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  • 51.
    Li, Fengfu
    et al.
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada and National Research Council, Ottawa, Ontario, Canada.
    Carlsson, David
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada and National Research Council, Ottawa, Ontario, Canada.
    Lohmann, Chris
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada and Universitäts-Augenklinik, University of Regensburg, Regensburg, Germany.
    Suuronen, Erik
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Vascotto, Sandy
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Kobuch, Karin
    Universitäts-Augenklinik, University of Regensburg, Regensburg, Germany.
    Sheardown, Heather
    Department of Chemical Engineering, McMaster University, Hamilton, Ontario, Canada.
    Munger, Rejean
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Nakamura, Masatsugu
    Santen Pharmaceutical Company, Ltd., Ikoma-Shi, Japan .
    Griffith, May
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Cellular and nerve regeneration within a biosynthetic extracellular matrix for corneal transplantation2003Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, nr 26, s. 15346-15351Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our objective was to determine whether key properties of extracellular matrix (ECM) macromolecules can be replicated within tissue-engineered biosynthetic matrices to influence cellular properties and behavior. To achieve this, hydrated collagen and N-isopropylacrylamide copolymer-based ECMs were fabricated and tested on a corneal model. The structural and immunological simplicity of the cornea and importance of its extensive innervation for optimal functioning makes it an ideal test model. In addition, corneal failure is a clinically significant problem. Matrices were therefore designed to have the optical clarity and the proper dimensions, curvature, and biomechanical properties for use as corneal tissue replacements in transplantation. In vitro studies demonstrated that grafting of the laminin adhesion pentapeptide motif, YIGSR, to the hydrogels promoted epithelial stratification and neurite in-growth. Implants into pigs corneas demonstrated successful in vivo regeneration of host corneal epithelium, stroma, and nerves. In particular, functional nerves were observed to rapidly regenerate in implants. By comparison, nerve regeneration in allograft controls was too slow to be observed during the experimental period, consistent with the behavior of human cornea transplants. Other corneal substitutes have been produced and tested, but here we report an implantable matrix that performs as a physiologically functional tissue substitute and not simply as a prosthetic device. These biosynthetic ECM replacements should have applicability to many areas of tissue engineering and regenerative medicine, especially where nerve function is required.

  • 52.
    Liin, Sara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Miami, FL 33136 USA.
    Silverå Ejneby, Malin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Barro-Soria, Rene
    University of Miami, FL 33136 USA.
    Alexander Skarsfeldt, Mark
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Larsson, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Miami, FL 33136 USA.
    Starck Härlin, Frida
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Miami, FL 33136 USA.
    Parkkari, Teija
    University of Eastern Finland, Finland.
    Hjorth Bentzen, Bo
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Schmitt, Nicole
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Peter Larsson, H.
    University of Miami, FL 33136 USA.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 18, s. 5714-5719Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the beta-subunit KCNE1 form the cardiac I-Ks channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as I-Ks channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. We further show that KCNE1 coexpression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogs with a decreased pK(a) value, to preserve their negative charge at neutral pH, restore the sensitivity to open I-Ks channels. PUFA analogs with a positively charged head group inhibit I-Ks channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act antiarrhythmically in embryonic rat cardiomyocytes and in isolated perfused hearts from guinea pig.

  • 53. Lindberg, Mikael
    et al.
    Tibell, Lena
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Oliveberg, Mikael
    Commmon denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state2002Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, s. 16607-16612Artikel i tidskrift (Refereegranskat)
  • 54.
    Lindström, Tom
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk Biologi. Linköpings universitet, Tekniska högskolan. University of Sydney, Australia .
    Brown, Gregory P.
    University of Sydney, Australia .
    Sisson, Scott A.
    University of New S Wales, Australia .
    Phillips, Benjamin L.
    James Cook University, Australia .
    Shine, Richard
    University of Sydney, Australia .
    Rapid shifts in dispersal behavior on an expanding range edge2013Ingår 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. 13452-13456Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dispersal biology at an invasion front differs from that of populations within the range core, because novel evolutionary and ecological processes come into play in the nonequilibrium conditions at expanding range edges. In a world where species range limits are changing rapidly, we need to understand how individuals disperse at an invasion front. We analyzed an extensive dataset from radio-tracking invasive cane toads (Rhinella marina) over the first 8 y since they arrived at a site in tropical Australia. Movement patterns of toads in the invasion vanguard differed from those of individuals in the same area postcolonization. Our model discriminated encamped versus dispersive phases within each toads movements and demonstrated that pioneer toads spent longer periods in dispersive mode and displayed longer, more directed movements while they were in dispersive mode. These analyses predict that overall displacement per year is more than twice as far for toads at the invasion front compared with those tracked a few years later at the same site. Studies on established populations (or even those a few years postestablishment) thus may massively underestimate dispersal rates at the leading edge of an expanding population. This, in turn, will cause us to underpredict the rates at which invasive organisms move into new territory and at which native taxa can expand into newly available habitat under climate change.

  • 55.
    Liu, Yuan
    et al.
    Beijing Univ Chem Technol, Peoples R China; Univ Nebraska, NE 68588 USA.
    Huang, Yingying
    Chinese Acad Sci, Peoples R China; Dalian Univ Technol, Peoples R China.
    Zhu, Chongqin
    Univ Nebraska, NE 68588 USA; Univ Penn, PA 19104 USA; Univ Penn, PA 19104 USA.
    Li, Hui
    Beijing Univ Chem Technol, Peoples R China.
    Zhao, Jijun
    Dalian Univ Technol, Peoples R China.
    Wang, Lu
    Univ Sci and Technol China, Peoples R China.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Francisco, Joseph S.
    Univ Nebraska, NE 68588 USA; Univ Penn, PA 19104 USA; Univ Penn, PA 19104 USA.
    Zeng, Xiao Cheng
    Beijing Univ Chem Technol, Peoples R China; Univ Nebraska, NE 68588 USA.
    An ultralow-density porous ice with the largest internal cavity identified in the water phase diagram2019Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 26, s. 12684-12691Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The recent back-to-back findings of low-density porous ice XVI and XVII have rekindled the century-old field of the solid-state physics and chemistry of water. Experimentally, both ice XVI and XVII crystals can be produced by extracting guest atoms or molecules enclosed in the cavities of preformed ice clathrate hydrates. Herein, we examine more than 200 hypothetical low-density porous ices whose structures were generated according to a database of zeolite structures. Hitherto unreported porous EMT ice, named according to zeolite nomenclature, is identified to have an extremely low density of 0.5 g/cm(3) and the largest internal cavity (7.88 angstrom in average radius). The EMT ice can be viewed as dumbbell-shaped motifs in a hexagonal close-packed structure. Our first-principles computations and molecular dynamics simulations confirm that the EMT ice is stable under negative pressures and exhibits higher thermal stability than other ultralow-density ices. If all cavities are fully occupied by hydrogen molecules, the EMT ice hydrate can easily outperform the record hydrogen storage capacity of 5.3 wt % achieved with sII hydrogen hydrate. Most importantly, in the reconstructed temperature-pressure (T-P) phase diagram of water, the EMT ice is located at deeply negative pressure regions below ice XVI and at higher temperature regions next to FAU. Last, the phonon spectra of empty-sII, FAU, EMT, and other zeolite-like ice structures are computed by using the dispersion corrected vdW-DF2 functional. Compared with those of ice XI (0.93 g/cm(3)), both the bending and stretching vibrational modes of the EMT ice are blue-shifted due to their weaker hydrogen bonds.

  • 56.
    Lundmark, Katarzyna
    et al.
    Division of Pathology, Karolinska University Hospital, Huddinge, Sweden.
    Westermark, Gunilla
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Olsén, Arne
    Department of Clinical Immunology, Göteborg University, Göteborg, Sweden.
    Westermark, Per
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism2005Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, nr 17, s. 6098-6102Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Secondary, or amyloid protein A (AA), amyloidosis is a complication of chronic inflammatory diseases, both infectious and noninfectious. AA constitutes the insoluble fibrils, which are deposited in different organs, and is a major N-terminal part of the acute phase protein serum AA. It is not known why only some patients with chronic inflammation develop AA amyloidosis. Nucleation is a widely accepted mechanism in amyloidogenesis. Preformed amyloid-like fibrils act as nuclei in amyloid fibril formation in vitro, and AA amyloid fibrils and synthetic amyloid-like fibrils also may serve as seed for fibril formation in vivo. In addition to amyloid fibrils, there is a variety of similar nonmammalian protein fibrils with β-pleated structure in nature. We studied three such naturally occurring protein fibrils: silk from Bombyx mori, Sup35 from Saccharomyces cerevisiae, and curli from Escherichia coli. Our results show that these protein fibrils exert amyloid-accelerating properties in the murine experimental AA amyloidosis, suggesting that such environment factors may be important risk factors in amyloidogenesis.

  • 57.
    Lundmark, Katarzyna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet.
    Westermark, Gunilla T.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Nyström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Murphy, Charles L.
    Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN 37996, USA.
    Solomon, Alan
    Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN 37996, USA.
    Westermark, Per
    Department of Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
    Transmissibility of systemic amyloidosis by a prion-like mechanism2002Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, nr 10, s. 6979-6984Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this “amyloid enhancing factor” (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.

  • 58.
    Lundström, Patrik
    et al.
    Lund University, Department of Biophysical Chemistry.
    Mulder, Frans A. A.
    Lund University, Department of Biophysical Chemistry.
    Akke, Mikael
    Lund University, Department of Biophysical Chemistry.
    Correlated dynamics of consecutive residues reveal transient and cooperative unfolding of secondary structure in proteins2005Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, nr 47, s. 16984-16989Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nuclear spin relaxation is a powerful method for studying molecular dynamics at atomic resolution. Recent methods development in biomolecular NMR spectroscopy has enabled detailed investigations of molecular dynamics that are critical for biological function, with prominent examples addressing allostery, enzyme catalysis, and protein folding. Dynamic processes with similar correlation times are often detected in multiple locations of the molecule, raising the question of whether the underlying motions are correlated (corresponding to concerted fluctuations involving many atoms distributed across extended regions of the molecule) or uncorrelated (corresponding to independent fluctuations involving few atoms in localized regions). Here, we have used C-13(alpha)(i - 1)/C-13(alpha)(i) differential multiple-quantum spin relaxation to provide direct evidence for correlated dynamics of consecutive amino acid residues in the protein sequence. By monitoring overlapping pairs of residues (i - 1 and i, i and i + 1, etc.), we identified correlated motions that extend through continuous segments of the sequence. We detected significant correlated conformational transitions in the native state of the E140Q mutant of the calmodulin C-terminal domain. Previous work has shown that this domain exchanges between two major conformational states that resemble the functionally relevant open and closed states of the WT protein, with a mean correlation time of approximate to 20 mu s. The present results reveal that an entire alpha-helix undergoes partial unraveling in a transient and cooperative manner.

  • 59.
    Mansson, Robert
    et al.
    University of California, San Diego, USA .
    Welinder, Eva
    University of California, San Diego, USA .
    Åhsberg, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Lin, Yin C.
    University of California, San Diego, USA .
    Benner, Christopher
    University of California, San Diego, USA .
    Glass, Christopher K.
    University of California, San Diego, USA .
    Lucas, Joseph S.
    University of California, San Diego, USA .
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Murre, Cornelis
    University of California, San Diego, USA .
    Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 51, s. 21028-21033Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D(+) cell stage. We demonstrate that this phenotype closely resembles the arrest in B-cell development observed in EBF1-deficient mice. Consistent with these observations, we find that the transcription signatures of FOXO1- and EBF1-deficient LY6D(+) progenitors are strikingly similar, indicating a common set of target genes. Furthermore, we found that depletion of EBF1 expression in LY6D(+) CLPs severely affects FOXO1 mRNA abundance, whereas depletion of FOXO1 activity in LY6D(+) CLPs ablates EBF1 transcript levels. We generated a global regulatory network from EBF1 and FOXO1 genome-wide transcription factor occupancy and transcription signatures derived from EBF1- and FOXO1-deficient CLPs. This analysis reveals that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage.

  • 60.
    Mazzolini, Monica
    et al.
    International School for Advanced Studies, Trieste, Italy.
    Facchetti, Giuseppe
    International School for Advanced Studies, Trieste, Italy.
    Andolfi, Laura
    Cluster for Biomedicine, Trieste, Italy.
    Proietti Zaccaria, Remo
    Istituto Italiano di Tecnologia, Genova, Italy.
    Tuccio, Salvatore
    Istituto Italiano di Tecnologia, Genova, Italy.
    Treu, Johannes
    Rapp OptoElectronic, Wedel, Germany.
    Altafini, Claudio
    International School for Advanced Studies, Trieste, Italy.
    Di Fabrizio, Enzo
    King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
    Torre, Vincent
    International School for Advanced Studies, Trieste, Italy.
    The phototransduction machinery in the rod outer segment has a strong efficacy gradient2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 20, s. E2715-E272Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rod photoreceptors consist of an outer segment (OS) and an inner segment. Inside the OS a biochemical machinery transforms the rhodopsin photoisomerization into electrical signal. This machinery has been treated as and is thought to be homogenous with marginal inhomogeneities. To verify this assumption, we developed a methodology based on special tapered optical fibers (TOFs) to deliver highly localized light stimulations. By using these TOFs, specific regions of the rod OS could be stimulated with spots of light highly confined in space. As the TOF is moved from the OS base toward its tip, the amplitude of saturating and single photon responses decreases, demonstrating that the efficacy of the transduction machinery is not uniform and is 5–10 times higher at the base than at the tip. This gradient of efficacy of the transduction machinery is attributed to a progressive depletion of the phosphodiesterase along the rod OS. Moreover we demonstrate that, using restricted spots of light, the duration of the photoresponse along the OS does not increase linearly with the light intensity as with diffuse light.

  • 61.
    Meredith, E.J.
    et al.
    Division of Immunity and Infection, Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, United Kingdom.
    Holder, M.J.
    Division of Immunity and Infection, Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, United Kingdom.
    Rosén, Anders
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Lee, A.D.
    Ear, Nose, and Throat (ENT) Department, University Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom.
    Dyer, M.J.S.
    Medical Research Council Toxicology Unit, Leicester University, Leicester LE1 9HN, United Kingdom.
    Barnes, N.M.
    Division of Neuroscience, University of Birmingham, Birmingham B15 2TT, United Kingdom.
    Gordon, J.
    Division of Immunity and Infection, Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, United Kingdom.
    Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma2006Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, nr 36, s. 13485-13490Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human B lymphocytes and derived lines from a spectrum of B cell malignancy were studied for expression of dopaminergic pathway components and for their cytostatic response to the catecholamine and related, potentially therapeutic compounds. Proliferating normal lymphocytes and dividing malignant clones rapidly arrested on exposure to dopamine in the low (=10 µM) micromolar range. The antiparkinsonian drugs L-DOPA and apomorphine (particularly) were similarly antiproliferative. With the exception of D4, dopamine receptors D1-D5 were variably expressed among normal and neoplastic B cell populations, as was the dopamine transporter. Transcripts for D1 and D2 were frequently found, whereas D3 and D5 revealed restricted expression, dopamine transporter was detected in most cases. Nevertheless, pharmacological analysis disclosed that dopamine targeted cycling B cells independent of these structures. Rather, oxidative stress constituted the primary mechanism: the catecholamine's actions being mimicked by hydrogen peroxide and reversed by exogenous catalase, and evidence for the intracellular redox protein thioredoxin contributing protection. Among proliferating clones, growth arrest was accompanied by cell death in populations deplete in antiapoptotic Bcl-2: resting lymphocytes escaping low micromolar dopamine toxicity. Dysregulated bcl-2 expression, although preventing oxidative-induced caspase-dependent apoptosis, by itself conferred only minor protection against dopamine cytostasis. The selective impact of dopamine on lymphocytes that are in active cycle indicates an axis for therapeutic intervention not only in B cell neoplasia but also in lymphoproliferative disturbances generally. Rational tailoring of drug delivery systems already in development for Parkinson's disease could provide ideal vehicles for carrying the oxidative hit directly to the target populations. © 2006 by The National Academy of Sciences of the USA.

  • 62.
    Metson, Genevieve
    et al.
    Department of Natural Resource Sciences, McGill University, QC, Canada.
    Smith, Val
    Department of Ecology and Evolutionary Biology, University of Kansas, USA.
    Cordell, Dana
    Institute for Sustainable Futures, University of Technology, Sydney, Australia.
    Vaccari, David
    Department of Civil, Environmental, and Ocean Engineering, Stevens Institute of Technology, Hoboken, USA.
    Elser, James
    School of Life Sciences, Arizona State University, USA.
    Bennett, Elena
    Department of Natural Resource Sciences and School of the Environment, McGill University, Canada.
    Phosphorus is a key component of the resource demands for meat, eggs, and dairy production in the United States2014Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 46, s. E4906-E4907Artikel i tidskrift (Refereegranskat)
  • 63.
    Mitov, Venelin
    et al.
    Swiss Fed Inst Technol, Switzerland; Swiss Inst Bioinformat SIB, Switzerland.
    Bartoszek, Krzysztof
    Linköpings universitet, Institutionen för datavetenskap, Statistik och maskininlärning. Linköpings universitet, Filosofiska fakulteten.
    Stadler, Tanja
    Swiss Fed Inst Technol, Switzerland; Swiss Inst Bioinformat SIB, Switzerland.
    Automatic generation of evolutionary hypotheses using mixed Gaussian phylogenetic models2019Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 34, s. 16921-16926Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Phylogenetic comparative methods are widely used to understand and quantify the evolution of phenotypic traits, based on phylogenetic trees and trait measurements of extant species. Such analyses depend crucially on the underlying model. Gaussian phylogenetic models like Brownian motion and Ornstein-Uhlenbeck processes are the workhorses of modeling continuous-trait evolution. However, these models fit poorly to big trees, because they neglect the heterogeneity of the evolutionary process in different lineages of the tree. Previous works have addressed this issue by introducing shifts in the evolutionary model occurring at inferred points in the tree. However, for computational reasons, in all current implementations, these shifts are "intramodel," meaning that they allow jumps in 1 or 2 model parameters, keeping all other parameters "global" for the entire tree. There is no biological reason to restrict a shift to a single model parameter or, even, to a single type of model. Mixed Gaussian phylogenetic models (MGPMs) incorporate the idea of jointly inferring different types of Gaussian models associated with different parts of the tree. Here, we propose an approximate maximum-likelihood method for fitting MGPMs to comparative data comprising possibly incomplete measurements for several traits from extant and extinct phylogenetically linked species. We applied the method to the largest published tree of mammal species with body-and brain-mass measurements, showing strong statistical support for an MGPM with 12 distinct evolutionary regimes. Based on this result, we state a hypothesis for the evolution of the brain-body-mass allometry over the past 160 million y.

  • 64.
    Newton, Matilda S.
    et al.
    University of Otago, New Zealand.
    Guo, Xiaohu
    Uppsala University, Sweden.
    Söderholm, Annika
    Uppsala University, Sweden.
    Näsvall, Joakim
    Uppsala University, Sweden.
    Lundström, Patrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Andersson, Dan I.
    Uppsala University, Sweden.
    Selmer, Maria
    Uppsala University, Sweden.
    Patrick, Wayne M.
    University of Otago, New Zealand.
    Structural and functional innovations in the real-time evolution of new (beta alpha)(8) barrel enzymes2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 18, s. 4727-4732Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    New genes can arise by duplication and divergence, but there is a fundamental gap in our understanding of the relationship between these genes, the evolving proteins they encode, and the fitness of the organism. Here we used crystallography, NMR dynamics, kinetics, and mass spectrometry to explain the molecular innovations that arose during a previous real-time evolution experiment. In that experiment, the (beta alpha)(8) barrel enzyme HisA was under selection for two functions (HisA and TrpF), resulting in duplication and divergence of the hisA gene to encode TrpF specialists, HisA specialists, and bifunctional generalists. We found that selection affects enzyme structure and dynamics, and thus substrate preference, simultaneously and sequentially. Bifunctionality is associated with two distinct sets of loop conformations, each essential for one function. We observed two mechanisms for functional specialization: structural stabilization of each loop conformation and substrate-specific adaptation of the active site. Intracellular enzyme performance, calculated as the product of catalytic efficiency and relative expression level, was not linearly related to fitness. Instead, we observed thresholds for each activity above which further improvements in catalytic efficiency had little if any effect on growth rate. Overall, we have shown how beneficial substitutions selected during real-time evolution can lead to manifold changes in enzyme function and bacterial fitness. This work emphasizes the speed at which adaptive evolution can yield enzymes with sufficiently high activities such that they no longer limit the growth of their host organism, and confirms the (beta alpha)(8) barrel as an inherently evolvable protein scaffold.

  • 65.
    Nilsson, Peter
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska högskolan.
    Rydberg, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Organisk Kemi. Linköpings universitet, Tekniska högskolan.
    Baltzer, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Organisk Kemi. Linköpings universitet, Tekniska högskolan.
    Inganäs, Olle
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska högskolan.
    Self-assembly of synthetic peptides control conformation and optical properties of a zwitterionic polythiophene derivative2003Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, nr 18, s. 10170-10174Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The optical transitions of a chiral, three-substituted polythiophene with an amino acid function can be tuned by interactions with synthetic peptides. The addition of a positively charged peptide with a random-coil formation will force the polymer to adopt a nonplanar conformation, and the intensity of the emitted light is increased and blue-shifted. After the addition of a negatively charged peptide with a random-coil conformation, the backbone of the polymer adopts a planar conformation and an aggregation of the polymer chains occurs, seen as a red shift and a decrease of the intensity of the emitted light. By adding the positively charged peptide designed to form a four-helix bundle with the negatively charged peptide, the polymer aggregates are disrupted and the intensity of the emitted light is increased because of separation of the polymer chains. This technique could be used as a platform for making novel sensors and biomolecular switches.

  • 66.
    Nilsson, Peter
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska högskolan.
    Rydberg, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Organisk Kemi. Linköpings universitet, Tekniska högskolan.
    Baltzer, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska högskolan.
    Inganäs, Olle
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska högskolan.
    Twisting macromolecular chains: self-assembly of a chiral supermolecule from nonchiral polythiophene polyanions and random-coil synthetic peptides2004Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, nr 31, s. 11197-11202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The self-assembly of a negatively charged conjugated polythiophene derivative and a positively charged synthetic peptide will create a chiral, well ordered supermolecule. This supermolecule has the three-dimensional ordered structure of a biomolecule and the electronic properties of a conjugated polymer. The molecular complex being formed clearly affects the conformation of the polymer backbone. A main-chain chirality, such as a predominantly one-handed helical structure induced by the acid–base complexation between the conjugated polymer and the synthetic peptide, is seen. The alteration of the polymer backbone influences the optical properties of the polymer, seen as changes in the absorption, emission, and Raman spectra of the polymer. The complexation of the polythiophene and the synthetic peptide also induce a change from random-coil to helical structure of the synthetic peptide. The supermolecule described in this article may be used in a wide range of applications such as biomolecular devices, artificial enzymes, and biosensors.

  • 67.
    Pantazis, Antonios
    et al.
    Division of Molecular Medicine, Department of Anesthesiology, University of California, Los Angeles, CA 90095, USA.
    Savalli, Nicoletta
    Division of Molecular Medicine, Department of Anesthesiology, University of California, Los Angeles, CA 90095, USA.
    Sigg, Daniel
    dPET, Spokane, WA 99223, USA.
    Neely, Alan
    Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile.
    Olcese, Riccardo
    Division of Molecular Medicine, Department of Anesthesiology, Department of Physiology, Cardiovascular Research Laboratories, and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
    Functional heterogeneity of the four voltage sensors of a human L-type calcium channel2014Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 51, s. 18381-18386Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Excitation-evoked Ca(2+) influx is the fastest and most ubiquitous chemical trigger for cellular processes, including neurotransmitter release, muscle contraction, and gene expression. The voltage dependence and timing of Ca(2+) entry are thought to be functions of voltage-gated calcium (CaV) channels composed of a central pore regulated by four nonidentical voltage-sensing domains (VSDs I-IV). Currently, the individual voltage dependence and the contribution to pore opening of each VSD remain largely unknown. Using an optical approach (voltage-clamp fluorometry) to track the movement of the individual voltage sensors, we discovered that the four VSDs of CaV1.2 channels undergo voltage-evoked conformational rearrangements, each exhibiting distinct voltage- and time-dependent properties over a wide range of potentials and kinetics. The voltage dependence and fast kinetic components in the activation of VSDs II and III were compatible with the ionic current properties, suggesting that these voltage sensors are involved in CaV1.2 activation. This view is supported by an obligatory model, in which activation of VSDs II and III is necessary to open the pore. When these data were interpreted in view of an allosteric model, where pore opening is intrinsically independent but biased by VSD activation, VSDs II and III were each found to supply ∼50 meV (∼2 kT), amounting to ∼85% of the total energy, toward stabilizing the open state, with a smaller contribution from VSD I (∼16 meV). VSD IV did not appear to participate in channel opening.

  • 68.
    Poxson, David
    et al.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Karady, Michal
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 901 83 Umeå, Sweden..
    Gabrielsson, Roger
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Alkattan, Aziz Yousif Aziz
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Gustavsson, Anna
    Umeå Plant Science Centre, Department of Plant Physiology, Umeå University, 901 87 Umeå, Sweden..
    Doyle, Siamsa M.
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 901 83 Umeå, Sweden..
    Robert, Stéphanie
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 901 83 Umeå, Sweden..
    Ljung, Karin
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 901 83 Umeå, Sweden..
    Grebe, Markus
    Umeå Plant Science Centre, Department of Plant Physiology, Umeå University, 901 87 Umeå, Sweden.; Plant Physiology, Institute of Biochemistry and Biology, University of Potsdam, 14476 Potsdam, Golm, Germany..
    Simon, Daniel
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Berggren, Magnus
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Regulating plant physiology with organic electronics.2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 18, s. 4597-4602Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The organic electronic ion pump (OEIP) provides flow-free and accurate delivery of small signaling compounds at high spatiotemporal resolution. To date, the application of OEIPs has been limited to delivery of nonaromatic molecules to mammalian systems, particularly for neuroscience applications. However, many long-standing questions in plant biology remain unanswered due to a lack of technology that precisely delivers plant hormones, based on cyclic alkanes or aromatic structures, to regulate plant physiology. Here, we report the employment of OEIPs for the delivery of the plant hormone auxin to induce differential concentration gradients and modulate plant physiology. We fabricated OEIP devices based on a synthesized dendritic polyelectrolyte that enables electrophoretic transport of aromatic substances. Delivery of auxin to transgenic Arabidopsis thaliana seedlings in vivo was monitored in real time via dynamic fluorescent auxin-response reporters and induced physiological responses in roots. Our results provide a starting point for technologies enabling direct, rapid, and dynamic electronic interaction with the biochemical regulation systems of plants.

  • 69.
    Rasmussen, Jay
    et al.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany; University of Tubingen, Germany.
    Mahler, Jasmin
    University of Tubingen, Germany.
    Beschorner, Natalie
    University of Tubingen, Germany.
    Kaeser, Stephan A.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Haesler, Lisa M.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Baumann, Frank
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Nyström, Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Portelius, Erik
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Blennow, Kaj
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Lashley, Tammaryn
    UCL, England.
    Fox, Nick C.
    UCL, England.
    Sepulveda-Falla, Diego
    University of Medical Centre Hamburg Eppendorf, Germany; University of Antioquia, Colombia; University of Antioquia, Colombia.
    Glatzel, Markus
    University of Medical Centre Hamburg Eppendorf, Germany.
    Oblak, Adrian L.
    Indiana University of School Med, IN 46202 USA.
    Ghetti, Bernardino
    Indiana University of School Med, IN 46202 USA.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Staufenbiel, Matthias
    University of Tubingen, Germany.
    Walker, Lary C.
    Emory University, GA 30329 USA.
    Jucker, Mathias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimers disease2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 49, s. 13018-13023Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-beta peptide (A beta) has been shown to adopt distinct structural conformations with different biological activities, we asked whether A beta can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of beta-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimers disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of A beta nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to A beta plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic A beta-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic A beta among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between A beta conformation and clinical phenotype.

  • 70.
    Rice, William
    et al.
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Linder, Jodell
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Friberg, Urban
    Umeå universitet, Institutionen för ekologi, miljö och geovetenskap.
    Lew, Timothy
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Morrow, Edward
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Stewart, Andrew
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Inter-locus antagonistic coevolution as an engine of speciation: assessment with hemiclonal analysis2005Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, nr Suppl. 1, s. 6527-6534Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One of Ernst Mayr's legacies is the consensus that the allopatry model is the predominant mode of speciation in most sexually reproducing lineages. In this model, reproductive isolation develops as a pleiotropic byproduct of the genetic divergence that develops among physically isolated populations. Presently, there is no consensus concerning which, if any, evolutionary process is primarily responsible for driving the specific genetic divergence that leads to reproductive isolation. Here, we focus on the hypothesis that inter-locus antagonistic coevolution drives rapid genetic divergence among allopatric populations and thereby acts as an important “engine” of speciation. We assert that only data from studies of experimental evolution, rather than descriptive patterns of molecular evolution, can provide definitive evidence for this hypothesis. We describe and use an experimental approach, called hemiclonal analysis, that can be used in theDrosophila melanogaster laboratory model system to simultaneously screen nearly the entire genome for both standing genetic variation within a population and the net-selection gradient acting on the variation. Hemiclonal analysis has four stages: (i) creation of a laboratory “island population”; (ii) cytogenetic cloning of nearly genome-wide haplotypes to construct hemiclones; (iii) measurement of additive genetic variation among hemiclones; and (iv) measurement of the selection gradient acting on phenotypic variation among hemiclones. We apply hemiclonal analysis to test the hypothesis that there is ongoing antagonistic coevolution between the sexes in the D. melanogaster laboratory model system and then discuss the relevance of this analysis to natural systems.

  • 71.
    Rincon-Cortes, Millie
    et al.
    Nathan S Kline Institute Psychiat Research, NY 10962 USA; NYU, NY 10016 USA; NYU, NY 10016 USA.
    Barr, Gordon A.
    Childrens Hospital Philadelphia, PA 19104 USA; University of Penn, PA 19104 USA.
    Marie Mouly, Anne
    University of Lyon 1, France.
    Shionoya, Kiseko
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Nunez, Bestina S.
    Nathan S Kline Institute Psychiat Research, NY 10962 USA.
    Sullivan, Regina M.
    Nathan S Kline Institute Psychiat Research, NY 10962 USA; NYU, NY 10016 USA; NYU, NY 10016 USA.
    Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 3, s. 881-886Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Children form a strong attachment to their caregiver-even when that caretaker is abusive. Paradoxically, despite the trauma experienced within this relationship, the child develops a preference for trauma-linked cues-a phenomenon known as trauma bonding. Although infant trauma compromises neurobehavioral development, the mechanisms underlying the interaction between infant trauma bonding (i.e., learned preference for trauma cues) and the long-term effects of trauma (i.e., depressive-like behavior, amygdala dysfunction) are unknown. We modeled infant trauma bonding by using odor-shock conditioning in rat pups, which engages the attachment system and produces a life-long preference for the odor that was paired with shock. In adulthood, this trauma-linked odor rescues depressive-like behavior and amygdala dysfunction, reduces corticosterone (CORT) levels, and exerts repair-related changes at the molecular level. Amygdala microarray after rescue implicates serotonin (5-HT) and glucocorticoids (GCs), and a causal role was verified through microinfusions. Blocking amygdala 5-HT eliminates the rescue effect; increasing amygdala 5-HT and blocking systemic CORT mimics it. Our findings suggest that infant trauma cues share properties with antidepressants and safety signals and provide insight into mechanisms by which infant trauma memories remain powerful throughout life.

  • 72.
    Rockström, Johan
    et al.
    Stockholm Environment Institute/Stockholm Resilience Centre, Kräftriket 2, SE 10691 Stockholm, Sweden.
    Lannerstad, Mats
    Linköpings universitet, Institutionen för tema, Tema vatten i natur och samhälle. Linköpings universitet, Filosofiska fakulteten.
    Falkenmark, Malin
    Stockholm Resilience Centre, Kräftriket 2, SE 10691 Stockholm, Sweden.
    Assessing the water challenge of a new green revolution in developing countries2007Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, nr 15, s. 6253-6260Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This article analyzes the water implications in 92 developing countries of first attaining the 2015 hunger target of the United Nations Millennium Development Goals and then feeding a growing population on an acceptable standard diet. The water requirements in terms of vapor flows are quantified, potential water sources are identified, and impacts on agricultural land expansion and water tradeoffs with ecosystems are analyzed. This article quantifies the relative contribution from infiltrated rainwater/green water in rain-fed agriculture, and liquid water/blue water from irrigation, and how far water productivity (WP) gains can go in reducing the pressure on freshwater resources. Under current WP levels, another 2,200 km3·yr−1 of vapor flow is deemed necessary to halve hunger by 2015 and 5,200 km3·yr−1 in 2050 to alleviate hunger. A nonlinear relationship between vapor flow and yield growth, particularly in low-yielding savanna agro-ecosystems, indicates a high potential for WP increase. Such WP gains may reduce additional water needs in agriculture, with 16% in 2015 and 45% by 2050. Despite an optimistic outlook on irrigation development, most of the additional water will originate from rain-fed production. Yield growth, increasing consumptive use on existing rain-fed cropland, and fodder from grazing lands may reduce the additional rain-fed water use further by 43–47% until 2030. To meet remaining water needs, a cropland expansion of ≈0.8% yr−1, i.e., a similar rate as over the past 50 years (≈0.65% yr−1), seems unavoidable if food production is to occur in proximity to local markets.

  • 73.
    Shapiguzov, Alexey
    et al.
    University of Geneva, Switzerland.
    Ingelsson, Björn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Samol, Iga
    University of Geneva, Switzerland.
    Andres, Charles
    University of Neuchatel, Switzerland.
    Kessler, Felix
    University of Neuchatel, Switzerland.
    Rochaix, Jean-David
    University of Geneva, Switzerland.
    Vener, Alexander
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Goldschmidt-Clermont, Michel
    University of Geneva, Switzerland.
    The PPH1 phosphatase is specifically involved in LHCII dephosphorylation and state transitions in Arabidopsis2010Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, nr 10, s. 4782-4787Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ability of plants to adapt to changing light conditions depends on a protein kinase network in the chloroplast that leads to the reversible phosphorylation of key proteins in the photosynthetic membrane. Phosphorylation regulates, in a process called state transition, a profound reorganization of the electron transfer chain and remodeling of the thylakoid membranes. Phosphorylation governs the association of the mobile part of the light-harvesting antenna LHCII with either photosystem I or photosystem II. Recent work has identified the redox-regulated protein kinase STN7 as a major actor in state transitions, but the nature of the corresponding phosphatases remained unknown. Here we identify a phosphatase of Arabidopsis thaliana, called PPH1, which is specifically required for the dephosphorylation of light-harvesting complex II (LHCII). We show that this single phosphatase is largely responsible for the dephosphorylation of Lhcb1 and Lhcb2 but not of the photosystem II core proteins. PPH1, which belongs to the family of monomeric PP2C type phosphatases, is a chloroplast protein and is mainly associated with the stroma lamellae of the thylakoid membranes. We demonstrate that loss of PPH1 leads to an increase in the antenna size of photosystem I and to a strong impairment of state transitions. Thus phosphorylation and dephosphorylation of LHCII appear tobe specifically mediated by the kinase/phosphatase pair STN7 and PPH1. These two proteins emerge as key players in the adaptation of the photosynthetic apparatus to changes in light quality and quantity.

  • 74.
    Sigurdson, Christina J
    et al.
    UniversitätsSpital Zürich.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Organisk Kemi. Linköpings universitet, Tekniska högskolan.
    Hornemann, Simone
    Institut für Molekularbiologie und Biophysik, ETH Zürich.
    Heikenwalder, Mathias
    UniversitätsSpital Zürich.
    Manco, Giuseppe
    UniversitätsSpital Zürich.
    Schwarz, Petra
    UniversitätsSpital Zürich.
    Ott, David
    UniversitätsSpital Zürich.
    Rülicke, Thomas
    University of Veterinary Medicine Vienna.
    Liberski, Pawel P
    Medical University Lodz.
    Julius, Christian
    UniversitätsSpital Zürich.
    Falsig, Jeppe
    UniversitätsSpital Zürich.
    Stitz, Lothar
    ETH Zürich.
    Wüthrich, Kurt
    Institut für Molekularbiologie und Biophysik, ETH Zürich.
    Aguzzi, Adriano
    UniversitätsSpital Zürich.
    De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis.2009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 1, s. 304-309Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Most transmissible spongiform encephalopathies arise either spontaneously or by infection. Mutations of PRNP, which encodes the prion protein, PrP, segregate with phenotypically similar diseases. Here we report that moderate overexpression in transgenic mice of mPrP(170N,174T), a mouse PrP with two point mutations that subtly affect the structure of its globular domain, causes a fully penetrant lethal spongiform encephalopathy with cerebral PrP plaques. This genetic disease was reproduced with 100% attack rate by intracerebral inoculation of brain homogenate to tga20 mice overexpressing WT PrP, and from the latter to WT mice, but not to PrP-deficient mice. Upon successive transmissions, the incubation periods decreased and PrP became more protease-resistant, indicating the presence of a strain barrier that was gradually overcome by repeated passaging. This shows that expression of a subtly altered prion protein, with known 3D structure, efficiently generates a prion disease.

  • 75.
    Slovic, Paul
    et al.
    Decis Research, OR 97401 USA; University of Oregon, OR 97403 USA.
    Västfjäll, Daniel
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi. Linköpings universitet, Filosofiska fakulteten. Decis Research, OR 97401 USA.
    Erlandsson, Arvid
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi. Linköpings universitet, Filosofiska fakulteten. Lund University, Sweden.
    Gregory, Robin
    Decis Research, OR 97401 USA; ChoiceWorks Ltd, Canada.
    Iconic photographs and the ebb and flow of empathic response to humanitarian disasters2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 4, s. 640-644Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The power of visual imagery is well known, enshrined in such familiar sayings as "seeing is believing" and "a picture is worth a thousand words." Iconic photos stir our emotions and transform our perspectives about life and the world in which we live. On September 2, 2015, photographs of a young Syrian child, Aylan Kurdi, lying face-down on a Turkish beach, filled the front pages of newspapers worldwide. These images brought much-needed attention to the Syrian war that had resulted in hundreds of thousands of deaths and created millions of refugees. Here we present behavioral data demonstrating that, in this case, an iconic photo of a single child had more impact than statistical reports of hundreds of thousands of deaths. People who had been unmoved by the relentlessly rising death toll in Syria suddenly appeared to care much more after having seen Aylans photograph; however, this newly created empathy waned rather quickly. We briefly examine the psychological processes underlying these findings, discuss some of their policy implications, and reflect on the lessons they provide about the challenges to effective intervention in the face of mass threats to human well-being.

  • 76.
    Solomon, A.
    et al.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37920, United States.
    Richey, T.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States.
    Murphy, C.L.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States.
    Weiss, D.T.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States.
    Wall, J.S.
    Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, United States.
    Westermark, Gunilla
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Westermark, P.
    Department of Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden.
    Amyloidogenic potential of foie gras2007Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, nr 26, s. 10998-11001Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human cerebral and systemic amyloidoses and prion-associated spongiform encephalopathies are acquired or inherited protein folding disorders in which normally soluble proteins or peptides are converted into fibrillar aggregates. This is a nucleation-dependent process that can be initiated or accelerated by fibril seeds formed from homologous or heterologous amyloidogenic precursors that serve as an amyloid enhancing factor (AEF) and has pathogenic significance in that disease may be transmitted by oral ingestion or parenteral administration of these conformationally altered components. Except for infected brain tissue, specific dietary sources of AEF have not been identified. Here we report that commercially available duck- or goose-derived foie gras contains birefringent congophilic fibrillar material composed of serum amyloid A-related protein that acted as a potent AEF in a transgenic murine model of secondary (amyloid A protein) amyloidosis. When such mice were injected with or fed amyloid extracted from foie gras, the animals developed extensive systemic pathological deposits. These experimental data provide evidence that an amyloid-containing food product hastened the development of amyloid protein A amyloidosis in a susceptible population. On this basis, we posit that this and perhaps other forms of amyloidosis may be transmissible, akin to the infectious nature of prion-related illnesses. © 2007 by The National Academy of Sciences of the USA.

  • 77.
    Sproul, Duncan
    et al.
    University of Edinburgh, UK.
    Nestor, Colm
    University of Edinburgh, UK.
    Culley, Jayne
    University of Edinburgh, UK.
    Dickson, Jacqueline H
    University of Edinburgh, UK.
    Dixon, J Michael
    University of Edinburgh, UK.
    Harrison, David J
    University of Edinburgh, UK.
    Meehan, Richard R
    University of Edinburgh, UK.
    Sims, Andrew H
    University of Edinburgh, UK.
    Ramsahoye, Bernard H
    University of Edinburgh, UK.
    Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 11, s. 4364-4369Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aberrant promoter hypermethylation is frequently observed in cancer. The potential for this mechanism to contribute to tumor development depends on whether the genes affected are repressed because of their methylation. Many aberrantly methylated genes play important roles in development and are bivalently marked in ES cells, suggesting that their aberrant methylation may reflect developmental processes. We investigated this possibility by analyzing promoter methylation in 19 breast cancer cell lines and 47 primary breast tumors. In cell lines, we defined 120 genes that were significantly repressed in association with methylation (SRAM). These genes allowed the unsupervised segregation of cell lines into epithelial (EPCAM+ve) and mesenchymal (EPCAM-ve) lineages. However, the methylated genes were already repressed in normal cells of the same lineage, and >90% could not be derepressed by treatment with 5-aza-2'-deoxycytidine. The tumor suppressor genes APC and CDH1 were among those methylated in a lineage-specific fashion. As predicted by the epithelial nature of most breast tumors, SRAM genes that were methylated in epithelial cell lines were frequently aberrantly methylated in primary tumors, as were genes specifically repressed in normal epithelial cells. An SRAM gene expression signature also correctly identified the rare claudin-low and metaplastic tumors as having mesenchymal characteristics. Our findings implicate aberrant DNA methylation as a marker of cell lineage rather than tumor progression and suggest that, in most cases, it does not cause the repression with which it is associated.

  • 78.
    Stavrinidou, Eleni
    et al.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Gabrielsson, Roger
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Nilsson, K. Peter R.
    Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi.
    Singh, Sandeep Kumar
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Franco- Gonzalez, Juan Felipe
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Volkov, Anton V.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Jonsson, Magnus P.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Grimoldi, Andrea
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Elgland, Mathias
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Zozoulenko, Igor V.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Simon, Daniel
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Berggren, Magnus
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    In vivo polymerization and manufacturing of wires and supercapacitors in plants2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 11, s. 2807-2812Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Electronic plants, e-Plants, are an organic bioelectronic platform that allows electronic interfacing with plants. Recently we have demonstrated plants with augmented electronic functionality. Using the vascular system and organs of a plant, we manufactured organic electronic devices and circuits in vivo, leveraging the internal structure and physiology of the plant as the template, and an integral part of the devices. However, this electronic functionality was only achieved in localized regions, whereas new electronic materials that could be distributed to every part of the plant would provide versatility in device and circuit fabrication and create possibilities for new device concepts. Here we report the synthesis of such a conjugated oligomer that can be distributed and form longer oligomers and polymer in every part of the xylem vascular tissue of a Rosa floribunda cutting, forming long-range conducting wires. The plant’s structure acts as a physical template, whereas the plant’s biochemical response mechanism acts as the catalyst for polymerization. In addition, the oligomer can cross through the veins and enter the apoplastic space in the leaves. Finally, using the plant’s natural architecture we manufacture supercapacitors along the stem. Our results are preludes to autonomous energy systems integrated within plants and distribute interconnected sensor-actuator systems for plant control and optimization

  • 79.
    Strambi, Angela
    et al.
    University of Siena, Department of Chemistry.
    Durbeej, Bo
    University of Siena, Department of Chemistry.
    Ferre, Nicolas
    University of Provence.
    Olivucci, Massimo
    University of Siena, Department of Chemistry.
    Anabaena sensory rhodopsin is a light-driven unidirectional rotor2010Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, nr 50, s. 21322-21326Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The implementation of multiconfigurational quantum chemistry methods into a quantum-mechanics/molecular-mechanics protocol has allowed the construction of a realistic computer model for the sensory rhodopsin of the cyanobacterium Anabaena PCC 7120. The model, which reproduces the absorption spectra of both the all-trans and 13-cis forms of the protein and their associated K and L intermediates, is employed to investigate the light-driven steps of the photochromic cycle exhibited by the protein. It is found that the photoisomerizations of the all-trans and 13-cis retinal chromophores occur through unidirectional, counterclockwise 180 deg rotations of the =C14-C15= moiety with respect to the Lys210-linked end of the chromophore axis. Thus, the sequential interconversions of the all-trans and 13-cis forms during a single photochromic cycle yield a complete (360 deg) unidirectional rotation of the =C14-C15= moiety. This finding implies that Anabaena sensory rhodopsin is a biological realization of a light-driven molecular rotor.

  • 80.
    Strimbu, Clark Elliott
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Columbia Univ, NY 10032 USA.
    Prasad, Sonal
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Hakizimana, Pierre
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Control of hearing sensitivity by tectorial membrane calcium2019Ingår 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. 5756-5764Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    When sound stimulates the stereocilia on the sensory cells in the hearing organ, Ca2+ ions flow through mechanically gated ion channels. This Ca2+ influx is thought to be important for ensuring that the mechanically gated channels operate within their most sensitive response region, setting the fraction of channels open at rest, and possibly for the continued maintenance of stereocilia. Since the extracellular Ca2+ concentration will affect the amount of Ca2+ entering during stimulation, it is important to determine the level of the ion close to the sensory cells. Using fluorescence imaging and fluorescence correlation spectroscopy, we measured the Ca2+ concentration near guinea pig stereocilia in situ. Surprisingly, we found that an acellular accessory structure close to the stereocilia, the tectorial membrane, had much higher Ca2+ than the surrounding fluid. Loud sounds depleted Ca2+ from the tectorial membrane, and Ca2+ manipulations had large effects on hair cell function. Hence, the tectorial membrane contributes to control of hearing sensitivity by influencing the ionic environment around the stereocilia.

  • 81.
    Tegnér, Jesper
    et al.
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologiska Beräkningar.
    Yeung, M.K.S.
    Center for BioDynamics, Department of Biomedical Engineering, Boston University, Boston, MA 02215, United States.
    Hasty, J.
    Center for BioDynamics, Department of Biomedical Engineering, Boston University, Boston, MA 02215, United States, Department of Bioengineering, Univ. of California at San Diego, San Diego, CA 92093-0412, United States.
    Collins, J.J.
    Center for BioDynamics, Department of Biomedical Engineering, Boston University, Boston, MA 02215, United States.
    Reverse engineering gene networks: Integrating genetic perturbations with dynamical modeling2003Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, nr 10, s. 5944-5949Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    While the fundamental building blocks of biology are being tabulated by the various genome projects, microarray technology is setting the stage for the task of deducing the connectivity of large-scale gene networks. We show how the perturbation of carefully chosen genes in a microarray experiment can be used in conjunction with a reverse engineering algorithm to reveal the architecture of an underlying gene regulatory network. Our iterative scheme identifies the network topology by analyzing the steady-state changes in gene expression resulting from the systematic perturbation of a particular node in the network. We highlight the validity of our reverse engineering approach through the successful deduction of the topology of a linear in numero gene network and a recently reported model for the segmentation polarity network in Drosophila melanogaster. Our method may prove useful in identifying and validating specific drug targets and in deconvolving the effects of chemical compounds.

  • 82.
    Tritsaris, Katerina
    et al.
    Panum Institute, University of Copenhagen, Denmark.
    Myren, Maja
    Panum Institute, University of Copenhagen, Denmark.
    Ditlev, Sisse B.
    Panum Institute, University of Copenhagen, Denmark.
    Hübschmann, Martin V.
    Panum Institute, University of Copenhagen, Denmark.
    van der Blom, Ida
    Novo Nordisk A/S, Måløv, Denmark.
    Hansen, Anker Jon
    Novo Nordisk A/S, Måløv, Denmark.
    Olsen, Uffe B.
    Novo Nordisk A/S, Måløv, Denmark.
    Cao, Renhai
    Karolinska Institutet, Stockholm, Sweden.
    Zhang, Junhang
    Karolinska Institutet, Stockholm, Sweden.
    Jia, Tanghong
    Shandong University, Jinan, China .
    Wahlberg, Eric
    Karolinska Institutet, Stockholm, Sweden.
    Dissing, Steen
    Panum Institute, University of Copenhagen, Denmark.
    Cao, Yihai
    Karolinska Institutet, Stockholm, Sweden.
    IL-20 is an arteriogenic cytokine that remodels collateral networks and improves functions of ischemic hind limbs2007Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, nr 39, s. 15364-15369Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Successful therapeutic angiogenesis for the treatment of ischemic disorders relies on selection of optimal proangiogenic or arteriogenic agents that are able to promote establishment of functional collateral networks. Here, we show that IL-20, a pleiotropic inflammatory cytokine, displays an imperative effect on vascular remodeling. Stimulation of both large and microvascular endothelial cells with IL-20 leads to activation of receptor-dependent multiple intracellular signaling components, including increased phosphorylation levels of JAK2/STAT5, Erk1/2, and Akt; activation of small GTP-binding proteins Rac and Rho; and intracellular release of calcium. Surprisingly, IL-20 significantly promotes endothelial cell tube formation without affecting their proliferation and motility. These findings suggest that the vascular function of IL-20 involves endothelial cell organization, vessel maturation, and remodeling. Consistent with this notion, delivery of IL-20 to the ischemic muscle tissue significantly improves arteriogenesis and blood perfusion in a rat hind-limb model. Our findings provide mechanistic insights on vascular functions of IL-20 and define therapeutic implication of this cytokine for the treatment of ischemic disorders.

  • 83.
    von Castelmur, Eleonore
    et al.
    Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland.
    Marino, Marco
    Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland.
    Svergun, Dmitri I
    European Molecular Biology Laboratory, Hamburg Outstation, c/o Deutsches Elektronen Synchrotron (DESY), Hamburg, Germany; Institute of Crystallography, Russian Academy of Sciences, Moscow, Russia.
    Kreplak, Laurent
    M. E. Müller Institute for Structural Biology, Biozentrum, University of Basel, Basel, Switzerland.
    Ucurum-Fotiadis, Zöhre
    Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland.
    Konarev, Petr V
    European Molecular Biology Laboratory, Hamburg Outstation, c/o Deutsches Elektronen Synchrotron (DESY), Hamburg, Germany; Institute of Crystallography, Russian Academy of Sciences, Moscow, Russia.
    Urzhumtsev, Alexandre
    University-Nancy, Vandoeuvre-les-Nancy, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique-Institut National de la Santé et de la Recherche Médicale-Université Louis Pasteur, Illkirch, France.
    Labeit, Dietmar
    Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany.
    Labeit, Siegfried
    Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany.
    Mayans, Olga
    Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland; Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany.
    A regular pattern of Ig super-motifs defines segmental flexibility as the elastic mechanism of the titin chain2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 4, s. 1186-1191Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Myofibril elasticity, critical to muscle function, is dictated by the intrasarcomeric filament titin, which acts as a molecular spring. To date, the molecular events underlying the mechanics of the folded titin chain remain largely unknown. We have elucidated the crystal structure of the 6-Ig fragment I65-I70 from the elastic I-band fraction of titin and validated its conformation in solution using small angle x-ray scattering. The long-range properties of the chain have been visualized by electron microscopy on a 19-Ig fragment and modeled for the full skeletal tandem. Results show that conserved Ig-Ig transition motifs generate high-order in the structure of the filament, where conformationally stiff segments interspersed with pliant hinges form a regular pattern of dynamic super-motifs leading to segmental flexibility in the chain. Pliant hinges support molecular shape rearrangements that dominate chain behavior at moderate stretch, whereas stiffer segments predictably oppose high stretch forces upon full chain extension. There, librational entropy can be expected to act as an energy barrier to prevent Ig unfolding while, instead, triggering the unraveling of flanking springs formed by proline, glutamate, valine, and lysine (PEVK) sequences. We propose a mechanistic model based on freely jointed rigid segments that rationalizes the response to stretch of titin Ig-tandems according to molecular features.

  • 84.
    von Castelmur, Eleonore
    et al.
    aInstitute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, United Kingdom.
    Strümpfer, Johan
    Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL, USA; Beckman Institute, University of Illinois, Urbana, IL, USA.
    Franke, Barbara
    aInstitute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, United Kingdom.
    Bogomolovas, Julijus
    aInstitute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, United Kingdom; Department for Integrative Pathophysiology, Universitätsmedizin, Mannheim, Germany.
    Barbieri, Sonia
    aInstitute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, United Kingdom.
    Qadota, Hiroshi
    Department of Pathology, Emory University, Atlanta, GA, USA.
    Konarev, Petr V
    European Molecular Biology Laboratory, Hamburg Outstation, c/o DESY, Hamburg, Germany.
    Svergun, Dmitri I
    European Molecular Biology Laboratory, Hamburg Outstation, c/o DESY, Hamburg, Germany.
    Labeit, Siegfried
    Department for Integrative Pathophysiology, Universitätsmedizin, Mannheim, Germany.
    Benian, Guy M
    Department of Pathology, Emory University, Atlanta, GA, USA.
    Schulten, Klaus
    Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL, USA; Beckman Institute, University of Illinois, Urbana, IL, USA.
    Mayans, Olga
    aInstitute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, United Kingdom.
    Identification of an N-terminal inhibitory extension as the primary mechanosensory regulator of twitchin kinase2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 34, s. 13608-13613Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Titin-like kinases are an important class of cytoskeletal kinases that intervene in the response of muscle to mechanical stimulation, being central to myofibril homeostasis and development. These kinases exist in autoinhibited states and, allegedly, become activated during muscle activity by the elastic unfolding of a C-terminal regulatory segment (CRD). However, this mechano-activation model remains controversial. Here we explore the structural, catalytic, and tensile properties of the multidomain kinase region of Caenorhabditis elegans twitchin (Fn(31)-Nlinker-kinase-CRD-Ig(26)) using X-ray crystallography, small angle X-ray scattering, molecular dynamics simulations, and catalytic assays. This work uncovers the existence of an inhibitory segment that flanks the kinase N-terminally (N-linker) and that acts synergistically with the canonical CRD tail to silence catalysis. The N-linker region has high mechanical lability and acts as the primary stretch-sensor in twitchin kinase, while the CRD is poorly responsive to pulling forces. This poor response suggests that the CRD is not a generic mechanosensor in this kinase family. Instead, the CRD is shown here to be permissive to catalysis and might protect the kinase active site against mechanical damage. Thus, we put forward a regulatory model where kinase inhibition results from the combined action of both N- and C-terminal tails, but only the N-terminal extension undergoes mechanical removal, thereby affording partial activation. Further, we compare invertebrate and vertebrate titin-like kinases and identify variations in the regulatory segments that suggest a mechanical speciation of these kinase classes.

  • 85.
    Wang, Gang
    et al.
    Northwestern University, IL 60208 USA.
    Huang, Wei
    Northwestern University, IL 60208 USA.
    Eastham, Nicholas D.
    Northwestern University, IL 60208 USA.
    Fabiano, Simone
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten. Northwestern University, IL 60208 USA; Flexterra Inc, IL 60077 USA.
    Manley, Eric F.
    Northwestern University, IL 60208 USA; Argonne National Lab, IL 60439 USA.
    Zeng, Li
    Northwestern University, IL 60208 USA.
    Wang, Binghao
    Northwestern University, IL 60208 USA.
    Zhang, Xinan
    Northwestern University, IL 60208 USA.
    Chen, Zhihua
    Flexterra Inc, IL 60077 USA.
    Li, Ran
    Northwestern University, IL 60208 USA.
    Chang, Robert P. H.
    Northwestern University, IL 60208 USA.
    Chen, Lin X.
    Northwestern University, IL 60208 USA; Argonne National Lab, IL 60439 USA.
    Bedzyk, Michael J.
    Northwestern University, IL 60208 USA.
    Melkonyan, Ferdinand S.
    Northwestern University, IL 60208 USA.
    Facchetti, Antonio
    Northwestern University, IL 60208 USA; Flexterra Inc, IL 60077 USA.
    Marks, Tobin J.
    Northwestern University, IL 60208 USA.
    Aggregation control in natural brush-printed conjugated polymer films and implications for enhancing charge transport2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 47, s. E10066-E10073Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Shear-printing is a promising processing technique in organic electronics for microstructure/charge transport modification and large-area film fabrication. Nevertheless, the mechanism by which shear-printing can enhance charge transport is not well-understood. In this study, a printing method using natural brushes is adopted as an informative tool to realize direct aggregation control of conjugated polymers and to investigate the interplay between printing parameters, macromolecule backbone alignment and aggregation, and charge transport anisotropy in a conjugated polymer series differing in architecture and electronic structure. This series includes (i) semicrystalline hole-transporting P3HT, (ii) semicrystalline electron transporting N2200, (iii) low-crystallinity hole-transporting PBDTT-FTTE, and (iv) low-crystallinity conducting PEDOT:PSS. The (semi-)conducting films are characterized by a battery of morphology and microstructure analysis techniques and by charge transport measurements. We report that remarkably enhanced mobilities/conductivities, as high as 5.7x/3.9x, are achieved by controlled growth of nanofibril aggregates and by backbone alignment, with the adjusted R-2 (R-adj(2)) correlation between aggregation and charge transport as high as 95%. However, while shear-induced aggregation is important for enhancing charge transport, backbone alignment alone does not guarantee charge transport anisotropy. The correlations between efficient charge transport and aggregation are clearly shown, while mobility and degree of orientation are not always well-correlated. These observations provide insights into macroscopic charge transport mechanisms in conjugated polymers and suggest guidelines for optimization.

  • 86.
    Wang, Peng
    et al.
    Capital Medical University, Peoples R China; Logist University of Peoples Armed Police Force, Peoples R China.
    Li, Hui
    Capital Medical University, Peoples R China.
    Barde, Swapnali
    Karolinska Institute, Sweden.
    Zhang, Ming-Dong
    Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Sun, Jing
    Capital Medical University, Peoples R China.
    Wang, Tong
    Capital Medical University, Peoples R China.
    Zhang, Pan
    Capital Medical University, Peoples R China.
    Luo, Hanjiang
    Capital Medical University, Peoples R China.
    Wang, Yongjun
    Capital Medical University, Peoples R China.
    Yang, Yutao
    Capital Medical University, Peoples R China.
    Wang, Chuanyue
    Capital Medical University, Peoples R China.
    Svenningsson, Per
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Hokfelt, Tomas G. M.
    Karolinska Institute, Sweden.
    David Xu, Zhi-Qing
    Capital Medical University, Peoples R China.
    Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 32, s. E4726-E4735Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects.

  • 87.
    Wang, Suhao
    et al.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Fabiano, Simone
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Himmelberger, Scott
    Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA.
    Puzinas, Skomantas
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Crispin, Xavier
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Salleo, Alberto
    Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA.
    Berggren, Magnus
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Experimental evidence that short-range intermolecular aggregation is sufficient for efficient charge transport in conjugated polymers2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 34, s. 10599-10604Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Efficiency, current throughput, and speed of electronic devices are to a great extent dictated by charge carrier mobility. The classic approach to impart high carrier mobility to polymeric semiconductors has often relied on the assumption that extensive order and crystallinity are needed. Recently, however, this assumption has been challenged, because high mobility has been reported for semiconducting polymers that exhibit a surprisingly low degree of order. Here, we show that semiconducting polymers can be confined into weakly ordered fibers within an inert polymer matrix without affecting their charge transport properties. In these conditions, the semiconducting polymer chains are inhibited from attaining long-range order in the p-stacking or alkyl-stacking directions, as demonstrated from the absence of significant X-ray diffraction intensity corresponding to these crystallographic directions, yet still remain extended along the backbone direction and aggregate on a local length scale. As a result, the polymer films maintain high mobility even at very low concentrations. Our findings provide a simple picture that clarifies the role of local order and connectivity of domains.

  • 88.
    Wang, X.-J.
    et al.
    Center for Complex Systems, Brandeis University, Waltham, MA 02254, United States.
    Tegnér, Jesper
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologiska Beräkningar.
    Constantinidis, C.
    Section of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, United States, Wake Forest Univ. School of Medicine, Dept. of Neurobiology and Anatomy, Winston-Salem, NC 27157-1010, United States.
    Goldman-Rakic, P.S.
    Section of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, United States.
    Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory2004Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, nr 5, s. 1368-1373Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A conspicuous feature of cortical organization is the wide diversity of inhibitory interneurons, their differential computational functions remain unclear. Here we propose a local cortical circuit in which three major subtypes of interneurons play distinct roles. In a model designed for spatial working memory, stimulus tuning of persistent activity arises from the concerted action of widespread inhibition mediated by perisoma-targeting (parvalbumin-containing) interneurons and localized disinhibition of pyramidal cells via interneuron-targeting (calretinin-containing) interneurons. Moreover, resistance against distracting stimuli (a fundamental property of working memory) is dynamically controlled by dendrite-targeting (calbindin-containing) interneurons. The experimental observation of inverted tuning curves of monkey prefrontal neurons recorded during working memory supports a key model prediction. This work suggests a framework for understanding the division of labor and cooperation among different inhibitory cell types in a recurrent cortical circuit.

  • 89.
    Warren, Rebecca L.
    et al.
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Ramamoorthy, Sripriya
    Indian Institute Technology, India.
    Ciganovic, Nikola
    Imperial Coll, England.
    Zhang, Yuan
    Oregon Health and Science University, OR 97239 USA.
    Wilson, Teresa M.
    Oregon Health and Science University, OR 97239 USA.
    Petrie, Tracy
    Oregon Health and Science University, OR 97239 USA.
    Wang, Ruikang K.
    University of Washington, WA 98195 USA; University of Washington, WA 98195 USA.
    Jacques, Steven L.
    Oregon Health and Science University, OR 97239 USA.
    Reichenbach, Tobias
    Imperial Coll, England.
    Nuttall, Alfred L.
    Oregon Health and Science University, OR 97239 USA.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Oregon Health and Science University, OR 97239 USA.
    Minimal basilar membrane motion in low-frequency hearing2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 30, s. E4304-E4310Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Low-frequency hearing is critically important for speech and music perception, but no mechanical measurements have previously been available from inner ears with intact low-frequency parts. These regions of the cochlea may function in ways different from the extensively studied high-frequency regions, where the sensory outer hair cells produce force that greatly increases the sound-evoked vibrations of the basilar membrane. We used laser interferometry in vitro and optical coherence tomography in vivo to study the low-frequency part of the guinea pig cochlea, and found that sound stimulation caused motion of a minimal portion of the basilar membrane. Outside the region of peak movement, an exponential decline in motion amplitude occurred across the basilar membrane. The moving region had different dependence on stimulus frequency than the vibrations measured near the mechanosensitive stereocilia. This behavior differs substantially from the behavior found in the extensively studied high-frequency regions of the cochlea.

  • 90.
    Welinder, Eva
    et al.
    University of California San Diego.
    Mansson, Robert
    University of California San Diego.
    Mercer, Elinore M
    University of California San Diego.
    Bryder, David
    Lund University.
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Murre, Cornelis
    University of California San Diego.
    The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 42, s. 17402-17407Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent studies have identified a number of transcriptional regulators, including E proteins, EBF1, FOXO1, and PAX5, that act together to orchestrate the B-cell fate. However, it still remains unclear as to how they are linked at the earliest stages of B-cell development. Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A(+/-)HEB(-/)-mice is completely blocked at the LY6D(-) common lymphoid progenitor stage. We show that the transcription signatures of E2A-and HEB-ablated common lymphoid progenitors significantly overlap. Notably, we found that Foxo1 expression was substantially reduced in the LY6D-HEB-and E2A-deficient cells. Finally, we show that E2A binds to enhancer elements across the FOXO1 locus to activate Foxo1 expression, linking E2A and FOXO1 directly in a common pathway. In summary, the data indicate that the earliest event in B-cell specification involves the induction of FOXO1 expression and requires the combined activities of E2A and HEB.

  • 91.
    Wijeratne, Kosala
    et al.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Ail, Ujwala
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Brooke, Robert
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Vagin, Mikhail
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Liu, Xianjie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Ytors Fysik och Kemi. Linköpings universitet, Tekniska fakulteten.
    Fahlman, Mats
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Ytors Fysik och Kemi. Linköpings universitet, Tekniska fakulteten.
    Crispin, Xavier
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Bulk electronic transport impacts on electron transfer at conducting polymer electrode-electrolyte interfaces.2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, nr 7, s. 11899-11904Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Electrochemistry is an old but still flourishing field of research due to the importance of the efficiency and kinetics of electrochemical reactions in industrial processes and (bio-)electrochemical devices. The heterogeneous electron transfer from an electrode to a reactant in the solution has been well studied for metal, semiconductor, metal oxide, and carbon electrodes. For those electrode materials, there is little correlation between the electronic transport within the electrode material and the electron transfer occurring at the interface between the electrode and the solution. Here, we investigate the heterogeneous electron transfer between a conducting polymer electrode and a redox couple in an electrolyte. As a benchmark system, we use poly(3,4-ethylenedioxythiophene) (PEDOT) and the Ferro/ferricyanide redox couple in an aqueous electrolyte. We discovered a strong correlation between the electronic transport within the PEDOT electrode and the rate of electron transfer to the organometallic molecules in solution. We attribute this to a percolation-based charge transport within the polymer electrode directly involved in the electron transfer. We show the impact of this finding by optimizing an electrochemical thermogalvanic cell that transforms a heat flux into electrical power. The power generated by the cell increased by four orders of magnitude on changing the morphology and conductivity of the polymer electrode. As all conducting polymers are recognized to have percolation transport, we believe that this is a general phenomenon for this family of conductors.

  • 92.
    Wunderer, Julia
    et al.
    Univ Innsbruck, Austria.
    Lengerer, Birgit
    Univ Innsbruck, Austria; Univ Mons, Belgium.
    Pjeta, Robert
    Univ Innsbruck, Austria.
    Bertemes, Philip
    Univ Innsbruck, Austria.
    Kremser, Leopold
    Innsbruck Med Univ, Austria.
    Lindner, Herbert
    Innsbruck Med Univ, Austria.
    Ederth, Thomas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Hess, Michael W.
    Innsbruck Med Univ, Austria.
    Stock, David
    Univ Innsbruck, Austria.
    Salvenmoser, Willi
    Univ Innsbruck, Austria.
    Ladurner, Peter
    Univ Innsbruck, Austria.
    A mechanism for temporary bioadhesion2019Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 10, s. 4297-4306Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The flatworm Macrostomum lignano features a duo-gland adhesive system that allows it to repeatedly attach to and release from substrates in seawater within a minute. However, little is known about the molecules involved in this temporary adhesion. In this study, we show that the attachment of M. lignano relies on the secretion of two large adhesive proteins, M. lignano adhesion protein 1 (Mlig-ap1) and Mlig-ap2. We revealed that both proteins are expressed in the adhesive gland cells and that their distribution within the adhesive footprints was spatially restricted. RNA interference knockdown experiments demonstrated the essential function of these two proteins in flatworm adhesion. Negatively charged modified sugars in the surrounding water inhibited flatworm attachment, while positively charged molecules impeded detachment. In addition, we found that M. lignano could not adhere to strongly hydrated surfaces. We propose an attachment-release model where Mlig-ap2 attaches to the substrate and Mlig-ap1 exhibits a cohesive function. A small negatively charged molecule is secreted that interferes with Mlig-ap1, inducing detachment. These findings are of relevance for fundamental adhesion science and efforts to mitigate biofouling. Further, this model of flatworm temporary adhesion may serve as the starting point for the development of synthetic reversible adhesion systems for medicinal and industrial applications.

  • 93.
    Yang, Xiaojuan
    et al.
    Karolinska Institute, Sweden; Tongji University, Peoples R China.
    Zhang, Yin
    Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Andersson, Patrik
    Karolinska Institute, Sweden.
    Wang, Jian
    Karolinska Institute, Sweden.
    Tholander, Fredrik
    Karolinska Institute, Sweden.
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Morikawa, Hiromasa
    Karolinska Institute, Sweden.
    Tegner, Jesper
    Karolinska Institute, Sweden.
    Yang, Yunlong
    Karolinska Institute, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Sweden.
    Lim, Sharon
    Karolinska Institute, Sweden.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 22, s. E2900-E2909Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A-null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk(-/-) mice and mice treated with anti-VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.

  • 94.
    Yang, Xiaojuan
    et al.
    Karolinska Institute, Sweden .
    Zhang, Yin
    Karolinska Institute, Sweden .
    Yang, Yunlong
    Karolinska Institute, Sweden .
    Lim, Sharon
    Karolinska Institute, Sweden .
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Rak, Janusz
    McGill University, Canada .
    Cao, Yihai
    Karolinska Institute, Sweden .
    Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth2013Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 34, s. 13932-13937Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Placental growth factor (PIGF) remodels tumor vasculatures toward a normalized phenotype, which affects tumor growth, invasion and drug responses. However, the coordinative and spatiotemporal relation between PIGF and VEGF in modulation of tumor angiogenesis and vascular remodeling is less understood. Here we report that PlGF positively and negatively modulate tumor growth, angiogenesis, and vascular remodeling through a VEGF-dependent mechanism. In two independent tumor models, we show that PlGF inhibited tumor growth and angiogenesis and displayed a marked vascular remodeling effect, leading to normalized microvessels with infrequent vascular branches and increased perivascular cell coverage. Surprisingly, elimination of VEGF gene (i.e., VEGF-null) in PIGF-expressing tumors resulted in (i) accelerated tumor growth rates and angiogenesis and (ii) complete attenuation of PIGF-induced vascular normalization. Thus, PIGF positively and negatively modulates tumor growth, angiogenesis, and vascular remodeling through VEGF-dependent spatiotemporal mechanisms. Our data uncover molecular mechanisms underlying the complex interplay between PIGF and VEGF in modulation of tumor growth and angiogenesis, and have conceptual implication for antiangiogenic cancer therapy.

  • 95.
    Yang, Yunlong
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Zhang, Yin
    Karolinska Institute, Stockholm, Sweden.
    Cao, Ziquan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Ji, Hong
    Karolinska Institute, Stockholm, Sweden.
    Yang, Xiaojuan
    Karolinska Institute, Stockholm, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Stockholm, Sweden.
    Wahlberg, Eric
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Länne, Toste
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Sun, Baocun
    Tianjin Medical University, China.
    Cao, Yihai
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Stockholm, Sweden.
    Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues2013Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 29, s. 12018-12023Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs.

  • 96.
    Younis, Shady
    et al.
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden // Department of Animal Production, Ain Shams University, Shoubra El-Kheima, 11241 Cairo, Egypt.
    Kamel, Wael
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Falkeborn, Tina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk mikrobiologi.
    Wang, Hao
    Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
    Yu, Di
    Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Daniels, Robert
    Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
    Essand, Magnus
    Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Hinkula, Jorma
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
    Akusjärvi, Göran
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Andersson, Leif
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden // Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden // Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77483, USA.
    Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 6, s. E3808-E3816Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A–cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication.

  • 97.
    Yu, Jun
    et al.
    Yale University School of Medicine, New Haven, CT, USA.
    de Muinck, Ebo D.
    Dartmouth Medical School, Lebanon, NH, USA.
    Zhuang, Zhenwu
    Dartmouth Medical School, Lebanon, NH, USA.
    Drinane, Mary
    Dartmouth Medical School, Lebanon, NH, USA.
    Kauser, Katalin
    Berlex Biosciences, Richmond, CA, USA.
    Rubanyi, Gabor M.
    Berlex Biosciences, Richmond, CA, USA.
    Qian, Hu Sheng
    Berlex Biosciences, Richmond, CA, USA.
    Murata, Takahisa
    Yale University School of Medicine, New Haven, CT, USA.
    Escalante, Bruno
    Centro de Investigación y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico .
    Sessa, William C
    Yale University School of Medicine, New Haven, CT, USA.
    Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve2005Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, nr 31, s. 10999-11004Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The genetic loss of endothelial-derived nitric oxide synthase (eNOS) in mice impairs vascular endothelial growth factor (VEGF) and ischemia-initiated blood flow recovery resulting in critical limb ischemia. This result may occur through impaired arteriogenesis, angiogenesis, or mobilization of stem and progenitor cells. Here, we show that after ischemic challenge, eNOS knockout mice [eNOS (-/-)] have defects in arteriogenesis and functional blood flow reserve after muscle stimulation and pericyte recruitment, but no impairment in endothelial progenitor cell recruitment. More importantly, the defects in blood flow recovery, clinical manifestations of ischemia, ischemic reserve capacity, and pericyte recruitment into the growing neovasculature can be rescued by local intramuscular delivery of an adenovirus encoding a constitutively active allele of eNOS, eNOS S1179D, but not a control virus. Collectively, our data suggest that endogenous eNOS-derived NO exerts direct effects in preserving blood flow, thereby promoting arteriogenesis, angiogenesis, and mural cell recruitment to immature angiogenic sprouts.

  • 98.
    Yuan, Xi-Ming
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Li, Wei
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Dalen, Helge
    Deparment of Pathology, The Gade Institute, University of Bergen, Bergen N-5021, Norway.
    Lotem, Joseph
    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
    Kama, Rachel
    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
    Sachs, Leo
    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
    Brunk, Ulf T.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lysosomal destabilization in p53-induced apoptosis2002Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, nr 9, s. 6286-6291Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The tumor suppressor wild-type p53 can induce apoptosis. M1-t-p53 myeloid leukemic cells have a temperature-sensitive p53 protein that changes its conformation to wild-type p53 after transfer from 37 degrees C to 32 degrees C. We have now found that these cells showed an early lysosomal rupture after transfer to 32 degrees C. Mitochondrial damage, including decreased membrane potential and release of cytochrome c, and the appearance of apoptotic cells occurred later. Lysosomal rupture, mitochondrial damage, and apoptosis were all inhibited by the cytokine IL-6. Some other compounds can also inhibit apoptosis induced by p53. The protease inhibitor N-tosyl-l-phenylalanine chloromethyl ketone inhibited the decrease in mitochondrial membrane potential and cytochrome c release, the Ca(2+)-ATPase inhibitor thapsigargin inhibited only cytochrome c release, and the antioxidant butylated hydroxyanisole inhibited only the decrease in mitochondrial membrane potential. In contrast to IL-6, these other compounds that inhibited some of the later occurring mitochondrial damage did not inhibit the earlier p53-induced lysosomal damage. The results indicate that apoptosis is induced by p53 through a lysosomal-mitochondrial pathway that is initiated by lysosomal destabilization, and that this pathway can be dissected by using different apoptosis inhibitors. These findings on the induction of p53-induced lysosomal destabilization can also help to formulate new therapies for diseases with apoptotic disorders.

  • 99. Zak, Elena
    et al.
    Norling, Birgitta
    Maitra, Radhashree
    Huang, Fang
    Andersson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Pakrasi, Himadri
    The initial steps of biogenesis of cyanobacterial photosystems occur in plasma membranes2001Ingår 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. 13443-13448Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During oxygenic photosynthesis in cyanobacteria and chloroplasts of plants and eukaryotic algae, conversion of light energy to biologically useful chemical energy occurs in the specialized thylakoid membranes. Light-induced charge separation at the reaction centers of photosystems I and II, two multisubunit pigment-protein complexes in the thylakoid membranes, energetically drive sequential photosynthetic electron transfer reactions in this membrane system. In general, in the prokaryotic cyanobacterial cells, the thylakoid membrane is distinctly different from the plasma membrane. We have recently developed a two-dimensional separation procedure to purify thylakoid and plasma membranes from the genetically widely studied cyanobacterium Synechocystis sp. PCC 6803. Immunoblotting analysis demonstrated that the purified plasma membrane contained a number of protein components closely associated with the reaction centers of both photosystems. Moreover, these proteins were assembled in the plasma membrane as chlorophyll-containing multiprotein complexes, as evidenced from nondenaturing green gel and low-temperature fluorescence spectroscopy data. Furthermore, electron paramagnetic resonance spectroscopic analysis showed that in the partially assembled photosystem I core complex in the plasma membrane, the P700 reaction center was capable of undergoing light-induced charge separation. Based on these data, we propose that the plasma membrane, and not the thylakoid membrane, is the site for a number of the early steps of biogenesis of the photosynthetic reaction center complexes in these cyanobacterial cells.

  • 100.
    Zandi, Sasan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Åhsberg, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Tsapogas, Panagiotis
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Stjernberg, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Qian, Hong
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Single-cell analysis of early B-lymphocyte development suggests independent regulation of lineage specification and commitment in vivo2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 39, s. 15871-15876Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To better understand the process of B-lymphocyte lineage restriction, we have investigated molecular and functional properties in early B-lineage cells from Pax-5-deficient animals crossed to a B-lineage-restricted reporter mouse, allowing us to identify B-lineage-specified progenitors independently of conventional surface markers. Pax-5 deficiency resulted in a dramatic increase in the frequency of specified progenitor B-cellsmarked by expression of a lambda 5 (Igll1) promoter-controlled reporter gene. Gene expression analysis of ex vivo isolated progenitor cells revealed that Pax-5 deficiency has a minor impact on B-cell specification. However, single-cell in vitro differentiation analysis of ex vivo isolated cells revealed that specified B-lineage progenitors still displayed a high degree of plasticity for development into NK or T lineage cells. In contrast, we were unable to detect any major changes in myeloid lineage potential in specified Pax-5-deficient cells. By comparison of gene expression patterns in ex vivo isolated Pax-5-and Ebf-1-deficient progenitors, it was possible to identify a set of B-cell-restricted genes dependent on Ebf-1 but not Pax-5, supporting the idea that B-cell specification and commitment is controlled by distinct regulatory networks.

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