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  • 1.
    Abdollahi Sani, Negar
    et al.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Robertsson, Mats
    Linköpings universitet, Institutionen för teknik och naturvetenskap. Linköpings universitet, Tekniska högskolan.
    Cooper, Philip
    De La Rue Plc, Overton, Hampshire, UK .
    Wang, Xin
    Acreo AB, Norrköping, Sweden.
    Svensson, Magnus
    Acreo AB, Norrköping, Sweden.
    Andersson Ersman, Peter
    Acreo AB, Norrköping, Sweden.
    Norberg, Petronella
    Acreo AB, Norrköping, Sweden.
    Nilsson, Marie
    Acreo AB, Norrköping, Sweden.
    Nilsson, David
    Acreo AB, Norrköping, Sweden.
    Liu, Xianjie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Ytors Fysik och Kemi. Linköpings universitet, Tekniska högskolan.
    Hesselbom, Hjalmar
    Hesselbom Innovation and Development HB, Huddinge, Sweden .
    Akesso, Laurent
    De La Rue Plc, Overton, Hampshire, UK .
    Fahlman, Mats
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Ytors Fysik och Kemi. Linköpings universitet, Tekniska högskolan.
    Crispin, Xavier
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Engquist, Isak
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Berggren, Magnus
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan. Acreo AB, Norrköping, Sweden.
    Gustafsson, Goran
    Acreo AB, Norrköping, Sweden.
    All-printed diode operating at 1.6 GHz2014Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 33, s. 11943-11948Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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    fulltext
  • 2.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Zinc as chaperone-mimicking agent for retardation of amyloid beta peptide fibril formation2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 17, s. 5407-5412Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 3. Abraham, Nabil M.
    et al.
    Liu, Lei
    Jutras, Brandon Lyon
    Yadav, Akhilesh K.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Narasimhan, Sukanya
    Gopalakrishnan, Vissagan
    Ansari, Juliana M.
    Jefferson, Kimberly K.
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Jacobs-Wagner, Christine
    Fikrig, Erol
    Pathogen-mediated manipulation of arthropod microbiota to promote infection2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 5, s. E781-E790Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 4.
    Acerbi, Alberto
    et al.
    Department of Psychology, University of Bologna.
    Enquist, Magnus
    Stockholms universitet, Humanistiska fakulteten, Centrum för evolutionär kulturforskning. Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för etologi.
    Ghirlanda, Stefano
    Stockholms universitet, Humanistiska fakulteten, Centrum för evolutionär kulturforskning.
    Cultural evolution and individual development of openness and conservatism2009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 45, s. 18931-18935Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 5. Achen, M G
    et al.
    Jeltsch, M
    Kukk, E
    Mäkinen, Taija
    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).1998Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, nr 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 6. Adamczyk, Andrew J.
    et al.
    Cao, Jie
    Kamerlin, Shina C. Lynn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Warshel, Arieh
    Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 34, s. 14115-14120Artikel i tidskrift (Refereegranskat)
    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.

    Ladda ner fulltext (pdf)
    fulltext
  • 7. Agerberth, B
    et al.
    Gunne, H
    Odeberg, Jacob
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Kogner, P
    Boman, H G
    Gudmundsson, G H
    FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis.1995Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 92, nr 1, s. 195-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 8.
    Aguirre Rivera, Javier
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Larsson, Jimmy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Volkov, Ivan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Seefeldt, A. Carolin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Sanyal, Suparna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylärbiologi.
    Johansson, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Real-time measurements of aminoglycoside effects on protein synthesis in live cells2021Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, nr 9, artikel-id e2013315118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The spread of antibiotic resistance is turning many of the currently used antibiotics less effective against common infections. To address this public health challenge, it is critical to enhance our understanding of the mechanisms of action of these compounds. Aminoglycoside drugs bind the bacterial ribosome, and decades of results from in vitro biochemical and structural approaches suggest that these drugs disrupt protein synthesis by inhibiting the ribosome's translocation on the messenger RNA, as well as by inducing miscoding errors. So far, however, we have sparse information about the dynamic effects of these compounds on protein synthesis inside the cell. In the present study, we measured the effect of the aminoglycosides apramycin, gentamicin, and paromomycin on ongoing protein synthesis directly in live Escherichia coli cells by tracking the binding of dye-labeled transfer RNAs to ribosomes. Our results suggest that the drugs slow down translation elongation two- to fourfold in general, and the number of elongation cycles per initiation event seems to decrease to the same extent. Hence, our results imply that none of the drugs used in this study cause severe inhibition of translocation.

    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 9. Ahn, Young O.
    et al.
    Mahinthichaichan, Paween
    Lee, Hyun Ju
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ouyang, Hanlin
    Kaluka, Daniel
    Yeh, Syun-Ru
    Arjona, Davinia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rousseau, Denis L.
    Tajkhorshid, Emad
    Ädelroth, Pia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gennis, Robert B.
    Conformational coupling between the active site and residues within the K-C-channel of the Vibrio cholerae cbb(3)-type (C-family) oxygen reductase2014Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 42, s. E4419-E4428Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 10. Aizman, O.
    et al.
    Uhlen, P.
    Lal, M.
    Brismar, Hjalmar
    Aperia, A.
    Ouabain, a steroid hormone that signals with slow calcium oscillations2001Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 98, nr 23, s. 13420-13424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 11. Akopyan, Karen
    et al.
    Edgren, Tomas
    Wang-Edgren, Helen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Rosqvist, Roland
    Fahlgren, Anna
    Wolf-Watz, Hans
    Fallman, Maria
    Translocation of surface-localized effectors in type III secretion2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 4, s. 1639-1644Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

    Ladda ner fulltext (pdf)
    PNAS
  • 12.
    Akopyan, Karen
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Edgren, Tomas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Wang-Edgren, Helen
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Rosqvist, Roland
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Fahlgren, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Wolf-Watz, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Fällman, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Translocation of surface-localized effectors in type III secretion2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 4, s. 1639-1644Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 13. Alava, Mikko
    et al.
    Ardelius, John
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Aurell, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Kaski, P.
    Krishnamurthy, S.
    Orponen, P.
    Seitz, S
    Circumspect descent prevails in solving random constraint satisfaction problems2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 40, s. 15253-15257Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 14.
    Alavioon, Ghazal
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Hotzy, Cosima
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Nakhro, Khriezhanuo
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Rudolf, Sandra
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Scofield, Douglas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Zajitschek, Susanne
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi. Spanish Natl Res Council, Donana Biol Stn, Seville 41092, Spain.
    Maklakov, Alex A
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi. Univ East Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England.
    Immler, Simone
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi. Univ East Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England.
    Haploid selection within a single ejaculate increases offspring fitness2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, nr 30, s. 8053-8058Artikel i tidskrift (Refereegranskat)
    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.

  • 15. 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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Växtekologi och evolution.
    Bronikowski, Anne M.
    Reproductive aging patterns in primates reveal that humans are distinct2013Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 33, s. 13440-13445Artikel i tidskrift (Refereegranskat)
    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.

  • 16. 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.1991Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 88, nr 20, s. 9302-6Artikel i tidskrift (Refereegranskat)
    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].

  • 17.
    Ali, Muhammad Akhtar
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Younis, Shady
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Andersson, Leif
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Sjoblöm, Tobias
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 25, s. 7743-7748Artikel i tidskrift (Refereegranskat)
    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.

  • 18.
    Alimohammadi, Mohammad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Dubois, Noemie
    Sköldberg, Filip
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Hallgren, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Tradivel, Isabelle
    Hedstrand, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Haavik, Jan
    Husebye, Eystein
    Gustafsson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Rorsman, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Meloni, Antonella
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Vilattes, Bernard
    Kajosaari, Merja
    Egner, William
    Sargur, Ravishankar
    Amoura, Zahir
    Grimfeld, Alain
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Molekylär och morfologisk patologi.
    De Luca, Filippo
    Betterle, Corrado
    Perheentupa, Jaakko
    Kämpe, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Pulmonary Autoimmunity as a Feature of Autoimmune Polyendocrine Syndrome Type 1 and Identification of KCNRG as a Bronchial Autoantigen2009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 11, s. 4396-4401Artikel i tidskrift (Refereegranskat)
    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.

  • 19. Alkasalias, Twana
    et al.
    Alexeyenko, Andrey
    Hennig, Katharina
    Danielsson, Frida
    Lebbink, Robert Jan
    Fielden, Matthew
    Turunen, S. Pauliina
    Lehti, Kaisa
    Kashuba, Vladimir
    Madapura, Harsha S.
    Bozoky, Benedek
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Balland, Martial
    Guven, Hayrettin
    Klein, George
    Gad, Annica K. B.
    Pavlova, Tatiana
    RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 8, s. E1413-E1421Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 20. Allen, LT
    et al.
    Fox, EJP
    Blute, I
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Kelly, ZD
    Rochev, Y
    Keenan, AK
    Dawson,
    Interaction of soft condensed materials with living cells: Phenotype/transcriptome correlations for the hydrophobic effect2003Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, s. 6331-6336Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 21. Allgardsson, Anders
    et al.
    Berg, Lotta
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Akfur, Christine
    Hörnberg, Andreas
    Worek, Franz
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ekström, Fredrik J.
    Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-62016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 20, s. 5514-5519Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 22.
    Allgardsson, Anders
    et al.
    FOI Swedish Defence Research Agency, Sweden.
    Berg, Lotta
    Umeå University, Sweden.
    Akfur, Christine
    FOI Swedish Defence Research Agency, Sweden.
    Hörnberg, Andreas
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Processum.
    Worek, Franz
    Bundeswehr Institute of Pharmacology and Toxicology, Germany.
    Linusson, Anna
    Umeå University, Sweden.
    Ekström, Fredrik J.
    FOI Swedish Defence Research Agency, Sweden.
    Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-62016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 20, s. 5514-5519Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 23.
    Almås, Ingvild
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutet för internationell ekonomi. Norwegian School of Economics, Norway.
    Cappelen, Alexander W.
    Sørensen, Erik Ø.
    Tungodden, Bertil
    Global evidence on the selfish rich inequality hypothesis2022Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, nr 3, artikel-id e2109690119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report on a study of whether people believe that the rich are richer than the poor because they have been more selfish in life, using data from more than 26,000 individuals in 60 countries. The findings show a strong belief in the selfish rich inequality hypothesis at the global level; in the majority of countries, the mode is to strongly agree with it. However, we also identify important between- and within-country variation. We find that the belief in selfish rich inequality is much stronger in countries with extensive corruption and weak institutions and less strong among people who are higher in the income distribution in their society. Finally, we show that the belief in selfish rich inequality is predictive of people’s policy views on inequality and redistribution: It is significantly positively associated with agreeing that inequality in their country is unfair, and it is significantly positively associated with agreeing that the government should aim to reduce inequality. These relationships are highly significant both across and within countries and robust to including country-level or individual-level controls and using Lasso-selected regressors. Thus, the data provide compelling evidence of people believing that the rich are richer because they have been more selfish in life and perceiving selfish behavior as creating unfair inequality and justifying equalizing policies.

  • 24. Alonso-Mori, Roberto
    et al.
    Kern, Jan
    Gildea, Richard J
    Sokaras, Dimosthenis
    Weng, Tsu-Chien
    Lassalle-Kaiser, Benedikt
    Tran, Rosalie
    Hattne, Johan
    Laksmono, Hartawan
    Hellmich, Julia
    Glöckner, Carina
    Echols, Nathaniel
    Sierra, Raymond G
    Schafer, Donald W
    Sellberg, Jonas
    Kenney, Christopher
    Herbst, Ryan
    Pines, Jack
    Hart, Philip
    Herrmann, Sven
    Grosse-Kunstleve, Ralf W
    Latimer, Matthew J
    Fry, Alan R
    Messerschmidt, Marc M
    Miahnahri, Alan
    Seibert, M Marvin
    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 mode2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 47, s. 19103-19107Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 25. Alonso-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
    Stockholms universitet, Naturvetenskapliga fakulteten, Fysikum. SLAC National Accelerator Laboratory, USA.
    Kenney, Christopher
    Herbst, Ryan
    Pines, Jack
    Hart, Philip
    Herrmann, Sven
    Grosse-Kunstleve, Ralf W.
    Latimer, Matthew J.
    Fry, Alan R.
    Messerschmidt, Marc M.
    Miahnahri, Alan
    Seibert, M. Marvin
    Zwart, Petrus H.
    White, William E.
    Adams, Paul D.
    Bogan, Michael J.
    Boutet, Sébastien
    Williams, Garth J.
    Zouni, Athina
    Messinger, Johannes
    Glatzel, Pieter
    Sauter, Nicholas K.
    Yachandra, Vittal K.
    Yano, Junko
    Bergmann, Uwe
    Energy-dispersive X-ray emission spectroscopy using an X-ray free-electron laser in a shot-by-shot mode2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 47, s. 19103-19107Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 26. Alonso-Mori, Roberto
    et al.
    Kern, Jan
    Gildea, Richard J
    Sokaras, Dimosthenis
    Weng, Tsu-Chien
    Lassalle-Kaiser, Benedikt
    Tran, Rosalie
    Hattne, Johan
    Laksmono, Hartawan
    Hellmich, Julia
    Glöckner, Carina
    Echols, Nathaniel
    Sierra, Raymond G
    Schafer, Donald W
    Sellberg, Jonas
    Kenney, Christopher
    Herbst, Ryan
    Pines, Jack
    Hart, Philip
    Herrmann, Sven
    Grosse-Kunstleve, Ralf W
    Latimer, Matthew J
    Fry, Alan R
    Messerschmidt, Marc M
    Miahnahri, Alan
    Seibert, M Marvin
    Zwart, Petrus H
    White, William E
    Adams, Paul D
    Bogan, Michael J
    Boutet, Sébastien
    Williams, Garth J
    Zouni, Athina
    Messinger, Johannes
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    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 mode2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 47, s. 19103-19107Artikel i tidskrift (Refereegranskat)
    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.

  • 27. Alonso-Saez, Laura
    et al.
    Waller, Alison S.
    Mende, Daniel R.
    Bakker, Kevin
    Farnelid, Hanna
    Yager, Patricia L.
    Lovejoy, Connie
    Tremblay, Jean-Eric
    Potvin, Marianne
    Heinrich, Friederike
    Estrada, Marta
    Riemann, Lasse
    Bork, Peer
    Pedros-Alio, Carlos
    Bertilsson, Stefan
    Role for urea in nitrification by polar marine Archaea2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 44, s. 17989-17994Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 28. Alonso-Saéz, Laura
    et al.
    Waller, Allison S
    Mende, Daniel R
    Bakker, Kevin
    Farnelid, Hanna
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Yager, Patricia L
    Lovejoy, Connie
    Tremblay, Jean-Eric
    Potvin, Marianne
    Heinrich, Friederike
    Estrada, Marta
    Riemann, Lasse
    Marine Biological Section, University of Copenhagen, 3000 Helsingør, Denmark .
    Bork, Peer
    Pedros-Alio, Carlos
    Bertilsson, Stefan
    Role for urea in nitrification by polar marine Archaea2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 44, s. 17989-17994Artikel i tidskrift (Refereegranskat)
    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.

  • 29.
    Alonso-Sáez, Laura
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Limnologi.
    Waller, A. S.
    Mende, D. R.
    Bakker, K.
    Farnelid, H.
    Yager, P. L.
    Lovejoy, C.
    Tremblay, J. -E
    Potvin, M.
    Heinrich, Friederike
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Limnologi.
    Estrada, M.
    Riemann, L.
    Bork, P.
    Pedrós-Alió, C.
    Bertilsson, Stefan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Limnologi.
    Role for urea in nitrification by polar marine Archaea2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 44, s. 17989-17994Artikel i tidskrift (Refereegranskat)
    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.

  • 30.
    Alsmark, Cecilia M.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Frank, A. Carolin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Karlberg, E. Olof
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Legault, Boris-Antoine
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Ardell, David H.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Canbäck, Björn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Eriksson, Ann-Sofie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Näslund, A. Kristina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Handley, Scott A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Huvet, Maxime
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    La Scola, Bernard
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Holmberg, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Andersson, Siv G. E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    The louse-borne human pathogen Bartonella quintana is a genomic derivative of the zoonotic agent Bartonella henselae2004Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, nr 26, s. 9716-9721Artikel i tidskrift (Refereegranskat)
    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.

  • 31.
    Altmejd, Adam
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutet för social forskning (SOFI).
    Östergren, Olof
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutionen för folkhälsovetenskap.
    Björkegren, Evelina
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Nationalekonomiska institutionen.
    Persson, Torsten
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutet för internationell ekonomi. London School of Economics, London, United Kingdon.
    Inequality and COVID-19 in Sweden: Relative risks of nine bad life events, by four social gradients, in pandemic vs. prepandemic years2023Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, nr 46, artikel-id e2303640120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The COVID-19 pandemic struck societies directly and indirectly, not just challenging population health but disrupting many aspects of life. Different effects of the spreading virus—and the measures to fight it—are reported and discussed in different scientific fora, with hard-to-compare methods and metrics from different traditions. While the pandemic struck some groups more than others, it is difficult to assess the comprehensive impact on social inequalities. This paper gauges social inequalities using individual-level administrative data for Sweden’s entire population. We describe and analyze the relative risks for different social groups in four dimensions—gender, education, income, and world region of birth—to experience three types of COVID-19 incidence, as well as six additional negative life outcomes that reflect general health, access to medical care, and economic strain. During the pandemic, the overall population faced severe morbidity and mortality from COVID-19 and saw higher all-cause mortality, income losses and unemployment risks, as well as reduced access to medical care. These burdens fell more heavily on individuals with low income or education and on immigrants. Although these vulnerable groups experienced larger absolute risks of suffering the direct and indirect consequences of the pandemic, the relative risks in pandemic years (2020 and 2021) were conspicuously similar to those in prepandemic years (2016 to 2019)

  • 32.
    Ambati, Aditya
    et al.
    Stanford Univ, CA 94304 USA.
    Hillary, Ryan
    Stanford Univ, CA 94304 USA.
    Leu-Semenescu, Smaranda
    Sorbonne Univ, France.
    Ollila, Hanna M.
    Stanford Univ, CA 94304 USA.
    Lin, Ling
    Stanford Univ, CA 94304 USA.
    During, Emmanuel H.
    Stanford Univ, CA 94305 USA; Stanford Univ, CA 94305 USA.
    Farber, Neal
    Kleine Levin Syndrome Fdn, MA 02468 USA.
    Rico, Thomas J.
    Stanford Univ, CA 94304 USA.
    Faraco, Juliette
    Stanford Univ, CA 94304 USA.
    Leary, Eileen
    Stanford Univ, CA 94304 USA.
    Goldstein-Piekarski, Andrea N.
    Stanford Univ, CA 94305 USA; Vet Affairs Palo Alto Hlth Care Syst, CA 94304 USA.
    Huang, Yu-Shu
    Chang Gung Mem Hosp & Univ, Taiwan; Chang Gung Mem Hosp & Univ, Taiwan.
    Han, Fang
    Peking Univ Peoples Hosp, Peoples R China.
    Sivan, Yakov
    Tel Aviv Univ, Israel.
    Lecendreux, Michel
    Hosp Robert Debre, France; Hosp Robert Debre, France.
    Dodet, Pauline
    Sorbonne Univ, France.
    Honda, Makoto
    Tokyo Metropolitan Inst Med Sci, Japan.
    Gadoth, Natan
    Maynei Hayeshua Med Ctr, Israel; Tel Aviv Univ, Israel.
    Nevsimalova, Sona
    Charles Univ Prague, Czech Republic.
    Pizza, Fabio
    Univ Bologna, Italy; IRCCS, Italy.
    Kanbayashi, Takashi
    Univ Tsukuba, Japan.
    Peraita-Adrados, Rosa
    Univ Complutense Madrid, Spain; Univ Complutense Madrid, Spain.
    Leschziner, Guy D.
    Guys Hosp, England; Kings Coll London, England.
    Hasan, Rosa
    Univ Sao Paulo, Brazil.
    Canellas, Francesca
    Hosp Univ Son Espases, Spain.
    Kume, Kazuhiko
    Nagoya City Univ, Japan.
    Daniilidou, Makrina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Uppsala Univ, Sweden.
    Bourgin, Patrice
    Hop Univ Strasbourg, France.
    Rye, David
    Emory Univ, GA 30322 USA.
    Vicario, Jose L.
    Blood Ctr Community Madrid, Spain.
    Hogl, Birgit
    Innsbruck Med Univ, Austria.
    Hong, Seung Chul
    Catholic Univ Korea, South Korea.
    Plazzi, Guiseppe
    Univ Bologna, Italy; IRCCS, Italy.
    Mayer, Geert
    Philipps Univ Marburg, Germany.
    Landtblom, Anne-Marie
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Neurologiska kliniken i Linköping. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Uppsala Univ, Sweden.
    Dauvilliers, Yves
    Univ Montpellier, France; Univ Montpellier, France.
    Arnulf, Isabelle
    Sorbonne Univ, France.
    Mignot, Emmanuel Jean-Marie
    Stanford Univ, CA 94304 USA.
    Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci2021Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, nr 12, artikel-id e2005753118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 x 10(-9)) within the 3region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R-2 = 0.15; P &lt; 2.0 x 10(-22) at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

  • 33.
    Ambati, Aditya
    et al.
    Stanford Univ, Ctr Sleep Sci & Med, Sch Med, Palo Alto, CA 94304 USA..
    Hillary, Ryan
    Stanford Univ, Ctr Sleep Sci & Med, Sch Med, Palo Alto, CA 94304 USA..
    Leu-Semenescu, Smaranda
    Sorbonne Univ, Pitie Salpetriere Hosp, AP HP,Sleep Disorders,Inst Hosp Univ, Natl Reference Ctr Narcolepsy Idiopath Hypersomni, Paris, France..
    Ollila, Hanna M.
    Stanford Univ, Ctr Sleep Sci & Med, Sch Med, Palo Alto, CA 94304 USA..
    Lin, Ling
    Stanford Univ, Ctr Sleep Sci & Med, Sch Med, Palo Alto, CA 94304 USA..
    During, Emmanuel H.
    Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.;Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA..
    Farber, Neal
    Kleine Levin Syndrome Fdn, Boston, MA 02468 USA..
    Rico, Thomas J.
    Stanford Univ, Ctr Sleep Sci & Med, Sch Med, Palo Alto, CA 94304 USA..
    Faraco, Juliette
    Stanford Univ, Ctr Sleep Sci & Med, Sch Med, Palo Alto, CA 94304 USA..
    Leary, Eileen
    Stanford Univ, Ctr Sleep Sci & Med, Sch Med, Palo Alto, CA 94304 USA..
    Goldstein-Piekarski, Andrea N.
    Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.;Vet Affairs Palo Alto Hlth Care Syst, Sierra Pacific Mental Illness Res Educ & Clin Ctr, Palo Alto, CA 94304 USA..
    Huang, Yu-Shu
    Chang Gung Mem Hosp & Univ, Dept Child Psychiat, Taoyuan 33305, Taiwan.;Chang Gung Mem Hosp & Univ, Sleep Ctr, Taoyuan 33305, Taiwan..
    Han, Fang
    Peking Univ Peoples Hosp, Dept Pulm Med, Beijing 100044, Peoples R China..
    Sivan, Yakov
    Tel Aviv Univ, Safra Childrens Hosp, Sackler Fac Med, Sheba Med Ctr, IL-52621 Tel Aviv, Israel..
    Lecendreux, Michel
    Hosp Robert Debre, Pediat Sleep Ctr, France Ctr Narcolepsy & Idiopath Hypersomnia, F-75019 Paris, France.;Hosp Robert Debre, Natl Reference Ctr, France Ctr Narcolepsy & Idiopath Hypersomnia, F-75019 Paris, France..
    Dodet, Pauline
    Sorbonne Univ, Pitie Salpetriere Hosp, AP HP,Sleep Disorders,Inst Hosp Univ, Natl Reference Ctr Narcolepsy Idiopath Hypersomni, Paris, France..
    Honda, Makoto
    Tokyo Metropolitan Inst Med Sci, Dept Psychiat & Behav Sci, Sleep Disorders Project, Tokyo 1568506, Japan..
    Gadoth, Natan
    Maynei Hayeshua Med Ctr, Dept Neurol, IL-5154475 Bnei Braq, Israel.;Tel Aviv Univ, Sackler Fac Med, IL-6997801 Tel Aviv, Israel..
    Nevsimalova, Sona
    Charles Univ Prague, Gen Teaching Hosp, Fac Med 1, Dept Neurol, Prague 11636, Czech Republic..
    Pizza, Fabio
    Univ Bologna, Dept Biomed & Neuromotor Sci, I-40139 Bologna, Italy.;IRCCS, Ist Ricovero & Cura Carattere Sci, Inst Neurol Sci, I-40139 Bologna, Italy..
    Kanbayashi, Takashi
    Univ Tsukuba, Int Inst Integrat Sleep Med, Tsukuba, Ibaraki 3050005, Japan..
    Peraita-Adrados, Rosa
    Univ Complutense Madrid, Hosp Univ, Madrid 28040, Spain.;Univ Complutense Madrid, Inst Invest Gregorio Maranon, Madrid 28040, Spain..
    Leschziner, Guy D.
    Guys Hosp, Sleep Disorders Ctr, London SE1 9RT, England.;Kings Coll London, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England..
    Hasan, Rosa
    Univ Sao Paulo, Hosp Clin, Fac Med, Inst Psychiat, BR-05403010 Sao Paulo, Brazil..
    Canellas, Francesca
    Hosp Univ Son Espases, Fundacio Inst Invest Sanitaria Illes Balears, Palma De Mallorca 07120, Spain..
    Kume, Kazuhiko
    Nagoya City Univ, Dept Neuropharmacol, Nagoya, Aichi 4678601, Japan..
    Daniilidou, Makrina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Landtblom: Neurologi. Uppsala Univ, Dept Neurosci, S-75236 Uppsala, Sweden.;Linköping Univ, Dept Biomed & Clin Sci, S-58183 Linköping, Sweden..
    Bourgin, Patrice
    Hop Univ Strasbourg, Sleep Disorders Ctr, F-67091 Strasbourg, France..
    Rye, David
    Emory Univ, Dept Neurol, Atlanta, GA 30322 USA..
    Vicario, Jose L.
    Blood Ctr Community Madrid, Histocompatibil Dept, Madrid 28032, Spain..
    Hogl, Birgit
    Innsbruck Med Univ, Dept Neurol, A-6020 Innsbruck, Austria..
    Hong, Seung Chul
    Catholic Univ Korea, Coll Med, Dept Neuropsychiat, St Vincents Hosp, Seoul 16247, South Korea..
    Plazzi, Guiseppe
    Univ Bologna, Dept Biomed & Neuromotor Sci, I-40139 Bologna, Italy.;IRCCS, Ist Ricovero & Cura Carattere Sci, Inst Neurol Sci, I-40139 Bologna, Italy..
    Mayer, Geert
    Philipps Univ Marburg, Hephata Klin, D-35037 Marburg, Germany..
    Landtblom, Anne-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Landtblom: Neurologi. Uppsala Univ, Dept Neurosci, S-75236 Uppsala, Sweden.;Linköping Univ, Dept Biomed & Clin Sci, S-58183 Linköping, Sweden..
    Dauvilliers, Yves
    Univ Montpellier, CHU Montpellier, Natl Reference Ctr Orphan Dis, Narcolepsy Rare Hypersomnias Sleep Unit,Dept Neur, F-34000 Montpellier, France.;Univ Montpellier, Inst Neurosci Montpellier, INSERM, F-34000 Montpellier, France..
    Arnulf, Isabelle
    Sorbonne Univ, Pitie Salpetriere Hosp, AP HP,Sleep Disorders,Inst Hosp Univ, Natl Reference Ctr Narcolepsy Idiopath Hypersomni, Paris, France..
    Mignot, Emmanuel Jean-Marie
    Stanford Univ, Ctr Sleep Sci & Med, Sch Med, Palo Alto, CA 94304 USA..
    Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci2021Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, nr 12, artikel-id e2005753118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 x 10(-9)) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R-2 = 0.15; P < 2.0 x 10(-22) at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

  • 34. Ambikan, Anoop T.
    et al.
    Elaldi, Nazif
    Svensson-Akusjärvi, Sara
    Bagci, Binnur
    Pektas, Ayse Nur
    Hewson, Roger
    United Kingdom Health Security Agency, Porton Down, Salisbury, Wiltshire SP4 0JG, United Kingdom.
    Bagci, Gokhan
    Arasli, Mehmet
    Appelberg, Sofia
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Sood, Vikas
    Végvári, Ákos
    Benfeitas, Rui
    Gupta, Soham
    Cetin, Ilhan
    Mirazimi, Ali
    Neogi, Ujjwal
    Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection2023Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, nr 37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection. The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.

  • 35. Ambort, D.
    et al.
    Johansson, M.E.V.
    Gustafsson, J. K.
    Nilsson, Harriet
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Medicinteknik och hälsosystem, Strukturell bioteknik. Department of Biosciences and Nutrition, Karolinska Institutet.
    Ermund, A.
    Johansson, B.R.
    Koeck, Philip J. B.
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik. Department of Biosciences and Nutrition, Karolinska Institutet.
    Hebert, Hans
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik. Department of Biosciences and Nutrition, Karolinska Institutet.
    Hansson, G.C.
    Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 15, s. 5645-5650Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 36.
    Andersson, A.
    et al.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Olofsson, T.
    Department of Hematology, Lund University Hospital, SE-221 85 Lund, Sweden.
    Lindgren, D.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Nilsson, B.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Ritz, C.
    Department of Complex System Division, Theoretical Physics, Lund University, S-221 00 Lund, Sweden.
    Eden, P.
    Department of Complex System Division, Theoretical Physics, Lund University, S-221 00 Lund, Sweden.
    Lassen, C.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Rade, J.
    Center for Mathematical Sciences, Lund University, S-221 00 Lund, Sweden.
    Fontes, M.
    Center for Mathematical Sciences, Lund University, S-221 00 Lund, Sweden.
    Morse, H.
    Department of Pediatrics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Heldrup, J.
    Department of Pediatrics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Behrendtz, Mikael
    Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Mitelman, F.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Hoglund, M.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Johansson, B.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Fioretos, T.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations2005Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, nr 52, s. 19069-19074Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 37. Andersson, Charlotta S.
    et al.
    Högbom, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    A Mycobacterium tuberculosis ligand-binding Mn/Fe protein reveals a new cofactor in a remodeled R2-protein scaffold2009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 14, s. 5633-5638Artikel i tidskrift (Refereegranskat)
    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.

  • 38.
    Andersson, Dan I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Evolving promiscuously2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 4, s. 1199-1200Artikel i tidskrift (Övrigt vetenskapligt)
  • 39.
    Andersson, Dan I
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Hughes, Diarmaid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Muller's ratchet decreases fitness of a DNA-based microbe1996Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 93, nr 2, s. 906-907Artikel i tidskrift (Refereegranskat)
    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.

  • 40.
    Andersson, David A.
    et al.
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap.
    Simak, Sergei I.
    Skorodumova, Natalia V.
    Abrikosov, Igor A.
    Johansson, Börje
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik.
    Optimization of ionic conductivity in doped ceria2006Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, nr 10, s. 3518-3521Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 41.
    Andersson, David A.
    et al.
    Royal Institute of Technology.
    Simak, Sergey
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk Fysik.
    Skorodumova, Natalia V.
    Uppsala University.
    Abrikosov, Igor
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk Fysik.
    Johansson, Börje
    Uppsala University.
    Optimization of ionic conductivity in doped ceria2006Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, s. 3518-3521Artikel i tidskrift (Refereegranskat)
  • 42.
    Andersson, Ove
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    Glass-liquid transition of water at high pressure2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 27, s. 11013-11016Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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  • 43.
    Andersson, Siv G. E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Stress management strategies in single bacterial cells2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 15, s. 3921-3923Artikel i tidskrift (Övrigt vetenskapligt)
  • 44.
    Andrade, Pedro
    et al.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Pinho, Catarina
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Perez i de lanuza, Guillem
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Afonso, Sandra
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Brejcha, Jindrich
    Charles Univ Prague, Fac Sci, Dept Philosophy & Hist Sci, Prague 12800 2, Czech Republic;Natl Museum, Dept Zool, Prague 19300, Czech Republic;Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    Rubin, Carl-Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Pereira, Paulo
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Sabatino, Stephen J.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Bellati, Adriana
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Pellitteri-Rosa, Daniele
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Bosakova, Zuzana
    Charles Univ Prague, Fac Sci, Dept Analyt Chem, Prague 12843 2, Czech Republic.
    Bunikis, Ignas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Carretero, Miguel A.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Feiner, Nathalie
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Marsik, Petr
    Czech Univ Life Sci Prague, Fac Agrobiol Food & Nat Resources, Dept Food Sci, Prague 16521 6, Czech Republic.
    Pauperio, Francisco
    Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Salvi, Daniele
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Aquila, Dept Hlth Life & Environm Sci, I-67100 Laquila, Italy.
    Soler, Lucile
    Natl Bioinformat Infrastruct Sweden, Sci Life Lab, S-75123 Uppsala, Sweden.
    While, Geoffrey M.
    Univ Tasmania, Sch ol Biol Sci, Hobart, Tas 7005, Australia;Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
    Uller, Tobias
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Font, Enrique
    Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Carneiro, Miguel
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Regulatory changes in pterin and carotenoid genes underlie balanced color polymorphisms in the wall lizard2019Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 12, s. 5633-5642Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 45. Antonelli, A
    et al.
    Nylander, Johan
    Stockholms universitet, Naturvetenskapliga fakulteten, Botaniska institutionen.
    Persson, C
    Sanmartín, I
    Tracing the impact of the Andean uplift on Neotropical plant evolution: evidence from the coffee family2009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 24, s. 9749-9754Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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  • 46.
    Antzutkin, Oleg
    et al.
    Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, Industriell miljö- och processteknik.
    Balbach, John J.
    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda.
    Leapman, Richard D.
    Division of Bioengineering and Physical Science, Office of Research Services, National Institutes of Health, Bethesda.
    Rizzo, Nancy W.
    Division of Bioengineering and Physical Science, Office of Research Services, National Institutes of Health, Bethesda.
    Reed, Jennifer
    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda.
    Tycko, Robert
    National Institutes of Health, Bethesda.
    Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of β-sheets in Alzheimer's β-amyloid fibrils2000Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, nr 24, s. 13045-13050Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 47. Aparicio, S
    et al.
    Morrison, A
    Gould, A
    Gilthorpe, Jonathan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Chaudhuri, C
    Rigby, P
    Krumlauf, R
    Brenner, S
    Detecting conserved regulatory elements with the model genome of the Japanese puffer fish, Fugu rubripes.1995Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 92, nr 5, s. 1684-1688Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 48. Arapan, S.
    et al.
    Mao, H.
    Ahuja, Rajeev
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap.
    Prediction of incommensurate crystal structure in Ca at high pressure2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 52, s. 20627-20630Artikel i tidskrift (Refereegranskat)
    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.

  • 49.
    Arapan, Sergiu
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och materialvetenskap.
    Mao, Ho-kwang
    Ahuja, Rajeev
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och materialvetenskap.
    Prediction of incommensurate crystal structure in Ca at high pressure2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 52, s. 20627-20630Artikel i tidskrift (Refereegranskat)
    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.

  • 50.
    Arifin, Maria I.
    et al.
    Univ Calgary, Canada; Univ Calgary, Canada.
    Kaczmarczyk, Lech
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Zeng, Doris
    Univ Calgary, Canada; Univ Calgary, Canada.
    Hannaoui, Samia
    Univ Calgary, Canada; Univ Calgary, Canada.
    Lee, Chi
    Univ Calgary, Canada; Univ Calgary, Canada.
    Chang, Sheng Chun
    Univ Calgary, Canada; Univ Calgary, Canada.
    Mitchell, Gordon
    Canadian Food Inspection Agcy, Canada.
    McKenzie, Debbie
    Univ Alberta, Canada.
    Beekes, Michael
    Robert Koch Inst, Germany.
    Jackson, Walker
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Gilch, Sabine
    Univ Calgary, Canada; Univ Calgary, Canada.
    Heterozygosity for cervid S138N polymorphism results in subclinical CWD in gene-targeted mice and progressive inhibition of prion conversion2023Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, nr 15, artikel-id e2221060120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prions are proteinaceous infectious particles that replicate by structural conversion of the host-encoded cellular prion protein (PrPC), causing fatal neurodegenerative diseases in mammals. Species-specific amino acid substitutions (AAS) arising from single nucleotide polymorphisms within the prion protein gene (Prnp) modulate prion disease patho-genesis, and, in several instances, reduce susceptibility of homo-or heterozygous AAS carriers to prion infection. However, a mechanistic understanding of their protective effects against clinical disease is missing. We generated gene-targeted mouse infection models of chronic wasting disease (CWD), a highly contagious prion disease of cervids. These mice express wild-type deer or PrPC harboring the S138N substitution homo-or heterozygously, a polymorphism found exclusively in reindeer (Rangifer tarandus spp.) and fallow deer (Dama dama). The wild-type deer PrP-expressing model recapitulated CWD pathogenesis including fecal shedding. Encoding at least one 138N allele pre-vented clinical CWD, accumulation of protease-resistant PrP (PrPres) and abnormal PrP deposits in the brain tissue. However, prion seeding activity was detected in spleens, brains, and feces of these mice, suggesting subclinical infection accompanied by prion shedding. 138N-PrPC was less efficiently converted to PrPres in vitro than wild-type deer (138SS) PrPC. Heterozygous coexpression of wild-type deer and 138N-PrPC resulted in dominant-negative inhibition and progressively diminished prion conversion over serial rounds of protein misfolding cyclic amplification. Our study indicates that heterozy-gosity at a polymorphic Prnp codon can confer the highest protection against clinical CWD and highlights the potential role of subclinical carriers in CWD transmission.

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