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Force required to move an atom or molecule Exactly how much force do you need to move an atom or a molecule along a surface? Markus Ternes and colleagues at the IBM Research Division Almaden Research Center and the University of Regensburg (Germany) combined the techniques of scanning tunneling microscopy (STM) and atomic force microscopy in a single instrument to get the answer for individual cobalt atoms and CO molecules. The investigators set up a quartz tuning fork so that one prong was fixed and the other, with a tip at its end, was hanging free. The free prong acted as a cantilever; changes in its bending were measured as the quartz deformed and produced small piezoelectric currents. The free prong was oscillated at constant amplitude. A force between the tip and the surface changed the resonant frequency of the prong. By recording the change in frequency as a function of the tip–surface distance, Ternes and colleagues quantified the interaction forces between the tip and the atom or molecule. The investigators discovered that
The images show the 2D moving a cobalt atom potential landscapes of on Pt(111) needed a (a) the tip–sample interaction lateral force of 210 pN energies during the mathat was independent nipulation of (a) cobalt and of the vertical force. (b) CO on a Cu(111) surFor cobalt on Cu(111), face. The energy scales it only took 17 pN to of the color-coded images get the atom moving, are shifted so that U = 0 at suggesting that the lat(b) the preferred adsorption eral force depended on site for cobalt and CO. The the chemical identity of superimposed ball-andthe surface. For both stick model represents surfaces, the cobalt the Cu(111) lattice. The atom’s force on the tip size of each image is 550 was nearly spherically × 480 pm. (Adapted with symmetric. In contrast, permission. Copyright the forces in manipu0 40 80 120 160 2008 American Associalating a CO molecule U (meV) tion for the Advancement deviated from spherical of Science.) symmetry. Forces for cobalt and CO on Cu(111) differed dramatithan that for cobalt atoms. The invescally, even though they have similar tigators say that their experiments can tunneling conductance in STM experilead to a better understanding of the ments. The investigators measured a controlled bottom-up assembly mecha160 pN lateral force for CO molecules nisms needed to create nanoscale dethat was an order of magnitude larger vices. (Science 2008, 319, 1066–1069)
High-throughput encapsulation and passive sorting of single cells Traditionally, digital microfluidic methods
new microfluidic device that encapsulates
rates are tuned so that only the bigger
for cell encapsulation have been based
single cells in picoliter droplets and sorts
droplets that encapsulate cells float into
on Poisson statistics and thus required a
them by passive hydrodynamic effects.
the upper channel, and the empty droplets
compromise between encapsulation rate
In the new apparatus, cells are fo-
stream into the lower channel.
and yield. Moreover, these procedures use
cused in the center channel by two paral-
an active sorting method, such as flow cy-
lel oil streams; the key to self-sorting after
sorting cancerous T lymphocytes from
tometry. To overcome problems with the
encapsulation is that the oil streams flow
blood, and they showed that their device
Poisson-based encapsulation methods,
at different rates. The central focusing
can encapsulate and sort up to 160 cells/s
Max Chabert and Jean-Louis Viovy of the
channel is split into upper and lower chan-
with 99% purity. (Proc. Natl. Acad. Sci.
Curie Institute (France) have designed a
nels by a y-shaped junction. The oil flow
U.S.A. 2008, 105, 3191–3196)
© 2008 American Chemical Societ y
The researchers tested the system by
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NMR metabonomic profiling of bipolar disorder lar individuals. High-resolution magic-angle spinning (MAS) 1HNMR spectra showed significant increases in the concentrations of myoinositol, creatine, Lactate glutamate, lactate, and phosphocholine in the bipolar brain Acetate Phosphocholine Aspartate Lactate NAA Creatine GABA samples. In addition, the auMyoinositol Glutamine GABA thors analyzed rat brain samples CH2 lipids Glutamate CH3 1 with H NMR to discover metalipids bolic changes caused by treatment with valproate and lithium. 4.0 3.5 3.0 2.5 2.0 1.5 1.0 Some of the compounds that Chemical shift (ppm) were higher in the bipolar samples were lower in the post-lithi- A high-resolution MAS 1H-NMR spectrum of human um and post-valproate samples, prefrontal cortex tissue with key brain metabolites but the two drugs exhibited dis- labeled. Metabolites that are higher in bipolar brain samples are labeled red, and unchanging metabolites tinct metabonomic profiles. are labeled black. The group’s results sugabout metabolic disturbances in the bigest that an imbalance between excitatopolar brain to design better drugs to treat ry and inhibitory neurotransmission plays the disorder. (Mol. Psychiatry 2008, DOI a key role in bipolar disorder. Ultimately, 10.1038/sj.mp.4002130) the team hopes to apply the information
Despite the relatively high prevalence of bipolar disorder, researchers do not understand what causes the condition or how the drugs prescribed to treat it act in the brain. In an attempt to link bipolar disorder and its treatment to changes on the molecular level, Sabine Bahn and colleagues at the University of Cambridge (U.K.), the U.S. National Institute of Mental Health, and Imperial College London have performed 1H-NMR metabonomic analyses on human and rat brain tissues. Previously, scientists have used in vivo magnetic resonance spectroscopy (MRS) to study bipolar disorder. With the higher resolution and sensitivity of 1H NMR, Bahn’s team was able to quantify more metabolites than could be measured with MRS. The group analyzed human brain tissue postmortem from the region of the brain known to be affected by bipolar disorder (the prefrontal cortex), and they compared the metabonomic profiles of healthy and bipo-
Gerard McLoughlin
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A NIMS enzyme assay Gary Siuzdak, Chi-Huey Wong, and colleagues at Scripps Research Institute, the University of California Merced, and Lawrence Berkeley National Laboratory report a method to study the enzymatic activity of complex biological samples by using nanostructure initiator MS (NIMS). NIMS is a laser desorption/ionization technique in which analytes are adsorbed from liquid-coated nanostructured surfaces. The researchers call their new technique the Nimzyme assay; in it, enzyme substrates are attached via a fluorinated tag to the fluorous phase, a unique material that is immiscible with aqueous and organic phases. A crude cell lysate is flooded onto the surface, allowed to react, and then washed away before NIMS analysis. 3062
with the lysate. The scientists also used their Nimzyme assay to analyze the crude lysate of a therSchematic of the Nimzyme assay. (a) Substrates are immobilized mophilic microbial in the fluorous phase of the NIMS surface. (b) The surface is community obtained incubated with a crude cell lysate. (c) After washing, the surface from a hot spring in is analyzed by NIMS. Scale bar = 2 µm. (Adapted with permission. Yellowstone National Copyright 2008 National Academy of Sciences, U.S.A.) Park. They could determine the optimal The researchers used the Nimzyme pH and temperature of the galactosiassay to look at two enzymatic reacdase reaction. tions: hydrolysis of lactose by β-1,4The researchers note that their assay galactosidase and modification of the has sensitivity comparable to more trasame substrate by α-2,3-sialyltransferditional fluorescent enzyme assays and ase. They first analyzed crude E. coli that their technique can be extended to lysates and found that they could obstudy a multitude of other enzymatic tain relatively clean mass spectra after activities. (Proc. Natl. Acad. Sci. U.S.A. reaction of their immobilized substrates 2008, 105, 3678–3683)
(a)
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(c)
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New mechanism proposed for corona-ion-dependent signal enhancement 20 Hz Trigger Delay generator Delay generator
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Kaveh Jorabchi, Michael Westphall, and Lloyd Smith at the University of Wisconsin Madison recently proposed a new mechanism to explain why the analyte ion signal in UV laser desorption (LD) MS is enhanced when sample droplets are in the presence of corona ions. The pulsing electronics in the group’s new apparatus decoupled three parameters: corona cation generation, electric field generation in the droplet region, and laser firing. The authors concluded that droplet charging rather than gas-phase ion–neutral reactions is responsible for the increase in signal. Accordingly, they call the new mechanism charge-assisted LD/ionization (CALDI). Because the majority of gaseous molecules formed by LD are neutral, Smith’s group was studying the role of corona discharge in LD MS to improve ionization efficiency. Corona discharge is the ionization of the gaseous molecules near the tip of a pointed conductor when a strong electric field is applied to the conductor. The results from the team’s pulsed experiments indicated that the generation of analyte ions is independent of the presence and density of corona ions, so they deduced that gas-phase corona ion–neutral reactions were not responsible for ionization of the analytes. The authors propose that in CALDI,
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Experimental apparatus for pulsed corona ion production, laser desorption, and ion extraction. (Adapted with permission. Copyright 2008 American Society for Mass Spectrometry.)
the electrically isolated droplet adsorbs corona ions, becomes charged, and then forms an asymmetric charge distribution in the presence of an external electric field. Then the side of the droplet closest to the MS inlet sees an enhanced electric field, and ion for-
mation is facilitated during the laser pulse. The researchers are currently trying to understand the role of gas-phase charge separation and direct desorption of charged droplets and clusters. (J. Am. Soc. Mass Spectrom. 2008, DOI 10.1016/j.jasms.2008.02.012)
No MAGIC in Science paper Science will most probably retract a paper published by Tae Kook Kim and col-
the paper 3 years ago (2005, 77, 417 A). The chair of the Internal Investigation
chair informed them that preliminary findings were sufficient to convince the chair
leagues at the Korea Advanced Institute
Committee at KAIST notified the Science
that “the two papers do not contain any
of Science and Technology (KAIST) and
editors that the paper, as well as another
scientific truth” (Science 2008, 319, 1335).
CGK Co. (Korea) (Science 2008, 319, 1468–
paper by the same group (Nat. Chem. Biol.
1469). The authors had described a nov-
2006, 2, 369–374), is being investigated
joon Won, has admitted scientific miscon-
el technology called magnetism-based
after scientists at CGK, a company found-
duct. Editors of the two journals say they
interaction capture (MAGIC) to identi-
ed by Kim, struggled to get MAGIC to
are waiting to hear from all the authors, or
fy intracellular targets of small molecules
work. The editors of Science expressed
be informed about the investigation’s final
(Science 2005, 309, 121–125). AC profiled
their concern about the paper after the
outcome, before retracting the papers.
The first author of the two papers, Jae-
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Shape and volume affect biochemical reactions If you’ve ever watched a time-lapse movie
on/off and tuned by volume changes. The
ated or boosted in a network of vesicles
of a cell undergoing division, you’ll appre-
rate of volume change has to overwhelm
and nanotubes—the Golgi–endoplasmic
ciate that a cell’s shape and volume aren’t
the overall rate of product formation; the
reticulum network would be an exam-
static. Owe Orwar and colleagues at the
volume resulting from the expansion has
ple—as the arrangement of the network
Chalmers University of Technology (Swe-
to be large enough to dilute the substrate
is manipulated. Orwar and colleagues
den) suggest that the dynamic changes in
concentration well below the Michae-
studied fluorescently labeled alkaline
cellular shape and volume influence the
lis–Menten constant K M . Orwar and col-
phosphatase as the enzyme and fluores-
rates of biochemical reactions going on in-
leagues extended their calculations to the
cein diphosphate as the substrate. They
side the cells. They demonstrate the fea-
enzymes involved in the mitochondria’s
showed that the reaction system was ex-
sibility of the idea by analyzing enzymatic
Krebs cycle, thereby demonstrating that
tremely sensitive to changes in network
reactions in biomimetic networks of mi-
organelles can regulate the rates of enzy-
topology, with the chemical reactions be-
croscale vesicles and nanotubes as well
matic reactions by shrinking or expanding
ing initiated or boosted in certain places
as by carrying out theoretical calculations.
their volume.
as a function of vesicle–nanotube con-
The investigators first showed that in a solitary vesicle, reactions can be turned
The Chalmers investigators next examined whether a reaction could be initi-
nectivity. (Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 4099–4104)
A new optical technique for breath analysis
Calibration
Vertical diffraction Breath can be analyzed Mode-locked fiber laser Cylindrical VIPA etalon grating for a variety of comlens Enhancement cavity pounds by an array of techniques. For example, GC/MS can separate and measure a large number Horizontal of biomarkers in human diffraction breath. However, GC/ MS instruments are large Imaging lens and complex and require Dry scroll N2 a long period of time to InGaAs camera pump perform a measurement. Now, Jun Ye, Michael A schematic of the cavity-enhanced optical frequency comb spectrometer breath-analysis system. (AdaptThorpe, and colleagues at the University of Colo- ed with permission. Copyright 2008 Optical Society of America.) rado have developed a fast breath-analysis system based on cav- unique for each kind of atom or molecule. samples of human breath. They could identify each component, even though ity-enhanced optical frequency comb The instrument analyzes not only the signals for these molecules occur in spectroscopy. which frequencies of light are missing a highly congested region of the specIn this form of spectroscopy, an ultraphotons but also how many photons of fast laser creates a wide-bandwidth optical a particular frequency have disappeared. trum. The authors note that their system can also be used to look for other frequency comb, which includes a multiFrom these data, researchers can idenbiomarkers relevant to particular distude of frequencies in the visible and NIR tify the components in a sample by the regions of the electromagnetic spectrum. unique molecular fingerprint of each in- eases and that their instrument can be packaged into a box roughly the size of The comb is coupled to an optical cavity dividual analyte. a large microwave oven, making it porcontaining one or more molecules, which As a proof of principle, Ye, Thorpe, table and easy to use in a field setting. absorb photons of particular frequenand colleagues analyzed H 2O, CO2, CO, CH4, and NH3 by this method in (Opt. Express 2008, 16, 2387–2397) cies. The pattern of photon absorption is 3064
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Single-particle counting of quantum dots 600 400 Photon counts/ms
Lawrence Johnson and Chun-yang Zhang at York College of the City University of New York have developed a method to quantify quantum dot (QD) concentration via single-particle counting. QD concentration is usually measured using either absorption or fluorescence spectroscopy, but the absorption coefficient and quantum yield values for QDs vary with conditions such as pH and ionic strength. For a successful quantification by these means, the absorption coefficient or quantum yield must be determined separately under each set of conditions by laborious and time-consuming techniques. In Johnson and Zhang’s method, each QD is detected by the fluorescence that it emits. The QDs are passed through a 50 μm capillary tube
200 0 600 400 200 0
0
1
2 3 Time (s)
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Simultaneous detection of 605QDs (blue) and 700QDs (red) in a mixture by singleparticle counting.
where they are excited with a laser and their emitted photons are detected by photodiodes. As a proof-of-principle experiment, the researchers looked at 605-nm-emit-
5
ting streptavidin-coated CdSe/ZnS core–shell QDs (605QDs). They found that they could achieve an S/N of up to 200, which allowed them to unambiguously identify each 605QD as it moved through their system. Similar results were obtained with QDs that emitted at other wavelengths. The researchers say that advantages of their system include a sample size 5 orders of magnitude smaller than that of conventional spectrometric techniques and the ability to quickly and easily assay QDs in a variety of buffer solutions and organic solvents. They also note that their system allows them to simultaneously count more than one type of QD in a mixture, which is not possible with conventional techniques. (J. Am. Chem. Soc. 2008, 130, 3750–3751)
Microfabricated zone plate for optical trapping The integration of optical tweezers into
diffracted light constructively interferes at
microfluidic chips would open up ways
the desired focus to create an image.
to sort and manipulate particles and car-
Crozier and colleagues fabricated their
ry out biophysical force measurements.
zone plate on a glass slide with rings of
But the short working distance, size, and
gold as the opaque regions. They formed
cost of microscopic lenses hinder their in-
a liquid sample cell by sandwiching a lay-
tegration into microfluidic chips. Kenneth
er of water between the zone plate and a
Crozier and colleagues at Harvard Univer-
coverslip. Fluorescent 2 µm diam beads
sity have now fabricated a Fresnel zone
were trapped in the sample cell at the zone
plate capable of producing well-calibrat-
plate focus. By comparing the trapping
ed optical traps in microfluidic systems.
properties of the zone plate to those of tra-
A zone plate—sometimes called a
ditional optical tweezers, Crozier and col-
Fresnel zone plate—focuses light by dif-
leagues determined that zone-plate optical
fraction. It consists of a series of radi-
tweezers had a stiffness similar to that of
ally symmetrical rings, known as Fres-
conventional optical tweezers.
nel zones, that alternate between opaque
10 µm
The investigators point out that un-
Optical micrograph of the zone plate shows the radial patterns of gold (bright) and glass (dark). (Adapted with permission. Copyright 2008 American Institute of Physics.) crometers without the particles mov-
and transparent. When light hits the plate,
like traditional optical tweezers, once a
ing out of position with respect to the
it diffracts around the opaque zones. The
particle is trapped by the zone plate, the
sample cell. (Appl. Phys. Lett. 2008, DOI
zones are spaced in such a way that the
sample cell can be translated tens of mi-
10.1063/1.2837538)
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