Inverting a Standard Experiment Sometimes Produces Different Results

In the standard laboratory tests of the biological activity of nanoparticles, cells are plated on the bottom of a dish and culture medium containing nanoparticles is poured on top of them.

It seems straightforward enough. But recently Washington University in St. Louis scientist Younan Xia started to worry about the in vitro experiments his lab was doing with gold nanoparticles.

What if the cells were upside down, he wondered? Would that make a difference? Would it change their uptake rate?

"People assumed that if they prepared a suspension, the suspension was going to have the same concentration everywhere, including at the surface of the cells," says Xia, PhD, the James M. McKelvey Professor in the Department of Biomedical Engineering.

A battery of experiments in Xia's lab with both the standard and upside-down setups showed that nanoparticles above certain sizes and weights will settle out. So concentrations of the nanoparticles near the cell surfaces are different from those in the bulk solution and cellular uptake rates are higher.

As the scientists conclude in theNature Nanotechnologyarticle describing the experiments,"Studies on the cellular uptake of nanoparticles that have been conducted with cells in the upright configuration may have given rise to erroneous and misleading data."

Topsies and Turveys

Scientists have felt they could safely assume that the concentration of nanoparticles in the fluid next to the cells, which drives cellular uptake, was the same as the initial concentration of nanoparticles in the medium because the particles are small enough to be easily lofted by Brownian motion, the random motion of the molecules in the liquid.

Gravity, by this accounting, did not override this force for diffusion and the nanoparticles stayed in solution instead of settling out.

"We started to wonder, however, because our nanoparticles are made of gold," Xia says."Gold is nontoxic but it is also very heavy, so it was conceivable relatively large nanoparticles might settle."

Since it is impossible to measure the exact concentration of gold nanoparticles at the surface of a cell, Xia and coworkers designed a simple experiment to test whether settling changed the concentration there and the cellular uptake.

Xia's lab tested gold nanospheres of three sizes, nanocages of two edge lengths, and nanorods, some with surface coatings that picked up serum proteins in solution and others coated with a chemical that acts as an antifouling agent.

After the cells were incubated in the nanoparticle-bearing medium, the concentration of the nanoparticles in the medium was measured spectroscopically and the number of particles each cell had taken up was calculated from the difference in the concentrations.

In the literature, Xia says, there are reports that the cellular uptake of nanoparticles depends on the nanoparticles' size, shape and surface coating.

His lab's experiments showed that these characteristics are secondary, relevant only insofar as they affect the sedimentation and diffusion velocities of the nanoparticles.

For small, light particles, there was no disparity between the cells in the upright and the upside-down configurations. In the case of larger, heavier particles, however, sedimentation dominated, and the upright cells took in more nanoparticles than the upside-down cells.

"All earlier work may need to be re-evaluated to account for the effects of sedimentation on nanoparticle dosimetry," the authors conclude.

"It's no different from medicines that have to be shaken to suspend a powder in a water. If you don't shake the bottle," Xia says,"you end up under- or overdosing yourself."

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Nanotechnologists Must Take Lessons from Nature

In the workaday world, engineers and scientists go to great lengths to make the devices we use as perfect as possible. When we flip on a light switch or turn the key on the car, we expect the lights to come on and the engine to start every time, with only rare exceptions. They have done so by using a top-down design process combined with the application of large amounts of energy to increase reliability by suppressing natural variability.

However, this brute-force approach will not work in the nanoscale world that scientists are beginning to probe in the search for new electrical and mechanical devices. That is because objects at this scale behave in a fundamentally different fashion than larger-scale objects, argue Peter Cummings, John R. Hall Professor Chemical Engineering at Vanderbilt University, and Michael Simpson, professor of materials science and engineering at University of Tennessee, Knoxville, in an article in the April issue of theACS Nanojournal.

'Noise' makes a difference

The defining difference between the behaviors of large-scale and nanoscale objects is the role that"noise" plays. To scientists noise isn't limited to unpleasant sounds; it is any kind of random disturbance. At the level of atoms and molecules, noise can take the form of random motion, which dominates to such an extent that it is extremely difficult to make reliable devices.

Nature, however, has managed to figure out how to put these fluctuations to work, allowing living organisms to operate reliably and far more efficiently than comparable human-made devices. It has done so by exploiting the contrarian behavior that random behavior allows.

"Contrarian investing is one strategy for winning in the stock market," Cummings said,"but it may also be a fundamental feature of all natural processes and holds the key to many diverse phenomena, including the ability of the human immunodeficiency virus to withstand modern medicines."

In their paper, Cummings and Simpson maintain that in any given population, random fluctuations -- the"noise" -- cause a small minority to act in a fashion contrary to the majority and can help the group respond to changing conditions. In this fashion, less perfection can actually be good for the whole.

Mimicking cells

At Oak Ridge National Laboratory, where the two researchers work, they are exploring this basic principle through a combination of creating virtual simulations and constructing physical cell mimics, synthetic systems constructed on the biological scale that exhibit some cell-like characteristics.

That is the lesson of nature, where a humble bacterial cell outperforms our best computer chips by a factor of 100 million, and it does this in part by being less than perfect."Instead of trying to make perfect decisions based on imperfect information, the cell plays the odds with an important twist: it hedges its bets. Sure, most of the cells will place bets on the likely winner, but an important few will put their money on the long shot," Simpson said."That is the lesson of nature, where a humble bacterial cell outperforms our best computer chips by a factor of 100 million, and it does this in part by being less than perfect."

Following the lead of nature means understanding the role of chance. For example, in the AIDS virus, most infected cells are forced to produce new viruses that infect other cells. But a few of the infected cells flip the virus into a dormant state that escapes detection.

"Like ticking bombs, these dormant infections can become active sometime later, and it is these contrarian events that are the main factor preventing the eradication of AIDS," Simpson said.

"Our technology has fought against this chance using a brute force approach that consumes a lot of power," Cummings said. As a result, one of the factors limiting the building of more powerful computers is the grid-busting amount of energy they require.

Yet residing atop the cabinets of these supercomputers, basking in the heat generated in the fight to suppress the element of chance, the lowly bacteria show us another way.

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Origami Not Just for Paper Anymore: DNA, Folded Into Complex Shapes, Could Have a Big Impact on Nanotechnology

Trying to build DNA structures on a large scale was once considered unthinkable. But about five years ago, Caltech computational bioengineer Paul Rothemund laid out a new design strategy called DNA origami: the construction of two-dimensional shapes from a DNA strand folded over on itself and secured by short"staple" strands. Several years later, William Shih's lab at Harvard Medical School translated this concept to three dimensions, allowing design of complex curved and bent structures that opened new avenues for synthetic biological design at the nanoscale.

A major hurdle to these increasingly complex designs has been automation of the design process. Now a team at MIT, led by biological engineer Mark Bathe, has developed software that makes it easier to predict the three-dimensional shape that will result from a given DNA template. While the software doesn't fully automate the design process, it makes it considerably easier for designers to create complex 3-D structures, controlling their flexibility and potentially their folding stability.

"We ultimately seek a design tool where you can start with a picture of the complex three-dimensional shape of interest, and the algorithm searches for optimal sequence combinations," says Bathe, the Samuel A. Goldblith Assistant Professor of Applied Biology."In order to make this technology for nanoassembly available to the broader community -- including biologists, chemists, and materials scientists without expertise in the DNA origami technique -- the computational tool needs to be fully automated, with a minimum of human input or intervention."

Bathe and his colleagues described their new software in the Feb. 25 issue ofNature Methods. In that paper, they also provide a primer on creating DNA origami with collaborator Hendrik Dietz at the Technische Universitaet Muenchen."One bottleneck for making the technology more broadly useful is that only a small group of specialized researchers are trained in scaffolded DNA origami design," Bathe says.

Programming DNA

DNA consists of a string of four nucleotide bases known as A, T, G and C, which make the molecule easy to program. According to nature's rules, A binds only with T, and G only with C."With DNA, at the small scale, you can program these sequences to self-assemble and fold into a very specific final structure, with separate strands brought together to make larger-scale objects," Bathe says.

Rothemund's origami design strategy is based on the idea of getting a long strand of DNA to fold in two dimensions, as if laid on a flat surface. In his first paper outlining the method, he used a viral genome consisting of approximately 8,000 nucleotides to create 2-D stars, triangles and smiley faces.

That single strand of DNA serves as a"scaffold" for the rest of the structure. Hundreds of shorter strands, each about 20 to 40 bases in length, combine with the scaffold to hold it in its final, folded shape.

"DNA is in many ways better suited to self-assembly than proteins, whose physical properties are both difficult to control and sensitive to their environment," Bathe says.

Bathe's new software program interfaces with a software program from Shih's lab called caDNAno, which allows users to manually create scaffolded DNA origami from a two-dimensional layout. The new program, dubbed CanDo, takes caDNAno's 2-D blueprint and predicts the ultimate 3-D shape of the design. This resulting shape is often unintuitive, Bathe says, because DNA is a flexible object that twists, bends and stretches as it folds to form a complex 3-D shape.

According to Rothemund, the CanDo program should allow DNA origami designers to more thoroughly test their DNA structures and tweak them to fold correctly."While we have been able to design the shape of things, we have had no tools to easily design and analyze the stresses and strains in those shapes or to design them for specific purposes," he says.

At the molecular-level, stress in the double helix of DNA decreases the folding stability of the structure and introduces local defects, both of which have hampered progress in the scaffolded DNA origami field.

Postdoctoral researcher Do-Nyun Kim and graduate student Matthew Adendorff, both of the Bathe lab, are now furthering CanDo's capabilities and optimizing the scaffolded DNA origami design process.

Building nanoscale tools

Once scientists have a reliable way to assemble DNA structures, the next question is what to do with them. One application scientists are excited about is a"DNA carrier" that can transport drugs to specific destinations in the body such as tumors, where the carrier would release the cargo based on a specific chemical signal from the target cancer cell.

Another possible application of scaffolded DNA origami could help reproduce part of the light-harvesting apparatus of photosynthetic plant cells. Researchers hope to recreate that complex series of about 20 protein subunits, but to do that, components must be held together in specific positions and orientations. That's where DNA origami could come in.

"DNA origami enables the nanoscale construction of very precise architectural arrangements. Researchers are exploiting this unique property to pursue a number of applications at the nanoscale, including a synthetic photocell," Bathe says."While applications such as this are still quite far off on the horizon, we believe that predictive engineering software tools are essential for progress in this direction."

Novel applications may also grow out of a new competition being held at Harvard this summer, called BIOMOD. Undergraduate teams from about a dozen schools, including MIT, Harvard and Caltech, will try to design nanoscale biomolecules for robotics, computing and other applications.

In the meantime, Bathe is focusing on further developing CanDo to enable automated DNA origami design."Once you have an automated computational tool that allows you to design complex shapes in a precise way, I think we're in a much better position to exploit this technology for interesting applications," he says.

For DNA origami to have a broad impact, it needs to become routine to simply order up DNA parts to build any configuration you can dream up, Bathe says. He notes:"Once non-specialists can design arbitrary 3-D nanostructures using DNA origami, their imaginations can run free."

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New 'Nanobead' Approach Could Revolutionize Sensor Technology

When fully developed as a hand-held, portable sensor, like something you might see in a science fiction movie, it will provide a whole diagnostic laboratory on a single chip.

The research could revolutionize the size, speed and accuracy of chemical detection systems around the world.

New findings on this"microfluidic sensor" were recently reported inSensors and Actuators B: Chemical, a professional journal, and the university is pursuing a patent on related technologies. The collaborative studies were led by Vincent Remcho, an OSU professor of chemistry, and Pallavi Dhagat, an assistant professor in the OSU School of Electrical Engineering and Computer Science.

The key, scientists say, is tapping into the capability of ferromagnetic iron oxide nanoparticles -extraordinarily tiny pieces of rust. The use of such particles in the new system can not only detect chemicals with sensitivity and selectivity, but they can be incorporated into a system of integrated circuits to instantly display the findings.

"The particles we're using are 1,000 times smaller than those now being used in common diagnostic tests, allowing a device to be portable and used in the field," said Remcho, who is also associate dean for research and graduate programs in the OSU College of Science.

"Just as important, however, is that these nanoparticles are made of iron," he said."Because of that, we can use magnetism and electronics to make them also function as a signaling device, to give us immediate access to the information available."

According to Dhagat, this should result in a powerful sensing technology that is fast, accurate, inexpensive, mass-producible, and small enough to hold in your hand.

"This could completely change the world of chemical assays," Dhagat said.

Existing assays are often cumbersome and time consuming, using biochemical probes that require expensive equipment, expert personnel or a complex laboratory to detect or interpret.

In the new approach, tiny nanoparticles could be attached to these biochemical probes, tagging along to see what they find. When a chemical of interest is detected, a"ferromagnetic resonance" is used to relay the information electronically to a tiny computer and the information immediately displayed to the user. No special thin films or complex processing is required, but the detection capability is still extremely sensitive and accurate.

Essentially, the system might be used to detect almost anything of interest in air or water. And the use of what is ordinary, rusty iron should help address issues of safety in the resulting nanotechnology product.

Rapid detection of chemical toxins used in bioterrorism would be possible, including such concerns as anthrax, ricin or smallpox, where immediate, accurate and highly sensitive tests would be needed. Partly for that reason, the work has been supported by a four-year grant from the Army Research Laboratory, in collaboration with the Oregon Nanoscience and Microtechnologies Institute.

However, routine and improved monitoring of commercial water treatment and supplies could be pursued, along with other needs in environmental monitoring, cargo inspections, biomedical applications in research or medical care, pharmaceutical drug testing, or even more common uses in food safety.

Other OSU researchers working on this project include Tim Marr, a graduate student in electrical engineering, and Esha Chatterjee, a graduate chemistry student.

The concept has been proven in the latest study, scientists say, and work is continuing with microfluidics research to make the technology robust and durable for extended use in the field.

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Solar Power Goes Viral: Researchers Use Virus to Improve Solar-Cell Efficiency

In a solar cell, sunlight hits a light-harvesting material, causing it to release electrons that can be harnessed to produce an electric current. The new MIT research, published online in the journalNature Nanotechnology, is based on findings that carbon nanotubes -- microscopic, hollow cylinders of pure carbon -- can enhance the efficiency of electron collection from a solar cell's surface.

Previous attempts to use the nanotubes, however, had been thwarted by two problems. First, the making of carbon nanotubes generally produces a mix of two types, some of which act as semiconductors (sometimes allowing an electric current to flow, sometimes not) or metals (which act like wires, allowing current to flow easily). The new research, for the first time, showed that the effects of these two types tend to be different, because the semiconducting nanotubes can enhance the performance of solar cells, but the metallic ones have the opposite effect. Second, nanotubes tend to clump together, which reduces their effectiveness.

And that's where viruses come to the rescue. Graduate students Xiangnan Dang and Hyunjung Yi -- working with Angela Belcher, the W. M. Keck Professor of Energy, and several other researchers -- found that a genetically engineered version of a virus called M13, which normally infects bacteria, can be used to control the arrangement of the nanotubes on a surface, keeping the tubes separate so they can't short out the circuits, and keeping the tubes apart so they don't clump.

The system the researchers tested used a type of solar cell known as dye-sensitized solar cells, a lightweight and inexpensive type where the active layer is composed of titanium dioxide, rather than the silicon used in conventional solar cells. But the same technique could be applied to other types as well, including quantum-dot and organic solar cells, the researchers say. In their tests, adding the virus-built structures enhanced the power conversion efficiency to 10.6 percent from 8 percent -- almost a one-third improvement.

This dramatic improvement takes place even though the viruses and the nanotubes make up only 0.1 percent by weight of the finished cell."A little biology goes a long way," Belcher says. With further work, the researchers think they can ramp up the efficiency even further.

The viruses are used to help improve one particular step in the process of converting sunlight to electricity. In a solar cell, the first step is for the energy of the light to knock electrons loose from the solar-cell material (usually silicon); then, those electrons need to be funneled toward a collector, from which they can form a current that flows to charge a battery or power a device. After that, they return to the original material, where the cycle can start again. The new system is intended to enhance the efficiency of the second step, helping the electrons find their way: Adding the carbon nanotubes to the cell"provides a more direct path to the current collector," Belcher says.

The viruses actually perform two different functions in this process. First, they possess short proteins called peptides that can bind tightly to the carbon nanotubes, holding them in place and keeping them separated from each other. Each virus can hold five to 10 nanotubes, each of which is held firmly in place by about 300 of the virus's peptide molecules. In addition, the virus was engineered to produce a coating of titanium dioxide (TiO2), a key ingredient for dye-sensitized solar cells, over each of the nanotubes, putting the titanium dioxide in close proximity to the wire-like nanotubes that carry the electrons.

The two functions are carried out in succession by the same virus, whose activity is"switched" from one function to the next by changing the acidity of its environment. This switching feature is an important new capability that has been demonstrated for the first time in this research, Belcher says.

In addition, the viruses make the nanotubes soluble in water, which makes it possible to incorporate the nanotubes into the solar cell using a water-based process that works at room temperature.

Prashant Kamat, a professor of chemistry and biochemistry at Notre Dame University who has done extensive work on dye-sensitized solar cells, says that while others have attempted to use carbon nanotubes to improve solar cell efficiency,"the improvements observed in earlier studies were marginal," while the improvements by the MIT team using the virus assembly method are"impressive."

"It is likely that the virus template assembly has enabled the researchers to establish a better contact between the TiO2 nanoparticles and carbon nanotubes. Such close contact with TiO2 nanoparticles is essential to drive away the photo-generated electrons quickly and transport it efficiently to the collecting electrode surface."

Kamat thinks the process could well lead to a viable commercial product:"Dye-sensitized solar cells have already been commercialized in Japan, Korea and Taiwan," he says. If the addition of carbon nanotubes via the virus process can improve their efficiency,"the industry is likely to adopt such processes."

Belcher and her colleagues have previously used differently engineered versions of the same virus to enhance the performance of batteries and other devices, but the method used to enhance solar cell performance is quite different, she says.

Because the process would just add one simple step to a standard solar-cell manufacturing process, it should be quite easy to adapt existing production facilities and thus should be possible to implement relatively rapidly, Belcher says.

The research team also included Paula Hammond, the Bayer Professor of Chemical Engineering; Michael Strano, the Charles (1951) and Hilda Roddey Career Development Associate Professor of Chemical Engineering; and four other graduate students and postdoctoral researchers. The work was funded by the Italian company Eni, through the MIT Energy Initiative's Solar Futures Program.

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Collecting the Sun's Energy: Novel Electrode for Flexible Thin-Film Solar Cells

The scarcity of raw materials and increasing usage of rare metals is making electronic components and devices more and more costly. Such rare metals are used, for example, to make the transparent electrodes found in mobile phone touchscreen displays, liquid-crystal displays, organic LEDs and thin-film solar cells. The material of choice in these cases is indium tin oxide (ITO), a largely transparent mixed oxide. Because ITO is relatively expensive, however, it is uneconomic to use in large area applications such as solar cells.

The search for alternatives

Indium-free transparent oxides do exist, but with demand for them increasing they too are tending to become scarce. In addition, the principal disadvantages such as brittleness remain. The search for alternative coatings which are both transparent and electrically conductive is therefore intense, with materials such as conductive polymers, carbon nanotubes or graphenes coming under scrutiny. Carbon-based electrodes, however, generally show excessive surface resistance values which make them poor electrical conductors. If a metallic grid is integrated into the organic layer, it reduces not just its resistance but also its mechanical stability. If a solar cell made out of this material is bent, the electrode layers break and are no longer conductive. The challenge thus consists of manufacturing flexible yet stable conductive substrates, ideally in a cost-effective industrial rolling process.

One solution: woven electrodes

One particularly promising possibility is the use of a transparent flexible woven polymer, which Empa has developed together with the company Sefar AG in a project financially supported by the Swiss Commission for Technology and Innovation (CTI). Sefar, which specializes in precision fabrics, is able to produce the woven polymer economically and in large quantities using a roll to roll process similar to the way newspapers are printed. Metal wires woven into the material ensure that it is electrically conductive. In a second process step the material is embedded in an inert plastic layer which does not, however, completely cover the metal filaments, thus retaining its conductivity. The electrode which results is transparent, stable and yet flexible. The Empa researchers then applied a series of coatings to this new substrate to create a novel organic solar cell whose efficiency is compatible to conventional ITO-based cells. In addition, the woven electrode is significantly more stable when deformed than commercially available flexible plastic substrates to which a thin layer of conductive ITO has been applied.

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RNA Nanoparticles Constructed to Safely Deliver Long-Lasting Therapy to Cells

In two new publications in the journal Molecular Therapy, University of Cincinnati (UC) biomedical engineering professor Peixuan Guo, PhD, details successful methods of producing large RNA nanoparticles and testing their safety in the delivery of therapeutics to targeted cells.

The articles, in advance online publication, represent"two very important milestones in RNA nanotherapy," says Guo.

"One problem in RNA therapy is the requirement for the generation of relatively large quantities of RNA," he says."In this research, we focused on solving the most challenging problem of industry-scale production of large RNA molecules by a bipartite approach, finding that pRNA can be assembled from two pieces of smaller RNA modules."

Guo, Dane and Mary Louise Miller Endowed Chair of biomedical engineering, serves as director of the National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer Platform Partnership Program at UC. He has focused his research on RNA for decades, pioneering its use as a versatile building block for nanotechnology, or for the engineering of functional systems at the molecular scale. In 1987, he discovered a packaging RNA (pRNA) in the bacteriophage phi29 virus which can gear a motor to package DNA into the viral protein shell. In 1998, his lab discovered that pRNA can self-assemble or be engineered into nanoparticles to gear the motor.

In his most recent research, Guo and colleagues detail multiple approaches for the construction of a functional 117-base pRNA molecule containing small interfering RNA (siRNA). siRNA has already been shown to be an efficient tool for silencing genes in cells, but previous attempts have produced chemically modified siRNA lasting only 15-45 minutes in the body and often inducing undesired immune responses.

"The pRNA particles we constructed to harbor siRNA have a half life of between five and 10 hours in animal models, are non-toxic and produce no immune response," says Guo."The tenfold increase of circulation time in the body is important in drug development and paves the way towards clinical trials of RNA nanoparticles as therapeutic drugs."

Guo says the size of the constructed pRNA molecule is crucial for the effective delivery of therapeutics to diseased tissues.

"RNA nanoparticles must be within the range of 15 to 50 nanometers," he says,"large enough to be retained by the body and not enter cells randomly, causing toxicity, but small enough to enter the targeted cells with the aid of cell surface receptions.

In the paper,"Assembly of Therapeutic pRNA-siRNA Nanoparticles Using Bipartite Approach," Guo and his colleagues used two synthetic RNA fragments to create the 117-base pRNA, which was able to further assemble with other pRNA molecules and function in the bacteriophage phi29 viral motor to package DNA.

"The two-piece approach in pRNA synthesis overcame challenges of size limitations in chemical synthesis of RNA nanoparticles," Guo wrote."The resulting nanoparticles were competent in delivering and releasing therapeutics to cells and silencing the genes within them. The ability to chemically synthesize these nanoparticles allows for further chemical modification of RNA for stability and specific targeting."

The second publication,"Pharmacological Characterization of Chemically Synthesized Monomeric phi29 pRNA Nanoparticles for Systemic Delivery," builds on that research, demonstrating that modified three-dimensional pRNA nanoparticles were readily manufactured through the two-piece approach. The modified nanoparticles were resistant to common enzymes that can attack and degrade RNA and remained chemically and metabolically stable.

Furthermore, when delivered to target cells in an animal model, the nanoparticles were non-toxic and did not induce an immune response, enabling the nanoparticles to bind to cancer cells in vivo.

Previous studies have encased therapeutic siRNA in a polymer coating or liposome for delivery to cells.

"To our knowledge, this is the first naked RNA nanoparticles to have been comprehensively examined pharmacologically in vivo and demonstrated to be safe, as well as deliver itself to tumor tissues by a specific targeting mechanism," he says."It suggests that the pRNA nanoparticles without coating have all the preferred pharmacological features to serve as an efficient nanodelivery platform for broad medical applications."

Co-authors of"Assembly of Therapeutic pRNA-siRNA Nanoparticles Using Bipartite Approach" include Yi Shu, Mathieu Cinier, Sejal Fox and Nira Ben-Johnathan of the University of Cincinnati.

Co-authors of"Pharmacological Characterization of Chemically Synthesized Monomeric phi29 pRNA Nanoparticles for Systemic Delivery" include Sherine Abdelmawla and Songchuan Guo of Kylin Therapeutics and Purdue University, Limin Zhang, Sai M Pulukuri, Prithviraj Patankar, Patrick Conley, Joseph Trebley and Qi-Xiang Li of Kylin Therapeutics.

This study was funded by National Cancer Institute, National Institute of Biomedical Imaging and Bioengineering, National Institute of General Medical Sciences and Kylin Therapeutics Inc. Guo is co-founder of Kylin Therapuetics.

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Scientists Engineer Nanoscale Vaults to Encapsulate 'Nanodisks' for Drug Delivery

The development of new methods that use engineered nanomaterials to transport drugs and release them directly into cells holds great potential in this area. And while several such drug-delivery systems -- including some that use dendrimers, liposomes or polyethylene glycol -- have won approval for clinical use, they have been hampered by size limitations and ineffectiveness in accurately targeting tissues.

Now, researchers at UCLA have developed a new and potentially far more effective means of targeted drug delivery using nanotechnology.

In a study to be published in the May 23 print issue of the journalSmall, they demonstrate the ability to package drug-loaded"nanodisks" into vault nanoparticles, naturally occurring nanoscale capsules that have been engineered for therapeutic drug delivery. The study represents the first example of using vaults toward this goal.

The UCLA research team was led by Leonard H. Rome and included his colleagues Daniel C. Buehler and Valerie Kickhoefer from the UCLA Department of Biological Chemistry; Daniel B. Toso and Z. Hong Zhou from the UCLA Department of Microbiology, Immunology and Molecular Genetics; and the California NanoSystems Institute (CNSI) at UCLA.

Vault nanoparticles are found in the cytoplasm of all mammalian cells and are one of the largest known ribonucleoprotein complexes in the sub-100-nanometer range. A vault is essentially barrel-shaped nanocapsule with a large, hollow interior -- properties that make them ripe for engineering into a drug-delivery vehicles. The ability to encapsulate small-molecule therapeutic compounds into vaults is critical to their development for drug delivery.

Recombinant vaults are nonimmunogenic and have undergone significant engineering, including cell-surface receptor targeting and the encapsulation of a wide variety of proteins.

"A vault is a naturally occurring protein particle and so it causes no harm to the body," said Rome, CNSI associate director and a professor of biological chemistry."These vaults release therapeutics slowly, like a strainer, through tiny, tiny holes, which provides great flexibility for drug delivery."

The internal cavity of the recombinant vault nanoparticle is large enough to hold hundreds of drugs, and because vaults are the size of small microbes, a vault particle containing drugs can easily be taken up into targeted cells.

With the goal of creating a vault capable of encapsulating therapeutic compounds for drug delivery, UCLA doctoral student Daniel Buhler designed a strategy to package another nanoparticle, known as a nanodisk (ND), into the vault's inner cavity, or lumen.

"By packaging drug-loaded NDs into the vault lumen, the ND and its contents would be shielded from the external medium," Buehler said."Moreover, given the large vault interior, it is conceivable that multiple NDs could be packaged, which would considerably increase the localized drug concentration."

According to researcher Zhou, a professor of microbiology, immunology and molecular genetics and director of the CNSI's Electron Imaging Center for NanoMachines, electron microscopy and X-ray crystallography studies have revealed that both endogenous and recombinant vaults have a thin protein shell enclosing a large internal volume of about 100,000 cubic nanometers, which could potentially hold hundreds to thousands of small-molecular-weight compounds.

"These features make recombinant vaults an attractive target for engineering as a platform for drug delivery," Zhou said."Our study represents the first example of using vaults toward this goal."

"Vaults can have a broad nanosystems application as malleable nanocapsules," Rome added.

The recombinant vaults are engineered to encapsulate the highly insoluble and toxic hydrophobic compound all-trans retinoic acid (ATRA) using a vault-binding lipoprotein complex that forms a lipid bilayer nanodisk.

The research was supported by the UC Discovery Grant Program, in collaboration with the research team's corporate sponsor, Abraxis Biosciences Inc., and by the Mather's Charitable Foundation and an NIH/NIBIB Award.

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Functioning Synapse Created Using Carbon Nanotubes: Devices Might Be Used in Brain Prostheses or Synthetic Brains

The team, which was led by Professor Alice Parker and Professor Chongwu Zhou in the USC Viterbi School of Engineering Ming Hsieh Department of Electrical Engineering, used an interdisciplinary approach combining circuit design with nanotechnology to address the complex problem of capturing brain function.

In a paper published in the proceedings of the IEEE/NIH 2011 Life Science Systems and Applications Workshop in April 2011, the Viterbi team detailed how they were able to use carbon nanotubes to create a synapse.

Carbon nanotubes are molecular carbon structures that are extremely small, with a diameter a million times smaller than a pencil point. These nanotubes can be used in electronic circuits, acting as metallic conductors or semiconductors.

"This is a necessary first step in the process," said Parker, who began the looking at the possibility of developing a synthetic brain in 2006."We wanted to answer the question: Can you build a circuit that would act like a neuron? The next step is even more complex. How can we build structures out of these circuits that mimic the function of the brain, which has 100 billion neurons and 10,000 synapses per neuron?"

Parker emphasized that the actual development of a synthetic brain, or even a functional brain area is decades away, and she said the next hurdle for the research centers on reproducing brain plasticity in the circuits.

The human brain continually produces new neurons, makes new connections and adapts throughout life, and creating this process through analog circuits will be a monumental task, according to Parker.

She believes the ongoing research of understanding the process of human intelligence could have long-term implications for everything from developing prosthetic nanotechnology that would heal traumatic brain injuries to developing intelligent, safe cars that would protect drivers in bold new ways.

For Jonathan Joshi, a USC Viterbi Ph.D. student who is a co-author of the paper, the interdisciplinary approach to the problem was key to the initial progress. Joshi said that working with Zhou and his group of nanotechnology researchers provided the ideal dynamic of circuit technology and nanotechnology.

"The interdisciplinary approach is the only approach that will lead to a solution. We need more than one type of engineer working on this solution," said Joshi."We should constantly be in search of new technologies to solve this problem."

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New Kid on the Plasmonic Block: Researchers Find Plasmonic Resonances in Semiconductor Nanocrystals

"We have demonstrated well-defined localized surface plasmon resonances arising from p-type carriers in vacancy-doped semiconductor quantum dots that should allow for plasmonic sensing and manipulation of solid-state processes in single nanocrystals," says Berkeley Lab director Paul Alivisatos, a nanochemistry authority who led this research."Our doped semiconductor quantum dots also open up the possibility of strongly coupling photonic and electronic properties, with implications for light harvesting, nonlinear optics, and quantum information processing."

Alivisatos is the corresponding author of a paper in the journalNature Materialstitled"Localized surface plasmon resonances arising from free carriers in doped quantum dots." Co-authoring the paper were Joseph Luther and Prashant Jain, along with Trevor Ewers.

The term"plasmonics" describes a phenomenon in which the confinement of light in dimensions smaller than the wavelength of photons in free space make it possible to match the different length-scales associated with photonics and electronics in a single nanoscale device. Scientists believe that through plasmonics it should be possible to design computer chip interconnects that are able to move much larger amounts of data much faster than today's chips. It should also be possible to create microscope lenses that can resolve nanoscale objects with visible light, a new generation of highly efficient light-emitting diodes, and supersensitive chemical and biological detectors. There is even evidence that plasmonic materials can be used to bend light around an object, thereby rendering that object invisible.

The plasmonic phenomenon was discovered in nanostructures at the interfaces between a noble metal, such as gold or silver, and a dielectric, such as air or glass. Directing an electromagnetic field at such an interface generates electronic surface waves that roll through the conduction electrons on a metal, like ripples spreading across the surface of a pond that has been plunked with a stone. Just as the energy in an electromagnetic field is carried in a quantized particle-like unit called a photon, the energy in such an electronic surface wave is carried in a quantized particle-like unit called a plasmon. The key to plasmonic properties is when the oscillation frequency between the plasmons and the incident photons matches, a phenomenon known as localized surface plasmon resonance (LSPR). Conventional scientific wisdom has held that LSPRs require a metal nanostructure , where the conduction electrons are not strongly attached to individual atoms or molecules. This has proved not to be the case as Prashant Jain, a member of the Alivisatos research group and one of the lead authors of the Nature Materials paper, explains.

"Our study represents a paradigm shift from metal nanoplasmonics as we've shown that, in principle, any nanostructure can exhibit LSPRs so long as the interface has an appreciable number of free charge carriers, either electrons or holes," Jain says."By demonstrating LSPRs in doped quantum dots, we've extended the range of candidate materials for plasmonics to include semiconductors, and we've also merged the field of plasmonic nanostructures, which exhibit tunable photonic properties, with the field of quantum dots, which exhibit tunable electronic properties."

Jain and his co-authors made their quantum dots from the semiconductor copper sulfide, a material that is known to support numerous copper-deficient stoichiometries. Initially, the copper sulfide nanocrystals were synthesized using a common hot injection method. While this yielded nanocrystals that were intrinsically self-doped with p-type charge carriers, there was no control over the amount of charge vacancies or carriers.

"We were able to overcome this limitation by using a room-temperature ion exchange method to synthesize the copper sulfide nanocrystals," Jain says."This freezes the nanocrystals into a relatively vacancy-free state, which we can then dope in a controlled manner using common chemical oxidants."

By introducing enough free electrical charge carriers via dopants and vacancies, Jain and his colleagues were able to achieve LSPRs in the near-infrared range of the electromagnetic spectrum. The extension of plasmonics to include semiconductors as well as metals offers a number of significant advantages, as Jain explains.

"Unlike a metal, the concentration of free charge carriers in a semiconductor can be actively controlled by doping, temperature, and/or phase transitions," he says."Therefore, the frequency and intensity of LSPRs in dopable quantum dots can be dynamically tuned. The LSPRs of a metal, on the other hand, once engineered through a choice of nanostructure parameters, such as shape and size, is permanently locked-in."

Jain envisions quantum dots as being integrated into a variety of future film and chip-based photonic devices that can be actively switched or controlled, and also being applied to such optical applications as in vivo imaging. In addition, the strong coupling that is possible between photonic and electronic modes in such doped quantum dots holds exciting potential for applications in solar photovoltaics and artificial photosynthesis

"In photovoltaic and artificial photosynthetic systems, light needs to be absorbed and channeled to generate energetic electrons and holes, which can then be used to make electricity or fuel," Jain says."To be efficient, it is highly desirable that such systems exhibit an enhanced interaction of light with excitons. This is what a doped quantum dot with an LSPR mode could achieve."

The potential for strongly coupled electronic and photonic modes in doped quantum dots arises from the fact that semiconductor quantum dots allow for quantized electronic excitations (excitons), while LSPRs serve to strongly localize or confine light of specific frequencies within the quantum dot. The result is an enhanced exciton-light interaction. Since the LSPR frequency can be controlled by changing the doping level, and excitons can be tuned by quantum confinement, it should be possible to engineer doped quantum dots for harvesting the richest frequencies of light in the solar spectrum.

Quantum dot plasmonics also hold intriguing possibilities for future quantum communication and computation devices.

"The use of single photons, in the form of quantized plasmons, would allow quantum systems to send information at nearly the speed of light, compared with the electron speed and resistance in classical systems," Jain says."Doped quantum dots by providing strongly coupled quantized excitons and LSPRs and within the same nanostructure could serve as a source of single plasmons."

Jain and others in Alivsatos' research group are now investigating the potential of doped quantum dots made from other semiconductors, such as copper selenide and germanium telluride, which also display tunable plasmonic or photonic resonances. Germanium telluride is of particular interest because it has phase change properties that are useful for memory storage devices.

"A long term goal is to generalize plasmonic phenomena to all doped quantum dots, whether heavily self-doped or extrinsically doped with relatively few impurities or vacancies," Jain says.

This research was supported by the DOE Office of Science.

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New Biosensor Microchip Could Speed Up Drug Development, Researchers Say

A single centimeter-sized array of the nanosensors can simultaneously and continuously monitor thousands of times more protein-binding events than any existing sensor. The new sensor is also able to detect interactions with greater sensitivity and deliver the results significantly faster than the present"gold standard" method.

"You can fit thousands, even tens of thousands, of different proteins of interest on the same chip and run the protein-binding experiments in one shot," said Shan Wang, a professor of materials science and engineering, and of electrical engineering, who led the research effort.

"In theory, in one test, you could look at a drug's affinity for every protein in the human body," said Richard Gaster, MD/PhD candidate in bioengineering and medicine, who is the first author of a paper describing the research that is in the current issue ofNature Nanotechnology,available online now.

The power of the nanosensor array lies in two advances. First, the use of magnetic nanotags attached to the protein being studied -- such as a medication -- greatly increases the sensitivity of the monitoring.

Second, an analytical model the researchers developed enables them to accurately predict the final outcome of an interaction based on only a few minutes of monitoring data. Current techniques typically monitor no more than four simultaneous interactions and the process can take hours.

"I think their technology has the potential to revolutionize how we do bioassays," said P.J. Utz, associate professor of medicine (immunology and rheumatology) at Stanford University Medical Center, who was not involved in the research.

A microchip with a nanosensor array (orange squares) is shown with a different protein (various colors) attached to each sensor. Four proteins of a potential medication (blue Y-shapes), with magnetic nanotags attached (grey spheres), have been added. One medication protein is shown binding with a protein on a nanosensor.

Members of Wang's research group developed the magnetic nanosensor technology several years ago and demonstrated its sensitivity in experiments in which they showed that it could detect a cancer-associated protein biomarker in mouse blood at a thousandth of the concentration that commercially available techniques could detect. That research was described in a 2009 paper inNature Medicine.

The researchers tailor the nanotags to attach to the particular protein being studied. When a nanotag-equipped protein binds with another protein that is attached to a nanosensor, the magnetic nanotag alters the ambient magnetic field around the nanosensor in a small but distinct way that is sensed by the detector.

"Let's say we are looking at a breast cancer drug," Gaster said."The goal of the drug is to bind to the target protein on the breast cancer cells as strongly as possible. But we also want to know: How strongly does that drug aberrantly bind to other proteins in the body?"

To determine that, the researchers would put breast cancer proteins on the nanosensor array, along with proteins from the liver, lungs, kidneys and any other kind of tissue that they are concerned about. Then they would add the medication with its magnetic nanotags attached and see which proteins the drug binds with -- and how strongly.

"We can see how strongly the drug binds to breast cancer cells and then also how strongly it binds to any other cells in the human body such as your liver, kidneys and brain," Gaster said."So we can start to predict the adverse affects to this drug without ever putting it in a human patient."

It is the increased sensitivity to detection that comes with the magnetic nanotags that enables Gaster and Wang to determine not only when a bond forms, but also its strength.

"The rate at which a protein binds and releases, tells how strong the bond is," Gaster said. That can be an important factor with numerous medications.

"I am surprised at the sensitivity they achieved," Utz said."They are detecting on the order of between 10 and 1,000 molecules and that to me is quite surprising."

The nanosensor is based on the same type of sensor used in computer hard drives, Wang said.

"Because our chip is completely based on existing microelectronics technology and procedures, the number of sensors per area is highly scalable with very little cost," he said.

Although the chips used in the work described in theNature Nanotechnologypaper had a little more than 1,000 sensors per square centimeter, Wang said it should be no problem to put tens of thousands of sensors on the same footprint.

"It can be scaled to over 100,000 sensors per centimeter, without even pushing the technology limits in microelectronics industry," he said.

Wang said he sees a bright future for increasingly powerful nanosensor arrays, as the technology infrastructure for making such nanosensor arrays is in place today.

"The next step is to marry this technology to a specific drug that is under development," Wang said."That will be the really killer application of this technology."

Other Stanford researchers who participated in the research and are coauthors of theNature Nanotechnologypaper are Liang Xu and Shu-Jen Han, both of whom were graduate students in materials science and engineering at the time the research was done; Robert Wilson, senior scientist in materials science and engineering; and Drew Hall, graduate student in electrical engineering. Other coauthors are Drs. Sebastian Osterfeld and Heng Yu from MagArray Inc. in Sunnyvale. Osterfeld and Yu are former alumni of the Wang Group.

Funding for the research came from the National Cancer Institute, the National Science Foundation, the Defense Advanced Research Projects Agency, the Gates Foundation and National Semiconductor Corporation.

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Super-Small Transistor Created: Artificial Atom Powered by Single Electrons

The researchers report inNature Nanotechnologythat the transistor's central component -- an island only 1.5 nanometers in diameter -- operates with the addition of only one or two electrons. That capability would make the transistor important to a range of computational applications, from ultradense memories to quantum processors, powerful devices that promise to solve problems so complex that all of the world's computers working together for billions of years could not crack them.

In addition, the tiny central island could be used as an artificial atom for developing new classes of artificial electronic materials, such as exotic superconductors with properties not found in natural materials, explained lead researcher Jeremy Levy, a professor of physics and astronomy in Pitt's School of Arts and Sciences. Levy worked with lead author and Pitt physics and astronomy graduate student Guanglei Cheng, as well as with Pitt physics and astronomy researchers Feng Bi, Daniela Bogorin,and Cheng Cen. The Pitt researchers worked with a team from the University of Wisconsin at Madison led by materials science and engineering professor Chang-Beom Eom, including research associates Chung Wun Bark, Jae-Wan Park, and Chad Folkman. Also part of the team were Gilberto Medeiros-Ribeiro, of HP Labs, and Pablo F. Siles, a doctoral student at the State University of Campinas in Brazil.

Levy and his colleagues named their device SketchSET, or sketch-based single-electron transistor, after a technique developed in Levy's lab in 2008 that works like a microscopic Etch A Sketch^TM, the drawing toy that inspired the idea. Using the sharp conducting probe of an atomic force microscope, Levy can create such electronic devices as wires and transistors of nanometer dimensions at the interface of a crystal of strontium titanate and a 1.2 nanometer thick layer of lanthanum aluminate. The electronic devices can then be erased and the interface used anew.

The SketchSET -- which is the first single-electron transistor made entirely of oxide-based materials -- consists of an island formation that can house up to two electrons. The number of electrons on the island -- which can be only zero, one, or two -- results in distinct conductive properties. Wires extending from the transistor carry additional electrons across the island.

One virtue of a single-electron transistor is its extreme sensitivity to an electric charge, Levy explained. Another property of these oxide materials is ferroelectricity, which allows the transistor to act as a solid-state memory. The ferroelectric state can, in the absence of external power, control the number of electrons on the island, which in turn can be used to represent the 1 or 0 state of a memory element. A computer memory based on this property would be able to retain information even when the processor itself is powered down, Levy said. The ferroelectric state also is expected to be sensitive to small pressure changes at nanometer scales, making this device potentially useful as a nanoscale charge and force sensor.

The research inNature Nanotechnologyalso was supported in part by grants from the U.S. Defense Advanced Research Projects Agency (DARPA), the U.S. Army Research Office, the National Science Foundation, and the Fine Foundation.

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New Fracture Resistance Mechanisms Provided by Graphene

The research, lead by Assistant Professor Erica L. Corral from the Materials Science and Engineering Department at the University of Arizona in Tucson, and Professor Nikhil Koratkar from the Department of Mechanical, Aerospace and Nuclear Engineering at Rensselaer Polytechnic Institute in Troy, New York, was recently published inACS Nano, the monthly journal of the American Chemical Society.

"Our work on graphene ceramic composites is the first of its kind in the open literature and shows mechanisms for toughening using two-dimensional graphene sheets that have yet to be seen in ceramic composites," said Corral."We have significantly increased the toughness of a ceramic and made the first observations of graphene that arrest crack propagation and force the crack to change directions in not just two but also three dimensions."

These observations will lead to a new approach for composite design using graphene in ceramics that has not been possible using conventional fiber reinforcements, says Corral."The high surface area and unique two-dimensional sheet geometry seem to be better at arresting crack growth in ceramics over conventional fibers that are one-dimensional reinforcements," she said.

"This is a classic example of highly successful interdisciplinary research across universities that was unheard of 15 or 20 years ago, but is now becoming critically important if we are to continue to make breakthrough discoveries and maintain the competiveness of the United States in the 21st century," said Prof. Koratkar of the Rensselaer Polytechnic Institute. Koratkar met Dr. Corral at a National Science Foundation-sponsored nanoscience conference where she delivered a talk on her work in carbon nanotube ceramic composites.

Koratkar was impressed with Corral's presentation, and approached her regarding the possibility of exploring the use of graphene to increase toughening in brittle ceramics."Over the next year we leveraged my lab's expertise in the synthesis of bulk quantities of graphene platelets and the expertise of Corral's group in ceramic composite fabrication and testing," Koratkar said."Our results published inACS Nanoshow the tremendous promise that graphene shows in toughening ceramics that are notoriously brittle and prone to failure. This work could open up an entirely new graphene ceramic nanocomposites field of study," he says.

This is the first published work describing the use of graphene nanofiller to reinforce ceramics and will appear in the journalACS Nano. This discovery -- measured to increase fracture resistance of the resulting ceramic nanocomposite by over 200 percent -- could potentially be used to enhance toughness for a range of ceramic materials, enabling their widespread use in high-performance, structural applications that require operating temperatures greater than 1,000 degrees Celsius while maintaining structural integrity.

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Magnetic New Graphene Discovery

The finding by a team of Maryland researchers, led by Physics Professor Michael S. Fuhrer of the UMD Center for Nanophysics and Advanced Materials is the latest of many amazing properties discovered for graphene.

A honeycomb sheet of carbon atoms just one atom thick, graphene is the basic constituent of graphite. Some 200 times stronger than steel, it conducts electricity at room temperature better than any other known material (a 2008 discovery by Fuhrer, et. al). Graphene is widely seen as having great, perhaps even revolutionary, potential for nanotechnology applications. The 2010 Nobel Prize in physics was awarded to scientists Konstantin Novoselov and Andre Geim for their 2004 discovery of how to make graphene.

In their new graphene discovery, Fuhrer and his University of Maryland colleagues have found that missing atoms in graphene, called vacancies, act as tiny magnets -- they have a"magnetic moment." Moreover, these magnetic moments interact strongly with the electrons in graphene which carry electrical currents, giving rise to a significant extra electrical resistance at low temperature, known as the Kondo effect. The results appear in the paper"Tunable Kondo effect in graphene with defects" published this month inNature Physics.

The Kondo effect is typically associated with adding tiny amounts of magnetic metal atoms, such as iron or nickel, to a non-magnetic metal, such as gold or copper. Finding the Kondo effect in graphene with vacancies was surprising for two reasons, according to Fuhrer.

"First, we were studying a system of nothing but carbon, without adding any traditionally magnetic impurities. Second, graphene has a very small electron density, which would be expected to make the Kondo effect appear only at extremely low temperatures," he said.

The team measured the characteristic temperature for the Kondo effect in graphene with vacancies to be as high as 90 Kelvin, which is comparable to that seen in metals with very high electron densities. Moreover the Kondo temperature can be tuned by the voltage on an electrical gate, an effect not seen in metals. They theorize that the same unusual properties of that result in graphene's electrons acting as if they have no mass also make them interact very strongly with certain kinds of impurities, such as vacancies, leading to a strong Kondo effect at a relatively high temperature.

Fuhrer thinks that if vacancies in graphene could be arranged in just the right way, ferromagnetism could result."Individual magnetic moments can be coupled together through the Kondo effect, forcing them all to line up in the same direction," he said.

"The result would be a ferromagnet, like iron, but instead made only of carbon. Magnetism in graphene could lead to new types of nanoscale sensors of magnetic fields. And, when coupled with graphene's tremendous electrical properties, magnetism in graphene could also have interesting applications in the area of spintronics, which uses the magnetic moment of the electron, instead of its electric charge, to represent the information in a computer.

"This opens the possibility of 'defect engineering' in graphene -- plucking out atoms in the right places to design the magnetic properties you want," said Fuhrer.

This research was supported by grants from the National Science Foundation and the Office of Naval Research.

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Scientists Finely Control Methane Combustion to Get Different Products

The research was conducted by scientists at the Georgia Institute of Technology and the University of Ulm. It appears in the April 14, 2011, edition ofThe Journal of Physical Chemistry C.

"_­The beauty of this process is that it allows us to selectively control the products of this catalytic system, so that if one wishes to create formaldehyde, and potentially methyl alcohol, one burns methane by tuning its reaction with oxygen to run at lower temperatures, but if it's ethylene one is after, the reaction can be tuned to run at room temperature," said Uzi Landman, Regents' and Institute Professor of Physics and director of the Center for Computational Materials Science at Georgia Tech.

Reporting last year in the journalAngewandte Chemie International Edition, a team that included theorists Landman and Robert Barnett from Georgia Tech and experimentalists Thorsten Bernhardt and Sandra Lang from the University of Ulm, found that by using gold dimer cations as catalysts, they can convert methane into ethylene at room temperature.

This time around, the team has discovered that, by using the same gas-phase gold dimer cation catalyst, methane partially combusts to produce formaldehyde at temperatures below 250 Kelvin or -9 degrees Fahrenheit. What's more, in both the room temperature reaction-producing ethylene, and the formaldehyde generation colder reaction, the gold dimer catalyst is freed at the end of the reaction, thus enabling the catalytic cycle to repeat again and again.

The temperature-tuned catalyzed methane partial combustion process involves activating the methane carbon-to-hydrogen bond to react with molecular oxygen. In the first step of the reaction process, methane and oxygen molecules coadsorb on the gold dimer cation at low temperature. Subsequently, water is released and the remaining oxygen atom binds with the methane molecule to form formaldehyde. If done at higher temperatures, the oxygen molecule comes off the gold catalyst, and the adsorbed methane molecules combine to form ethylene through the elimination of hydrogen molecules.

In both the current work, as well as in the earlier one, Bernhardt's team at Ulm conducted experiments using a radio-frequency trap, which allows temperature-controlled measurement of the reaction products under conditions that simulate realistic catalytic reactor environment. Landman's team at Georgia Tech performed first-principles quantum mechanical simulations, which predicted the mechanisms of the catalyzed reactions and allowed a consistent interpretation of the experimental observations.

In future work, the two research groups plan to explore the use of multi-functional alloy cluster catalysts in low temperature-controlled catalytic generation of synthetic fuels and selective partial combustion reactions.

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DNA Nanoforms: Miniature Architectural Forms -- Some No Larger Than Viruses -- Constructed Through DNA Origami

Such diminutive forms may ultimately find their way into a wide array of devices, from ultra-tiny computing components to nanomedical sentries used to target and destroy aberrant cells or deliver therapeutics at the cellular or even molecular level.

In the April 15 issue ofScience, the Yan group describes an approach that capitalizes on (and extends) the architectural potential of DNA. The new method is an important step in the direction of building nanoscale structures with complex curvature -- a feat that has eluded conventional DNA origami methods."We are interested in developing a strategy to reproduce nature's complex shapes," said Yan.

The technique of DNA origami was introduced in 2006 by computer scientist Paul W.K. Rothemund of Caltech. It relies on the self-assembling properties of DNA's four complementary base pairs, which fasten together the strands of the molecule's famous double-helix. When these nucleotides, labeled A, T, C, and G, interact, they join to one another according to a simple formula -- A always pairs with T and C with G.

Nanodesigners like Yan treat the DNA molecule as a versatile construction material -- one they hope to borrow from nature and adapt for new purposes.

In traditional DNA origami, a two-dimensional shape is first conceptualized and drawn. This polygonal outline is then filled in using short segments of double-stranded DNA, arranged in parallel. These segments may be likened to pixels -- digital elements used to create words and images displayed on a computer screen.

Indeed, Rothemund and others were able to use pixel-like segments of DNA to compose a variety of elegant 2-dimensional shapes, (stars, rhomboids, snowflake forms, smiley faces, simple words and even maps), as well as some rudimentary 3-dimensional structures. Each of these relies on the simple rules of self-assembly guiding nucleotide base paring.

Once the desired shape has been framed by a length of single-stranded DNA, short DNA"staple strands" integrate the structure and act as the glue to hold the desired shape together. The nucleotide sequence of the scaffold strand is composed in such a way that it runs through every helix in the design, like a serpentine thread knitting together a patchwork of fabric. Further reinforcement is provided by the staple strands, which are also pre-designed to attach to desired regions of the finished structure, through base pairing.

"To make curved objects requires moving beyond the approximation of curvature by rectangular pixels. People in the field are interested in this problem. For example, William Shih's group at Harvard Medical School recently used targeted insertion and deletion of base pairs in selected segments within a 3D building block to induce the desired curvature. Nevertheless, it remains a daunting task to engineer subtle curvatures on a 3D surface," stated Yan.

"Our goal is to develop design principles that will allow researchers to model arbitrary 3D shapes with control over the degree of surface curvature. In an escape from a rigid lattice model, our versatile strategy begins by defining the desired surface features of a target object with the scaffold, followed by manipulation of DNA conformation and shaping of crossover networks to achieve the design," Liu said.

To achive this idea, Yan's graduate student Dongran Han began by making simple 2-dimensional concentric ring structures, each ring formed from a DNA double helix. The concentric rings are bound together by means of strategically placed crossover points. These are regions where one of the strands in a given double helix switches to an adjacent ring, bridging the gap between concentric helices. Such crossovers help maintain the structure of concentric rings, preventing the DNA from extending.

Varying the number of nucleotides between crossover points and the placement of crossovers allows the designer to combine sharp and rounded elements in a single 2D form, as may be seen in figure 1 a& b, (with accompanying images produced by atomic force microscopy, revealing the actual structures that formed through self-assembly). A variety of such 2D designs, including an opened 9-layer ring and a three-pointed star, were produced.

The network of crossover points can also be designed in such a way as to produce combinations of in-plane and out-of-plane curvature, allowing for the design of curved 3D nanostructures. While this method shows considerable versatility, the range of curvature is still limited for standard B form DNA, which will not tolerate large deviations from its preferred configuration -- 10.5 base pairs/turn. However, as Jeanette Nangreave, one of the paper's co-authors explains,"Hao recognized that if you could slightly over twist or under twist these helices, you could produce different bending angles."

Combining the method of concentric helices with such non-B-form DNA (with 9-12 base pairs/turn), enabled the group to produce sophisticated forms, including spheres, hemispheres, ellipsoid shells and finally -- as a tour de force of nanodesign -- a round-bottomed nanoflask, which appears unmistakably in a series of startling transmission electron microscopy images (see figure 1, c-f ).

"This is a good example of teamwork in which each member brings their unique skills to the project to make things happen." The other authors include Suchetan Pal and Zhengtao Deng, who also made significant contributions in imaging the structures.

Yan hopes to further expand the range of nanoforms possible through the new technique. Eventually, this will require longer lengths of single-stranded DNA able to provide necessary scaffolding for larger, more elaborate structures. He credits his brilliant student (and the paper's first author) Dongran Han with a remarkable ability to conceptualize 2- and 3D nanoforms and to navigate the often-perplexing details of their design. Ultimately however, more sophisticated nanoarchitectures will require computer-aided design programs -- an area the team is actively pursuing.

The successful construction of closed, 3D nanoforms like the sphere has opened the door to many exciting possibilities for the technology, particularly in the biomedical realm. Nanospheres could be introduced into living cells for example, releasing their contents under the influence of endonucleases or other digestive components. Another strategy might use such spheres as nanoreactors -- sites where chemicals or functional groups could be brought together to accelerate reactions or carry out other chemical manipulations.

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Physicists Create Clouds of Impenetrable Gases That Bounce Off Each Other

While this experiment involved clouds of lithium atoms, cooled to near absolute zero, the findings could also help explain the behavior of similar systems such as neutron stars, high-temperature superconductors, and quark-gluon plasma, the hot soup of elementary particles that formed immediately after the Big Bang. A paper describing the work will appear in the April 14 issue ofNature.

The researchers, led by MIT assistant professor of physics Martin Zwierlein, carried out their experiment with an isotope of lithium that belongs to a class of particles called fermions. All building blocks of matter -- electrons, protons, neutrons and quarks -- are fermions.

Different states of fermionic matter are distinguished by their mobility. For example, electrons can be mobile, as in a metal; immobile, as in an insulator; or flow without resistance, as in a superconductor. However, for many types of material, including high-temperature superconductors, it is not known what circumstances induce fermions to form a given state of matter. This is especially true of materials with strongly interacting fermions, meaning they are more likely to collide with each other (also called scattering).

In this study, the researchers set out to model strongly interacting systems, using lithium gas atoms to stand in for electrons. By tuning the lithium atoms' energy states with a magnetic field, they made the atoms interact with each other as strongly as the laws of nature allow, meaning that they scatter every time they encounter another atom.

To eliminate any effects of heat energy, the researchers cooled the gas to about 50 billionths of one Kelvin, close to absolute zero (-273 degrees Celsius). They used magnetic forces to separate the gas into two clouds, labeled"spin up" and"spin down, then made the clouds collide in a trap formed by laser light. Instead of passing through each other, as gases would normally do, the clouds repelled in dramatic fashion.

"When we saw that these ultra dilute puffs of gas bounce off each other, we were completely amazed," says graduate student Ariel Sommer, lead author of theNaturepaper.

The gas clouds did eventually diffuse into each other, but in several cases it took an entire second or more -- an extremely long time for events occurring at microscopic scales.

The research, conducted at the MIT-Harvard Center for Ultracold Atoms, is part of a program aimed at using ultracold atoms as easily controllable model systems to study the properties of complex materials, such as high-temperature superconductors and novel magnetic materials that have applications in data storage and improving energy efficiency.

In future work, the researchers plan to confine the lithium gases to two-dimensions, which will allow them to simulate the two-dimensional state in which electrons exist in high-temperature superconductors.

Their work can also be used to model the behavior of other strongly interacting systems, such as high-density neutron stars, which are only a few tens of kilometers in diameter but more massive than our sun.

Another substance that interacts as strongly as the atoms in the ultracold lithium gas clouds created at MIT is quark-gluon plasma, which existed at the universe's formation and has been recreated in particle colliders by colliding atomic nuclei at energies corresponding to a trillion degrees.

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Better Lasers for Optical Communications

"All indications are that this technology could be useful at both industrial and scientific levels," explains Eli Kapon, head of EPFL's Laboratory of Physics of Nanostructures. More than fifteen years of research were required to arrive at this result, work that"has caused many headaches and demanded significant investment."

To obtain the right wavelength, the EPFL researchers adapted the lasers' size. In parallel, the EMPA scientists designed a nanometer-scale grating for the emitter in order to control the light's polarization. They were able to achieve this feat by vaporizing long molecules containing gold atoms with a straw-like tool operating above the lasers. Using an electron microscope, they were able to arrange and attach gold particles to the surface of each laser with extreme precision. Thus deposited, the grating serves as a filter for polarizing the light, much like the lenses of sunglasses are used to polarize sunlight.

Industrial and scientific advantages

This technique, developed in collaboration with EMPA, has many advantages. It allows a high-speed throughput of several gigabits a second with reduced transmission errors. The lasers involved are energy-efficient, consuming up to ten times less than their traditional counterparts, thanks to their small size. The technique is very precise and efficient, due to the use of the electron microscope.

"This progress is very satisfying," adds Kapon, who also outlines some possible applications."These kinds of lasers are also useful for studying and detecting gases using spectroscopic methods. We will thus make gains in precision by improving detector sensitivity."

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World's Smallest Wedding Rings: Interlocking Rings of DNA Visible Through Scanning Force Microscope

From a scientific perspective, the structure is a milestone in the field of DNA nanotechnology, since the two rings of the catenan are, as opposed to the majority of the DNA nano-architectures that have already been realized, not fixed formations, but -- depending on the environmental conditions -- freely pivotable. They are therefore suitable as components of molecular machines or of a molecular motor.

"We still have a long way to go before DNA structures such as the catenan can be used in everyday items," says Prof Alexander Heckel,"but structures of DNA can, in the near future, be used to arrange and study proteins or other molecules that are too small for a direct manipulation, by means of auto-organization." This way, DNA nano-architectures could become a versatile tool for the nanometer world, to which access is difficult.

In the manufacture of DNA nano-architecture, the scientists take advantage of the pairing rules of the four DNA nucleobases, according to which two natural DNA strands can also find each other (in DNA nano-architecture, the base order is without biological significance). An A on one strand pairs with T on the other strand and C is complementary to G. The trick is to create the sequences of the DNA strands involved in such a manner as to ensure that the desired structure builds up on its own without direct intervention on the experimenter's part. If only certain parts of the strands used complement each other, branches and junctions can be created.

As reported by Schmidt and Heckel in the journalNano Letters, they first created two C-shaped DNA fragments for the catenans. With the help of special molecules that act as sequence-specific glue for the double helix, they arranged the"Cs" in such a ways as to create two junctions, with the open ends of the"Cs" pointing away from each other. The catenan was created by adding two strands that attach to the ends of the two ring fragments, which are still open. Thorsten Schmidt dedicated the publication to his wife Dr Diana Gonçalves Schmidt, who also appreciates the work on scientific level, since she was also a part of Alexander Heckel's work group.

Since they are much smaller than the wavelengths of visible light, the rings cannot be seen with a standard microscope."You would have to string together about 4000 such rings to even achieve the diameter of a human hair," says Thorsten Schmidt. He therefore displays the catenans with a scanning force microscope, which scans the rings that have been placed on a surface with an extremely fine tip.

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Nano Fitness: Helping Enzymes Stay Active and Keep in Shape

One key challenge is the stability of enzymes, a particular type of protein that speeds up, or catalyzes, chemical reactions. Taken out of their natural environment in the cell or body, enzymes can quickly lose their shape and denature. Everyday examples of enzymes denaturing include milk going sour, or eggs turning solid when boiled.

Rensselaer Polytechnic Institute Professor Marc-Olivier Coppens has developed a new technique for boosting the stability of enzymes, making them useful under a much broader range of conditions. Coppens confined lysozyme and other enzymes inside carefully engineered nanoscale holes, or nanopores. Instead of denaturing, these embedded enzymes mostly retained their 3-D structure and exhibited a significant increase in activity.

"Normally, when you put an enzyme on a surface, its activity goes down. But in this study, we discovered that when we put enzymes in nanopores -- a highly controlled environment -- the enzymatic activity goes up dramatically," said Coppens, a professor in the Department of Chemical and Biological Engineering at Rensselaer."The enzymatic activity turns out to be very dependent on the local environment. This is very exciting."

Results of the study were published last month by the journalPhysical Chemistry Chemical Physics.

Researchers at Rensselaer and elsewhere have made important discoveries by wrapping enzymes and other proteins around nanomaterials. While this immobilizes the enzyme and often results in high stability and novel properties, the enzyme's activity decreases as it loses its natural 3-D structure.

Coppens took a different approach, and inserted enzymes inside nanopores. Measuring only 3-4 nanometers (nm) in size, the enzyme lysozyme fits snugly into a nanoporous material with well-controlled pore size between 5 nm and 12 nm. Confined to this compact space, the enzymes have a much harder time unfolding or wiggling around, Coppens said.

The discovery raises many questions and opens up entirely new possibilities related to biology, chemistry, medicine, and nanoengineering, Coppens said. He envisions this technology could be adapted to better control nanoscale environments, as well as increase the activity and selectivity of different enzymes. Looking forward, Coppens and colleagues will employ molecular simulations, multiscale modeling methods, and physical experiments to better understand the fundamental mechanics of confining enzymes inside nanopores.

The study was co-authored by Lung-Ching Sang, a former Rensselaer graduate student in the Department of Chemical and Biological Engineering.

This research was supported by the National Science Foundation, via the Nanoscale Science and Engineering Center for Directed Assembly of Nanostructures at Rensselaer. The project was also supported by the International Center for Materials Nanoarchitectonics of the National Institute for Materials Science, Japan.

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New Research Advances Understanding of Lead Selenide Nanowires

Now, a research team at the University of Pennsylvania's schools of Engineering and Applied Science and Arts and Sciences has shown how to control the characteristics of semiconductor nanowires made of a promising material: lead selenide.

Led by Cherie Kagan, professor in the departments of Electrical and Systems Engineering, Materials Science and Engineering and Chemistry and co-director of Pennergy, Penn's center focused on developing alternative energy technologies, the team's research was primarily conducted by David Kim, a graduate student in the Materials Science and Engineering program.

The team's work was published online in the journalACS Nanoand will be featured in the Journal's April podcast.

The key contribution of the team's work has to do with controlling the conductive properties of lead selenide nanowires in circuitry. Semiconductors come in two types,nandp, referring to the negative or positive charge they can carry. The ones that move electrons, which have a negative charge, are called"n-type." Their"p-type" counterparts don't move protons but rather the absenceof an electron -- a"hole" -- which is the equivalent of moving a positive charge.

Before they are integrated into circuitry, the semiconductor nanowire must be"wired up" into a device. Metal electrodes must be placed on both ends to allow electricity to flow in and out; however, the"wiring" may influence the observed electrical characteristics of the nanowires, whether the device appears to ben-type orp-type. Contamination, even from air, can also influence the device type. Through rigorous air-free synthesis, purification and analysis, they kept the nanowires clean, allowing them to discover the unique properties of these lead selenide nanomaterials.

Researchers designed experiments allowing them to separate the influence of the metal"wiring" on the motion of electrons and holes from that of the behavior intrinsic to the lead selenide nanowires. By controlling the exposure of the semiconductor nanowire device to oxygen or the chemical hydrazine, they were able to change the conductive properties betweenp-type andn-type. Altering the duration and concentration of the exposure, the nanowire device type could be flipped back and forth.

"If you expose the surfaces of these structures, which are unique to nanoscale materials, you can make themp-type, you can make themn-type, and you can make them somewhere in between, where it can conduct both electrons and holes," Kagan said."This is what we call 'ambipolar.'"

Devices combining onen-type and onep-type semiconductor are used in many high-tech applications, ranging from the circuits of everyday electronics, to solar cells and thermoelectrics, which can convert heat into electricity.

"Thinking about how we can build these things and take advantage of the characteristics of nanoscale materials is really what this new understanding allows," Kagan said.

Figuring out the characteristics of nanoscale materials and their behavior in device structures are the first steps in looking forward to their applications.

These lead selenide nanowires are attractive because they may be synthesized by low-cost methods in large quantities.

"Compared to the big machinery you need to make other semiconductor devices, it's significantly cheaper," Kagan said."It doesn't look much more complicated than the hoods people would recognize from when they had to take chemistry lab."

In addition to the low cost, the manufacturing process for lead selenide nanowires is relatively easy and consistent.

"You don't have to go to high temperatures to get mass quantities of these high-quality lead selenide nanowires," Kim said."The techniques we use are high yield and high purity; we can use all of them."

And because the conductive qualities of the lead selenide nanowires can be changed while they are situated in a device, they have a wider range of functionality, unlike traditional silicon semiconductors, which must first be"doped" with other elements to make them"p" or"n."

The Penn team's work is a step toward integrating these nanomaterials in a range of electronic and optoelectronic devices, such as photo sensors.

The research was conducted by Kim and Kagan, along with Materials Science and Engineering undergraduate and graduate students Tarun R. Vemulkar and Soong Ju Oh; Weon-Kyu Koh, a graduate student in Chemistry; and Christopher B. Murray, a professor in Chemistry and in Materials Science and Engineering.

This work was supported with funding from the National Science Foundation Division of Materials Research, the National Science Foundation Solar Program and the National Science Foundation Nano-Bio Interface Center.

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Are We Only a Hop, Skip and Jump Away from Controlled Molecular Motion?

Controlling how molecules move on surfaces could be the key to more potent drugs that block the attachment of viruses to cells, and will also speed development of new materials for electronics and energy applications. The study is the culmination of a EU-funded collaboration between Tyndall National Institute, UCC researcher Dr. Damien Thompson and colleagues at University of Twente in the Netherlands. Dr. Thompson performed computer simulations that enabled a greater understanding of how two-legged molecules move along patterned surfaces, in a kind of molecular hopscotch.

Widespread industrial uptake of nanotechnology requires cheap, easy and robust solutions that allow manipulation of matter at the smallest scales and so a key enabling feature will be the ability to move material around molecule by molecule. One of the major difficulties is the very different physics that operates at the scale of atoms and molecules; water, for example, feels more like treacle to a molecule, and molecules tend to huddle and stick together due to microscopic forces between their atoms. Dr. Thompson explains:"The experiments performed by the group at Twente were very elegant. They involved making two-legged molecules and using a fluorescence microscope to watch how they move along a wet surface. The molecules are hydrophobic, meaning they don't like water, and the surface was pockmarked with hydrophobic cavities so a weak glueing interaction, based on a mutual dislike of water, drives the interaction between the molecules and the surface.

While the energetics of this type of interaction was worked out over a decade ago by George Whitesides's group at Harvard, it's usefulness for materials development was limited because little was known until now on the paths that the molecules take."

Because the molecules have multiple legs, they display a surprisingly rich behaviour at the surface, beyond simply attaching/detaching, with Dr. Thompson's computer simulations complementing the experiments and showing the different mechanisms by which the molecules move. The motion switches from walking to hopping to flying, as the environment changes.

Dr. Thompson continues:"Access to high performance computing facilities enabled us to model the different pathways and aid interpretation of the microscopy results. We ran most of the simulations on our own Science Foundation Ireland-supported computing clusters at Tyndall, and also did a few larger-scale calculations at the Irish Center for High End Computing. It's an exciting time for research as experiments and simulations are finally on the same page; the experiments can finally drill down far enough to see molecule-scale features while advances in computing mean we can routinely model systems composed of hundreds of thousands, and even millions, of atoms."

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Common Nanoparticles Found to Be Highly Toxic to Arctic Ecosystem

"Millions of tonnes of nanoparticles are now manufactured every year, including silver nanoparticles which are popular as antibacterial agents," says Virginia Walker, a professor in the Department of Biology."We started to wonder what the impact of all these nanoparticles might be on the environment, particularly on soil."

The team acquired a sample of soil from the Arctic as part of their involvement in the International Polar Year initiative. The soil was sourced from a remote Arctic site as they felt that this soil stood the greatest chance of being uncontaminated by any nanoparticles.

"We hadn't thought we would see much of an impact, but instead our results indicate that silver nanoparticles can be classified as highly toxic to microbial communities. This is particularly concerning when you consider the vulnerability of the arctic ecosystem."

Dr. Walker further noted that although technological progress is important, the world has a history of welcoming innovations prior to reflecting on their impact on the environment. Such examples include the discovery of the insecticide DDT, the use of the drug thalidomide during pregnancy and the widespread use of synthetic fertilizers.

The researchers first examined the indigenous microbe communities living in the uncontaminated soil samples before adding three different kinds of nanoparticles, including silver. The soil samples were then left for six months to see how the addition of the nanoparticles affected the microbe communities. What the researchers found was both remarkable and concerning.

The original analysis of the uncontaminated soil had identified a beneficial microbe that helps fix nitrogen to plants. As plants are unable to fix nitrogen themselves and nitrogen fixation is essential for plant nutrition, the presence of these particular microbes in soil is vital for plant growth. The analysis of the soil sample six months after the addition of the silver nanoparticles showed negligible quantities of the important nitrogen-fixing species remaining and laboratory experiments showed that they were more than a million times susceptible to silver nanoparticles than other species.

These pioneering findings by Queen's researchers Niraj Kumar and Virginia Walker and Dowling College's Vishal Shah have been published April 6 in theJournal of Hazardous Materials.

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Chemical Engineers Have Designed Molecular Probe to Study Disease

Their work, reported in the journalChemistry& Biology, describes a new strategy to build molecular probes to visualize, measure, and learn about the activities of enzymes, called proteases, on the surface of cancer cells.

Patrick Daugherty, senior author and professor of chemical engineering at UCSB, explained that the probes are effective at understanding proteases involved in tumor metastasis.

"Tumor metastasis is widely regarded as the cause of death for cancer patients," said Daugherty."It's not usually the primary tumor that causes death. Metastasis is mediated by proteases, like the one we are studying here. These proteases can enable tumor cells to separate and degrade surrounding tissue, and then migrate to sites distant from the primary tumor. The tumor doesn't just fall apart. There are many events that must occur for a tumor to release cancerous cells into the blood stream that can circulate and end up in other tissues such as liver or bone."

The probes allowed the researchers, for the first time, to measure directly the activity of a protease involved in metastasis. They did this by adding their probe into a dish of tumor cells. They then measured the activity of this protease that breaks down collagen -- the single most abundant protein (by mass) in the human body.

"We have immediate plans to use similar probes to effectively distinguish metastatic HER2 positive tumors, one of the most commonly used biomarkers of breast cancer," said Daugherty."A significant fraction of patients have HER2 positive tumors but we don't know which of those tumors is going to metastasize yet. But our ability to make these probes can allow us to identify which of those HER2 positive tumors have the ability to break down that surrounding tissue, to detach from the primary tumor, and to establish a separate tumor somewhere else in the body."

The authors designed the molecular probe to be recognized by a single protease rather than by the many proteases that are present in human tissues. That is half of the probe. The other half of the probe involves an optical technique used to measure activity. This approach relies upon the use of two engineered fluorescent proteins, derived from marine organisms, that absorb and emit light in a process called FRET, or Forster resonance energy transfer.

To prepare the probes, the researchers introduced a gene that encodes the probe into the bacteria E. coli. Then they produced and purified significant quantities of the probe. All of the information needed for the probe is encoded by a DNA sequence. The probes are easy and inexpensive to produce, as well as easily shared with other researchers.

In addition to studying cancer, similarly constructed probes have ramifications for studying Alzheimer's disease, arthritis and connective tissue diseases, bacterial infections, viruses, and many other diseases.

"The fact that you can generalize the concept, and the way you make these probes, to many systems, makes it attractive," said Daugherty."We happen to study the activity of this protease and a certain type of tumor cells that are derived from cancer patients. But you could apply this to hundreds of molecules and really develop a working understanding of how groups of proteases function together in cell biology."

In individuals with rheumatoid arthritis, for example, there is increased production of proteases, including the one studied by Daugherty's team. This protease mediates collagen breakdown and joint destruction."If you've got an enzyme that can chew up collagen and you've got lots of collagen in your joints, then you would expect that you would see more rapid degradation of the joint by those proteases," said Daugherty.

Daugherty's research group has created approximately 25 probes analogous to the one presented in the paper. They are building a panel of about 100 probes and will use this panel to characterize how different proteases function. This investigation could lead to new drug therapies for a variety of diseases.

The first author on the paper is Daugherty's former graduate student, Abeer Jabaiah, who is applying a similar process to another protease involved in tumor metastasis as a postdoctoral fellow in Daugherty's lab. Funding for this work was provided by the National Institutes of Health through the National Cancer Institute's Center of Cancer Nanotechnology Excellence and the National Heart, Lung, and Blood Institute's Program of Excellence in Nanotechnology.

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