Unwinding the Differences of the Mammalian PERIOD Clock Proteins from Crystal Structure to Cellular Function

Total Page:16

File Type:pdf, Size:1020Kb

Unwinding the Differences of the Mammalian PERIOD Clock Proteins from Crystal Structure to Cellular Function Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function Nicole Kuceraa,1, Ira Schmalenb, Sven Henniga,1, Rupert Öllingerc, Holger M. Straussd,2, Astrid Grudzieckic, Caroline Wieczoreka,3, Achim Kramerc, and Eva Wolfb,4,5 aMax Planck Institute of Molecular Physiology, Department of Structural Biology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany; bMax Planck Institute of Biochemistry, Department of Structural Cell Biology, Am Klopferspitz 18, 82152 Martinsried, Germany; dNanolytics, Gesellschaft für Kolloidanalytik mbH, Am Mühlenberg 11, 14476 Potsdam, Germany; and cLaboratory of Chronobiology, Charité—Universitätsmedizin Berlin, 10098 Berlin, Hessische Strasse 3-4, 10115 Berlin, Germany Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved January 4, 2012 (received for review August 16, 2011) The three PERIOD homologues mPER1, mPER2, and mPER3 consti- the mBMAL1/mCLOCK transcription factor complex. Addition- tute central components of the mammalian circadian clock. They ally, the PAS domains of NPAS2, mCLOCK, and mPER2 have been contain two PAS (PER-ARNT-SIM) domains (PAS-A and PAS-B), which reportedtobindheme(13–16).Inthecircadianclock,mPER1and mediate homo- and heterodimeric mPER-mPER interactions as well mPER2 proteins are found in large protein complexes, likely estab- as interactions with transcription factors and kinases. Here we pre- lishing multiple interactions via their PAS domains, the central sent crystal structures of PAS domain fragments of mPER1 and CKIε∕δ binding domain and the C-terminal mCRY binding region mPER3 and compare them with the previously reported mPER2 (17–19). structure. The structures reveal homodimers, which are mediated Studies with mPER knockout mice showed that mPER1 and by interactions of the PAS-B β-sheet surface including a highly con- mPER2 are more essential for circadian rhythmicity than mPER3 served tryptophan (Trp448mPER1, Trp419mPER2, Trp359mPER3). mPER1 (20–22). mPER2 appears to positively regulate the expression of homodimers are additionally stabilized by interactions between clock genes (mper1, mper2, mcry1, mbmal1) in vivo (20, 21), BIOCHEMISTRY the PAS-A domains and mPER3 homodimers by an N-terminal possibly by interacting with REV-ERBα and thereby modulating region including a predicted helix-loop-helix motive. We have ver- its effect on mBMAL1 transcription (23). In contrast, mPER1 ified the existence of these homodimer interfaces in solution and knockout leads to decreased peak amounts of mPER2 and inside cells using analytical gel filtration and luciferase complemen- mCRY proteins in the nucleus, suggesting that mPER1 regulates tation assays and quantified their contributions to homodimer their stability and/or nuclear entry through protein-protein inter- stability by analytical ultracentrifugation. We also show by fluor- actions (20). The subtle effect of mPER3 deficiency on circadian escence recovery after photobleaching analyses that destabiliza- behavior implies that mPER3 is more important for output func- tion of the PAS-B/tryptophan dimer interface leads to a faster tions. Indeed, mPER3 interacts with the nuclear receptor PPAR-γ mobility of mPER2 containing complexes in human U2OS cells. via an N-terminal region including both PAS domains and a pre- Our study reveals structural and quantitative differences between ceding predicted helix-loop-helix motive (24). This interaction the homodimeric interactions of the three mouse PERIOD homolo- represses the PPAR-γ activity and thereby inhibits the adipogen- gues, which are likely to contribute to their distinct clock functions. esis of mesenchymal stem cells. The importance of the per3 gene is also shown by its implication in the delayed sleep phase ∣ ∣ ∣ circadian clock PAS domains PERIOD proteins protein interactions syndrome and the morning or evening sleep timing preferences observed in human populations (25, 26). n mammalians many physiological, behavioral, and biochemical To provide insights into the molecular mechanisms underlying Iprocesses are regulated in a day-time dependent (circadian) the distinct functions and molecular interactions of the three manner. The approximately 24 h period is generated by a circa- mPER homologues, we have solved crystal structures of the PAS dian clock, which is operated by molecular feedback loops. In the domain regions of mPER1 and mPER3 and compared them with main feedback loop, the bHLH (basic-helix-loop-helix)-PAS our mPER2 structure (27). In addition to a conserved PAS-B/ (PER-ARNT-SIM) transcription factors mBMAL1/2, mCLOCK, tryptophan dimer interface, mPER1- and mPER3 homodimers and NPAS2 activate the expression of three PERIOD proteins (mPER1, mPER2, and mPER3) as well as two cryptochromes, mCRY1 and mCRY2. The mPER and mCRY proteins inhibit Author contributions: N.K., I.S., S.H., R.Ö., H.M.S., A.K., and E.W. designed research; N.K., their own transcription, completing the circle of negative feed- I.S., S.H., R.Ö., H.M.S., A.G., and C.W. performed research; A.G. and C.W. contributed new reagents/analytic tools; N.K., I.S., S.H., R.Ö., H.M.S., A.K., and E.W. analyzed data; and N.K. back. The daily regulated expression of mBMAL1 is ensured by and E.W. wrote the paper. a stabilizing feedback loop, in which the heme binding nuclear The authors declare no conflict of interest. receptor REV-ERBα/β represses mBMAL1 expression, whereas This article is a PNAS Direct Submission. ROR-α/β activates it (1, 2). Recently, nontranscriptional circadian Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, oscillations of peroxiredoxin oxidation-reduction, hemoglobin www.pdb.org [PDB ID codes 4DJ2 (mPER1) and 4DJ3 (mPER3)]. dimer-tetramer transitions, and NADH/NADPH oscillations have 1Present address: Western Australian Institute for Medical Research Rear 50 Murray Street been described in human red blood cells, which are interconnected Perth, WA 6000 Australia. with the transcriptional feedback loops in nucleated cells (3, 4). 2Present address: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. The PERIOD proteins and the transcription factors mBMAL1/ 3Present address: Max Planck Institute for Neurological Research, Gleuelerstr. 50, 50931 2, mCLOCK, and NPAS2 contain two tandemly organized PAS do- Cologne, Germany. mains (PAS-A and PAS-B). The PAS domains mediate homo- and 4Present address: Adolf-Butenandt-Institute, Department of Physiological Chemistry, heterodimeric interactions between the mPER homologues (5–8) Butenandtstrasse. 5, 81377 Munich, Germany. as well as interactions of the mPERs with mBMAL1/2, mCLOCK, 5To whom correspondence should be addressed. E-mail: [email protected]. – and NPAS2 (9 12). These interactions regulate the stability and This article contains supporting information online at www.pnas.org/lookup/suppl/ cellular localization of the mPERs and modulate the activity of doi:10.1073/pnas.1113280109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1113280109 PNAS Early Edition ∣ 1of6 Downloaded by guest on September 26, 2021 are stabilized by interfaces located within the PAS-A domain and Ta b l e S 2 ). The mPER homodimers are stabilized by interac- (mPER1) or a predicted helix-loop-helix region N-terminal to tions between the antiparallel PAS-B β-sheet surfaces. Central to 448 the PAS-A domain (mPER3). These additional interfaces lead this interface are the conserved tryptophans Trp mPER1 and 359 419 to increased affinities compared to the mPER2 PAS domain Trp mPER3 [corresponding to Trp mPER2; (27)] as well as 444 ∕ 355 ¼ 415 homodimers. We also provide evidence that the PAS domains of two phenylalanines, Phe mPER1 Phe mPER3 ( Phe mPER2) mPER1 and mPER3 might be able to bind heme. Furthermore, 454 ∕ 365 ð¼ 425 Þ A D and Phe mPER1 Phe mPER3 Phe mPER2 (Fig. 1 and , we show by luciferase complementation assays that the mPER Figs. S2A and S3C). homodimers observed in our crystal structures are also formed in The mPER2 homodimer also involved interactions of the PAS- HEK293 cells. Moreover, our fluorescence recovery after photo- A domain with helix αE and the PAS-B domain of the dimerizing bleaching (FRAP) analyses reveal that destabilization of the PAS- molecule (27) (Fig. S2B). These interactions are not observed B/tryptophan dimer interface generates faster moving mPER2 in the mPER1 and mPER3 structures because the relative orien- containing complexes in human U2OS cells. tation of the monomers is changed in these two homologues A Results (Fig. S3 ; Table S2). Instead, a second homodimer interface is observed in the PAS-A domains of mPER1 and mPER3, which Crystal Structures of Mouse PERIOD1 and Mouse PERIOD3. We have α determined crystal structures of the fragments mPER1[191–502] is mostly mediated by contacts between their antiparallel C B E B and mPER3[108–411], which include the two PAS domains helices (Fig. 1 and , Fig. S2 ). Central to this interface is a 267 179 (PAS-A and PAS-B), the αE helix C-terminal to PAS-B and about tyrosine residue, Tyr mPER1 and Tyr mPER3. In mPER1, the 25 residues N-terminal to PAS-A (Fig. 1, Fig. S1, and Table S1). presence of two glycine residues (Gly264 and Gly268) allows for Both structures revealed noncrystallographic homodimers a close approach of the two αC helices (Fig. 1B). In mPER3, the (Fig. 1 A and D). Each monomer contains two canonical PAS do- αC helices do not approach each other as closely as in mPER1, 264 mains with a five-stranded antiparallel β-sheet (βA-βE) covered on likely due to the exchange of Gly mPER1 to a bulky arginine α α α α α A D 176 E B one face by -helices ( A, A*, B, C) (Fig. 1 and , Fig. S1, (Arg mPER3) (Fig. 1 , Fig. S2 ). A molecule 1 B C PAS-A PAS-B C`* Pro272 Gln237 C` A’ B’ C’ Thr271 E` Thr213 Thr219 Gly268 Tyr267 D’ N Ser221 A B A’* Thr209 A’ E D C C E B D B’ 3.6 Tyr233 E C Leu202 Leu205 Gly264 Ile208 Trp278 N Thr271 Trp448 Tyr200 Ile325 E Pro260 Leu338 N N molecule 2 PAS-B D molecule 1 E F Lys127 Glu252 PAS-A D’ A’ PAS-B E A’ 3.79 D A D C C` Thr131 E` B’ B 3.91 N B C’ 4.55 C His124 Arg227 E 8.44 B’ E Thr118 Tyr179 Leu250 His145 Leu120 Leu248 Arg176 3.73 C Trp190 Thr182 N 2.77 Tyr112 Trp359 N PAS-B molecule 2 Fig.
Recommended publications
  • The Nobel Prize Sweden.Se
    Facts about Sweden: The Nobel Prize sweden.se The Nobel Prize – the award that captures the world’s attention The Nobel Prize is considered the most prestigious award in the world. Prize- winning discoveries include X-rays, radioactivity and penicillin. Peace Laureates include Nelson Mandela and the 14th Dalai Lama. Nobel Laureates in Literature, including Gabriel García Márquez and Doris Lessing, have thrilled readers with works such as 'One Hundred Years of Solitude' and 'The Grass is Singing'. Every year in early October, the world turns Nobel Day is 10 December. For the prize its gaze towards Sweden and Norway as the winners, it is the crowning point of a week Nobel Laureates are announced in Stockholm of speeches, conferences and receptions. and Oslo. Millions of people visit the website At the Nobel Prize Award Ceremony in of the Nobel Foundation during this time. Stockholm on that day, the Laureates in The Nobel Prize has been awarded to Physics, Chemistry, Physiology or Medicine, people and organisations every year since and Literature receive a medal from the 1901 (with a few exceptions such as during King of Sweden, as well as a diploma and The Nobel Banquet is World War II) for achievements in physics, a cash award. The ceremony is followed a magnificent party held chemistry, physiology or medicine, literature by a gala banquet. The Nobel Peace Prize at Stockholm City Hall. and peace. is awarded in Oslo the same day. Photo: Henrik Montgomery/TT Henrik Photo: Facts about Sweden: The Nobel Prize sweden.se Prize in Economic Sciences prize ceremonies.
    [Show full text]
  • EMBO Facts & Figures
    excellence in life sciences Reykjavik Helsinki Oslo Stockholm Tallinn EMBO facts & figures & EMBO facts Copenhagen Dublin Amsterdam Berlin Warsaw London Brussels Prague Luxembourg Paris Vienna Bratislava Budapest Bern Ljubljana Zagreb Rome Madrid Ankara Lisbon Athens Jerusalem EMBO facts & figures HIGHLIGHTS CONTACT EMBO & EMBC EMBO Long-Term Fellowships Five Advanced Fellows are selected (page ). Long-Term and Short-Term Fellowships are awarded. The Fellows’ EMBO Young Investigators Meeting is held in Heidelberg in June . EMBO Installation Grants New EMBO Members & EMBO elects new members (page ), selects Young EMBO Women in Science Young Investigators Investigators (page ) and eight Installation Grantees Gerlind Wallon EMBO Scientific Publications (page ). Programme Manager Bernd Pulverer S Maria Leptin Deputy Director Head A EMBO Science Policy Issues report on quotas in academia to assure gender balance. R EMBO Director + + A Conducts workshops on emerging biotechnologies and on H T cognitive genomics. Gives invited talks at US National Academy E IC of Sciences, International Summit on Human Genome Editing, I H 5 D MAN 201 O N Washington, DC.; World Congress on Research Integrity, Rio de A M Janeiro; International Scienti c Advisory Board for the Centre for Eilish Craddock IT 2 015 Mammalian Synthetic Biology, Edinburgh. Personal Assistant to EMBO Fellowships EMBO Scientific Publications EMBO Gold Medal Sarah Teichmann and Ido Amit receive the EMBO Gold the EMBO Director David del Álamo Thomas Lemberger Medal (page ). + Programme Manager Deputy Head EMBO Global Activities India and Singapore sign agreements to become EMBC Associate + + Member States. EMBO Courses & Workshops More than , participants from countries attend 6th scienti c events (page ); participants attend EMBO Laboratory Management Courses (page ); rst online course EMBO Courses & Workshops recorded in collaboration with iBiology.
    [Show full text]
  • Nobel Prize Physicists Meet at Lindau
    From 28 June to 2 July 1971 the German island town of Lindau in Nobel Prize Physicists Lake Constance close to the Austrian and Swiss borders was host to a gathering of illustrious men of meet at Lindau science when, for the 21st time, Nobel Laureates held their reunion there. The success of the first Lindau reunion (1951) of Nobel Prize win­ ners in medicine had inspired the organizers to invite the chemists and W. S. Newman the physicists in turn in subsequent years. After the first three-year cycle the United Kingdom, and an audience the dates of historical events. These it was decided to let students and of more than 500 from 8 countries deviations in the radiocarbon time young scientists also attend the daily filled the elegant Stadttheater. scale are due to changes in incident meetings so they could encounter The programme consisted of a num­ cosmic radiation (producing the these eminent men on an informal ber of lectures in the mornings, two carbon isotopes) brought about by and personal level. For the Nobel social functions, a platform dis­ variations in the geomagnetic field. Laureates too the Lindau gatherings cussion, an informal reunion between Thus chemistry may reveal man­ soon became an agreeable occasion students and Nobel Laureates and, kind’s remote past whereas its long­ for making or renewing acquain­ on the last day, the traditional term future could well be shaped by tances with their contemporaries, un­ steamer excursion on Lake Cons­ the developments mentioned by trammelled by the formalities of the tance to the island of Mainau belong­ Mössbauer, viz.
    [Show full text]
  • A Nobel Synthesis
    MILESTONES IN CHEMISTRY Ian Grayson A nobel synthesis IAN GRAYSON Evonik Degussa GmbH, Rodenbacher Chaussee 4, Hanau-Wolfgang, 63457, Germany he first Nobel Prize for chemistry was because it is a scientific challenge, as he awarded in 1901 (to Jacobus van’t Hoff). described in his Nobel lecture: “The synthesis T Up to 2010, the chemistry prize has been of brazilin would have no industrial value; awarded 102 times, to 160 laureates, of whom its biological importance is problematical, only four have been women (1). The most but it is worth while to attempt it for the prominent area for awarding the Nobel Prize sufficient reason that we have no idea how for chemistry has been in organic chemistry, in to accomplish the task” (4). which the Nobel committee includes natural Continuing the list of Nobel Laureates in products, synthesis, catalysis, and polymers. organic synthesis we arrive next at R. B. This amounts to 24 of the prizes. Reading the Woodward. Considered by many the greatest achievements of the earlier organic chemists organic chemist of the 20th century, he who were recipients of the prize, we see that devised syntheses of numerous natural they were drawn to synthesis by the structural Alfred Nobel, 1833-1896 products, including lysergic acid, quinine, analysis and characterisation of natural cortisone and strychnine (Figure 1). 6 compounds. In order to prove the structure conclusively, some In collaboration with Albert Eschenmoser, he achieved the synthesis, even if only a partial synthesis, had to be attempted. It is synthesis of vitamin B12, a mammoth task involving nearly 100 impressive to read of some of the structures which were deduced students and post-docs over many years.
    [Show full text]
  • Book Reviews
    86 Bull. Hist. Chem., VOLUME 31, Number 2 (2006) BOOK REVIEWS Drug Discovery—A History. Walter Sneader, John Wiley, mercury is particularly interesting. Study of this sub- New York, 2005, Cloth, 468 pp, $65. stance eventually led to the discovery of arsphenamine, an organomercurial used to treat syphilis and much later stimulated the discovery of the potent diuretic ethacrynic I count myself fortunate to own copies of Walter acid. This and other interesting stories set forth in this Sneader’s books on drug discovery: The Evolution of section help us to understand the evolutionary nature of Modern Medicines (1985), Drug Prototypes and Their drug discovery from a historical perspective. Exploitation (1996) and Drug Discovery – A History Part 2 – Drugs from Naturally Occurring Proto- (2005). While it is true that each book generally ad- types. In this section of the book Sneader covers three dresses the topic of drug discovery with significant important topics in the history of drug discovery. Plants, overlap in the material covered, it also is true that the hormones, and microorganisms proved to be rich sources most recent work is much more than a third edition of of new medicines after advances in science permitted an existing book. As the title promises, the focus is on isolation and purification of active components. Here history. Because chemical structures are included with we are provided with the historical background that the text, I found the content of this book to be uniquely led to initial discovery of useful activity, followed by satisfying to a chemist interested in history. The material isolation and purification of the active substance, struc- in this book is organized by the source of drug prototypes ture determination, total synthesis, and in some cases rather then chronological order of discovery or thera- manufacture of the drug.
    [Show full text]
  • Nobel Laureates with Their Contribution in Biomedical Engineering
    NOBEL LAUREATES WITH THEIR CONTRIBUTION IN BIOMEDICAL ENGINEERING Nobel Prizes and Biomedical Engineering In the year 1901 Wilhelm Conrad Röntgen received Nobel Prize in recognition of the extraordinary services he has rendered by the discovery of the remarkable rays subsequently named after him. Röntgen is considered the father of diagnostic radiology, the medical specialty which uses imaging to diagnose disease. He was the first scientist to observe and record X-rays, first finding them on November 8, 1895. Radiography was the first medical imaging technology. He had been fiddling with a set of cathode ray instruments and was surprised to find a flickering image cast by his instruments separated from them by some W. C. Röntgenn distance. He knew that the image he saw was not being cast by the cathode rays (now known as beams of electrons) as they could not penetrate air for any significant distance. After some considerable investigation, he named the new rays "X" to indicate they were unknown. In the year 1903 Niels Ryberg Finsen received Nobel Prize in recognition of his contribution to the treatment of diseases, especially lupus vulgaris, with concentrated light radiation, whereby he has opened a new avenue for medical science. In beautiful but simple experiments Finsen demonstrated that the most refractive rays (he suggested as the “chemical rays”) from the sun or from an electric arc may have a stimulating effect on the tissues. If the irradiation is too strong, however, it may give rise to tissue damage, but this may to some extent be prevented by pigmentation of the skin as in the negro or in those much exposed to Niels Ryberg Finsen the sun.
    [Show full text]
  • 5 Reshaping the Fritz Haber Institute
    5 Reshaping the Fritz Haber Institute In the Federal Republic of Germany in the 1960s loomed a generation change that, when it arrived, would bring manifold and deep-running transformations. Reference points include the growth of mass consumer culture, the politics of détente, the independence movements in developing and emerging nations, and the emergence worldwide of new philosophical currents, new political constel- lations and new lifestyles, to which the natural sciences decisively contributed, e.g. through the birth control pill.1 Today, these fundamental societal changes are often bundled together and bound to the symbolic year of 1968, but the processes that heralded their arrival took shape years earlier and actually cul- minated closer to 1970. The MPG and even the FHI would recapitulate key aspects of these movements in microcosm, albeit somewhat modified and delayed. At the FHI, Rudolf Brill would provide the first impetus toward fundamental change. This may at first appear surprising since Brill belonged to the pre-war generation, which was reflected in his overall stance on the management of the Institute as well as his scientific accomplishments. But in opposition to these stood his sup- port for his young colleague Jochen H. Block, through which he sought to promote the novel field of catalysis research. The replacement of Brill and the retirement of long-standing scientific members from the FHI in the not-too-distant future presented an occasion, thoroughly typical for the MPG, for a well-planned and comprehensive, scientific
    [Show full text]
  • Karl Ziegler Mülheim an Der Ruhr, 8
    Historische Stätten der Chemie Karl Ziegler Mülheim an der Ruhr, 8. Mai 2008 Karl Ziegler, Bronzebüste, gestaltet 1964 von Professor Herbert Kaiser-Wilhelm-/Max-Planck-Institut für Kohlenforschung, Mülheim Kühn, Mülheim an der Ruhr (Foto T. Hobirk 2008; Standort Max- an der Ruhr. Oben: Altbau von 1914 am Kaiser-Wilhelm-Platz. Unten: Plancn k-Institut für Kohlenforschung, Mülheim an der Ruhr). Laborhochhaus von 1967 an der Ecke Lembkestraße/Margaretenplatz (Fotos G. Fink, M. W. Haenel, um 1988). Gesellschaft Deutscher Chemiker 1 137051_GDCh_Broschuere_Historische_StaettenK2.indd 1 02.09.2009 16:13:26 Uhr Mit dem Programm „Historische Stätten der Chemie“ würdigt die Gesellschaft Deutscher Chemiker (GDCh) Leistungen von geschichtlichem Rang in der Chemie. Zu den Zielen des Programms gehört, die Erinnerung an das kulturelle Erbe der Chemie wach zu halten und diese Wis- senschaft sowie ihre historischen Wurzeln stärker in das Blickfeld der Öffentlichkeit zu rücken. So werden die Wirkungsstätten von Wissenschaftlerinnen oder Wissen- schaftlern als Orte der Erinnerung in einem feierlichen Akt ausgezeichnet. Außerdem wird eine Broschüre er- stellt, die das wissenschaftliche Werk der Laureaten einer breiten Öffentlichkeit näherbringt und die Tragweite ihrer Arbeiten im aktuellen Kontext beschreibt. Am 8. Mai 2008 gedachten die GDCh und das Max- Planck-Institut für Kohlenforschung in Mülheim an der Ruhr des Wirkens von KARL ZIEGLER, der mit seinen bahnbrechenden Arbeiten auf dem Gebiet der organischen Chemie zu den Begründern der metallorganischen
    [Show full text]
  • List of Nobel Laureates 1
    List of Nobel laureates 1 List of Nobel laureates The Nobel Prizes (Swedish: Nobelpriset, Norwegian: Nobelprisen) are awarded annually by the Royal Swedish Academy of Sciences, the Swedish Academy, the Karolinska Institute, and the Norwegian Nobel Committee to individuals and organizations who make outstanding contributions in the fields of chemistry, physics, literature, peace, and physiology or medicine.[1] They were established by the 1895 will of Alfred Nobel, which dictates that the awards should be administered by the Nobel Foundation. Another prize, the Nobel Memorial Prize in Economic Sciences, was established in 1968 by the Sveriges Riksbank, the central bank of Sweden, for contributors to the field of economics.[2] Each prize is awarded by a separate committee; the Royal Swedish Academy of Sciences awards the Prizes in Physics, Chemistry, and Economics, the Karolinska Institute awards the Prize in Physiology or Medicine, and the Norwegian Nobel Committee awards the Prize in Peace.[3] Each recipient receives a medal, a diploma and a monetary award that has varied throughout the years.[2] In 1901, the recipients of the first Nobel Prizes were given 150,782 SEK, which is equal to 7,731,004 SEK in December 2007. In 2008, the winners were awarded a prize amount of 10,000,000 SEK.[4] The awards are presented in Stockholm in an annual ceremony on December 10, the anniversary of Nobel's death.[5] As of 2011, 826 individuals and 20 organizations have been awarded a Nobel Prize, including 69 winners of the Nobel Memorial Prize in Economic Sciences.[6] Four Nobel laureates were not permitted by their governments to accept the Nobel Prize.
    [Show full text]
  • Program Book
    The Genetics Society of America Conferences 15th International Xenopus Conference August 24-28, 2014 • Pacific Grove, CA PROGRAM GUIDE LEGEND Information/Guest Check-In Disabled Parking E EV Charging Station V Beverage Vending Machine N S Ice Machine Julia Morgan Historic Building W Roadway Pedestrian Pathway Outdoor Group Activity Area Program and Abstracts Meeting Organizers Carole LaBonne, Northwestern University John Wallingford, University of Texas at Austin Organizing Committee: Julie Baker, Stanford Univ Chris Field, Harvard Medical School Carmen Domingo, San Francisco State Univ Anna Philpott, Univ of Cambridge 9650 Rockville Pike, Bethesda, Maryland 20814-3998 Telephone: (301) 634-7300 • Fax: (301) 634-7079 E-mail: [email protected] • Web site: genetics-gsa.org Thank You to the Following Companies for their Generous Support Platinum Sponsor Gold Sponsors Additional Support Provided by: Carl Zeiss Microscopy, LLC Monterey Convention & Gene Tools, LLC Visitors Bureau Leica Microsystems Xenopus Express 2 Table of Contents General Information ........................................................................................................................... 5 Schedule of Events ............................................................................................................................. 6 Exhibitors ........................................................................................................................................... 8 Opening Session and Plenary/Platform Sessions ............................................................................
    [Show full text]
  • Krebs Collection Books (Octavos)
    Special Collections and Archives: Krebs Collection A collection of around 1250 items from the library of Sir Hans Krebs, Lecturer and subsequently Professor of Biochemistry at Sheffield from 1935 to 1954, and Nobel Prize Winner in 1953 for his work, along with Fritz Lipmann, in discovering in living organisms the series of chemical reactions known as the tricarboxylic acid cycle. For further biographical details, see the collection level description for the Krebs Papers (MS 116). The Krebs Collection consists of over 800 books and periodicals, which have been individually catalogued, and over 400 pamphlets, newspaper cuttings and reprints of journal articles, which have been listed. Some of the material has been annotated by Krebs. Books (octavos) International Neurochemical Conference (1965 : Oxford, England) Variation in chemical composition of the nervous system : as determined by developmental and genetic factors ; edited by G.B. Ansell on behalf of the National Committee of the International Neurochemical Conference, Oxford, 1965. - Oxford : Symposium Publications Division, Pergamon Press, 1966. [M0139812SH] Western Bank Library KREBS COLLECTION 1; 200673119 Reference. Inscribed with Hans Krebs' initials on half-title page. Western Bank Library KREBS COLLECTION 2; 200673120 Reference Ardenne, Manfred, Baron von, 1907- Eine glückliche Jugend im Zeichen der Technik ; Manfred von Ardenne. - Leipzig; Jena; Berlin : Urania Verlag, 1965. [M0135153SH] Western Bank Library KREBS COLLECTION 3; 200673014 Reference. Inscription on flyleaf by the author dated 7/7/66, and letter in reply from Krebs dated 14/7/66, pasted in at the back of the book. Ardenne, Manfred, Baron von, 1907- Ein glückliches Leben für Technik und Forschung : Autobiographie ; Manfred von Ardenne.
    [Show full text]
  • ALS and FTLD Associated FUS in Zebrafish
    Aus dem Adolf-Butenandt-Institut der Ludwig-Maximilians-Universität München Lehrstuhl: Stoffwechselbiochemie Vorstand: Prof. Dr. rer. nat. Dr. h.c. Christian Haass ALSandFTLDassociatedFUSinzebrafish- investigating disease mechanisms in vivo - Dissertation - zum Erwerb des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Laura-Carolin Hasenkamp aus Düsseldorf 2015 Gedruckt mit Genehmigung der Medizinischen Fakultät der Ludwig-Maximilians-Universität München Betreuer: Prof. Dr. rer. nat. Dr. h. c. Christian Haass Zweitgutachterin: Dr. rer. nat. Dorothee Dormann Dekan: Prof. Dr. med. dent. Reinhard Hickel Tag der mündlichen 04.04.2016 Prüfung: Eidesstattliche Versicherung Ich, Laura-Carolin Hasenkamp, erkläre hiermit an Eides statt, dass ich die vorliegende Dissertation mit dem Thema ’ALSandFTLDassociatedFUSinzebrafish- investigating disease mechanisms in vivo’ selbstständig verfasst, mich ausser der angegebenen keiner weiteren Hilfsmittel bedient und alle Erkenntnisse, die aus dem Schrifttum ganz oder annähernd übernommen sind, als solche kenntlich gemacht und nach ihrer Herkunft unter Bezeichnung der Fundstelle einzeln nachgewiesen habe. Ich erkläre des Weiteren, dass die hier vorgelegte Dissertation nicht in gleicher oder ähnlicher Form bei einer anderen Stelle zur Erlangung eines akademischen Grades ein- gereicht wurde. München, den (Laura-Carolin Hasenkamp) However bad life may seem, there is always something you can do, and succeed at. While there is life, there is hope. Stephen Hawking Table of contents List of figures XIV List of abbreviations XV 1 Abstract 1 2 Zusammenfassung 3 3 Introduction 5 3.1NeurodegenerativeDiseases........................ 5 3.2Frontotemporallobardegeneration.................... 6 3.2.1 Clinical classification & symptoms ................. 6 3.3 Amyotrophic lateral sclerosis ........................ 7 3.3.1 Clinical classification & symptoms ................
    [Show full text]