Scientists Listen to Faint Sounds Inside Insects Using Atomic Force Microscopy

A team of Clarkson University scientists led by Prof. Igor Sokolov are using atomic force microscopy (AFM) to record sounds emanating from inside living insects like flies, mosquitoes and ladybugs.
AFM is one of major scientific tools responsible for the emergence of modern nanotechnology.
The unprecedented sensitivity of AFM allowed the Clarkson team to record sub-nano oscillations of very faint amplitude (less than the size of one atom) at high frequencies (up to 1,000 hertz or cycles per second). Previous work in the study of insects was only done at up to 5 hertz. The sounds are recorded by touching the surface of the bugs with an AFM probe.
The study of these sounds may allow researchers to discover unknown features and physiology of insects. Sokolov hopes these discoveries may help in finding solutions to the problems caused by insect pests.
"Insects are of general interest not only as the most numerous and diverse group of animals on the planet, but also as highly efficient bio-machines varying greatly in size," says Sokolov. "Some are major agricultural pests and competitors of humans for crops. Mosquitoes and other insects are important vectors of plant, animal, and human diseases. Also, vast lands of the earth are still underdeveloped because they are occupied by blood-sucking insects."
You can listen to audio files of the internal sounds of mosquitoes, flies, and ladybugs at: http://ftp.aip.org/epaps/appl_phys_lett/E-APPLAB-96-038950 .

The team consisted of Sokolov, who has appointments in Physics, and Chemistry and Biomolecular Science; Maxim Dokukin, a physics postdoctoral fellow; and Nataliia Guz, a physics graduate student; and Sergey Vasilyev, instrumental scientist. The other members of Sokolov's group, physics graduate students Dmytro Volkov, Ravi Gaikwad, and Shyuzhene Li, work on biosensors, self-assembly of particles, and the study of skin aging.

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New Nanoscale Electrical Phenomenon Discovered

At the scale of the very small, physics can get peculiar. A University of Michigan biomedical engineering professor has discovered a new instance of such a nanoscale phenomenon -- one that could lead to faster, less expensive portable diagnostic devices and push back frontiers in building micro-mechanical and "lab on a chip" devices.
By leveraging the unique properties of nanoscale gold to "squeeze" light into tiny holes in the surface of the device, the researchers have doubled the detectivity of a quantum dot-based infrared detector. With some refinements, the researchers expect this new technology should be able to enhance detectivity by up to 20 times.
This study is the first in more than a decade to demonstrate success in enhancing the signal of an infrared detector without also increasing the noise, said project leader Shawn-Yu Lin, professor of physics at Rensselaer and a member of the university's Future Chips Constellation and Smart Lighting Engineering Research Center.
"Infrared detection is a big priority right now, as more effective infrared satellite imaging technology holds the potential to benefit everything from homeland security to monitoring climate change and deforestation," said Lin, who in 2008 created the world's darkest material as well as a coating for solar panels that absorbs 99.9 percent of light from nearly all angles.
"We have shown that you can use nanoscopic gold to focus the light entering an infrared detector, which in turn enhances the absorption of photons and also enhances the capacity of the embedded quantum dots to convert those photons into electrons. This kind of behavior has never been seen before," he said.
Results of the study were published online recently by the journal Nano Letters. The paper also will appear in a forthcoming issue of the journal's print edition. The U.S. Air Force Office of Scientific Research funded this study.
The detectivity of an infrared photodetector is determined by how much signal it receives, divided by the noise it receives. The current state-of-the art in photodetectors is based on mercury-cadmium-telluride (MCT) technology, which has a strong signal but faces several challenges including long exposure times for low-signal imaging. Lin said his new study creates a roadmap for developing quantum dot infrared photodetectors (QDIP) that can outperform MCTs, and bridge the innovation gap that has stunted the progress of infrared technology over the past decade.
The surface plasmon QDIPs are long, flat structures with countless tiny holes on the surface. The solid surface of the structure that Lin built is covered with about 50 nanometers -- or 50 billionths of a meter -- of gold. Each hole is about 1.6 microns -- or 1.6 millionths of a meter -- in diameter, and 1 micron deep. The holes are filled with quantum dots, which are nanoscale crystals with unique optical and semiconductor properties.
The interesting properties of the QDIP's gold surface help to focus incoming light directly into the microscale holes and effectively concentrate that light in the pool of quantum dots. This concentration strengthens the interaction between the trapped light and the quantum dots, and in turn strengthens the dots' ability to convert those photons into electrons. The end result is that Lin's device creates an electric field up to 400 percent stronger than the raw energy that enters the QDIP.
The effect is similar to what would result from covering each tiny hole on the QDIP with a lens, but without the extra weight, and minus the hassle and cost of installing and calibrating millions of microscopic lenses, Lin said.
Lin's team also demonstrated in the journal paper that the nanoscale layer of gold on the QDIP does not add any noise or negatively impact the device's response time. Lin plans to continue honing this new technology and use gold to boost the QDIP's detectivity, by both widening the diameter of the surface holes and more effective placement of the quantum dots.
"I think that, within a few years, we will be able to create a gold-based QDIP device with a 20-fold enhancement in signal from what we have today," Lin said. "It's a very reasonable goal, and could open up a whole new range of applications from better night-vision goggles for soldiers to more accurate medical imaging devices."
Co-authors of the paper are Rensselaer Senior Research Scientist James Bur, graduate student Chun-Chieh Chang, and Research Associate Yong-Sung Kim; Yagya D. Sharma, Rajeev V. Shenoi, and Sanjay Krishna of the Center for High Technology Materials at the University of New Mexico, Albuquerque; and Danhong Huang of the Space Vehicles Directorate at the Air Force Research Laboratory, Kirtland Air Force Base.
source:sciencedaily.com

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Stem Cells: In Search of a Master Controller

With thousands of scientists across the globe searching for ways to use adult stem cells to fight disease, there's a growing emphasis on finding the "master regulators" that guide the differentiation of stem cells. New research from Rice University and the University of Cambridge suggests that a closely connected trio of regulatory proteins fulfills that role in hematopoietic stem cells (HSCs), the self-renewing cells the body uses to make new blood cells.
The results appear in the online journal PLoS Computational Biology. Working with experimentalists at Cambridge, Rice bioengineers Oleg Igoshin and Jatin Narula created a computer model that accurately describes the observed behavior of the three regulatory proteins that are collectively known as the "Scl-Gata2-Fli1 triad."
"We don't yet have the experimental verification that this is the master-level regulator for HSCs, but based on our model, we can say that it has all the properties that we would expect to find in a master-level regulator," said Igoshin, an assistant professor in bioengineering at Rice.
All plants and animals have stem cells, a constantly replenished feedstock of unspecialized progenitor cells that have the ability to become any of several specialized types of cell. An HSC is a type of adult stem cell that forms new blood cells. In a healthy human adult, HSCs are used to form about 100 billion new white and red blood cells each day.
But HSCs also need to be able to self-renew, or make the additional stem cells needed to replenish the body's supply. Self-renewal becomes particularly important after significant blood loss through injury or when patients receive bone marrow transplants.
Igoshin and Narula, a graduate student, worked with experimentalists Aileen Smith and Berthold Gottgens at the Cambridge Institute for Medical Research to create a mathematical model that accurately describes the complex interplay among the three HSC regulatory proteins in the Scl-Gata2-Fli1 triad. Based on previous studies at Cambridge, it was obvious that the triad plays an essential role in HSC development. In creating their computer model, Igoshin and Narula were able to quantify the way the three interact and thus shed light on their combined role in regulating HSCs.
To qualify as a master regulator, the triad needed to meet two criteria. It had to act as a "bistable" switch, a one-way button that toggled from the "replenish HSC" state to the "differentiate" state. Second, it needed to ignore extraneous signals and throw the switch only when a signal persisted.
"In examining the results from the model, we found the triad did have the characteristics of a master regulator," Narula said. "The first time it's switched on, all the cells stay on. It also handles deactivation in a controlled manner, so that some cells differentiate and get deactivated and others don't. Finally, it has the ability to discern whether or not the level of signal is present only for a short burst or for a significantly long time."
Igoshin said additional experimental research is needed to verify the computer model's prediction that the Scl-Gata2-Fli1 triad is the master-level controller for HSCs. However, he said the prediction is particularly intriguing in light of previous studies that suggest other similarly wired regulatory triads are key players in other types of stem cells, including embryonic stem cells.
"It's possible that this triad motif is reused elsewhere," Igoshin said. "The proteins could be different in each case, but the motif structure of their interconnections is common and may be repeated elsewhere in nature. That's one of the most intriguing aspects of this research."
The research was supported by Rice University, the National Science Foundation, and Leukemia and Lymphoma Research UK.
source:sciencedaily.com

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Stem Cells: In Search of a Master Controller

With thousands of scientists across the globe searching for ways to use adult stem cells to fight disease, there's a growing emphasis on finding the "master regulators" that guide the differentiation of stem cells. New research from Rice University and the University of Cambridge suggests that a closely connected trio of regulatory proteins fulfills that role in hematopoietic stem cells (HSCs), the self-renewing cells the body uses to make new blood cells.
The results appear in the online journal PLoS Computational Biology. Working with experimentalists at Cambridge, Rice bioengineers Oleg Igoshin and Jatin Narula created a computer model that accurately describes the observed behavior of the three regulatory proteins that are collectively known as the "Scl-Gata2-Fli1 triad."
"We don't yet have the experimental verification that this is the master-level regulator for HSCs, but based on our model, we can say that it has all the properties that we would expect to find in a master-level regulator," said Igoshin, an assistant professor in bioengineering at Rice.
All plants and animals have stem cells, a constantly replenished feedstock of unspecialized progenitor cells that have the ability to become any of several specialized types of cell. An HSC is a type of adult stem cell that forms new blood cells. In a healthy human adult, HSCs are used to form about 100 billion new white and red blood cells each day.
But HSCs also need to be able to self-renew, or make the additional stem cells needed to replenish the body's supply. Self-renewal becomes particularly important after significant blood loss through injury or when patients receive bone marrow transplants.
Igoshin and Narula, a graduate student, worked with experimentalists Aileen Smith and Berthold Gottgens at the Cambridge Institute for Medical Research to create a mathematical model that accurately describes the complex interplay among the three HSC regulatory proteins in the Scl-Gata2-Fli1 triad. Based on previous studies at Cambridge, it was obvious that the triad plays an essential role in HSC development. In creating their computer model, Igoshin and Narula were able to quantify the way the three interact and thus shed light on their combined role in regulating HSCs.
To qualify as a master regulator, the triad needed to meet two criteria. It had to act as a "bistable" switch, a one-way button that toggled from the "replenish HSC" state to the "differentiate" state. Second, it needed to ignore extraneous signals and throw the switch only when a signal persisted.
"In examining the results from the model, we found the triad did have the characteristics of a master regulator," Narula said. "The first time it's switched on, all the cells stay on. It also handles deactivation in a controlled manner, so that some cells differentiate and get deactivated and others don't. Finally, it has the ability to discern whether or not the level of signal is present only for a short burst or for a significantly long time."
Igoshin said additional experimental research is needed to verify the computer model's prediction that the Scl-Gata2-Fli1 triad is the master-level controller for HSCs. However, he said the prediction is particularly intriguing in light of previous studies that suggest other similarly wired regulatory triads are key players in other types of stem cells, including embryonic stem cells.
"It's possible that this triad motif is reused elsewhere," Igoshin said. "The proteins could be different in each case, but the motif structure of their interconnections is common and may be repeated elsewhere in nature. That's one of the most intriguing aspects of this research."
The research was supported by Rice University, the National Science Foundation, and Leukemia and Lymphoma Research UK.
source:sciencedaily.com

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Aiming to Cure Deafness, Scientists First to Create Functional Inner-Ear Cells

Deep inside the ear, specialized cells called hair cells detect vibrations in the air and translate them into sound. Ten years ago, Stefan Heller, PhD, professor of otolaryngology at the Stanford University School of Medicine, came up with the idea that if you could create these cells in the laboratory from stem cells, it would go a long way toward helping scientists understand the molecular basis of hearing in order to develop better treatments for deafness.
After years of lab work, researchers in Heller's lab will report in the May 14 issue of Cell that they have found a way to develop mouse cells that look and act just like the animal's inner-ear hair cells -- the linchpin to our sense of hearing and balance -- in a petri dish.
If they can further perfect the recipe to generate hair cells in the millions, it could lead to significant scientific and clinical advances along the path to curing deafness in the future, they said.
"This gives us real hope that there might be some kind of therapy for regenerating hair cells," said David Corey, PhD, professor of neurobiology at Harvard University who was not involved in the study. "It could take a decade or more, but it's a possibility."
Using both embryonic stem cells from mice as well as reprogrammed mouse fibroblasts (a type of relatively undifferentiated cell found in many parts of the body), the researchers present a step-by-step guide on how to coax these cells into the sensory cells that normally reside in the inner ear.
"We knew it was really working when we saw them in the electron microscope," Heller said. "They really looked like they were more or less taken out of the ear."
Humans are born with 30,000 cochlear and vestibular hair cells per ear. (By contrast, one retina harbors about 120 million photoreceptors.) When a significant number of these cells are lost or damaged, hearing loss occurs. The major reason for hearing loss and certain balance disorders is that -- unlike other species such as birds -- humans and other mammals are unable to spontaneously regenerate these hearing cells.
As the population has aged and noise pollution has grown more severe, health experts now estimate that one in three adults over the age of 65 has developed a handicapping hearing loss due to the destruction of these limited number of hair cells.
One of the roadblocks to understanding the molecular basis of hearing is the paucity of hair cells available for study, Heller said. While researchers will ultimately need human hair cells, the mouse version is a good model for the initial phases of experimentation, he said. In addition to using mouse embryonic stem cells, the researchers used fibroblasts that had been reprogrammed to behave like stem cells: These are known as induced pluripotent stem cells, or iPS cells.
"Our study offers a protocol to generate millions of functional hair cells from a renewable source," Heller said. "We can now generate these cells and don't have to go through dozens of mice for a single experiment. This allows us to do molecular studies with much higher efficiency."
The study details how the researchers succeeded in coaxing the mouse embryonic stem cells and the iPS cells through different phases of development that occur in the womb. According to lead author Kazuo Oshima, MD, PhD, a research instructor at Stanford who works in Heller's lab, they started by turning the stem and iPS cells into the type of cells that form a young embryo's ectoderm -- the embryo's outer layer of cells that eventually differentiate into many tissues and structures, such as skin and nerve cells. Next they used specific growth factors to transform them into "otic-progenitor" cells (otic means ear). And after that, they varied the chemical soup in the dish, so that the cells clustered in a manner similar to hair cells and developed stereociliary bundles, which are also characteristic of hair cells.
"We looked at how the ear develops in an embryo, at the developmental steps, and mimicked these steps in a culture dish," Heller said.
Hair cells in the inner ear contain tiny clumps of hair-like projections, known as stereocilia. Sound vibrations cause the stereocilia to bend slightly, causing mechanical vibrations that are then converted into an electrochemical signal that the brain interprets as sound.
The cells in the petri dish, under close examination, had this same structure.
"These cells have a very intriguing structure," Heller said. "They look like they have hair tufts of stereocilia."
More importantly, further study showed that the cells also responded to mechanical stimulation by producing currents just like hair cells. Using a probe, researchers stimulated the bundles and recorded the currents that were evoked. Co-author Anthony Ricci, PhD, associate professor of otolaryngology, was responsible for this step of the work.
Heller, a leader in stem-cell based research on the inner ear, has recently been focused on two paths for possible cures for deafness: drug therapy -- which could be as simple as an application of ear drops -- and stem cell transplantation into the inner ear.
Both paths could be further advanced by the ability to develop hair-cell-like cells, he said. "We could now test thousands of drugs in a culture dish," he explained. "It is impossible to achieve such a scale in animals. Within a decade or so we could reap the benefits of this type of screening."
The lab's research into the regeneration of hair cells for transplantation into the inner ear to cure deafness will also continue.
"We made hair-cell-like cells in a petri dish," said Oshima. "This is an important step toward development of future therapies."
The study was funded by grants from the National Institute of Health, the California Institute for Regenerative Medicine and by a Neuroscience of Brain Disorders Award from the McKnight Endowment Fund for Neuroscience.
Other Stanford co-authors include postdoctoral scholars Kunyoo Shin, PhD; Mark Diensthuber, MD; and Anthony Peng, PhD.

source:sciencedaily.com

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Building Organs Block by Block: Tissue Engineers Create a New Way to Assemble Artificial Tissues, Using 'Biological Legos'

Tissue engineering has long held promise for building new organs to replace damaged livers, blood vessels and other body parts. However, one major obstacle is getting cells grown in a lab dish to form 3-D shapes instead of flat layers.
Researchers at the MIT-Harvard Division of Health Sciences and Technology (HST) have come up with a new way to overcome that challenge, by encapsulating living cells in cubes and arranging them into 3-D structures, just as a child would construct buildings out of blocks.
The new technique, dubbed "micromasonry," employs a gel-like material that acts like concrete, binding the cell "bricks" together as it hardens. Ali Khademhosseini, assistant professor of HST, and former HST postdoctoral associate Javier Gomez Fernandez describe the work in a paper published online in the journal Advanced Materials.
The tiny cell bricks hold potential for building artificial tissue or other types of medical devices, says Jennifer Elisseeff, associate professor of biomedical engineering at Johns Hopkins University, who was not involved in the research. "They're very elegant and have a lot of flexibility in how you grow them," she says. "It's very creative."
Controlled structure
To obtain single cells for tissue engineering, researchers have to first break tissue apart, using enzymes that digest the extracellular material that normally holds cells together. However, once the cells are free, it's difficult to assemble them into structures that mimic natural tissue microarchitecture.
Some scientists have successfully built simple tissues such as skin, cartilage or bladder on biodegradable foam scaffolds. "That works, but it often lacks a controlled microarchitecture," says Khademhosseini, who is also an assistant professor at Brigham and Women's Hospital. "You don't get tissues with the same complexity as normal tissues."
The HST researchers built their "biological Legos" by encapsulating cells within a polymer called polyethylene glycol (PEG), which has many medical uses. Their version of the polymer is a liquid that becomes a gel when illuminated, so when the PEG-coated cells are exposed to light, the polymer hardens and encases the cells in cubes with side lengths ranging from 100 to 500 millionths of a meter.
Once the cells are in cube form, they can be arranged in specific shapes using templates made of PDMS, a silicon-based polymer used in many medical devices. Both template and cell cubes are coated again with the PEG polymer, which acts as a glue that holds the cubes together as they pack themselves tightly onto the scaffold surface.
After the cubes are arranged properly, they are illuminated again, and the liquid holding the cubes together solidifies. When the template is removed, the cubes hold their new structure.
Gomez Fernandez and Khademhosseini used this method to build tubes that could function as capillaries, potentially helping to overcome one of the most persistent problems with engineered organs -- lack of an immediate blood supply. "If you build an organ, but you can't provide nutrients, it is going to die," says Gomez Fernandez, now a postdoctoral fellow at Harvard. They hope their work could also lead to a new way to make artificial liver or cardiac tissue.
Other researchers have developed a technique called organ printing to create complex 3-D tissues, but that process requires a robotic machine that is not in widespread use. The new technique does not require any special equipment. "You can reproduce this in any lab," says Gomez Fernandez. "It's very simple."
To get to the point where these engineered tissues could become clinically useful, "the short-term next step is really looking at different cell types and the viability of tissue growth," says Elisseeff. The researchers are now doing that, and they are also exploring the use of different polymers that could replace PEG and offer more control over cell placement.
source:sciencedaily.com

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Hangover' Molecule in Brain Found

Scientists have discovered the molecule in the brain that leads to hangovers. The neuropeptide, a brain-signalling molecule, is believed to cause the body to experience withdrawal symptoms as the brain tries to adapt to different intoxication levels.
The neuroscientists from the University of Southampton's School of Biological Sciences studied the simple brains of C. elegans worms, which have a makeup similar enough to the human brain when intoxicated or dependent on alcohol.
What they found was striking.
Basically, when a worm brain (similarly, a human brain) is exposed to drinking over a long period of time, it becomes accustomed to certain intoxication levels. The brain experiences a series of withdrawal symptoms when the drinking stops.
Typically, these hangover symptoms can include anxiety and agitation, even seizures.
"This research showed the worms displaying effects of the withdrawal of alcohol and enables us to define how alcohol affects signalling in nerve circuits which leads to changes in behavior," said professor Lindy Holden-Dye, a neuroscientist of the University's School of Biological Sciences and member of Southampton Neurosciences Group (SoNG), who led the study.
When the worms were given small doses of alcohol during their withdrawal their irritable behaviors eased. Unfortunately, this approach to combating a hangover also increases the chances for alcohol dependency.
Alcohol dependency and abuse are among the most common mental disorders. This study, published in PLoS One journal, showed hope for an average 13 percent of the adult population that suffers from these disorders.
This study identifies where and also how alcohol consumption affect the nervous system and the brain in a way that hasn’t been revealed until now.
"This is leading to new ideas for the treatment of alcoholism," Holden-Dye said. "Our study provides a very effective experimental system to tackle this problem."

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3-D 'Occupational Therapy' for Children: Virtual Muscle Machine for Kids With Disabilities

It was her love of ballet that led her to work with children who have motor disabilities. The retired dancer, now an occupational therapist, is pioneering a new "virtual" method to analyze movement patterns in children ― and more effectively treat those with debilitating motor disorders.Dr. Dido Green of Tel Aviv University's Department of Occupational Therapy in the School of Health Professionals is using a "virtual tabletop" called the ELEMENTS SYSTEM, developed by her partners at Australia's Royal Melbourne Institute of Technology, to "move" kids with disabilities and provide home-based treatments using virtual reality tools. Combining new three-dimensional exercises with two-dimensional graphical movement games already programmed into the tabletop (which resembles an early video game), she reports not only success but also enthusiasm among her young patients.
"I've been working with children with movement disorders for the last 20 years," says Dr. Green. "By the time I meet these children, they're sick of us. They've been 'over-therapied,' and it's difficult to get them to practice their exercises and prescribed treatment regimes."
Fun for kids from three to fifteen

"The virtual tabletop appealed to children as young as three and as old as 15," Dr. Green reports. "The movement-oriented games allowed them to 'make music' and reach targets in ways that are normally neither comfortable nor fun in the therapeutic setting," she explains.
Dr. Green determined that children with partial paralysis and motor dysfunction resulting from disorders such as cerebral palsy may be helped by giving them a new interface to explore. Building upon earlier research she conducted at the Evelina Children's Hospital in London, Dr. Green found that virtual reality applications enhance the skill sets learned by her patients.
Coupled with new technology involving 3D Movement Analysis, a technique she is now integrating into research at Tel Aviv University, Dr. Green hopes to develop this virtual tabletop-type game into new and effective therapy treatment regimes.
"Traditional approaches are labor-intensive and their results limited," Dr. Green says. "Our research aims to create a complete system for therapist, parent and child. It could bring daily treatments into the home and provides therapists with a complete solution to track and analyze improvements or setbacks in the most accurate way to date."
From the virtual to the real world

In children who attended sessions with her interface for three days a week over a period of about one month, Dr. Green found some impressive results. One child with a paralyzed hand was able to perform more complicated movements, culminating in a "eureka!" moment when she opened a door for the first time in her life. The girl was also able to gain control over some motor movements essential for basic life tasks, such as buttoning sweaters, opening doors, or going to the washroom. These are skills some children never develop with current therapy regimes.
In the near future, Dr. Green hopes to develop the technique for remote rehabilitation, enabling children to practice movements at home with parental supervision. Therapists located elsewhere could "log in" with a webcam and computer to coach the students or monitor their progress.
The researcher also plans to analyze brain function using trans-cranial magnetic brain stimulation. Currently, brain function relating to motor activities is analyzed with magnetic resonance imaging (MRI). But many children are too impatient to sit in an MRI machine, so clinicians need a more accurate means of analyzing movement in children with disabilities to develop individualized therapy regimes.

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IBM Research Creates World's Smallest 3D Map; Brings Low-Cost, Ease of Use to Creation of Nanoscale Objects

IBM scientists have created a 3D map of the earth so small that 1,000 of them could fit on one grain of salt.* The scientists accomplished this through a new, breakthrough technique that uses a tiny, silicon tip with a sharp apex -- 100,000 times smaller than a sharpened pencil -- to create patterns and structures as small as 15 nanometers at greatly reduced cost and complexity. This patterning technique opens new prospects for developing nanosized objects in fields such as electronics, future chip technology, medicine, life sciences, and optoelectronics.
To demonstrate the technique's unique capability, the team created several 3D and 2D patterns, using different materials for each one as reported in the scientific journals Science and Advanced Materials:

• A 25-nanometer-high 3D replica of the Matterhorn, a famous Alpine mountain that soars 4,478 m (14,692 ft) high, was created in molecular glass, representing a scale of 1:5 billion.**
• Complete 3D map of the world measuring only 22 by 11 micrometers was "written" on a polymer. At this size, 1,000 world maps could fit on a grain of salt. In the relief, one thousand meters of altitude correspond to roughly eight nanometers (nm). It is composed of 500,000 pixels, each measuring 20 nm2, and was created in only 2 minutes and 23 seconds.
• 2D nano-sized IBM logo was etched 400-nm-deep into silicon, demonstrating the viability of the technique for typical nanofabrication applications.
• 2D high-resolution 15-nm dense line patterning.

The science behind the technique
The core component of the new technique, which was developed by a team of IBM scientists, is a tiny, very sharp silicon tip measuring 500 nanometers in length and only a few nanometers at its apex.
"Advances in nanotechnology are intimately linked to the existence of high-quality methods and tools for producing nanoscale patterns and objects on surfaces," explains physicist Dr. Armin Knoll of IBM Research -- Zurich. "With its broad functionality and unique 3D patterning capability, this nanotip-based patterning methodology is a powerful tool for generating very small structures."
The tip, similar to the kind used in atomic force microscopes, is attached to a bendable cantilever that controllably scans the surface of the substrate material with the accuracy of one nanometer -- a millionth of a millimeter. By applying heat and force, the nano-sized tip can remove substrate material based on predefined patterns, thus operating like a "nanomilling" machine with ultra-high precision.
Similar to using a milling machine, more material can be removed to create complex 3D structures with nanometer precision by modulating the force or by readdressing individual spots. To create the 3D replica of the Matterhorn, for example, 120 individual layers of material were successively removed from the molecular glass substrate.
Comparing to e-beam lithography
The new IBM technique achieves resolutions as high as 15 nanometers -- with a potential of going even smaller. Using existing methods such as e-beam lithography,*** it is becoming increasingly challenging to fabricate patterns at resolutions below 30 nanometers, where the technical limitations of that method are reached.
What's more, compared to expensive e-beam-lithography tools that require several processing steps and equipment that can easily fill a laboratory, the tool created by IBM scientists -- which can sit on a tabletop -- promises improved and extended capabilities at very high resolutions, but at one-fifth to one tenth of the cost and with far less complexity.
Yet another advantage of the nanotip-based technique is the ability to assess the pattern directly by using the same tip to create an image of the written structures, as the IBM scientists demonstrated in their experiments.
Potential applications range from the fast prototyping of nano-sized devices for future computer chips to the production of well defined micron-sized optical elements like aspheric lenses and lens-arrays for optoelectronics and on-chip optical communication.
Materials breakthrough
In the two publications, the scientists describe their novel 3D-nanopatterning methodology for two very distinct and promising types of substrate materials: a polymer called polyphthalaldehyde and a molecular glass similar to substrate materials used in conventional nanofabrication techniques, so-called resists. Identifying these two materials was a key factor for the breakthrough performance and reliability of the technique.
In their search for suitable and efficient substrate materials, the scientists concentrated on organic materials that could be used as resists, thereby following the same philosophy as used for today's semiconductor technology, which is important for further integration.
"The material was a 'make it or break it' issue," explains Jim Hedrick, scientist at IBM Research -- Almaden. "We had to find and synthesize materials which form mechanically tough glasses and yet can be easily thermally decomposed into non-reactive volatile units."
The molecular glass that was used in the Matterhorn experiment consists of snow-flake-like molecules, measuring about one nanometer and having an almost spherical shape. At a tip temperature above 330 degrees C (626 degrees F), the hydrogen bonds that hold the molecules together break, allowing the molecular parts to become mobile and to escape from the surface. A particular strength of the material is that the patterned molecular glass can be transferred by means of conventional etching techniques to, for example, silicon, which is common in the semiconductor industry. Molecular glass was first proposed in the late 1990s by Mitsuru Ueda of Yamagata University, Japan, for use as high-resolution photoresists and was thereafter developed by Chris Ober of Cornell University.
The nanosized 3D world map was created in a polymer called polyphthalaldehyde, a polymer originally developed by IBM Fellow Hiroshi Ito in the 1980s. Exposed to substantially elevated temperatures, the components of this chain-like organic molecule unzip and fall into volatile pieces. A self-amplified reaction causes the molecule to decompose and then accelerates the entire patterning process by being even faster than the mechanical motion of the tip.
IBM and nanotechnology
IBM has been a pioneer in nanoscience and nanotechnology ever since the development of the scanning tunneling microscope (STM) in 1981 by IBM Fellows Gerd Binnig and Heinrich Rohrer. For this invention, which made it possible to image individual atoms and later on to manipulate them, Binnig and Rohrer were awarded the Nobel Prize in Physics in 1986. The atomic force microscope, an offspring of the STM, was invented by Binnig in 1986. The STM is widely regarded as the instrument that opened the door to the nanoworld.
In fact it was 20 years ago this month that IBM Fellow Don Eigler reported the first controlled movement of individual atoms, famously using a scanning tunneling microscope to spell out the letters "I B M" with 35 xenon atoms.
These historic breakthroughs laid a solid foundation for IBM's continued research in nanoscience.
Contributing to this rich history for years to come, a new world-class collaborative nanoscale research lab is currently under construction on the campus of IBM Research -- Zurich. This state-of-the-art nanotech center, which will open next year, is part of a strategic partnership in nanotechnology between IBM Research and ETH Zurich, one of Europe's leading technical universities.
Notes
* Taking 0.3 mm as the average size of a grain of salt, 1000 maps would span the diameter.
** One nanometer in the vertical pattern corresponds to 57 altitude meters.
*** This method selectively exposes a surface to a beam of electrons, thereby creating patterns in a film, called a resist. The resist serves as a template for transferring the pattern to various materials, for example silicon, by means of etching. It is one of the most versatile and mature methods used today, but it is very costly and complex.

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Nanodots Breakthrough May Lead to 'a Library on One Chip'

A researcher at North Carolina State University has developed a computer chip that can store an unprecedented amount of data -- enough to hold an entire library's worth of information on a single chip. The new chip stems from a breakthrough in the use of nanodots, or nanoscale magnets, and represents a significant advance in computer-memory technology.
"We have created magnetic nanodots that store one bit of information on each nanodot, allowing us to store over one billion pages of information in a chip that is one square inch," says Dr. Jay Narayan, the John C. Fan Distinguished Chair Professor of Materials Science and Engineering at NC State and author of the research.
The breakthrough is that these nanodots are made of single, defect-free crystals, creating magnetic sensors that are integrated directly into a silicon electronic chip. These nanodots, which can be made uniformly as small as six nanometers in diameter, are all precisely oriented in the same way -- allowing programmers to reliably read and write data to the chips.
The chips themselves can be manufactured cost-effectively, but the next step is to develop magnetic packaging that will enable users to take advantage of the chips -- using something, such as laser technology, that can effectively interact with the nanodots.
The research, which was funded by the National Science Foundation, was presented as an invited talk April 7 at the 2011 Materials Research Society Spring Meeting in San Francisco.
NC State's Department of Materials Science and Engineering is part of the university's College of Engineering.

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Informatics Moves Into Nanomedicine

According to what researchers from Facultad de Informática and other institutions have advanced in an article just published in the medical journal Pediatric Research (Vol.6, No. 5, 2010), nanoparticles are poised to play a key role in medical research in the coming decades, when nanomedicine will become part of medical practice. The article discusses the huge impact that informatics will have in the immediate future on vanguard medicine and innovation in a field, translational nanoinformatics, that is set to translate advances in basic nanomedical research into clinical applications of growing importance.
The article, the first review of this new discipline published in a high impact journal, analyses the latest research in nanoinformatics, including its applications to paediatrics, and also examines the discipline's scientific foundations, and research and projects in this field, including their potential applications and problems.
The authors, who are partners of the European ACTION Grid project, coordinated by the UPM, explain that nanoinformatics uses informatics techniques to process and analyse the information on the physico-chemical structure and properties of nanoparticles, their environments and applications, and can therefore be said to be a discipline that acts as a catalyst and speeds up research into nanomedicine.
Expanding nanomedicine
They also point out that the development of nanomedicine is still in its infancy, although some nanoparticles and nanodevices have already been approved or are about to be approved by the United States Food and Drug Administration, including, for example, superparamagnetic nanoparticles to detect metastases in some types of cancer or new devices that combine microfluids or nanosensors to detect tumours.
These applications of nanomaterials open up new prospects for personalized medicine, the authors add, indicating that classical clinical studies need to be redesigned to adapt to the advances taking place in genomics, proteomics and pharmacogenetics. "The introduction of nanoparticles that can target different molecules or groups of atoms with high precision can significantly advance the personalization of clinical procedures," the article says.
The authors place special emphasis on the paediatric applications of nanomedicine that can effectively contribute to the treatment of childhood disorders like asthma, cystic fibrosis, respiratory infections or lung cancer.
They also refer to the possible secondary effects of such therapies, stating that the problems detected in this respect are often related to the dose and the mechanism of action of a nanoparticle therapy rather than the properties of the nanoparticles themselves.
Importance of informatics
The authors also relate that their previous research focused on the integration of genomics with medical information systems, a process that proved to be more difficult than originally anticipated, but raises major challenges for personalized medicine. From the computational viewpoint, the integration of data at the nano level poses even greater difficulties parallel to those faced at higher scales by bioinformatics and medical informatics.
Both the European Commission and the United States Government are collaborating on new projects with a view to the development of an inventory of nanoparticles that includes techniques for modelling nanoparticle properties, as well as nanoparticle interaction with biological systems.
Along similar lines, the authors explain that they have developed a new approach for automatically creating an index of bioinformatics resources with information automatically extracted from research article abstracts using text mining techniques.
They note in this respect that ontologies have demonstrated that they are a more than satisfactory support for a computational approach to the systematization of knowledge, particularly in biomedicine, and are likely to play an equivalent role in structuring information in nanomedicine. In fact, ontologies have played an important role in the development of nanoportals, like caNanoLab, a specialized web site for nanoparticle cancer treatment.
Integration of biomedical data at the nano level
Even though many current nanoinformatics applications look very similar to comparable systems already built in medical and bioinformatics, a profound change is actually afoot in informatics, and researchers are coming up with new approaches for integrating data and knowledge at the nano level.
The possibility of biomolecular devices acting not only in vitro but also in vivo within diseased human organisms is also opening up new prospects, where biomolecular automata could even intervene to intelligently deliver drugs to the diseased regions of the human body just where they are needed.
In this respect, the authors note that research on a "Doctor in a Cell" is already in progress. This is a genetically modified cell that can operate in a human body. It contains a biological computer that can process and analyse external biological signals, emit a diagnosis and deliver the desired molecular therapeutic signal to treat the patient.
The conclusion is that informatics will play a crucial role in the development and implementation of nanoparticles and nanodevices and their application in both the laboratory and living organisms. The authors add that informaticians will have a decisive impact on nanomedicine by creating new simulation models and methods.
All this will change not only the training of physicians and informaticians in the near future, but will also modify current healthcare models.
The article is authored by Víctor Maojo and Alfonso Rodríguez Patón, both from the Artificial Intelligence Department at the UPM's Facultad de Informática, Fernando Martín Sánchez, from the Department of Medical Bioinformatics at the Instituto Nacional de Salud Carlos III, Casimir Kulikowski, from the Department of Computational Science at the Rutgers State University in New Jersey, and Martin Fritts, from the National Cancer Institute at Frederick (USA).

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The Next Big Thing Is Small: Nanotechnology Could Lead To Radical Improvements For Space Exploration

When it comes to taking the next "giant leap" in space exploration, NASA is thinking small -- really small.
In laboratories around the country, NASA is supporting the burgeoning science of nanotechnology. The basic idea is to learn to deal with matter at the atomic scale -- to be able to control individual atoms and molecules well enough to design molecule-size machines, advanced electronics and "smart" materials.
If visionaries are right, nanotechnology could lead to robots you can hold on your fingertip, self-healing spacesuits, space elevators and other fantastic devices. Some of these things may take 20+ years to fully develop; others are taking shape in the laboratory today.
Thinking Small
Simply making things smaller has its advantages. Imagine, for example, if the Mars rovers Spirit and Opportunity could have been made as small as a beetle, and could scurry over rocks and gravel as a beetle can, sampling minerals and searching for clues to the history of water on Mars. Hundreds or thousands of these diminutive robots could have been sent in the same capsules that carried the two desk-size rovers, enabling scientists to explore much more of the planet's surface -- and increasing the odds of stumbling across a fossilized Martian bacterium!
But nanotech is about more than just shrinking things. When scientists can deliberately order and structure matter at the molecular level, amazing new properties sometimes emerge.
An excellent example is that darling of the nanotech world, the carbon nanotube. Carbon occurs naturally as graphite -- the soft, black material often used in pencil leads -- and as diamond. The only difference between the two is the arrangement of the carbon atoms. When scientists arrange the same carbon atoms into a "chicken wire" pattern and roll them up into miniscule tubes only 10 atoms across, the resulting "nanotubes" acquire some rather extraordinary traits. Nanotubes:
* have 100 times the tensile strength of steel, but only 1/6 the weight;
* are 40 times stronger than graphite fibers;
* conduct electricity better than copper;
* can be either conductors or semiconductors (like computer chips), depending on the arrangement of atoms;
* and are excellent conductors of heat.
Much of current nanotechnology research worldwide focuses on these nanotubes. Scientists have proposed using them for a wide range of applications: in the high-strength, low-weight cable needed for a space elevator; as molecular wires for nano-scale electronics; embedded in microprocessors to help siphon off heat; and as tiny rods and gears in nano-scale machines, just to name a few.
Nanotubes figure prominently in research being done at the NASA Ames Center for Nanotechnology (CNT). The center was established in 1997 and now employs about 50 full-time researchers.
"[We] try to focus on technologies that could yield useable products within a few years to a decade," says CNT director Meyya Meyyappan. "For example, we're looking at how nano-materials could be used for advanced life support, DNA sequencers, ultra-powerful computers, and tiny sensors for chemicals or even sensors for cancer."
A chemical sensor they developed using nanotubes is scheduled to fly a demonstration mission into space aboard a Navy rocket next year. This tiny sensor can detect as little as a few parts per billion of specific chemicals--like toxic gases--making it useful for both space exploration and homeland defense. CNT has also developed a way to use nanotubes to cool the microprocessors in personal computers, a major challenge as CPUs get more and more powerful. This cooling technology has been licensed to a Santa Clara, California, start-up called Nanoconduction, and Intel has even expressed interest, Meyyappan says.
Designing the future
If these near-term uses of nanotechnology seem impressive, the long-term possibilities are truly mind-boggling.
The NASA Institute for Advanced Concepts (NIAC), an independent, NASA-funded organization located in Atlanta, Georgia, was created to promote forward-looking research on radical space technologies that will take 10 to 40 years to come to fruition.
For example, one recent NIAC grant funded a feasibility study of nanoscale manufacturing--in other words, using vast numbers of microscopic molecular machines to produce any desired object by assembling it atom by atom!
That NIAC grant was awarded to Chris Phoenix of the Center for Responsible Nanotechnology.
In his 112 page report, Phoenix explains that such a "nanofactory" could produce, say, spacecraft parts with atomic precision, meaning that every atom within the object is placed exactly where it belongs. The resulting part would be extremely strong, and its shape could be within a single atom's width of the ideal design. Ultra-smooth surfaces would need no polishing or lubrication, and would suffer virtually no "wear and tear" over time. Such high precision and reliability of spacecraft parts are paramount when the lives of astronauts are at stake.
Although Phoenix sketched out some design ideas for a desktop nanofactory in his report, he acknowledges that -- short of a big-budget "Nanhatten Project," as he calls it -- a working nanofactory is at least a decade away, and possibly much longer.
Taking a cue from biology, Constantinos Mavroidis, director of the Computational Bionanorobotics Laboratory at Northeastern University in Boston, is exploring an alternative approach to nanotech: Rather than starting from scratch, the concepts in Mavroidis's NIAC-funded study employ pre-existing, functional molecular "machines" that can be found in all living cells: DNA molecules, proteins, enzymes, etc.
Shaped by evolution over millions of years, these biological molecules are already very adept at manipulating matter at the molecular scale -- which is why a plant can combine air, water, and dirt and produce a juicy red strawberry, and a person's body can convert last night's potato dinner into today's new red blood cells. The rearranging of atoms that makes these feats possible is performed by hundreds of specialized enzymes and proteins, and DNA stores the code for making them.
Making use of these "pre-made" molecular machines -- or using them as starting points for new designs -- is a popular approach to nanotechnology called "bio-nanotech."
"Why reinvent the wheel?" Mavroidis says. "Nature has given us all this great, highly refined nanotechnology inside of living things, so why not use it -- and try to learn something from it?"
The specific uses of bio-nanotech that Mavroidis proposes in his study are very futuristic. One idea involves draping a kind of "spider's web" of hair-thin tubes packed with bio-nanotech sensors across dozens of miles of terrain, as a way to map the environment of some alien planet in great detail. Another concept he proposes is a "second skin" for astronauts to wear under their spacesuits that would use bio-nanotech to sense and respond to radiation penetrating the suit, and to quickly seal over any cuts or punctures.
Futuristic? Certainly. Possible? Maybe. Mavroidis admits that such technologies are probably decades away, and that technology so far in the future will probably be very different from what we imagine now. Still, he says he believes it's important to start thinking now about what nanotechnology might make possible many years down the road.
Considering that life itself is, in a sense, the ultimate example of nanotech, the possibilities are exciting indeed.

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New Therapy for Cocaine Toxicity: Enzyme Break Downs Cocaine Into Inactive Products Nearly 1,000 Times Faster Than Human Body Does

Cocaine toxicity due to drug overdose results in more than half a million emergency room visits annually. Despite these alarming statistics, there is no Food and Drug Administration-approved pharmacotherapy specifically designed to treat cocaine toxicity. Emergency medical personnel are limited to treating only the immediate life-threatening symptoms of patients, while toxic levels of cocaine and its metabolic break-down products persist and continue to damage the cardiovascular system, liver and brain.
However, researchers have now developed and tested a modified enzyme that can break down cocaine into inactive products nearly 1,000 times faster than the human body does regularly. This engineered enzyme, called CocE, may be an excellent candidate for clinical use.
The difficulty in designing a therapy for cocaine toxicity stems from the drug's complex mechanism of action. Cocaine can block multiple targets in the brain and body, which accounts for this drug's cardiovascular and anesthetic effects, as well as its strong addictive properties. In addition, many of the metabolites of cocaine formed by the body (such as norcocaine and cocaethylene) have similar and sometimes stronger effects than cocaine itself.
Due to the myriad of action sites that would need to be blocked to eliminate the toxic physiological effects of cocaine and its by-products, the best strategy to treating toxicity from overdose is to directly eliminate the drug.
Remy L. Brim and colleagues at the University of Michigan, in collaboration with Columbia University and the University of Kentucky, have been researching the potential of cocaine esterase (CocE) to block cocaine toxicity by eliminating cocaine. CocE is an enzyme originally isolated from a soil bacterium found around the roots of the coca plant, that can break down cocaine into the same metabolites as the natural human enzyme butyrylcholinesterase, only much more rapidly.
CocE, however, is naturally unstable at the normal body temperature of 37°C. To enhance the thermal stability of the enzyme, the investigators used a series of biochemical and computational approaches to modify the enzyme.
The thermally stable CocE was found to effectively degrade cocaine and two of cocaine's active metabolites, norcocaine and cocaethylene, and not degrade benzoylecgonine, the metabolite used in urinalyses for recent cocaine use. The researchers also evaluated CocE's ability to break down cocaine in the presence of drugs commonly co-abused with cocaine, and observed no reduction in CocE's action in the presence of alcohol, nicotine, and morphine, among others.
These promising results, in combination with previous studies that show CocE can reverse cocaine-induced cardiovascular changes, seizures, convulsions and lethality in rodent models, suggest that CocE may be a good candidate for clinical treatment of cocaine toxicity.
Brim will present this research, which was supported by the National Institutes of Health, the National Institute of Drug Abuse, and Reckitt Benckiser, at the American Society for Pharmacology and Experimental Therapeutics annual meeting in a poster titled "Ability of bacterial cocaine esterase to hydrolyze active cocaine metabolites, and function in the presence of commonly co-abused drugs."

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New Protein Involved in Longevity Identified

Researchers in the Department of Biochemistry and Molecular Biology at Thomas Jefferson University have found that the level of a single protein in the tiny roundworm C. elegans determines how long it lives. Worms born without this protein, called arrestin, lived about one-third longer than normal, while worms that had triple the amount of arrestin lived one-third less.
The research also showed that arrestin interacts with several other proteins within cells to regulate longevity. The human version of one of these proteins is PTEN, a well-known tumor suppressor. The study, to be published in the online edition of the Journal of Biological Chemistry, was chosen by the journal as the "Paper of the Week" -- considered in the top one percent of published articles.

Because most proteins in worms have human counterparts, these findings may have relevance to human biology and the understanding of cancer development, said Jeffrey L. Benovic, Ph.D., professor and chair of the department.

"The links we have found in worms suggest the same kind of interactions occur in mammals although human biology is certainly more complicated. We have much work to do to sort out these pathways, but that is our goal," said Dr. Benovic.

Researchers use the roundworm as a model because it offers a simple system to study the function of genes and proteins that are relevant to human biology. The worm, for example, has one arrestin gene, whereas humans have four. Worms only have 302 neurons compared to the 100 billion or so in the human brain. In addition, their short lifespan of two to three weeks allows for timely observation of effects on longevity.

Dr. Benovic and the study's first author, Aimee Palmitessa, Ph.D., a postdoctoral research fellow, studied signaling pathways activated by G protein-coupled receptors. These receptors bind to all kinds of hormones, sensory stimuli (such as light, odorants and tastants), neurotransmitters, etc., which then activate a cascade of signals inside the cell. They regulate many physiological processes and are the target for about half of the drugs currently on the market.

"When it comes to receptors, worms are actually more complex," said Dr. Benovic. "Humans have about 800 different kinds of G protein-coupled receptors while the worm has about 1,800. It relies upon these receptors to respond to sensory stimuli as well as various neurotransmitters and hormones."

Arrestins were initially found to turn off the activation of G protein-coupled receptors inside cells. "Their name comes from the fact that they arrest the activity of receptors, so the worm offers a good way to study how its single arrestin protein interacts with protein receptors," says Dr. Benovic. Two of the four arrestins that humans have are devoted to regulating receptors that respond to visual stimuli while the other two regulate most other receptors.

In this study, Dr. Palmitessa deleted the single arrestin gene in worms to see what would happen, and found, to her surprise, that these worms lived significantly longer. She also found that over-expressing arrestin in worms shortened their lifespan. "A little less arrestin is good -- at least for worms," Dr. Benovic reported.

This isn't the first discovery made regarding longevity in worms. Researchers have already found that activity of the insulin-like growth factor-1 (IGF-1) receptor can influence longevity in worms -- a finding that has also been replicated in fruit flies, mice, and humans. Like arrestin, a little less IGF-1 receptor activity is good, Dr. Benovic explained. Further research has shown that caloric restriction can also reduce IGF-1 receptor activation and, conversely, over-expression of the IGF-1 receptor is found in some human cancers.

In this study, Dr. Benovic and Dr. Palmitessa dug a little deeper and found that in the worms, arrestin interacted with two other proteins that play a critical role in its ability to regulate longevity. One of those proteins is the tumor suppressor PTEN; mutations in PTEN are involved in a number of different cancers.

Dr. Benovic said the connection between human arrestin and PTEN is not clear. "We don't know at this point if human arrestins regulate PTEN function or if anything happens to arrestin levels during the development of cancer," he said. "Do increasing levels turn off more PTEN, thus promoting cancer, or do levels decrease and allow PTEN to be more active?

"If it turns out to be the first scenario -- that increasing amounts of arrestin turn off the tumor suppressor activity of PTEN, then it may be possible to selectively inhibit that process," he says. "We have some interesting work ahead."

The study was funded in part by the National Institutes of Health.

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