski, Anne M.
    Reproductive aging patterns in primates reveal that humans are distinct2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 33, p. 13440-13445Article in journal (Refereed)
    Abstract [en]

    Women rarely give birth after similar to 45 y of age, and they experience the cessation of reproductive cycles, menopause, at similar to 50 y of age after a fertility decline lasting almost two decades. Such reproductive senescence in mid-lifespan is an evolutionary puzzle of enduring interest because it should be inherently disadvantageous. Furthermore, comparative data on reproductive senescence from other primates, or indeed other mammals, remains relatively rare. Here we carried out a unique detailed comparative study of reproductive senescence in seven species of nonhuman primates in natural populations, using long-term, individual-based data, and compared them to a population of humans experiencing natural fertility and mortality. In four of seven primate species we found that reproductive senescence occurred before death only in a small minority of individuals. In three primate species we found evidence of reproductive senescence that accelerated throughout adulthood; however, its initial rate was much lower than mortality, so that relatively few individuals experienced reproductive senescence before death. In contrast, the human population showed the predicted and well-known pattern in which reproductive senescence occurred before death for many women and its rate accelerated throughout adulthood. These results provide strong support for the hypothesis that reproductive senescence in midlife, although apparent in natural-fertility, natural-mortality populations of humans, is generally absent in other primates living in such populations.

  • 15. Alheim, K
    et al.
    Andersson, C
    Tingsborg, S
    Ziolkowska, M
    Schultzberg, M
    Bartfai, T
    Interleukin 1 expression is inducible by nerve growth factor in PC12 pheochromocytoma cells.1991In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 88, no 20, p. 9302-6Article in journal (Refereed)
    Abstract [en]

    Expression of the cytokine interleukin 1 alpha (IL-1 alpha) was demonstrated in the rat PC12 pheochromocytoma cell line by (i) immunohistochemistry using rabbit polyclonal antisera raised against the recombinant murine IL-1 alpha, (ii) an ELISA, and (iii) a specific cell conversion bioassay based on the use of LBRM33-1A5 cells. IL-1 alpha mRNA was demonstrated in the PC12 cells, by PCR amplification. Constitutive expression of IL-1 alpha in PC12 cells was demonstrated in all experiments, although the cellular levels of IL-1 alpha-like immunoreactivity varied. The expression of IL-1 alpha, as studied at the mRNA level, was inducible by mouse nerve growth factor (7S NGF), and the gene product level was inducible in a dose- and time-dependent fashion by 7S NGF. The maximum induction corresponds to a 600% increase in IL-1 alpha-like immunoreactivity above the expression level found in noninduced cells and occurred after a 3-day incubation of the cells with NGF at 0.75 micrograms/ml of culture medium. The significance of the ability of NGF to induce IL-1 expression lies in the fact that IL-1 itself also acts as a growth factor that promotes glial proliferation and, even more importantly, IL-1 itself induces the expression of NGF at peripheral nerve injury [Lindholm, D., Heumann, R., Meyer, M. & Thoenen, H. (1987) Nature (London) 330, 658-659].

  • 16.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjoblöm, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 25, p. 7743-7748Article in journal (Refereed)
    Abstract [en]

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

  • 17.
    Alimohammadi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Dubois, Noemie
    Sköldberg, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tradivel, Isabelle
    Hedstrand, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Haavik, Jan
    Husebye, Eystein
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Meloni, Antonella
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Vilattes, Bernard
    Kajosaari, Merja
    Egner, William
    Sargur, Ravishankar
    Amoura, Zahir
    Grimfeld, Alain
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    De Luca, Filippo
    Betterle, Corrado
    Perheentupa, Jaakko
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Pulmonary Autoimmunity as a Feature of Autoimmune Polyendocrine Syndrome Type 1 and Identification of KCNRG as a Bronchial Autoantigen2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 11, p. 4396-4401Article in journal (Refereed)
    Abstract [en]

    Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a putative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be predominantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.

  • 18. Alkasalias, Twana
    et al.
    Alexeyenko, Andrey
    Hennig, Katharina
    Danielsson, Frida
    Lebbink, Robert Jan
    Fielden, Matthew
    Turunen, S. Pauliina
    Lehti, Kaisa
    Kashuba, Vladimir
    Madapura, Harsha S.
    Bozoky, Benedek
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Balland, Martial
    Guven, Hayrettin
    Klein, George
    Gad, Annica K. B.
    Pavlova, Tatiana
    RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 8, p. E1413-E1421Article in journal (Refereed)
    Abstract [en]

    Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins over-expressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of a-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.

  • 19. Allen, LT
    et al.
    Fox, EJP
    Blute, I
    YKI – Ytkemiska institutet.
    Kelly, ZD
    Rochev, Y
    Keenan, AK
    Dawson,
    Interaction of soft condensed materials with living cells: Phenotype/transcriptome correlations for the hydrophobic effect2003In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, p. 6331-6336Article in journal (Refereed)
    Abstract [en]

    The assessment of biomaterial compatibility relies heavily on the analysis of macroscopic cellular responses to material interaction. However, new technologies have become available that permit a more profound understanding of the molecular basis of cell-biomaterial interaction. Here, both conventional phenotypic and contemporary transcriptomic (DNA microarray-based) analysis techniques were combined to examine the interaction of cells with a homologous series of copolymer films that subtly vary in terms of surface hydrophobicity. More specifically, we used differing combinations of N-isopropylacrylamide, which is presently used as an adaptive cell culture substrate, and the more hydrophobic, yet structurally similar, monomer N-tert-butylacrylamide. We show here that even discrete modifications with respect to the physiochemistry of soft amorphous materials can lead to significant impacts on the phenotype of interacting cells. Furthermore, we have elucidated putative links between phenotypic responses to cell-biomaterial interaction and global gene expression profile alterations. This case study indicates that high-throughput analysis of gene expression not only can greatly refine our knowledge of cell-biomaterial interaction, but also can yield novel biomarkers for potential use in biocompatibility assessment

  • 20. Allgardsson, Anders
    et al.
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Akfur, Christine
    Hörnberg, Andreas
    Worek, Franz
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekström, Fredrik J.
    Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-62016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 20, p. 5514-5519Article in journal (Refereed)
    Abstract [en]

    Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.

  • 21.
    Allgardsson, Anders
    et al.
    FOI Swedish Defence Research Agency, Sweden.
    Berg, Lotta
    Umeå University, Sweden.
    Akfur, Christine
    FOI Swedish Defence Research Agency, Sweden.
    Hörnberg, Andreas
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Processum.
    Worek, Franz
    Bundeswehr Institute of Pharmacology and Toxicology, Germany.
    Linusson, Anna
    Umeå University, Sweden.
    Ekström, Fredrik J.
    FOI Swedish Defence Research Agency, Sweden.
    Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-62016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 20, p. 5514-5519Article in journal (Refereed)
    Abstract [en]

    Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.

  • 22. Alonso-Mori, Roberto
    et al.
    Kern, Jan
    Gildea, Richard J
    Sokaras, Dimosthenis
    Weng, Tsu-Chien
    Lassalle-Kaiser, Benedikt
    Tran, Rosalie
    Hattne, Johan
    Laksmono, Hartawan
    Hellmich, Julia
    Glöckner, Carina
    Echols, Nathaniel
    Sierra, Raymond G
    Schafer, Donald W
    Sellberg, Jonas
    Kenney, Christopher
    Herbst, Ryan
    Pines, Jack
    Hart, Philip
    Herrmann, Sven
    Grosse-Kunstleve, Ralf W
    Latimer, Matthew J
    Fry, Alan R
    Messerschmidt, Marc M
    Miahnahri, Alan
    Seibert, M Marvin
    Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA 94025; .
    Zwart, Petrus H
    White, William E
    Adams, Paul D
    Bogan, Michael J
    Boutet, Sébastien
    Williams, Garth J
    Zouni, Athina
    Messinger, Johannes
    Glatzel, Pieter
    Sauter, Nicholas K
    Yachandra, Vittal K
    Yano, Junko
    Bergmann, Uwe
    Energy-dispersive X-ray emission spectroscopy using an X-ray free-electron laser in a shot-by-shot mode2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 47, p. 19103-19107Article in journal (Refereed)
    Abstract [en]

    The ultrabright femtosecond X-ray pulses provided by X-ray free-electron lasers open capabilities for studying the structure and dynamics of a wide variety of systems beyond what is possible with synchrotron sources. Recently, this "probe-before-destroy" approach has been demonstrated for atomic structure determination by serial X-ray diffraction of microcrystals. There has been the question whether a similar approach can be extended to probe the local electronic structure by X-ray spectroscopy. To address this, we have carried out femtosecond X-ray emission spectroscopy (XES) at the Linac Coherent Light Source using redox-active Mn complexes. XES probes the charge and spin states as well as the ligand environment, critical for understanding the functional role of redox-active metal sites. Kβ(1,3) XES spectra of Mn(II) and Mn(2)(III,IV) complexes at room temperature were collected using a wavelength dispersive spectrometer and femtosecond X-ray pulses with an individual dose of up to >100 MGy. The spectra were found in agreement with undamaged spectra collected at low dose using synchrotron radiation. Our results demonstrate that the intact electronic structure of redox active transition metal compounds in different oxidation states can be characterized with this shot-by-shot method. This opens the door for studying the chemical dynamics of metal catalytic sites by following reactions under functional conditions. The technique can be combined with X-ray diffraction to simultaneously obtain the geometric structure of the overall protein and the local chemistry of active metal sites and is expected to prove valuable for understanding the mechanism of important metalloproteins, such as photosystem II.

  • 23. Alonso-Mori, Roberto
    et al.
    Kern, Jan
    Gildea, Richard J.
    Sokaras, Dimosthenis
    Weng, Tsu-Chien
    Lassalle-Kaiser, Benedikt
    Tran, Rosalie
    Hattne, Johan
    Laksmono, Hartawan
    Hellmich, Julia
    Glöckner, Carina
    Echols, Nathaniel
    Sierra, Raymond G.
    Schafer, Donald W.
    Sellberg, Jonas
    Stockholm University, Faculty of Science, Department of Physics. SLAC National Accelerator Laboratory, USA.
    Kenney, Christopher
    Herbst, Ryan
    Pines, Jack
    Hart, Philip
    Herrmann, Sven
    Grosse-Kunstleve, Ralf W.
    Latimer, Matthew J.
    Fry, Alan R.
    Messerschmidt, Marc M.
    Miahnahri, Alan
    Seibert, M. Marvin
    Zwart, Petrus H.
    White, William E.
    Adams, Paul D.
    Bogan, Michael J.
    Boutet, Sébastien
    Williams, Garth J.
    Zouni, Athina
    Messinger, Johannes
    Glatzel, Pieter
    Sauter, Nicholas K.
    Yachandra, Vittal K.
    Yano, Junko
    Bergmann, Uwe
    Energy-dispersive X-ray emission spectroscopy using an X-ray free-electron laser in a shot-by-shot mode2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 47, p. 19103-19107Article in journal (Refereed)
    Abstract [en]

    The ultrabright femtosecond X-ray pulses provided by X-ray free-electron lasers open capabilities for studying the structure and dynamics of a wide variety of systems beyond what is possible with synchrotron sources. Recently, this probe-before-destroy approach has been demonstrated for atomic structure determination by serial X-ray diffraction of microcrystals. There has been the question whether a similar approach can be extended to probe the local electronic structure by X-ray spectroscopy. To address this, we have carried out femtosecond X-ray emission spectroscopy (XES) at the Linac Coherent Light Source using redox-active Mn complexes. XES probes the charge and spin states as well as the ligand environment, critical for understanding the functional role of redox-active metal sites. K beta(1,3) XES spectra of Mn-II and Mn-2(III,IV) complexes at room temperature were collected using a wavelength dispersive spectrometer and femtosecond X-ray pulses with an individual dose of up to > 100 MGy. The spectra were found in agreement with undamaged spectra collected at low dose using synchrotron radiation. Our results demonstrate that the intact electronic structure of redox active transition metal compounds in different oxidation states can be characterized with this shot-by-shot method. This opens the door for studying the chemical dynamics of metal catalytic sites by following reactions under functional conditions. The technique can be combined with X-ray diffraction to simultaneously obtain the geometric structure of the overall protein and the local chemistry of active metal sites and is expected to prove valuable for understanding the mechanism of important metalloproteins, such as photosystem II.

  • 24. Alonso-Mori, Roberto
    et al.
    Kern, Jan
    Gildea, Richard J
    Sokaras, Dimosthenis
    Weng, Tsu-Chien
    Lassalle-Kaiser, Benedikt
    Tran, Rosalie
    Hattne, Johan
    Laksmono, Hartawan
    Hellmich, Julia
    Glöckner, Carina
    Echols, Nathaniel
    Sierra, Raymond G
    Schafer, Donald W
    Sellberg, Jonas
    Kenney, Christopher
    Herbst, Ryan
    Pines, Jack
    Hart, Philip
    Herrmann, Sven
    Grosse-Kunstleve, Ralf W
    Latimer, Matthew J
    Fry, Alan R
    Messerschmidt, Marc M
    Miahnahri, Alan
    Seibert, M Marvin
    Zwart, Petrus H
    White, William E
    Adams, Paul D
    Bogan, Michael J
    Boutet, Sébastien
    Williams, Garth J
    Zouni, Athina
    Messinger, Johannes
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Glatzel, Pieter
    Sauter, Nicholas K
    Yachandra, Vittal K
    Yano, Junko
    Bergmann, Uwe
    Energy-dispersive X-ray emission spectroscopy using an X-ray free-electron laser in a shot-by-shot mode2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 47, p. 19103-19107Article in journal (Refereed)
    Abstract [en]

    The ultrabright femtosecond X-ray pulses provided by X-ray free-electron lasers open capabilities for studying the structure and dynamics of a wide variety of systems beyond what is possible with synchrotron sources. Recently, this "probe-before-destroy" approach has been demonstrated for atomic structure determination by serial X-ray diffraction of microcrystals. There has been the question whether a similar approach can be extended to probe the local electronic structure by X-ray spectroscopy. To address this, we have carried out femtosecond X-ray emission spectroscopy (XES) at the Linac Coherent Light Source using redox-active Mn complexes. XES probes the charge and spin states as well as the ligand environment, critical for understanding the functional role of redox-active metal sites. Kβ(1,3) XES spectra of Mn(II) and Mn(2)(III,IV) complexes at room temperature were collected using a wavelength dispersive spectrometer and femtosecond X-ray pulses with an individual dose of up to >100 MGy. The spectra were found in agreement with undamaged spectra collected at low dose using synchrotron radiation. Our results demonstrate that the intact electronic structure of redox active transition metal compounds in different oxidation states can be characterized with this shot-by-shot method. This opens the door for studying the chemical dynamics of metal catalytic sites by following reactions under functional conditions. The technique can be combined with X-ray diffraction to simultaneously obtain the geometric structure of the overall protein and the local chemistry of active metal sites and is expected to prove valuable for understanding the mechanism of important metalloproteins, such as photosystem II.

  • 25. Alonso-Saez, Laura
    et al.
    Waller, Alison S.
    Mende, Daniel R.
    Bakker, Kevin
    Farnelid, Hanna
    Yager, Patricia L.
    Lovejoy, Connie
    Tremblay, Jean-Eric
    Potvin, Marianne
    Heinrich, Friederike
    Estrada, Marta
    Riemann, Lasse
    Bork, Peer
    Pedros-Alio, Carlos
    Bertilsson, Stefan
    Role for urea in nitrification by polar marine Archaea2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 44, p. 17989-17994Article in journal (Refereed)
    Abstract [en]

    Despite the high abundance of Archaea in the global ocean, their metabolism and biogeochemical roles remain largely unresolved. We investigated the population dynamics and metabolic activity of Thaumarchaeota in polar environments, where these microorganisms are particularly abundant and exhibit seasonal growth. Thaumarchaeota were more abundant in deep Arctic and Antarctic waters and grew throughout the winter at surface and deeper Arctic halocline waters. However, in situ single-cell activity measurements revealed a low activity of this group in the uptake of both leucine and bicarbonate (<5% Thaumarchaeota cells active), which is inconsistent with known heterotrophic and autotrophic thaumarchaeal lifestyles. These results suggested the existence of alternative sources of carbon and energy. Our analysis of an environmental metagenome from the Arctic winter revealed that Thaumarchaeota had pathways for ammonia oxidation and, unexpectedly, an abundance of genes involved in urea transport and degradation. Quantitative PCR analysis confirmed that most polar Thaumarchaeota had the potential to oxidize ammonia, and a large fraction of them had urease genes, enabling the use of urea to fuel nitrification. Thaumarchaeota from Arctic deep waters had a higher abundance of urease genes than those near the surface suggesting genetic differences between closely related archaeal populations. In situ measurements of urea uptake and concentration in Arctic waters showed that small-sized prokaryotes incorporated the carbon from urea, and the availability of urea was often higher than that of ammonium. Therefore, the degradation of urea may be a relevant pathway for Thaumarchaeota and other microorganisms exposed to the low-energy conditions of dark polar waters.

  • 26. Alonso-Saéz, Laura
    et al.
    Waller, Allison S
    Mende, Daniel R
    Bakker, Kevin
    Farnelid, Hanna
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Yager, Patricia L
    Lovejoy, Connie
    Tremblay, Jean-Eric
    Potvin, Marianne
    Heinrich, Friederike
    Estrada, Marta
    Riemann, Lasse
    Marine Biological Section, University of Copenhagen, 3000 Helsingør, Denmark .
    Bork, Peer
    Pedros-Alio, Carlos
    Bertilsson, Stefan
    Role for urea in nitrification by polar marine Archaea2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 44, p. 17989-17994Article in journal (Refereed)
    Abstract [en]

    Despite the high abundance of Archaea in the global ocean, their metabolism and biogeochemical roles remain largely unresolved. We investigated the population dynamics and metabolic activity of Thaumarchaeota in polar environments, where these microorganisms are particularly abundant and exhibit seasonal growth. Thaumarchaeota were more abundant in deep Arctic and Antarctic waters and grew throughout the winter at surface and deeper Arctic halocline waters. However, in situ single-cell activity measurements revealed a low activity of this group in the uptake of both leucine and bicarbonate (<5% Thaumarchaeota cells active), which is inconsistent with known heterotrophic and autotrophic thaumarchaeal lifestyles. These results suggested the existence of alternative sources of carbon and energy. Our analysis of an environmental metagenome from the Arctic winter revealed that Thaumarchaeota had pathways for ammonia oxidation and, unexpectedly, an abundance of genes involved in urea transport and degradation. Quantitative PCR analysis confirmed that most polar Thaumarchaeota had the potential to oxidize ammonia, and a large fraction of them had urease genes, enabling the use of urea to fuel nitrification. Thaumarchaeota from Arctic deep waters had a higher abundance of urease genes than those near the surface suggesting genetic differences between closely related archaeal populations. In situ measurements of urea uptake and concentration in Arctic waters showed that small-sized prokaryotes incorporated the carbon from urea, and the availability of urea was often higher than that of ammonium. Therefore, the degradation of urea may be a relevant pathway for Thaumarchaeota and other microorganisms exposed to the low-energy conditions of dark polar waters.

  • 27.
    Alonso-Sáez, Laura
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Waller, A. S.
    Mende, D. R.
    Bakker, K.
    Farnelid, H.
    Yager, P. L.
    Lovejoy, C.
    Tremblay, J. -E
    Potvin, M.
    Heinrich, Friederike
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Estrada, M.
    Riemann, L.
    Bork, P.
    Pedrós-Alió, C.
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Role for urea in nitrification by polar marine Archaea2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 44, p. 17989-17994Article in journal (Refereed)
    Abstract [en]

    Despite the high abundance of Archaea in the global ocean, their metabolism and biogeochemical roles remain largely unresolved. We investigated the population dynamics and metabolic activity of Thaumarchaeota in polar environments, where these microorganisms are particularly abundant and exhibit seasonal growth. Thaumarchaeota were more abundant in deep Arctic and Antarctic waters and grew throughout the winter at surface and deeper Arctic halocline waters. However, in situ single-cell activity measurements revealed a low activity of this group in the uptake of both leucine and bicarbonate (<5% Thaumarchaeota cells active), which is inconsistent with known heterotrophic and autotrophic thaumarchaeal lifestyles. These results suggested the existence of alternative sources of carbon and energy. Our analysis of an environmental metagenome from the Arctic winter revealed that Thaumarchaeota had pathways for ammonia oxidation and, unexpectedly, an abundance of genes involved in urea transport and degradation. Quantitative PCR analysis confirmed that most polar Thaumarchaeota had the potential to oxidize ammonia, and a large fraction of them had urease genes, enabling the use of urea to fuel nitrification. Thaumarchaeota from Arctic deep waters had a higher abundance of urease genes than those near the surface suggesting genetic differences between closely related archaeal populations. In situ measurements of urea uptake and concentration in Arctic waters showed that small-sized prokaryotes incorporated the carbon from urea, and the availability of urea was often higher than that of ammonium. Therefore, the degradation of urea may be a relevant pathway for Thaumarchaeota and other microorganisms exposed to the low-energy conditions of dark polar waters.

  • 28.
    Alsmark, Cecilia M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Frank, A. Carolin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Karlberg, E. Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Legault, Boris-Antoine
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Ardell, David H.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Canbäck, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Eriksson, Ann-Sofie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Näslund, A. Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Handley, Scott A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Huvet, Maxime
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    La Scola, Bernard
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Holmberg, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    The louse-borne human pathogen Bartonella quintana is a genomic derivative of the zoonotic agent Bartonella henselae2004In: 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. 9716-9721Article in journal (Refereed)
    Abstract [en]

    We present the complete genomes of two human pathogens, Bartonella quintana (1,581,384 bp) and Bartonella henselae (1,931,047 bp). The two pathogens maintain several similarities in being transmitted by insect vectors, using mammalian reservoirs, infecting similar cell types (endothelial cells and erythrocytes) and causing vasculoproliferative changes in immunocompromised hosts. A primary difference between the two pathogens is their reservoir ecology. Whereas B. quintana is a specialist, using only the human as a reservoir, B. henselae is more promiscuous and is frequently isolated from both cats and humans. Genome comparison elucidated a high degree of overall similarity with major differences being B. henselae specific genomic islands coding for filamentous hemagglutinin, and evidence of extensive genome reduction in B. quintana, reminiscent of that found in Rickettsia prowazekii. Both genomes are reduced versions of chromosome I from the highly related pathogen Brucella melitensis. Flanked by two rRNA operons is a segment with similarity to genes located on chromosome II of B. melitensis, suggesting that it was acquired by integration of megareplicon DNA in a common ancestor of the two Bartonella species. Comparisons of the vector-host ecology of these organisms suggest that the utilization of host-restricted vectors is associated with accelerated rates of genome degradation and may explain why human pathogens transmitted by specialist vectors are outnumbered by zoonotic agents, which use vectors of broad host ranges.

  • 29. Ambort, D.
    et al.
    Johansson, M.E.V.
    Gustafsson, J. K.
    Nilsson, Harriet
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology.
    Ermund, A.
    Johansson, B.R.
    Koeck, Philip J. B.
    KTH, School of Technology and Health (STH), Structural Biotechnology (Closed 20130701).
    Hebert, Hans
    KTH, School of Technology and Health (STH), Structural Biotechnology (Closed 20130701).
    Hansson, G.C.
    Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 15, p. 5645-5650Article in journal (Refereed)
    Abstract [en]

    MUC2, the major colonic mucin, forms large polymers by N-terminal trimerization and C-terminal dimerization. Although the assembly process for MUC2 is established, it is not known how MUC2 is packed in the regulated secretory granulae of the goblet cell. When the N-terminal VWD1-D2-D'D3 domains (MUC2-N) were expressed in a goblet-like cell line, the protein was stored together with full-length MUC2. By mimicking the pH and calcium conditions of the secretory pathway we analyzed purified MUC2-N by gel filtration, density gradient centrifugation, and transmission electron microscopy. At pH 7.4 the MUC2-N trimer eluted as a single peak by gel filtration. At pH 6.2 with Ca2+ it formed large aggregates that did not enter the gel filtration column but were made visible after density gradient centrifugation. Electron microscopy studies revealed that the aggregates were composed of rings also observed in secretory granulae of colon tissue sections. TheMUC2-N aggregates were dissolved by removing Ca2+ and raising pH. After release from goblet cells, the unfolded full-length MUC2 formed stratified layers. These findings suggest a model for mucin packing in the granulae and the mechanism for mucin release, unfolding, and expansion.

  • 30.
    Andersson, A.
    et al.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Olofsson, T.
    Department of Hematology, Lund University Hospital, SE-221 85 Lund, Sweden.
    Lindgren, D.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Nilsson, B.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Ritz, C.
    Department of Complex System Division, Theoretical Physics, Lund University, S-221 00 Lund, Sweden.
    Eden, P.
    Department of Complex System Division, Theoretical Physics, Lund University, S-221 00 Lund, Sweden.
    Lassen, C.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Rade, J.
    Center for Mathematical Sciences, Lund University, S-221 00 Lund, Sweden.
    Fontes, M.
    Center for Mathematical Sciences, Lund University, S-221 00 Lund, Sweden.
    Morse, H.
    Department of Pediatrics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Heldrup, J.
    Department of Pediatrics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Behrendtz, Mikael
    Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Mitelman, F.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Hoglund, M.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Johansson, B.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Fioretos, T.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no 52, p. 19069-19074Article in journal (Refereed)
    Abstract [en]

    Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)/PBX1. IGH@/MYC. ETV6(TEL)/RUNX1(AML1). 11q23/MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies. © 2005 by The National Academy of Sciences of the USA.

  • 31. Andersson, Charlotta S.
    et al.
    Högbom, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    A Mycobacterium tuberculosis ligand-binding Mn/Fe protein reveals a new cofactor in a remodeled R2-protein scaffold2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 14, p. 5633-5638Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis R2c is the prototype for a recently discovered group of ribonucleotide reductase R2 proteins that use a heterodinuclear Mn/Fe redox cofactor for radical generation and storage. Here, we show that the Mycobacterium tuberculosis protein Rv0233, an R2 homologue and a potential virulence factor, contains the heterodinuclear manganese/iron-carboxylate cofactor but displays a drastic remodeling of the R2 protein scaffold into a ligand-binding oxidase. The first structural characterization of the heterodinuclear cofactor shows that the site is highly specific for manganese and iron in their respective positions despite a symmetric arrangement of coordinating residues. In this protein scaffold, the Mn/Fe cofactor supports potent 2-electron oxidations as revealed by an unprecedented tyrosine-valine crosslink in the active site. This wolf in sheep's clothing defines a distinct functional group among R2 homologues and may represent a structural and functional counterpart of the evolutionary ancestor of R2s and bacterial multicomponent monooxygenases.

  • 32.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evolving promiscuously2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 4, p. 1199-1200Article in journal (Other academic)
  • 33.
    Andersson, Dan I
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Muller's ratchet decreases fitness of a DNA-based microbe1996In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 93, no 2, p. 906-907Article in journal (Refereed)
    Abstract [en]

    Muller proposed that an asexual organism will inevitably accumulate deleterious mutations, resulting in an increase of the mutational load and an inexorable, ratchet-like, loss of the least mutated class [Muller, H.J. (1964) Mutat. Res. 1, 2-9]. The operation of Muller's ratchet on real populations has been experimentally demonstrated only in RNA viruses. However, these cases are exceptional in that the mutation rates of the RNA viruses are extremely high. We have examined whether Muller's ratchet operates in Salmonella typhimurium, a DNA-based organism with a more typical genomic mutation rate. Cells were grown asexually under conditions expected to result in high genetic drift, and the increase in mutational load was determined. S. typhimurium accumulated mutations under these conditions such that after 1700 generations, 1% of the 444 lineages tested had suffered an obvious loss of fitness, as determined by decreased growth rate. These results suggest that in the absence of sex and with high genetic drift, genetic mechanisms, such as back or compensatory mutations, cannot compensate for the accumulation of deleterious mutations. In addition, we measured the appearance of auxotrophs, which allowed us to calculate an average spontaneous mutation rate of approximately 0.3-1.5 x 10(-9) mutations per base pair per generation. This rate is measured for the largest genetic target studied so far, a collection of about 200 genes.

  • 34.
    Andersson, David A.
    et al.
    KTH, School of Industrial Engineering and Management (ITM), Materials Science and Engineering.
    Simak, Sergei I.
    Skorodumova, Natalia V.
    Abrikosov, Igor A.
    Johansson, Börje
    KTH, School of Industrial Engineering and Management (ITM), Materials Science and Engineering, Applied Material Physics.
    Optimization of ionic conductivity in doped ceria2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 10, p. 3518-3521Article in journal (Refereed)
    Abstract [en]

    Oxides with the cubic fluorite structure, e.g., ceria (CeO2), are known to be good solid electrolytes when they are doped with cations of lower valence than the host cations. The high ionic conductivity of doped ceria makes it an attractive electrolyte for solid oxide fuel cells, whose prospects as an environmentally friendly power source are very promising. In these electrolytes, the current is carried by oxygen ions that are transported by oxygen vacancies, present to compensate for the lower charge of the dopant cations. Ionic conductivity in ceria is closely related to oxygen-vacancy formation and migration properties. A clear physical picture of the connection between the choice of a dopant and the improvement of ionic conductivity in ceria is still lacking. Here we present a quantum-mechanical first-principles study of the influence of different trivalent impurities on these properties. Our results reveal a remarkable correspondence between vacancy properties at the atomic level and the macroscopic ionic conductivity. The key parameters comprise migration barriers for bulk diffusion and vacancy-dopant interactions, represented by association (binding) energies of vacancy-dopant clusters. The interactions can be divided into repulsive elastic and attractive electronic parts. In the optimal electrolyte, these parts should balance. This finding offers a simple and clear way to narrow the search for superior dopants and combinations of dopants. The ideal dopant should have an effective atomic number between 61 (Pm) and 62 (Sm), and we elaborate that combinations of Nd/Sm and Pr/Gd show enhanced ionic conductivity, as compared with that for each element separately.

  • 35.
    Andersson, David A.
    et al.
    Royal Institute of Technology.
    Simak, Sergey
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics .
    Skorodumova, Natalia V.
    Uppsala University.
    Abrikosov, Igor
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics .
    Johansson, Börje
    Uppsala University.
    Optimization of ionic conductivity in doped ceria2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, p. 3518-3521Article in journal (Refereed)
  • 36.
    Andersson, Ove
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Glass-liquid transition of water at high pressure2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 27, p. 11013-11016Article in journal (Refereed)
    Abstract [en]

    The knowledge of the existence of liquid water under extreme conditions and its concomitant properties are important in many fields of science. Glassy water has previously been prepared by hyperquenching micron-sized droplets of liquid water and vapor deposition on a cold substrate (ASW), and its transformation to an ultraviscous liquid form has been reported on heating. A densified amorphous solid form of water, high-density amorphous ice (HDA), has also been made by collapsing the structure of ice at pressures above 1 GPa and temperatures below approximately 140 K, but a corresponding liquid phase has not been detected. Here we report results of heat capacity C(p) and thermal conductivity, in situ, measurements, which are consistent with a reversible transition from annealed HDA to ultraviscous high-density liquid water at 1 GPa and 140 K. On heating of HDA, the Cp increases abruptly by (3.4 ± 0.2) J mol-1 K-1 before crystallization starts at (153 ± 1) K. This is larger than the Cp rise at the glass to liquid transition of annealed ASW at 1 atm, which suggests the existence of liquid water under these extreme conditions.

  • 37.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Stress management strategies in single bacterial cells2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 15, p. 3921-3923Article in journal (Other academic)
  • 38.
    Andrade, Pedro
    et al.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Pinho, Catarina
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Perez i de lanuza, Guillem
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Afonso, Sandra
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Brejcha, Jindrich
    Charles Univ Prague, Fac Sci, Dept Philosophy & Hist Sci, Prague 12800 2, Czech Republic;Natl Museum, Dept Zool, Prague 19300, Czech Republic;Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pereira, Paulo
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Sabatino, Stephen J.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Bellati, Adriana
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Pellitteri-Rosa, Daniele
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Bosakova, Zuzana
    Charles Univ Prague, Fac Sci, Dept Analyt Chem, Prague 12843 2, Czech Republic.
    Bunikis, Ignas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Carretero, Miguel A.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Feiner, Nathalie
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Marsik, Petr
    Czech Univ Life Sci Prague, Fac Agrobiol Food & Nat Resources, Dept Food Sci, Prague 16521 6, Czech Republic.
    Pauperio, Francisco
    Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Salvi, Daniele
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Aquila, Dept Hlth Life & Environm Sci, I-67100 Laquila, Italy.
    Soler, Lucile
    Natl Bioinformat Infrastruct Sweden, Sci Life Lab, S-75123 Uppsala, Sweden.
    While, Geoffrey M.
    Univ Tasmania, Sch ol Biol Sci, Hobart, Tas 7005, Australia;Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
    Uller, Tobias
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Font, Enrique
    Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Carneiro, Miguel
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Regulatory changes in pterin and carotenoid genes underlie balanced color polymorphisms in the wall lizard2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 12, p. 5633-5642Article in journal (Refereed)
    Abstract [en]

    Reptiles use pterin and carotenoid pigments to produce yellow, orange, and red colors. These conspicuous colors serve a diversity of signaling functions, but their molecular basis remains unresolved. Here, we show that the genomes of sympatric color morphs of the European common wall lizard (Podarcis muralis), which differ in orange and yellow pigmentation and in their ecology and behavior, are virtually undifferentiated. Genetic differences are restricted to two small regulatory regions near genes associated with pterin [sepiapterin reductase (SPR)] and carotenoid [beta-carotene oxygenase 2 (BCO2)] metabolism, demonstrating that a core gene in the housekeeping pathway of pterin biosynthesis has been coopted for bright coloration in reptiles and indicating that these loci exert pleiotropic effects on other aspects of physiology. Pigmentation differences are explained by extremely divergent alleles, and haplotype analysis revealed abundant transspecific allele sharing with other lacertids exhibiting color polymorphisms. The evolution of these conspicuous color ornaments is the result of ancient genetic variation and cross-species hybridization.

  • 39. Antonelli, A
    et al.
    Nylander, Johan
    Stockholm University, Faculty of Science, Department of Botany.
    Persson, C
    Sanmartín, I
    Tracing the impact of the Andean uplift on Neotropical plant evolution: evidence from the coffee family2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 24, p. 9749-9754Article in journal (Refereed)
    Abstract [en]

    Recent phylogenetic studies have revealed the major role played by the uplift of the Andes in the extraordinary diversification of the Neotropical flora. These studies, however, have typically considered the Andean uplift as a single, time-limited event fostering the evolution of highland elements. This contrasts with geological reconstructions indicating that the uplift occurred in discrete periods from west to east and that it affected different regions at different times. We introduce an approach for integrating Andean tectonics with biogeographic reconstructions of Neotropical plants, using the coffee family (Rubiaceae) as a model group. The distribution of this family spans highland and montane habitats as well as tropical lowlands of Central and South America, thus offering a unique opportunity to study the influence of the Andean uplift on the entire Neotropical flora. Our results suggest that the Rubiaceae originated in the Paleotropics and used the boreotropical connection to reach South America. The biogeographic patterns found corroborate the existence of a long-lasting dispersal barrier between the Northern and Central Andes, the "Western Andean Portal.'' The uplift of the Eastern Cordillera ended this barrier, allowing dispersal of boreotropical lineages to the South, but gave rise to a huge wetland system ("Lake Pebas'') in western Amazonia that prevented in situ speciation and floristic dispersal between the Andes and Amazonia for at least 6 million years. Here, we provide evidence of these events in plants

  • 40.
    Antzutkin, Oleg
    et al.
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Sustainable Process Engineering.
    Balbach, John J.
    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda.
    Leapman, Richard D.
    Division of Bioengineering and Physical Science, Office of Research Services, National Institutes of Health, Bethesda.
    Rizzo, Nancy W.
    Division of Bioengineering and Physical Science, Office of Research Services, National Institutes of Health, Bethesda.
    Reed, Jennifer
    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda.
    Tycko, Robert
    National Institutes of Health, Bethesda.
    Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of β-sheets in Alzheimer's β-amyloid fibrils2000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 24, p. 13045-13050Article in journal (Refereed)
    Abstract [en]

    Senile plaques associated with Alzheimer's disease contain deposits of fibrils formed by 39- to 43-residue β-amyloid peptides with possible neurotoxic effects. X-ray diffraction measurements on oriented fibril bundles have indicated an extended β-sheet structure for Alzheimer's β-amyloid fibrils and other amyloid fibrils, but the supramolecular organization of the β-sheets and other structural details are not well established because of the intrinsically noncrystalline, insoluble nature of amyloid fibrils. Here we report solid-state NMR measurements, using a multiple quantum (MQ) 13C NMR technique, that probe the β-sheet organization in fibrils formed by the full-length, 40-residue β-amyloid peptide (Aβ1-40). Although an antiparallel β-sheet organization often is assumed and is invoked in recent structural models for full-length β-amyloid fibrils, the MQNMR data indicate an in-register, parallel organization. This work provides site-specific, atomic-level structural constraints on full-length β-amyloid fibrils and applies MQNMR to a significant problem in structural biology.

  • 41. Aparicio, S
    et al.
    Morrison, A
    Gould, A
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Chaudhuri, C
    Rigby, P
    Krumlauf, R
    Brenner, S
    Detecting conserved regulatory elements with the model genome of the Japanese puffer fish, Fugu rubripes.1995In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 92, no 5, p. 1684-1688Article in journal (Refereed)
    Abstract [en]

    Comparative vertebrate genome sequencing offers a powerful method for detecting conserved regulatory sequences. We propose that the compact genome of the teleost Fugu rubripes is well suited for this purpose. The evolutionary distance of teleosts from other vertebrates offers the maximum stringency for such evolutionary comparisons. To illustrate the comparative genome approach for F. rubripes, we use sequence comparisons between mouse and Fugu Hoxb-4 noncoding regions to identify conserved sequence blocks. We have used two approaches to test the function of these conserved blocks. In the first, homologous sequences were deleted from a mouse enhancer, resulting in a tissue-specific loss of activity when assayed in transgenic mice. In the second approach, Fugu DNA sequences showing homology to mouse sequences were tested for enhancer activity in transgenic mice. This strategy identified a neural element that mediates a subset of Hoxb-4 expression that is conserved between mammals and teleosts. The comparison of noncoding vertebrate sequences with those of Fugu, coupled to a transgenic bioassay, represents a general approach suitable for many genome projects.

  • 42. Arapan, S.
    et al.
    Mao, H.
    Ahuja, Rajeev
    KTH, School of Industrial Engineering and Management (ITM), Materials Science and Engineering.
    Prediction of incommensurate crystal structure in Ca at high pressure2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 52, p. 20627-20630Article in journal (Refereed)
    Abstract [en]

    Ca shows an interesting high-pressure phase transformation sequence, but, despite similar physical properties at high pressure and affinity in the electronic structure with its neighbors in the periodic table, no complex phase has been identified for Ca so far. We predict an incommensurate high-pressure phase of Ca from first principle calculations and describe a procedure of estimating incommensurate structure parameters by means of electronic structure calculations for periodic crystals. Thus, by using the ab initio technique for periodic structures, one can get not only reliable information about the electronic structure and structural parameters of an incommensurate phase, but also identify and predict such phases in new elements.

  • 43.
    Arapan, Sergiu
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Materials Science.
    Mao, Ho-kwang
    Ahuja, Rajeev
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Materials Science.
    Prediction of incommensurate crystal structure in Ca at high pressure2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 52, p. 20627-20630Article in journal (Refereed)
    Abstract [en]

    Ca shows an interesting high-pressure phase transformation sequence, but, despite similar physical properties at high pressure and affinity in the electronic structure with its neighbors in the periodic table, no complex phase has been identified for Ca so far. We predict an incommensurate high-pressure phase of Ca from first principle calculations and describe a procedure of estimating incommensurate structure parameters by means of electronic structure calculations for periodic crystals. Thus, by using the ab initio technique for periodic structures, one can get not only reliable information about the electronic structure and structural parameters of an incommensurate phase, but also identify and predict such phases in new elements.

  • 44.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adenovirus E3 protein modulates leukocyte functions2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 50, p. 19976-19977Article in journal (Other academic)
  • 45.
    Arnqvist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Edvardsson, M
    Friberg, U
    Nilsson, T
    Sexual conflict promotes speciation in insects2000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 19, p. 10460-10464Article in journal (Refereed)
  • 46.
    Arnqvist, Göran
    et al.
    Department of Ecology and Environmental Science, Animal Ecology, University of Umeå, Umeå, Sweden.
    Edvardsson, Martin
    Department of Ecology and Environmental Science, Animal Ecology, University of Umeå, Umeå, Sweden.
    Friberg, Urban
    Department of Ecology and Environmental Science, Animal Ecology, University of Umeå, Umeå, Sweden.
    Nilsson, Tina
    Department of Ecology and Environmental Science, Animal Ecology, University of Umeå, Umeå, Sweden.
    Sexual conflict promotes speciation in insects.2000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 19, p. 10460-10464Article in journal (Refereed)
    Abstract [en]

    Speciation rates among extant lineages of organisms vary extensively, but our understanding of the causes of this variation and, therefore, the processes of speciation is still remarkably incomplete. Both theoretical and empirical studies have indicated that sexual selection is important in speciation, but earlier discussions have focused almost exclusively on the potential role of female mate choice. Recent findings of postmating reproductive conflicts of interest between the sexes suggest a quite different route to speciation. Such conflicts may lead to perpetual antagonistic coevolution between males and females and may thus generate rapid evolutionary divergence of traits involved in reproduction. Here, we assess this hypothesis by contrasting pairs of related groups of insect species differing in the opportunity for postmating sexual conflict. Groups where females mate with many males exhibited speciation rates four times as high as in related groups where females mate only once. Our results not only highlight the general importance of postmating sexual selection in speciation, but also support the recent suggestion that sexual conflict is a key engine of speciation.

  • 47. Aronson, Richard B
    et al.
    Smith, Kathryn E
    Vos, Stephanie C
    McClintock, James B
    Amsler, Margaret O
    Moksnes, Per-Olav
    Ellis, Daniel S
    Kaeli, Jeffrey
    Singh, Hanumant
    Bailey, John W
    Schiferl, Jessica C
    van Woesik, Robert
    Martin, Michael A
    Steffel, Brittan V
    Deal, Michelle E
    Lazarus, Steven M
    Havenhand, Jonathan N
    Swalethorp, Rasmus
    Kjellerup, Sanne
    Thatje, Sven
    No barrier to emergence of bathyal king crabs on the Antarctic shelf.2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490Article in journal (Refereed)
    Abstract [en]

    Cold-water conditions have excluded durophagous (skeleton-breaking) predators from the Antarctic seafloor for millions of years. Rapidly warming seas off the western Antarctic Peninsula could now facilitate their return to the continental shelf, with profound consequences for the endemic fauna. Among the likely first arrivals are king crabs (Lithodidae), which were discovered recently on the adjacent continental slope. During the austral summer of 2010‒2011, we used underwater imagery to survey a slope-dwelling population of the lithodid Paralomis birsteini off Marguerite Bay, western Antarctic Peninsula for environmental or trophic impediments to shoreward expansion. The population density averaged ∼4.5 individuals × 1,000 m(-2) within a depth range of 1,100‒1,500 m (overall observed depth range 841-2,266 m). Images of juveniles, discarded molts, and precopulatory behavior, as well as gravid females in a trapping study, suggested a reproductively viable population on the slope. At the time of the survey, there was no thermal barrier to prevent the lithodids from expanding upward and emerging on the outer shelf (400- to 550-m depth); however, near-surface temperatures remained too cold for them to survive in inner-shelf and coastal environments (<200 m). Ambient salinity, composition of the substrate, and the depth distribution of potential predators likewise indicated no barriers to expansion of lithodids onto the outer shelf. Primary food resources for lithodids-echinoderms and mollusks-were abundant on the upper slope (550-800 m) and outer shelf. As sea temperatures continue to rise, lithodids will likely play an increasingly important role in the trophic structure of subtidal communities closer to shore.

  • 48.
    Aspan, A
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Comparative Physiology.
    Huang, TS
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Comparative Physiology.
    Cerenius, Lage
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Comparative Physiology.
    Söderhäll, Kenneth
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Comparative Physiology.
    CDNA CLONING OF PROPHENOLOXIDASE FROM THE FRESH-WATER CRAYFISH PACIFASTACUS-LENIUSCULUS AND ITS ACTIVATION1995In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 92, no 4, p. 939-943Article in journal (Refereed)
    Abstract [en]

    Prophenoloxidase (proPO), an enzyme that is the terminal component of the so-called proPO activating system, a defense and recognition system in crustaceans and insects, has been purified and cloned from a crayfish blood cell cDNA library. The deduced ami

  • 49. Attems, Johannes
    et al.
    Alpar, Alan
    Spence, Lauren
    McParland, Shane
    Heikenwalder, Mathias
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tanila, Heikki
    Hökfelt, Tomas G. M.
    Harkany, Tibor
    Clusters of secretagogin-expressing neurons in the aged human olfactory tract lack terminal differentiation2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 16, p. 6259-6264Article in journal (Refereed)
    Abstract [en]

    Expanding the repertoire of molecularly diverse neurons in the human nervous system is paramount to characterizing the neuronal networks that underpin sensory processing. Defining neuronal identities is particularly timely in the human olfactory system, whose structural differences from nonprimate macrosmatic species have recently gained momentum. Here, we identify clusters of bipolar neurons in a previously unknown outer "shell" domain of the human olfactory tract, which express secretagogin, a cytosolic Ca2+ binding protein. These "shell" neurons are wired into the olfactory circuitry because they can receive mixed synaptic inputs. Unexpectedly, secretagogin is often coexpressed with polysialylated-neural cell adhesion molecule, beta-III-tubulin, and calretinin, suggesting that these neurons represent a cell pool that might have escaped terminal differentiation into the olfactory circuitry. We hypothesized that secretagogin-containing "shell" cells may be eliminated from the olfactory axis under neurodegenerative conditions. Indeed, the density, but not the morphological or neurochemical integrity, of secretagogin-positive neurons selectively decreases in the olfactory tract in Alzheimer's disease. In conclusion, secretagogin identifies a previously undescribed cell pool whose cytoarchitectonic arrangements and synaptic connectivity are poised to modulate olfactory processing in humans.

  • 50.
    Aucouturier, Jean-Julien
    et al.
    Univ Paris 06, IRCAM, CNRS, STMS,UMR9912, F-74005 Paris, France..
    Johansson, Petter
    Uppsala University, The Swedish Collegium for Advanced Study in the Social Sciences (SCASSS). Lund Univ, Lund Univ Cognit Sci, S-22100 Lund, Sweden..
    Hall, Lars
    Lund Univ, Lund Univ Cognit Sci, S-22100 Lund, Sweden..
    Segnini, Rodrigo
    Siemens Healthcare, Tokyo 1418644, Japan..
    Mercadie, Lolita
    Nippon Telegraph & Tel NTT Corp, Commun Sci Labs, Yokohama, Kanagawa 2430198, Japan.;Univ Bourgogne, CNRS, LEAD, UMR5022, F-21000 Dijon, France..
    Watanabe, Katsumi
    Waseda Univ, Fac Sci & Engn, Dept Intermedia Art & Sci, Tokyo 1698555, Japan.;Univ Tokyo, Res Ctr Adv Sci & Technol, Tokyo 1538904, Japan..
    Covert digital manipulation of vocal emotion alter speakers' emotional states in a congruent direction2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 4, p. 948-953Article in journal (Refereed)
    Abstract [en]

    Research has shown that people often exert control over their emotions. By modulating expressions, reappraising feelings, and redirecting attention, they can regulate their emotional experience. These findings have contributed to a blurring of the traditional boundaries between cognitive and emotional processes, and it has been suggested that emotional signals are produced in a goal-directed way and monitored for errors like other intentional actions. However, this interesting possibility has never been experimentally tested. To this end, we created a digital audio platform to covertly modify the emotional tone of participants' voices while they talked in the direction of happiness, sadness, or fear. The result showed that the audio transformations were being perceived as natural examples of the intended emotions, but the great majority of the participants, nevertheless, remained unaware that their own voices were being manipulated. This finding indicates that people are not continuously monitoring their own voice to make sure that it meets a predetermined emotional target. Instead, as a consequence of listening to their altered voices, the emotional state of the participants changed in congruence with the emotion portrayed, which was measured by both self-report and skin conductance level. This change is the first evidence, to our knowledge, of peripheral feedback effects on emotional experience in the auditory domain. As such, our result reinforces the wider framework of self-perception theory: that we often use the same inferential strategies to understand ourselves as those that we use to understand others.

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