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reverse transcription mechanism, primed by
2. Jacquier, A. Trends Biochem. Sci. 15, 351-354 (1990).
wires attached at each corner. One of these
target DNA, that is similar to group II retro-
3. Michel, F. & Ferat, J. Annu. Rev. Biochem. 64, 435-461 (1995).
possible modes is shown in colour. Because
4. Eskes, R., Yang, J., Lambowitz, A. M. & Perlman, P. S. Cell 88,
only specific modes are allowed, the phonon
spectrum is quantized in these nanobridges.
5. Matsuura, M. et al. Genes Dev. 11, 2910-2924 (1997). Thomas H. Eickbush is in the Department of
6. Cousineau, B. et al. Cell 94, 451-462 (1998).
Similarly, oscillations in the wires of the
Biology, University of Rochester, Rochester, New
7. Mohr, G., Smith, D., Belfort, M. & Lambowitz, A. M. Genes
nanoharp (Fig. 1a) can occur only at a par-
Dev. 14, 559-573 (2000).
ticular set of discrete frequencies, much as
8. Sharp, P. A. Cell 42, 397-400 (1985).
the strings in a full-sized harp are restricted
9. Cech, T. R. Int. Rev. Cytol. 93, 3-22 (1985).
1. Cousineau, B., Lawrence, S., Smith, D. & Belfort, M. Nature
10. Yang, J., Malik, H. & Eickbush, T. H. Proc. Natl Acad. Sci. USA
to resonate at certain frequencies. In the
404, 1018-1021 (2000). 96, 7847-7852 (1999).
nanoharp, these frequencies form the quan-tized spectrum of allowed wavelengths. Nanotechnology
affect the flow of heat? Dimensionality playsan important role here. Each nanobridgeshown in Fig. 1a is a one-dimensional (1D)
Heat flow through nanobridges
system, in which phonons are free to move
Leo P. Kouwenhoven and Liesbeth C. Venema
only in the longitudinal direction. In general,1D systems display many quantized trans-port phenomena, irrespective of what is
Schwab et al.1, various phonons are gener-
ated by heating (Fig. 1b). But only specific
other carriers)2. For instance, the flow of
one side, energy will flow to the coldend. In solid material, heat can be
atoms vibrating around their fixed, equilib-
quantized conductance in units of 2e2/h
rium positions. Insulating materials do not
(where h is the Planck constant and e is the
charge on an electron). In other words, each
vibrations can transport heat in insulators.
mode of electrical transport contributes a
These vibrations are not random: the atoms
maximum value (independent of the materi-
move collectively so that together they form
al involved) of 2e2/h to the conductance.
waves, called phonons. Objects in everyday
life, such as a ceramic cooking pot, contain
turned out to be a very general phenomenon.
many different types of phonons with vary-
It was first discovered in sub-micrometre-
ing wavelengths, which carry heat from the
scale semiconductor transistors3,4. Later,
hot to the cold end. But by making objects
smaller and smaller, today's trend in physics
systems of two metals connected by a single
emerge that are not evident in large materi-
als. On page 974 of this issue, Schwab et al.1
solution6. Besides electrons, analogous 1D
report an experiment involving an extremely
observed for photons, for pairs of electrons
nons. A nanometre is a billionth of a metre,
in superconductors, and for heat carried by
making the bridges about 500 atoms wide.
The authors find that the amount of heat that
can flow across the nanobridge is bound by
similar quantized behaviour. This may seem
an upper limit, set by the laws of quantum
transports charge and mass, whereas a heat
In the world of nanoscale objects, such as
the nanoharp shown in Fig. 1a, heat cannot
obey different quantum statistics. Nonethe-
length. Of all possible phonons, the one with
less, one single formula describes it all: the
the longest wavelength that just fits within
the material has the lowest energy. Longer
Figure 1 The nanoscale world. a, Parallel
reservoirs and is applicable to both electrons
nons) are not allowed. For smaller objects,
nanobridges forming a nanoharp. The sound in the bridges of the nanoharp is restricted to certain resonant frequencies, as in a full-sized
larity, the experimental requirements are
increases. When the object is so small that
harp. Both sound and heat are carried through
hugely different. Commercial batteries and
solids by phonons. The word phonon refers to
ampere meters are sufficiently sensitive to
thermal energy, k T (where k is the Boltz-
the Greek word 'phon' for sound. (Photo
measure quantized electrical conductance.
mann constant and T the temperature),
courtesy of H. G. Craighead, Cornell
(Note that (2e2/h)ǁ1 is equal to 13 kȉ, and is
University.) b, In the device created by Schwab
therefore an easy resistance to measure.) In
et al.1, phonons are generated in the central
contrast, for the observation of quantized
square by thermal heating. Some of these
wavelengths and characters can exist. Each
phonons can leave this region by way of the four
voirs, various technical difficulties have to be
leads to a specific mode of wave-like motion
suspended nanobridges. The colours indicate
solved. First, to achieve good thermal isola-
in an object, such as twisting or bending in
the local strain amplitude. (Simulation by D.
a wire. In the centre of the device created by
freely suspended (Fig. 1a). This is not an easy
NATURE | VOL 404 | 27 APRIL 2000 | www.nature.com
2000 Macmillan Magazines Ltd news and views
task on the scale of a hundred nanometres.
the striatum)4 and the deposition of polyglu-
In addition, a sensitive technique is needed
phonons is saturation of the thermal con-
tamine aggregates both within and outside
to heat one end of the wire and measure ductance at very low temperatures, precisely
nuclei (primarily in neurons of the brain's
the temperature difference between the two
at the quantum value Ț2k 2T/3h.
cortex)5,6. The precise relationship between
ends with millikelvin resolution. Schwab
This observation by Schwab et al. is the
the aggregation process and the malfunction
et al.1 have managed to construct such a
first demonstration of quantum physics in
and death of nerve cells is uncertain.
measurements at ultra-low-power levels.
express exon 1 of the HD gene with long
They find that a single phonon mode can at
counting, double-slit interference experi-
most contribute a quantum of Ț2k 2T/3h to
ments with single phonons, and many many features reminiscent of Huntington's
disease7. In this model, a late-onset, progres-
sively worsening movement disorder is pre-
transport, a sequence of conductance steps is
Leo P. Kouwenhoven and Liesbeth C. Venema are in
ceded by the formation of the characteristic
observed as the electronic states fill up. With
the Department of Applied Physics, Delft University
phonons, in contrast, the authors find a sin-
of Technology, PO Box 5046, 2600 GA Delft, The
time that symptoms appear, the binding of a
gle plateau at low temperatures, which then
particular neurotransmitter (dopamine) to
rises linearly with temperature at higher
temperatures. The reason is that electronic
as do levels of the messenger RNA encoding
states are either full or empty - the change
1. Schwab, K., Henriksen, E. A., Worlock, J. M. & Roukes, M. L.
that receptor10. The brains of Huntington's
in occupation occurs in a sharp, discontinu-
Nature 404, 974-977 (2000).
ous step. The occupation of phonon states
2. Van Houten, H. & Beenakker, C. W. J. Phys. Today 22-27 July
Yamamoto et al.1 have built on this work,
is actually regulated by the temperature (as
3. Van Wees, B. J. et al. Phys. Rev. Lett. 60, 848-850 (1988).
taking advantage of a conditional regulato-
4. Wharam, D. A. et al. J. Phys. C 21, 209-214 (1988).
ry system12 that allows the mutant exon 1
Ț2k 2T/3h on T). When the temperature is 5. Muller, C. J., van Ruitenbeek, J. M. & de Jongh, L. J. Phys. Rev.HD gene to be switched on or off. They
Lett. 69, 140-143 (1992).
found that, when the gene was switched on
6. Frank, S. et al. Science 280, 1744-1746 (1998).
occupied. But instead of a series of steps, 7. Imry, Y. & Landauer, R. Rev. Mod. Phys. 71, S306-S312 (1999).
in mice, it was expressed throughout theanimals' lifetime. The mice developed aprogressive neurological phenotype: onset
of a motor disorder was seen at 4 weeks ofage; a mild tremor was present by 20 weeks;and mice were clearly underactive by 36
In reverse gear
weeks. Yamamoto et al. detected nuclear
staining specific to the mutant HD gene, aswell as intranuclear and extranuclear polyg-lutamine aggregates, in brain sections of
polyglutamine tract of varying length. When
mice at 8 weeks. The brains of the mice were
the tract is 38 glutamines long or more, the
smaller than normal, with a marked reduc-
Cell, describe a mouse model of Hunt-ington's disease with a difference: the
protein gains toxic properties. On autopsy,
tion in the size of the striatum. A reduction
pathological features and symptoms of the
the brains of Huntington's patients show a
in binding of dopamine to its receptors was
disease can be reversed. These findings are
selective death of neuronal cells (mainly in
also seen. This is all in line with what would
both dramatic and unexpected, and indicate- with the obvious caveat that we do not yet
humans - that it may be possible to treat
Huntington's disease is an inherited, late-
onset neurodegenerative disease for whichthere is no known cure. In the Western worldit affects about 1 in 10,000 people, with aslightly larger number than this being at riskof developing the disease. Symptoms include
changes in personality, cognitive decline and
a movement disorder (such as uncontrol-lable, jerky movements, called chorea)2.
Patients suffering from Huntington's dis-
ease bear alterations in the HD gene3. Closeto the beginning of this gene - in a protein-coding part, exon 1 - is a region that
includes a variable number of a trinucleotide
motif (the cytosine/adenine/guanine, orCAG, motif). The only difference between
Figure 1 Progression and reversal of Huntington's disease in a mouse model. Red lines represent the
the HD gene in unaffected and affected indi-
relative progression of the various characteristics of Yamamoto et al.'s mutant mice1 over a 34-week
viduals is the number of copies of this motif. period. In one set of mice, the mutant gene was turned off at 18 weeks of age by adding the antibiotic doxycycline to the animals' drinking water. The blue lines represent the degree to which each of the
acid glutamine, and so the huntingtin pro-
characteristics shown was either halted or reversed when the gene was no longer expressed.
tein encoded by the HD gene contains a
Dopamine is a neurotransmitter; reactive glial cells are generally indicative of nerve cell loss. 2000 Macmillan Magazines Ltd
NATURE | VOL 404 | 27 APRIL 2000 | www.nature.com
Simultaneous Determination of Rosuvastatin and N-Desmethylrosuvastatin in Human Plasma using Negative Ion ESI-LC/MS/MS Linge Li, William Mylott, Bruce Hidy, and Rand Jenkins • PPD, Richmond, Virginia INTRODUCTION SUMMARY OF BIOANALYTICAL METHOD Calculations Figure 2. Plasma Blank with Internal Standard A bioanalytical method was developed for the Valida
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