authors also describe the presence of distinct

cytoplasmic accumulations of ataxin-2 in

motor neurons of patients with sporadic ALS
as well as those of patients with FTLD. The
authors therefore propose that Ataxin-2 serves
as a bridge, either directly or via RNA, to bring
TDP-43 to sites of a toxic function.
Notably, accumulations of ataxin-2 and
TDP-43 were distinct in patients with ALS,
whereas in patients with FTLD some co-local-
ization could be seen. Whether, in SCA2, the
interaction between these proteins is transient
or TDP-43 is sequestered into polyQ aggre-
gates remains unknown. The latter seems
more likely, because a recent study
11
found that
expression of long polyQ tracts in cultured cells
results in recruitment of TDP-43 into polyQ
aggregates, accompanied by reduced nuclear
function of this protein.
Elden and co-workers study
1
underscores
how an interplay between TDP-43 and ataxin-2
each of which was previously implicated in
divergent neurodegenerative diseases may
be central to the development of an increas-
ingly broad spectrum of disorders. Ataxin-2
polyQ expansion classically leads to the devel-
opment of ataxia and, in a few cases, to Parkin-
sons disease (reviewed in ref. 12). Intriguingly,
roughly 30% of patients with SCA2 also have
dementia, and in a few instances motor-neuron
degeneration precedes or follows the onset of
cerebellar ataxia. Considering the presence of
TDP-43 aggregates in Parkinsons disease and
in different forms of dementia, including FTLD
and 30% of Alzheimers disease cases, it is cru-
cial to determine the role of ataxin-2 polyQ-
tract length in different forms of dementia, and
whether mislocalization of ataxin-2 also occurs
in Parkinsons disease, FTLD and Alzheimers
disease.
Identification of an association between
ataxin-2 and ALS also provides additional
evidence that altered RNA processing may be
central to this disorder. Indeed, ataxin-2 itself
contains a structural motif for RNA binding
and has been proposed to influence RNA
translation and the formation of stress gran-
ules cytoplasmic foci of proteins and RNA
formed under conditions of stress. Similar roles
have been proposed for TDP-43 and another
RNA/DNA-binding protein, FUS/TLS, muta-
tion in either of which can cause ALS or FTLD
(reviewed in ref. 7).
Interaction between ataxin-2 and TDP-43
also seems to require RNA, with a complete
abolition of toxicity in yeast when wild-type
TDP-43 is substituted with a mutant that does
not bind RNA; despite forming aggregates, this
TDP-43 mutant is not toxic. It is not known
whether TDP-43 and ataxin-2 interact by bind-
ing to the same RNA or whether the two proteins
interact directly after TDP-43 binds to RNA. To
assess which RNAs might be mis processed by
loss of TDP-43 from the nucleus, and whether
RNAs are sequestered in the cytoplasm as part of
TDP-43 toxic aggregates, it will now be crucial
to determine how ataxin-2TDP-43 interaction
3. Pulst, S.-M. et al. Nature Genet. 14, 269276 (1996).
4. Sanpei, K. et al. Nature Genet.14, 277284 (1996).
5. Neumann, M. et al. Science 314, 130133 (2006).
6. Arai, T. et al. Biochem. Biophys. Res. Commun. 351, 602611
(2006).
7. Lagier-Tourenne, C., Polymenidou, M. & Cleveland, D. W.
Hum. Mol. Genet. 19, R46R64 (2010).
8. Gitcho, M. A. et al. Ann. Neurol. 63, 535538 (2008).
9. Sreedharan, J. et al. Science 319, 16681672 (2008).
10. Kabashi, E. et al. Nature Genet. 40, 572574 (2008).
11. Fuentealba, R. A. et al. J. Biol. Chem. doi:10.1074/
jbc.M110.125039 (2010).
12. Lastres-Becker, I., Rb, U. & Auburger, G. Cerebellum 7,
115124 (2008).
QUANTUM MECHANICS
The usefulness of uselessness
Andreas Winter
A game for three or more players called guess your neighbours input
reveals common ground between classical and quantum physics
at the expense of more exotic, super-quantum, theories of nature.
Why play games that quantum dice dont help
you win? Writing in Physical Review Letters
1
,
Almeida et al. provide a surprising twist on
the foundations of quantum mechanics and
tell us why we should be at least interested in
this question. When John Bell came up with
the first of his eponymous inequalities
2
, it was
to show that quantum mechanics is not just
incompatible with classical physics but that
it violates its deep conceptual tenets. Now,
Almeida et al.
1
show that there are useless
Bell inequalities that quantum mechanics
cannot violate. Instead, these inequalities can
provide insights into what distinguishes quan-
tum mechanics from even stranger theories of
nature.
Encounters with quantum mechanics
often produce a reaction of wonder, coupled
with bemusement. To understand nature, is it
really necessary to believe in complementarity
(such as waveparticle duality), fundamental
indeterminism and uncertainty relations? Is
it necessary to adopt the view that perfectly
sound physical quantities dont have a value
unless theyre measured? It was Bells great
insight
2
(which developed from the ideas of
Einstein, Podolsky and Rosen
3
) that under
the assumption of locality, which states that a
particle is affected directly only by its imme-
diate environments one can answer these
controversial questions experimentally
4,5
.
To begin, it is absolutely consistent to think
that the quantum indeterminism of a single
particle is not real in the sense that there
might be true values of all observables (even
complementary ones), which are governed by
an appropriate probability distribution. If these
variables remain somehow eternally hidden
from direct access, quantum mechanics can
be reproduced perfectly.
This is no longer the case, however, for sys-
tems of many particles, as can be understood
within the framework of non-local games
between distant players. In these games, each
player gets an input (setting), x, y, , from
a referee and has to respond with an answer
(outcome), a, b, . The players reply with-
out consulting the other players but potentially
using a pre-agreed strategy and pre-shared
randomness, a quantum state or something
even more exotic. This leads to a correlation of
the outcomes with each other depending on
the settings, this correlation being encoded in
conditional probabilities P(ab|xy).
Players of such games win or lose depending
on whether their collective inputs and outputs
satisfy a certain relation, W(ab, xy). The
players goal is to maximize the probability of
winning, P
win
. Figure 1 (overleaf) illustrates this
idea for the ClauserHorneShimonyHolt
(CHSH) game
4
. Classical playing strategies are
based on local realistic correlations: the play-
ers may share some information (independent
of x, y, ) but otherwise have to rely on local
instruction sets (a depending only on x, b only
on y, and so on). A Bell inequality is an upper
bound on P
win
under arbitrary, local realistic
correlations. If the players adopt a strategy
based on quantum entanglement, then they
can violate Bell inequalities by measuring local
observables.
It is a curious property of both classical and
quantum correlations that they are no-sig-
nalling: the choice of input at one site cannot
have an observable effect at another site. This
property allows classical probability and quan-
tum theory to coexist peacefully alongside Ein-
steins relativity, and it may be expected that any
contender theory of nature will have to share
this property. But when it was realized
6,7
that
there are no-signalling correlations beyond
those accessible in quantum mechanics, this
created a mystery of enduring appeal. What
are the underlying principles, in addition to
and the associated nuclear exclusion of TDP-43
perturb RNA processing.
Clotilde Lagier-Tourenne and Don W. Cleveland

are at the Ludwig Institute for Cancer Research
and Department of Cellular and Molecular
Medicine, University of California, San Diego,
La Jolla, California 92093-0670, USA.
e-mail: dcleveland@ucsd.edu
1. Elden, A. C. et al. Nature 466, 10691075 (2010).
2. Imbert, G. et al. Nature Genet. 14, 285291 (1996).
1053
NATURE|Vol 466|26 August 2010 NEWS & VIEWS
20 Macmillan Publishers Limited. All rights reserved 10
Last, Almeida et al. present a tantalizing
speculation. Maybe the no-signalling criter-
ion is to blame for the existence of useless Bell
in equalities in a multi-party situation; that
criterion is an inherently two-party statement.
If one found a proper extension to many play-
ers, these useless inequalities might become
trivial and go away. This would indeed provide
a new principle, bringing physicists closer to
understanding what makes quantum corre-
lations so special. But it is also possible that,
even for two players, there are useless facet
Bell inequalities and that even their existence
could lead to a positive insight.
Andreas Winter is in the Department of
Mathematics, University of Bristol, Bristol
BS8 1TW, UK, and at the Centre for Quantum
Technologies, National University of Singapore,
Block S15, 3 Science Drive 2, Singapore 117543.
e-mail: a.j.winter@bris.ac.uk
1. Almeida, M. L. et al. Phys. Rev. Lett. 104, 230404 (2010).
2. Bell, J. S. Physics 1, 195200 (1964).
3. Einstein, A., Podolsky, B. & Rosen, N. Phys. Rev. 47, 777780
(1935).
4. Clauser, J. F., Horne, M. A., Shimony, A. & Holt, R. A. Phys.
Rev. Lett. 23, 880884 (1969).
5. Aspect, A., Grangier, P. & Roger, G. Phys. Rev. Lett. 49,
9194 (1982).
6. Tsirelson, B. Hadronic J. Suppl. 8, 329345 (1993).
7. Popescu, S. & Rohrlich, D. Found. Phys. 24, 379385 (1994).
8. Gill, R. Bell inequalities holding for all quantum states:
problem 26B; available at www.imaph.tu-bs.de/qi/
problems/26.html (28 February 2006).
9. Linden, N., Popescu, S., Short, A. J. & Winter, A. Phys. Rev.
Lett. 99, 180502 (2007).
10. Acn, A. et al. Phys. Rev. Lett. 104, 140404 (2010).
11. Cirelson, B. S. Lett. Math. Phys. 4, 93100 (1980).
CANCER
Viruses backup plan
Kevin M. Ryan
Tumour viruses can cause cancer by altering gene expression and protein
activity in the host cell. Tumour adenoviruses, however, seem to go to great
lengths to ensure that one particular host cell protein, p53, is suppressed.
Analyses of tumour-causing viruses have been
instrumental in understanding cancer biology.
The first vertebrate oncogene, for example, was
discovered on the basis of its sequence simi-
larity to the cancer-causing gene of a chicken
retrovirus. Numerous tumour-suppressor
genes have also been identified because they
are cellular targets of tumour-causing DNA
viruses
1
. On page 1076 of this issue, Soria et al.
2

describe a previously unknown mechanism
that tumour-inducing adenoviruses use to
suppress the activity of the tumour-suppressor
protein p53. Their findings call for a revision
of the dogma on how these viruses make cells
cancerous.
Many tumour-inducing DNA viruses com-
monly cause abnormal activity of the cellular
transcription factor E2F1, through binding
to proteins of the retinoblastoma family such
as Rb, which would normally be bound to
E2F1 (refs 3, 4). In cells that are infected with
cancer-causing strains of adeno virus, the viral
E1A protein binds to proteins of the host cells
retino blastoma family, freeing E2F1 to promote
not only progression of the cell cycle a cen-
tral requirement of the viral life cycle but also
transcription of many viral genes
3
(Fig. 1a).
Stimulation of cell-cycle progression by E1A
would be too simple a route to inducing cancer,
and host cells often have safeguard mechanisms
to overcome a single precancerous change. In
this case, the host cell can counter the possible
change because deregulated E2F1 also acti-
vates the cellular ARF protein, which inhibits
MDM2 the main inhibitor of p53 (ref. 5).
In the absence of MDM2 activity, p53 levels
increase, either inhibiting cell-cycle progression
or destroying the infected cell.
no-signalling, that prevent nature from being
even more non-local? A flurry of recent work,
as discussed by Almeida et al.
1
, has addressed
this question by attempting to show that a
world with super-quantum correlations would
indeed be a stranger place one that would
differ markedly from the quantum universe as
we know it.
From the point of view of no-signalling
correlations, quantum correlations are mere
special cases, and even more special are local
realistic correlations, but it is this that makes
them more interesting. The no-signalling prop-
erty is entirely captured by the positivity of the
values P(ab|xy) after all, they are
probabilities and by certain identities
between them. All of these constraints are
expressed as Bell inequalities, properly called
trivial Bell inequalities. But, in the context of
no-signalling correlations, what is interesting
are the non-trivial ones, those that express
restrictions on correlations that are not a priori
implied by the no-signalling principle. It is thus
natural to ask if every non-trivial Bell inequality
is violated by quantum mechanics
8
.
Almeida et al.
1
now answer this question
in the negative, by describing and analysing a
non-local game, guess your neighbours input.
For any number of players greater than two,
their game results in a Bell inequality that is
true even for quantum correlations, yet it is
non-trivial because its violation is consistent
with no signalling. In fact, it is a facet inequal-
ity, meaning that it is not implied by any other
Bell inequality that is, the authors identify
a demonstrably useless yet necessary Bell
in equality. The corresponding experiment
would not be able to discriminate between clas-
sical and quantum physics. Instead, it would
distinguish both of these from the non-phys-
ical realm of no-signalling correlations. (For
two players, earlier investigations on a class of
games called non-local computation
9
showed
inviolable Bell inequalities but it was found
later that these are not facet inequalities;
M. L. Almeida, N. Brunner and P. Skrzypczyk,
personal communication.)
So why will experts get excited about
Almeida and colleagues result
1
? First, it has
an immediate application in showing that a
multi-party extension of Gleasons theorem
10
, a
notable contribution to quantum foundations,
fails for three or more parties. Second, and
more importantly, it ties in with other recent
attempts to find common ground between
classical and quantum physics that would
distinguish them from weird, no-signalling,
super-quantum theories.
Correlations
x y
a b
Player 1
Player 2
Figure 1 | The CHSH game. In this illustration
of the game, two cooperating players receive an
input, x, y (where x and y can be 0 or 1), from a
referee, and they have to reply with a, b (where
a and b can also be 0 or 1), respectively. The
games winning condition is that the parity of
a + b has to equal the product of x and y that
is, a and b have to be different from each other
if x = y =1 and equal to each other for the other
three possible combinations of x and y. If the
players adopt a classical strategy (that is, if they
are correlated according to the laws of classical
physics), only any three of the four pairs of
inputs (0,0), (0,1), (1,0) and (1,1) can
be satisfied, and the maximum probability of
winning, P
win
, is 0.75 (ref. 4). However, if they
adopt a strategy based on quantum correlations,
this value can be increased to 0.851 (refs 47, 11).
The maximum value of P
win
, P
win
= 1, is consistent
with no-signalling correlations
6,7
. Almeida
et al.
1
describe a game much like this, for three or
more players, in which quantum mechanics does
not provide an advantage over classical physics,
although no-signalling correlations do.
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NATURE|Vol 466|26 August 2010 NEWS & VIEWS
20 Macmillan Publishers Limited. All rights reserved 10