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1. Melissa: coordinating large-scale ensemble runs for deep learning and sensitivity analyses

Author

Schouler, Marc, Caulk, Robert Alexander, Meyer, Lucas, Terraz, Théophile, Conrads, Christoph, Friedemann, Sebastian, Agarwal, Achal, Baldonado, Juan Manuel, Pogodziński, Bartłomiej, Sekuła, Anna, Ribes, Alejandro, Raffin, Bruno, Data Aware Large Scale Computing (DATAMOVE ), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), EDF R&D (EDF R&D), EDF (EDF), Saclay Industrial Lab for Artificial Intelligence Research (SINCLAIR AI Lab), THALES [France]-TOTAL FINA ELF-EDF (EDF), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), European Project: 956560,REGALE, and European Project: 824158,H2020-EU.1.4. - EXCELLENT SCIENCE - Research Infrastructures ,EoCoE-II(2019)

Subjects
distributed systems, [PHYS]Physics [physics], [STAT]Statistics [stat], Supercomputing, Surrogate Modeling, Deep learning, Orchestration Framework, [INFO]Computer Science [cs], Sensitivity analysis
Abstract

International audience; Large-scale ensemble runs typically consist of executing thousands of physical simulation instances according to a range of different input parameters. These ensemble runs enable sensitivity analyses, deep surrogate trainings, reinforcement learning, and data assimilation, but they rely on volumes of data that are too large to store. For example, a recent data assimilation ensemble study generated 1.3 PB of data [@yashiro2020]. These enormous volumes of data hinder scientific analyses in two ways: first, the I/O speeds are the slowest component in supercomputers; the incongruence between slow read/write speeds compared to the rapid generation of data leads to a degradation and plateau of performance. Second, the file systems on supercomputers are not designed to allocate such large volumes of data to singular studies. To avoid this I/O limitation, scientists reduce their study size by running low resolution simulations or down-sampling output data in space and time. However, the I/O problem only becomes more pronounced as the speed and size of supercomputers continues to advance faster than I/O speeds of storage disks.

Published
2023
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2. Structural and Biochemical Features of OXA-517: a Carbapenem and Expanded-Spectrum Cephalosporin Hydrolyzing OXA-48 Variant

Author

Laura Dabos, Joanna E. Raczynska, Pierre Bogaerts, Agustin Zavala, Delphine Girlich, Remy A. Bonnin, Laurent Dortet, Aurélie Peyrat, Pascal Retailleau, Bogdan I. Iorga, Mariusz Jaskólski, Youri Glupczynski, Thierry Naas, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Laboratoire de biologie clinique, Team Resist [Le Kremlin-Bicêtre], Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, INSERM, UMR_S 999, Laboratoire d’Excellence (LabEx) en Recherche sur le Médicament et l’Innovation Thérapeutique (LERMIT), Université Paris Sud (Paris 11), French National Reference Center for Antibiotic Resistance: Carbapenemase producing Enterobacteriaceae [Le Kremlin-Bicêtre], Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), CHU UCL Namur, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-14-JAMR-0002,DesInMBL,Structure-guided design of pan inhibitors of metallo-ß-lactamases(2014), and ANR-10-LABX-0033,LERMIT,Research Laboratory on Drugs and Therapeutic Innovation(2010)

Subjects
Pharmacology, antibiotic resistance, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], oxacillinase, cephalosporin, Microbial Sensitivity Tests, extended-spectrum β-lactamase, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Ceftazidime, beta-Lactamases, Cephalosporins, Anti-Bacterial Agents, carbapenem, Infectious Diseases, Carbapenems, hydrolysis, Escherichia coli, Pharmacology (medical), Monobactams
Abstract

International audience; OXA-48-producing Enterobacterales have now widely disseminated throughout the world. Several variants have now been reported, differing by just a few amino-acid substitutions or deletions, mostly in the region of the loop β5-β6. As OXA-48 hydrolyzes carbapenems but lacks significant expanded-spectrum cephalosporin (ESC) hydrolytic activity, ESCs were suggested as a therapeutic option. Here, we have characterized OXA-517, a natural variant of OXA-48- with an Arg214Lys substitution and a deletion of Ile215 and Glu216 in the β5-β6 loop, capable of hydrolyzing at the same time ESC and carbapenems. MICs values of E. coli expressing blaOXA-517 gene revealed reduced susceptibility to carbapenems (similarly to OXA-48) and resistance to ESCs. Steady-state kinetic parameters revealed high catalytic efficiencies for ESCs and carbapenems. The blaOXA-517 gene was located on a ca. 31-kb plasmid identical to the prototypical IncL blaOXA-48-carrying plasmid except for an IS1R-mediated deletion of 30.7-kb in the tra operon. The crystal structure of OXA-517, determined to 1.86 Å resolution, revealed an expanded active site compared to that of OXA-48, which allows for accommodation of the bulky ceftazidime substrate. Our work illustrates the remarkable propensity of OXA-48-like carbapenemases to evolve through mutation/deletion in the β5-β6 loop to extend its hydrolysis profile to encompass most β-lactam substrates.

Published
2023
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3. Arrested in Glass: Actin within Sophisticated Architectures of Biosilica in Sponges

Author

Hermann Ehrlich, Magdalena Luczak, Rustam Ziganshin, Ivan Mikšík, Marcin Wysokowski, Paul Simon, Irena Baranowska‐Bosiacka, Patrycja Kupnicka, Alexander Ereskovsky, Roberta Galli, Sergey Dyshlovoy, Jonas Fischer, Konstantin R. Tabachnick, Iaroslav Petrenko, Teofil Jesionowski, Anna Lubkowska, Marek Figlerowicz, Viatcheslav N. Ivanenko, Adam P. Summers, Technishe Universität Bergakademie Freiberg (TU Bergakademie Freiberg), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry (IBCh RAS), Russian Academy of Sciences [Moscow] (RAS), Institute of Animal Physiology and Genetics of the Czech Academy of Sciences (IAPG / CAS), Czech Academy of Sciences [Prague] (CAS), Max Planck Institute for Chemical Physics of Solids (CPfS), Max-Planck-Gesellschaft, Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), and Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE)

Subjects
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], General Chemical Engineering, General Engineering, General Physics and Astronomy, Medicine (miscellaneous), General Materials Science, Glass, Silicon Dioxide, Biochemistry, Genetics and Molecular Biology (miscellaneous), ComputingMilieux_MISCELLANEOUS, Actins, Skeleton
Abstract

International audience; Actin is a fundamental member of an ancient superfamily of structural intracellular proteins and plays a crucial role in cytoskeleton dynamics, ciliogenesis, phagocytosis, and force generation in both prokaryotes and eukaryotes. It is shown that actin has another function in metazoans: patterning biosilica deposition, a role that has spanned over 500 million years. Species of glass sponges (Hexactinellida) and demosponges (Demospongiae), representatives of the first metazoans, with a broad diversity of skeletal structures with hierarchical architecture unchanged since the late Precambrian, are studied. By etching their skeletons, organic templates dominated by individual F-actin filaments, including branched fibers and the longest, thickest actin fiber bundles ever reported, are isolated. It is proposed that these actin-rich filaments are not the primary site of biosilicification, but this highly sophisticated and multi-scale form of biomineralization in metazoans is ptterned.

Published
2022
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4. Selective transduction of cerebellar Purkinje and granule neurons using delivery of AAV-PHP.eB and AAVrh10 vectors at axonal terminal locations

Author

Magdalena Surdyka, Ewelina Jesion, Anna Niewiadomska-Cimicka, Yvon Trottier, Żaneta Kalinowska-Pośka, Maciej Figiel, Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and univOAK, Archive ouverte

Subjects
Cellular and Molecular Neuroscience, AAVrh10, cerebellum, Purkinje cells, deep cerebellar nuclei, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, adeno-associated virus (AAV), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, retrograde, Molecular Biology, AAV-PHP.eB, granule cells
Abstract

Adeno-associated virus (AAV)-based brain gene therapies require precision without off-targeting of unaffected neurons to avoid side effects. The cerebellum and its cell populations, including granule and Purkinje cells, are vulnerable to neurodegeneration; hence, conditions to deliver the therapy to specific cell populations selectively remain challenging. We have investigated a system consisting of the AAV serotypes, targeted injections, and transduction modes (direct or retrograde) for targeted delivery of AAV to cerebellar cell populations. We selected the AAV-PHP.eB and AAVrh10 serotypes valued for their retrograde features, and we thoroughly examined their cerebellar transduction pattern when injected into lobules and deep cerebellar nuclei. We found that AAVrh10 is suitable for the transduction of neurons in the mode highly dependent on placing the virus at axonal terminals. The strategy secures selective transduction for granule cells. The AAV-PHP.eB can transduce Purkinje cells and is very selective for the cell type when injected into the DCN at axonal PC terminals. Therefore, both serotypes can be used in a retrograde mode for selective transduction of major neuronal types in the cerebellum. Moreover, ourin vivotransduction strategies are suitable for pre-clinical protocol development for gene delivery to granule cells by AAVrh10 and Purkinje cells by AAV-PHPeB.

Published
2022
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5. New Perspectives in Scheduling Theory

Author

Jacek Blazewicz, Benjamin Moseley, Erwin Pesch, Denis Trystram, Guochuan Zhang, Institute of Computing Science [Poznan], Poznan University of Technology (PUT), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Data Aware Large Scale Computing (DATAMOVE ), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Zhejiang University, Universität Siegen [Siegen], Handelshochschule Leipzig - Graduate School of Management (HHL), Tepper School of Business, and Carnegie Mellon University [Pittsburgh] (CMU)

Subjects
021103 operations research, 010201 computation theory & mathematics, Artificial Intelligence, [INFO.INFO-DS]Computer Science [cs]/Data Structures and Algorithms [cs.DS], 0211 other engineering and technologies, General Engineering, 0102 computer and information sciences, 02 engineering and technology, Management Science and Operations Research, [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], 01 natural sciences, Software, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; short paper, no abstract

Published
2021
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6. Small RNA fragments derived from multiple RNA classes – the missing element of multi-omics characteristics of the hepatitis C virus cell culture model

Author

Agnieszka Zmienko, Anna Hojka-Osinska, Agata Budkowska, Marek Figlerowicz, Anna Philips, Paulina Jackowiak, Lucyna Budzko, Patrick Maillard, Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Institute of Computing Science [Poznan], Poznan University of Technology (PUT), Hépacivirus et Immunité innée, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This study was financed by the National Science Centre grant awarded on the basis of a decision number DEC-2012/05/D/NZ2/02238, to PJ, and by the Polish Ministry of Science and Higher Education grant IP2012 014972, to PJ. Partial financial support was also provided by the European Union within the European Regional Development Fund through the MPD program and by the Polish Ministry of Science and Higher Education, under the KNOW program., We thank T. Wakita for providing us (Institut Pasteur, Paris, France) with JFH-1 infectious clone and C. Rice for Huh-7.5 cells. We are indebted to the Plateforme D’Imagerie Dynamique (PFID) of the Institut Pasteur 'Imagopole' for microscopy assistance. The RNA-Seq analysis was performed using the facilities of European Centre of Bioinformatics and Genomics (Poznan, Poland)., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Small RNA, RNA, Untranslated, genetic structures, lcsh:QH426-470, Hepatitis C virus, [SDV]Life Sciences [q-bio], lcsh:Biotechnology, Gene Dosage, Hepacivirus, Biology, medicine.disease_cause, Cell Line, Transcriptome, RNA fragments, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:TP248.13-248.65, microRNA, Genetics, medicine, Humans, tRF, Nucleic acid structure, skin and connective tissue diseases, Non-coding RNA, High-Throughput Nucleotide Sequencing, RNA, Genomics, 3. Good health, RNA silencing, lcsh:Genetics, 030104 developmental biology, HCV, RNA, Viral, Research Article, Biotechnology
Abstract

Background A pool of small RNA fragments (RFs) derived from diverse cellular RNAs has recently emerged as a rich source of functionally relevant molecules. Although their formation and accumulation has been connected to various stress conditions, the knowledge on RFs produced upon viral infections is very limited. Here, we applied the next generation sequencing (NGS) to characterize RFs generated in the hepatitis C virus (HCV) cell culture model (HCV-permissive Huh-7.5 cell line). Results We found that both infected and non-infected cells contained a wide spectrum of RFs derived from virtually all RNA classes. A significant fraction of identified RFs accumulated to similar levels as miRNAs. Our analysis, focused on RFs originating from constitutively expressed non-coding RNAs, revealed three major patterns of parental RNA cleavage. We found that HCV infection induced significant changes in the accumulation of low copy number RFs, while subtly altered the levels of high copy number ones. Finally, the candidate RFs potentially relevant for host-virus interactions were identified. Conclusions Our results indicate that RFs should be considered an important component of the Huh-7.5 transcriptome and suggest that the main factors influencing the RF biogenesis are the RNA structure and RNA protection by interacting proteins. The data presented here significantly complement the existing transcriptomic, miRnomic, proteomic and metabolomic characteristics of the HCV cell culture model. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3891-3) contains supplementary material, which is available to authorized users.

Published
2017
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7. Mitochondrial Transcriptome Control and Intercompartment Cross-Talk During Plant Development

Author

Etienne Delannoy, Daria Mileshina, Rana Khalid Iqbal, Romain Val, José M. Gualberto, André Dietrich, Jan Barciszewski, Frédérique Weber-Lotfi, Maciej Szymanski, Adnan Khan Niazi, Eliza Wyszko, Ludivine Soubigou-Taconnat, Marta M. Gabryelska, Institut de biologie moléculaire des plantes (IBMP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)), Institut National de la Recherche Agronomique (INRA)-Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Adam Mickiewicz University in Poznań (UAM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11), Polska Akademia Nauk (PAN), Institut National de la Recherche Agronomique (INRA)-Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Niazi, Adnan Khan, Delannoy, Etienne, Iqbal, Rana Khalid, and Dietrich, André

Subjects
0106 biological sciences, 0301 basic medicine, RNA, Mitochondrial, Arabidopsis, Down-Regulation, Plant Development, Mitochondrion, Biology, cytoplasmic male sterility (CMS), 01 natural sciences, Genome, Article, Transcriptome, retrograde regulation, 03 medical and health sciences, ribozyme, plant mitochondria, Gene Expression Regulation, Plant, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Tobacco, Arabidopsis thaliana, RNA, Catalytic, RNA, Messenger, lcsh:QH301-705.5, RNA trafficking, Cell Nucleus, Base Sequence, Cytoplasmic male sterility, anterograde regulation, signaling, RNA, General Medicine, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, biology.organism_classification, RNA tracking, Cell biology, Mitochondria, Up-Regulation, 030104 developmental biology, lcsh:Biology (General), RNA, Plant, Transfer RNA, Retrograde signaling, 010606 plant biology & botany
Abstract

We address here organellar genetic regulation and intercompartment genome coordination. We developed earlier a strategy relying on a tRNA-like shuttle to mediate import of nuclear transgene-encoded custom RNAs into mitochondria in plants. In the present work, we used this strategy to drive trans-cleaving hammerhead ribozymes into the organelles, to knock down specific mitochondrial RNAs and analyze the regulatory impact. In a similar approach, the tRNA mimic was used to import into mitochondria in Arabidopsis thaliana the orf77, an RNA associated with cytoplasmic male sterility in maize and possessing sequence identities with the atp9 mitochondrial RNA. In both cases, inducible expression of the transgenes allowed to characterise early regulation and signaling responses triggered by these respective manipulations of the organellar transcriptome. The results imply that the mitochondrial transcriptome is tightly controlled by a &ldquo, buffering&rdquo, mechanism at the early and intermediate stages of plant development, a control that is released at later stages. On the other hand, high throughput analyses showed that knocking down a specific mitochondrial mRNA triggered a retrograde signaling and an anterograde nuclear transcriptome response involving a series of transcription factor genes and small RNAs. Our results strongly support transcriptome coordination mechanisms within the organelles and between the organelles and the nucleus.

Published
2019
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8. Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease

Author

Pawel M. Switonski, Ronald M. Evans, Fanny Mochel, Weiwei Fan, Christopher E. Wall, Chenchen Niu, Chizuru Kinoshita, Farid Ichou, Jacqueline M. Ward, Alysson R. Muotri, Albert R. La Spada, Colleen A. Stoyas, Isaac Adanyeguh, Alexandra Durr, Richard S. Morrison, Bryce L. Sopher, Brett Collins, University of California [San Diego] (UC San Diego), University of California, Duke University [Durham], Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Polish Academy of Sciences (PAN), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Blood Glucose, Mitochondrial Diseases, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Purkinje cell, Medical Physiology, Nicotinamide adenine dinucleotide, Mitochondrion, Neurodegenerative, chemistry.chemical_compound, Purkinje Cells, Mice, 0302 clinical medicine, spinocerebellar ataxia, Neural Stem Cells, oxidative metabolism, 2.1 Biological and endogenous factors, Aetiology, lcsh:QH301-705.5, Kynurenine, Tryptophan, 3. Good health, Cell biology, Mitochondria, mitochondria, medicine.anatomical_structure, Phenotype, Adipose Tissue, Neurological, Spinocerebellar ataxia, Stem cell, trinucleotide repeat, Ataxin 7, induced pluripotent stem cells, Mitochondrial disease, mouse model, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Rare Diseases, medicine, Genetics, Animals, Humans, Spinocerebellar Ataxias, Metabolomics, nicotinamide adenine dinucleotide, Organelles, Ataxin-7, Neurosciences, Reproducibility of Results, ataxin-7, medicine.disease, Stem Cell Research, NAD, Brain Disorders, 030104 developmental biology, lcsh:Biology (General), chemistry, biology.protein, NAD+ kinase, Biochemistry and Cell Biology, Peptides, Trinucleotide Repeat Expansion, Energy Metabolism, polyglutamine, 030217 neurology & neurosurgery
Abstract

SUMMARY Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD+) production enzymes in SCA7 models. We observed NAD+ reductions in mitochondria of SCA7 patient NPCs using ratiometric fluorescent sensors and documented alterations in tryptophan-kynurenine metabolism in patients. Our results indicate that mitochondrial dysfunction, stemming from decreased NAD+, is a defining feature of SCA7., Graphical Abstract, In Brief Ward et al. document altered metabolism and mitochondrial dysfunction in SCA7 patients, mice, and human stem cell-derived neurons. They link these abnormalities to reduced nicotinamide adenine dinucleotide in specific subcellular compartments. Given the role of mitochondrial impairment in neurodegeneration, their results have therapeutic implications for SCA7 and related neurological disorders.

Published
2019
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9. RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme

Author

Greggory M. Rice, Dong Zhang, Yi Xiao, François Major, Joseph A. Piccirilli, Thomas H. Mann, Fang-Chieh Chou, Marcin Biesiada, Clarence Yu Cheng, Feng Ding, Arpit Tandon, Dinshaw J. Patel, Kevin M. Weeks, Alexander J. Becka, Joanna Sarzynska, John SantaLucia, Ryszard W. Adamiak, Kalli Kappel, Rhiju Das, Wipapat Kladwang, Zhichao Miao, Michal J. Boniecki, Robert T. Batey, Katarzyna J. Purzycka, Tomasz Zok, Caleb Geniesse, Aiming Ren, Wayne K. Dawson, Maciej Antczak, Janusz M. Bujnicki, Shi-Jie Chen, Andrey Krokhotin, Jian Wang, Katarzyna Pachulska-Wieczorek, Siqi Tian, Nikolay V. Dokholyan, Xiaojun Xu, Marcin Magnus, Grzegorz Łach, Marta Szachniuk, Stanislaw Dunin-Horkawicz, Jeremiah J. Trausch, Eric Westhof, Benfeard Williams, Mariusz Popenda, Adrian R. Ferré-D'Amaré, Department of Ecology [Warsaw], Institute of Zoology [Warsaw], Faculty of Biology [Warsaw], University of Warsaw (UW)-University of Warsaw (UW)-Faculty of Biology [Warsaw], University of Warsaw (UW)-University of Warsaw (UW), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Hangzhou Dianzi University (HDU), Poznan Supercomputing and Networking Center (PSNC), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, 0301 basic medicine, Riboswitch, S-Adenosylmethionine, Glutamine, Aptamer, [SDV]Life Sciences [q-bio], Computational biology, Ligands, Bioinformatics, Article, Nucleic acid secondary structure, 03 medical and health sciences, Endoribonucleases, RNA, Catalytic, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Binding site, Molecular Biology, ComputingMilieux_MISCELLANEOUS, biology, Ribozyme, RNA, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Aptamers, Nucleotide, Ribonucleotides, Aminoimidazole Carboxamide, Small molecule, 030104 developmental biology, Rna structure prediction, biology.protein, Nucleic Acid Conformation, Dinucleoside Phosphates
Abstract

RNA-Puzzles is a collective experiment in blind 3D RNA structure prediction. We report here a third round of RNA-Puzzles. Five puzzles, 4, 8, 12, 13, 14, all structures of riboswitch aptamers and puzzle 7, a ribozyme structure, are included in this round of the experiment. The riboswitch structures include biological binding sites for small molecules (S-adenosyl methionine, cyclic diadenosine monophosphate, 5-amino 4-imidazole carboxamide riboside 5′-triphosphate, glutamine) and proteins (YbxF), and one set describes large conformational changes between ligand-free and ligand-bound states. The Varkud satellite ribozyme is the most recently solved structure of a known large ribozyme. All puzzles have established biological functions and require structural understanding to appreciate their molecular mechanisms. Through the use of fast-track experimental data, including multidimensional chemical mapping, and accurate prediction of RNA secondary structure, a large portion of the contacts in 3D have been predicted correctly leading to similar topologies for the top ranking predictions. Template-based and homology-derived predictions could predict structures to particularly high accuracies. However, achieving biological insights from de novo prediction of RNA 3D structures still depends on the size and complexity of the RNA. Blind computational predictions of RNA structures already appear to provide useful structural information in many cases. Similar to the previous RNA-Puzzles Round II experiment, the prediction of non-Watson–Crick interactions and the observed high atomic clash scores reveal a notable need for an algorithm of improvement. All prediction models and assessment results are available at http://ahsoka.u-strasbg.fr/rnapuzzles/.

Published
2017
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10. Nuclear spin–lattice relaxation and complex motion of macromolecules in solution

Author

L. Latanowicz, Zofia Gdaniec, Faculty of Biological Sciences, University of Zielona Góra, Institute of Bioorganic Chemistry [Poznań], and Polska Akademia Nauk = Polish Academy of Sciences (PAN)

Subjects
010304 chemical physics, Spins, Chemistry, Hydrogen bond, Isotropy, Biophysics, Spectral density, 010402 general chemistry, Condensed Matter Physics, 01 natural sciences, Molecular physics, 0104 chemical sciences, Nuclear magnetic resonance, Intramolecular force, Lattice (order), Physical Sciences, 0103 physical sciences, [PHYS.COND]Physics [physics]/Condensed Matter [cond-mat], Physical and Theoretical Chemistry, Maxima, Anisotropy, Molecular Biology
Abstract

International audience; The NMR spectral densities of a complex motion consisting of combination of anisotropic overall motion and internal motion have been derived. Two approximations of the equations derived for the cases of slow, Jslow(), and fast, Jfast(), internal motions are presented. These equations imply that reduction in spectral density of overall motion can be observed if the maxima of internal and overall motions spectral densities versus temperature are well separated, so for the fast internal motion. Slow intramolecular motion influences the values of spectral densities of the overall motion if one of the two spins performs a motion as for example a proton in double minimum of the 15N-H.....N hydrogen bond. The analysis presented reveals small differences between the temperature dependencies of spectral densities of the isotropic and anisotropic overall motions. The theory is illustrated by the 13C protonated carbon spin-lattice relaxation of -cyclodextrin macromolecule, using the expected motional parameters: DII/D  5 at room temperature and for a fast or slow internal motion.

Published
2011
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11. The genome of the vervet ( Chlorocebus aethiops sabaeus )

Author

Nicoletta Archidiacono, Jennifer F. Hughes, George M. Weinstock, Yoon Jung, Christopher A. Schmitt, Angela Noll, Nelson B. Freimer, Matthew J. Jorgensen, Jennifer J. Tuscher, Nam Tran, Jason M. Brenchley, David H. O’Connor, Matthew W. Hahn, Eugene Redmond, Alex Nisbett, Roland Zahn, Hannes Svardal, Gary P. Schroth, Raquel García-Pérez, Magnus Nordborg, Nikoleta Juretic, Michael J. Montague, Gregg W.C. Thomas, Michel M. Dione, Julie A. Karl, Anna J. Jasinska, Wesley C. Warren, Jay R. Kaplan, Richard K. Wilson, Patrick Minx, Bronwen Aken, Mariano Rocchi, Colby Chiang, Françoise Thibaud-Nissen, Jessica Wasserscheid, Vasily Ramensky, Oi Wa Choi, Gennady Churakov, Roscoe Stanyon, Yu S. Huang, David Webb, Brian J. Raney, Jörn E. Schmitz, Milinn Kremitzki, Beatrice Jacquelin, Michaela Müller-Trutwin, Juergen Schmitz, Rishi Nag, Tomas Marques-Bonet, LaDeana W. Hillier, Martin Antonio, Tina Graves, Trudy R. Turner, Kim Kyung, Ken Dewar, Chad Tomlinson, Roger W. Wiseman, Oronzo Capozzi, The McDonnell Genome Institute (MGI), Washington University in Saint Louis (WUSTL), Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], University of California [Los Angeles] (UCLA), University of California-University of California, Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Institució Catalana de Recerca i Estudis Avançats (ICREA), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Gregor Mendel Institute of Molecular Plant Biology (GMI), Austrian Academy of Sciences (OeAW), University of Bari Aldo Moro (UNIBA), Whitehead Institute, Massachusetts Institute of Technology (MIT), McGill University = Université McGill [Montréal, Canada], University of Wisconsin - Milwaukee, University of the Free State [South Africa], University of Wisconsin-Madison, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Crucell Holland B.V, St. Kitts Biomedical Research Foundation, Régulation des Infections Rétrovirales, Institut Pasteur [Paris], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Medical Research Council Unit The Gambia (MRC), Illumina Incorporated [San Diego, CA, USA], Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Indiana University [Bloomington], Indiana University System, University of California [Santa Cruz] (UCSC), University of California, European Molecular Biology Laboratory [Hinxton], Institute of Experimental Pathology (ZMBE), Westfälische Wilhelms-Universität Münster (WWU), Institute for Evolution and Biodiversity (IEB), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), National Center for Biotechnology Information (NCBI), The Jackson Laboratory [Bar Harbor] (JAX), Funding to R.K.W. was provided by NIH-NHGRI grant 5U54HG00307907. Support for the Vervet Research Colony was provided by NIH grant RR019963/OD010965 to J.R.K. Funding to N.B.F. was provided by NIH grants R01RR016300 and R01OD010980. The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) provided funding to M.C.M.-T. Funding to M.R. and R.S. was provided by the Ministero della Universita’ e della Ricerca. Funding to K.D. was provided by Genome Canada and Genome Quebec. B.A. and R.N. acknowledge support from the Wellcome Trust (grant number WT095908) and the European Molecular Biology Laboratory., We thank the following organizations for providing sampling permits and permissions: Ethiopian Wildlife Conservation Authority, Zambia Wildlife Authority, Wildlife Division, Forestry Commission, Republic of Ghana, and Gambia Department of Parks and Wildlife Management. We thank Dr. James L. Blanchard and Dr. Ivona Pandrea for vervet samples used to characterize MHC. We thank Josh McMichael and Josh Peck for figure assistance. We thank Joanne Nelson and Barbara Gillam for data submission. We thank the members of the library production group led by Catrina Fronick and sequencing led by Matt Cordes. We also thank the Medical Research Council Unit (MRC), The Gambia for their assistance, as well as all the veterinarians who worked with us to safely obtain samples., National Institutes of Health (US), National Human Genome Research Institute (US), Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), Agence Nationale de la Recherche (France), Ministero dell'Istruzione, dell'Università e della Ricerca, Genome Canada, EMBO, Wellcome Trust, University of California (UC)-University of California (UC), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), University of the Free State [South Africa] (UFS), Institut Pasteur [Paris] (IP), University of California [Santa Cruz] (UC Santa Cruz), University of California (UC), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), and Università degli Studi di Firenze = University of Florence (UniFI)

Subjects
animal diseases, [SDV]Life Sciences [q-bio], Chlorocebus aethiops, Cercopithecus aethiops, Medical and Health Sciences, Major Histocompatibility Complex, MESH: Animals, MESH: Genetic Variation, MESH: Phylogeny, Genetics (clinical), Phylogeny, MESH: Evolution, Molecular, Gene Rearrangement, education.field_of_study, Cercopithecini, Genome, biology, MESH: Genomics, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], MESH: Karyotype, Genomics, Biological Sciences, 3. Good health, Rhesus macaque, Phylogeography, MESH: Phylogeography, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDE]Environmental Sciences, Complete Genome assembly, primates, cercopithecini, Infection, Biotechnology, MESH: Computational Biology, Resource, Evolution, Bioinformatics, MESH: Gene Rearrangement, Population, Karyotype, Simis, Old World monkey, MESH: Molecular Sequence Annotation, [SDV.BID]Life Sciences [q-bio]/Biodiversity, Chromosome Painting, Evolution, Molecular, MESH: Major Histocompatibility Complex, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], parasitic diseases, Genetics, Animals, MESH: Genome, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genètica animal, MESH: Chromosome Painting, Human Genome, Molecular, Computational Biology, Genetic Variation, Molecular Sequence Annotation, Gene rearrangement, biology.organism_classification, MESH: Cercopithecus aethiops, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Evolutionary biology, African Green Monkey
Abstract

Warren, Wesley C. et al., We describe a genome reference of the African green monkey or vervet (Chlorocebus aethiops). This member of the Old World monkey (OWM) superfamily is uniquely valuable for genetic investigations of simian immunodeficiency virus (SIV), for which it is the most abundant natural host species, and of a wide range of health-related phenotypes assessed in Caribbean vervets (C. a. sabaeus), whose numbers have expanded dramatically since Europeans introduced small numbers of their ancestors from West Africa during the colonial era. We use the reference to characterize the genomic relationship between vervets and other primates, the intra-generic phylogeny of vervet subspecies, and genome-wide structural variations of a pedigreed C. a. sabaeus population. Through comparative analyses with human and rhesus macaque, we characterize at high resolution the unique chromosomal fission events that differentiate the vervets and their close relatives from most other catarrhine primates, in whom karyotype is highly conserved. We also provide a summary of transposable elements and contrast these with the rhesus macaque and human. Analysis of sequenced genomes representing each of the main vervet subspecies supports previously hypothesized relationships between these populations, which range across most of sub-Saharan Africa, while uncovering high levels of genetic diversity within each. Sequence-based analyses of major histocompatibility complex (MHC) polymorphisms reveal extremely low diversity in Caribbean C. a. sabaeus vervets, compared to vervets from putatively ancestral West African regions. In the C. a. sabaeus research population, we discover the first structural variations that are, in some cases, predicted to have a deleterious effect; future studies will determine the phenotypic impact of these variations., Funding to R.K.W. was provided by NIH-NHGRI grant 5U54HG00307907. Support for the Vervet Research Colony was provided by NIH grant RR019963/OD010965 to J.R.K. Funding to N.B.F. was provided by NIH grants R01RR016300 and R01OD010980. The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) provided funding to M.C.M.-T. Funding to M.R. and R.S. was provided by the Ministero della Universita’ e della Ricerca. Funding to K.D. was provided by Genome Canada and Genome Quebec. B.A. and R.N. acknowledge support from the Wellcome Trust (grant number WT095908) and the European Molecular Biology Laboratory.

Published
2015
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12. New perspectives in scheduling theory

Author

Denis Trystram, Erwin Pesch, Guochuan Zhang, Jacek Blazewicz, Institute of Computing Science [Poznan], Poznan University of Technology (PUT), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Faculty of Economics and Business Administration (RSBE), Universität Siegen [Siegen], PrograMming and scheduling design fOr Applications in Interactive Simulation (MOAIS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), College of Computer Science [Hangzhou] (HDU), Hangzhou Dianzi University (HDU), Laboratoire d'Informatique de Grenoble (LIG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), and Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Supply chain management, Computer science, General Engineering, Scheduling (production processes), Management Science and Operations Research, computer.software_genre, Industrial engineering, Variety (cybernetics), Set (abstract data type), Production planning, Grid computing, Artificial Intelligence, State (computer science), [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Heuristics, computer, Software, ComputingMilieux_MISCELLANEOUS
Abstract

Traditionally,machine scheduling research is concernedwith the sequencing of tasks on one machine or on several parallel or different machines, subject to a set of constraints. Over the years, researchers have studied a huge variety of problems, developing numerous heuristics, approximation and exact algorithms, and complexity results. Some of these problems are interesting because of their intractability. Others are interesting because of their applications in production planning, personnel planning, scheduling in parallel and distributed systems, etc. For the most recent introduction to the state of the art, see Blazewicz et al. (2007). In recent years, researchers have begun studying the scheduling problems derived from new applications and settings. For example, there are scheduling problems in decentralized systems and selfish organizations, grid computing

Published
2015
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13. Distinctive structural motifs of RNA G-quadruplexes composed of AGG, CGG and UGG trinucleotide repeats

Author

Zofia Gdaniec, Ryszard Kierzek, Magdalena Malgowska, Dorota Gudanis, Valérie Gabelica, Eliza Wyszko, Gabelica, Valérie, Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Laboratoire de spectrométrie de masse, Université de Liège-Groupe Interdisciplinaire de Génoprotéomique Appliquée-Département de Chimie, ARN : régulations naturelle et artificielle, Université Bordeaux Segalen - Bordeaux 2-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM), National Science Center [N N301 707040 to Z.G., UMO-2013/08/A/ST5/00295, UMO-2011/03/B/NZ1/00576and UMO-2011/0/B/ST5/011098 to R.K.], Ministry of Science and Higher Education [N N301 255536 to Z.G.], Ministry of Science and Higher Education, European Fund for Regional Development [UDA-POIG.02.01.00–30–182/09 to Z.G.], EU COST action MP0802 [STSM n◦11227 to M.M.], and Fonds de la Recherche Scientifique-FNRS [research associate position and FRFC grant 2.4528.11 to V.G.]

Subjects
Circular dichroism, RNA Folding, Stereochemistry, Electrospray ionization, Biology, 010402 general chemistry, G-quadruplex, 01 natural sciences, 03 medical and health sciences, Trinucleotide Repeats, Structural Biology, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecule, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Structural motif, Gene, 030304 developmental biology, 0303 health sciences, RNA, Molecular biology, 0104 chemical sciences, NMR spectra database, G-Quadruplexes, HeLa Cells
Abstract

Trinucleotide repeats are microsatellite sequences that are polymorphic in length. Their expansion in specific genes underlies a number of neurodegenerative disorders. Using ultraviolet-visible, circular dichroism, nuclear magnetic resonance (NMR) spectroscopies and electrospray ionization mass spectrometry, the structural preferences of RNA molecules composed of two and four repeats of AGG, CGG and UGG in the presence of K+, Na+ and NH4+ were analysed. (AGG)2A, (AGG)4A, p(UGG)2U and p(UGG)4U strongly prefer folding into G-quadruplexes, whereas CGG-containing sequences can adopt different types of structure depending on the cation and on the number of repeats. In particular, the two-repeat CGG sequence folds into a G-quadruplex in potassium buffer. We also found that each G-quadruplex fold is different: A:(G:G:G:G)A hexads were found for (AGG)2A, whereas mixed G:C:G:C tetrads and U-tetrads were observed in the NMR spectra of G(CGG)2C and p(UGG)2U, respectively. Finally, our NMR study highlights the influence of the strand sequence on the structure formed, and the influence of the intracellular environment on the folding. Importantly, we highlight that although potassium ions are prevalent in cells, the structures observed in the HeLa cell extract are not always the same as those prevailing in biophysical studies in the presence of K+ ions.

Published
2014
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14. Mitotic B-type cyclins are differentially regulated by phytohormones and during yellow lupine nodule development

Author

Joanna Jeleńska, Eva Kondorosi, Joanna Deckert, Andrzej B. Legocki, Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Laboratory of Plant Ecophysiology, Adam Mickiewicz University in Poznań (UAM), Institut des sciences du végétal (ISV), and Centre National de la Recherche Scientifique (CNRS)

Subjects
0106 biological sciences, Plant Science, Biology, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Auxin, Botany, Gene expression, Genetics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Gene, Mitosis, 030304 developmental biology, Cyclin, chemistry.chemical_classification, 0303 health sciences, food and beverages, General Medicine, Meristem, Cell cycle, Cell biology, chemistry, Cytokinin, Agronomy and Crop Science, 010606 plant biology & botany
Abstract

The progression of cell cycle in eukaryotes is controlled by protein complexes composed of p34 protein kinase and cyclin subunits. Recently, we have described four B1 type mitotic cyclin in yellow lupine. The presence of several closely related cyclin genes within the same plant species raised the question about tissue specificity of respective cyclins or their different regulations by plant-specific signals. Therefore, we examined the expression pattern of four B1 cyclins in various lupine tissues, with special emphasis put on developing root nodules. We also studied the effect of phytohormones on the level of respective cyclin mRNAs. As expected, cyclin transcript accumulation was restricted to proliferating tissues. Detailed analysis by reverse transcription-PCR and using primers specific to each cyclin allow to establish that different genes are engaged in cell divisions of various meristematic tissues. All four genes were activated during nodule development, however, the Cyc3 and Cyc4 genes mostly at the early stages of nodulation, whereas the Cyc1 and Cyc2 genes within the mature nodule organs. The expression of cyclins was regulated differently by plant growth factors. Both auxin and cytokinin induced the Cyc1 and Cyc4 genes and their transcript level was also abundant within the root, shoot and floral meristems. The precise localisation of cyclin transcripts by in situ hybridisation revealed that lupine nodule meristem was active during the whole process of nodule development, even in old organs. © 2000 Elsevier Science Ireland Ltd. All rights reserved.

Published
2000
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15. Novel dual discounting functions for the Internet shopping optimization problem: new algorithms

Author

Pierre-François Dutot, Denis Trystram, Jedrzej Musial, Jacek Blazewicz, Nathanaël Cheriere, Institute of Computing Science [Poznan], Poznan University of Technology (PUT), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), PrograMming and scheduling design fOr Applications in Interactive Simulation (MOAIS), Laboratoire d'Informatique de Grenoble (LIG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), and Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Optimization, Mathematical optimization, Optimization problem, Computational complexity theory, Computer science, 02 engineering and technology, Management Science and Operations Research, Scheduling (computing), Artificial Intelligence, 020204 information systems, Discrete optimization, 0202 electrical engineering, electronic engineering, information engineering, Engineering(all), Discounting, Supply chain management, business.industry, General Engineering, Facility location problem, Computational complexity, Internet shopping, Applications, 020201 artificial intelligence & image processing, The Internet, [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], business, Algorithm, Software, Algorithms
Abstract

International audience; One of the very important topics in discrete optimization, motivated by practical applications, is Internet shopping, which is becoming increasingly popular each year. More classical versions of the Internet shopping optimization problem (ISOP) are closely related to the facility location problem and some scheduling problems and have been intensively studied in the literature. In this paper, extensions of the problem are defined and studied. The issue is to buy all the necessary products for a minimum total possible price. This includes all prices of products as well as shipping costs. Studies in this paper include the ISOP with price sensitive discounts and a newly defined optimization problem: the ISOP including two different discounting functions, namely a shipping cost function as well as a price discounting function. First, these are formulated as mathematical programming problems. Then, some algorithms are constructed and extensively tested in a computational experiment.

Published
2014
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16. Dual Discounting Functions for Internet Shopping Optimization Problem

Author

Blazewicz, Jacek, Bouvry, Pascal, Musial, Jedrzej, Pecero, Johnatan, Trystram, Denis, Institute of Computing Science [Poznan], Poznan University of Technology (PUT), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Computer Science and Communications Research Unit [Luxembourg] (CSC), Laboratory of Advanced Software SYstems [Luxembourg] (LASSY), Université du Luxembourg (Uni.lu)-Université du Luxembourg (Uni.lu), Laboratoire d'Informatique de Grenoble (LIG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), PrograMming and scheduling design fOr Applications in Interactive Simulation (MOAIS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], ComputingMilieux_MISCELLANEOUS
Abstract

International audience; no abstract

Published
2013

17. Preemptive scheduling of independent tasks on multi-cores with GPU

Author

Blazewicz, Jacek, Kedad-Sidhoum, Safia, Monna, Florence, Mounié, Grégory, Trystram, Denis, Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Institute of Computing Science [Poznan], Poznan University of Technology (PUT), Recherche Opérationnelle (RO), Laboratoire d'Informatique de Paris 6 (LIP6), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), PrograMming and scheduling design fOr Applications in Interactive Simulation (MOAIS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire d'Informatique de Grenoble (LIG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], ComputingMilieux_MISCELLANEOUS
Abstract

International audience; no abstract

Published
2013

18. Guest editorial: special issue of the workshop 'New trends in scheduling', Frejus sept. 2010

Author

Bender, Michael, Blazewicz, Jacek, Pesch, Erwin, Trystram, Denis, Zhang, Guochuan, Physique théorique (THEORIE), Centre d'Etudes Nucléaires de Bordeaux Gradignan (CENBG), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Institute of Computing Science [Poznan], Poznan University of Technology (PUT), Faculty of Economics and Business Administration (RSBE), Universität Siegen [Siegen], Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), PrograMming and scheduling design fOr Applications in Interactive Simulation (MOAIS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), College of Computer Science [Hangzhou] (HDU), Hangzhou Dianzi University (HDU), Bender, Michael and Blazewicz, Jacek and Pesch, Erwin and Trystram, Denis and Zhang, and Guochuan

Subjects
[INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], ComputingMilieux_MISCELLANEOUS
Abstract

International audience; no abstract

Published
2013

19. Guest editorial for the special issue 'New challenges in scheduling theory'

Author

Bender, Michael, Blazewicz, Jacek, Pesch, Erwin, Trystram, Denis, Zhang, Guochuan, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Institute of Computing Science [Poznan], Poznan University of Technology (PUT), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Faculty of Economics and Business Administration (RSBE), Universität Siegen [Siegen], PrograMming and scheduling design fOr Applications in Interactive Simulation (MOAIS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), College of Computer Science [Hangzhou] (HDU), Hangzhou Dianzi University (HDU), Bender, Michael and Blazewicz, Jacek and Pesch, Erwin and Trystram, Denis and Zhang, Guochuan, Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire d'Informatique de Grenoble (LIG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Inria Grenoble - Rhône-Alpes, and Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)

Subjects
[INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2010
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20. EFFECT OF THE FREQUENCY OF INTRAMOLECULAR MOTIONS ON THE NMR RELAXATION IN LIQUID STATE TEMPERATURE REGIME

Author

L. Latanowicz, Zofia Gdaniec, Faculty of Biological Sciences, University of Zielona Góra, Institute of Bioorganic Chemistry [Poznań], and Polska Akademia Nauk = Polish Academy of Sciences (PAN)

Subjects
010304 chemical physics, Proton, Isotropy, Relaxation (NMR), Biophysics, 010402 general chemistry, Condensed Matter Physics, Rotation, 01 natural sciences, Molecular physics, 0104 chemical sciences, chemistry.chemical_compound, Nuclear magnetic resonance, chemistry, Intramolecular force, 0103 physical sciences, Physical Sciences, Physical and Theoretical Chemistry, Anisotropy, Molecular Biology, Methyl group, Spin-½
Abstract

International audience; Equations for the spectral densities of complex motion of a spin pair undergoing internal motion and isotropic/anisotropic overall rotation have been considered. The fluctuations of the interproton distances, caused by internal motion, have been taken into account in the theoretical equations. A method allowing a distinction between the isotropic and the anisotropic overall rotation of molecules has been proposed. The effect of the activation parameters of internal motions (known from the solid state study) on the measured T1 relaxation of the 13C and 1H - 1H cross-relaxation rates has been analysed for methyl-β-D-galactopyranoside in DMSO-d6 solution. The conformational trans-gauche jumps of the methylene group are not fast enough to affect the T1 value of carbon C6 in the liquid state temperatures regime. Only the methyl group rotation is a very fast internal motion. This motion influences the carbon C7 relaxation and methyl protons - anomeric proton cross - relaxation. The values of interatomic distances between anomeric H(C1) and H(C5) as well as the three methyl protons H(C7) have been calculated from the cross-relaxation rates. The distance H(C1) - H (C7) fluctuates due to the rotation of methyl group. The application of the "model - free approach" to study molecular dynamics in solutions is discussed.

Published
2009
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21. Conformations of flanking bases in HIV-1 RNA DIS kissing complexes studied by molecular dynamics

Author

Petr Kulhánek, Jiří Šponer, Tadeusz Kulinski, Joanna Sarzynska, Eric Ennifar, Kamila Réblová, Jaroslav Koča, Eva Fadrná, Institute of Biophysics, Czech Academy of Sciences [Prague] (CAS), National Centre for Biomolecular Research, Masaryk University [Brno] (MUNI), Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Czech Academy of Sciences [Prague] (ASCR), Masaryk University, and Polska Akademia Nauk (PAN)

Subjects
Models, Molecular, Base pair, Stereochemistry, Biophysics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 01 natural sciences, Hiv 1 rna, 03 medical and health sciences, Molecular dynamics, Flanking maneuver, Large ribosomal subunit, Nucleic Acids, 0103 physical sciences, Computer Simulation, Binding site, Base Pairing, 030304 developmental biology, 0303 health sciences, Binding Sites, 010304 chemical physics, Chemistry, RNA, Crystallography, Haloarcula marismortui, Models, Chemical, HIV-1, Nucleic Acid Conformation, RNA, Viral, Transcription Initiation Site, Dimerization
Abstract

International audience; Explicit solvent molecular dynamics simulations (in total almost 800 ns including locally enhanced sampling runs) were applied with different ion conditions and with two force fields (AMBER and CHARMM) to characterize typical geometries adopted by the flanking bases in the RNA kissing-loop complexes. We focus on flanking base positions in multiple x-ray and NMR structures of HIV-1 DIS kissing complexes and kissing complex from the large ribosomal subunit of Haloarcula marismortui. An initial x-ray open conformation of bulged-out bases in HIV-1 DIS complexes, affected by crystal packing, tends to convert to a closed conformation formed by consecutive stretch of four stacked purine bases. This is in agreement with those recent crystals where the packing is essentially avoided. We also observed variants of the closed conformation with three stacked bases, while nonnegligible populations of stacked geometries with bulged-in bases were detected, too. The simulation results reconcile differences in positions of the flanking bases observed in x-ray and NMR studies. Our results suggest that bulged-out geometries are somewhat more preferred, which is in accord with recent experiments showing that they may mediate tertiary contacts in biomolecular assemblies or allow binding of aminoglycoside antibiotics.

Published
2007
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22. Lupine leghemoglobin I: Expression in transgenic Lotus and tobacco tissues

Author

Wojciech M. Karlowski, Andrzej B. Legocki, Pawel M. Strozycki, Annik Petit, Yves Dessaux, Institute of Bioorganic Chemistry [Poznań], Polska Akademia Nauk = Polish Academy of Sciences (PAN), Institut des sciences du végétal (ISV), and Centre National de la Recherche Scientifique (CNRS)

Subjects
0106 biological sciences, MESH: Sequence Homology, Amino Acid, Lotus, GUS reporter system, Genetically modified crops, MESH: Base Sequence, 01 natural sciences, Hemoglobins, Glucuronic Acid, MESH: Reverse Transcriptase Polymerase Chain Reaction, Lotus corniculatus, MESH: Tobacco, MESH: Phylogeny, Promoter Regions, Genetic, Phylogeny, 0303 health sciences, MESH: Leghemoglobin, Reverse Transcriptase Polymerase Chain Reaction, food and beverages, Plants, Genetically Modified, Leghemoglobin, MESH: Promoter Regions (Genetics), MESH: Hemoglobins, Biochemistry, MESH: Glucuronic Acid, MESH: Plants, Toxic, DNA, Complementary, Transgene, Molecular Sequence Data, MESH: Transformation, Genetic, Biology, MESH: Sequence Homology, Nucleic Acid, 03 medical and health sciences, Transformation, Genetic, Sequence Homology, Nucleic Acid, Tobacco, Genetics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Molecular Biology, Gene, 030304 developmental biology, MESH: Molecular Sequence Data, Base Sequence, Sequence Homology, Amino Acid, Promoter, MESH: DNA, Complementary, biology.organism_classification, Plants, Toxic, MESH: Plants, Genetically Modified, 010606 plant biology & botany
Abstract

The proximal parts of the promoters of the genes for symbiotic-type hemoglobins are generally conserved, but the promoter of the lbI gene of lupine (LulbI) shows some unusual structural features. It lacks typical organ-specific elements characteristic of all the leghemoglobin gene promoters described thus far. We have analysed its functional activity in transgenic Lotus corniculatus. A fusion construct between the lbI promoter and the GUS reporter gene was expressed mainly in the central zone of the root nodule, but the product was also detected in the non-nodule root zone and in roots in tissue culture. In roots of transgenic tobacco, the activity of the promoter was only 24% lower than in Lotus nodules. LulbI promoter activity was also detected in tobacco leaves. Lupine hemoglobin I has a higher sequence identity to symbiotic-type hemoglobins and thus it groups within the "Class II" hemoglobins.

23. Homocysteine thiolactone contributes to the prognostic value of fibrin clot structure/function in coronary artery disease.

Author

Sikora M, Skrzydlewski P, Perła-Kaján J, and Jakubowski H

Subjects
Humans, Fibrin metabolism, Prognosis, Vitamin B 12, Folic Acid, Homocysteine, Risk Factors, Coronary Artery Disease, Vitamin B Complex, Myocardial Infarction drug therapy, Thrombosis drug therapy
Abstract

Fibrin clot structure/function contributes to cardiovascular disease. We examined sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Absmax) in relation to outcomes in coronary artery disease (CAD) patients. Effects of B-vitamin/folate therapy on CLT and Absmax were studied. Plasma samples were collected from 1,952 CAD patients randomized in a 2 x 2 factorial design to (i) folic acid, vitamins B12, B6; (ii) folic acid, vitamin B12; (iii) vitamin B6; (iv) placebo for 3.8 years in the Western Norway B-Vitamin Intervention Trial. Clot lysis time (CLT) and maximum absorbance (Absmax) were determined using a validated turbidimetric assay. Acute myocardial infarction (AMI) and mortality were assessed during a 7-year follow-up. Data were analyzed using bivariate and multiple regression. Survival free of events was studied using Kaplan Mayer plots. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Baseline urinary homocysteine (uHcy)-thiolactone and plasma cysteine (Cys) were significantly associated with CLT while plasma total Hcy was significantly associated with Absmax, independently of fibrinogen, triglycerides, vitamin E, glomerular filtration rate, body mass index, age, sex plasma creatinine, CRP, HDL-C, ApoA1, and previous diseases. B-vitamins/folate did not affect CLT and Absmax. Kaplan-Meier analysis showed associations of increased baseline CLT and Absmax with worse outcomes. In Cox regression analysis, baseline CLT and Absmax (>cutoff) predicted AMI (CLT: HR 1.58, 95% CI 1.10-2.28; P = 0.013. Absmax: HR 3.22, CI 1.19-8.69; P = 0.021) and mortality (CLT: HR 2.54, 95% CI 1.40-4.63; P = 0.002. Absmax: 2.39, 95% CI 1.17-4.92; P = 0.017). After adjustments for other prognostic biomarkers these associations remained significant. Cys and uHcy-thiolactone, but not tHcy, were significant predictors of AMI in Cox regression models that included CLT. Conclusions uHcy-thiolactone and plasma Cys are novel determinants of CLT, an important predictor of adverse CAD outcomes. CLT and Absmax were not affected by B-vitamin/folate therapy, which could account for the lack of efficacy of such therapy in CAD. Trial registration: URL: http://clinicaltrials.gov. Identifier: NCT00354081., Competing Interests: The authors have declared that no competing interests exist.

Published
2022
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24. Cystathionine β-synthase gene inactivation dysregulates major urinary protein biogenesis and impairs sexual signaling in mice.

Author

Bretes E, Wróblewski J, Wyszczelska-Rokiel M, and Jakubowski H

Subjects
Animals, Cystathionine beta-Synthase genetics, Cystathionine beta-Synthase metabolism, DNA Repair Enzymes genetics, Female, Gene Silencing, Male, Mice, Poly-ADP-Ribose Binding Proteins genetics, Proteins metabolism, DNA Repair Enzymes metabolism, Poly-ADP-Ribose Binding Proteins metabolism, Protein Biosynthesis
Abstract

Reproductive success in mice depends on sexually dimorphic major urinary proteins (Mup) that facilitate interactions between females and males. Deletion of cystathionine β-synthase (Cbs) gene, a metabolic gene important for homeostasis of one-carbon metabolism, impairs reproduction by causing female infertility in mice. Here, we examined Mup biogenesis and sexual signaling in Cbs -/- versus Cbs +/- mice. We found significantly reduced levels of total urinary Mup protein in male and female Cbs -/- versus Cbs +/- mice. SDS-PAGE/Western blot, ESI-MS, and RT-qPCR analyses of the liver, plasma, and urinary proteins identified a male-specific Mup20 in Cbs -/- , but not in Cbs +/- females. The 18 893 Da Mup20 became the most abundant in urine of Cbs -/- females and males. Effects of Cbs genotype on 18 645 Da, 18 693 Da, and 18 709 Da Mup species abundance were Mup- and sex-specific. Cbs genotype-dependent changes in hepatic Mups and Mup20 expression were similar at the protein and mRNA level. Changes in Mups, but not in Mup20, can be explained by downregulation of hepatic Zhx2 and Ghr receptors in Cbs -/- mice. Behavioral testing showed that Cbs +/- females ignored Cbs -/- male urine but were attracted to Cbs +/- male urine. Cbs +/- males ignored urine of Cbs -/- males but countermarked urine of other Cbs +/- males and were attracted to urines of Cbs -/- as well as Cbs +/- females. Cbs -/- males did not countermark urine of Cbs +/- males but were attracted to urines of Cbs +/- females. Taken together, these findings show that Cbs, a metabolic gene, interacts with the processes involved in Mup biogenesis that are essential for the maintenance of sexual dimorphism and signaling and suggest that dysregulation of these interactions impairs reproductive fitness in mice., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Published
2022
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25. Identification of an Isoflavonoid Transporter Required for the Nodule Establishment of the Rhizobium - Fabaceae Symbiotic Interaction.

Author

Biała-Leonhard W, Zanin L, Gottardi S, de Brito Francisco R, Venuti S, Valentinuzzi F, Mimmo T, Cesco S, Bassin B, Martinoia E, Pinton R, Jasiński M, and Tomasi N

Abstract

Nitrogen (N) as well as Phosphorus (P) are key nutrients determining crop productivity. Legumes have developed strategies to overcome nutrient limitation by, for example, forming a symbiotic relationship with N-fixing rhizobia and the release of P-mobilizing exudates and are thus able to grow without supply of N or P fertilizers. The legume-rhizobial symbiosis starts with root release of isoflavonoids that act as signaling molecules perceived by compatible bacteria. Subsequently, bacteria release nod factors, which induce signaling cascades allowing the formation of functional N-fixing nodules. We report here the identification and functional characterization of a plasma membrane-localized MATE-type transporter (LaMATE2) involved in the release of genistein from white lupin roots. The LaMATE2 expression in the root is upregulated under N deficiency as well as low phosphate availability, two nutritional deficiencies that induce the release of this isoflavonoid. LaMATE2 silencing reduced genistein efflux and even more the formation of symbiotic nodules, supporting the crucial role of LaMATE2 in isoflavonoid release and nodulation. Furthermore, silencing of LaMATE2 limited the P-solubilization activity of lupin root exudates. Transport assays in yeast vesicles demonstrated that LaMATE2 acts as a proton-driven isoflavonoid transporter., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Biała-Leonhard, Zanin, Gottardi, de Brito Francisco, Venuti, Valentinuzzi, Mimmo, Cesco, Bassin, Martinoia, Pinton, Jasiński and Tomasi.)

Published
2021
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26. ENHO, RXRA, and LXRA polymorphisms and dyslipidaemia, related comorbidities and survival in haemodialysis patients.

Author

Grzegorzewska AE, Niepolski L, Świderska MK, Mostowska A, Stolarek I, Warchoł W, Figlerowicz M, and Jagodziński PP

Subjects
Adipogenesis genetics, Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Blood Proteins immunology, Cholesterol, HDL blood, Cholesterol, LDL blood, Comorbidity, Cross-Sectional Studies, Dyslipidemias immunology, Dyslipidemias mortality, Dyslipidemias therapy, Epistasis, Genetic, Female, Genotype, Humans, Intercellular Signaling Peptides and Proteins, Interleukin-12 Subunit p40 genetics, Interleukin-12 Subunit p40 immunology, Interleukin-18 genetics, Interleukin-18 immunology, Kaplan-Meier Estimate, Liver X Receptors immunology, Male, Middle Aged, Myocardial Infarction immunology, Myocardial Infarction mortality, Myocardial Infarction therapy, Peptides immunology, Renal Insufficiency, Chronic immunology, Renal Insufficiency, Chronic mortality, Renal Insufficiency, Chronic therapy, Retinoid X Receptor alpha immunology, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer pathology, Triglycerides blood, Blood Proteins genetics, Dyslipidemias genetics, Liver X Receptors genetics, Myocardial Infarction genetics, Peptides genetics, Polymorphism, Single Nucleotide, Renal Dialysis, Renal Insufficiency, Chronic genetics, Retinoid X Receptor alpha genetics
Abstract

Background: The energy homeostasis-associated gene (ENHO), retinoid X receptor alpha gene (RXRA), and liver X receptor alpha gene (LXRA) are involved in adipogenic/lipogenic regulation. We investigated whether single-nucleotide polymorphisms in these genes (ENHO rs2281997, rs72735260; RXRA rs749759, rs10776909, rs10881578; LXRA rs2279238, rs7120118, rs11039155) are associated with dyslipidaemia, related comorbidities and survival of haemodialysis (HD) patients also tested for T-helper (Th) cell interleukin genes (IL)., Methods: The study was carried out in 873 HD patients. Dyslipidaemia was diagnosed by the recommendations of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines (2003); atherogenic dyslipidaemia was referred to if the TG/HDL cholesterol ratio was equal to or higher than 3.8. Genotyping of ENHO SNPs, LXRA SNPs, and IL12A rs568408 was carried out using HRM analysis. RXRA SNPs, IL12B rs3212227, and IL18 rs360719 were genotyped using PCR-RFLP analysis. The circulating adropin concentration was determined in 126 patients by enzyme-linked immunosorbent assay. Survival probability was analysed using the Kaplan-Meier method in 440 patients followed through 7.5 years., Results: Dyslipidaemia by K/DOQI was diagnosed in 459 patients (91% revealed hyper-LDL- cholesterolaemia), atherogenic dyslipidaemia was diagnosed in 454 patients, and 231 patients were free of dyslipidaemia by both criteria. The variant allele (T) of ENHO rs2281997 was associated with the hyper-LDL cholesterolaemic pattern of dyslipidaemia by K/DOQI. The frequency of atherogenic dyslipidaemia was lower in T-allele bearers than in CC-genotype patients. The rs2281997 T allele was associated with lower cardiovascular mortality in HD patients showing atherogenic dyslipidaemia. ENHO, RXRA, and LXRA showed epistatic interactions in dyslipidaemia. Circulating adropin was lower in atherogenic dyslipidaemia than in non-atherogenic conditions. RXRA rs10776909 was associated with myocardial infarction. Bearers of LXRA rs2279238, rs7120118 or rs11039155 minor alleles showed higher mortality. ENHO SNP positions fell within the same DNase 1 hypersensitivity site expressed in the Th1 cell line. Epistatic interactions occurred between rs2281997 and Th1 IL SNPs (rs360719, rs568408)., Conclusions: Atherogenic dyslipidaemia occurs in HD patients in whom ENHO encodes less adropin. ENHO, RXRA, and LXRA SNPs, separately or jointly, are associated with dyslipidaemia, myocardial infarction, and survival in HD patients. Differences in the availability of transcription binding sites may contribute to these associations.

Published
2018
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27. The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice.

Author

Khayati K, Antikainen H, Bonder EM, Weber GF, Kruger WD, Jakubowski H, and Dobrowolski R

Subjects
Animals, Cell Line, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Multiprotein Complexes genetics, TOR Serine-Threonine Kinases genetics, Autophagy physiology, Gene Expression Regulation physiology, Homocysteine metabolism, Multiprotein Complexes metabolism, Neurons metabolism, TOR Serine-Threonine Kinases metabolism
Abstract

The molecular mechanisms leading to and responsible for age-related, sporadic Alzheimer's disease (AD) remain largely unknown. It is well documented that aging patients with elevated levels of the amino acid metabolite homocysteine (Hcy) are at high risk of developing AD. We investigated the impact of Hcy on molecular clearance pathways in mammalian cells, including in vitro cultured induced pluripotent stem cell-derived forebrain neurons and in vivo neurons in mouse brains. Exposure to Hcy resulted in up-regulation of the mechanistic target of rapamycin complex 1 (mTORC1) activity, one of the major kinases in cells that is tightly linked to anabolic and catabolic pathways. Hcy is sensed by a constitutive protein complex composed of leucyl-tRNA-synthetase and folliculin, which regulates mTOR tethering to lysosomal membranes. In hyperhomocysteinemic human cells and cystathionine β-synthase-deficient mouse brains, we find an acute and chronic inhibition of the molecular clearance of protein products resulting in a buildup of abnormal proteins, including β-amyloid and phospho-Tau. Formation of these protein aggregates leads to AD-like neurodegeneration. This pathology can be prevented by inhibition of mTORC1 or by induction of autophagy. We conclude that an increase of intracellular Hcy levels predisposes neurons to develop abnormal protein aggregates, which are hallmarks of AD and its associated onset and pathophysiology with age.-Khayati, K., Antikainen, H., Bonder, E. M., Weber, G. F., Kruger, W. D., Jakubowski, H., Dobrowolski, R. The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice., (© FASEB.)

Published
2017
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28. Panel of serum metabolites discriminates cancer patients and healthy participants of lung cancer screening - a pilot study.

Author

Roś-Mazurczyk M, Wojakowska A, Marczak Ł, Polański K, Pietrowska M, Polanska J, Dziadziuszko R, Jassem J, Rzyman W, and Widlak P

Subjects
Aged, Case-Control Studies, Female, Gas Chromatography-Mass Spectrometry, Healthy Volunteers, Humans, Lung Neoplasms diagnostic imaging, Male, Middle Aged, Pilot Projects, ROC Curve, Sensitivity and Specificity, Tomography, X-Ray Computed, Biomarkers, Tumor blood, Lung Neoplasms blood, Metabolome
Abstract

Introduction: Blood biomarkers may support early diagnosis of lung cancer by enabling pre-selection of candidates for computed tomography screening or discrimination between benign and malignant screening-detected nodules. We aimed to identify features of serum metabolome distinguishing individuals with early-detected lung cancer from healthy participants of the lung cancer screening program., Methods: Blood samples were collected in the course of a low-dose computed tomography screening program performed in the Gdansk district (Northern Poland). The analysis included 31 patients with screening-detected lung cancer and the pair-matched group of 92 healthy controls. The gas chromatography coupled to mass spectrometry (GC/MS) approach was used to identify and quantify small metabolites present in serum., Results: There were several metabolites detected in the sera whose abundances discriminated patients with lung cancer from controls. Majority of the differentiating components were downregulated in cancer samples, including amino acids, carboxylic acids and tocopherols, whereas benzaldehyde was the only compound significantly upregulated. A classifier including nine serum metabolites allowed separation of cancer and control samples with 100% sensitivity and 95% specificity., Conclusions: Signature of serum metabolites discriminating between cancer patients and healthy participants of the early lung cancer screening program was identified using a GC/MS metabolomics approach. This signature, though not validated in an independent dataset, deserves further investigation in a larger cohort study.

Published
2017
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29. N-Homocysteinylation impairs collagen cross-linking in cystathionine β-synthase-deficient mice: a novel mechanism of connective tissue abnormalities.

Author

Perła-Kajan J, Utyro O, Rusek M, Malinowska A, Sitkiewicz E, and Jakubowski H

Subjects
Animals, Collagen Type I, alpha 1 Chain, Cystathionine beta-Synthase genetics, Homocysteine metabolism, Homocystinuria genetics, Lysine metabolism, Mice, Knockout, Peptides metabolism, Collagen Type I metabolism, Connective Tissue metabolism, Cystathionine beta-Synthase metabolism, Homocysteine analogs & derivatives, Hyperhomocysteinemia metabolism
Abstract

Cystathionine β-synthase (CBS) deficiency, a genetic disorder in homocysteine (Hcy) metabolism in humans, elevates plasma Hcy-thiolactone and leads to connective tissue abnormalities that affect the cardiovascular and skeletal systems. However, the underlying mechanism of these abnormalities is not understood. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates N-homocysteinylated protein. Because lysine residues are involved in collagen cross-linking, N-homocysteinylation of these lysines should impair cross-linking. Using a Tg-I278T Cbs -/- mouse model of hyperhomocysteinemia (HHcy) which replicates the connective tissue abnormalities observed in CBS-deficient patients, we found that N-Hcy-collagen was elevated in bone, tail, and heart of Cbs -/- mice, whereas pyridinoline cross-links were significantly reduced. Plasma deoxypyridinoline cross-link and cross-linked carboxyterminal telopeptide of type I collagen were also significantly reduced in the Cbs -/- mice. Lysine oxidase activity and mRNA level were not reduced by the Cbs -/- genotype. We also showed that collagen carries S-linked Hcy bound to the thiol of N-linked Hcy. In vitro experiments showed that Hcy-thiolactone modifies lysine residues in collagen type I α-1 chain. Residue K 160 , located in the nonhelical N-telopeptide region and involved in pyridinoline cross-link formation, was also N-homocysteinylated in vivo Taken together, our findings showed that N-homocysteinylation of collagen in Cbs -/- mice impairs its cross-linking. These findings explain, at least in part, connective tissue abnormalities observed in HHcy.-Perła-Kajan, J., Utyro, O., Rusek, M., Malinowska, A., Sitkiewicz, E., Jakubowski, H. N-Homocysteinylation impairs collagen cross-linking in cystathionine β-synthase-deficient mice: a novel mechanism of connective tissue abnormalities., (© FASEB.)

Published
2016
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30. Quantification of urinary S- and N-homocysteinylated protein and homocysteine-thiolactone in mice.

Author

Jakubowski H

Subjects
Animals, Chromatography, High Pressure Liquid, Mice, Cystathionine beta-Synthase urine, Homocysteine analogs & derivatives, Homocysteine urine, Urinalysis methods
Abstract

Homocysteine (Hcy) and its metabolites Hcy-thiolactone, N-Hcy-protein, and S-Hcy-protein are implicated in vascular and neurological diseases. However, quantification of these metabolites remains challenging. Here I describe streamlined assays for these metabolites based on their conversion to Hcy-thiolactone. Free Hcy-thiolactone is extracted from the urine with chloroform/methanol. Total Hcy is converted to Hcy-thiolactone in the presence of 1 N HCl. Major urinary protein (MUP)-bound S-linked Hcy is liberated from the protein by reduction with dithiothreitol and converted to Hcy-thiolactone. Acid hydrolysis of MUP with 6 N HCl liberates N-linked Hcy as Hcy-thiolactone, which is then extracted with chloroform/methanol. Ferritin is used as an N-Hcy-protein standard and an authentic Hcy-thiolactone is used to monitor the efficiency of extraction. Hcy-thiolactone (free, derived from total Hcy, or from MUP-bound N-linked or S-linked Hcy) is separated by a cation exchange high-performance liquid chromatography, post-column derivatized with o-phthaldialdehyde, and quantified by fluorescence. Using these assays with as little as 2-20 μL of urine I show that MUP carry N-linked and S-linked Hcy and that N-Hcy-MUP and S-Hcy-MUP and Hcy-thiolactone are severely elevated in cystathionine β-synthase-deficient mice. These assays will facilitate examination of the role of protein-related Hcy metabolites in health and disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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31. Aminoacyl-tRNA synthetases and the evolution of coded peptide synthesis: the Thioester World.

Author

Jakubowski H

Subjects
Amino Acid Sequence, Aminoacylation, Biocatalysis, Catalytic Domain, Genetic Code, Molecular Sequence Data, Origin of Life, Peptides genetics, Sulfhydryl Compounds chemistry, Amino Acids, Sulfur chemical synthesis, Amino Acyl-tRNA Synthetases chemistry, Evolution, Molecular, Peptide Biosynthesis genetics, Peptides chemistry
Abstract

Coded peptide synthesis must have been preceded by a prebiotic stage, in which thioesters played key roles. Fossils of the Thioester World are found in extant aminoacyl-tRNA synthetases (AARSs). Indeed, studies of the editing function reveal that AARSs have a thiol-binding site in their catalytic modules. The thiol-binding site confers the ability to catalyze aminoacyl~coenzyme A thioester synthesis and peptide bond formation. Genomic comparisons show that AARSs are structurally related to proteins involved in sulfur and coenzyme A metabolisms and peptide bond synthesis. These findings point to the origin of the amino acid activation and peptide bond synthesis functions in the Thioester World and suggest that the present-day AARSs had originated from ancestral forms that were involved in noncoded thioester-dependent peptide synthesis., (© 2016 Federation of European Biochemical Societies.)

Published
2016
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32. Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells.

Author

Gurda D, Handschuh L, Kotkowiak W, and Jakubowski H

Subjects
Atherosclerosis metabolism, Cells, Cultured, Homocysteine pharmacology, Homocysteine physiology, Humans, Hyperhomocysteinemia metabolism, Metabolic Networks and Pathways, Transcriptional Activation, Homocysteine analogs & derivatives, Human Umbilical Vein Endothelial Cells metabolism, Transcriptome
Abstract

Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis. In addition to Hcy, related metabolites accumulate in HHcy but their role in endothelial dysfunction is unknown. Here, we examine how Hcy-thiolactone, N-Hcy-protein, and Hcy affect gene expression and molecular pathways in human umbilical vein endothelial cells. We used microarray technology, real-time quantitative polymerase chain reaction, and bioinformatic analysis with PANTHER, DAVID, and Ingenuity Pathway Analysis (IPA) resources. We identified 47, 113, and 30 mRNAs regulated by N-Hcy-protein, Hcy-thiolactone, and Hcy, respectively, and found that each metabolite induced a unique pattern of gene expression. Top molecular pathways affected by Hcy-thiolactone were chromatin organization, one-carbon metabolism, and lipid-related processes [-log(P value) = 20-31]. Top pathways affected by N-Hcy-protein and Hcy were blood coagulation, sulfur amino acid metabolism, and lipid metabolism [-log(P value)] = 4-11; also affected by Hcy-thiolactone, [-log(P value) = 8-14]. Top disease related to Hcy-thiolactone, N-Hcy-protein, and Hcy was 'atherosclerosis, coronary heart disease' [-log(P value) = 9-16]. Top-scored biological networks affected by Hcy-thiolactone (score = 34-40) were cardiovascular disease and function; those affected by N-Hcy-protein (score = 24-35) were 'small molecule biochemistry, neurological disease,' and 'cardiovascular system development and function'; and those affected by Hcy (score = 25-37) were 'amino acid metabolism, lipid metabolism,' 'cellular movement, and cardiovascular and nervous system development and function.' These results indicate that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.

Published
2015
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33. Paraoxonase 1 deficiency and hyperhomocysteinemia alter the expression of mouse kidney proteins involved in renal disease.

Author

Suszyńska-Zajczyk J, Sikora M, and Jakubowski H

Subjects
Animals, Aryldialkylphosphatase genetics, Gene Expression, Mice, Inbred C57BL, Proteome metabolism, Aryldialkylphosphatase deficiency, Hyperhomocysteinemia metabolism, Kidney metabolism
Abstract

Scope: Hyperhomocysteinemia (HHcy) is associated with kidney disease and leads to atherosclerosis and thrombosis. Paraoxonase 1 (Pon1), a hydrolase that participates in homocysteine (Hcy) metabolism and is carried in the circulation on high-density lipoprotein, has also been linked to kidney disease and atherothrombosis. Pon1-knockout mice are susceptible to atherosclerosis and exhibit a kidney-associated phenotype, polyuria or urine dilution. We hypothesize that HHcy and Pon1 deficiency are toxic to kidney function because they impair metabolic pathways important for normal kidney homeostasis., Methods and Results: We examined changes in the mouse kidney proteome induced by Pon1 gene deletion and dietary HHcy, using 2D IEF/SDS-PAGE gel electrophoresis and MALDI-TOF mass spectrometry. We found that the expression of ten mouse kidney proteins was altered by the Pon1(-/-) genotype or HHcy. Proteins involved in metabolism of lipid (ApoA-I), protein (Hspd1), carbohydrate (Pdhb, Fbp1-isoform2, Eno1), and energy (Ndufs8, Ldhd) were down-regulated. Proteins involved in lipid transport (Pebp1), oxidative stress response (Prdx2), and cellular detoxification (Glo1) were up-regulated. The kidney proteins altered by HHcy or Pon1 are also altered in renal disease., Conclusion: Our findings suggest that excess Hcy is toxic because it deregulates the expression of proteins involved in diverse cellular processes-from lipid, protein, carbohydrate, and energy metabolisms to detoxification and antioxidant defenses-that are essential for normal kidney homeostasis. Dysregulation of these processes can account for the involvement of HHcy and reduced Pon1 in kidney disease. Our findings also show that Pon1 plays an important role in maintaining normal kidney homeostasis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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34. Bleomycin hydrolase and hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis.

Author

Suszyńska-Zajczyk J, Wróblewski J, Utyro O, Luczak M, Marczak L, and Jakubowski H

Subjects
Animals, Homeostasis, Hyperhomocysteinemia chemically induced, Male, Methionine administration & dosage, Mice, Inbred C57BL, Proteome metabolism, Transcriptome, Cysteine Endopeptidases metabolism, Hyperhomocysteinemia metabolism, Liver metabolism
Abstract

The liver is the major contributor to homocysteine (Hcy) metabolism and fatty liver disease is associated with hyperhomocysteinemia. Bleomycin hydrolase (Blmh) is an aminohydrolase that also participates in Hcy metabolism by hydrolyzing Hcy-thiolactone. To gain insight into hepatic functions of Blmh, we analyzed the liver proteome of Blmh(-/-) and Blmh(+/+) mice in the absence and presence of diet-induced (high methionine) hyperhomocysteinemia using 2D IEF/SDS-PAGE gel electrophoresis and MALDI-TOF mass spectrometry. We identified eleven liver proteins whose expression was significantly altered as a result of the Blmh gene inactivation. The differential expression (Blmh(-/-) vs. Blmh(+/+)) of four liver proteins was lower, of two proteins was higher, and was further modified in mice fed with a hyperhomocysteinemic high-Met diet. The down-regulated proteins are involved in lipoprotein metabolism (ApoA1, ApoE), antigen processing (Psme1), energy metabolism (Atp5h, Gamt), methylglyoxal detoxification (Glo1), oxidative stress response (Sod1), and inactivation of catecholamine neurotransmitters (Comt). The two up-regulated proteins are involved in nitric oxide generation (Ddah1) and xenobiotic detoxification (Sult1c1). We also found that livers of Blmh(-/-) mice expressed a novel variant of glyoxalase domain-containing protein 4 (Glod4) by a post-transcriptional mechanism. Our findings suggest that Blmh interacts with diverse cellular processes-from lipoprotein metabolism, nitric oxide regulation, antigen processing, and energy metabolism to detoxification and antioxidant defenses-that are essential for liver homeostasis and that modulation of these interactions by hyperhomocysteinemia underlies the involvement of Hcy in fatty liver disease.

Published
2014
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35. Paraoxonase 1 and dietary hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis.

Author

Suszyńska-Zajczyk J and Jakubowski H

Subjects
Animals, Aryldialkylphosphatase genetics, Homeostasis, Hyperhomocysteinemia genetics, Methionine adverse effects, Mice, Aryldialkylphosphatase metabolism, Hyperhomocysteinemia metabolism, Liver metabolism
Abstract

Homocysteine (Hcy), a product of methionine metabolism, is elevated by the consumption of a high-methionine diet that can cause fatty liver disease. Paraoxonase 1 (Pon1), a hydrolase expressed mainly in the liver and carried in the circulation on high-density lipoprotein, participates in Hcy metabolism. Low Pon1 activity is linked to fatty liver disease. We hypothesize that hyperhomocysteinemia and low Pon1 induce changes in gene expression that could impair liver homeostasis. To test this hypothesis, we analyzed the liver proteome of Pon1(-/-) and Pon1(+/+) mice fed a high methionine diet (1% methionine in the drinking water) for 8 weeks using 2D IEF/SDS-PAGE gel electrophoresis and MALDI-TOF mass spectrometry. We identified seven liver proteins whose expression was significantly altered in Pon1(-/-) mice. In animals fed with a control diet, the expression of three liver proteins involved in lipoprotein metabolism (ApoE), iron metabolism (Ftl), and regulation of nitric oxide generation (Ddah1) was up-regulated by the Pon1(-/-) genotype. In mice fed with a high-methionine diet, expression of four liver proteins was up-regulated and of three proteins was down-regulated by the Pon1(-/-) genotype. The up-regulated proteins are involved in lipoprotein metabolism (ApoE), energy metabolism (Atp5h), oxidative stress response (Prdx2), and nitric oxide regulation (Ddah1). The down-regulated proteins are involved in energy metabolism (Gamt), iron metabolism (Ftl), and catechol metabolism (Comt). Expression of one protein (Ftl) was up-regulated both by the Pon1(-/-) genotype and a high-methionine diet. Our findings suggest that Pon1 interacts with diverse cellular processes - from lipoprotein metabolism, nitric oxide regulation, and energy metabolism to iron transport and antioxidant defenses - that are essential for normal liver homeostasis and modulation of these interactions by a high-methionine diet may contribute to fatty liver disease.

Published
2014

36. Inactivation of the paraoxonase 1 gene affects the expression of mouse brain proteins involved in neurodegeneration.

Author

Suszyńska-Zajczyk J, Luczak M, Marczak L, and Jakubowski H

Subjects
Animals, Aryldialkylphosphatase genetics, Diet, Electrophoresis, Polyacrylamide Gel, Homocysteine administration & dosage, Methionine administration & dosage, Mice, Inbred C57BL, Mice, Knockout, Neurodegenerative Diseases metabolism, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Aryldialkylphosphatase deficiency, Brain metabolism
Abstract

Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Paraoxonase 1 (Pon1) participates in Hcy metabolism and is also linked to AD. The inactivation of the Pon1 gene in mice causes the accumulation of Hcy-thiolactone in the brain and increases the susceptibility to Hcy-thiolactone-induced seizures. To gain insight into the brain-related Pon1 function, we used two-dimensional IEF/SDS-PAGE gel electrophoresis and MALDI-TOF/TOF mass spectrometry to study brain proteomes of Pon1-/- and Pon1+/+ mice fed with a hyperhomocysteinemic high-methionine (Met) or a control diet. We found that: 1) proteins involved in brain-specific function (Nrgn), antioxidant defenses (Sod1, DJ-1), and cytoskeleton assembly (Tbcb, CapZa2) were differentially expressed in brains of Pon1-null mice; 2) proteins involved in brain-specific function (Ncald, Nrgn, Stmn1), antioxidant defenses (Prdx2, DJ-1), energy metabolism (Ak1), cell cycle (GDI1, Ran), cytoskeleton assembly (Tbcb), and unknown function (Hdhd2) showed differential expression in brains of Pon1-null fed with a hyperhomocysteinemic high-Met diet; 3) most proteins regulated by the Pon1-/- genotype were also regulated by the high-Met diet; 4) the proteins differentially expressed in Pon1-null mouse brains play important roles in neural development, learning, plasticity, and aging and are linked to neurodegenerative diseases, including AD. Taken together, our findings suggest that Pon1 interacts with diverse cellular processes from energy metabolism and anti-oxidative defenses to cell cycle, cytoskeleton dynamics, and synaptic plasticity essential for normal brain homeostasis and that these interactions are modulated by hyperhomocysteinemia and account for the involvement of Hcy and Pon1 in AD.

Published
2014
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37. Identification of serum proteome components associated with progression of non-small cell lung cancer.

Author

Pietrowska M, Jelonek K, Michalak M, Roś M, Rodziewicz P, Chmielewska K, Polański K, Polańska J, Gdowicz-Kłosok A, Giglok M, Suwiński R, Tarnawski R, Dziadziuszko R, Rzyman W, and Widłak P

Subjects
Adenocarcinoma diagnosis, Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Apolipoprotein A-I blood, Blood Proteins analysis, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell pathology, Case-Control Studies, Disease Progression, Early Diagnosis, Female, Haptoglobins analysis, Humans, Lung Neoplasms diagnosis, Lung Neoplasms pathology, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Staging, Proteome analysis, Serum Amyloid A Protein analysis, beta 2-Glycoprotein I blood, Adenocarcinoma blood, Biomarkers, Tumor blood, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Squamous Cell blood, Lung Neoplasms blood
Abstract

The aim of the present study was to perform comparative analysis of serum from patients with different stages of non-small cell lung cancer (NSCLC) using the three complementary proteomic approaches to identify proteome components associated with the progression of cancer. Serum samples were collected before any treatment from 200 patients with NSCLC, including 103 early stage, 64 locally advanced and 33 metastatic cancer samples, and from 200 donors without malignancy. The low-molecular-weight fraction of serum proteome was MALDI-profiled in all samples. Serum proteins were characterized using 2D-PAGE and LC-MS/MS approaches in a representative group of 30 donors. Several significant differences were detected between serum samples collected from patients with early stage cancer and patients with locally advanced cancer, as well as between patients with metastatic cancer and patients with local disease. Of note, serum components discriminating samples from early stage cancer and healthy persons were also detected. In general, about 70 differentiating serum proteins were identified, including inflammatory and acute phase proteins already reported to be associated with the progression of lung cancer (serum amyloid A or haptoglobin). Several differentiating proteins, including apolipoprotein H or apolipoprotein A1, were not previously associated with NSCLC. No significant differences in patterns of serum proteome components were detected between patients with adenocarcinoma and squamous cell carcinoma. In conclusion, we identified the biomarker candidates with potential importance for molecular proteomic staging of NSCLC. Additionally, several serum proteome components revealed their potential applicability in early detection of the lung cancer.

Published
2014

38. Identification of N-homocysteinylation sites in plasma proteins.

Author

Sikora M, Marczak Ł, Kubalska J, Graban A, and Jakubowski H

Subjects
Blood Proteins metabolism, Homocysteine metabolism, Humans, Peptides blood, Blood Proteins analysis, Homocysteine analysis, Homocystinuria blood, Peptides analysis, Protein Processing, Post-Translational
Abstract

A protocol for the identification of N-homocysteinylation sites in plasma proteins is described. Human plasma or purified fibrinogen is subjected to trypsin digestion and analysis of N-Hcy-peptides by liquid chromatography/mass spectroscopy (LC/MS). Human fibrinogen is isolated from the plasma by the glycine precipitation method. Identification of N-Hcy-Lys-peptides in tryptic digests of in vivo-derived samples is facilitated by the use of N-Hcy-albumin and N-Hcy-fibrinogen synthesized in vitro from commercially available human proteins. This protocol allows identification of N-homocysteinylation sites at Lys4, Lys12, Lys137, and Lys525 in albumin directly in trypsin-digested human serum samples. N-Hcy-Lys562, N-Hcy-Lys344, and N-Hcy-Lys385 were identified in human fibrinogen from patients with cystathionine β-synthase deficiency. The protocol can be completed in 4 days.

Published
2014
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39. Hyperhomocysteinemia and bleomycin hydrolase modulate the expression of mouse brain proteins involved in neurodegeneration.

Author

Suszyńska-Zajczyk J, Luczak M, Marczak L, and Jakubowski H

Subjects
Analysis of Variance, Animals, Cysteine Endopeptidases genetics, Disease Models, Animal, Electrophoresis, Gel, Two-Dimensional, Genotype, Homocysteine metabolism, Hyperhomocysteinemia genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Proteomics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Brain metabolism, Cysteine Endopeptidases metabolism, Gene Expression Regulation genetics, Hyperhomocysteinemia pathology, Nerve Tissue Proteins metabolism
Abstract

Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Bleomycin hydrolase (BLMH) participates in Hcy metabolism and is also linked to AD. The inactivation of the Blmh gene in mice causes accumulation of Hcy-thiolactone in the brain and increases susceptibility to Hcy-thiolactone-induced seizures. To gain insight into brain-related Blmh function, we used two-dimensional IEF/SDS-PAGE gel electrophoresis and MALDI-TOF/TOF mass spectrometry to examine brain proteomes of Blmh-/- mice and their Blmh+/+ littermates fed with a hyperhomocysteinemic high-Met or a control diet. We found that: (1) proteins involved in brain-specific function (Ncald, Nrgn, Stmn1, Stmn2), antioxidant defenses (Aop1), cell cycle (RhoGDI1, Ran), and cytoskeleton assembly (Tbcb, CapZa2) were differentially expressed in brains of Blmh-null mice; (2) hyperhomocysteinemia amplified effects of the Blmh-/- genotype on brain protein expression; (3) proteins involved in brain-specific function (Pebp1), antioxidant defenses (Sod1, Prdx2, DJ-1), energy metabolism (Atp5d, Ak1, Pgam-B), and iron metabolism (Fth) showed differential expression in Blmh-null brains only in hyperhomocysteinemic animals; (4) most proteins regulated by the Blmh-/- genotype were also regulated by high-Met diet, albeit in the opposite direction; and (5) the differentially expressed proteins play important roles in neural development, learning, plasticity, and aging and are linked to neurodegenerative diseases, including AD. Taken together, our findings suggest that Blmh interacts with diverse cellular processes from energy metabolism and anti-oxidative defenses to cell cycle, cytoskeleton dynamics, and synaptic plasticity essential for normal brain homeostasis and that modulation of these interactions by hyperhomocysteinemia underlies the involvement of Hcy in AD.

Published
2014
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40. Multivalent display system on filamentous bacteriophage pVII minor coat protein.

Author

Kwaśnikowski P, Kristensen P, and Markiewicz WT

Subjects
Animals, Blotting, Western, Carrier Proteins genetics, Carrier Proteins immunology, Cattle, Enzyme-Linked Immunosorbent Assay, Escherichia coli virology, Humans, Immunoglobulin Fragments immunology, Immunoglobulin Variable Region immunology, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins immunology, Serum Albumin, Bovine immunology, Streptavidin metabolism, Ubiquitin immunology, Bacteriophage M13 genetics, Capsid Proteins genetics, Immunoglobulin Fragments genetics, Immunoglobulin Variable Region genetics, Peptide Library
Abstract

The systems for display of foreign peptides and polypeptides on filamentous bacteriophage have exploited genetic fusion to all of the five coat proteins. Multivalent display systems allowing selection of low affinity antibody fragments have been devised for fusions to gene III. However, since pIII has to interact with the bacterial receptors during the infection process, reduced infectivity can be observed. Alternative display systems utilizing other coat protein have been examined. These, however, take advantage of phagemid systems, in which a mixture of fusion and non-fusion coat proteins becomes displayed, thus preventing multivalent display. In this paper, we describe genetically stable fusion of scFv fragments to gene VII directly in the phage genome, thus giving rise to a multivalent display system where infectivity is not comprised. A hundred-fold enrichments factor can be obtained in model selection. Our results demonstrate that the small size of pVII (33 amino acids) is not structurally compromised by fusion of scFv antibody fragments at their N-terminus, thus demonstrating the feasibility of utilizing pVII as a fusion partner.

Published
2005
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