GORDON
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`RESEARCH
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`CONFERENCES
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`Page 1 of 10
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`ILMN EXHIBIT 1042
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`Page 1 of 10
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`ILMN EXHIBIT 1042
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`

`
`O
`
`‘
`Volume 291
`
`e 1443 THISWEEK IN SCIENCE
`23 February 2001 Number 5508
`|g1;:::yV0""5
`
`1441
`
`5Cl'ENCE ONLINE
`
`144?’
`
`EDITORIAL
`
`1453 NETWATCH
`
`1565 NEW PRODUCTS
`
`1456 CONTACTSCIENCE
`1568
`S NEWS 8‘ NOTES
`
`1449 EDITORS’ CHOICE
`
`
`
`1
`H°3V°“l)' Setting
`for science
`
`1460
`
`1461
`
`1463
`
`Ngws 0|: THE WEEK
`PALEOANTHROPOLO-G‘I": Scientists Spar Over
`claim‘ °f Eadie“ H""‘a“ "“‘°‘*°'
`Imam: Fusion Scientists Urge Closer Look
`at "53
`2002 SPENDING: First Bush Budget May Put
`Science on Diet
`
`1463
`
`SCIENCESCOPE
`
`1464
`
`‘. 1 465
`1557
`
`EUROPEAN SCIENCE: Max Planck Takes an
`E-pub[is]-ling plunge
`_
`_
`_
`.
`NEUROBIOLOGY: A Discrlrnmatlng Taste for
`Bitter
`
`Lh;Ol'|:;Erhlll;I"4ldS:ll!::::.cfi::.Il't to Hear Charges
`1466
`1466 Asmopfllslcsl cluster Reveals Earllfs
`lllppllllg Magnetlc Field
`PLANETARY SCIENCE: strange Doings on a
`NEgn-st.-"ck gsteroid
`PALEONTOLOGY: Whiff of Gas Points to
`Impact Mass Extinction
`
`14-67
`
`71469
`1530
`
`1470
`
`1470
`
`1471
`
`1472
`
`1475
`
`1476
`
`1477
`
`1481
`
`ASTROPHYSICS: New Headaches for
`U's"R"“ia" E"P°"'""°"t
`ENDANGERED SPECIES: west‘; Energy Woes
`Threete" Selmen Run!
`HIGH-ENERGY PHYSICS: B-Meson Factories
`Make a "Number From Hell"
`
`NEWS FOCUS
`
`PAPAL 5C'ENCE= 5'35"-""15"-‘ and "~e“B‘°"|
`Advance Together at Po11tificalAcademy
`Vatican Observatory Takes Long View-of
`Exploring the Heavens
`
`COMPUTER MODELS: Paleontologists Learn
`to shake up Vlrlual Bones
`SUPERCONDUCTIVITY: Material Sets Record
`for Metal Compounds
`CHINESE NADEHY OF 5CIENCE5= ln China.
`Publish or Perish ls Becoming the New
`R
`lit
`ea y
`RANDOM SAMPLES
`
`I
`SCIENCE S COMPASS
`
`1437 Lzrrzgs
`
`BOOKS ETAL.
`
`What Is a Planet? M. Mccaughrean. N. Reid, C. finney, D.
`Kirkpatrick, L. Hillenbrand. A. Burgasser. J. Gizis. s. Hawley.
`Response M. R. Zapatero Osario. ADHD: Disorder or
`Discipline Problem? 5. V. Faraone and J. Biederman.
`Politics of the Census D. W. Murray. Response K. Prewitt.
`Corrections and Clarifications
`
`1493
`
`1495
`
`F"'__"°N‘ The Dl_a$'l°‘ls A‘ Ughtmam
`reviewed byJ- '-Ielnle
`TECHNOLOGY. The Electric vehicle andthe
`8 rd
`H.‘
`A .
`h
`.
`cl b
`u e’? of ‘story D‘
`' Klrsc ' rewewe
`y
`L 5' Remh
`
`1491
`
`POLICY FORUM
`DEMOGRAPHY: Prospects for Human
`Longevity 5. J. Olshansky, B. A. Cames.
`A. Désesquelles
`
`
`
`1
`The benefits of
`paying attention
`
`fo El N"
`D
`1496 Efifispffidiltifi Sl
`ow an“ r
`mo
`:51-l
`JACOEE
`T '
`'
`1497
`PALEOCLIMATE: Was the Medievalwann
`Period Global? W. S. Broecker
`
`11499
`1550
`1547
`1502
`
`y1503
`1541
`
`y 1505
`1534
`
`y15D6
`155°
`
`CELL c1rcLE: centrioles at the Checkpoint
`A. W. Murray
`ELECTRONICS: Toward Paperlike Displays
`J‘ A‘ R°ger5
`IMMUNOLOGY: B Cell Receptor
`Rehabilitation—Pausing to Reflect
`L 8. King and J. G. Monroe
`
`EVOLUTION: A Horn for an Eye P. H. Harvey
`and C.J. Godfrey
`
`NEUROSCIENCE: Drums Keep Pounding a
`Rhythm in the Brain M. P. Stryker
`
`1438
`
`23 FEBRUARY 2001
`
`VOL 291
`
`SCIENCE www.sciencemag.org
`
`
`
`Page 2 of 10
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`

`
`
`
`1544
`
`NO way to treat a
`microbe
`
`RESEARCH
`
`71511
`
`RESEARCH ARTICLE
`
`Variability in the El Nir'1o—Southern
`Oscillation Through a Glacial-lnterglacial
`Cycle A. W. Tudhope. C. P. Chilcott. M. T.
`Mcculioch. E. R. Cook. J. Chappell. R. M.
`Ellam. D.W. Lea. J. M. Lough. G. B. Shimmield
`
`1517
`
`1519
`
`1 523
`
`1527
`
`REPORTS
`
`Observation of d,z_,z—Like
`Superconducting Gap in an Electron-
`Doped High-Temperature Superconductor
`T. Sato. T. |(amiyama.T.Takahasl1i. K.
`Kurahashi. K.Yamada
`
`Rapid Electron Tunneling Through
`Oligophenylenevinylene Bridges
`H. D. Sikes. J. F. Smalley. S. P. Dudek. A. R.
`Cook, M. D. Newton, C. E. D. Chidsey. S. W.
`Feldberg
`
`Automated Solid-Phase Synthesis of
`Oligosaccharides 0. J. Plante. E. R. Palmacci.
`P. H. Seeberger
`
`Redox State of Mars‘ Upper Mantle and
`Crust from Eu Anomalies in Shergottite
`Pyroxenes M.Wadhwa
`
`
`
`1 553
`
`Helping
`nucleotides to
`
`exchange
`
`.1530
`1469
`
`V1534
`1505
`
`1 537
`
`71541
`1503
`
`1544
`
`V1547
`1499
`1550
`
`11550
`1499
`154?
`
`1 553
`
`Impact Event at the Pennian-Triassic
`Boundary: Evidence from Extraterrestrial
`Noble Gases in Fullerenes L Becker. R. J.
`Poreda.A. (3. Hunt. T. E. Bunch. M. Rampino
`Costs and the Diversification of
`Exaggerated Animal Structures D. J. Emlen
`
`TCR-Induced Transmembrane Signaling by
`Peptidefl-IHC Class II Via Associated
`lg-DUB Dimers P. Lang. J. C. Stolpa. B. A.
`Freiberg. F. Crawford, J. Kappler. A. Kupfer.
`J. C. Cambier
`
`Contribution of Receptor Editing to the
`Antibody Repertoire R. Caseilas. T.-A. Y.
`Shih. M. Kleinewietfeld. J. Rakonjac. D.
`Nernazee. K. Rajewsky. M. C. Nussenzweig
`
`Induction of Direct Antimicrobial Activity
`Through Mammalian Toll-Like Receptors
`S.T|1oma-Uszynski. S. Stenger. 0. Takeuchi.
`M.T. Ochoa. M. Engele. P.A. Sieling. P. F.
`Barnes. M. Roilinghoff. P. L. Bélcskei. M.
`Wagner. S. Akira. M. V. Norgard. J. T. Beiisle.
`P.J. Godowski. B. R. Bloom, R. L. Modlin
`
`Requirement of a Centrosomal Activity
`for Cell Cycle Progression Through G1 into
`5 Phase E. H. Hinchcliffe. F. J. Miller. M.
`Cham, A. Khodjakov. G. Sluder
`
`Centrosome—Dependent Exit of
`Cytokinesis in Animal Cells M. Piel.
`J. Nordberg. U. Euteneuer. M. Bornens
`
`Structure of a B-agi"Hsc70 Complex:
`Convergent Functional Evolution of
`Hsp7O Nucleotide Exchange Factors
`H. Sondermann. C. Scheufler. C. Schneider. J.
`Hohfeld. F.-U. Hartl. I. Moarefi
`
`V1557
`1465
`
`Taste Receptor Cells That Discriminate
`Between Bitter Stimuli A. Caicedo and S. D.
`
`Roper
`
`‘x1560
`1506
`
`Modulation of oscillatory Neuronal
`Synchronization by Selective Visual
`Attention P. Fries, J. H. Reynolds. A. E. Rorie.
`R. Desimone
`
`
`
`COVER 1 569
`When rotated above a critical
`frequency. a single quantum of
`circulation. known as a vortex.
`forms in a gaseous Bose-
`Einstein condensate. marking
`the breakdown of superfluidity
`in a quantum fluid. The vortex
`core appears in this absorption
`image of the rubidium atom
`cloud as a hole in the density
`profile. The Gordon Research
`Conference on Atomic Physics
`will meet atW'I1lian1s College on
`17 to 22 June. The summer and
`international conference sched-
`
`ules begin on p. ‘[569. Ilmage:
`Kirkw. Madison. Frédéric Chevy.
`Jean Dalibardilaboratoire
`Kastler Brossel. Ecole Nonnale
`Supérieure. Paris]
`
`
`
`1 527
`
`How rusty is the
`Red Planet?
`
`hi
`
`AMERICAN
`ASSOCIATION FOR THE
`01:
`
`5
`
`Cl ENCE
`
`SCIENCE [ISSN 0036-8075} is published weekly on Friday. except H1-eiast week in December. by the American Association for the Advancement of Science. 1200 New Work
`M-enue. NW. Washington. DC 20005. Periodicab Mail postage [publication No. 484460} paid at Washington. DC. and additional mailing offices. Copyright E 2001 by the American
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`SCIENCE
`
`VOL291
`
`23 FEBRUARYZUO1
`
`1439
`
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`Page 3 of 10
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`Page 4 of10
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`Page 4 of 10
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`

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`1 4-56
`
`23 FEBRUARY 2001 VOL 291
`
`SCIENCE www.sciencemag.org
`
`
`
`Page 5 of 10
`
`

`
`REPORTS
`
`25. The experimental rate constants and activation
`energies can be used to obtain a minimum H“
`value (16). With a density of states of 0.3 ev- ‘ per
`gold atom. a reorganization energy of 0.9 ev, and
`a rate constant of 3 x 105 s“. nonadiabatic
`electrochemical Marcus theory gives a minimum
`Hag value of 52 cm“ at 298 K. The calculated H“
`in the case of the n = 4 model compound was 2.6
`cm“. Calculated H“ values cannot be directly
`compared with experimental Heb values because
`the model system has a ierrocene group where the
`experimental system has gold atoms. To account
`for this difference, we assume tight coupling be-
`tween the bridge and one carbon atom of the
`ferrocene in the model system and tight coupling
`between the bridge and one gold atom in the
`
`experimental system. Additionally, we assume that
`the additional vinylene in the model system is
`equivalent to the methyl thiol in the experimental
`system. The quantum calculation gives a wave
`function amplitude on the ferrocenyl carbon of
`0.14. Division of the calculated H“ by this coeffi-
`cient yields a more appropriate value of 18 cm‘ ‘
`for comparison with the lower limit of the exper-
`imental H_,, value. This value is within a factor of 3
`of the minimum obtained from experiment. Given
`the uncertainties in the calculation. we consider
`this result consistent with the conclusion that the
`rate is not limited by the electronic coupling.
`26, L D. Zusrrian. Chem. Phys. 49. 295 (1980).
`2?. J. Barthel, l(. Bachhuber. R. Buchner. H. Hettenauer.
`Chem. Phys. ten. 165. 369 (1990), T, = (e1feD)1'D.
`
`where -r,_ is the longitudinal polarization time. S” is
`the infinite-frequency dielectric constant. :0 is the
`static dielectric constant, and 1-D is the Debye relax-
`ation time.
`23. c.. K. Rowe. 5. E. Creager. Langmuir r, 2307 (1991).
`29. H.D.S. acknowledges an NSF Graduate Fellowship.
`S.P.D. acknowledges support from National Research
`Service Award 5 T32 GM03412 from the National
`Institute of General Medical Science. H.D.S.. 5.9.0..
`and C.E.D.C. aclcnowledge support
`from the NSF
`(CHE-941320] and the Stanford Office of Technol-
`ogy Licensing. J.F.S.. A.it.C. M.D.N.. and S.W.F. ac-
`knowledge support from the Chemical Sciences Divi-
`slon. Department of Energy (oz-iicoz-sacnioeasj.
`
`13 September 2000; accepted 1? January 2001
`
`Automated Solid-Phase
`
`Synthesis of Oligosaccharides
`Obadiah J. Plante. Emma R. Palmacci. Peter H. Seeberger"‘
`
`Traditionally, access to structurally defined complex carbohydrates has been
`very laborious. Although recent advancements in solid-phase synthesis have
`made the construction of complex oligosaccharides less tedious. a high level of
`technical expertise is still necessary to obtain the desired structures. We
`describe the automated chemical synthesis of several oligosaccharides on
`a solid-phase synthesizer. A branched dodecasaccharide was synthesized
`through the use of glycosyl phosphate building blocks and an octenediol
`functionalized resin. The target oligosaccharide was readily obtained after
`cleavage from the solid support. Access to certain complex oligosaccharides
`now has become feasible in a fashion much like the construction of oli-
`gopeptides and oligonucleotides.
`
`The understanding of oligosaccharides and gly-
`coconjugatcs in nature is still in its infancy (1).
`Cell surface glycoconjugates are involved in sig-
`nal transduction pathways and cellular recog-
`nition processes and have been implicated in
`many disease states (2). A major impedi-
`merit to the rapidly growing field of molec-
`ular glycobiology is the lack of pure, struc-
`turally defined carbohydrates and glycocon-
`jugates. These biomolecules are often found
`in low concentrations and in microhetcrogcv
`neous font: in nature, greatly complicating
`their identification and isolation. The pro-
`curement of sufficient quantities of defined
`oligosaccharidcs required for detailed bio-
`physical and biochemical studies therefore
`relies on efficient synthetic methods.
`Although much progress has been made
`in oligosaccharide synthesis (3), the con-
`struction of complex carbohydrates remains
`time consuming and is carried out by a
`small number of specialized laboratories.
`The necessary functionalizarion of all hy-
`droxyl groups present on a monosaccharide
`is one of the main challenges in oligosac-
`charidc construction. The development of a
`
`
`Department of Chemistry. Massachusetts Institute of
`Technology, Cambridge. MA 02139. USA.
`‘To whom correspondence should be addressed. E-
`mail: seeberg@mit.edu
`
`protecting group scheme that allows for the
`manipulation of individual hydroxyl groups
`is pivotal for the success of the synthetic
`route. Permanent protecting groups, such as
`benzyl ethers, are installed at positions
`where a free hydrcxyl will be present in the
`final deprotccted molecule. Temporary pro-
`tecting groups, such as esters, are used to
`mask hydroxyls that will be exposed at a
`certain stage of the synthesis. The liberated
`hydroxyl group then serves as a nuclcophile
`in the reaction with a glycosylating agent.
`The stereospecific formation of glycosidic
`bonds is the central challenge in carbohydrate
`chemistry (Fig. 1). The chemical formation of a
`glycosidic linkage involves activation of a gly-
`cosyl donor to create a reactive eleclrophilic
`species that couples with a nucleophilic acceptor
`hydroxyl. This coupling reaction can take two
`possible pathways resulting in formation of ei-
`ther or- or B-anorners. Current methods to con-
`trol the stereochemistry of the anomcric center
`rely on the participation of a neighboring func-
`tionality, such as an ester-protecting group on
`the C2 hyd.roxyl. Fonnation of a cyclic oxonium
`ion intermediate shields one face of the moie-
`
`leading exclusively to the formation of
`cule,
`trans-glycosidic linkages. Cis-glycosidic bonds
`are difficult to construct with high specificity
`because neighboring group participation is not
`possible.
`
`The evolution of a solid-phase paradigm for
`the construction of oligosaccharides was initiat-
`ed with Frechet’s synthesis of di- and trisaccha-
`rides on a polymer support in 197] (4 ). Since
`then, solid-phase oligosaccharidc synthesis has
`seen many advancements. Various glycosyl do-
`nors, such as anomeric sulfoxides (5) and anhy-
`drosugars (5), have been applied to the synthesis
`of carbohydrates on a polymer support. Several
`linkers serving to connect the growing oligosac-
`charide chain to the polymer support have been
`introduced with different reactivities and cleav-
`
`age procedures (6). Notably, a combinatorial
`split-and-mix approach on a support resulted in
`the synthesis of a library of N-acylated di- and
`trisaccharides (7). Although advancements in
`solid-phase chemistry have allowed for the con-
`struction of complex molecules, the manipula-
`tions remain tedious and time consuming.
`Ultimately, a general, automated method
`for oligosaccharidc assembly will allow for
`the rapid preparation of structures of interest.
`Oligonucleotides {8} and oligopeptides (9)
`are now routinely prepared in an efficient
`manner on automated synthesizers with solid-
`phase strategies. The solid-phase paradigm
`iends itself particularly well to automation of
`oligosaccharide synthesis as the repetitive na-
`ture of glycosylation and deprotcction can
`easily be framed into a coupling cycle. Ex-
`cess reagents can be used to drive reactions to
`completion. and resin washes can remove any
`soluble impurities. Only a single purification
`step is necessary after the sugar is liberated
`from the solid support.
`Mindful of the advantages of solid-sup-
`port synthesis, we considered several key
`issues for the development of an automated
`oligosaccharide synthesizer: (i) an instrument
`capable of performing repetitive chemical
`manipulations at variable temperatures, (ii)
`the design of an overall synthetic strategy
`with either the reducing or the nonreducing
`end of the growing carbohydrate chain at-
`tached to the support (I0), (iii) selection of a
`polymer and linker that are inert to all reac-
`tion conditions during the synthesis but
`cleaved efficientiy when desired. (iv) protect-
`ing group straiegies consistent with the com-
`plexity of the target oligosaccharidc, and (v)
`
`www.sciencemag.org SCIENCE VOL 291
`
`23 FEBRUARY 2001
`
`1 523
`
`
`
`Page 6 of 10
`
`

`
`stereospecific and high yielding glycosyla-
`tion reactions.
`Rather than designing a new machine, we
`opted to reengineer an existing apparatus used
`in automated peptide synthesis {H}. Several
`adaptations were necessary before the peptide
`synthesizer could be used for carbohydrate syn-
`thesis (12). Using this modified peptide synthe-
`sizer, we undertook a systematic investigation
`of the variables involved in automated soiid-
`
`phase oligosaccharide synthesis. We chose the
`“acceptor bound” strategy for solid-phase oli-
`gosaccharide synthesis {I3}. In this method. the
`reactive glycosylaung agent is delivered in so-
`lution while the nucieophilic acceptor hytiroxyl
`group is exposed on the solid support. Produc-
`tive coupling events result
`in support-bound
`oligosaccharides that are purified by simply
`washing the soluble side products through a
`filter. Removal of a temporary protecting group
`on the newly formed saccharide unit reveals
`
`REPORTS
`
`another hydroxyl group, thereby continuing the
`coupling cycle.
`To explore the compatibility of glycosylat-
`ing agents and protecting groups with a solid-
`phase linker and a polymer support, we inves-
`tigated the construction of polymarmosides.
`The synthesis of or-mannosides has been the
`focus of substantial research because of their
`
`occurrence in biological structures such as gly-
`colipids and N-linked glycoproteins (14, 15}. A
`series of or-( l—>2) mannosides (Scheme l, 3 to
`5) served as our initial targets for automation
`because structures of this type have been syn-
`thesized previously in solution and on the solid
`support U6}. Trichloroacetimidate donor 2 was
`chosen as the donor building block because it
`can be prepared on a multigram scale, is acti-
`vated at room temperature, and bears a C2-ester
`functionality to control the anomeric configura-
`tion of the polymer U 7}. Activation of 2 was
`carried out under acidic conditions with the
`
`H0
`
`r
`no
`ycosyl Donor
`
`GI
`
`I
`
`I
`
`no
`so
`
`H0
`
`HO -ammer
`/“\\ / "0
`no
`to
`is
`'\_{O R\ no
`go
`no
`H
`R0
`Glycosyl Acceptor
`
`FIO
`
`on
`
`“.0 or-anomer
`0
`
`"°$§'S,
`
`HO
`
`OH
`
`HO
`
`HO
`no
`x T. no
`
`no
`B0
`H0
`
`/“\ Ho
`
`:):o
`issues in the synthesis of carbohydrates: Oligosacchatides require the
`Fig. 1. Stereochemical
`formation of a particular stereoisomer (or or [3 anomer) during each coupling event. The use of
`participating groups. such as esters. leads to exclusive formation of trans-glycosidic linkages.
`
`‘is
`R
`
`9°
`R0
`
`no
`
`T. B-anomer
`R
`
`H
`
`ano
`BnO
`B
`
`Cleavage and purification
`
`
`
`
`
`H l Deprotection
`mi’
`59,,
`NaOMe!MeOH
`ca”;
`
`n
`
`Ac
`
`B B
`
`8
`8
`B
`
`
`
`B
`Bnfl
`B
`
`
`\
`
`Lewis acid trimethylsilyl trifluoromethanesul-
`fonate (TMSOTf). Removai of the acetyl ester-
`protecting group was accomplished under basic
`conditions with sodium methoxide.
`To allow for the use of