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the rate at which GDP dissociates fromthe molecules and GTP associates withthem. Conversely, GTPase-activating pro-teins accelerate the rate at which these pro-teins hydrolyse GTP to GDP, and so facilitateinactivation4.

Once activated, Rho, Rac and Cdc42direct the assembly of actin monomers intodynamic filaments that can serve a varietyof purposes. The formation of actin stressfibres, for example, is stimulated by activatedRho and helps to maintain cell shape. Bycontrast, the formation of actin-rich lamel-lipodia and filopodia, stimulated by activat-ed Rac and Cdc42, respectively, allows cellsto form membrane ruffles and protrusions.Rho, Rac and Cdc42 also affect transcriptionof cellular response genes by activating otherfactors including NF-kB, mitogen-activatedprotein kinase and the c-Jun amino-terminalkinase.

Earlier studies had shown that Salmonellaexploits Rac and Cdc42 to alter the structureand function of the cytoskeleton. Thebacteria produce a protein known as SopE,which is injected into the cytoplasm of thehost cell through a so-called type-III secre-tion apparatus. The SopE protein binds toRac and Cdc42, and acts as a guanine-nucleotide-exchange factor to tip the bal-ance towards the activated, GTP-boundforms of these signalling molecules5. Theactivated GTPases stimulate the formationof membrane ruffles that engulf the bacteria,allowing them to reach their preferred sitein specialized intracellular vacuoles. Earlierstudies had also identified a protein knownas SptP, which is also injected by Salmonellainto host cells via the type-III secretion sys-tem6. The SptP protein seemed intriguingbecause of its modular structure (whichincludes a tyrosine phosphatase domain),and because it induces cytoskeletal changeswhen microinjected into cells. But its func-tion in infection was unclear because amutant unable to produce SptP has no defectin invasion.

Fu and Galán2 now resolve this paradox.They report that cells infected with a mutantstrain of Salmonella that cannot expressSptP continue to show evidence ofcytoskeletal disruption hours after infection— long after cells infected with wild-typeSalmonella recover their shape. They foundthat simultaneous microinjection of cellswith both purified SptP and SopE does notalter the cytoskeleton. But microinjection ofeither protein alone has dramatic effects.The authors also showed that SptP bindspreferentially to the GTP-bound form ofRac, and that SptP stimulates the GTPaseactivity of Rac and Cdc42. In other words, itacts as a GTPase-activating protein. Theythen went on to identify a sequence motifpresent in both SptP and eukaryoticGTPase-activating proteins, and showedthat if they mutated a critical arginine

residue in this region they ended up with aprotein that can bind Rac but cannot acti-vate its GTPase activity. A strain of Salmo-nella that produces this mutant form of SptPbehaves just like a strain that produces noSptP at all. So, Salmonella interacts withGTPases that regulate actin structure andfunction at two points, both to activate themand to deactivate them (Fig. 1).

The authors suggest that expression ordelivery of SopE and SptP must be controlledin a way that allows the proper sequence ofevents to unfold during Salmonella infec-tion. More work needs to be done to appreci-ate this finely coordinated balance. Giventhat SptP’s tyrosine phosphatase activity isnot required for its effects on the cytoskele-ton, SptP probably has other, as-yet-uniden-tified functions. And the fact that other bac-terial pathogens express molecules resem-bling SptP indicates that similar strategiesmay be widespread, and that they could

potentially be exploited for therapeutic pur-poses.

The results of these studies should alsostimulate general interest in an understudiedaspect of infectious diseases. With all theattention paid to virulence factors that injurethe host, the mechanisms that limit thisdamage remain all but ignored. Conceivably,a broad array of microbial ‘regressins’ mightexist to ameliorate the havoc wrought bytheir ‘aggressins’. After all, death of the hostrarely serves the microbe.

Michael S. Donnenberg is in the Department ofMedicine, University of Maryland, 10 South PineStreet, Baltimore, Maryland 21201, USA.e-mail: mdonnenb@umaryland.edu1. Takeuchi, A. Am. J. Pathol. 50, 109–136 (1967).2. Fu, Y. X. & Galán, J. E. Nature 401, 293–297 (1999).3. Hall, A. Science 279, 509–514 (1998).4. Sasaki, T. & Takai, Y. Biochem. Biophys. Res. Comm. 245,

641–645 (1998).5. Hardt, W. D., Chen, L. M., Schuebel, K. E., Bustelo, X. R. &

Galán, J. E. Cell 93, 815–826 (1998).6. Fu, Y. X. & Galán, J. E. Mol. Microbiol. 27, 359–368 (1998).

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NATURE | VOL 401 | 16 SEPTEMBER 1999 | www.nature.com 219

Cosmology

Universal peekabooAdam G. Riess

Near the end of the millennium, newobservations and analyses are suggest-ing answers to some of the most pro-

found and ageless questions. What is theextent of the Universe? How old is it? Whatis its shape? What is its ultimate fate? Theanswers to these questions have come fromphilosophers and religious leaders, but in therealm of experimental science answers arenow coming from exploding stars and thegentle tug of gravity. Recent astronomicalobservations suggest that the Universe maybe influenced by a positive ‘cosmologicalconstant’ that affects its evolution. On page252 of this issue1, Zehavi and Dekel presenta synthesis of several observations that tight-ens the case for a positive cosmological con-stant. The likely implications for the Uni-verse of a positive cosmological constant areeternal, accelerating expansion.

This is an unusual moment in the historyof cosmology, in which we are starting tolook at the evolution of our Universe froman empirical rather than a theoretical pointof view. Observations of astrophysicalphenomena are providing meaningfulconstraints on the most elusive cosmologicalparameters, Vm and VL, which togetherdetermine the energy density of the entireUniverse (Vm measures the energy densityfound in ‘normal’ gravitating matter, such asgalaxies and black holes; VL describes theenergy density found in exotic ‘vacuumenergy’, better known as the cosmologicalconstant). In normalized units, a sum of onefor all energy densities in the Universe is the

exact amount required to flatten the fabricof space–time. Specific regions of the two-dimensional parameter space defined by Vm

and VL (Fig. 1, overleaf) imply simpleanswers to the previously mentioned ‘bigquestions’.

The difficulty in modern observationalcosmology is that we do not know of a singlecontrolled experiment that would revealthe individual values of the cosmologicalparameters. Rather, cosmologists must coaxnature into revealing the values of the para-meters by combining data from ongoingastrophysical activity. Although data fromdifferent techniques will constrain a differ-ent mix of the cosmological parameters, wecan combine such observations in the hopethat they will converge on a single set of val-ues. This has led to the birth of ‘peekaboo’cosmology, in which cosmologists overlayindependent constraints on the allowedcosmological parameter space until only anarrow space or window remains throughwhich we can peek to find answers to ourquestions about the Universe2–6.

A narrow region of this parameter spacepermitting a positive cosmological constanthas recently been identified by observationsof distant, exploding white-dwarf stars, calledtype Ia supernovae (SNe Ia)7,8. By observingthe apparent brightness of high redshift (ordistant) SNe Ia, the High-z Supernova Team7,9

and the Supernova Cosmology Project8 foundSNe Ia to be surprisingly dim for their red-shifts, implying that a positive cosmologicalconstant has been accelerating the expansion

© 1999 Macmillan Magazines Ltd

of the Universe since the Big Bang. Yet becausegravitating matter and a positive cosmologi-cal constant pull and push the expansion ofthe Universe in opposite ways, the data fromSNe Ia alone still allow for many combina-tions of Vm and VL.

Another approach derives a constraint ona different mix of the cosmological parame-ters by quantifying the degree to which localmass in different parts of the Universe tugs onnearby galaxies. Although most of the appar-ent motion of galaxies results from the expan-sion of the Universe, some excess or ‘peculiar’velocity arises from the gravitational pull ofnearby mass concentrations10. Zehavi andDekel1 obtained limits on Vm of the Universeby using observations of these peculiar veloc-ities. These measurements favour Vm ! 1,which is a notable result from researcherswho once provided the strongest evidence insupport of a Universe flattened by mass (thatis, Vm 4 1)11.

The area of parameter space highlightedby combining these peculiar velocity resultswith the supernova results is seductivelyclose to the theoretical preference for a geo-

metrically flat Universe. Yet, the danger ofblindly combining (and trusting) the resultsof different measurements is to lose sight ofthe systematic uncertainties involved inindividual techniques. For the peculiarvelocity methods, if one or more assump-tions are not valid (for example, that the ini-tial mass fluctuations are normally distrib-uted) then the implications may not be cor-rect. Similar challenges face the conclusionsdrawn from supernovae data, such as thepossibility of supernova evolution12,13 orexotic intergalactic dust, which could scatterlight from supernovae making them appearfurther away than they are14.

By pushing the observations of super-novae to greater distances (and thereforefurther back in time) it should be possibleto conclusively confirm or refute the initialindications that we are living in an accelerat-ing Universe. We expect a younger, smallerUniverse to be denser and to experiencegreater deceleration from gravity, so theapparent brightness of supernovae shoulddecrease more slowly with distance than islikely to occur under the influence of system-atic effects.

Finally, measurements of tiny ripples inthe radiation left over from the hot Big Bang— the cosmic microwave background — arebeginning to point towards a Universe whichis geometrically flat. These first hints willsoon be surpassed by data from the MAP andPlanck satellites due early next year. By com-bining enough independent constraints itshould be possible to arrive at a set of cosmo-logical parameters that is not vulnerableto systematic uncertainties in any singlemeasurement. Although some cosmologistshave voiced concern that the recent studiesimply that we live at a special time — that is,shortly after the transition from a decelerat-ing to an accelerating Universe — can therebe any time more special than when we firstbegin to learn the answers to our Universalquestions?

Adam G. Riess is at the Space Telescope Institute,Baltimore, Maryland 21218, USA.e-mail: ariess@stsci.edu1. Zehavi, I. & Dekel, A. Nature 401, 252–254 (1999).

2. Turner, M. S. Publ. Astron. Soc. Pacif. 111, 264–273

(1999).

3. Eisenstein, D., Hu, W. & Tegmark, M. Astrophys. J. 518, 2–23

(1999).

4. Lineweaver, C. H. Astrophys. J. 505, 69–73 (1998).

5. Garnavich, P. M. et al. Astrophys. J. 509, 74–79 (1998).

6. Bahcall, N. P. et al. Science 284, 1481–1488 (1999).

7. Riess, A. G. et al. Astron. J. 116, 1009–1038 (1998).

8. Perlmutter, S. et al. Astrophys. J. 517, 565–586 (1999).

9. Schmidt, B. P. et al. Astrophys. J. 507, 46–63 (1998).

10.Strauss, M. A. & Willick, J. A. Phys. Rep. 261, 271–431

(1995).

11.Nusser, A. & Dekel, A. Astrophys. J. 405, 437–448 (1993).

12.Drell, P. S., Laredo, T. J. & Wasserman, I.

http://xxx.lanl.gov/abs/astro-ph/9905027

13.Riess, A. G., Filippenko, A. V., Li, W. & Schmidt, B. P. Astron. J.

(in the press). http://xxx.lanl.gov/abs/astro-ph/9907038

14.Aguirre, A. & Haiman, Z. http://xxx.lanl.gov/abs/astro-

ph/9907039

15.Roos, M. & Harun-or-Rashid, S. M.

http://xxx.lanl.gov/abs/astro-ph/9901234

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NATURE | VOL 401 | 16 SEPTEMBER 1999 | www.nature.com 221

Figure 1 Window on the Universe. To discoverthe values of the parameters Vm (mass density)and VL (cosmological constant) that define theevolution of the Universe, cosmologists overlaydata from different astrophysical techniques tocreate a window in the allowed parameter space.Zehavi and Dekel1 have combined data fromstudies of supernova and peculiar velocities tostrengthen the case for a positive cosmologicalconstant. The results of a similar study15 usingnine independent astrophysical measures areshown here. The cross marks their best guess,where Vm 4 0.3 and VL 4 0.7, and the contoursrepresent relative confidence limits of 68% and98%. The solid line corresponds to a flatUniverse (Vm & VL 4 1), separating an openUniverse from a closed one. The dotted line (VL

4 0) separates a Universe that will expandforever from one that will eventually collapse inthe Big Crunch, whereas the dashed lineseparates a Universe with an expansion rate thatis decelerating from one that is accelerating.

ClosedOpen

Accelerating

Decelerating

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

–0.10.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

Expand forever

Eventually collapse

m

Λ

ΩΩ

ΩΩ

100 YEARS AGOOne result of the rapid growth of seismologyis the suggestion of Dr. Mario Baratta thatprovision should be made by insuranceagainst the damage to buildings caused byearthquakes in certain countries. He showsthat, since the beginning of the seventeenthcentury, less than forty earthquakes havebeen responsible for deaths of more than150,000 persons in Italy alone. Moreover, totake but one example, the great loss of lifeduring the Ischian earthquake of 1883 wasdue to the fact that the buildings hadalready been damaged by the earthquakesof 1828 and 1881. Dr. Baratta points outsome of the conditions that must determinethe amount of the premium that should bedemanded by insurance societies. The mostimportant is the degree of seismicity of thedistrict; but this would be modified byothers, such as the nature of the surface-rocks, the character of the buildings, &c.One advantage of compulsory insuranceagainst earthquakes in a country like Italywould be that partially damaged buildingswould be at once rebuilt or repaired, andthis would tend to diminish the loss of life inthe future. From Nature 14 September 1899.

50 YEARS AGOSocial Biology and WelfareBy Sybil Neville-Rolfe…In 1905, at the age of twenty, the widow of anaval officer announced to her relatives herintention “to study prostitution and venerealdisease and try to get rid of them”. Sheknew of no organisation or senior friendunder whose tutelage she could begin. Withcourage and energy, Mrs. Neville-Rolfeplunged into the obscurity and obscurantismsurrounding the problems of sex irregularity;learning the hard way, but backed by theirrepressible gifts of her personality, she hasgiven the last forty-five years to by nomeans unsuccessful efforts to induce thepublic and officials, both at home andabroad, to face squarely and openly some ofthe biological and social factors involved inhealthy and unhealthy sex and familyrelationships in the community. …Unfortunately, the book itself is not a usefulcontribution to the campaign for a rational,humane and continuously constructiveapproach to the problems of social hygiene,the complexities of which grow the more weknow about the field. … Mrs Neville-Rolfe’sgifts are more those of a crusader than of awriter. From Nature 17 September 1949.