Robustness of E. coli metabolic network revealed
Tsuruoka, Yamagata, (Japan)March 25, 2007 : Scientists at the Institute for Advanced Biosciences of Keio University located in Tsuruoka City, Yamagata prefecture report in an advanced on-line publication released today in Science magazine (Science Express) a first-of-a-kind quantitative picture of molecular components of the common intestinal bacterium E. coli. Using multiple state-of-the-art analytical technologies, the group studied this unicellular organism at an unprecedented depth to reveal the remarkable overall robustness of its metabolic network to gene deletion and changes in growth conditions.
All cells need to convert energy sources such as simple sugars into ATP, an energy storing and exchange molecule, and other cellular building blocks that are essential for cellular growth and survival. This cellular process, called "energy metabolism" is one of the most fundamental and well-conserved in living cells and its machinery involves about 100 different genes and their encoded proteins.
Making use of a set of nearly 4000 single gene mutants in E. coli the same group previously developed (Keio collection), the researchers selected specific genes whose activity is known to be associated with the main reactions of central energy metabolism. In addition, the non-mutated or wild type cells were also grown at different rates to observe the response to such changes. An exhaustive global survey of intracellular components was then performed using the latest analytical technologies such as DNA microarrays, two-dimensional gel electrophoresis and capillary electrophoresis mass spectrometry (CE-MS) to quantify messenger RNA, proteins, and metabolites. The researchers also performed a more detailed and precise analysis of 85 different intracellular RNAs, 57 enzyme proteins, and about 130 metabolites representing most components of energy metabolism and simultaneously also derived the metabolic fluxes through most reactions by combining quantitative measurements with a computational model of energy metabolism.
Deletion of energy metabolism genes, in most cases, did not result in large compensatory changes in the level of RNA, proteins, or metabolites. On the other hand, while significant changes in RNA and protein levels were seen upon changes in growth rate, the overall metabolite levels remained stable. The results thus demonstrate with a level of details until now never achieved, that E. coli can use different and complementary strategies to maintain a stable metabolic state, according to the circumstances, and also compensate for mutations through functional redundancy in its metabolic network.
The CE-MS methods developed at IAB, which allow to analyze hundreds of intracellular metabolites simultaneously together with an original approach to targeted protein quantification using liquid-chromatography mass spectrometry (LC-MS) that bypasses the common but inconvenient use of isotopic labels, were instrumental in providing the level of quantitative detail necessary.
Masaru Tomita, head of the project and institute remarks “I am proud of this extraordinary and unparalleled large-scale study which was in large part made possible by combining original technologies developed at IAB in Tsuruoka with the help of the local government. I also think that the rich and peaceful natural environment where our institute is located contributed to catalyze this large team effort. We now hope to apply the fruits of this study toward medical and environmental problems and also imagine applications in the food industry.”
Understanding a simple bacterium in a more systematic way is expected to have repercussions in many other organisms too due to the similarities in the core components of metabolic pathways from bacteria to animals and humans. For example eventual applications in the field of cancer biology for developing novel anti-cancer drugs targeting cellular metabolism, and improvements in industrial production of alternative energy sources such as bio-ethanol or environmentally-friendly bio-plastics could be imagined. In addition, computational and systems biologists around the world, attempting to understand the cell in its entirety, have long wanted to put their hands on the type of quantitative data this study provides. It is thus a significant step in the emerging field of quantitative biology that is likely to find even broader applications.
IAB is a research institute closely associated with the Faculty of Environment and Information Studies at Keio University. It employs about 65 scientists and offers an innovative undergraduate bioinformatics program and graduate program in systems biology in which a total of about 130 students are enrolled. Keio University is the oldest modern comprehensive institution of higher education in Japan, with over 30 000 students distributed over several campuses in the Tokyo area in addition to the Tsuruoka Town Campus (TTCK) established in 2001 in Yamagata prefecture.
For more information contact:
Akiko Shiozawa
Public Relations Officer
Institute for Advanced Biosciences
Keio University
Tel: +81-235-29-0802
Fax: +81-235-29-0809
e-mail: akiko@ttck.keio.ac.jp
http://www.iab.keio.ac.jp/

Green tea may help to fight lung cancer

A possible mechanism for green tea’s anticancer activities is reported online this week in Laboratory Investigation. The reported effect of green tea extract on lung cancer cells supports the increasing evidence of green tea’s anticancer properties.

With an estimated 162,246 deaths in 2006, lung cancer is the most common cause of cancer-related death in the USA. The active constituents of green tea - called polyphenols - are recognized antioxidants, but the extent of any anticancer activity remains unclear. Although animal studies offer strong evidence for the anticancer effect of green tea in several organs, including the lung, human population-based studies have shown green tea to increase, decrease, and have no effect on the risk of lung cancer.

Qing-Yi Lu and colleagues now report that, in lung cancer cells, green tea extract (GTE) promotes the polymerization of the cell protein actin. This action counteracts the depolymerisation of actin that characterizes the early stage of cancer development. Researchers also pointed to annexin-I, the actin-binding protein that mediates the effect of GTE on actin, as a novel potential target for GTE-based cancer therapy. The authors suggest that further research and clinical trials are needed to determine how their results relate to actual green tea consumption.

Author contact:

Jian Yu Rao (University of California at Los Angeles, CA, USA)
Tel: +1 310 794 1567; Email: jrao@mednet.ucla.edu
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New Big Dating Site- http://www.medianowonline.com/dating1.htm

Fossil sheds light on middle ear evolution (pp 288-293)
The three tiny bones found in the mammalian middle ear are known to have evolved from components of the reptilian lower jaw. But the transition can now be seen in fossil form.

Zhe-Xi Luo and colleagues describe the fossilized remains of a primitive mammal that probably lived around 125 million years ago. The animal’s middle-ear bones remain connected to the lower jaw by Meckel’s cartilage, and the transition to the mammalian state is associated with a corresponding remodelling of the lower back region.

But the situation is not as clear-cut as it seems. The evolutionary relationships of the fossil suggest that either the modern-style middle ear evolved independently twice, or evolved and then was lost in at least one ancient lineage.

CONTACT
Zhe-Xi Luo (Carnegie Museum of Natural History, Pittsburgh, PA, USA)
Tel: +1 412 622 6578; E-mail: luoz@carnegiemnh.org

Leigh Kish (Media Contact, Carnegie Museum of Natural History, Pittsburgh, PA, USA)

Tel: +1 412 578 2571; E-mail: kishl@carnegiemuseums.org

Planetary science: The aftermath of a catastrophic collision
Scientists have discovered a new family of bodies in the Kuiper belt that they think are the remnants of a catastrophic collision with the belt's third largest object, 2003 EL61. The discovery may have implications for understanding the dynamics of the outer Solar System and the surfaces of Kuiper belt objects.

Michael E. Brown and colleagues found bodies with similar surface properties and orbital dynamics to the dwarf-planet-sized object 2003 EL61. From this, they inferred that something hit this large Kuiper belt object and created a family of objects, along with its satellite system.

There are many families of asteroids in the main asteroid belt that are the remnants of a catastrophic impact. But in the region beyond Neptune, no collisionally created families have hitherto been found. The newly spotted objects are probably fragments of the ejected ice mantle of 2003 EL61.

CONTACT
Michael E. Brown (California Institute of Technology, Pasadena, CA, USA)
Tel: +1 626 395 8423; E-mail: mbrown@caltech.edu

Alessandro Morbidelli (Laboratoire Cassiopee, Nice, France) N&V author
Tel: +33 4 92 00 31 26; E-mail: morby@obs-nice.fr

Surprise addition to flowering plant family tree
Biologists have added a new addition to the base of the flowering plant family tree. The classification, reported in this week’s Nature, should help those trying to fathom the evolutionary history of angiosperms.

Hydatellaceae are a small, obscure family of aquatic herb usually reckoned to be flowering plants akin to grasses. But a new study of their anatomy and molecular biology by Sean W. Graham and co-workers now places them, surprisingly, next to the water lilies as among the most primitive flowering plants.

Although the relationship of flowering plants to other seed plants remains controversial, great progress has been made in identifying some of the most primitive members of the angiosperm family tree. These include water lilies, magnolias and the New Caledonian shrub Amborella trichopoda. The addition of Hydatellaceae at the same level should help biologists as they puzzle over the evolution of the distinctive reproductive structures whose appearance led to the dominance of flowering plants seen in modern ecosystems.

This week’s Nature also includes a package of features about Carl Linnaeus’ legacy as it applies to modern debates concerning conservation and taxonomy. Celebrating the 300th anniversary of Linnaeus’ birthday, the package also includes two commentaries on the future of Linnaean science - not to mention a portrait of his pet racoon.

CONTACTSean W. Graham (University of British Columbia, Vancouver, Canada)
Tel: +1 604 822 4816; E-mail: swgraham@interchange.ubc.ca

James A. Doyle (University of California Davis, CA, USA) Co-author
Tel: +1 530 752 7591; E-mail: jadoyle@ucdavis.edu

Else Marie Friis (The Swedish Museum of Natural History, Stockholm, Sweden) N&V author

Tel: +46 8 5195 4155; E-mail: elsemarie.friis@nrm.se

Developmental biology: Fruit flies shed light on blood cell development
Researchers have shown that a signalling centre in the fruitfly lymph gland controls the maintenance of blood cell precursors. The findings suggest that Drosophila could prove a useful model for studying blood development and immunity.

Blood precursor cells yield all of the different cells found in the blood system. In fruitflies, at least, this system is controlled by signals generated in part of the lymph gland called the posterior signalling centre (PSC), two Nature papers report. Signalling occurs via the JAK/STAT and Notch pathways, already well known for their roles in cell proliferation and differentiation, teams lead by Utpal Banerjee and Michele Crozatier report. And the PSC starts to form early in embryonic development.

Drosophila is relatively easy to modify genetically and so widely used in research. Modification of the genes highlighted in these papers is likely to shed light on the mechanics of blood development. And Drosophila studies also yield the prospect of direct in vivo imaging of blood cell precursors interacting with their stem cell niche.

CONTACTUtpal Banerjee (University of California, Los Angeles, CA, USA) Author paper [1]
Tel: +1 310 206 5439; E-mail: banerjee@mbi.ucla.edu

Michele Crozatier (CNRS-Centre de Biologie du Developpement, Toulouse, France) Author paper [2]
Tel: +33 5 61 55 82 90; E-mail: crozat@cict.fr

Researchers Create World's First Ideal Anti-Reflection Coating
NEW YORK- A team of researchers from Rensselaer Polytechnic Institute has created the world's first material that reflects virtually no light. Reporting in the March issue of Nature Photonics, they describe an optical coating made from the material that enables vastly improved control over the basic properties of light. The research could open the door to much brighter LEDs, more efficient solar cells, and a new class of "smart" light sources that adjust to specific environments, among many other potential applications.
Most surfaces reflect some light -- from a puddle of water all the way to a mirror. The new material has almost the same refractive index as air, making it an ideal building block for anti-reflection coatings. It sets a world record by decreasing the reflectivity compared to conventional anti-reflection coatings by an order of magnitude.
A fundamental property called the refractive index governs the amount of light a material reflects, as well as other optical properties such as diffraction, refraction, and the speed of light inside the material. "The refractive index is the most fundamental quantity in optics and photonics. It goes all the way back to Isaac Newton, who called it the 'optical density,'" said E. Fred Schubert, the Wellfleet Senior Constellation Professor of the Future Chips Constellation at Rensselaer and senior author of the paper.


Schubert and his coworkers have created a material with a refractive index of 1.05, which is extremely close to the refractive index of air and the lowest ever reported. Window glass, for comparison, has a refractive index of about 1.45.


Incredible New Things in Optics and Photonics


Scientists have attempted for years to create materials that can eliminate unwanted reflections, which can degrade the performance of various optical components and devices. "We started thinking, there is no viable material available in the refractive index range 1.0-1.4," Schubert said. "If we had such a material, we could do incredible new things in optics and photonics."
So the team created one. Using a technique called oblique angle deposition, the researchers deposited silica nanorods at an angle of precisely 45 degrees on top of a thin film of aluminum nitride, which is a semiconducting material used in advanced light-emitting diodes (LEDs). From the side, the films look much like the cross section of a piece of lawn turf with the blades slightly flattened.
The technique allows the researchers to strongly reduce or even eliminate reflection at all wavelengths and incoming angles of light, Schubert said. Conventional anti-reflection coatings, although widely used, work only at a single wavelength and when the light source is positioned directly perpendicular to the material.
A Broad Spectrum of Applications
The new optical coating could find use in just about any application where light travels into or out of a material, such as:
-- More efficient solar cells. The new coating could increase the amount
of light reaching the active region of a solar cell by several
percent, which could have a major impact on its performance.
"Conventional coatings are not appropriate for a broad spectral source
like the sun," Schubert said. "The sun emits light in the ultraviolet,
infrared, and visible spectral range. To use all the energy provided
by the sun, we don't want any energy reflected by the solar cell
surface."
-- Brighter LEDs. LEDs are increasingly being used in traffic signals,
automotive lighting, and exit signs, because they draw far less
electricity and last much longer than conventional fluorescent and
incandescent bulbs. But current LEDs are not yet bright enough to
replace the standard light bulb. Eliminating reflection could improve
the luminance of LEDs, which could accelerate the replacement of
conventional light sources by solid-state sources.
-- "Smart" lighting. Not only could improved LEDs provide significant
energy savings, they also offer the potential for totally new
functionalities. Schubert's new technique allows for vastly improved
control of the basic properties of light, which could allow "smart"
light sources to adjust to specific environments. Smart light sources
offer the potential to alter human circadian rhythms to match changing
work schedules, or to allow an automobile to imperceptibly communicate
with the car behind it, according to Schubert.
-- Optical interconnects. For many computing applications, it would be
ideal to communicate using photons, as opposed to the electrons that
are found in electrical circuits. This is the basis of the burgeoning
field of photonics. The new materials could help achieve greater
control over light, helping to sustain the burgeoning photonics
revolution, Schubert said.
-- High-reflectance mirrors. The idea of anti-reflection coatings also
could be turned on its head, according to Schubert. The ability to
precisely control a material's refractive index could be used to make
extremely high-reflectance mirrors, which are used in many optical
components including telescopes, optoelectronic devices, and sensors.
-- Black body radiation. The development could also advance fundamental
science. A material that reflects no light is known as an ideal "black
body." No such material has been available to scientists, until now.
Researchers could use an ideal black body to shed light on quantum
mechanics, the much-touted theory from physics that explains the
inherent "weirdness" of the atomic realm.
Schubert and his coworkers have only made several samples of the new material to prove it can be done, but the oblique angle evaporation technique is already widely used in industry, and the design can be applied to any type of substrate -- not just an expensive semiconductor such as aluminum nitride.
Schubert is featured in an interview about the research in the same issue of Nature Photonics.
Several other Rensselaer researchers also were involved with the project: Professors Shawn-Yu Lin and Jong Kyu Kim; and graduate students J.-Q. Xi, Martin F. Schubert, and Minfeng Chen.
The research is funded primarily by the National Science Foundation, with additional support from the U.S. Department of Energy, the U.S. Army Research Office, the New York State Office of Science, Technology and Academic Research (NYSTAR), Sandia National Laboratories, and the Samsung Advanced Institute of Technology in Korea. The substrates were provided by Crystal IS, a manufacturer of single-crystal aluminum nitride substrates for the production of high-power, high-temperature, and optoelectronic devices such as blue and ultraviolet lasers.
Under Schubert's leadership, the Future Chips Constellation focuses on innovations in materials and devices, in solid state and smart lighting, and applications such as sensing, communications, and biotechnology. A new concept in academia, Rensselaer constellations are led by outstanding faculty in fields of strategic importance. Each constellation is focused on a specific research area and comprises a multidisciplinary mix of senior and junior faculty and postdoctoral and graduate students.

A method to regrow teeth
Scientists have for the first time successfully replaced natural teeth in mice with teeth that were created in a Petri dish from single cells. Takashi Tsuji and colleagues started with the two cell types that develop into a tooth –mesenchymal and epithelial cells. First they grew each cell type separately to get larger quantities of cells and then injected them into a drop of collagen – a substance which ‘glues’ cells together in an organism. The cells developed into a budding tooth with high efficiency, and when transplanted into the cavity of an extracted tooth in a mouse developed normally and showed the same composition and structure as natural teeth.The authors provide further evidence that this method can be applied to any organ that develops from these cell types by regrowing a follicle that eventually forms a whisker in a mouse.
Author contact:Takashi Tsuji (Tokyo University of Science, Chiba, Japan)Tel: +81 4 7122 9711; E-mail: t-tsuji@nifty.com

Behaviour of Western Scrub-Jays
Western scrub-jays can save for the future. These prudent members of the corvid family can spontaneously plan for tomorrow without reference to their current motivational state.Nicola Clayton and colleagues studied the behaviour of western scrub-jays under different feeding conditions. The birds first experienced ‘training’ during which they were placed in two different compartments on alternate mornings for six days. In one compartment they were always given breakfast and in the other they were not. After training the birds were unexpectedly given food in the evening. The authors report that the birds stored more of this evening food when in the compartment in which they had not been given breakfast - as they would expect to be hungry again the next morning - relative to the one in which they had.In a similar experiment, the birds also differentially stored a particular food in the compartment in which that type of food would not be available the next morning, demonstrating future planning and ensuring a choice of food the following breakfast. Such forward planning challenges the belief, still held by many, that making provision for the future is a uniquely human skill.
CONTACT-Nicola Clayton (University of Cambridge, UK)Tel: +44 1223 333 559; E-mail: nsc22@cam.ac.uk Sara J. Shettleworth (University of Toronto, Canada) N&V authorTel: +1 416 978 5201; E-mail: shettle@psych.utoronto.ca

Chemistry: Halogen soup
Chemists have developed a simple method for making testosterone-like molecules containing halogen atoms. Halogenated natural products have been isolated from marine organisms and are often biologically active, so it's hoped the methodology will boost the development of novel therapeutics.Kazuaki Ishihara and his colleagues mixed a simple halogen-containing 'donor’, a compound that contained phosphorus, and a small-molecule scaffold and thus isolated complex products containing halogen atoms. The reaction is selective for a specific product, giving the manufacturer a high degree of control over the three-dimensional structure of the end products.The simple manufacturing process, described in this week's issue of Nature, uses simple ingredients to form complicated molecules and may enable chemists and biochemists to understand how similar halogenated natural products are made in nature.
CONTACT-Kazuaki Ishihara (Nagoya University, Japan)Tel: +81 52 789 3331; E-mail: ishihara@cc.nagoya-u.ac.jp Phil S. Baran (Scripps Research Institute, La Jolla, CA, USA) N&V authorTel: +1 858 784 7373; E-mail: pbaran@scripps.edu

Glaciology: Subglacial lakes discovered in East Antarctica
Scientists identify large, subglacial lakes in East Antarctica, which are situated at the start of fast-flowing ice streams. The lakes cover an area similar to that of Lake Vostok - the largest of more than 140 lakes already discovered - and could be contributing significantly to the dynamics of the overlying ice sheet.Ice streams are large ‘rivers’ of fast-flowing ice within continental ice sheets that transport inland ice towards the sea. Previous studies have revealed several large bodies of water trapped under the East Antarctic ice sheet but, until now, all the lakes discovered in this region have been self-contained and isolated from the onset of rapid ice flow.Michael Studinger and colleagues used satellite radar imagery and ice-surface elevations to reveal four, flat, featureless regions of ice surface surrounded by troughs and ridges - typical ice surface morphology of subglacial lakes. The lakes are located right at the onset of the Recovery Glacier ice stream in East Antarctica and are apparently linked to rapid ice flow across a 280-km-wide region, adding 35 thousand million tons of ice per year into the sea. The authors suggest that these lakes should be taken into account when predicting the fate of ice sheets with the changing climate of the world.
CONTACT-Michael Studinger (Columbia University, Palisades, NY, USA)Tel: +1 845 365 8598; E-mail: mstuding@ldeo.columbia.edu
The following co-author may also be available:Robin E. Bell (Columbia University, Palisades, NY, USA)E-mail: robinb@ldeo.columbia.edu Jack Kohler (Norwegian Polar Institute, Tromso, Norway) N&V authorTel: +47 77 75 06 55; E-mail: jack.kohler@npolar.no

Honey, I Shrunk Oble!
The National Institute of Physics, University of the Philippines (UP) has miniaturized the Oblation (UP’s trademark) as part of its project on micro-fabrication of functional micro-devices using non-linear multi-photon absorption. The research project aims to use micro-structures as components in an integrated miniaturized laboratory.
The University of the Philippines’ National Institute of Physics (NIP) through its Instrumentation Physics Laboratory has figured out how to miniaturize the Oblation (University of the Philippines’ trademark) using femtosecond-pulse near-infrared laser. The light-sculptured three-dimensional microscopic Oblation measures around 20 micrometers in length and 10 micrometers in width. The miniaturization of the Oblation is part of Wavefront Engineering Team’s (WET) research project on micro-fabrication of functional micro-devices using non-linear multi-photon absorption. The research intends to fabricate structures in the micrometer scale with the final aim of using the micro-structures as components in an integrated miniaturized laboratory or a micro-machine functioning under a microscope.The WET is headed by Dr. Vincent Ricardo Daria, Associate Professor at NIP, and is composed of researchers and students, namely: Dr. Darwin Palima (Adjunct Professor), Godofredo Bautista (Ph.D Physics student), Anthony Montecillo (MS Material Science and Engineering student), Jacqueline Romero (MS Physics student), Andrew Banas (BS Physics student), Atchong Hilario (BS Applied Physics student) and Reniel Cabral (BS Applied Physics student). Joaquin Jose Escay who graduated BS Applied Physics in March 2006 also did significant programming work for the project.The micro-oblation is a solid plastic formed by light, which is used to chisel the sculpture. According to Dr. Daria, the miniaturization of the Oblation is a way to test the resolution of their micro-fabrication system. When asked why they chose to miniaturize UP’s trademark, Daria said “pag-paliit ng oble nagpapatunay na gawa natin ito dito sa UP” (fabrication of the micro-oblation demonstrates that this micro-structure was built here in UP.) WET’s goal is to use light-sculptured devices as components in a miniaturized micro-laboratory. After the fabrication process, the micro-components can also be actuated by light. Light is a form of energy and therefore has momentum. When the momentum of light is transferred to the light-sculptured micro-components, these components will move and become a part of a micro-machine. Hence, using these miniaturized components, WET will make micro-machines fabricated and controlled by light. The miniaturization and fabrication of components is just an intermediate step in building a scientific breakthrough. The research is expected to produce a scientific tool to be used by biologists and chemists. This tool would help the scientists have a more controlled environment in conducting experiments. According to Dr. Daria, most of the experiments are done in bulk or in macro-scale and so data gathering and analysis is usually achieved via statistical methods. In doing the experiment using a smaller (microscopic) scale, the interactions and chemical reactions would be more localized and can aid in major scientific breakthroughs.WET is now in the stage of testing and fabricating components. In the long run, the researchers want to have these components compiled in their system and eventually create micro-machines. The research project is funded by the Department of Science and Technology-Philippine Council for Advanced Science and Technology, Research and Development (DOST-PCASTARD). Dr. Daria also received a grant amounting to P 2.3M from DOST-Institutional Development Program for setting up a system for programmable phase using a spatial light modulator – an essential component of the project that can also be used for other research ventures. UP provided the femtosecond-pulse Titanium: Sapphire laser, which is the near-infrared light source for micro-fabrication.
Associated links
http://www.ovcrd.upd.edu.ph

Rust diseases – a threat to global food security
Next week, some of Australia’s and the world’s foremost experts in the field of rust diseases will be in Sydney to attend a symposium on the topic – “Rust Diseases: Threats to Global Food Security in the Context of Climate Change.”
Rust diseases – a threat to global food securityChronic food shortages caused by cereal rusts have happened in the past – and today international agricultural agencies are on the alert again because of a new threat in Eastern Africa, a rust known as Ug99.A virulent disease of wheat, Ug99 has the potential to wipe out a quarter of the world’s wheat crop.Next week, some of Australia’s and the world’s foremost experts in the field of rust diseases will be in Sydney to attend a symposium on the topic – “Rust Diseases: Threats to Global Food Security in the Context of Climate Change.”The symposium has been organised by the NSW Centre for Plant and Animal Biosecurity, an alliance between the NSW Department of Primary Industries and the University of Sydney.High on the agenda is the threat to global food security from Ug99, which last month was reported to have jumped from eastern Africa and is now infecting wheat in Yemen in the Arabian Peninsula.Countries in the predicted pathway of Ug99 grow more than 65 million hectares of wheat a year.NSW Department of Primary Industries (DPI) Principal Research Scientist, Dr Colin Wellings said: “There is international concern that this new stem rust could destroy vast quantities of wheat and threaten food security at a time that world wheat stocks are at a historic low.“The potential for the disease to move into Central Asia is enormous and alarming.”Speakers at the symposium include the facilitator of the Global Rust Initiative (GRI), Dr Richard Ward, who is based at the international plant breeding centre CIMMYT in Mexico.GRI was set up in 2005 in response to recurring epidemics of Ug99 in Kenya and Ethiopia. (In the early 1950s, a major stem rust epidemic in North America destroyed up to 40 percent of that continent’s spring wheat crop.)Dr Ward says that “the potential for a serious international epidemic of stem rust based on Ug99 has galvanized considerable global concern to secure wheat yield protection through breeding for rust resistance.”In NSW, wheat growers are on alert because of the discovery of a new stripe rust which disarms a resistance gene that has been bred into some popular varieties of wheat.Dr Wellings believes that growers have two to three years before the new stripe rust becomes problematic for wheat varieties carrying the Yr17 resistance gene.“If this proves to be the case, then there should be time for farmers to change the varieties they are planting.”Dr Wellings said that for nearly a century, DPI and University of Sydney scientists have been working to find new genes which confer resistance and breed them into Australian cereal varieties.He said that in 1973 a stem rust outbreak caused “historic and massive losses” in crops in northern NSW and Queensland. This galvanised government and industry to take a national approach to work towards being prepared for new incursions.
The Cooperative Research Centre (CRC) for National Plant Biosecurity is a major sponsor of the symposium.Speakers at the symposium include:Mr Terry Enright, Chairman, Grains Research and Development CorporationProf John Lovett, Chairman, CRC for National Plant BiosecurityDr Sanjaya Rajaram, ICARDA-CIMMYT, SyriaDr Les Szabo, US Department of Agriculture Dr Rick Ward, Global Rust InitiativeProfessor Robert Park and Dr Harbans Bariana, University of SydneyThe symposium is being held on 21 and 22 February at the Elizabeth Macarthur Agricultural Institute at Menangle, in Sydney’s south-west. The program is at: http://www.agric.usyd.edu.au/news/index.shtml

Fruit flies identified from DNA ‘signature’
A discovery that enables the most economically important fruit fly species to be identified from their DNA ‘signature’ could avert future devastating fruit fly outbreaks, according to scientists from the NSW Department of Primary Industries (DPI).
A discovery that enables the most economically important fruit fly species to be identified from their DNA ‘signature’ could avert future devastating fruit fly outbreaks, according to scientists from the NSW Department of Primary Industries (DPI). Molecular biologists and entomologists from DPI have developed the means to identify selected species of fruit fly from segments of their DNA. This enables fruit fly to be developed from larvae or incomplete adultsMolecular biologist Dr Deb Hailstones said the discovery greatly increased the likelihood of an outbreak of fruit fly being contained early. “Previously, fruit fly species could only be identified accurately visually from mature adults. This meant there could be a delay of weeks before an accurate assessment can be made of a species, and whether it is an economic threat.The new method of identification relies on use of a molecular key development by DPI entomologist, Peter Gillespie. Dr Hailstones said the key sets out a means for amplifying and comparing target sections of DNA that the different species of fruit fly have in common.“It is not yet able to distinguish between the hundreds of species of fruit flies known to damage fruits and vegetables. However we can identify patterns of DNA that are typical of the 30 species of greatest significance for Australian horticulture.”The technique enables this group of economically important species to be identified from larvae or from incomplete adults.Older methods require fruit flies to be identified morphologically, from their physical characteristics, which means that specimens of adult flies have to be supplied – and they have to be complete. Dr Hailstones said the molecular key will be useful for border surveillance and quarantine and for the problem specimens where eggs or early maggots are found in produce.“Instead of fruit rotting at borders or in quarantine while scientists wait until visual tests can be done, the insects can be identified from their DNA almost immediately”, she said.The key has been proposed as an Australian standard and will be updated as soon as new discoveries are made.Fruit flies are amongst the world’s most destructive horticultural pests and a major outbreak can cost many millions of dollars. In 1995 in north Queensland, an outbreak of papaya fruit fly cost industry an estimated $100 million. The research was undertaken by staff from the Agricultural Scientific Collections Unit in Orange and the Elizabeth Macarthur Agricultural Institute.
Contact: Dr Deborah Hailstones on 4640 6442

Scientists identify wheat germplasm suitable for acid soils
NSW Department of Primary Industries (DPI) scientists have identified a major new source of wheat germplasm tolerant of aluminium toxicity, paving the way for the breeding of new bread wheat varieties able to grow in acid soils.
31 January 2007Scientists from DPI in Wagga Wagga and Tamworth screened hundreds of ancient landrace wheats collected from around the world as part of a research effort to find aluminium (Al) tolerant bread wheats. Landraces are the ancestors of modern wheat cultivars. Most sources of Al tolerance in Australian wheat can be traced back to Brazil or China, and according to DPI molecular biologist Dr Harsh Raman, the new genetic material found appears to be different from that used in current breeding programs.An initial laboratory study of 250 landraces found 35 were Al tolerant. After a root tip stain was applied, root regrowth was measured and 33 of these were found to increase their root length after exposure to Al.The tolerant landraces come from eight countries - Bulgaria, Croatia, India, Italy, Nepal, Spain, Tunisia and Turkey – and Dr Raman said that subsequent molecular analysis indicated that they are from diverse genetic backgrounds.“Conventional breeding has reduced the available gene pool of wheat, possibly reducing the availability of useful or novel genes adapted to stress such as that induced by aluminium.”Landraces have already proved a valuable source of important genes, such as those conferring reduced height used extensively in Australian wheat breeding programs.Dr Raman said the new landraces could be used to expand the genetic base currently available and may also hold other important genes.“Given that there is mostly more than one stress factor placed on a plant at any one time, the possibility exists that landraces that are adapted to one stress may carry useful adaptations to other stresses such as salinity, nutrient deficiencies and foliar and root diseases.”Acid soils are one of Australian farming’s worst environmental problems.About 70 percent of Australian soils are associated with extremes in pH. Low pH releases aluminium at levels which are toxic to many crop species, constraining root growth and uptake of water and nutrients. In NSW, acid soils are estimated to cause losses of up to $400 million dollars each year. The landrace germplasm examined for this research came from the Australian Winter Cereals Collection, located at Tamworth. Initial findings were reported in the international journal Genetic Resources and Crop Evolution. The research was funded under the NSW Government’s Biofirst strategy. Media inquiries: Joanne Finlay on 6391 3171 or 0428 491 813.

Immunology: HIV reveals vulnerable side
Researchers have snuck a detailed peek at the crystal structure of a known broadly neutralizing human immunodeficiency virus (HIV-1) antibody as it binds to a specific part of HIV-1. The find, reported in this week’s Nature, is important because the binding site represents a chink in HIV’s armour that could help guide future vaccine development.HIV keeps one step ahead of the human immune system by mutating frequently and changing its shape. But certain parts of the virus must remain relatively unchanged so that it can continue to bind to and enter human cells. gp120, a glycoprotein that juts out from the surface of the virus and binds to CD4 receptor on host cells, is one such region, making it a target for vaccine development.Peter D. Kwong and colleagues made variants of stable gp120 that could be recognized by antibodies. They then looked in detail at the binding of one antibody, called b12, to the glycoprotein and found that the antibody approaches in an orientation very similar to that of CD4. Although other antibodies bind at this sight, b12 is the only one that binds and neutralizes a relatively broad range of HIV-1 isolates, so the results may help explain why.CONTACTPeter D. Kwong (National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA)Tel: +1 301 594 8685; E-mail: pdkwong@nih.gov

Sleep deprivation impairs subsequent learning
Sleep deprivation may impair memory for subsequent experiences by altering the function of the hippocampus, reports a paper in the March issue of Nature Neuroscience. Previous research has shown that sleep occurring after an experience can be critical to learning and memory but this new study shows why sleep before an experience is also critical, and that memory systems do not function normally without it.Matthew Walker and colleagues deprived people of a night’s sleep and then asked them to observe and remember a large set of picture slides for a subsequent recognition test. Brain activity was monitored with fMRI – functional magnetic resonance imaging – while subjects viewed the slides. Following a full night of sleep, the subjects were then queried about the slides on the next day. The researchers found that sleep-deprived subjects showed decreased activity in the hippocampus – a brain region important for memory – relative to control subjects who were not sleep-deprived while viewing the pictures; sleep-deprived people also had poorer subsequent recall abilities. The relationship of activation in other brain areas to activation in the hippocampus was also altered, suggesting that sleep deprivation alters memory-encoding strategies.
Author contact:
Matthew Walker (Harvard Medical School, Boston, MA, USA)Tel: +1 617 731 6378; E-mail: mwalker@hms.harvard.edu

In utero protein regulation
A novel strategy for regulating a protein important in development is described online in Nature this week. Michael T. Longaker and colleagues report that, in mice, glycogen synthase kinase-3beta (GSK-3beta) can be artificially controlled from within the mother's uterus, in a reversible and time-controlled manner.GSK-3beta plays an integral part in a variety of biological processes, although its specific developmental roles remain unclear. In the present study the authors used an existing chemically regulated form of the GSK-3beta gene, whereby expression of the GSK-3beta protein is controlled by the presence or absence of the drug rapamycin. Using this approach combined with conventional mutant analysis they defined a specific requirement for GSK-3beta in midline development: mice that did not express the protein had cleft palate, incomplete fusion of the ribs and a split sternum.In addition, the authors were able to rescue some of the developmental defects using maternal rapamycin treatment to restore internal GSK-3beta activity during two distinct windows of gestation. They propose that their studies provide an improved method for defining the timing and level of protein expression during development, a detailed knowledge of which is essential for rescuing developmental defects.Author contact:Michael T. Longaker (Stanford University Medical Center, CA, USA)Tel: +1 650 736 1707; E-mail: longaker@stanford.edu

Viral highways: spreading from cell to cell
A number of retroviruses, including HIV, induce cells to form long bridges along which the virus particles move from infected cells to uninfected cells, according to a paper in the March issue of Nature Cell Biology.Viral transmission has long been recognized to be more efficient between infected and target cells that are in direct contact with each other. Exactly how viruses move from one cell to another is unclear, although structures called virological synapses, which contain the virus particle and form between areas of cell–cell contact, are thought to be important in this process. In the present study Walther Mothes and colleagues describe a novel mode of cell–cell transmission for three retroviruses – murine leukaemic virus, human immunodeficiency virus and avian leucosis virus – along the outside of long, thin intercellular bridges. These bridges seem to be stabilized by an association between a viral protein expressed by the infected cell and a viral-receptor protein in the target cell. Mutants of these proteins that cannot interact destabilize the bridges and markedly reduce viral spreading from cell to cell. This mode of transmission is observed in a variety of different cells, suggesting that it may be a general mechanism of viral spreading.Whether these intercellular viral highways represent a predominant mode of viral transmission, their relative importance for different viruses, and their relationship to virological synapses are open questions. However, interference with the bridge structures described by Mothes and colleagues may provide a new avenue to limit the infectivity of a number of key viral diseases.
Author contact:
Walter Mothes (Yale School of Medicine, New Haven, CT, USA)Tel: +1 203 737 2203; E-mail: walter.mothes@yale.edu

Human adult stem cells can regenerate muscle
Human adult stem cells isolated from human adult blood vessels are able to regenerate muscle in a mouse model of muscular dystrophy, according to a study published online this week in Nature Cell Biology.The lure of a cure for muscle-wasting diseases has lead researchers to explore the regeneration potential of stem cells isolated from the walls of blood vessels. In a recent Nature paper Giulio Cossu and colleagues showed that such cells isolated from young golden retrievers regenerated the muscles of dystrophic dogs when injected into their circulation. A new study by the same team demonstrates that cells with similar properties can be isolated from human juvenile and adult blood vessels.The same researchers isolated this type of stem cell from juvenile dystrophic patients and grew them in cell culture. Muscular dystrophy is linked to a mutation in dystrophin, a gene required for muscle formation, and the authors genetically modified the stem cells to make them express the corrected version of the gene. After injection into the blood vessels of dystrophic mice, these cells found their way to skeletal muscle, which they were able to partly regenerate. Importantly, the cells were shown to reconstitute the muscle’s own stem cell population. The authors suggest that the isolation of these stem cells raises hope for treating muscular dystrophy using the patient’s own cells.
Author contact:
Giulio Cossu (Stem Cell Research Institute, Rome, Italy)Tel: +39 02 2643 4954; E-mail: cossu.giulio@hsr.it

Human adult stem cells can regenerate muscle
Human adult stem cells isolated from human adult blood vessels are able to regenerate muscle in a mouse model of muscular dystrophy, according to a study published online this week in Nature Cell Biology.The lure of a cure for muscle-wasting diseases has lead researchers to explore the regeneration potential of stem cells isolated from the walls of blood vessels. In a recent Nature paper Giulio Cossu and colleagues showed that such cells isolated from young golden retrievers regenerated the muscles of dystrophic dogs when injected into their circulation. A new study by the same team demonstrates that cells with similar properties can be isolated from human juvenile and adult blood vessels.The same researchers isolated this type of stem cell from juvenile dystrophic patients and grew them in cell culture. Muscular dystrophy is linked to a mutation in dystrophin, a gene required for muscle formation, and the authors genetically modified the stem cells to make them express the corrected version of the gene. After injection into the blood vessels of dystrophic mice, these cells found their way to skeletal muscle, which they were able to partly regenerate. Importantly, the cells were shown to reconstitute the muscle’s own stem cell population. The authors suggest that the isolation of these stem cells raises hope for treating muscular dystrophy using the patient’s own cells.
Author contact:
Giulio Cossu (Stem Cell Research Institute, Rome, Italy)Tel: +39 02 2643 4954; E-mail: cossu.giulio@hsr.it

Common genetic variant protects against breast cancer
Scientists have confirmed that a common genetic variant – CASP8 – offers modest protection against breast cancer, according to a study to be published online this week in Nature Genetics. The report provides some of the strongest evidence so far that common variants affect the risk of developing breast cancer, and the size of the collaboration sets an important precedent for future studies.Rare mutations in the genes BRCA1 and BRCA2 significantly raise an individual’s risk of breast cancer, but account for only a fraction of the overall variation in genetic risk. More common variants that have a smaller effect on individual risk have been difficult to find, largely due to the size of the studies needed to identify variants of small effect in a convincing manner.The Breast Cancer Association Consortium, which comprises more than 20 collaborating research groups, examined 9 previously reported breast cancer susceptibility variants in at least 10,000 affected women and 10,000 disease-free women in a study led by Angela Cox. For 8 of the 9 genes, the Consortium reported either no association with breast cancer risk, or marginal evidence for an association. For a variant in the gene CASP8, however, they found a significant association. The particular variant assessed in the study is found in approximately 13% of women of European descent, and is protective, lowering the risk of breast cancer by approximately 10%.
Author contact:
Angela Cox (Sheffield University Medical School, UK)Tel: +44 1142712373; E-mail: a.cox@shef.ac.uk

Large-scale survey of mutations in cancer
One of the largest surveys of mutations in human cancers is reported online this week in Nature Genetics. The study provides a preview of results that may be generated by even larger projects such as The Cancer Genome Atlas, set to begin soon.Previous attempts at cataloguing mutations in different types of cancer have relied on DNA sequencing, which can be too expensive when applied to a large number of tumors. Levi Garraway and colleagues applied a previously developed technique called mass spectrometric genotyping to identify the frequency and distribution of 238 known mutations in 17 oncogenes in 1,000 tumors. The genotyping approach is more sensitive than the sequencing approach, identifying more mutations, and simultaneously detects mutations in multiple oncogenes in a cost-effective manner.The authors report that mutations in three of the oncogenes were not found in any of the tumors, while mutations in the other genes were observed in only 30% of the tumors, indicating that many cancer-causing events remain to be discovered. There were relatively few examples where a specific mutation was found more than once, suggesting that mutations occurring at high frequency will be uncommon.
Author contact:
Levi Garraway (Dana-Farber Cancer Institute, Boston, MA, USA)Tel: +1 617 632 6689; E-mail: levi_garraway@dfci.harvard.edu

Genetic indicators of type 2 diabetes risk
Geneticists have identified five different areas of DNA base-pair change that contribute significantly towards the risk of developing type 2 diabetes mellitus. The finding helps tease apart the complex mix of genetic and environmental factors that contribute to the disease, and may guide the direction of future therapeutics.Constantin Polychronakos and colleagues used high-density arrays to look for the occurrence of over 390,000 single nucleotide polymorphisms (SNPs) - particular regions of DNA containing a single base-pair change - in the genomes of over 2,000 patients with type 2 diabetes and more than 2,000 controls. They identified four different SNP-containing regions that conferred a significant risk to developing the disease, and confirmed an already known association between the TCF7L2 gene and type 2 diabetes. These five genetic regions together might account for 70% of the genetic risk, the authors say.The important variants occur in genes related to the control of insulin secretion and pancreatic development. One gene encodes a protein that helps move zinc ions around and is found solely in the secretory vesicles of beta-cells, which make and release insulin. The finding, published online by Nature this week, has possible dietary implications and hints that therapies targeting zinc may be worth a shot.
Author contact:
Constantin Polychronakos (McGill University, Montreal, Quebec Canada)Tel: +1 514 934 4315; E-mail: constantin.polychronakos@mcgill.caNelson B. Freimer (UCLA, Los Angeles, CA, USA)Tel: +1 310 794 9571; E-mail: nfreimer@mednet.ucla.edu (N&V author)

Diagnosis and treatment insights for an unusual childhood Cancer Syndrome An unusual case of a young girl with a colon cancer syndrome caused by recessive mutations in the mismatch repair gene MSH6 is described in the February issue of Nature Clinical Practice Oncology. Individuals with mutations in MSH6 are at an increased risk of developing cancer; however, a childhood cancer syndrome caused by these mutations has only recently been recognized.In this article, Richard Scott and colleagues report how a 13-year-old girl who was treated for a brain tumor and leukemia was subsequently diagnosed with multiple colon cancers and skin lesions, despite an absence of hereditary colon cancer. Recessive mutations in the MSH6 gene were identified in this patient and she was successfully treated with surgery and chemotherapy.This case study broadens the tumor spectrum associated with recessive MSH6 mutations and discusses the implications for treatment in such individuals. Many mismatch repair deficiency syndromes are treated with the drug temozolomide, but preclinical and clinical data show that it can cause resistance and may promote further genetic abnormality. Mutations in MSH6 and other mismatch repair genes should be considered in any child presenting with malignancy and abnormal skin pigmentation. Early diagnosis is important so that genetic testing and screening can be offered to relatives, and could also help avoid ineffective chemotherapeutic agents such as temozolomide.
Author contact:Richard Scott (Institute of Cancer Research, Surrey, UK)Tel: +44 208 7224 455; E-mail: richard.scott@icr.ac.uk Editor contact:Lisa Hutchinson (Editor, Nature Clinical Practice Oncology)Tel: +44 20 7843 4837; Email: l.hutchinson@nature.com

Gene Segment Identified in Virulent Human H5N1 Viruses
Key discovery may enable development of vaccines, therapeutics
BOSTON, Jan. 27, 2007 -- Viruses whose genomes constantly mutate, such as the H5N1 "bird flu," are driving a race to find relatively unchanging segments of their genomes; successful identification of these segments may allow more successful vaccines and therapeutics to be developed. Replikins are short fragments of the genomes of infectious organisms, which have been found to be related quantitatively to rapid replication and epidemic outbreaks (1,2). Scientists at Replikins, LLC have just identified a specific site in the human H5N1 virus genome which contains a dramatically higher concentration of replikins than the rest of the virus, and named it the Replikin Peak Gene(TM) (RPG). Two of the replikin components of RPG have been found to be conserved over 88 years in the following high-mortality and pandemic virus strains: H1N1, H2N2, H3N2, H5N1, and H7N7. This discovery makes possible very specific targeting with vaccines and other treatments; these Replikin peptides also form the basis for a pan-strain influenza vaccine, for which trials are underway. New quantitative virus protein sequence search software, FluForecast(R), available as a service from Replikins Ltd., was central to this work. RPG was isolated by comparing the replikin concentration (Replikin Count(TM)) of RPG to seven other defined areas of the H5N1 genome (Figure). The Replikin Count(TM) of RPG, was found to be associated with the pB1 area of the human H5N1 virus genome, and was increased tenfold from 2003 to 2006, during the current bird flu epidemics, when it was 4 to 10 times greater than that of the other genomic sections of the virus (hemagglutinin, neuraminidase, pA, pB2, ns, matrix, nucleocapsid)(p<0.001). In contrast to 'in vivo' or 'in vitro' localization of a gene, this method may be thought of as "in silico" identification or isolation of a gene. References:
1. BogochS, BogochES. Replikins: The Chemistry of Rapid
Replication. Begell Press, New York, 2005.
2. http://www.replikins.com

Smart Nanocarriers to Combat Tumors

IBN’s technology spells hope for cancer patients who suffer from painful side-effects of chemotherapy

SINGAPORE – A ‘smart’ nanocarrier technology developed by a team of researchers at the Institute of Bioengineering and Nanotechnology (IBN) is set to vastly improve the way cancer patients are treated.
Anticancer drugs are now being administered to patients using methods that cause the indiscriminate killing of both diseased and healthy cells. Such chemotherapy leads to side-effects, such as nausea, fatigue, and hair loss, and makes the patient weak and frail. Between 1998 and 2002, 38,447 people in Singapore were diagnosed with some type of cancer, while 20,289 died of the disease. Hence, there is a crucial need for the development of more effective cancer therapy, which not only minimizes side-effects but also directly targets diseased cells.
Scientists at IBN have found a way to tackle this problem through the use of anticancer drug delivery vehicles that transport drugs only to where they are needed in the body. This method significantly reduces or even eliminates the severe side-effects typically induced by conventional chemotherapeutics.
The team led by IBN Group Leader Dr Yi-Yan Yang has created ‘smart’ nanocarriers that can house anticancer drugs in their inner cores. Such polymeric core-shell nanoparticles are small in size (generally less than 200 nm), with shells that protect enclosed bioactive compounds against degradation and digestive fluids.
These nanocarriers, which are both pH-sensitive and temperature-sensitive, are structurally stable in the normal physiological environment. However, in slightly acidic environments that are characteristic of tumor tissues and endosomes (a cell component), they deform and precipitate, thus releasing the enclosed drug molecules.
“Previous attempts by other scientists involved the use of core-shell nanoparticles that were only sensitive to temperature. Drug delivery may be controlled by superficially heating and cooling the environment of the nanoparticles,” said lead scientist Dr Yang.
“The novelty of our invention compared to carriers that are only temperature-sensitive is the ability of IBN’s core-shell nanoparticles to target drugs to deep tissues or cell compartments without changes in temperature.”
Dr Yang explained that once IBN’s ‘smart’ nanocarriers encounter cancer tissues, they form a hydrophobic shell that allows them to adhere to tumor sites. Biological signals are also tagged onto the shell of these nanoparticles, enabling them to recognize and zoom in on tumor sites. After being taken up by cancer cells, the nanocarriers can absorb protons in the endosomes and release their payload into the cell’s cytoplasm, and subsequently its nucleus.
So far, the IBN team has proven that their core-shell nanoparticles can deliver anticancer drugs much more efficiently into cancer cells, compared to current techniques. Their in vivo studies using a mouse breast tumor model has also shown that doxorubicin (an anti-cancer drug) loaded in these smart nanoparticles can suppress tumor growth more efficiently than free doxorubicin.
“IBN’s ‘smart’ nanocarriers do not show significant cytotoxicity, and offer great potential in targeting drugs to tumor tissues with high efficacy,” added Dr Yang. “This invention may also be used in in vitro and animal studies for drug discovery.”
The prospects for IBN’s technology are significant, with the cancer drug delivery market expected to grow to US$15.4 billion by the year 2007.
The team’s findings were recently published in the leading journal Advanced Materials (1), and a United States patent has been filed on the invention.
(1) K. S. Soppimath, C. W. Tan and Y. Y. Yang, "pH-Triggered Thermally Responsive Polymer Core-Shell Nanoparticles for Targeted Drug Delivery", Advanced Materials 17 (2005) 318-323.
For more information on IBN, please log on to www.ibn.a-star.edu.sg.

Smart Nanocarriers to Combat Tumors

IBN’s technology spells hope for cancer patients who suffer from painful side-effects of chemotherapy

SINGAPORE – A ‘smart’ nanocarrier technology developed by a team of researchers at the Institute of Bioengineering and Nanotechnology (IBN) is set to vastly improve the way cancer patients are treated.
Anticancer drugs are now being administered to patients using methods that cause the indiscriminate killing of both diseased and healthy cells. Such chemotherapy leads to side-effects, such as nausea, fatigue, and hair loss, and makes the patient weak and frail. Between 1998 and 2002, 38,447 people in Singapore were diagnosed with some type of cancer, while 20,289 died of the disease. Hence, there is a crucial need for the development of more effective cancer therapy, which not only minimizes side-effects but also directly targets diseased cells.
Scientists at IBN have found a way to tackle this problem through the use of anticancer drug delivery vehicles that transport drugs only to where they are needed in the body. This method significantly reduces or even eliminates the severe side-effects typically induced by conventional chemotherapeutics.
The team led by IBN Group Leader Dr Yi-Yan Yang has created ‘smart’ nanocarriers that can house anticancer drugs in their inner cores. Such polymeric core-shell nanoparticles are small in size (generally less than 200 nm), with shells that protect enclosed bioactive compounds against degradation and digestive fluids.
These nanocarriers, which are both pH-sensitive and temperature-sensitive, are structurally stable in the normal physiological environment. However, in slightly acidic environments that are characteristic of tumor tissues and endosomes (a cell component), they deform and precipitate, thus releasing the enclosed drug molecules.
“Previous attempts by other scientists involved the use of core-shell nanoparticles that were only sensitive to temperature. Drug delivery may be controlled by superficially heating and cooling the environment of the nanoparticles,” said lead scientist Dr Yang.
“The novelty of our invention compared to carriers that are only temperature-sensitive is the ability of IBN’s core-shell nanoparticles to target drugs to deep tissues or cell compartments without changes in temperature.”
Dr Yang explained that once IBN’s ‘smart’ nanocarriers encounter cancer tissues, they form a hydrophobic shell that allows them to adhere to tumor sites. Biological signals are also tagged onto the shell of these nanoparticles, enabling them to recognize and zoom in on tumor sites. After being taken up by cancer cells, the nanocarriers can absorb protons in the endosomes and release their payload into the cell’s cytoplasm, and subsequently its nucleus.
So far, the IBN team has proven that their core-shell nanoparticles can deliver anticancer drugs much more efficiently into cancer cells, compared to current techniques. Their in vivo studies using a mouse breast tumor model has also shown that doxorubicin (an anti-cancer drug) loaded in these smart nanoparticles can suppress tumor growth more efficiently than free doxorubicin.
“IBN’s ‘smart’ nanocarriers do not show significant cytotoxicity, and offer great potential in targeting drugs to tumor tissues with high efficacy,” added Dr Yang. “This invention may also be used in in vitro and animal studies for drug discovery.”
The prospects for IBN’s technology are significant, with the cancer drug delivery market expected to grow to US$15.4 billion by the year 2007.
The team’s findings were recently published in the leading journal Advanced Materials (1), and a United States patent has been filed on the invention.
(1) K. S. Soppimath, C. W. Tan and Y. Y. Yang, "pH-Triggered Thermally Responsive Polymer Core-Shell Nanoparticles for Targeted Drug Delivery", Advanced Materials 17 (2005) 318-323.
For more information on IBN, please log on to www.ibn.a-star.edu.sg.

Quantum dots: Nano-probes of the future

IBN has pioneered methods to enable these nanocrystals to be used as powerful tools in bio-imaging and drug targeting

SINGAPORE– A team of researchers at the Institute of Bioengineering and Nanotechnology (IBN) has successfully addressed one of the biggest challenges facing the use of quantum dots in biomedical applications.
The group, led by IBN Executive Director Prof. Jackie Y. Ying, has invented methods that effectively give these unique materials water-soluble and non-toxic qualities, enabling them to be used as powerful fluorescent probes in biological labeling and diagnostics.
Quantum dots, also known as nano-crystals, are a special class of semiconductors that are extremely small in size (2-6 nanometers). These nanometer-sized particles are able to display any chosen color in the entire ultraviolet-visible spectrum through a simple change in their size or composition. They have shown great promise in wide-ranging applications, as solar cells and photodetectors.
More importantly, their strong and stable photoluminescent properties make them promising candidates for use in bio-imaging applications – they can emit different colors, based on pre-determined biological tags/signals. This means that scientists can attach quantum dots to a given protein or receptor to observe normal or abnormal cell functions. Unlike conventional organic dyes, quantum dots have enormous photostability, or the ability to fluoresce for several months. This allows them to track cell processes for longer periods of time and to shed more light on molecular interactions.
Nevertheless, the major disadvantages involving the use of quantum dots, particularly in biological applications, are their toxicity and insolubility (they would need to be soluble to be taken up by cells). Their surfaces would also need to be modified to enable the linking of bio-molecules. Previous efforts to tackle these problems involve synthetic methods that were too complicated or ineffective in maintaining the quantum dots’ stability or photoluminescent properties.
IBN scientists, however, have been able to pioneer a simple and efficient one-step procedure to render these quantum dots water-soluble and non-toxic (1).
According to Senior Research Scientist Dr. S. Tamil Selvan, IBN’s method of coating the particles with silica involves a simple water-in-oil reverse microemulsion procedure. The silica coating provides an effective non-toxic barrier and enables bio-molecules to adhere to the particles’ surface.
“This highly economical procedure produces robust and water-soluble quantum dots that have great potential to be used commercially in bio-imaging applications,” said Dr. Selvan.
The researchers have gone one step further by designing silica-coated composites of quantum dots and magnetic nanoparticles (2).
The hybrid composite is created easily and economically using reverse microemulsion synthesis. “Besides exhibiting the attractive qualities of water-soluble quantum dots, these nano-scale composites display magnetic properties, which are useful in magnetic cell separation, magnetic resonance imaging (MRI) contrast enhancement and magnetic transport of anti-cancer drugs,” said Dr. Dong Kee Yi, a Post-doctoral Fellow at IBN.
“Quantum dots pave the way for new methods of observing cellular processes in cells and small animals,” said Prof Ying. “It is hoped that this technology would allow for the precise diagnosis and treatment of diseases like cancer.” Different genetic markers of a tumor can be ‘color-coded’ with quantum dots, for instance, to enable the accurate identification, localization and treatment of cancer cells.
“IBN’s silica coating techniques are not limited to semiconductor quantum dots,” added Prof Ying. “They could also be used on a variety of hydrophobic materials such as metallic and magnetic particles, as demonstrated in our research.”
(1) S. T. Selvan, T. T. Tan, and J. Y. Ying, “Robust, Non-cytotoxic, Silica-Coated Quantum Dots for Biological Applications,” Advanced Materials, in press.
(2) D. K. Yi, S. T. Selvan, S. S. Lee, G. C. Papaefthymiou, D. Kundaliya, and J. Y. Ying, “Silica-coated Nanocomposites of Magnetic Nanoparticles and Quantum Dots,” Journal of the American Chemical Society, 127 (2005) 4990-4991.
About the Institute of Bioengineering and Nanotechnology (IBN)
The Institute of Bioengineering and Nanotechnology (IBN) is a member of the Agency for Science, Technology and Research (A*STAR). Established in March 2003, the Institute’s mission is to establish a broad knowledge base and conduct innovative research at the interface of bioengineering and nanotechnology. Positioned at the frontiers of engineering, IBN is focused on creating knowledge and cultivating talent to develop technology platforms that will spur the growth of new industries. IBN also fosters an exciting, multidisciplinary research environment for the training of students and young researchers to spearhead biomedical advancement in Singapore.
For more information on IBN, please log on to www.ibn.a-star.edu.sg.

Drug-loaded gels for targeted disease treatment and tissue regeneration
Hydrogels developed by IBN scientists can potentially make chemotherapy and tissue regeneration more convenient and safe
SINGAPORE– Scientists at the Institute of Bioengineering and Nanotechnology (IBN) have invented an injectable and biodegradable gel that can deliver drugs at targeted sites or act as a scaffold for tissue repair.This “hydrogel” is formed by simple injections at the desired site, where drugs or cells contained in the gel can be released at a controlled rate. No surgery is required, and the gel will degrade after the disease is treated or when the tissue has regenerated.IBN’s hydrogel is almost 90 percent composed of water. Another unique feature of the invention is the ease with which the hydrogel can be formed in the body without the need for surgery. Conventional hydrogels are normally manufactured in the labs before they are surgically implanted into a specific location in the body. IBN scientists, however, have devised a simple method of forming the hydrogel directly at the target site through the injection of two types of solution – a fluid drug-loaded biodegradable polymer and an enzyme which acts as the gelation catalyst.Previous efforts in this area have been unsuccessful at addressing a number of problems, including the conventional use of toxic catalysts and chemicals, which affect the bioactivity of the drugs and cells, causing tissue damage. IBN’s hydrogel, however, is formed using hyaluronic acid-tyramine conjugates with enzyme – both of which are non-toxic in nature.The chemically cross-linked hydrogel is also better than those produced using physical interactions, such as ionic and hydrophobic reactions, because it can retain its stability for a long time in the body. As this chemical cross-linkage can be achieved by an injected enzyme, this system does not need any harsh gelation trigger such as high temperature and toxic chemicals. In addition, IBN’s hydrogel is biodegradable. It does not need to be surgically removed after treatment, as it can decompose safely in the body.“Our hydrogel system can be effectively applied in cancer therapy, drug delivery and tissue engineering because it is convenient and safe, and it can deliver therapeutic proteins and cells without loss in their bioactivity,” said Dr Motoichi Kurisawa, the lead scientist of the project.“For example, in the area of tissue engineering, we can develop injectable hydrogel systems for bone and cartilage regeneration with the hydrogel acting as a scaffold and drug or cell delivery reservoir. In addition, this hydrogel is ideal for tissue regeneration as it offers a benign environment that is close to conditions in a body due to its high biocompatibility and water content,” said Dr Kurisawa.“For chemotherapeutic treatment, we can load the hydrogel with chemotherapeutics, which can be released only at the targeted malignant site, thus minimizing potential side effects on normal cells or tissues,” he added.This research was featured in a recent issue of Chemical Communications (1).(1) 1 M. Kurisawa, J. E. Chung, Y. Y. Yang, S. J. Gao and H. Uyama, “Injectable Biodegradable Hydrogels Composed of Hyaluronic Acid-Tyramine Conjugates for Drug Delivery and Tissue Engineering,” Chemical Communications, (2005) 4312-4314.The Institute of Bioengineering and Nanotechnology (IBN) is a member of the Agency for Science, Technology and Research (A*STAR), Singapore. Established in 2003, the Institute’s mission is to establish a broad knowledge base and conduct innovative research at the interface of bioengineering and nanotechnology. Positioned at the frontiers of engineering, IBN is focused on creating knowledge and cultivating talent to develop technology platforms that will spur the growth of new industries. IBN also fosters an exciting, multidisciplinary research environment for the training of students and young researchers to spearhead biomedical advancement in Singapore. For more information, please visit: www.ibn.a-star.edu.sg

Imitating Nature’s Scaffolding
Scientists at IBN have produced artificial fibers that act as ‘templates’ to grow new tissue

SINGAPORE – A team of researchers at the Institute of Bioengineering and Nanotechnology (IBN) has successfully created artificial fibers with nanometer-sized features that can be used to grow cells and tissue structures.These ‘fibrous scaffolds’ have been imbued with features of the natural extracellular matrix, the ground substance in which cells are embedded and a vital component in the engineering of human tissues.This research was recently published in the March issue of the leading journal Advanced Materials (1). The work on the “Three-Dimensional Reconstituted Extracellular Matrix Scaffolds for Tissue Engineering” also won an Outstanding Paper Award at the 12th International Conference on Biomedical Engineering in December 2005 (2).Scaffolds are ‘templates’ upon which the desired cell type or precursor is seeded for the growth of different tissues. Signaling molecules can also be incorporated into these structures to instruct or regulate cell growth and differentiation. Using IBN’s fibrous scaffolds, tissue engineers, for example, would be able to take a patient’s own cells, grow it into tissue in the lab, and subsequently implant the developed tissue back into the patient.While much work has been done to engineer suitable scaffolds, conventional production methods involve the use of high temperatures, organic solvents and/or a leaching step to develop porosity. Such conditions compromise the biological activity of proteins, and thus pose problems in the incorporation of biological molecules within the scaffolds.IBN, however, has been able to create fibers by interfacial polyelectrolyte complexation, which is a mild, aqueous-based process that takes place at ambient temperature. A method called ‘hydroentanglement’ that employs water pressure is then used to entangle the fibers into scaffolds. Previous work in this area was hampered by the tendency of the fibers to clump and form a dense monolith of low porosity. IBN scientists solved this problem by incorporating silica, an inorganic material that is found in simple marine organisms and some forms of glass, effectively crosslinking the fibers to obtain porous 3-D scaffolds. The porosity or permeability of the scaffold is important because a scaffold with a high surface-to-volume ratio provides for better interaction of cells with the matrix, and thus a better environment for the culture of various cell types for tissue engineering.Results have shown that cells could adhere and grow well on IBN’s fibrous scaffolds after they were incorporated with components such as collagen, fibronectin and cell-adhesion peptides. “We have created scaffolds based on natural polymers and extracellular matrix components that can be specially tailored for the adhesion and proliferation of a variety of cells,” said IBN Principal Research Scientist Dr Andrew Wan, who is the team leader of the project. “Hence, these scaffolds would have many potential applications in the engineering of tissues as implants, or as in vitro models for drug development“.A US patent has been filed on the invention.(1) A. C. A. Wan, B. C. U. Tai, K.-J. Leck, and J. Y. Ying, “Silica-Incorporated Polyelectrolyte-Complex Fibers as Tissue-Engineering Scaffolds,” Advanced Materials, 18 (2006), 641-644.(2) A. C. A. Wan, B. C. U. Tai, K.-J. Leck, S. Pek, S. Gao, and J. Y. Ying, “Three-Dimensional Reconstituted Extracellular Matrix Scaffolds for Tissue Engineering,” 12th International Conference on Biomedical Engineering, Singapore, December 2005. Outstanding Paper Award.A member of A*STAR’s Biomedical Sciences Institutes (Co. Reg. No. 199702109N)About the Institute of Bioengineering and Nanotechnology (IBN)The Institute of Bioengineering and Nanotechnology (IBN) is a member of the Agency for Science, Technology and Research (A*STAR). Established in March 2003, the Institute’s mission is to establish a broad knowledge base and conduct innovative research at the interface of bioengineering and nanotechnology. Positioned at the frontiers of engineering, IBN is focused on creating knowledge and cultivating talent to develop technology platforms that will spur the growth of new industries. IBN also fosters an exciting, multidisciplinary research environment for the training of students and young researchers to spearhead biomedical advancement in Singapore.For more information on IBN, please log on to www.ibn.a-star.edu.sg.
For queries, please contact:Adeline GohDID: +65 6824 7004 or HP: +65 9686 3160Email: agoh@ibn.a-star.edu.sgNidyah SaniDID: +65 6824 7005 or HP: +65 9762 9720Email: nidyah@ibn.a-star.edu.sg

Nanocarriers that can kill tumors with drugs and DNA
A breakthrough technology developed at IBN can potentially lead to more effective treatment methods for cancers
SINGAPORE– A team of scientists in Singapore has developed nanoparticles that can carry both small molecular anticancer drugs and nucleic acids simultaneously for improved cancer therapy. This groundbreaking work was published online in Nature Materials (1) on September 24, 2006, a leading materials science journal.The uniqueness of the new technology from the Institute of Bioengineering and Nanotechnology (IBN) lies in the design of a special biodegradable carrier (cationic core-shell nanoparticle), which can enclose drug molecules and allow therapeutic nucleic acids to bind onto it.It can efficiently introduce DNA into a cell to be incorporated into its genetic make-up, i.e. induce high gene expression level, especially in both human and mouse breast cancer cell lines, and mouse breast cancer model. The co-delivery of small molecular drugs with nucleic acids can improve gene transfection efficiency, reduce side-effects of these drugs, and achieve the synergistic effect of drug and gene therapy for the more effective treatment of cancer.Results have shown that the co-delivery of an anti-cancer drug (paclitaxel) with a highly potent anti-tumor ‘messenger molecule’ (IL-12 encoded plasmid (2) ) using the carrier suppressed cancer growth more efficiently than the delivery of either paclitaxel or the plasmid in mice bearing 4T1 breast cancer.In collaboration with Nanyang Technological University, experiments were also conducted to co-deliver paclitaxel and small interfering RNA (siRNA) targeting a protein that prevents cell death (Bcl-2) to MDA-MB-231 human breast cancer cell line. The cancer cells became more susceptible to the effects of the drug, due to the additional effect of the siRNA targeting Bcl-23.This special carrier can also be potentially used to co-deliver therapeutic nucleic acids to prevent cancer cells from developing resistance to multiple drugs4. This, coupled with the simultaneous delivery of specific anticancer drugs, could enhance the therapeutic effects of such drugs.Other scientists in this field have tried to use liposomes made from cationic (charged) lipids to transport drugs and DNA. The carrier developed at IBN is self-assembled from a biodegradable cationic copolymer. Hence, it is more easily produced and its size and characteristics are more easily controlled compared to liposomes. More importantly, it can deliver nucleic acids more effectively.“These nanocarriers developed by our team have a variety of applications in medication and as a gene transfection agent for biological research,” said Dr Yi-Yan Yang, who led the project team comprising Yong Wang, Shujun Gao, Wen-Hui Ye and Ho Sup Yoon. “They provide an interesting approach to improving the efficiency of cancer treatments.”United States and PCT (Patent Cooperation Treaty) patents have been filed by IBN on the invention.(1) Y. Wang, S. Gao, W.-H. Ye, H. S. Yoon and Y. Y. Yang, “Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer,” Nature Materials, published online on September 24, 2006.Note: This paper was subsequently published in the October 2006 Vol 5 issue (pp 791-796) of Nature Materials.(2) IL-12 is a highly potent anti-tumor cytokine, and may also overcome paclitaxel-mediated T cell suppression.A member of A*STAR’s Biomedical Sciences Institutes (Co. Reg. No. 199702109N)(3) The suppression of the anti-apoptotic activity of Bcl-2 by the siRNA made the cells more sensitive to paclitaxel, leading to greater cytotoxicity of paclitaxel.(4) The therapeutic nucleic acid may be a vector encoding an antisense molecule directed against the P-glycoprotein mRNA in the target cell. Such a system can inhibit P-glycoprotein expression by the target, and hence, incapacitate its ability to establish multi-drug resistance, a common trait among cancer cells. This, together with the cytotoxic effects of the anti-cancer drug, should enhance the therapeutic effect of the system.About the Institute of Bioengineering and Nanotechnology (IBN)The Institute of Bioengineering and Nanotechnology (IBN) is a member of the Agency for Science, Technology and Research (A*STAR). Established in March 2003, the Institute’s mission is to establish a broad knowledge base and conduct innovative research at the interface of bioengineering and nanotechnology. Positioned at the frontiers of engineering, IBN is focused on creating knowledge and cultivating talent to develop technology platforms that will spur the growth of new industries. IBN also fosters an exciting, multidisciplinary research environment for the training of students and young researchers to spearhead biomedical advancement in Singapore.
please contact:Adeline GohDID: +65 6824 7004 or HP: +65 9686 3160Email: agoh@ibn.a-star.edu.sgNidyah SaniDID: +65 6824 7005 or HP: +65 9762 9720Email: nidyah@ibn.a-star.edu.sg

Gambling on consciousness
Gambling may provide a new window onto consciousness, according to a paper in the February issue of Nature Neuroscience. Assessing whether someone is aware of something is a notoriously difficult problem that is fundamental to investigating the basis of consciousness. This paper offers a new solution to this classic experimental dilemma by showing that people place bets only when they are aware of what they are betting on.Alan Cowey and colleagues asked participants to do several tasks in which performance is believed to occur without awareness for some of the time. For instance, when asked to classify letter strings into groups according to whether they obey a grammatical rule, participants who have seen examples of the rule in practice can perform at high levels while being unable to explain the rule. Similarly, patients with damage to the visual cortex can often make rudimentary visual judgments about stimuli that they deny seeing.Cowey and colleagues asked people to place a bet on whether or not their response was correct when they completed a trial of each of these tasks. They found that betting and task performance do not go hand in hand. Rather, participants place high bets on trials only when they are aware of the basis of their judgment – for example, when they recognize the rule governing their choices, or they consciously perceive the stimuli they are localizing. This method of measuring awareness is a significant advance over previous techniques because bets are placed without introspection about awareness, which can change what people consciously know.Author contact:Navindra Persaud (University of Oxford, UK)Tel: +44 7767 054 820; E-mail: navindra.persaud@univ.ox.ac.uk

For goodness sake
The detection of ‘agency’, the presence of an active participant in a situation, involves a brain region that is more active in altruistic people, reports a study in the February issue of Nature Neuroscience. Altruism, the tendency of people to help others without obvious benefit to themselves, remains a scientific puzzle.Scott Huettel and colleagues scanned the brains of people while they were either playing a simple computer game to earn money for charity or just watching the computer play the game by itself. Knowing that the computer is earning money for a good cause makes it easier to imagine an active intentional ‘mind’ behind that screen, apparently turning the game into a social situation involving altruistic behaviour. Figuring out social relationships generally involves activation of the posterior superior temporal sulcus (pSTS) on the right side of the brain. The authors indeed saw activity in this region specifically when participants were just watching the game.The authors also asked participants to answer questions designed to assess their tendency toward altruistic behavior, and found that the magnitude of pSTS activation strongly correlated with individual levels of altruism measured in response to these questions. Thus it seems that a specific brain response to a simulated altruistic situation may be directly related to a person’s real-life unselfish behavior.Author contact:Scott Huettel (Duke University, Durham, NC, USA)Tel: +1 919 681 9527; E-mail: scott.huettel@duke.edu

Nanocrystals used as dopants
Nanocrystals can mimic atoms in solid-state devices by altering the electrical properties — for example conductance — according to a report by Jeffrey Urban and colleagues in the February issue of Nature Materials.The researchers investigated the electrical properties of films obtained by the aggregation of PbTe and Ag2Te nanocrystals. When comparing the conductivity of films with different proportions of the two constituents, they found that when both types of crystals were present, the conductivity could be up to three orders of magnitude higher than in either of the single-component cases.Nanocrystal assemblies can be seen as materials in which the nanocrystals — which consist of thousands of atoms — act as the basic elements, with the advantage that the structure can be designed very precisely. The extension of the nanocrystal–atom analogy to the concept of doping (adding an impurity to alter the electrical properties) opens unexpected opportunities for the design of solid-state devices based on these aggregates, as it also allows very accurate control of the electrical properties.Author contact:Jeffrey J. Urban (IBM TJ Watson Research Center, Yorktown Heights, New York, USA)Tel: +1 914 945 1436; E-mail: urban@post.harvard.edu

Gene regulation: Non-coding RNA interferes with transcription
A non-coding RNA represses expression of a cell-cycle-regulated gene by directly interfering with the binding of transcription factors, a paper published online this week by Nature suggests. The discovery expands our knowledge of the diverse mechanisms used by non-coding RNAs in regulating gene expression.Transcription factors are known to bind to the promoter regions of genes and initiate the production of RNA transcripts. Alexandre Akoulitchev and colleagues find that a non-coding RNA – an RNA molecule that is not translated into protein – forms a complex with the major promoter region of the human dihydrofolate reductase (DHFR) gene, which in turn interferes with the binding of transcription factors. The non-coding RNA is only produced in quiescent cells, leading to repression of the DHFR gene in these conditions.Author contact:Alexandre Akoulitchev (University of Oxford, UK)Tel: +44 1865 275 614, E-mail: alexandre.akoulitchev@path.ox.ac.uk

Fetal Alcohol Syndrome: are cholesterol supplements the answer?
Each day in the United States, as many as 87 to 103 babies are born with alcohol related defects; annually, an estimated $75 million to $9.7 billion is spent on the care of these infants. The consumption of alcohol during pregnancy places the fetus at risk of developing FASD.
Cholesterol supplementation prevents fetal alcohol spectrum defects (FASD) in alcohol-exposed zebrafish embryos according to an article published online this week in Laboratory Investigation. The study from Yin-Xiong Li and colleagues details the mechanism and prevention of FASD and has implications for potential preventative prenatal intervention.Each day in the United States, as many as 87 to 103 babies are born with alcohol related defects; annually, an estimated $75 million to $9.7 billion is spent on the care of these infants. The consumption of alcohol during pregnancy places the fetus at risk of developing FASD, which include numerous abnormalities, such as neurological, craniofacial, and cardiac malformations. Using the zebrafish model, the authors found that alcohol interferes with embryonic development by disrupting cholesterol-dependent activation of a critical signaling molecule, called sonic hedgehog. They also showed that cholesterol supplementation of the alcohol-exposed embryos restored the functionality of the molecular pathway and prevented development of FASD-like defects.In addition, the authors report that FASD-like defects in zebrafish resulted from minimal fetal alcohol exposure, equivalent to a 55-kilogram woman drinking one 12-ounce beer. Their findings suggest that even small amounts of alcohol consumption may be unsafe for pregnant women and also indicate that cholesterol supplementation may be a potential means to prevent FASD.Author ContactYin-Xiong Li (Duke University Medical Center, Durham, NC, USA)Tel: +1 919 668 2310; Email: yinxiong.li@mc.duke.edu

Inhalant abuse: 'Sniffing' toluene for a high
Toluene, a commonly abused toxic compound, is shown to stimulate dopamine release in specific regions of the rat brain known as drug reward pathways, according to research published online in Neuropsychopharmacology this week. Until now it has been unclear whether toluene affects reward centers in the brain, and where, so ultimately this knowledge could help in developing strategies to prevent and treat addiction to substances containing toluene. Toluene is found in paint thinners, varnishes and even nail polish remover. Researchers demonstrate that toluene directly stimulates dopamine neurons causing dopamine release. Dopamine is a neurotransmitter and is released by reward centers in the brain causing a feeling of euphoria. The results suggest that the brain likely also interprets sniffing toluene as rewarding which can result in further abuse and possibly future use of other drugs.Besides showing where in the brain toluene acts, the researchers also demonstrate that, surprisingly, toluene substances are most effective when used at low concentrations. Since toluene is rapidly absorbed in the brain, this might explain why the preferred mode of delivery is by "huffing" or "sniffing". Sniffing is frequently considered a harmless recreational or party drug but unlike other drugs, even a single session of inhaling the compound can disrupt heart rhythms enough to cause cardiac arrest and lower oxygen levels enough to cause suffocation.Despite a decline in overall adolescent drug use since the late 90's, recreational use of inhalants is increasing. Inhalant abuse is now considered the fourth most abused drug among US teens according to NIDA. Because inhalants activate the same area of the brain that other drugs of abuse affect - such as cocaine and methamphetamines - future research will involve the investigation of their combined interactions on the brain.Author contact:Arthur C. Riegel (The Vollom Institute, Portland, OR, USA)Tel: +1 503 494 4723, E-mail: riegela@ohsu.eud PRESS CONTACTS…For media inquiries relating to editorial content/policy for the Journal Neuropsychopharmacology:Joyce-Rachel John (NPG Academic Journals, New York)Tel: +1 212 726 9214; E-mail: j.john@natureny.com For media inquiries relating to embargo policy for the Journal Neuropsychopharmacology:Ruth Francis (Nature London)Tel: +44 20 7843 4562; E-mail: r.francis@nature.com For media inquiries relating to the American College of Neuropsychopharmacology:Tel: +1 615 324 2360; E-mail: acnp@acnp.org