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  • 1. 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.

  • 2. 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.

  • 3.
    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.

  • 4. 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.

  • 5. 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].

  • 6.
    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.

  • 7.
    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.

  • 8. 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.

  • 9.
    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.

  • 10.
    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.

  • 11. 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.

  • 12.
    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)
  • 13.
    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.

  • 14.
    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)
  • 15.
    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.

  • 16.
    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)
  • 17.
    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

  • 18.
    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.

  • 19. Augsten, Martin
    et al.
    Hägglöf, Christina
    Olsson, Eleonor
    Stolz, Claudia
    Tsagozis, Panagiotis
    Levchenko, Tetyana
    Frederick, Mitchell J.
    Borg, Åke
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Egevad, Lars
    Östman, Arne
    CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 9, p. 3414-3419Article in journal (Refereed)
    Abstract [en]

    This study explored the role of secreted fibroblast-derived factors in prostate cancer growth. Analyses of matched normal and tumor tissue revealed up-regulation of CXCL14 in cancer-associated fibroblasts of a majority of prostate cancer. Fibroblasts over-expressing CXCL14 promoted the growth of prostate cancer xenografts, and increased tumor angiogenesis and macrophage infiltration. Mechanistic studies demonstrated that autocrine CXCL14-stimulation of fibroblasts stimulate migration and ERK-dependent proliferation of fibroblasts. CXCL14-stimulation of monocyte migration was also demonstrated. Furthermore, CXCL14-producing fibroblasts, but not recombinant CXCL14, enhanced in vitro proliferation and migration of prostate cancer cells and in vivo angiogenesis. These studies thus identify CXCL14 as a novel autocrine stimulator of fibroblast growth and migration, with multi-modal tumor-stimulatory activities. In more general terms, our findings suggest autocrine stimulation of fibroblasts as a previously unrecognized mechanism for chemokine-mediated stimulation of tumor growth, and suggest a novel mechanism whereby cancer-associated fibroblasts achieve their pro-tumorigenic phenotype.

  • 20. Awano, Tomoyuki
    et al.
    Johnson, Gary S.
    Wade, Claire M.
    Katz, Martin L.
    Johnson, Gayle C.
    Taylor, Jeremy F.
    Perloski, Michele
    Biagi, Tara
    Baranowska, Izabella
    Long, Sam
    March, Philip A.
    Olby, Natasha J.
    Shelton, G. Diane
    Khan, Shahnawaz
    O'Brien, Dennis P.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Coates, Joan R.
    Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 8, p. 2794-2799Article in journal (Refereed)
    Abstract [en]

    Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.

  • 21. Ayer-LeLievre, C
    et al.
    Olson, L
    Ebendal, T
    Hallböök, F
    Persson, H
    Nerve growth factor mRNA and protein in the testis and epididymis of mouse and rat.1988In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 85, no 8, p. 2628-32Article in journal (Refereed)
    Abstract [en]

    In situ hybridization using beta-nerve growth factor (NGF) DNA probes was used to demonstrate NGF mRNA in spermatocytes and early spermatids of adult mouse. NGF mRNA-containing cells were also identified in the epithelium of convoluted ducts in mouse corpus epididymidis. Blot-hybridization analysis of RNA prepared from mouse testis and epididymis as well as from rat epididymis confirmed the presence of a 1.3-kilobase (kb) NGF mRNA in these tissues. In the rat testis, however, only a 1.5-kb NGF mRNA was found, corresponding in size to a minor NGF mRNA detected in the rat brain, heart, and epididymis. By using affinity-purified anti-NGF antibodies, NGF-like immunoreactivity was observed in germ cells of rat and mouse testis and in the lumen of epididymis. Extracts of both mouse epididymis and testis stimulated fiber outgrowth in cultured sympathetic ganglia, and the effect was blocked by antibodies to mouse NGF. A two-site enzyme immunoassay showed the presence of 10 and 70 ng of NGF per g of tissue in the mouse testis and epididymis, respectively. Furthermore, RNA blot analysis showed the presence of mRNA for the NGF receptor in mouse testis. These results suggest a nonneurotrophic role for NGF in the male reproductive system, possibly in survival maturation and/or motility of spermatozoa.

  • 22. Bach, Anders
    et al.
    Clausen, Bettina H.
    Moller, Magda
    Vestergaard, Bente
    Chi, Celestine N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Round, Adam
    Sorensen, Pernille L.
    Nissen, Klaus B.
    Kastrup, Jette S.
    Gajhede, Michael
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kristensen, Anders S.
    Lundström, Patrik
    Lambertsen, Kate L.
    Stromgaard, Kristian
    A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 9, p. 3317-3322Article in journal (Refereed)
    Abstract [en]

    Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.

  • 23.
    Baltekin, Özden
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Boucharin, Alexis
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Elf, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Antibiotic susceptibility testing in less than 30 min using direct single-cell imaging2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 34, p. 9170-9175Article in journal (Refereed)
    Abstract [en]

    The emergence and spread of antibiotic-resistant bacteria are aggravated by incorrect prescription and use of antibiotics. A core problem is that there is no sufficiently fast diagnostic test to guide correct antibiotic prescription at the point of care. Here, we investigate if it is possible to develop a point-of-care susceptibility test for urinary tract infection, a disease that 100 million women suffer from annually and that exhibits widespread antibiotic resistance. We capture bacterial cells directly from samples with low bacterial counts (10(4) cfu/mL) using a custom-designed microfluidic chip and monitor their individual growth rates using microscopy. By averaging the growth rate response to an antibiotic over many individual cells, we can push the detection time to the biological response time of the bacteria. We find that it is possible to detect changes in growth rate in response to each of nine antibiotics that are used to treat urinary tract infections in minutes. In a test of 49 clinical uropathogenic Escherichia coli (UPEC) isolates, all were correctly classified as susceptible or resistant to ciprofloxacin in less than 10 min. The total time for antibiotic susceptibility testing, from loading of sample to diagnostic readout, is less than 30 min, which allows the development of a point-of-care test that can guide correct treatment of urinary tract infection.

  • 24.
    Barg, Sebastian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Knowles, M. K.
    Chen, X.
    Midorikawa, M.
    Almers, Wolfhard
    Syntaxin clusters assemble reversibly at sites of secretory granules in live cells2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 48, p. 20804-20809Article in journal (Refereed)
    Abstract [en]

    Syntaxin resides in the plasma membrane, where it helps to catalyze membrane fusion during exocytosis. The protein also forms clusters in cell-free and granule-free plasma-membrane sheets. We imaged the interaction between syntaxin and single secretory granules by two-color total internal reflection microscopy in PC12 cells. Syntaxin-GFP assembled in clusters at sites where single granules had docked at the plasma membrane. Clusters were intermittently present at granule sites, as syntaxin molecules assembled and disassembled in a coordinated fashion. Recruitment to granules required the N-terminal domain of syntaxin, but not the entry of syntaxin into SNARE complexes. Clusters facilitated exocytosis and disassembled once exocytosis was complete. Syntaxin cluster formation defines an intermediate step in exocytosis.

  • 25.
    Barg, Sebastian
    et al.
    Department of Physiological Sciences, Lund University, Lund.
    Renström, Erik
    Department of Physiological Sciences, Lund University, Lund.
    Berggren, Per-Olof
    The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institute, Stockholm.
    Bertorello, Alejandro
    The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institute, Stockholm.
    Bokvist, Krister
    Novo Nordisk AyS, Bagsvaerd.
    Braun, Matthias
    Physiologisches Institut, Universität des Saarlandes, HomburgySaar.
    Eliasson, Lena
    Department of Physiological Sciences, Lund University, Lund.
    Holmes, William E
    Novo Nordisk AyS, Bagsvaerd.
    Köhler, Martin
    The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institute, Stockholm.
    Rorsman, Patrik
    Department of Physiological Sciences, Lund University, Lund.
    Thévenod, Frank
    Physiologisches Institut, Universität des Saarlandes, HomburgySaar.
    The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic beta cells is mediated by a 65-kDa mdr-like P-glycoprotein1999In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 96, no 10, p. 5539-44Article in journal (Refereed)
    Abstract [en]

    Intracellular application of the sulfonylurea tolbutamide during whole-cell patch-clamp recordings stimulated exocytosis >5-fold when applied at a cytoplasmic Ca2+ concentration of 0.17 microM. This effect was not detectable in the complete absence of cytoplasmic Ca2+ and when exocytosis was elicited by guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS). The stimulatory action could be antagonized by the sulfonamide diazoxide, by the Cl--channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), by intracellular application of the antibody JSB1 [originally raised against a 170-kDa multidrug resistance (mdr) protein], and by tamoxifen (an inhibitor of the mdr- and volume-regulated Cl- channels). Immunocytochemistry and Western blot analyses revealed that JSB1 recognizes a 65-kDa protein in the secretory granules. This protein exhibited no detectable binding of sulfonylureas and is distinct from the 140-kDa sulfonylurea high-affinity sulfonylurea receptors also present in the granules. We conclude that (i) tolbutamide stimulates Ca2+-dependent exocytosis secondary to its binding to a 140-kDa high-affinity sulfonylurea receptor in the secretory granules; and (ii) a granular 65-kDa mdr-like protein mediates the action. The processes thus initiated culminate in the activation of a granular Cl- conductance. We speculate that the activation of granular Cl- fluxes promotes exocytosis (possibly by providing the energy required for membrane fusion) by inducing water uptake and an increased intragranular hydrostatic pressure.

  • 26.
    Belliveau, Nathan M.
    et al.
    CALTECH, Div Biol & Biol Engn, Pasadena, USA.
    Barnes, Stephanie L.
    CALTECH, Div Biol & Biol Engn, Pasadena, USA.
    Ireland, William T.
    CALTECH, Dept Phys, Pasadena, USA.
    Jones, Daniel L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sweredoski, Michael J.
    CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, USA.
    Moradian, Annie
    CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, USA.
    Hess, Sonja
    CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, CA 91125 USA;MedImmune, Antibody Discovery & Prot Engn, Gaithersburg, USA.
    Kinney, Justin B.
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, USA.
    Phillips, Rob
    CALTECH, Div Biol & Biol Engn, Pasadena, USA;CALTECH, Dept Phys, Pasadena, CA 91125 USA;CALTECH, Dept Appl Phys, Pasadena, CA 91125 USA.
    Systematic approach for dissecting the molecular mechanisms of transcriptional regulation in bacteria2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 21, p. E4796-E4805Article in journal (Refereed)
    Abstract [en]

    Gene regulation is one of the most ubiquitous processes in biology. However, while the catalog of bacterial genomes continues to expand rapidly, we remain ignorant about how almost all of the genes in these genomes are regulated. At present, characterizing the molecular mechanisms by which individual regulatory sequences operate requires focused efforts using low-throughput methods. Here, we take a first step toward multipromoter dissection and show how a combination of massively parallel reporter assays, mass spectrometry, and information-theoretic modeling can be used to dissect multiple bacterial promoters in a systematic way. We show this approach on both well-studied and previously uncharacterized promoters in the enteric bacterium Escherichia coli. In all cases, we recover nucleotide-resolution models of promoter mechanism. For some promoters, including previously unannotated ones, the approach allowed us to further extract quantitative biophysical models describing input-output relationships. Given the generality of the approach presented here, it opens up the possibility of quantitatively dissecting the mechanisms of promoter function in E. coli and a wide range of other bacteria.

  • 27.
    Bengoechea-Alonso, Maria T
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Ericsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Hyperphosphorylation regulates the activity of SREBP1 during mitosis2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no 33, p. 11681-11686Article in journal (Refereed)
    Abstract [en]

    The sterol regulatory element-binding protein (SREBP) family of transcription factors controls the biosynthesis of cholesterol and other lipids, and lipid synthesis is critical for cell growth and proliferation. We were, therefore, interested in the expression and activity of SREBPs during the cell cycle. We found that the expression of a number of SREBP-responsive promoter-reporter genes were induced in a SREBP-dependent manner in cells arrested in G(2)/M. In addition, the mature forms of SREBP1a and SREBP1c were hyperphosphorylated in mitotic cells, giving rise to a phosphoepitope recognized by the mitotic protein monoclonal-2 (MPM-2) antibody. In contrast, SREBP2 was not hyperphosphorylated in mitotic cells and was not recognized by the MPM-2 antibody. The MPM-2 epitope was mapped to the C terminus of mature SREBP1, and the mitosis-specific hyperphosphorylation of SREBP1 depended on this domain of the protein. The transcriptional and DNA-binding activity of SREBP1 was enhanced in cells arrested in G(2)/M, and these effects depended on the C-terminal domain of the protein. In part, these effects could be explained by our observation that mature SREBP1 was stabilized in G(2)/M. In agreement with these observations, we found that the synthesis of cholesterol was increased in G(2)/M-arrested cells. Thus, our results demonstrate that the activity of mature SREBP1 is regulated by phosphorylation during the cell cycle, suggesting that SREBP1 may provide a link between lipid synthesis, proliferation, and cell growth.

  • 28.
    Bensing, Sophie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fetissov, Serguei
    Mulder, Jan
    Perheentupa, Jaakko
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Husebye, Eystein S.
    Oscarson, Mikael
    Ekwall, Olov
    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 Women's and Children's Health.
    Crock, Patricia A.
    Hökfelt, Tomas
    Hulting, Anna-Lena
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pituitary autoantibodies in autoimmune polyendocrine syndrome type 12007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 3, p. 949-954Article in journal (Refereed)
    Abstract [en]

    Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies (Aabs) toward intracellular enzymes are a hallmark for APS1 and serve as diagnostic markers and predictors for disease manifestations. In this study, we aimed to identify pituitary autoantigens in patients with APS1. A pituitary cDNA expression library was screened with APS1 sera and a tudor domain containing protein 6 (TDRD6) cDNA clone was isolated. Positive immunoreactivity against in vitro translated TDRD6 fragments was shown in 42/86 (49%) APS1 patients but not in patients with other autoimmune diseases or in healthy controls. By using immunohistochemistry, sera from 3/6 APS1 patients with growth hormone (GH) deficiency showed immunostaining of a small number of guinea pig anterior pituitary cells, and 40-50% of these cells were GH-positive. No such immunostaining was seen with sera from healthy controls. The APS1 Aab-positive, GH-negative cells may represent a novel subpopulation of anterior pituitary cells. In addition, 4/6 patient sera showed staining of a fiber-plexus in the pituitary intermediate lobe recognizing enzymes of monoamine and GABA synthesis. Thus, we have identified TDRD6 as a major autoantigen in APS1 patients and shown that several sera from GH-deficient patients stain specific cell populations and nerves in the pituitary gland.

  • 29.
    Bergquist, Jonas
    et al.
    Department of Clinical Neuroscience, Section for Neurochemistry.
    Tarkowski, A
    of Clinical Immunology and Rheumatology, Goteborg University,.
    Ekman, R
    Department of Clinical Neuroscience, Section for Neurochemistry.
    Ewing, A
    Department of Chemistry, Pennsylvania State University, University Park,.
    Discovery of endogenous catecholamines in lymphocytes and evidence for catecholamine regulation of lymphocyte function via an autocrine loop.1994In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 91, no 26, p. 12912-6Article in journal (Refereed)
    Abstract [en]

    Evidence has been obtained that catecholamines and their metabolites are present in single lymphocytes and extracts of T- and B-cell clones by use of capillary electrophoresis with electrochemical detection. Pharmacological inhibition of tyrosine hydroxylase reduces observed catecholamine levels, suggesting catecholamine synthesis by lymphocytes. Intracellular dopamine levels are shown to be increased by extra-cellular dopamine, suggesting a cellular-uptake mechanism. Furthermore, incubation with either dopamine or L-dihydroxyphenylalanine, a precursor of dopamine, results in a dose-dependent inhibition of lymphocyte proliferation and differentiation. Together, these results suggest the presence of an autocrine loop whereby lymphocytes down-regulate their own activity.

  • 30. Bergthorsson, Ulfar
    et al.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Roth, John R.
    Ohno's dilemma: evolution of new genes under continuous selection2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 43, p. 17004-17009Article in journal (Refereed)
    Abstract [en]

    New genes with novel functions arise by duplication and divergence, but the process poses a problem. After duplication, an extra gene copy must rise to sufficiently high frequency in the population and remain free of common inactivating lesions long enough to acquire the rare mutations that provide a new selectable function. Maintaining a duplicated gene by selection for the original function would restrict the freedom to diverge. (We refer to this problem as Ohno's dilemma). A model is described by which selection continuously favors both maintenance of the duplicate copy and divergence of that copy from the parent gene. Before duplication, the original gene has a trace side activity (the innovation) in addition to its original function. When an altered ecological niche makes the minor innovation valuable, selection favors increases in its level (the amplification), which is most frequently conferred by increased dosage of the parent gene. Selection for the amplified minor function maintains the extra copies and raises the frequency of the amplification in the population. The same selection favors mutational improvement of any of the extra copies, which are not constrained to maintain their original function (the divergence). The rate of mutations (per genome) that improve the new function is increased by the multiplicity of target copies within a genome. Improvement of some copies relaxes selection on others and allows their loss by mutation (becoming pseudogenes). Ultimately one of the extra copies is able to provide all of the new activity.

  • 31. Berhane, Kiflu
    et al.
    Widersten, Mikael
    Engström, Åke
    Kozarich, John W.
    Mannervik, Bengt
    Detoxication of base propenals and other α,β-unsaturated aldehyde products of radical reactions and lipid peroxidation by human glutathione transferases1994In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 91, p. 1480-1484Article in journal (Refereed)
  • 32. Berrah, Nora
    et al.
    Fang, Li
    Murphy, Brendan
    Osipov, Timur
    Ueda, Kiyoshi
    Kukk, Edwin
    Feifel, Raimund
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Soft X-Ray Physics.
    van der Meulen, Peter
    Salen, Peter
    Schmidt, Henning T.
    Thomas, Richard D.
    Larsson, Mats
    Richter, Robert
    Prince, Kevin C.
    Bozek, John D.
    Bostedt, Christoph
    Wada, Shin-ichi
    Piancastelli, Maria N.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Surface and Interface Science.
    Tashiro, Motomichi
    Ehara, Masahiro
    Double-core-hole spectroscopy for chemical analysis with an intense X-ray femtosecond laser2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 41, p. 16912-16915Article in journal (Refereed)
    Abstract [en]

    Theory predicts that double-core-hole (DCH) spectroscopy can provide a new powerful means of differentiating between similar chemical systems with a sensitivity not hitherto possible. Although DCH ionization on a single site in molecules was recently measured with double-and single-photon absorption, double-core holes with single vacancies on two different sites, allowing unambiguous chemical analysis, have remained elusive. Here we report that direct observation of double-core holes with single vacancies on two different sites produced via sequential two-photon absorption, using short, intense X-ray pulses from the Linac Coherent Light Source free-electron laser and compare it with theoretical modeling. The observation of DCH states, which exhibit a unique signature, and agreement with theory proves the feasibility of the method. Our findings exploit the ultrashort pulse duration of the free-electron laser to eject two core electrons on a time scale comparable to that of Auger decay and demonstrate possible future X-ray control of physical inner-shell processes.

  • 33.
    Beyerlein, Kenneth
    et al.
    Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Hamburg, Germany.
    Jönsson, Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Alonso-Mori, Roberto
    SLAC National Accelerator Laboratory, USA.
    Aquila, Andrew
    SLAC National Accelerator Laboratory, USA.
    Bajt, Sasa
    Photon Science, DESY, Hamburg, Germany.
    Barty, Anton
    Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Hamburg, Germany.
    Bean, Richard
    Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Hamburg, Germany.
    Koglin, Jason E.
    SLAC National Accelerator Laboratory, USA.
    Messerschmidt, Marc
    SLAC National Accelerator Laboratory, USA.
    Ragazzon, Davide
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Soklaras, Dimosthenis
    SLAC National Accelerator Laboratory, USA.
    Williams, Garth J.
    SLAC National Accelerator Laboratory, USA.
    Hau-Riege, Stefan
    Lawrence Livermore National Laboratory, USA.
    Boutet, Sebastien
    SLAC National Accelerator Laboratory, USA.
    Chapman, Henry N.
    Center for Free-Electron Laser Science,Deutsches Elektronen-Synchrotron, Hamburg, Germany; Department of Physics, University of Hamburg, Hamburg, Germany; Centre for Ultrafast Imaging, University of Hamburg, Hamburg, Germany .
    Timneanu, Nicusor
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. Center for Free-Electron Laser Science,Deutsches Elektronen-Synchrotron, Hamburg, Germany.
    Ultrafast non-thermal heating of water initiated by an X-ray laser2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 22, p. 5652-5657Article in journal (Refereed)
    Abstract [en]

    X-ray Free-Electron Lasers have opened the door to a new era in structural biology, enabling imaging of biomolecules and dynamics that were impossible to access with conventional methods. A vast majority of imaging experiments, including Serial Femtosecond Crystallography, use a liquid jet to deliver the sample into the interaction region. We have observed structural changes in the carrying water during X-ray exposure, showing how it transforms from the liquid phase to a plasma. This ultrafast phase transition observed in water provides evidence that any biological structure exposed to these X-ray pulses is destroyed during the X-ray exposure.The bright ultrafast pulses of X-ray Free-Electron Lasers allow investigation into the structure of matter under extreme conditions. We have used single pulses to ionize and probe water as it undergoes a phase transition from liquid to plasma. We report changes in the structure of liquid water on a femtosecond time scale when irradiated by single 6.86 keV X-ray pulses of more than 106 J/cm2. These observations are supported by simulations based on molecular dynamics and plasma dynamics of a water system that is rapidly ionized and driven out of equilibrium. This exotic ionic and disordered state with the density of a liquid is suggested to be structurally different from a neutral thermally disordered state.

    The full text will be freely available from 2018-10-17 08:00
  • 34.
    Birgner, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lundblad, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mendez, José Alfredo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Smith, Casey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    le Grevés, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Galter, Dagmar
    Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Olson, Lars
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
    Trudeau, Louis-Eric
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioural activation2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 1, p. 389-394Article in journal (Refereed)
    Abstract [en]

    The “One neuron-one neurotransmitter” concept has been challenged frequently during the last three decades, and the coexistence of neurotransmitters in individual neurons is now regarded as a common phenomenon. The functional significance of neurotransmitter coexistence is, however, less well understood. Several studies have shown that a subpopulation of dopamine (DA) neurons in the ventral tegmental area (VTA) expresses the vesicular glutamate transporter 2 (VGLUT2) and has been suggested to use glutamate as a cotransmitter. The VTA dopamine neurons project to limbic structures including the nucleus accumbens, and are involved in mediating the motivational and locomotor activating effects of psychostimulants. To determine the functional role of glutamate cotransmission by these neurons, we deleted VGLUT2 in DA neurons by using a conditional gene-targeting approach in mice. A DAT-Cre/Vglut2Lox mouse line (Vglut2f/f;DAT-Cre mice) was produced and analyzed by in vivo amperometry as well as by several behavioral paradigms. Although basal motor function was normal in the Vglut2f/f;DAT-Cre mice, their risk-taking behavior was altered. Interestingly, in both home-cage and novel environments, the gene targeted mice showed a greatly blunted locomotor response to the psychostimulant amphetamine, which acts via the midbrain DA system. Our results show that VGLUT2 expression in DA neurons is required for normal emotional reactivity as well as for psychostimulant-mediated behavioral activation.

  • 35. Bize, Ariane
    et al.
    Karlsson, Erik A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Ekefjärd, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Quax, F.
    Pina, Mery
    Prevost, Marie-Christine
    Forterre, Patrick
    Tenaillon, Olivier
    Bernander, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Prangishvili, David
    A unique virus release mechanism in the Archaea2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 27, p. 11306-11311Article in journal (Refereed)
    Abstract [en]

    Little is known about the infection cycles of viruses infecting cells from Archaea, the third domain of life. Here, we demonstrate that the virions of the archaeal Sulfolobus islandicus rod-shaped virus 2 (SIRV2) are released from the host cell through a mechanism, involving the formation of specific cellular structures. Large pyramidal virus-induced protrusions transect the cell envelope at several positions, rupturing the S-layer; they eventually open out, thus creating large apertures through which virions escape the cell. We also demonstrate that massive degradation of the host chromosomes occurs because of virus infection, and that virion assembly occurs in the cytoplasm. Furthermore, intracellular viral DNA is visualized by flow cytometry. The results show that SIRV2 is a lytic virus, and that the host cell dies as a consequence of elaborated mechanisms orchestrated by the virus. The generation of specific cellular structures for a distinct step of virus life cycle is known in eukaryal virus-host systems but is unprecedented in cells from other domains.

  • 36.
    Björkholm, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Harish, Ajith
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Hagström, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Ernst, Andreas M.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Mitochondrial genomes are retained by selective constraints on protein targeting2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 33, p. 10154-10161Article in journal (Refereed)
    Abstract [en]

    Mitochondria are energy-producing organelles in eukaryotic cells considered to be of bacterial origin. The mitochondrial genome has evolved under selection for minimization of gene content, yet it is not known why not all mitochondrial genes have been transferred to the nuclear genome. Here, we predict that hydrophobic membrane proteins encoded by the mitochondrial genomes would be recognized by the signal recognition particle and targeted to the endoplasmic reticulum if they were nuclear-encoded and translated in the cytoplasm. Expression of the mitochondrially encoded proteins Cytochrome oxidase subunit 1, Apocytochrome b, and ATP synthase subunit 6 in the cytoplasm of HeLa cells confirms export to the endoplasmic reticulum. To examine the extent to which the mitochondrial proteome is driven by selective constraints within the eukaryotic cell, we investigated the occurrence of mitochondrial protein domains in bacteria and eukaryotes. The accessory protein domains of the oxidative phosphorylation system are unique to mitochondria, indicating the evolution of new protein folds. Most of the identified domains in the accessory proteins of the ribosome are also found in eukaryotic proteins of other functions and locations. Overall, one-third of the protein domains identified in mitochondrial proteins are only rarely found in bacteria. We conclude that the mitochondrial genome has been maintained to ensure the correct localization of highly hydrophobic membrane proteins. Taken together, the results suggest that selective constraints on the eukaryotic cell have played a major role in modulating the evolution of the mitochondrial genome and proteome.

  • 37.
    Blomqvist, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics, Condensed Matter Theory.
    Araújo, C. Moysés
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics, Condensed Matter Theory.
    Srepusharawoot, P.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics, Condensed Matter Theory.
    Ahuja, Rajeev
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics, Condensed Matter Theory.
    Li-decorated metal-organic framework-5: A route to achieving a suitable hydrogen storage medium2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 51, p. 20173-Article in journal (Refereed)
    Abstract [en]

    A significant improvement in molecular hydrogen uptake properties is revealed by our ab initio calculations for Li-decorated metal-organic framework 5. We have found that two Li atoms are strongly adsorbed on the surfaces of the six-carbon rings, one on each side, carrying a charge of +0.9e per Li atom. Each Li can cluster three H-2 molecules around itself with a binding energy of 12 kJ (mol H-2)(-1). Furthermore, we show from ab initio molecular dynamics simulations with a hydrogen loading of 18 H2 per formula unit that a hydrogen uptake of 2.9 wt % at 200 K and 2.0 wt % at 300 K is achievable. To our knowledge, this is the highest hydrogen storage capacity reported for metal-organic framework 5 under such thermodynamic conditions.

  • 38. Bogdanowicz, Wiesław
    et al.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Branicki, Wojciech
    Lembring, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gajewska, Marta
    Kupiec, Tomasz
    Genetic identification of putative remains of the famous astronomer Nicolaus Copernicus2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 30, p. 12279-12282Article in journal (Refereed)
    Abstract [en]

    We report the results of mitochondrial and nuclear DNA analyses of skeletal remains exhumed in 2005 at Frombork Cathedral in Poland, that are thought to be those of Nicolaus Copernicus (1473-1543). The analyzed bone remains were found close to the altar Nicolaus Copernicus was responsible for during his tenure as priest. The mitochondrial DNA (mtDNA) profiles from 3 upper molars and the femurs were identical, suggesting that the remains originate from the same individual. Identical mtDNA profiles were also determined in 2 hairs discovered in a calendar now exhibited at Museum Gustavianum in Uppsala, Sweden. This calendar was the property of Nicolaus Copernicus for much of his life. These findings, together with anthropological data, support the identification of the human remains found in Frombork Cathedral as those of Nicolaus Copernicus. Up-to-now the particular mtDNA haplotype has been observed only 3 times in Germany and once in Denmark. Moreover, Y-chromosomal and autosomal short tandem repeat markers were analyzed in one of the tooth samples, that was much better preserved than other parts of the skeleton. Molecular sex determination revealed that the skeleton is from a male individual, and this result is consistent with morphological investigations. The minimal Y-chromosomal haplotype determined in the putative remains of Nicolaus Copernicus has been observed previously in many countries, including Austria, Germany, Poland, and the Czech Republic. Finally, an analysis of the SNP located in the HERC2 gene revealed the C/C genotype that is predominant in blue-eyed humans, suggesting that Copernicus may have had a light iris color.

  • 39.
    Bolnick, Daniel
    et al.
    University of Texas.
    Svanbäck, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Limnology.
    Araujo, Mario
    Univ Estadual Campinas, Inst Biol, Programa Posgrad Ecol, Brazil.
    Persson, Lennart
    Umeå Universitet.
    Comparative support for the niche variation hypothesis that more generalized populations also are more heterogeneous2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 24, p. 10075-10079Article in journal (Refereed)
    Abstract [en]

    There is extensive evidence that some species of ecological generalists, which use a wide diversity of resources, are in fact heterogeneous collections of relatively specialized individuals. This within-population variation, or "individual specialization," is a key requirement for frequency-dependent interactions that may drive a variety of types of evolutionary diversification and may influence the population dynamics and ecological interactions of species. Consequently, it is important to understand when individual specialization is likely to be strong or weak. The niche variation hypothesis (NVH) suggests that populations tend to become more generalized when they are released from interspecific competition. This niche expansion was proposed to arise via increased variation among individuals rather than increased individual niche breadth. Consequently, we expect ecological generalists to exhibit stronger individual specialization, but this correlation has been repeatedly rejected by empiricists. The drawback with previous empirical tests of the NVH is that they use morphological variation as a proxy for niche variation, ignoring the role of behavior and complex phenotype-function relationships. Here, we used diet data to directly estimate niche variation among individuals. Consistent with the NVH, we show that more generalized populations also exhibit more niche variation. This trend is quite general, appearing in all five case studies examined: three-spine stickleback, Eurasian perch, Anolis lizards, intertidal gastropods, and a community of neotropical frogs. Our results suggest that generalist populations may tend to be more ecologically variable. Whether this translates into greater genetic variation, evolvability, or ecological stability remains to be determined.

  • 40. Bourgeois, Frederic
    et al.
    Ekholm, Tobias
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Algebra, Geometry and Logic.
    Eliashberg, Yakov
    Symplectic homology product via Legendrian surgery2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 20, p. 8114-8121Article in journal (Refereed)
    Abstract [en]

    This research announcement continues the study of the symplectic homology of Weinstein manifolds undertaken by the authors [Bourgeois F, Ekholm T, Eliashberg Y (2009) arXiv:0911.0026] where the symplectic homology, as a vector space, was expressed in terms of the Legendrian homology algebra of the attaching spheres of critical handles. Here, we express the product and Batalin-Vilkovisky operator of symplectic homology in that context.

  • 41.
    Boussau, Bastien
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Karlberg, Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Frank, Carolin
    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.
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Computational inference of scenarios for alpha-proteobecterial genome evolution2004In: 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. 9722-9727Article in journal (Refereed)
    Abstract [en]

    The alpha-proteobacteria, from which mitochondria are thought to have originated, display a 10-fold genome size variation and provide an excellent model system for studies of genome size evolution in bacteria. Here, we use computational approaches to infer ancestral gene sets and to quantify the flux of genes along the branches of the alpha-proteobacterial species tree. Our study reveals massive gene expansions at branches diversifying plant-associated bacteria and extreme losses at branches separating intracellular bacteria of animals and humans. Alterations in gene numbers have mostly affected functional categories associated with regulation, transport, and small-molecule metabolism, many of which are encoded by paralogous gene families located on auxiliary chromosomes. The results suggest that the alpha-proteobacterial ancestor contained 3,000-5,000 genes and was a free-living, aerobic, and motile bacterium with pili and surface proteins for host cell and environmental interactions. Approximately one third of the ancestral gene set has no homologs among the eukaryotes. More than 40% of the genes without eukaryotic counterparts encode proteins that are conserved among the alpha-proteobacteria but for which no function has yet been identified. These genes that never made it into the eukaryotes but are widely distributed in bacteria may represent bacterial drug targets and should be prime candidates for future functional characterization.

  • 42. Bragazza, Luca
    et al.
    Freeman, Chris
    Jones, Timothy
    Rydin, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Ecological Botany.
    Limpens, Juul
    Fenner, Nathalie
    Ellis, Tim
    Gerdol, Renato
    Hajek, Michal
    Hajek, Tomas
    Lacumin, Paola
    Kutnar, Lado
    Tahvanainen, Teemu
    Toberman, Hannah
    Atmospheric nitrogen deposition promotes carbon loss from peat bogs2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 51, p. 19386-19389Article in journal (Refereed)
    Abstract [en]

    Peat bogs have historically represented exceptional carbon (C) sinks because of their extremely low decomposition rates and consequent accumulation of plant remnants as peat. Among the factors favoring that peat accumulation, a major role is played by the chemical quality of plant litter itself, which is poor in nutrients and characterized by polyphenols with a strong inhibitory effect on microbial breakdown. Because bogs receive their nutrient supply solely from atmospheric deposition, the global increase of atmospheric nitrogen (N) inputs as a consequence of human activities could potentially alter the litter chemistry with important, but still unknown, effects on their C balance. Here we present data showing the decomposition rates of recently formed litter peat samples collected in nine European countries under a natural gradient of atmospheric N deposition from approximate to 0.2 to 2 g center dot m(-2)center dot yr(-1). We found that enhanced decomposition rates for material accumulated under higher atmospheric N supplies resulted in higher carbon dioxide (CO2) emissions and dissolved organic carbon release. The increased IN availability favored microbial decomposition (i) by removing N constraints on microbial metabolism and (ii) through a chemical amelioration of litter peat quality with a positive feedback on microbial enzymatic activity. Although some uncertainty remains about whether decay-resistant Sphagnum will continue to dominate litter peat, our data indicate that, even without such changes, increased N deposition poses a serious risk to our valuable peatland C sinks.

  • 43. Braun, Tatjana
    et al.
    Orlova, Albina
    Valegård, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Lindas, Ann-Christin
    Schroeder, Gunnar F.
    Egelman, Edward H.
    Archaeal actin from a hyperthermophile forms a single-stranded filament2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 30, p. 9340-9345Article in journal (Refereed)
    Abstract [en]

    The prokaryotic origins of the actin cytoskeleton have been firmly established, but it has become clear that the bacterial actins form a wide variety of different filaments, different both from each other and from eukaryotic F-actin. We have used electron cryomicroscopy (cryo-EM) to examine the filaments formed by the protein crenactin (a crenarchaeal actin) from Pyrobaculum calidifontis, an organism that grows optimally at 90 degrees C. Although this protein only has similar to 20% sequence identity with eukaryotic actin, phylogenetic analyses have placed it much closer to eukaryotic actin than any of the bacterial homologs. It has been assumed that the crenactin filament is double-stranded, like F-actin, in part because it would be hard to imagine how a single-stranded filament would be stable at such high temperatures. We show that not only is the crenactin filament single-stranded, but that it is remarkably similar to each of the two strands in F-actin. A large insertion in the crenactin sequence would prevent the formation of an F-actin-like double-stranded filament. Further, analysis of two existing crystal structures reveals six different subunit-subunit interfaces that are filament-like, but each is different from the others in terms of significant rotations. This variability in the subunit-subunit interface, seen at atomic resolution in crystals, can explain the large variability in the crenactin filaments observed by cryo-EM and helps to explain the variability in twist that has been observed for eukaryotic actin filaments.

  • 44. Bravi, Luca
    et al.
    Rudini, Noemi
    Cuttano, Roberto
    Giampietro, Costanza
    Maddaluno, Luigi
    Ferrarini, Luca
    Adams, Ralf H.
    Corada, Monica
    Boulday, Gwenola
    Tournier-Lasserve, Elizabeth
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lampugnani, Maria Grazia
    Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 27, p. 8421-8426Article in journal (Refereed)
    Abstract [en]

    Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of beta-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a beta-catenin-driven transcription program that leads to endothelial-tomesenchymal transition. TGF-beta/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate beta-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.

  • 45. Brusini, Irene
    et al.
    Carneiro, Miguel
    Wang, Chunliang
    Rubin, Carl-Johan
    Ring, Henrik
    Afonso, Sandra
    Blanco-Aguiar, José A.
    Ferrand, Nuno
    Rafati, Nima
    Villafuerte, Rafael
    Smedby, Örjan
    Damberg, Peter
    Hallböök, Finn
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Andersson, Leif
    Changes in brain architecture are consistent with altered fear processing in domestic rabbits2018In: 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]

    A common feature of all domestic animals is their tame behavior and lack of fear for humans. Consistent with this, we have previously demonstrated that genes with a role in brain or neural development have been particularly targeted during rabbit domestication. Here we show, using high-resolution magnetic resonance imaging, that domestic rabbits have an altered brain architecture consistent with reduced emotional processing, including attention to behaviorally relevant stimulation, such as fear detection, learning, expression, and control, as well as compromised information processing. The results, here based on rabbits, are significant for understanding both domestication-induced reorganization of brain architecture and how adaptions in brain territories and networks supporting emotion, cognition, and behavior coincide with an altered behavioral repertoire.The most characteristic feature of domestic animals is their change in behavior associated with selection for tameness. Here we show, using high-resolution brain magnetic resonance imaging in wild and domestic rabbits, that domestication reduced amygdala volume and enlarged medial prefrontal cortex volume, supporting that areas driving fear have lost volume while areas modulating negative affect have gained volume during domestication. In contrast to the localized gray matter alterations, white matter anisotropy was reduced in the corona radiata, corpus callosum, and the subcortical white matter. This suggests a compromised white matter structural integrity in projection and association fibers affecting both afferent and efferent neural flow, consistent with reduced neural processing. We propose that compared with their wild ancestors, domestic rabbits are less fearful and have an attenuated flight response because of these changes in brain architecture.

  • 46.
    Bryhn, Andreas C.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences.
    Håkanson, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences.
    Coastal eutrophication: whether N and/or P should be abated depends on the dynamic mass balance2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 1, p. E3-E3Article in journal (Refereed)
  • 47.
    Brännvall, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kirsebom, Leif A
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Metal ion cooperativity in ribozyme cleavage of RNA2001In: 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. 12943-12947Article in journal (Refereed)
    Abstract [en]

    Combinations of chemical and genetic approaches were used to study the function of divalent metal ions in cleavage of RNA by the ribozyme RNase P RNA. We show that different divalent metal ions have differential effects on cleavage site recognition and rescue of cleavage activity by mixing divalent metal ions that do not promote cleavage by themselves. We conclude that efficient and correct cleavage is the result of cooperativity between divalent metal ions bound at different sites in the RNase P RNA-substrate complex. Complementation of a mutant RNase P RNA phenotype as a result of divalent metal ion replacement is demonstrated also. This finding together with other data indicate that one of the metal ions involved in this cooperativity is positioned near the cleavage site. The possibility that the Mg2+/Ca2+ ratio might regulate the activity of biocatalysts that depend on RNA for activity is discussed.

  • 48.
    Butorin, Sergei M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Kvashnina, Kristina O.
    European Synchrotron, F-38043 Grenoble, France.;Helmholtz Zentrum Dresden Rossendorf, Inst Resource Ecol, D-01314 Dresden, Germany..
    Vegelius, Johan R.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Meyer, Daniel
    Univ Montpellier, Ecole Natl Super Chim Montpellier, Inst Chim Separat Marcoule, CNRS,UMR Commissariat Energie Atom & Energie Atom, F-30207 Bagnols Sur Ceze, France..
    Shuh, David K.
    Lawrence Berkeley Natl Lab, Div Chem Sci, Berkeley, CA 94720 USA..
    High-resolution X-ray absorption spectroscopy as a probe of crystal-field and covalency effects in actinide compounds2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 29, p. 8093-8097Article in journal (Refereed)
    Abstract [en]

    Applying the high-energy resolution fluorescence-detection (HERFD) mode of X-ray absorption spectroscopy (XAS), we were able to probe, for the first time to our knowledge, the crystalline electric field (CEF) splittings of the 5f shell directly in the HERFD-XAS spectra of actinides. Using ThO2 as an example, data measured at the Th 3d edge were interpreted within the framework of the Anderson impurity model. Because the charge-transfer satellites were also resolved in the HERFD-XAS spectra, the analysis of these satellites revealed that ThO2 is not an ionic compound as previously believed. The Th 6d occupancy in the ground state was estimated to be twice that of the Th 5f states. We demonstrate that HERFD-XAS allows for characterization of the CEF interaction and degree of covalency in the ground state of actinide compounds as it is extensively done for 3d transition metal systems.

  • 49. Caleman, Carl
    et al.
    Hub, Jochen S.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    van Maaren, Paul J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Atomistic simulation of ion solvation in water explains surface preference of halides2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 17, p. 6838-6842Article in journal (Refereed)
    Abstract [en]

    Water is a demanding partner. It strongly attracts ions, yet some halide anions-chloride, bromide, and iodide-are expelled to the air/water interface. This has important implications for chemistry in the atmosphere, including the ozone cycle. We present a quantitative analysis of the energetics of ion solvation based on molecular simulations of all stable alkali and halide ions in water droplets. The potentials of mean force for Cl-, Br-, and I-have shallow minima near the surface. We demonstrate that these minima derive from more favorable water-water interaction energy when the ions are partially desolvated. Alkali cations are on the inside because of the favorable ion-water energy, whereas F-is driven inside by entropy. Models attempting to explain the surface preference based on one or more ion properties such as polarizability or size are shown to lead to qualitative and quantitative errors, prompting a paradigm shift in chemistry away from such simplifications.

  • 50.
    Calosci, Nicoletta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chi, Celestine N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Richter, Barbara
    Camilloni, Carlo
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Travaglini-Allocatelli, Carlo
    Gianni, Stefano
    Vendruscolo, Michele
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Comparison of successive transition states for folding reveals alternative early folding pathways of two homologous proteins2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 49, p. 19241-19246Article in journal (Refereed)
    Abstract [en]

    The energy landscape theory provides a general framework for describing protein folding reactions. Because a large number of studies, however, have focused on two-state proteins with single well-defined folding pathways and without detectable intermediates, the extent to which free energy landscapes are shaped up by the native topology at the early stages of the folding process has not been fully characterized experimentally. To this end, we have investigated the folding mechanisms of two homologous three-state proteins, PTP-BL PDZ2 and PSD-95 PDZ3, and compared the early and late transition states on their folding pathways. Through a combination of Phi value analysis and molecular dynamics simulations we obtained atomic-level structures of the transition states of these homologous three-state proteins and found that the late transition states are much more structurally similar than the early ones. Our findings thus reveal that, while the native state topology defines essentially in a unique way the late stages of folding, it leaves significant freedom to the early events, a result that reflects the funneling of the free energy landscape toward the native state.

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