Mystery of the reverse-wired eyeball solved

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From a practical standpoint, the wiring of the human eye – a product of our evolutionary baggage – doesn’t make a lot of sense. In vertebrates, photoreceptors are located behind the neurons in the back of the eye – resulting in light scattering by the nervous fibers and blurring of our vision. Recently, researchers at the Technion – Israel Institute of Technology have confirmed the biological purpose for this seemingly counterintuitive setup.

“The retina is not just the simple detector and neural image processor, as believed until today,” said Erez Ribak, a professor at the Technion – Israel Institute of Technology. “Its optical structure is optimized for our vision purposes.” Ribak and his co-authors will describe their work during the 2015 American Physical Society March Meeting, on Thursday, March 5 in San Antonio, Texas.

Ribak’s interest in the optical structure of the retina stems from his previous work applying astrophysics and astronomy techniques to improve the ability of scientists and ophthalmologists to view the retina at high detail.

Previous experiments with mice had suggested that Müller glia cells, a type of metabolic cell that crosses the retina, play an essential role in guiding and focusing light scattered throughout the retina. To test this, Ribak and his colleagues ran computer simulations and in-vitro experiments in a mouse model to determine whether colors would be concentrated in these metabolic cells. They then used confocal microscopy to produce three-dimensional views of the retinal tissue, and found that the cells were indeed concentrating light into the photoreceptors.

“For the first time, we’ve explained why the retina is built backwards, with the neurons in front of the photoreceptors, rather than behind them,” Ribak said.

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Methane-based and Oxygen-free life form

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A new type of methane-based, oxygen-free life form that can metabolize and reproduce similar to life on Earth has been modeled by a team of Cornell University researchers.

Taking a simultaneously imaginative and rigidly scientific view, chemical engineers and astronomers offer a template for life that could thrive in a harsh, cold world – specifically Titan, the giant moon of Saturn. A planetary body awash with seas not of water, but of liquid methane, Titan could harbor methane-based, oxygen-free cells.

Graduate student James Stevenson, astronomer Jonathan Lunine and chemical engineer Paulette Clancy, with a Cassini image of Titan in the foreground of Saturn, and an azotosome, the theorized cell membrane on Titan. Photo Credit: Cornell University Photography.

Their theorized cell membrane, composed of small organic nitrogen compounds and capable of functioning in liquid methane temperatures of 292 degrees below zero, is published in Science Advances, Feb. 27. The work is led by chemical molecular dynamics expert Paulette Clancy and first author James Stevenson, a graduate student in chemical engineering. The paper’s co-author is Jonathan Lunine, director for Cornell’s Center for Radiophysics and Space Research.

Lunine is an expert on Saturn’s moons and an interdisciplinary scientist on the Cassini-Huygens mission that discovered methane-ethane seas on Titan. Intrigued by the possibilities of methane-based life on Titan, and armed with a grant from the Templeton Foundation to study non-aqueous life, Lunine sought assistance about a year ago from Cornell faculty with expertise in chemical modeling. Clancy, who had never met Lunine, offered to help.

“We’re not biologists, and we’re not astronomers, but we had the right tools,” Clancy said. “Perhaps it helped, because we didn’t come in with any preconceptions about what should be in a membrane and what shouldn’t. We just worked with the compounds that we knew were there and asked, ‘If this was your palette, what can you make out of that?'”

On Earth, life is based on the phospholipid bilayer membrane, the strong, permeable, water-based vesicle that houses the organic matter of every cell. A vesicle made from such a membrane is called a liposome. Thus, many astronomers seek extraterrestrial life in what’s called the circumstellar habitable zone, the narrow band around the sun in which liquid water can exist. But what if cells weren’t based on water, but on methane, which has a much lower freezing point?

The engineers named their theorized cell membrane an “azotosome,” “azote” being the French word for nitrogen. “Liposome” comes from the Greek “lipos” and “soma” to mean “lipid body;” by analogy, “azotosome” means “nitrogen body.”

The azotosome is made from nitrogen, carbon and hydrogen molecules known to exist in the cryogenic seas of Titan, but shows the same stability and flexibility that Earth’s analogous liposome does. This came as a surprise to chemists like Clancy and Stevenson, who had never thought about the mechanics of cell stability before; they usually study semiconductors, not cells.

The engineers employed a molecular dynamics method that screened for candidate compounds from methane for self-assembly into membrane-like structures. The most promising compound they found is an acrylonitrile azotosome, which showed good stability, a strong barrier to decomposition, and a flexibility similar to that of phospholipid membranes on Earth. Acrylonitrile – a colorless, poisonous, liquid organic compound used in the manufacture of acrylic fibers, resins and thermoplastics – is present in Titan’s atmosphere.

Excited by the initial proof of concept, Clancy said the next step is to try and demonstrate how these cells would behave in the methane environment – what might be the analogue to reproduction and metabolism in oxygen-free, methane-based cells.

Lunine looks forward to the long-term prospect of testing these ideas on Titan itself, as he put it, by “someday sending a probe to float on the seas of this amazing moon and directly sampling the organics.”

Stevenson said he was in part inspired by science fiction writer Isaac Asimov, who wrote about the concept of non-water-based life in a 1962 essay, “Not as We Know It.”

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The above story is based on materials provided by Cornell University.

The lower size limit of life – ultra-small bacteria

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Scientists have captured the first detailed microscopy images of ultra-small bacteria that are believed to be about as small as life can get. The research was led by scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory and the University of California, Berkeley. The existence of ultra-small bacteria has been debated for two decades, but there hasn’t been a comprehensive electron microscopy and DNA-based description of the microbes until now.

The cells have an average volume of 0.009 cubic microns (one micron is one millionth of a meter). About 150 of these bacteria could fit inside an Escherichia coli cell and more than 150,000 cells could fit onto the tip of a human hair.

The scientists report their findings Friday, Feb. 27, in the journal Nature Communications.

The diverse bacteria were found in groundwater and are thought to be quite common. They’re also quite odd, which isn’t a surprise given the cells are close to and in some cases smaller than several estimates for the lower size limit of life. This is the smallest a cell can be and still accommodate enough material to sustain life. The bacterial cells have densely packed spirals that are probably DNA, a very small number of ribosomes, hair-like appendages, and a stripped-down metabolism that likely requires them to rely on other bacteria for many of life’s necessities.

The bacteria are from three microbial phyla that are poorly understood. Learning more about the organisms from these phyla could shed light on the role of microbes in the planet’s climate, our food and water supply, and other key processes.

“These newly described ultra-small bacteria are an example of a subset of the microbial life on earth that we know almost nothing about,” says Jill Banfield, a Senior Faculty Scientist in Berkeley Lab’s Earth Sciences Division and a UC Berkeley professor in the departments of Earth and Planetary Science and Environmental Science, Policy and Management.

“They’re enigmatic. These bacteria are detected in many environments and they probably play important roles in microbial communities and ecosystems. But we don’t yet fully understand what these ultra-small bacteria do,” says Banfield.

Banfield is a co-corresponding author of the Nature Communications paper with Birgit Luef, a former postdoctoral researcher in Banfield’s group who is now at the Norwegian University of Science and Technology, Trondheim.

“There isn’t a consensus over how small a free-living organism can be, and what the space optimization strategies may be for a cell at the lower size limit for life. Our research is a significant step in characterizing the size, shape, and internal structure of ultra-small cells,” says Luef.

The scientists set out to study bacteria from phyla that lack cultivated representatives. Some of these bacteria have very small genomes, so the scientists surmised the bacteria themselves might also be very small.

To concentrate these cells in a sample, they filtered groundwater collected at Rifle, Colorado through successively smaller filters, down to 0.2 microns, which is the size used to sterilize water. The resulting samples were anything but sterile. They were enriched with incredibly tiny microbes, which were flash frozen to -272 degrees Celsius in a first-of-its-kind portable version of a device called a cryo plunger. This ensured the microbes weren’t damaged in their journey from the field to the lab.

The frozen samples were transported to Berkeley Lab, where Luef, with the help of Luis Comolli of Berkeley Lab’s Life Sciences Division, characterized the cells’ size and internal structure using 2-D and 3-D cryogenic transmission electron microscopy. The images also revealed dividing cells, indicating the bacteria were healthy and not starved to an abnormally small size.

The bacteria’s genomes were sequenced at the Joint Genome Institute, a DOE Office of Science User Facility located in Walnut Creek, California, under the guidance of Susannah Tringe. The genomes were about one million base pairs in length. In addition, metagenomic and other DNA-based analyses of the samples were conducted at UC Berkeley, which found a diverse range of bacteria from WWE3, OP11, and OD1 phyla.

This combination of innovative fieldwork and state-of-the-art microscopy and genomic analysis yielded the most complete description of ultra-small bacteria to date.

Among their findings: Some of the bacteria have thread-like appendages, called pili, which could serve as “life support” connections to other microbes. The genomic data indicates the bacteria lack many basic functions, so they likely rely on a community of microbes for critical resources.

The scientists also discovered just how much there is yet to learn about ultra-small life.

“We don’t know the function of half the genes we found in the organisms from these three phyla,” says Banfield.

The scientists also used the Advanced Light Source, a DOE Office of Science User Facility located at Berkeley Lab, where Hoi-Ying Holman of the Earth Sciences Division helped determine the majority of the cells in the samples were bacteria, not Archaea.

The research is a significant contribution to what’s known about ultra-small organisms. Recently, scientists estimated the cell volume of a marine bacterium at 0.013 cubic microns, but they used a technique that didn’t directly measure the cell diameter. There are also prior electron microscopy images of a lineage of Archaea with cell volumes as small as 0.009 cubic microns, similar to these bacteria, including results from some of the same researchers. Together, the findings highlight the existence of small cells with unusual and fairly restricted metabolic capacities from two of the three major branches of the tree of life.

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The above story is based on materials provided by Berkeley Lab for the U.S. Department of Energy’s Office of Science.

Brain’s Decision-Making Structure Revealed

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A key part of the brain involved with decision making, the striatum, appears to operate hierarchically – much like a traditional corporation with executives, middle managers and employees, according to researchers at the Okinawa Institute of Science and Technology (OIST) Graduate University in Japan.

The striatum is part of the inner core of the brain that processes decisions and movements. OIST researchers investigated how the striatum’s three regions — the ventral, dorsomedial and dorsolateral — work together.

The striatum is part of the basal ganglia, the inner core of the brain that processes decisions and movements. Neuroscientists have thought the three regions of the striatum – ventral, dorsomedial and dorsolateral – have very distinct roles in motivation, adaptive decisions and routine actions, respectively.

However, OIST researchers found these parts do not operate in isolation, but work together in a coordinated hierarchy – like a traditional company with executives making decisions, delegating to middle managers and employees carrying out specific tasks.

“The three parts have not been investigated simultaneously in the same task before,” said Dr. Mokoto Ito, a researcher in OIST’s Neural Computation Unit and lead paper author. “We found the different parts work for the same behaviors, but in different roles.”

Their findings were published online on February 24 in The Journal of Neuroscience.

To observe what each part does, the researchers hooked up tiny electrodes to rats’ brains. The electrodes measured how frequently neurons in each section fired during a task, in which rats picked between two holes based on the probability of getting a sugar pellet reward. During fixed trials, the reward probability was held at different rates for the two holes, so the rats’ responses would become habitual over several weeks. During free-choice trials, the probability of reward jumped around, requiring the rats to adapt and evaluate their options more carefully.

The researchers found that while the three striatum regions have distinct roles, they work together in different phases in a trial.

“They do not work for separate behaviors,” said Prof. Kenji Doya, who heads OIST’s Neural Computation Unit and paper co-author. “It’s probably better to understand these different parts from a hierarchical control viewpoint.”

The ventral striatum (VS) was most active early on, when the rat decided whether it would participate in the activity or not. The dorsomedial striatum (DMS) changed firing levels as the rat evaluated the expected reward for each option while making a decision to turn left or right. The dorsolateral striatum (DLS) fired short bursts at a variety of times throughout the task, suggesting the involvement with the control of fine motor movements.

This is akin to a company’s president deciding to make a new product, middle managers evaluating different design and sales options, and employees building specific parts.

Neuroscientists have long thought there are separate circuits for routine actions and actions in continuously changing environments. If true, the DLS would be more active if the probability is fixed, while the DMS would be more active in free-choice tasks that require the rat to learn and adapt. To the researchers’ surprise, there was little difference in DMS and DLS firing during fixed and free-choice tasks in this study.

That was not the only unexpected result. OIST’s Neural Computation Unit works on adaptive robots learning how to autonomously behave based on reward feedback. The core component of the robots’ algorithm is the “action value,” which keeps track of the probability for a positive outcome.

“The same variable we use for robot learning was also found in the rat’s brain,” Doya said. “This is quite a striking observation.”

This strongly suggests rats analyzed the potential benefit of choosing the left or right hole, and that analysis was constantly updated after each trial – the same way the robot algorithm works.

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The above story is based on materials provided by Okinawa Institute of Science and Technology – OIST, Laura Petersen.

Neurons controlling appetite made from skin cells

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Researchers have for the first time successfully converted adult human skin cells into neurons of the type that regulate appetite, providing a patient-specific model for studying the neurophysiology of weight control and testing new therapies for obesity. The study, led by researchers at Columbia University Medical Center (CUMC) and at the New York Stem Cell Foundation (NYSCF), was published last month in the online issue of the Journal of Clinical Investigation.

Columbia researchers have developed a method to generate hypothalamic-like neurons from human pluripotent stem cells. The hypothalamic cells, which are ordinarily inaccessible for direct investigation, will help the researchers study obesity. Photo Credit: Laboratory of Rudolph Leibel

In a separate study, which appeared in the February 10 issue of the journal Development, Kevin Eggan, PhD, Florian Merkle, and Alexander Schier of Harvard University have also succeeded in creating hypothalamic neurons from iPS cells. These neurons help to regulate behavioral and basic physiological functions in the human body, including, in addition to appetite, hypertension, sleep, mood, and some social disorders. The investigators at Columbia and Harvard shared ideas during the course of the research, and these studies are co-validating.

“Mice are a good model for studying obesity in humans, but it would better to have human cells for testing. Unfortunately, the cells that regulate appetite are located in an inaccessible part of the brain, the hypothalamus. So, until now, we’ve had to make do with a mouse model or with human cells harvested at autopsy. This has greatly limited our ability to study fundamental aspects of human obesity,” said senior author Rudolph L. Leibel, MD, the Christopher J. Murphy Memorial Professor of Diabetes Research, professor of pediatrics and medicine, and co-director of the Naomi Berrie Diabetes Center at CUMC.

To make the neurons, human skin cells were first genetically reprogrammed to become induced pluripotent stem (iPS) cells. Like natural stem cells, iPS cells are capable of developing into any kind of adult cell when given a specific set of molecular signals in a specific order. The iPS cell technology has been used to create a variety of adult human cell types, including insulin-producing beta cells and forebrain and motor neurons. “But until now, no one has been able to figure out how to convert human iPS cells into hypothalamic neurons,” said co-author Dieter Egli, PhD, assistant professor of pediatrics (in developmental cell biology), a member of the Naomi Berrie Diabetes Center, and a senior research fellow at NYSCF.

“This is a wonderful example of several institutions coming together to collaborate and advance research in pursuit of new therapeutic interventions. The ability to make this type of neuron brings us one step closer to the development of new treatments for obesity,” said Susan L. Solomon, CEO of NYSCF.

The CUMC/NYSCF team determined which signals are needed to transform iPS cells into arcuate hypothalamic neurons, a neuron subtype that regulates appetite. The transformation process took about 30 days. The neurons were found to display key functional properties of mouse arcuate hypothalamic neurons, including the ability to accurately process and secrete specific neuropeptides and to respond to metabolic signals such as insulin and leptin.

“We don’t think that these neurons are identical to natural hypothalamic neurons, but they are close and will still be useful for studying the neurophysiology of weight control, as well as molecular abnormalities that lead to obesity,” said Dr. Leibel. “In addition, the cells will allow us to evaluate potential obesity drugs in a way never before possible.”

“This shows,” said Dr. Eggan, “how improved understanding of stem cell biology is making an impact on our ability to study, understand, and eventually treat disorders of the nervous system. Because there are so few hypothalamic neurons of a given type, they have been notoriously difficult to study. The successful work by both groups shows that this problem has been cracked.”

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Simple paper strip can diagnose Ebola within 10 minutes

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When diagnosing a case of Ebola, time is of the essence. However, existing diagnostic tests take at least a day or two to yield results, preventing health care workers from quickly determining whether a patient needs immediate treatment and isolation.

A new test from MIT researchers could change that: The device, a simple paper strip similar to a pregnancy test, can rapidly diagnose Ebola, as well as other viral hemorrhagic fevers such as yellow fever and dengue fever.

A new paper diagnostic device can detect Ebola as well as other viral hemorrhagic fevers in about 10 minutes. The device (pictured here) has silver nanoparticles of different colors that indicate different diseases. On the left is the unused device, opened to reveal the contents inside. On the right, the device has been used for diagnosis; the colored bands show positive tests. Photo Credits: Jose Gomez-Marquez, Helena de Puig, and Chun-Wan Yen

“As we saw with the recent Ebola outbreak, sometimes people present with symptoms and it’s not clear what they have,” says Kimberly Hamad-Schifferli, a visiting scientist in MIT’s Department of Mechanical Engineering and a member of the technical staff at MIT’s Lincoln Laboratory. “We wanted to come up with a rapid diagnostic that could differentiate between different diseases.”

Hamad-Schifferli and Lee Gehrke, the Hermann L.F. von Helmholtz Professor in MIT’s Institute for Medical Engineering and Science (IMES), are the senior authors of a paper describing the new device in the journal Lab on a Chip. The paper’s lead author is IMES postdoc Chun-Wan Yen, and other authors are graduate student Helena de Puig, IMES postdoc Justina Tam, IMES instructor Jose Gomez-Marquez, and visiting scientist Irene Bosch.

Color-coded test

Currently, the only way to diagnose Ebola is to send patient blood samples to a lab that can perform advanced techniques such as polymerase chain reaction (PCR), which can detect genetic material from the Ebola virus. This is very accurate but time-consuming, and some areas of Africa where Ebola and other fevers are endemic have limited access to this kind of technology.

The new device relies on lateral flow technology, which is used in pregnancy tests and has recently been exploited for diagnosing strep throat and other bacterial infections. Until now, however, no one has applied a multiplexing approach, using multicolored nanoparticles, to simultaneously screen for multiple pathogens.

“For many hemorrhagic fever viruses, like West Nile and dengue and Ebola, and a lot of other ones in developing countries, like Argentine hemorrhagic fever and the Hantavirus diseases, there are just no rapid diagnostics at all,” says Gehrke, who began working with Hamad-Schifferli four years ago to develop the new device.

Unlike most existing paper diagnostics, which test for only one disease, the new MIT strips are color-coded so they can be used to distinguish among several diseases. To achieve that, the researchers used triangular nanoparticles, made of silver, that can take on different colors depending on their size.

The researchers created red, orange, and green nanoparticles and linked them to antibodies that recognize Ebola, dengue fever, and yellow fever. As a patient’s blood serum flows along the strip, any viral proteins that match the antibodies painted on the stripes will get caught, and those nanoparticles will become visible. This can be seen by the naked eye; for those who are colorblind, a cellphone camera could be used to distinguish the colors.

“When we run a patient sample through the strip, if you see an orange band you know they have yellow fever, if it shows up as a red band you know they have Ebola, and if it shows up green then we know that they have dengue,” Hamad-Schifferli says.

This process takes about 10 minutes, allowing health care workers to rapidly perform triage and determine if patients should be isolated, helping to prevent the disease from spreading further.

Warren Chan, an associate professor at the University of Toronto Institute of Biomaterials and Biomedical Engineering, says he is impressed with the device because it not only offers faster diagnosis, but also requires smaller patient blood samples, as just one test strip can detect multiple diseases. “It’s a step up from what everyone else is doing,” says Chan, who was not involved in the research. “They’re targeting diseases that are really relevant to what’s going on in the world at this point, and have shown that they can detect them simultaneously.”

Faster triage

The researchers envision their new device as a complement to existing diagnostic technologies, such as PCR.

“If you’re in a situation in the field with no power and no special technologies, if you want to know if a patient has Ebola, this test can tell you very quickly that you might not want to put that patient in a waiting room with other people who might not be infected,” says Gehrke, who is also a professor of microbiology and immunology at Harvard Medical School. “That initial triage can be very important from a public health standpoint, and there could be a follow-up test later with PCR or something to confirm.”

The researchers hope to obtain Food and Drug Administration approval to begin using the device in areas where the Ebola outbreak is still ongoing. In order to do that, they are now testing the device in the lab with engineered viral proteins, as well as serum samples from infected animals.

This type of device could also be customized to detect other viral hemorrhagic fevers or other infectious diseases, by linking the silver nanoparticles to different antibodies.

“Thankfully the Ebola outbreak is dying off, which is a good thing,” Gehrke says. “But what we’re thinking about is what’s coming next. There will undoubtedly be other viral outbreaks. It might be Sudan virus, it might be another hemorrhagic fever. What we’re trying to do is develop the antibodies needed to be ready for the next outbreak that’s going to happen.”

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The above story is based on materials provided by MIT News.

Optogenetic stimulation of the brain to control pain

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A new study by a University of Texas at Arlington physics team in collaboration with bioengineering and psychology researchers shows for the first time how a small area of the brain can be optically stimulated to control pain.

Samarendra Mohanty, an assistant professor of physics, leads the Biophysics and Physiology Lab in the UT Arlington College of Science. He is co-author on a paper published online Wednesday by the journal PLOS ONE.

Samarendra Mohanty, an assistant professor of physics, leads the Biophysics and Physiology Lab in the UT Arlington College of Science. Photo Credit: UT Arlington

Researchers found that by using specific frequency of light to modulate a very small region of the brain called the anterior cingulate cortex, or ACC, they could considerably lessen pain in laboratory mice. Existing electrode based ACC stimulation lacks specificity and leads to activation of both excitatory and inhibitory neurons.

“Our results clearly demonstrate, for the first time, that optogenetic stimulation of inhibitory neurons in ACC leads to decreased neuronal activity and a dramatic reduction of pain behavior,” Mohanty said. “Moreover, we confirmed optical modulation of specific electrophysiological responses from different neuronal units in the thalamus part of the brain, in response to particular types of pain-stimuli.”

The research focused on chemical irritants and mechanical pain, such as that experienced following a pinprick or pinch. Mohanty said the results could lead to increased understanding of pain pathways and strategies for managing chronic pain, which often leads to severe impairment of normal psychological and physical functions.

“While reducing the sensation for chronic pain by optical stimulation, we still want to sense certain types of pain because they tell us to move our hands or legs away from something that is too hot or that might otherwise hurt us if we get too close,” Mohanty said.

Young-tae Kim, a UT Arlington associate professor of bioengineering and study co-author, said the research could “possibly lead to less invasive methods for treating more severe types of pain without losing important emotional, sensing and behavioral functions.”

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Temporary Tattoo Offers Needle-Free Way to Monitor Glucose Levels

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Nanoengineers at the University of California, San Diego have tested a temporary tattoo that both extracts and measures the level of glucose in the fluid in between skin cells.

This first-ever example of the flexible, easy-to-wear device could be a promising step forward in noninvasive glucose testing for patients with diabetes.

Nanoengineers at the University of California, San Diego have tested a temporary tattoo that both extracts and measures the level of glucose in the fluid in between skin cells. The device is flexible and easy to wear. Photo Credits: Jacobs School of Engineering/UC San Diego

The sensor was developed and tested by graduate student Amay Bandodkar and colleagues in Professor Joseph Wang’s laboratory at the NanoEngineering Department and the Center for Wearable Sensors at the Jacobs School of Engineering at UC San Diego. Bandodkar said this “proof-of-concept” tattoo could pave the way for the Center to explore other uses of the device, such as detecting other important metabolites in the body or delivering medicines through the skin.

At the moment, the tattoo doesn’t provide the kind of numerical readout that a patient would need to monitor his or her own glucose. But this type of readout is being developed by electrical and computer engineering researchers in the Center for Wearable Sensors. “The readout instrument will also eventually have Bluetooth capabilities to send this information directly to the patient’s doctor in real-time or store data in the cloud,” said Bandodkar.

The research team is also working on ways to make the tattoo last longer while keeping its overall cost down, he noted. “Presently the tattoo sensor can easily survive for a day. These are extremely inexpensive–a few cents–and hence can be replaced without much financial burden on the patient.”

The Center “envisions using these glucose tattoo sensors to continuously monitor glucose levels of large populations as a function of their dietary habits,” Bandodkar said. Data from this wider population could help researchers learn more about the causes and potential prevention of diabetes, which affects hundreds of millions of people and is one of the leading causes of death and disability worldwide.

People with diabetes often must test their glucose levels multiple times per day, using devices that use a tiny needle to extract a small blood sample from a fingertip. Patients who avoid this testing because they find it unpleasant or difficult to perform are at a higher risk for poor health, so researchers have been searching for less invasive ways to monitor glucose.

In their report in the journal Analytical Chemistry, Wang and his co-workers describe their flexible device, which consists of carefully patterned electrodes printed on temporary tattoo paper. A very mild electrical current applied to the skin for 10 minutes forces sodium ions in the fluid between skin cells to migrate toward the tattoo’s electrodes. These ions carry glucose molecules that are also found in the fluid. A sensor built into the tattoo then measures the strength of the electrical charge produced by the glucose to determine a person’s overall glucose levels.

“The concentration of glucose extracted by the non-invasive tattoo device is almost hundred times lower than the corresponding level in the human blood,” Bandodkar explained. “Thus we had to develop a highly sensitive glucose sensor that could detect such low levels of glucose with high selectivity.”

A similar device called GlucoWatch from Cygnus Inc. was marketed in 2002, but the device was discontinued because it caused skin irritation, the UC San Diego researchers note. Their proof-of-concept tattoo sensor avoids this irritation by using a lower electrical current to extract the glucose.

Wang and colleagues applied the tattoo to seven men and women between the ages of 20 and 40 with no history of diabetes. None of the volunteers reported feeling discomfort during the tattoo test, and only a few people reported feeling a mild tingling in the first 10 seconds of the test.

To test how well the tattoo picked up the spike in glucose levels after a meal, the volunteers ate a carb-rich meal of a sandwich and soda in the lab. The device performed just as well at detecting this glucose spike as a traditional finger-stick monitor.

The researchers say the device could be used to measure other important chemicals such as lactate, a metabolite analyzed in athletes to monitor their fitness. The tattoo might also someday be used to test how well a medication is working by monitoring certain protein products in the intercellular fluid, or to detect alcohol or illegal drug consumption.

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Bioplastic — Greener Than Ever

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Plastic waste is one of today’s major environmental concerns. Most types of plastic do not biodegrade but break up into ever smaller pieces while remaining a polymer.

Also, most types are made from oil, a rapidly dwindling resource. But there are promising alternatives, and one of them is polylactic acid (PLA): it is biodegradable and made from renewable resources. Manufacturers use PLA for disposable cups, bags and other sorts of packaging. The demand for PLA is constantly rising and has been estimated to reach about one megaton per year by 2020.

The use of biodegradable plastic packaging made of polylactic acid (PLA) is spreading. Since this year, PLA cups are available also in the ETH canteens. Photo Credits: Bo Cheng / ETH Zurich

The research groups of ETH professors Konrad Hungerbühler and Javier Pérez-Ramírez at the Institute for Chemical and Bioengineering are now introducing a new method to produce lactic acid. The process is more productive, cost-effective and climate-friendly than sugar fermentation, which is the technology currently used to produce lactic acid. The new method’s greatest advantage is that it makes use of a waste feedstock: glycerol.

Waste product of biofuel manufacturing

Glycerol is a by-product in the manufacturing of first-generation biofuels and as such is not high-grade but contains residues of ash and methanol. “Nobody knows what to do with this amount of waste glycerol”, says Merten Morales, a PhD student in the Safety and Environmental Technology group of professor Hungerbühler. This waste substance is becoming more and more abundant, with 3 megatons in 2014 expected to increase to over 4 megatons by 2020. Because of its impurity, glycerol is not suitable for the chemical or pharmaceutical industry. Moreover, it does not burn well and is thus not a good energy source. “Normally, it should go through waste water treatment, but to save money and because it is not very toxic, some companies dispose of it in rivers or feed it to livestock. But there are concerns about how this affects the animals.”

Making use of this waste feedstock by converting it into lactic acid already constitutes an advantage that makes the new method more eco-friendly. In this procedure, glycerol is first converted enzymatically to an intermediate called dihydroxyacetone, which is further processed to produce lactic acid by means of a heterogeneous catalyst.

High-performance catalyst

The researchers of the Advanced Catalysis Engineering group of professor Pérez-Ramírez designed a catalyst with high reactivity and a long life span. It consists of a microporous mineral, a zeolite, whose structure facilitates chemical reactions within the pores. The close collaboration between the two research groups allowed the catalyst to be improved step by step while at the same time performing the life cycle assessment of the procedure as a whole. “Without the assessment and comparison with the conventional method, we might have been happy with an initial catalyst design used for our study, which turned out to be less eco-friendly than fermentation”, explains Pierre Dapsens, a PhD student in the Pérez-Ramírez group. By improving several aspects of the catalyst design, the researchers were finally able to surpass sugar fermentation both from an environmental and an economic point of view.

Industrial processes are often turned “sustainable” simply by switching to a renewable resource. “However, taking the whole process into account – from the source of the feedstock to the final product and including waste management – you will often find that a supposedly sustainable production method is not necessarily more sustainable than the conventional one”, adds Cecilia Mondelli, a senior scientist in the Advanced Catalysis Engineering group who is also involved in the study.

A third less CO2

Taking into account the energy saved by using the waste feedstock glycerol and the improved productivity, the new procedure reduces the overall CO2 emission by 30 per cent compared to fermentation: per kilogram of lactic acid produced, 6 kilograms of CO2 are emitted with the new method compared to 7.5 kilograms with the conventional technology. Also, by lowering the overall cost of the process, the researchers calculated a 17-fold increase of the profit possible by using the new process. “Our calculations are even rather conservative”, says Morales. “We assumed a glycerol feedstock of relatively good quality. But it also works with low-quality glycerol, which is even cheaper.” Thus, manufacturers could increase their profit even further.

“Although today’s major bioplastic companies are based in the US, the process is relatively simple and could be implemented in other countries that produce biofuel and the by-product glycerol”, concludes Dapsens.

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Hidden gene gives hopes for improving brain function

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U.S. and Australian scientists have found the mechanism a novel gene uses to affect brain function and elicit behavior related to neuropsychiatric disease.

Timothy W. Bredy, assistant professor of neurobiology & behavior at UC Irvine, and colleagues at the University of Queensland and the Garvan Institute of Medical Research in Sydney discovered that a gene called Gomafu might be key to understanding how our brain rapidly responds to stressful experiences.

By looking across the entire genome for genes that are responsive to experience, they found Gomafu – which has recently been associated with schizophrenia – to be dynamically regulated in the adult brain.

“When Gomafu is turned off, this results in the kind of behavioural changes that are seen in anxiety and schizophrenia,” said Bredy, who is also affiliated with UCI’s Center for the Neurobiology of Learning and Memory and UQ’s Queensland Brain Institute.

The gene is a long, noncoding RNA and was found within a section of the genome most commonly associated with “junk” DNA – the 98 per cent of the human genome that, until recently, was thought to have no function. This is the first time long, noncoding RNA activity has been detected in the brain in response to experience

“Early biologists thought that DNA sequences that do not make protein were remnants of our evolutionary history, but the fact is these sequences are actually highly dynamic and exert a profound influence on us,” Bredy said.

Bredy and colleagues also found that noncoding genes such as Gomafu might represent a potent surveillance system that has evolved so that the brain can rapidly respond to changes in the environment. He added that a disruption of this network in the brain might contribute to the development of neuropsychiatric disorders.

These findings also will help to resolve the current controversy surrounding genome-wide association studies, where the majority of gene mutations that correlate with specific neuropsychiatric disorders are found within vast stretches of noncoding DNA sequences.

The scientists hope this finding will enable better prediction of vulnerability and resilience to developing a neuropsychiatric disease, with the primary goal to garner better treatment approaches across the lifespan.

Study results appeared online Feb. 10 in Biological Psychiatry. Paola A. Spadaro, Charlotte R. Flavell, Jocelyn Widagdo, Vikram S. Ratnu, Michael Troup and Chikako Ragan with the University of Queensland, and John S. Mattick with the Garvan Institute of Medical Research contributed to the study, which was supported by the National Health & Medical Research Council of Australia, the Australian Research Council and the U.S. National Institute of Mental Health (grant 1R21MH103812).

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Widely used food additives promotes colitis, obesity and metabolic syndrome

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Emulsifiers, which are added to most processed foods to aid texture and extend shelf life, can alter the gut microbiota composition and localization to induce intestinal inflammation that promotes the development of inflammatory bowel disease and metabolic syndrome, new research shows.

This photo shows bacteria that are present deeper in the mucus layer that lines the intestine and closer to the epithelium than they should be. Photo Credit: Dr. Benoit Chassaing

The research, published Feb. 25 in Nature, was led by Georgia State University Institute for Biomedical Sciences’ researchers Drs. Benoit Chassaing and Andrew T. Gewirtz, and included contributions from Emory University, Cornell University and Bar-Ilan University in Israel.

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, afflicts millions of people and is often severe and debilitating. Metabolic syndrome is a group of very common obesity-related disorders that can lead to type-2 diabetes, cardiovascular and/or liver diseases. Incidence of IBD and metabolic syndrome has been markedly increasing since the mid-20th century.

The term “gut microbiota” refers to the diverse population of 100 trillion bacteria that inhabit the intestinal tract. Gut microbiota are disturbed in IBD and metabolic syndrome. Chassaing and Gewirtz’s findings suggest emulsifiers might be partially responsible for this disturbance and the increased incidence of these diseases.

“A key feature of these modern plagues is alteration of the gut microbiota in a manner that promotes inflammation,” says Gewirtz.

“The dramatic increase in these diseases has occurred despite consistent human genetics, suggesting a pivotal role for an environmental factor,” says Chassaing. “Food interacts intimately with the microbiota so we considered what modern additions to the food supply might possibly make gut bacteria more pro-inflammatory.”

Addition of emulsifiers to food seemed to fit the time frame and had been shown to promote bacterial translocation across epithelial cells. Chassaing and Gewirtz hypothesized that emulsifiers might affect the gut microbiota to promote these inflammatory diseases and designed experiments in mice to test this possibility.

The team fed mice two very commonly used emulsifiers, polysorbate 80 and carboxymethylcellulsose, at doses seeking to model the broad consumption of the numerous emulsifiers that are incorporated into almost all processed foods. They observed that emulsifier consumption changed the species composition of the gut microbiota and did so in a manner that made it more pro-inflammatory. The altered microbiota had enhanced capacity to digest and infiltrate the dense mucus layer that lines the intestine, which is normally, largely devoid of bacteria. Alterations in bacterial species resulted in bacteria expressing more flagellin and lipopolysaccharide, which can activate pro-inflammatory gene expression by the immune system.

Such changes in bacteria triggered chronic colitis in mice genetically prone to this disorder, due to abnormal immune systems. In contrast, in mice with normal immune systems, emulsifiers induced low-grade or mild intestinal inflammation and metabolic syndrome, characterized by increased levels of food consumption, obesity, hyperglycemia and insulin resistance.

The effects of emulsifier consumption were eliminated in germ-free mice, which lack a microbiota. Transplant of microbiota from emulsifiers-treated mice to germ-free mice was sufficient to transfer some parameters of low-grade inflammation and metabolic syndrome, indicating a central role for the microbiota in mediating the adverse effect of emulsifiers.

The team is now testing additional emulsifiers and designing experiments to investigate how emulsifiers affect humans. If similar results are obtained, it would indicate a role for this class of food additive in driving the epidemic of obesity, its inter-related consequences and a range of diseases associated with chronic gut inflammation.

While detailed mechanisms underlying the effect of emulsifiers on metabolism remain under study, the team points out that avoiding excess food consumption is of paramount importance.

“We do not disagree with the commonly held assumption that over-eating is a central cause of obesity and metabolic syndrome,” Gewirtz says. “Rather, our findings reinforce the concept suggested by earlier work that low-grade inflammation resulting from an altered microbiota can be an underlying cause of excess eating.”

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Optical nanoantennas set the stage for a NEMS lab-on-a-chip revolution

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Newly developed tiny antennas, likened to spotlights on the nanoscale, offer the potential to measure food safety, identify pollutants in the air and even quickly diagnose and treat cancer, according to the Australian scientists who created them. The new antennas are cubic in shape. They do a better job than previous spherical ones at directing an ultra-narrow beam of light where it is needed, with little or no loss due to heating and scattering, they say.

This is a schematic representation of unidirectional cubic nanoantennas inducing directionality to omnidirectional nanoemitters (light sources, e.g., spasers, quantum dots), to precisely focus light with adjustable beam width and intensity, which can be tuned by adjusting the length of nanocube chain or intercube spacing. These ultra-narrow directional beams can play multiple roles in lab-on-a-chip devices such as illumination sources in microfluidic analysis or minute deflection registers in nanocantilever based sensors. All these signals are further detected in the photodetectors and get processed by on-chip signal processing circuitry for bio-molecular identification. Photo Credit: D. Sikdar and M. Premaratne/Monash University

In a paper published in the Journal of Applied Physics, from AIP Publishing, Debabrata Sikdar of Monash University in Victoria, Australia, and colleagues describe these and other envisioned applications for their nanocubes in “laboratories-on-a-chip.” The cubes, composed of insulating, rather than conducting or semiconducting materials as were the spherical versions, are easier to fabricate as well as more effective, he says.

Sikdar’s paper presents analysis and simulation of 200-nanometer dielectric (nonconductive) nanoncubes placed in the path of visible and near-infrared light sources. The nanocubes are arranged in a chain, and the space between them can be adjusted to fine-tune the light beam as needed for various applications. As the separation between cubes increases, the angular width of the beam narrows and directionality improves, the researchers say.

“Unidirectional nanoantennas induce directionality to any omnidirectional light emitters like microlasers, nanolasers or spasers, and even quantum dots,” Sikdar said in an interview. Spasers are similar to lasers, but employ minute oscillations of electrons rather than light. Quantum dots are tiny crystals that produce specific colors, based on their size, and are widely used in color televisions. “Analogous to nanoscale spotlights, the cubic antennas focus light with precise control over direction and beam width,” he said.

The new cubic nanoantennas have the potential to revolutionize the infant field of nano-electromechanical systems (NEMS). “These unidirectional nanoantennas are most suitable for integrated optics-based biosensors to detect proteins, DNA, antibodies, enzymes, etc., in truly portable lab-on-a-chip platforms of the future,” Sikdar said. “They can also potentially replace the lossy on-chip IC (integrated circuit) interconnects, via transmitting optical signals within and among ICs, to ensure ultrafast data processing while minimizing device heating,” he added.

Sikdar and his colleagues plan to begin constructing unidirectional cubic NEMS antennas in the near future at the Melbourne Center for Nanofabrication. “We would like to collaborate with other research groups across the world, making all these wonders possible,” he said.

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The Body’s Transformers

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Like the shape-shifting robots of “Transformers” fame, a unique class of proteins in the human body also has the ability to alter their configuration. These so-named intrinsically disordered proteins (IDPs) lack a fixed or ordered three-dimensional structure, which can be influenced by exposure to various chemicals and cellular modifications.

Urea (left) binds more closely and numerously to the peptide surface compared to TMAO (right).

A new study by a team of UC Santa Barbara scientists looked at a particular IDP called tau, which plays a critical role in human physiology. Abundant in neurons located in the nervous system, tau stabilizes microtubules, the cytoskeletal elements essential for neuronal functions such as intracellular transport. Lacking a fixed 3-D structure, tau can change shape so that it forms clumps or aggregates, which are associated with Alzheimer’s disease and related dementias. The researchers’ findings appear online in the Proceedings of the National Academy of Sciences.

“In the brain, these proteins need to change shape very rapidly to adapt to different conditions,” said co-author Joan-Emma Shea, a professor in UCSB’s Department of Chemistry and Biochemistry. “It’s important to understand the relationship between protein shape and function and how can you change the shape. So we used these external agents, small molecules called osmolytes, to affect the shape or conformations of these proteins.”

The researchers not only conducted biological experiments but also ran computer simulations to understand how these small molecules change the shape of tau and, when they do so, how it affects the protein’s ability to aggregate. They found that tau’s structure — whether extended or compact — was associated with how easily it bound to other tau proteins to promote the aggregation process.

“Continual aggregation of tau can, over time, result in an accumulation of pathological aggregates known as neurofibrillary tangles,” said lead author Zachary Levine, a postdoctoral scholar in UCSB’s Department of Chemistry and Biochemistry and Department of Physics. These tangles have long been known to be associated with Alzheimer’s disease and related dementias.

“In our computer simulations, we looked at certain chemical interactions called hydrogen bonds,” Levine explained. “We found that IDPs containing a large number of hydrogen bonds tended to take on smaller, more compact structures, but when we chemically removed them, we could create more extended protein structures. This allowed us to fine-tune what conformations tau could adopt. That’s really attractive if, say, you wanted to design a drug that intervenes in the pathological folding of IDPs.”

In order for aggregates of tau to develop, extended forms of the protein must stick together in a long sheet. The researchers exposed tau fragments to the osmolyte urea, which binds to the extended structures and prevents two of them from coming together. They were able to show that urea stopped aggregation, but the reason it did so wasn’t clear. However, subsequent computer simulations were able to reveal the interaction of urea with the tau protein, exposing underlying chemical interactions that decreased the likelihood of protein aggregation.

“The chemical structure of urea is quite similar to the backbone of tau,” Levine said. “Urea mimics the protein structure and binds to the surface, stopping other pieces of tau from binding to one another because the binding sites are already occupied by urea.”

The scientists also experimented with another osmolyte, trimethylamine N-oxide (TMAO), which had the exact opposite effect. They found that TMAO-exposed tau formed helical structures, which have been shown in other studies to accelerate aggregation.

“With TMAO, you can see fibrils form, but with urea you don’t,” said co-author Nichole LaPointe, a researcher in UCSB’s Department of Molecular, Cellular and Developmental Biology (MCDB) and Neuroscience Research Institute (NRI) who conducted the experiments described in the paper. Fibrils are the beginning stages of harmful clumps or aggregates of tau. “So the predictions from the simulations are actually carrying forward into something pathologically relevant, which is the formation of these big aggregates.”

Only in recent years has technology advanced to the point where it can shed light on such microcellular functions. One of the interesting things to come out of this paper, according to co-author Stuart Feinstein, an MCDB professor and a co-director of the NRI, is the idea that various normal and pathological regulatory mechanisms alter the percentage of time proteins are spending in any one of these structures.

“The other great thing that comes out of this sort of collaborative research is the training of young students,” said Feinstein. “In bioengineering, physics or physical chemistry, you have a lot of established people who are trying to learn biology; on the other hand, there are a lot of established biologists who are trying to learn the more physical sciences, but in both cases, it is a retrofit. The people who intuitively understand both worlds are those trained in both disciplines in their 20s and 30s. And that — along with good science — is what comes out of a collaboration like this.”

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Flexible nanosensors for wearable devices

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Researchers from UPM have developed a manufacturing method of aluminum optical nanosensors on versatile substrates that can be used for wearable devices and smart labels.

Aluminum film with two optical sensors over a Scotch adhesive tape. The sensor area is 1 mm x 1 mm. Photo Credit: UPM

A new method developed at the Institute of Optoelectronics Systems and Microtechnology (ISOM) from the Universidad Politécnica de Madrid (UPM) will enable the fabrication of optical nanosensors capable of sticking on uneven surfaces and biological surfaces like human skin. This result can boost the use of wearable devices to monitor parameters such as temperature, breath and heart pressure. Besides, it is a low cost technology since they use materials like standard polycarbonate compact disks, aluminum films and adhesive tapes that would facilitate its implementation on the market.

Researchers from Semiconductor Devices Group of ISOM from UPM have not only designed a manufacturing method of optical nanosensors over a regular adhesive tape but also have shown their potential applications. These flexible nanosensors enable us to measure refractive index variations of the surrounding medium and this can be used to detect chemical substances. Besides, they display iridescent colors that can vary according to the viewing and illumination angle, this property facilitates the detection of position variations and surface topography to where they are stuck at a glance.

Nanosensors consist of dimensional nanohole arrays (250 nm) which are drilled into an aluminum layer (100 nm thick). In order to cause sensitivity to the surrounding mediums and iridescence effects, these nanostructures confine and disperse light according to the will of the engineer who designs them.

The creation method for flexible nanosensors consists, firstly, on manufacturing sensors over a compact disc (CDs) of traditional polycarbonate, and secondly, transferring these sensors to adhesive Scotch tapes by a simple stick-and-peel procedure. This way, the nanosensors go from the CD surface to the adhesive tape (flexible substrate). The stick-and-peel process can be watched at: http://1drv.ms/1Jgf6Hd

This new technology uses low cost materials such as polycarbonate CDs, aluminum, and regular adhesive tapes. The usage of noble metals to develop these types of sensors is common, but it is difficult mass production due to the high cost.

Aluminum is 25,000 times cheaper than gold and has excellent electrical and optical properties. Besides, CD surfaces provide adherence to aluminum that is strong enough to manufacture the sensors over the CDs and weak enough to be transferred to the adhesive tape.

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Novel computer model designed to understand cardiovascular diseases

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Researchers have developed a novel three-dimensional, multiscale and multicomponent model of endothelial cells monolayer, the inner lining of artery, to identify the cellular mechanisms involved in cardiovascular diseases (CVD). New research based on the model is able to identify the main cellular pathways involved in the initiation and progression of the disease.

The model allows researchers, for the first time, to see how changes in blood flow patterns are transmitted within cell monolayers and through the cellular components. In certain regions of the vasculature, an increased permeability of the blood vessel endothelium enhances the accumulation of cholesterol-laden low-density lipoprotein (LDL) along with the transmigration of neutrophil leukocytes (white blood cells) from the bloodstream into the vessel wall inner layer. In these regions, it is believed the disturbed blood flow is linked to the cellular shape change and activation of all related mechanisms.

This model also quantifies the intracellular and intercellular mechanical stresses in a confluent vascular monolayer, for the first time. The model is able to cross the boundaries between different length scales in order to provide a global view of potential locations for the disease activated by shear forces from blood.

The model allowed the researchers to answer the questions that experiments could not answer. For example, the model estimates the forces per molecule in the cell attachment points to the external cellular matrix and cell–cell adhesion points. The research suggests that direct force-induced activation by single molecules is possible at both signaling pathways.

Model can help drug development

The model could provide a solid basis for the design of most effective therapeutics to prevent the progression of CVDs. According to Dabaghmeshin, there are a lot of medicines for the disease but not all of them are effective because they are designed to treat the causes of the CVDs but not the cellular responses to the causes.

“The root is that there are pathways that become activated by e.g., age-related wall stiffness and if we can somehow prevent that activation, then that’s the point. The drug should aim to target the cellular responses to wall stiffness, rather than stiffness itself,” Dabaghmeshin explains.

The model can be also extended to other applications from studying microfluidics to nano-materials.

Cardiovascular diseases (CVDs) are the largest cause of death in Europe and responsible for 2 million deaths per year. CVDs are one of the leading causes of long term sickness and loss to the labor market and they cost the EU economy almost 110 billion euros a year. Therefore, CVDs are a major health problem in every country in EU. CVDs are some of world’s largest health problems. According to World Health organization (WHO) they are the number one cause of death in the world accounting for 30 percent of deaths worldwide and 42% in the EU.

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Scientists grow leg muscle from cells in a dish

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A team of researchers from Italy, Israel and the United Kingdom has succeeded in generating mature, functional skeletal muscles in mice using a new approach for tissue engineering. The scientists grew a leg muscle starting from engineered cells cultured in a dish to produce a graft. The subsequent graft was implanted close to a normal, contracting skeletal muscle where the new muscle was nurtured and grown. In time, the method could allow for patient-specific treatments for a large number of muscle disorders. The results are published in EMBO Molecular Medicine.

The scientists used muscle precursor cells – mesoangioblasts – grown in the presence of a hydrogel (support matrix) in a tissue culture dish. The cells were also genetically modified to produce a growth factor that stimulates blood vessel and nerve growth from the host. Cells engineered in this way express a protein growth factor that attracts other essential cells that give rise to the blood vessels and nerves of the host, contributing to the survival and maturation of newly formed muscle fibres. After the graft was implanted onto the surface of the skeletal muscle underneath the skin of the mouse, mature muscle fibres formed a complete and functional muscle within several weeks. Replacing a damaged muscle with the graft also resulted in a functional artificial muscle very similar to a normal Tibialis anterior.

Tissue engineering of skeletal muscle is a significant challenge but has considerable potential for the treatment of the various types of irreversible damage to muscle that occur in diseases like Duchenne muscular dystrophy. So far, attempts to re-create a functional muscle either outside or directly inside the body have been unsuccessful. In vitro-generated artificial muscles normally do not survive the transfer in vivo because the host does not create the necessary nerves and blood vessels that would support the muscle’s considerable requirements for oxygen.

“The morphology and the structural organisation of the artificial organ are extremely similar to if not indistinguishable from a natural skeletal muscle,” says Cesare Gargioli of the University of Rome, one of the lead authors of the study.

In future, irreversibly damaged muscles could be restored by implanting the patient’s own cells within the hydrogel matrix on top of a residual muscle, adjacent to the damaged area. “While we are encouraged by the success of our work in growing a complete intact and functional mouse leg muscle we emphasize that a mouse muscle is very small and scaling up the process for patients may require significant additional work,” comments EMBO Member Giulio Cossu, one of the authors of the study. The next step in the work will be to use larger animal models to test the efficacy of this approach before starting clinical studies.

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Magnetic Nanoparticles To Stop Strokes

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By loading magnetic nanoparticles with drugs and dressing them in biochemical camouflage, Houston Methodist researchers say they can destroy blood clots 100 to 1,000 times faster than a commonly used clot-busting technique.

Each nanoparticle is composed of an iron oxide core (red squares) that is swathed in albumin (grey) and the anti-clotting agent tPA (green). The iron oxide cubes are about 20 nm on a side. Photo Credit: Paolo Decuzzi laboratory

The finding, reported in Advanced Functional Materials (early online), is based on experiments in human blood and mouse clotting models. If the drug delivery system performs similarly well in planned human clinical trials, it could mean a major step forward in the prevention of strokes, heart attacks, pulmonary embolisms, and other dire circumstances where clots — if not quickly busted — can cause severe tissue damage and death.

“We have designed the nanoparticles so that they trap themselves at the site of the clot, which means they can quickly deliver a burst of the commonly used clot-busting drug tPA where it is most needed,” said Paolo Decuzzi, Ph.D., the study’s co-principal investigator.

Decuzzi leads the Houston Methodist Research Institute Dept. of Translational Imaging.

Decuzzi’s group coated iron oxide nanoparticles in albumin, a protein found naturally in blood. The albumin provides a sort of camouflage, giving the loaded nanoparticles time to reach their blood clot target before the body’s immune system recognizes the nanoparticles as invaders and attacks them. Iron oxide was chosen for the core because the researchers plan to use them for magnetic resonance imaging, remote guidance with external magnetic fields, and for further accelerating clot dissolution with localized magnetic heating.

The clot-busting drug loaded into the nanoparticles is tPA, tissue plasminogen activator, an enzyme that is also found naturally in blood at low concentrations. Typically, a small volume of concentrated tPA is injected into a stroke patient’s blood upstream of a confirmed or suspected clot. From there, some of the tPA reaches the clot, but much of it may cruise past or around the clot, potentially ending up anywhere in the circulatory system. tPA is typically used in emergency scenarios by health care staff, but it can be dangerous to patients who are prone to hemorrhage.

“Treating clots is a serious problem for all hospitals, and we take them very seriously as surgeons,” said cardiovascular surgeon and coauthor Alan Lumsden, M.D. “Although tPA and similar drugs can be very effective in rescuing our patients, the drug is broken down quickly in the blood, meaning we have to use more of it to achieve an effective clinical dose. Yet using more of the drug creates its own problems, increasing the risk of hemorrhage. If hemorrhage happens in the brain, it could be fatal.”

Lumsden, who is medical director of the Houston Methodist DeBakey Heart & Vascular Center, said the nanoparticles being developed in Decuzzi’s lab could solve both problems.

“The nanoparticle protects the drug from the body’s defenses, giving the tPA time to work,” he said. “But it also allows us to use less tPA, which could make hemorrhage less likely. We are excited to see if the technique works as phenomenally well for our patients as what we saw in these experiments.”

Decuzzi, Lumsden, and colleagues tested the effectiveness of tPA-loaded nanoparticles, using human tissue cultures to see where tPA landed and how long it took for the tPA to destroy fibrin-rich clots. In a series of in vivo experiments, the researchers introduced blood clots to a mouse model, injecting tPA-loaded nanoparticles into the bloodstream and using optical microscopy to follow the dissolution of the clots. In comparison to a control, the clots were destroyed about 100 times faster.

Although free tPA is usually injected at room temperature, a number of studies suggest tPA is most effective at higher temperatures (40 C or about 104 F). The same seems to be true for tPA delivered via Decuzzi’s iron oxide nanoparticles. By exposing the iron oxide nanoparticles to external, alternating magnetic fields, the researchers created friction and heat. Warmer tPA (42 C or about 108 F) was released faster and increased another 10 times (to 1,000) the rate of clot dissolution.

“We think it is possible to use a static magnetic field first to help guide the nanoparticles to the clot, then alternate the orientation of the field to increase the nanoparticles’ efficiency in dissolving clots,” Decuzzi said. Coauthor and Vascular Ultrasound Lab Medical Director Zsolt Garami, M.D., added, “By heating the clot, tPA worked better.”

Next steps in the research, Decuzzi said, will be testing the nanoparticles’ safety and effectiveness in other animal models, with the ultimate goal of human clinical trials. Decuzzi said his group will continue to examine the feasibility of using magnetic fields to guide and heat the nanoparticles.

“We are optimistic because the FDA has already approved the use of iron oxide as a contrast agent in MRIs,” Decuzzi said. “And we do not anticipate needing to use as much of the iron oxide at concentrations higher than what’s already been approved. The other chemical aspects of the nanoparticles are natural substances you already find in the bloodstream.”

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Prosthetic Hand Controlled by Patient’s Mind

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Three Austrian men have become the first in the world to undergo a new technique called “bionic reconstruction”, enabling them to use a robotic prosthetic hand controlled by their mind, according to new research published in The Lancet. All three men suffered for many years with brachial plexus injuries [1] and poor hand function as a result of motor vehicle and climbing accidents.

Southampton Hand Assessment Procedure for Participant 2 during final prosthesis testing.

The new technique was developed by Professor Oskar Aszmann, Director of the Christian Doppler Laboratory for Restoration of Extremity Function at the Medical University of Vienna, together with engineers from the Department of Neurorehabilitation Engineering of the University Medical Center Goettingen. It combines selective nerve and muscle transfers, elective amputation, and replacement with an advanced robotic prosthesis (using sensors that respond to electrical impulses in the muscles). Following comprehensive rehabilitation, the technique restored a high level of function, in all three recipients, aiding in activities of daily living.

“In effect, brachial plexus avulsion injuries represent an inner amputation, irreversibly separating the hand from neural control. Existing surgical techniques for such injuries are crude and ineffective and result in poor hand function”, explains Professor Aszmann. “The scientific advance here was that we were able to create and extract new neural signals via nerve transfers amplified by muscle transplantation. These signals were then decoded and translated into solid mechatronic hand function” [2]

Before amputation, all three patients spent an average of 9 months undergoing cognitive training, firstly to activate the muscles, and then to use the electrical signals to control a virtual hand. Once they had mastered the virtual environment, they practiced using a hybrid hand—a prosthetic hand attached to a splint-like device fixed to their non-functioning hand.

Three months after amputation, robotic prostheses gave all three recipients substantially better functional movement in their hands, improved quality of life, and less pain. For the first time since their accidents all three men were able to accomplish various everyday tasks such as picking up a ball, pouring water from a jug, using a key, cutting food with a knife, or using two hands to undo buttons.

Brachial plexus injuries occur when the nerves of the brachial plexus – the network of nerves that originate in the neck region and branch off to form the nerves that control movement and sensation in the upper limbs, including the shoulder, arm, forearm, and hand – are damaged. Brachial plexus injuries often occur as a result of trauma from high speed collisions, especially in motorcycle accidents, and in collision sports such as rugby and American Football [3].

According to Professor Aszmann, “So far, bionic reconstruction has only been done in our centre in Vienna. However, there are no technical or surgical limitations that would prevent this procedure from being done in centres with similar expertise and resources.”

Writing in a linked Comment, Professor Simon Kay who carried out the UK’s first hand transplant, and Daniel Wilks from Leeds Teaching Hospitals NHS Trust, Leeds, UK say, “The present findings—and others—are encouraging, because this approach provides additional neural inputs into prosthetic systems that otherwise would not exist. However, the final verdict will depend on long-term outcomes, which should include assessment of in what circumstances and for what proportion of their day patients wear and use their prostheses. Compliance declines with time for all prostheses, and motorised prostheses are heavy, need power, and are often noisy, as well as demanding skilled repair when damaged.”

[1] The brachial plexus is a network of nerves that originate in the neck region and branch off to form most of the other nerves that control movement and sensation in the upper limbs, including the shoulder, arm, forearm, and hand.

[2] Quotes direct from author and cannot be found in text of Article.

[3] Earlier studies have estimated that the incidence of brachial plexus injuries approaches 5% in motorcycle and snowmobile accidents [http://www.ncbi.nlm.nih.gov/pubmed/9179891] and one study found an incidence of brachial plexus injuries of 26% in the 2010 Canadian football season [http://www.ncbi.nlm.nih.gov/pubmed/23006981].

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Nanotechnology, Genetic Interference for Tumors?

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There are no effective available treatments for sufferers of Glioblastoma multiforme (GBM), the most aggressive and devastating form of brain tumor. The disease, always fatal, has a survival rate of only 6-18 months.

Now a new Tel Aviv University study may offer hope to the tens of thousands diagnosed with gliomas every year. A pioneer of cancer-busting nanoscale therapeutics, Prof. Dan Peer of TAU’s Department of Department of Cell Research and Immunology and Scientific Director of TAU’s Center for NanoMedicine has adapted an earlier treatment modality — one engineered to tackle ovarian cancer tumors — to target gliomas, with promising results.

Published recently in ACS Nano, the research was initiated by Prof. Zvi R. Cohen, Director of the Neurosurgical Oncology Unit and Vice Chair at the Neurosurgical Department at Sheba Medical Center at Tel Hashomer. The Israeli Cancer Association provided support for this research.

Trying a new approach to gliomas

“I was approached by a neurosurgeon insistent on finding a solution, any solution, to a desperate situation,” said Prof. Peer. “Their patients were dying on them, fast, and they had virtually no weapons in their arsenal. Prof. Zvi Cohen heard about my earlier nanoscale research and suggested using it as a basis for a novel mechanism with which to treat gliomas.”

Dr. Cohen had acted as the primary investigator in several glioma clinical trials over the last decade, in which new treatments were delivered surgically into gliomas or into the surrounding tissues following tumor removal. “Unfortunately, gene therapy, bacterial toxin therapy, and high-intensity focused ultrasound therapy had all failed as approaches to treat malignant brain tumors,” said Dr. Cohen. “I realized that we must think differently. When I heard about Dan’s work in the field of nanomedicine and cancer, I knew I found an innovative approach combining nanotechnology and molecular biology to tackle brain cancer.”

Dr. Peer’s new research is based on a nanoparticle platform, which transports drugs to target sites while minimizing adverse effects on the rest of the body. Prof. Peer devised a localized strategy to deliver RNA genetic interference (RNAi) directly to the tumor site using lipid-based nanoparticles coated with the polysugar hyaluronan (HA) that binds to a receptor expressed specifically on glioma cells. Prof. Peer and his team of researchers tested the therapy in mouse models affected with gliomas and control groups treated with standard forms of chemotherapy. The results were, according to the researchers, astonishing.

“We used a human glioma implanted in mice as our preclinical model,” said Prof. Peer. “Then we injected our designed particle with fluorescent dye to monitor its success entering the tumor cells. We were pleased and astonished to find that, a mere three hours later, the particles were situated within the tumor cells.”

A safer, more promising approach

Rather than chemotherapy, Prof. Peer’s nanoparticles contain nucleic acid with small interference RNAs, which silence the functioning of a key protein involved in cell proliferation. “Cancer cells, always dividing, are regulated by a specific protein,” said Prof. Peer. “We thought if we could silence this gene, they would die off. It is a basic, elegant mechanism and much less toxic than chemotherapy. This protein is not expressed in normal cells, so it only works where cells are highly proliferated.”

100 days following the treatment of four injections over 30 days, 60 percent of the afflicted mice were still alive. This represents a robust survival rate for mice, whose average life expectancy is only two years. The control mice died 30-34.5 days into treatment.

“This is a proof of concept study which can be translated into a novel clinical modality,” said Prof. Peer. “While it is in early stages, the data is so promising — it would be a crime not to pursue it.”

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The above story is based on materials provided by American Friends of Tel Aviv University.

Antibiotics give rise to new communities of harmful bacteria

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Most people have taken an antibiotic to treat a bacterial infection. Now researchers from the University of North Carolina at Chapel Hill and the University of San Diego, La Jolla, reveal that the way we often think about antibiotics – as straightforward killing machines – needs to be revised.

The work, led by Elizabeth Shank, an assistant professor of biology in the UNC-Chapel Hill College of Arts and Sciences as well as microbiology and immunology in the UNC-Chapel Hill School of Medicine, and Rachel Bleich, a graduate student in the UNC-Chapel Hill Eshelman School of Pharmacy, not only adds a new dimension to how we treat infections, but also might change our understanding of why bacteria produce antibiotics in the first place.

“For a long time we’ve thought that bacteria make antibiotics for the same reasons that we love them – because they kill other bacteria,” said Shank, whose work appears in the February 23 Early Edition of the Proceedings of the National Academy of Sciences. “However, we’ve also known that antibiotics can sometimes have pesky side-effects, like stimulating biofilm formation.”

Elizabeth Shank, an assistant professor of biology in the UNC-Chapel Hill College of Arts and Sciences

Shank and her team now show that this side-effect – the production of biofilms – is not a side-effect after all, suggesting that bacteria may have evolved to produce antibiotics in order to produce biofilms and not only for their killing abilities.

Biofilms are communities of bacteria that form on surfaces, a phenomenon dentists usually refer to as plaque. Biofilms are everywhere. In many cases, biofilms can be beneficial, such as when they protect plant roots from pathogens. But they can also harm, for instance when they form on medical catheters or feeding tubes in patients, causing disease.

“It was never that surprising that many bacteria form biofilms in response to antibiotics: it helps them survive an attack. But it’s always been thought that this was a general stress response, a kind of non-specific side-effect of antibiotics. Our findings indicate that this isn’t true. We’ve discovered an antibiotic that very specifically activates biofilm formation, and does so in a way that has nothing to do with its ability to kill.”

Shank and her team previously reported that the soil bacterium Bacillus cereus could stimulate the bacterium Bacillus subtilis to form a biofilm in response to an unknown secreted signal. B. subtilis is found in soil and the gastrointestinal tract of humans.

Using imaging mass spectrometry, they subsequently identified the signaling compound that induced biofilm production as thiocillin, a member of a class of antibiotics called thiazolyl peptide antibiotics, which are produced by a range of bacteria.

At that point, Shank and her colleagues knew thiocillin had two very specific and different functions, but they didn’t know why – and wanted to know how it worked. That’s when they modified thiocillin’s structure in a way that eliminated thiocillin’s antibiotic activity, but did not halt biofilm production.

“That suggests that antibiotics can independently and simultaneously induce potentially dangerous biofilm formation in other bacteria and that these activities may be acting through specific signaling pathways,” said Shank. “It has generated further discussion about the evolution of antibiotic activity, and the fact that some antibiotics being used therapeutically may induce biofilm formation in a strong and specific way, which has broad implications for human health.”

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The above story is based on materials provided by University of North Carolina at Chapel Hill.

How brain waves guide memory formation

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Our brains generate a constant hum of activity: As neurons fire, they produce brain waves that oscillate at different frequencies. Long thought to be merely a byproduct of neuron activity, recent studies suggest that these waves may play a critical role in communication between different parts of the brain.

Two areas of the brain — the hippocampus (yellow) and the prefrontal cortex (blue) — use two different brain-wave frequencies to communicate as the brain learns to associate unrelated objects. Photo Credit: Jose-Luis Olivares/MIT

A new study from MIT neuroscientists adds to that evidence. The researchers found that two brain regions that are key to learning — the hippocampus and the prefrontal cortex — use two different brain-wave frequencies to communicate as the brain learns to associate unrelated objects. Whenever the brain correctly links the objects, the waves oscillate at a higher frequency, called “beta,” and when the guess is incorrect, the waves oscillate at a lower “theta” frequency.

“It’s like you’re playing a computer game and you get a ding when you get it right, and a buzz when you get it wrong. These two areas of the brain are playing two different ‘notes’ for correct guesses and wrong guesses,” says Earl Miller, the Picower Professor of Neuroscience, a member of MIT’s Picower Institute for Learning and Memory, and senior author of a paper describing the findings in the Feb. 23 online edition of Nature Neuroscience.

Furthermore, these oscillations may reinforce the correct guesses while repressing the incorrect guesses, helping the brain learn new information, the researchers say.

Signaling right and wrong

Miller and lead author Scott Brincat, a research scientist at the Picower Institute, examined activity in the brain as it forms a type of memory called explicit memory — memory for facts and events. This includes linkages between items such as names and faces, or between a location and an event that took place there.

During the learning task, animals were shown pairs of images and gradually learned, through trial and error, which pairs went together. Each correct response was signaled with a reward.

As the researchers recorded brain waves in the hippocampus and the prefrontal cortex during this task, they noticed that the waves occurred at different frequencies depending on whether the correct or incorrect response was given. When the guess was correct, the waves occurred in the beta frequency, about 9 to 16 hertz (cycles per second). When incorrect, the waves oscillated in the theta frequency, about 2 to 6 hertz.

Previous studies by MIT’s Mark Bear, also a member of the Picower Institute, have found that stimulating neurons in brain slices at beta frequencies strengthens the connections between the neurons, while stimulating the neurons at theta frequencies weakens the connections.

Miller believes the same thing is happening during this learning task.

“When the animal guesses correctly, the brain hums at the correct answer note, and that frequency reinforces the strengthening of connections,” he says. “When the animal guesses incorrectly, the ‘wrong’ buzzer buzzes, and that frequency is what weakens connections, so it’s basically telling the brain to forget about what it just did.”

The findings represent a major step in revealing how memories are formed, says Howard Eichenbaum, director of the Center for Memory and Brain at Boston University.

“This study offers a very specific, detailed story about the role of different directions of flow, who’s sending information to whom, at what frequencies, and how that feedback contributes to memory formation,” says Eichenbaum, who was not part of the research team.

The study also highlights the significance of brain waves in cognitive function, which has only recently been discovered by Miller and others.

“Brain waves had been ignored for decades in neuroscience. It’s been thought of as the humming of a car engine,” Miller says. “What we’re discovering through this experiment and others is that these brain waves may be the infrastructure that supports neural communication.”

Enhancing memory

The researchers are now investigating whether they can speed up learning by delivering noninvasive electrical stimulation that oscillates at beta frequencies when the correct answer is given and at theta frequencies when the incorrect answer is given. “The idea is that you make the correct guesses feel more correct to the brain, and the incorrect guesses feel more incorrect,” Miller says.

This form of very low voltage electrical stimulation has already been approved for use in humans.

“This is a technique that people have used in humans, so if it works, it could potentially have clinical relevance for enhancing memory or treating neurological disorders,” Brincat says.

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The above story is based on materials provided by Massachusetts Institute of Technology.