Page 1 of 8
`
`_HBHXENMN.
`
`M0
`
`
`
`Page 1 of 8
`
`ILMN EXHIBIT 1041
`
`

`
`AMERICAN
`ASSOCIATION FOR THE
`ADVANCEMENT OF
`SCIENCE
`
`Astronomerei Tame a Workhorse Laser V 1470
`
`PERSPECTIVES
`
`Could the Internet Balkanize Science?
`M. Van .-'\lsti,‘iii~ 1‘ll1L1 E. Bri'njiili's.ucin
`
`1479
`
`Space Carbon: Neutral Pathways?
`J. R. Heath and R.
`S'.iyl-L-lilli,-‘
`
`The End of the Message—Another
`Link Between Yeast and Mammals
`}. 1.. Manley Ellitl Y. -l-'.-'Il(}l}.‘_E!lvZl
`
`High Anxiety
`D.Giili_linai1
`
`POLICY FORUM
`
`V 1480
`
`.7.
`
`1481
`
`F’
`
`1483
`
`The R5113 Portfolio: A Concept for
`Allocating Science and Technology Funds
`M.
`:\»1i:Cie-ary and l’. M. Smith
`
`1434
`
`REPO RTS
`
`1436
`Mechanism of the Zonal Displacements
`of the Pacific Warm P001: implications for ENSO
`J. Pic-niit. M.
`llltiil-l‘Llll.'1"l. C. Metikes. T. Dulcriiix.
`M. _i. Mi: Pl1;lLlL‘n
`
`F’
`Molar Tooth Diversity. Disparity,
`and Ecology in Cenozoic Ungulate Racliations
`J. _lern\':ill.
`1‘. Hunter. M. Fiirteliiis
`
`1489
`
`1492
`
`ISSN 00353075
`29 NOVEMBER 1995
`VOLUME 274
`NUMBER 3292
`
`
`
`& 1
`1
`Calming down a chaotic
`iaser
`
`NEWS & COMMENT
`
`Germany Joins the Biotech Race
`
`The Human Gene Hunt Scales Up
`
`UK. Universities: Top-Ranked
`Departments, 1991-95
`
`Japan Hopes to Cash In On
`industry-University Ties
`
`UT Southwestern: From A1-rm,’ Shocks
`‘0 Research Elite‘-i
`
`1454
`
`1456
`
`1456
`
`1457
`
`1459
`
`Grad Students Press for Right to Strike
`
`1461
`
`RESEARCH NEWS
`
`Sizing Up Evolutionary Racliations
`
`K 1462
`
`HIV’-5 Other Immune-System Targets:
`Macrophages
`
`First Blush for integrated Light Emitter
`
`Neuroscience's Meeting of the Minds
`
`in Washington
` / Found: ]upiter’s Missing Water
`
`Slow Leak Seen in Saturn’5 Rings
`
`Hubble Gives a Quasar House Tour
`
`1464
`
`1455
`
`1466
`
`1467
`
`1468
`
`1468
`
`
`
`
`Ecological Controls on the Evolutionary F‘
`Higher Yielding Perennials Point the
`
`Reciiven‘ of Post-Paleozoic Crinnitls
`M. Fiiiitc
`Way to New Crops
`
`
`
`DEPARTMENTS
`109am
`
`
`hulics at Bellevue, 19113-1919: R. Roizeri
`THIS WEEK IN SCIENCE
`
`1453
`SCIENCESCOPE
`ITORIAL
`
`New Politics in Science
`1471
`“"00" 5AM”-E5
`P_ G_ Rogers
`1478
`BOOK REVIEWS
`-
`
`National Militm-gr Establisluiteiits and the Adviizriceirient
`1447
`,_
`_
`l"'E-I-_l‘:E’R‘S
`D! Scam and T
`‘ reviewed by D‘ Pam ,
`'l£hi;ufi}reenEt%l'll,Ypothesi;:]., H. §31feenbergl'.3G.
`
`Ei.a0luu'on
`Social insect Colonies u G Mueller etc.
`W“ '
`1 5°” '
`‘min '='“‘=="'-‘=
`re‘
`01
`diction: S. A. Bentier, D. L. Geroff. ]. D. Rozzell 0
`PRODUCTS 8- MATERIAI-5
`EMF Report:
`is There Consensusi: i<. Florig -
`Low-Level Radiation: G. Siohrer 0 Women A1c0- Mas News 3, Notes
`
`1469
`
`1441
`1445
`
`_
`
`1 495
`.
`.
`.
`Clementine gets a chilling
`lunar echo
`
`'
`
`
`
`
`
`
`
`
`1555
`1557
`
`AAAS Board at Directors
`Sheila Jasariofi
`Rita Fl. Coiwall
`Heii'n'ng President. Criairrnan William A. Lester Jr.
`Jane Lubci-Ienw
`3;;-non A‘ Levin
`Preside”:
`Marcia C_ Linn
`"1
`k
`M“
`D
`Ml
`[J N
`"3559 aus
`'ed_S‘
`Chas
`‘ mace
`'
`P’95‘d9”3'9i9''-'i
`A""a 3- H°°59VB[l
`Joan E. Taylor
`Nancy S. Weitl-er
`
`1433
`
`William T. Golden
`Treasurer
`Fucham 3_ Nicholson
`Execufive omcer
`
`I SCIENCE HSSN D036-Mrs] is published iiiieekiy on Friday. eiieepi the last week In
`December. W “'9 ‘“"'""“""' ‘‘“°°“'''°''' 10! the M_V8rK=8I'MI11 01' Sc-_ieI'I°0. 1200 NW ‘_’DI1i
`.fl.venue.N1i\‘.Washlngtori_, DC
`Periodicals M_a.1I postage ipubiicalinn hie.-11?.-h150_ii:iaid al
`Washington. DC. and ElifllhoflaiI112-lIll|'lQ0lf|C95.CO|J'|fl|gl'lIla'l9'§-5 by the American Association ipr
`lhe Aovancemiani oi Scenes. The Iille SCJENCE is a rsgislerso trademark 01 Ina AMS. Domestic
`indiwduairnernbership and subscription :51 issuesi: $1D2{$55 aliocaladlo subscription}. Domestic
`instiiu1i0naIsuoscripti0ri!51 issues}:$25D. Foreign postage exira;Me:ir.o. Caribbean [surface ii-ia.iIi
`555: other nounlries [air assisl delivery] 590. First class. airmail. suidenl. and siiienius rates on
`request. Canadian rates wilh GET available upon request. GSTM254 3-B122. Friritad in the U.S.A.
`SCIENCE 0 VOL. 3?-1 0 29 N0\-"EMl’~ER I996
`
`
`
`Page 2 of 8
`
`

`
`
`
`Scanning electron micrograph depicting developing
`female spikelets in maize homozygous for the 2-391‘-
`mumf mutant allele (magnification X115). The muta-
`tion results in a loss of floral meristem determinacy that
`is manifested by the production of eittra silksfrom each
`
`COVER
`floret. The mutant phenotype was uncovered through a
`recently developed reverse genetics approach in maize.
`See page 153?. llmage: B. A. Ambrose and M. Mena.
`University of California. San Diego]
`
`1495
`The Clementine Bistatic Radar Experiment
`S. Nvtette. C. L. Lichtenherg, P. Spudis, R Bonner,
`W. Orr. E. Malarct. M. Roliiiisnn, E. M. Shoemriliter
`
`Stabilizing Lead—SaIt Diode Lasers:
`Understanding and Controlling Chaotic
`Frequency Emission
`G. Chin. L. R. Senesac. W. E. Blatsii, J. J. Hillman
`
`7 1498
`
`Solar Wind Magnetic Field Bending of
`Jovian Dust Trajectories
`H. A. Zoult, E. Griin, t\rl. Bnguhl. D. P. Hamilton.
`G. Linkcrt. J.—C. Liou. R. Forsyth. J. L. Phillips
`
`1 501
`
`Transporter Gene Regulatory Region
`K.—P. Leech. D. Bengel. A. Hells. S. 2. Sahnl. B.
`D.(3reer1herg, S. Perri. Benjamin, C. R. Miiller,
`D. H. Hamet, D. L. Murphy
`
`Discovering High-Affinity Ligands for
`Proteins: SAR by NMR
`3. B. Shuker. P. J. Hajdulc, R. P. Meadows. 3. W.
`Fesik
`
`1531
`
`Self-Sterility in Arabidopsis Due to
`Defective Pollen Tube Guidance
`L. K. Wilheliiii and D. Preuss
`
`1535
`
`The Little Ice Age and Medieval
`Warm Period in the Sargasso Sea
`L. D. Kt':lj_{Wit'I
`
`1504
`
`Diversification of C-Function Activity
`in Maize Flower Development
`M. Mona. B. A. Ambrose, R. B. Meeley. S. P.
`Briggs. M. F. Yanrtfslqr. R. Schmidt
`
`153?
`
`1 543
`Telomere
`
`;.
`length and
`HIV infection ;.'f
`
`
`
`A Combined Experimental and
`Theoretical Study on the Formation
`of interstellar C,H lsomers
`R.
`[. Kaiser. C. Ochsenfcltl. M. Hcad—Gnrdnn. Y.
`T. Lee. A. C}. Slllliki
`
`1503
`
`7'
`
`Essential Yeast Protein with Unexpected I 1511
`Similarity to Subunits of Mammalian Clvage
`and Polyadenylation Specificity Factor (CPSFl
`Ci. Chanfrc-.1u. S. M. Noble. C. Guthrie
`
`I 1514
`Sequence Similarity Between the
`73-Kilodalton Protein of Mammalian CPSF
`and a Subunit of Yeast Polyaclenylation Factor]
`A. Jenny. L.
`i\r1im'ielle-Sehastia. P.
`Preltcr. W.
`Keller
`
`K 1517
`Dependence of Yeast Pre-mRNA
`3’-End Processing on CFTI: A Sequence Homolog
`of the Mammalian AAUAAA-Binding Factor
`L}. Stuiiipland H. l..7rii1‘ttley
`
`Parallel Synthesis and Screening of
`a Solid Phase Carbohydrate Library-
`R. Liang. L. Yen. J. Loehach, M. Ge. Y. Uozumi. K.
`Seltanin-.1. N. Huron, J. Giltlerslccve, C. Thomp-
`son. A. Smith. K. Bis“-‘as. W. C. Still. D. Kahne
`
`1520
`
`1523
`Myc and Max Homologs in Drosophila
`I‘. Unllanr. Y. Shim. I‘. F.Clie11g.S. M. Parkliutst.
`R. N. El5t_'[‘IIl1ill1
`
`Association of Anxiety-Related Traits
`with a Polymorphism in the Serotonin
`
`E
`
`1527
`
`CRNF, a Molluscan Neuron-ophic Factor I 1540
`That Interacts with the p75 Neurotrophin
`Receptor
`l. Syed. W. C.
`M. Fainzilher, A. B. Smit. N.
`Wilderittg, P. M. Hermann, R. C. van dcr Schors.
`C. Jimenez. K. W. Li, J. van Minnen. A. C. M.
`Biilloch. C. F. lbeificz, W. P. M. (Jernert.-;
`
`1543
`
`T Cell Telomere Length in HIV-1
`Infection: No Evidence for Increased CD4‘
`T Cell Turnover
`K. C. Wolthers. G. B. A. Wisman, S. A. Otto,
`A.—lV[. dc Roda Husnian. N. Sch-aft. F. tle Wolf.
`Goudsmit, R. A. Cotitinho. A. (3. J. van tier Zee.
`L. hzlcyaard. F. Micdema
`
`TECHNICAL COMMENTS
`
`Genetic Data and the African Origin
`of Humans
`J. K. Pritcltard and M. W. Feldman; Resportie: N.
`Risclt. K. K. Kidd. S. A. Tishktiff
`
`1548
`
`1549
`Late Permian Extinctions
`R. E. Martin; (3. J. Vermeij and D. Dorritie; K.
`Caldeira: M. R. Rampino; Rcsptmsc: A. H. Knoll,
`R. K. Bamhach, D. Canfield.
`P. Grotzinger;
`Rrzsponsez P. B. Wign-all, R. Twitchett
`
`HLA Sequence Polymorphism and
`the Origin of Humans
`H. A. Erlich, T. F. Bergstriarn. M. Stoneking. U.
`Gyllensten: Response: F. Ayala
`
`1552
`
`[- Indicates accompanying feature
`Change of address: alhoiv a weeks, giving old and new addresses arid 5-digit account number.
`Postmaster: Send charine ol address Io Science. F'.0. Box 1311. Danbury. CT 06313-1311.
`Single copy sales: 5100 per issue prepaid includes surtace postage; bulk rates on request.
`Ruthoflzatlon to photocopy material for lntemat or personal use under circurrtstances not telling
`within Ihe lair use provisions ol the Copyngtil MI is granted by AAAS to libraries and other users
`registered with the Copyright Clearance Center [CC-Ci Transactional Fleooning Service, provided
`that $4.00 per article is Paid directly to CCC. 222 Rosewood Drive. Danvors. MA 01923. The
`identification code tor SoI'em:v.= as cross-aorsees $4.00. Science is indexed in the Readsire Guide to
`Penodicai Literature and In several specialized inoa res.
`
`_
`
`. {he .
`
`Get your daily news fix from Science's news team:
`http:Hivvvw.sciencenow.org:'
`SCIENCE 0 VOL. 274 0 29 NOVEMBER 1996
`
`Sci1~:NcENQ]V
`
`1439
`
`
`
`Page 3 of 8
`
`

`
`THIS WEEK IN SClENCE
`
`J
`
`'
`
`Z
`
`"
`
`" "
`
`"
`
`'
`
`edited by PHIL SZUROMI
`
`T cell turnover in HIV-1 infection
`
`One theory for why CD4‘ cell counts decline during the course of
`HIV-1 (human immunodeficiency virus—type 1) infection is that
`rapid turnover in the effort to replace these T cells exhausts their
`regeneration capacity. If so. then one would expect that the length
`of telomeres, the structures at the ends of chromosomes, would
`decrease in CD4‘ cells over time. Wolthers et al. (p. 1543) exam-
`ined telomere length in CD8‘ and CD4‘ cells from samples ob-
`tained over a several year period in I-IIV+ individuals and found
`that while telomere lengths decreased in CD8‘ cells, there was no
`significant change in CD4‘ cells. This difference was not caused
`by sortie change in telomere processing, as CD4’ cells from these
`individuals did show decreases in telomere length after division in
`cell culture. These results suggest that HIV-1 infection may inter-
`fere with cell renewal in CD4‘ Cells.
`
`et al. (p. 1520) describe the
`use of anomeric sulfoxides to
`
`produce a solid—phase library
`of about 1300 di— and trisac—
`
`charicles. They identified two
`ligands that bind more strongly
`to the Bauhinia purpurect lectin
`than does the natural ligand.
`
`Snail neurotrophic
`factor
`The existence of substances in
`
`mollusks that promote neu-
`ronal growth has been contro-
`versial. Fainzilberetal. (p. 1540)
`describe the isolation of a pep-
`tide from snails that can cause
`
`neuronal sprouting and growth.
`The new factor binds to one of
`
`the mammalian neurotrophic
`factor receptors—l-tnown as
`p?5——but the factor itselfshows
`no homology to any previously
`identified neurotrophins.
`
`Special delivery
`Fertilization in higher plants
`depends on growth of the pol-
`len tube, through which sperm
`cells are delivered to the ovule.
`
`Wilhelmi and Preuss (p. 1535)
`have identified two genes in
`
`
`
`Arabldopsis that, when mutated,
`disrupt the guidance mecha-
`nisms that direct each pollen
`tube to an available ovule. That
`
`both pollen and pistil tissue
`must carry the mutant genes in
`order for guidance to be dis-
`rupted suggests the genes may
`encode molecules that mediate
`cell—cell adhesion.
`
`1441
`
`fore, during, and after its clos-
`est approach to Jupiter in 1991
`and 1992, most of which appear
`to emanate from the direction
`
`oflupiter. Zook er al. (p. 1501}
`simulated the trajectory of the
`particles that impacted the
`detector backward in time to a
`
`specified point of origin near
`Jupiter and found that those
`dust grains that fit their model
`had to be faster and much
`
`smaller than had been previ-
`ously thought. These simula-
`tions provide a more accurate
`estimate of the particle charac-
`teristics and indicate the strong
`influence the solar magnetic
`field can have on accelerating
`jovian dust grains away from
`their source.
`
`Carbohydrate library
`Cell surface carbohydrates play
`an important role in biological
`recognition processes. Screen-
`ing strategies to identify ‘tarba-
`hydrate derivatives that bind to
`particular protein targets are
`hampered, however, by the syn-
`thetic difficulties because. un-
`like peptides and nucleic acids,
`stereochemistry must be con-
`trolled as monomers are added
`
`Pool moves
`
`The western equatorial Pacific
`Ocean is characterized by the
`warm pool, a region of higher
`sea surface temperatures. The
`warm pool drives the world's
`most intense atmospheric con-
`vection, and the migration of its
`eastern edge is an essential fea-
`ture of the El Nif'1o—Southern
`
`Oscillation. Picaut et al. (p.
`1486) investigated the migra-
`tion mechanism by deriving
`rLear—surface and surface current
`
`fields from buoy and satellite
`data,
`in combination with
`ocean model studies. Evidence
`
`for zonal convergence of water
`masses and a well-defined salin-
`
`ity front at the eastern edge of
`the warm pool was obtained,
`showing that zonal advection
`dominates the migration. The
`warm pool, composed of low-
`density fresher and warm water,
`is relatively isolated from the
`surrounding Pacific, explaining
`why it can easily be displaced by
`wind—driven currents.
`
`Open-ocean
`cllmate record
`Detailed climate records cover-
`
`ing the last several hundred to
`thousand years are needed to
`provide a base line with which
`to evaluate the effects of an-
`
`thropogenic emissions on cli-
`mate. Although there are sev-
`eral detailed records available
`
`on land (ice cores, for example),
`records for the open oceans
`have been difficult to obtain
`
`because a core with a high sed-
`imentation rate is required.
`Keigwin (p. 1504) now de-
`scribes a record from the Sar-
`
`gasso Sea that has sufficient
`resolution. The record shows
`
`1°C warmer than today during
`the Medieval Warm Period
`
`(about 1000 years ago).
`
`Ice on the moon?
`The Clementine spacecraft per-
`formed a bistatic radar experi-
`ment to identify the structure
`and composition of the lunar
`poles. Nozette er al. (p. 1495)
`believe that the same-sense po-
`laiization enhancement of the
`
`radar echo they observed in the
`permanently shadowed regions
`of the south pole are caused by
`the presence of ice. possibly
`mixed or covered with the
`
`rocky regolith. Although icy
`patches may not provide a
`unique solution for the radar
`signal, the authors suggest a
`mechanism for their presence:
`Volatiles, which degassed from
`the proto-moon or were brought
`in by comets, condensed and
`concentrated in the perma-
`nently shadowed patches of the
`lunar poles.
`
`that sea surface temperatures
`were about 1°C cooler than to-
`
`Fast, tiny dust
`The cosmic dust detector on
`
`day during the Little Ice Age
`(about 400 years ago) and about
`
`board the Ulysses spacecraft
`detected 11 streams of dust be-
`
`to a carbohydrate chain. Liang
`SCIENCE 0 VOL. 2'24 0 29 NOVEMBER 1996
`
`
`
`Page 4 of 8
`
`

`
`
`
`MEMBERSHIPJCIRCULATION
`Director: Michael Spinella
`Deputy Director: Marlene Zendell
`Iilernberservtoes: Donald Crowl. Manager: Mary Curry.
`Supervisor: Pat Butler. Laurie Baker. Yvette Caner
`Representatives
`Ifiarlteting: Dee Valencia. Manager; Jane Pennington.
`Europetvlanager; Hilary Bear. Assistantllrlanager; Lauri
`Sirois. Coordinator
`Research: Flenui-ca Chander. Manager
`Business and Finance: Robert Smariga. Manager:
`Nina Araujo de Kobes. Kimberly Parker. Coordinators
`Computer Specialist: Charles Munson
`AD\lEFl11S|NG AND FINANCE
`Associate Publisher: Beth Roener
`Advertising Sales Manager: Susan A. Meredith
`Recruitment Advertising Manager: Janis Crowley
`Business Manager: Deborah Rivera-Wienitold
`Finance: Randy Yi. Senior Analyst: Connie Dang. Fi-
`nancial Analyst
`Marketing: John Meyers. Manager: Allison Pritchard.
`Associate
`Electronic Media: David Gillikin. Manager; Mart: Croatli.
`Crystal Young, Production Associates
`Product Advertising: Carol Maddox. Trafiic Manager“,
`Natalie Britt, Sales Associate
`Product Advertising Sales: East CoastlE. Canada:
`Richard Teeiing. 201-904-9774, FAX 201 -904-9701 -
`Mldwestrsoutheestr Elizabeth lvloslto. 773-665-1150.
`FAX 773-665-2129 - West Coastiw. Canada: Neil
`Boylan. 415673-9265. FAX 415673-9267 - UK. Scari-
`dlnavia. France. Italy. Belgium. Netherlands: Andrew
`Davies. (44) 1-457-333-519. FAX (44) 1457338393 -
`Cern1enyiSwitzer|andrAustrte: Tracey Peers, (44) 1-
`260-297-530, FAX (44) 1-260-271-0212 - Japan: Mashry
`Yoshikawa. (31) 3-3235-5961. FAX (31) 3-3235-5352
`Recruitment Advertising: Terri Seiter Azie, Sales and
`Production Operations Manager: Celeste Miller. Sales
`Supervisor. Eric Banks. Troy Benitez. Bren Peters-
`Minnis, Bethany Ritchey. Sales: Debbie Cummings.
`European Sales Manager: Wendy Green. Production
`Associate; Nicoie Robinson. Advertising Assistant
`Recruitment Advertising Sales: US: Janis Crowley.
`202-325-5532. FAX 202-239-5742 - Europe: Debbie
`Cummings. (44) 1223-1302067, FAX (44) 1223-5762013
`- Australlarhiew zealand: Keith Sandeli. (61) 02-
`922-2977. FAX (61) 02-922-‘I100 ' Japan: Mashy
`‘toshiltawa, {B1} 3-3235-5961 . FAX (31) 3-3235-5352
`Assistant to Associate Publisher: Nancy Hicks
`Pennlssions: Lincoln Rlchman
`Exhibits Coordinator: Arlene Ennis
`Send materials to Science Advertising. 1200 New York
`Avenue. NW, Washington, DC 20005.
`SCIENCE EDITORIAL BOARD
`Charles J. Arntzen
`John J. Hoplield
`David Baltimore
`F. Clark Howell
`J. Michael Bishop
`Paul A Marks
`William F. Brinkman
`Yasutomi Nlenizuira
`E. Margaret Burbiclge
`Helen M. Fianney
`Pierre-Gilles cle Gennee
`Bengt Ssrnuelsson
`Joseph L. Golclstsin
`Ruben M. Snow
`Mary L. Good
`Edward C. Stone
`Harry B. Gray
`James D. Watson
`Richard N. Zare
`
`I Published bythe American Association rorthe Adveltoerrlertt oi
`Science {AAA3'_I. Sciencemrves its readers as aierurnlor the presen-
`Iation and cisutssion ol important issues related in the advancerneril of
`scenes. incbting Ihe presentation of nlinorily or contticling points of
`view. rather than by puI:iI'st'ing only material on which a consensus has
`been reached. Accordingly. all articles polished 'I1 So'ence—incbcling
`editorials. nerve and comment. andbools revlews—are signed and reltect
`the inciviclualvlews oi the authors and not otliclsl polntsotview adopted
`by the AAAS or the institutions with which the authors are ailiiialecl.
`I The American Association [or the Advancement or science was
`founded in 1348 and incorporated in 1374. its ooiectives are to Iurlher
`the work or sdeniisls. to iaoiliiale cooperation among them. to foster
`s<:'anti1k:ireedorn and resporisibility. to improve the etleotivenees of
`science in the promotion of human welfare. to advance education in
`sriance. and to increase public unoerslanting and appreciation of the
`imponenoe and prontise oi the methodsot science in human progress.
`
`INFORMATION RESOURCES
`
`SUBSCRIPTION SERVICES
`For change of address, missing issues, new orders and
`renewals. andpaymentquestions, please oomact AAAS
`at Danbury. CT: 800-731-4939 or Washington, DC:
`202-326-6417, FAX 202-842-1065. Mailing addresses:
`AAAS. PO. Box 1311, Danbury. CT 06813 or AAAS
`Member Services, 1200 New York Avenue. NW. Wash-
`ington, DC 20005 - Other AAAS Programs: 202-
`326-8400
`
`REPRINTS & PERMISSION
`Reprints: Ordering/Billing, B00-407-9191: Correc-
`tions.202-326-6501 - Permissions: 202-326-7074.
`FAX 202-682-0815
`
`INTERNET ADDRESSES
`science_editors@aaas.org (for general editorial que-
`ries): scienoe_news@aaas.org (for news queries):
`science_IeIIers@aaas.org (for letters to the editor):
`sciencegreviews@aa.as.org (for returning manuscript
`reviews): science@science~im.oo.uk (for the Europe
`Oifice); memoership@aaas.org (for member services):
`science_classifieds@aaas.org (for submitting classi-
`iied advertisements); science__advertising@aaas.org
`(for product advertising)
`lNFORMA11ON FOR CONTRIBUTORS
`See pages 93-94 oi the 5 January 1996 issue or
`
`access irttp:h'www.sciencemag.orglsciencelhon1el
`oon—inlo.shirnl.
`
`EDITORIAL at NEWS CONTACTS
`
`North America
`Address: 1200 New York Avenue. NW, Washington,
`DC 20005
`Editorial: 202-326-6501. FAX 202-289-7562
`News: 202-326-6500, FAX 202-371-9227 -
`Bureaus: Berkeley. CA: 510-841-1154. FAX 510-
`341-6339, San Diego. CA: 619-942-3252, FAX 619-
`942-4979, Chicago,
`IL: 312-360-1227. FAX 312-
`360-0537. Boston, MA: 617-566-7137, FAX 617-
`734-8088
`
`Europe
`Headquarters: 14 George IV Street. Cambridge. UK
`CB2 1 HH; (44) 1223-1302067, FAX (44) 1223-1302068
`Paris Correspondent: (33) 1-49-29-09-01. FAX (33)
`1-49-29-09-00
`
`Asia
`Japan Ofiice: Carl Kay. Esaka-cho 5-chome 11-10.
`Suits-shi. Osaka 564 Japan; (81) 6-368-1925, FAX
`(81) 6-365-6905; science@magical.egg.or.jp
`- News Bureau: (81 ) 3-3335-9925, FAX (81 ) 3-3335-
`4B98 - China Otlice: Hao Xin. (86)10-6255-9478;
`science@public3.bia.net.cn
`
`Frederick W. Alt
`Children's Hospital Boston
`Don L. Anderson
`California institute of
`Tea-analogy
`Michael Ashbumer
`Luhrv. of Cambridge
`Stepnen J. Benkovlc
`Psnrlsyrvania State Un.-"v.
`Man Bammein
`Mount Sinai Hospital,
`ro..-mg-0
`53m 313],
`tlniv. or Wrsoonsm,
`,1,§g¢fi5gn
`David E_ groom
`l-iarirerd institute rot
`international Develop.-'nent
`PM 30,91
`The Netherlands Cancer
`,ns,flU,e
`Henry pl. Bourne
`Univ. or Calltomia. San
`F
`.
`I mmsm
`Michael S. Brown
`Univ. at Texas Soutn-
`mien: Meolicsl Center
`JamesJ. Bull
`_
`Univ. of Texas alrtusun
`"“”"3""' °?""“°_
`Columbia Univ. College cl’
`P"”"°““3 5 5"‘9"°“'*
`Dennis W. Choi
`“""”"‘.9_‘°" “”“’- 3°"’°°"
`°‘fM9°m‘"9' 5'' Lows
`David Clapham
`Mayo Foundatror:
`1“dI"IE|'l|'lE E. Ciflfilfl
`Univ. of Melbourne.
`'°3"*"'”9
`J°""' M- c°'fi"'
`Tufts Univ. School of
`“WW9 I
`F. Fleming Cfim
`UL-tiv. or Wrscorrsin.
`“adi-W"
`Paul J. Crutzen
`MaxvPi'e.nc.kvtns.titt.rt ffir
`009"“
`James E. Dahiberg
`Univ. of Wisoortsirt Medical
`SW00‘. Hadiim
`R059“ D95i|'|'|0l"9
`National institute of Mental
`Health. Nll1'
`
`BOARD OF REVIEWING EDITORS
`Paul T. Englund
`Gottfried Sohatz
`Harvey F, Lodish
`Biozentrurn. Basal
`lrwrtlahead institute for
`Joltns Hqolrin-5 unrv.
`Sclhootot Medlnirie
`Jozei Schell
`Blornedrtal Research
`G. Ertl
`Max-Plattclrvlnstrlut nlr
`Richard Loelck
`Mex-Ptanclr-Gesellechaft
`Zrrohttmgforedlung
`Harvard Univ.
`Richard G. Fairbanks
`Ronald H. Schwartz
`Reinhard Ltihrrnsnn
`National lnstrtute of Allergy
`Lamont-Donerty Earth
`ii-‘tslihrt tL‘lr Mcabln.rlar-
`and infectious Diseases.
`blobs-'9md l"|-marina’-trim
`Observaiofllf
`mu
`der Pnilipps-Universttar
`Haber! 5- Fat
`U.S. Bureau of the Census
`Terrence J. Sejnowslrl
`RUTH |-II'l'|dfi|'|‘BB||
`sag; msflmig
`Queens UrIr'v.. Ballast
`Douglas T. Faaron
`l.r'nr‘v. of Camhnttge
`Christopher R. Sontenrllle
`Se-1h Marder
`Harry A. Fozzsrd
`Gamegle institute at
`camlmia -'”5'*’”‘-"'9 0’
`7719 U”iV- Di 9050890
`Washington
`Technology
`Thomas A. Steliz
`Dian? Mathis
`Roger I, M. Glass
`ya.)-5 Um-,,_
`rnsrrn.-r cle cnrmra
`Centers for Ehseese
`004'"-'0!
`Michael P, Stryker
`Broloelttue Strasbourg
`unrv. orcarrromra. Sen
`5'55" K- MGCOHM"
`Stephen P- G0"
`Ffindsco
`Stanford Univ.
`Univ. College or
`ciiir Tabin
`Mlhoflir 9- M98115
`-°"'.|’-‘ml?-'33 -5 5U’99°"*5
`Hanfimv “Q5638; School
`DUK9 Uflltf. #780536: C9l'lI'8l'
`Peter N. Goodlellow
`Smithtriine Beechsrn. UK
`John Jen Tel
`5‘a"'‘”‘' M‘°iz°'
`Peter Gross
`Academia Slnica, Taiwan
`1-'-"W 0' C-i'”W”'9- 53“?
`Max Planck lnslilule or
`Tomoyulci Talrahashi
`Shigeiada Nakanishi
`Biophysical Clrernistry
`um. at Tokyo
`_"‘3""’° ‘-""""-
`_
`C
`Masatoshi Tal-reichi
`K'"' "'i"”‘Y"‘
`.
`Pig”
`“mo Um.
`Research tnstrttrte of
`Paularqaway M‘
`Kelji Tanaira
`",°"""”‘°"' P"”’°‘°W-
`Rlt(ENtns.iti'u1'e
`""°”"“ .
`wwlofoxford
`M P H
`H
`David Tilman
`“we! A‘ “ml
`.
`MW Ofuwmsom S1. paw
`Univ. of Callomra. San
`lrnperlal College at
`3.
`rpm
`.
`‘
`‘
`.
`.
`Stetlan Normark
`mm‘: N Tjian
`'
`1
`F’3""‘°°
`Nobutaita Hirolrawa
`mmmew my
`Univ of Tokyo
`Tomas Hdkielt
`lrrtectrous Btisease Control
`Univ 0', Tokyo
`Karotlnske institute!
`Ben w' Owens?
`Ernil Fl‘ Unanue
`Baylor College of Medicine
`‘
`.
`1-asuku Hon]-O
`Swan L_ Pimm
`Wasliiriglon Univ. Srthool
`0.‘ Medicine. St. Louis
`Kym.’ Um-VI
`The Univ. of Tennessee,
`Susan D_ Iversan
`Derek van der Kooy
`Knoxville
`Univ. of Toronto
`Um-V. of am,”
`Yesnayau Pocirer
`Eric F. Johnson
`Geerai .1. Vermeij
`Univ. of Washington.
`Univ. of California, Davis
`Seartte
`‘the kappa Research
`I-"sh-‘Ute,
`Ralph S. Quairano
`3'3" V°99|st°".1
`Elliott Kleff
`Univ. orrvorrri ca.-orrna.
`-"’“"‘ ”°P’°”° °"“”°9l’
`Hawalfi Una,‘
`Clrepei Hill
`'3‘’‘‘‘‘’'
`_
`Jud)-[h K).-“bra
`Marlin Ha”
`Arthur Weiss _
`_
`unrv. or Wtsoonsrh.
`Univ. College London
`l-’-W *?°' 5‘-"l'”°l'"«'-‘F 35“
`Mnmrsm
`Douglas C. Rees
`F"3""'-‘SW
`Stephan M_ Kass)!“
`_
`_
`carrtomra Institute or
`Zena _W-Vb
`Harvard Univ.
`rachnotogy
`UHN. olcallfomra, San
`Michael Laaarbera
`T. M. Rice
`Fmndsm
`The l..-’niv. or Chicago
`Er)‘-r.r-:45,-(Q99;-pg,-_g, 25-rich
`George M. Whilesldes
`David C. Flubie
`H-il"|-’fll'd UM!’-
`Nicole Le Douarin
`lnslrlrrl d'Ernbryoiogie
`Unlversrtar Bayreuth
`Owen N. Wilts
`Celiulaire er Moleouiaire
`Eridti Ru-osiahti
`Uni'v. of Cefllbrnie, 1.08
`o'er CNHS
`The Burrrharn lnstitttte. GA
`Arrgeies
`
`SCIENCE 0 VOL.27-1- 9 29 NOVEMBER 1996
`
`1443
`
`
`
`Page 5 of 8
`
`

`
`standard cleavage and polyadenylation reaction (15)
`except that reactions were incubated for 60 min at
`30°C.
`20. S. Bienroth. W. Keller, E. Wahle, EMBO J. 12, 585
`(19931.
`21. A. Moreira. M. Wollerton. J. Monks, N. J. Proudfoot,
`EMBO J. 14. 3809 (19951.
`22. G. rvl. Gilmartin, E. 8. Flaming. J. Oetjen. B. R. Grav-
`eley. Genes Dev. 9. F2 (1995).
`23. A. Biiger, C. A. Fox. E. Wahle. M. Wickens_ ibid. 8.
`1106 (1994).
`24. F. W. Studier. A. H. Rosenberg. J. J. Dunn. J. W.
`Dubendorff. Methods Enzymol. 185. 60 {1 990).
`25. S. Heidmann, B. Obermaier, l<, Vogel. H. Domdey.
`Moi. Cell. Biol. 12, 4215 {1992}.
`26. S. Heidmann, C. Schindewolf, G. Slurnpf. H. Dom-
`
`dey. rbrd. 14, 4633 (1994).
`2?. J. Hani, G. Stumpf. H. Dcmciey. FEBS Lett. 365. 198
`[1 9951.
`28. For the reconstitution of specific polyadenylation. im-
`munodepteted extract (2 p.l} was mixed with 1 pl of
`partially purified PAP (contained in fraction 1 1} and 1
`]J.l of Mono 0 fractions 19 to 2?. The PAP-containing
`fraction was identified by an unspecific polyadenyla-
`tion assay as described i6}.
`29. We thank J. Hani for advice with the Oomputer search.
`U. Sterzer for technical assistance. H. WL"ir1 for materials.
`and A. Goppelt and K. Wiebauer for discussions and
`critical reading of the manuscript. This work was sup-
`ported by the Deutsche Forschungsgemeinschaft.
`
`21 June 1998: accepted 21 October 1996
`
`Parallel Synthesis and Screening of a Solid
`Phase Carbohydrate Library
`
`Fiui Liang, Lin Yan. Jennifer Loebach, Min Ge,
`Yasuhiro Uozumi, Klara Sekanina, Nina Horan,
`Jeff Gildersleeve, Chris Thompson, Andri Smith,
`Kaustav Biswas, W. Clark Still, Daniel Kahne*
`
`A solid phase carbohydrate library was synthesized and screened against Bauhinia
`purpurea lectin. The library, which contains approximately 1300 di- and trisaccharides.
`was synthesized with chemical encoding on TentaGel resin so that each head contained
`a single carbohydrate. .Two ligands that bind more tightly to the lectin than Ga|—|3—1 .3-
`Ga|l\lAc (the known ligand] have been identified. The strategy outlined can be used to
`identify carbohydrate-based ligands for any receptor; however, because the dertvatized
`beads mimic the polyvalent presentation of cell surface carbohydrates, the screen may
`prove especially valuable for discovering new compounds that bind to proteins partic-
`ipating in cell adhesion.
`
`surface carbohydrates play central
`Cell
`roles in many normal and pathological bi-
`ological recognition processes (I). For ex-
`ample, cell surface carbohydrates have been
`implicated in chronic inflammation, in vi-
`tal and bacterial infection, and in turt‘rori-
`genesis and metastasis
`Considerable ef-
`fort has been directed toward (i)
`tinder-
`standing how carbohydrates function as rec-
`ognition
`signals,
`and
`(ii)
`developing
`strategies to block undesirable interactions
`between cell
`surface carbohydrates
`and
`their protein targets. Ligands whose binding
`to the protein targets is better than that of
`the natural cell surface carbohydrates could
`provide an effective means of preventing or
`treating various diseases. But, progress in
`understanding how structure and function
`are related in biologically active carbohy-
`drates has been slow i)ecause obtaining syn-
`thetic carbohydrate derivatives for bio-
`
`Ft. Liang. L. Yan. J. Loebach. M. Ge. N. Horan. J. Glider-
`sieeve. C. Thompson, A. Smith K. Biswas. D. Kahne.
`Department of Chemistry, Princeton University. Prince-
`ton. NJ 08544. USA.
`Y. Uozumi, K. Sekanina. W. C. Still, Department of
`Chemistry, Columbia University. New York, NY 1002?,
`USA.
`
`' To whom correspondence should be addressed.
`
`In
`chemical studies is extremely difficult.
`contrast, excellent chemical and biological
`methods to obtain large quantities of pep-
`tides and nucleic acids have been available
`
`for decades. As a consequence, much more
`is known about these other biopolymers.
`Screening combinatorial libraries of corn-
`pounds is a very fast way to identify promising
`leads and elucidate strtrcture-activity relation-
`ships (3). The first combinatorial
`libraries
`were built around peptides and nucleic acids
`because the chemistry to make them already
`existed (4). The successful Lise of peptide and
`nucleic acid libraries has stimrtlated efforts to
`
`develop combinatorial approaches to make
`other classes of molecules (5). One obvious
`area where a cornbinatoriztl appl't)aCh could
`have tremendous impact
`is in carbohydrate
`chernistry and hiochernistry.
`For the time being, the most satisfactory
`chemical approaches to the construction of
`compound libraries involve synthesis of the
`molecules on a solid support (6). Despite the
`efforts made, over more than 20 years, there
`has been little progress in the solid phase
`synthesis of carbohydrates. Carbohydrates
`present special diffictrlties for solid phase syn-
`thesis because the bonds between monomers
`must be formed stcreospecifically and in high
`
`1520
`
`SCIENCE -
`
`VOL. 274
`
`'
`
`29 NOVEM BER 1996
`
`Page 6 of 8
`
`yield. Most glycosylation methods are ex-
`tremcly sensitive to structural variations in the
`glycosyl
`tlonor—acceptor pairs
`(7). Reaction
`conditions that provide excellent yields with
`one donor—acceptor pair may give virtually no
`product for another donor‘-acceptor pair. Fur-
`thermore, the stereochemical outcome is of-
`ten difficult
`to predict. The unreliability of
`most glycosylation methods has precluded the
`construction of a solid phase carbohydrate
`library, which requires the ability to make a
`wide range of different glycosidic linkages
`both stereoselectively and in high yield.
`Several years ago we discovered a glyco-
`sylation method that makes Lise of anomeric
`sulfoxides as glycosyl donors. Anomeric strif-
`oxides can be activated almost
`instanta-
`
`neously at low temperature regardless of the
`protecting groups on the sugar hydroxyl
`groups. The low temperature of reaction
`leads to excellent stereochemical control for
`
`a wide range of glycosyl donor—acceptor pairs
`while preventing side reactions so that it is
`possible to get nearly quantitative yields on
`the solid phase (8, 9). We now report the
`synthesis of a solid phase carbohydrate li-
`brary using the sulfoxide glycosylation reac-
`tion. The library was screened against a car-
`bohydrate binding protein, and two ligands
`that bind more tightly than the natural li-
`gand were identified. The strategy described
`can be used to identify carbohydrate—based
`ligands for any receptor; however,
`the on-
`bead screen may prove especially useful for
`discovering carbohydrate ligands that bind
`to their receptors in a polyvalent fashion.
`We designed the carbohydrate library to
`contain a diverse array of glycosidic link-
`ages. The library consists of approximately
`
`HO OH
`O
`
`H0
`
`OH
`
`H0 01-:
`0'
`
`0
`
`s-@—ocH,,c{o)NHrr
`
`H~N
`>0CH3
`
`1
`
`H0
`
`or-r
`o
`
`OH
`Hogefi
`H0 r-10$‘),
`o
`H —N\
`Fl
`
`3 -G oc r-r,,c(oiNi-i rr
`
`2
`
`rel’
`mm,
`3 n=§J\
`0
`
`A series: R‘ = TentaGe|
`B series: R’ = CHZCHZOCHS
`
`Fig. 1. Flelevant structures contained in the library.
`
`
`
`Page 6 of 8
`
`

`
`=~_a-rzimiim
`
`
`REPORTS
`
`including both
`1300 di- and trisaccharides,
`the or- and B—thiophenyl derivatives of the
`known B.
`purpurea
`ligand Gal-|3-l.3-
`GalNAc(lA) (Fig. 1) (l0).Br1u}u'ni'a piirpurea
`lectin is a protein that contains many carbo-
`hydrate binding sites. This lectin binds to
`carbohydrates on the surfaces of erythrocytes.
`causing them to agglutinate. The lectin is thus
`a good model system for cell adhesion proteins
`and other carbohydrate binding proteins that
`recognize cell surface carbohydrates.
`The library was synthesized with the use of
`a split and mix strategy from the monomers
`
`shown in Fig. 2 (l 1'}. Six different carbohy-
`drate monomers were attached separately to
`TentaGel resin. Then 12 different glycosyl
`sulfoxide donors were coupled separately to
`mixtures of beads containing all six mono-
`mers. The beads were recombined, the sugar
`azides were reduced to amines, and the beads
`were split again. The separate pools of beads
`were then N-acylated with different reagents.
`Finally. all the beads were recombined and
`deprotected. To facilitate identification of the
`products on each head, the beads were encod-
`ed with chemical tags at each combinatorial
`
`.
`Aflachmentro
`
`‘"5 995'”
`STEP 1
`
`0
`ll
`"Gran"
`
`2 ®
`NH —
`
`P‘
`
`o
`
`H
`T ._SPh
`
`(T2 9’J’°°5Y"
`d°"°'s)
`
`STEP2
`
`Amine
`ff
`Acyyay,-0,,
`|’,~
`fl’
`Depmecfion
`Assay
`+ WCNH
`& -IT .-.-—cNi-i Ge I-X
`°9°°d9
`a"
`STEP