Influenza Study: Meet Virus' New Enemy

Simon Fraser University virologist Masahiro Niikura and his doctoral student Nicole Bance are among an international group of scientists that has discovered a new class of molecular compounds capable of killing the influenza virus.

Working on the premise that too much of a good thing can be a killer, the scientists have advanced previous researchers' methods of manipulating an enzyme that is key to how influenza replicates and spreads.

Their new compounds will lead to a new generation of anti-influenza drugs that the virus' strains can't adapt to, and resist, as easily as they do Tamiflu. It's an anti-influenza drug that is becoming less effective against the constantly mutating flu virus.

These increasingly less adequate anti-influenza drugs are currently doctors' best weapons against influenza. They helped the world beat H1N1, swine flu, into submission four years ago.

The journal Science Express has just published online the scientists' study, revealing how to use their newly discovered compounds to interrupt the enzyme neuraminidase's facilitation of influenza's spread.

Tamiflu and another anti-influenza drug, Relenza, focus on interrupting neuraminidase's ability to help influenza detach from an infected cell's surface by digesting sialic acid, a sugar on the surface of the cell. The flu virus uses the same sugar to stick to the cell while invading it. Once attached, influenza can invade the cell and replicate.

This is where the newly discovered compounds come to the still-healthy cells' rescue. They clog up neuraminidase, stopping the enzyme from dissolving the sialic acid, which prevents the virus from escaping the infected cell and spreading.

The new compounds are also more effective because they're water-soluble. "They reach the patient's throat where the flu virus is replicating after being taken orally," says Niikura, a Faculty of Health Sciences associate professor.

"Influenza develops resistance to Relenza less frequently, but it's not the drug of choice like Tamiflu because it's not water-soluble and has to be taken as a nasal spray.

"Our new compounds are structurally more similar to sialic acid than Tamiflu. We expect this closer match will make it much more difficult for influenza to adapt to new drugs."

Ultimately, the new compounds will buy scientists more time to develop new vaccines for emerging strains of influenza that are resistant to existing vaccines.

Journal Reference:

1. Jin-Hyo Kim, Ricardo Resende, Tom Wennekes, Hong-Ming Chen, Nicole Bance, Sabrina Buchini, Andrew G. Watts, Pat Pilling, Victor A. Streltsov, Martin Petric, Richard Liggins, Susan Barrett, Jennifer L. McKimm-Breschkin, Masahiro Niikura, and Stephen G. Withers. Mechanism-Based Covalent Neuraminidase Inhibitors with Broad Spectrum Influenza Antiviral Activity. Science, 21 February 2013 DOI: 10.1126/science.1232552

Courtesy: ScienceDaily

Fruit Flies Force Their Young to Drink Alcohol for Their Own Good

The fruit fly study adds to the evidence "that using toxins in the environment to medicate offspring may be common across the animal kingdom," says biologist Todd Schlenke.

 When fruit flies sense parasitic wasps in their environment, they lay their eggs in an alcohol-soaked environment, essentially forcing their larvae to consume booze as a drug to combat the deadly wasps.

The discovery by biologists at Emory University is being published in the journal Science on February 22.

"The adult flies actually anticipate an infection risk to their children, and then they medicate them by depositing them in alcohol," says Todd Schlenke, the evolutionary geneticist whose lab did the research. "We found that this medicating behavior was shared by diverse fly species, adding to the evidence that using toxins in the environment to medicate offspring may be common across the animal kingdom."

Adult fruit flies detect the wasps by sight, and appear to have much better vision than previously realized, he adds. "Our data indicate that the flies can visually distinguish the relatively small morphological differences between male and female wasps, and between different species of wasps."

The experiments were led by Balint Zacsoh, who recently graduated from Emory with a degree in biology and still works in the Schlenke lab. The team also included Emory graduate student Zachary Lynch and postdoc Nathan Mortimer.

The larvae of the common fruit fly, Drosophila melanogaster, eat the rot, or fungi and bacteria, that grows on overripe, fermenting fruit. They have evolved a certain amount of resistance to the toxic effects of the alcohol levels in their natural habitat, which can range up to 15 percent.

Tiny, endoparasitoid wasps are major killers of fruit flies. The wasps inject their eggs inside the fruit fly larvae, along with venom that aims to suppress their hosts' cellular immune response. If the flies fail to kill the wasp egg, a wasp larva hatches inside the fruit fly larva and begins to eat its host from the inside out.

Last year, the Schlenke lab published a study showing how fruit fly larvae infected with wasps prefer to eat food high in alcohol. This behavior greatly improves the survival rate of the fruit flies because they have evolved high tolerance of the toxic effects of the alcohol, but the wasps have not.

"The fruit fly larvae raise their blood alcohol levels, so that the wasps living in their blood will suffer," Schlenke says. "When you think of an immune system, you usually think of blood cells and immune proteins, but behavior can also be a big part of an organism's immune defense."

For the latest study, the researchers asked whether the fruit fly parents could sense when their children were at risk for infection, and whether they then sought out alcohol to prophylactically medicate them.

Adult female fruit flies were released in one mesh cage with parasitic wasps and another mesh cage with no wasps. Both cages had two petri dishes containing yeast, the nourishment for lab-raised fruit flies and their larvae. The yeast in one of the petri dishes was mixed with 6 percent alcohol, while the yeast in the other dish was alcohol free. After 24 hours, the petri dishes were removed and the researchers counted the eggs that the fruit flies had laid.

The results were dramatic. In the mesh cage with parasitic wasps, 90 percent of the eggs laid were in the dish containing alcohol. In the cage with no wasps, only 40 percent of the eggs were in the alcohol dish.

"The fruit flies clearly change their reproductive behavior when the wasps are present," Schlenke says. "The alcohol is slightly toxic to the fruit flies as well, but the wasps are a bigger danger than the alcohol."

The fly strains used in the experiments have been bred in the lab for decades. "The flies that we work with have not seen wasps in their lives before, and neither have their ancestors going back hundreds of generations," Schlenke says. "And yet, the flies still recognize these wasps as a danger when they are put in a cage with them."

Further experiments showed that the flies are extremely discerning about differences in the wasps. They preferred to lay their eggs in alcohol when female wasps were present, but not if only male wasps were in the cage.

Theorizing that the flies were reacting to pheromones, the researchers conducted experiments using two groups of mutated fruit flies. One group lacked the ability to smell, and another group lacked sight. The flies unable to smell, however, still preferred to lay their eggs in alcohol when female wasps were present. The blind flies did not make the distinction, choosing the non-alcohol food for their offspring, even in the presence of female wasps.

"This result was a surprise to me," Schlenke says. "I thought the flies were probably using olfaction to sense the female wasps. The small, compound eyes of flies are believed to be more geared to detecting motion than high-resolution images."

The only obvious visual differences between the female and male wasps, he adds, is that the males have longer antennae, slightly smaller bodies, and lack an ovipositor.

Further experimentation showed that the fruit flies can distinguish different species of wasps, and will only choose the alcohol food in response to wasp species that infect larvae, not fly pupae. "Fly larvae usually leave the food before they pupate," Schlenke explains, "so there is likely little benefit to laying eggs at alcoholic sites when pupal parasites are present."

The researchers also connected the exposure to female parasitic wasps to changes in a fruit fly neuropeptide.

Stress, and the resulting reduced level of neuropeptide F, or NPF, has previously been associated with alcohol-seeking behavior in fruit flies. Similarly, levels of a homologous neuropeptide in humans, NPY, is associated with alcoholism.

"We found that when a fruit fly is exposed to female parasitic wasps, this exposure reduces the level of NPF in the fly brain, causing the fly to seek out alcoholic sites for oviposition," Schlenke says. "Furthermore, the alcohol-seeking behavior appears to remain for the duration of the fly's life, even when the parasitic wasps are no longer present, an example of long-term memory."

Finally, Drosophila melanogaster is not unique in using this offspring medication behavior. "We tested a number of fly species," Schlenke says, "and found that each fly species that uses rotting fruit for food mounts this immune behavior against parasitic wasps. Medication may be far more common in nature than we previously thought."

Journal References:

1. B. Z. Kacsoh, Z. R. Lynch, N. T. Mortimer, T. A. Schlenke. Fruit Flies Medicate Offspring After Seeing Parasites. Science, 2013; 339 (6122): 947 DOI: 10.1126/science.1229625
2. Neil F. Milan, Balint Z. Kacsoh, Todd A. Schlenke. Alcohol Consumption as Self-Medication against Blood-Borne Parasites in the Fruit Fly. Current Biology, 2012; 22 (6): 488 DOI: 10.1016/j.cub.2012.01.045

Courtesy: ScienceDaily

Discovery in HIV May Solve Efficiency Problems for Gene Therapy

A research team from Case Western Reserve University School of Medicine has discovered an approach that could make gene therapy dramatically more effective for patients.

Led by professor Eric Arts, PhD, the scientists discovered that the process of gene therapy is missing essential elements thereby reducing the effectiveness of this treatment. Re-introducing this element into their model system suggests that improvements for gene therapy areon the horizon.

The findings are detailed in the article, "A new genomic RNA packaging element in retroviruses and the interplay with ribosomal frameshifting," published today in the journal Cell Host & Microbe.

Advances in gene therapy offer promising treatment for genetic abnormalities, tumors and resistance to toxic chemotherapies. Such therapy has been used to treat cystic fibrosis, hemophilia, muscular dystrophy and sickle cell anemia.

But a failure to distribute enough modified genetic information to the patient's body has prohibited gene therapy from being more widely used.

Gene therapy relies mainly on viruses -- which transport genomes inside the cells they infect -- to deliver genetic material into a patient's cells. The virus-driven delivery tools are called "viral vectors."

Unfortunately, the success rate of viral vectors is uneven. For instance, adenoviruses, a cause for the common cold, and lentiviruses, such as HIV-1, are routinely converted into viral vectors. But adenovirus vectors don't last long, so therapy must be frequently re-administered. And lentiviral vectors, while stable, fail to deliver genetic material to enough defective human cells.

Arts, a professor of medicine in the Division of Infectious Diseases and HIV Medicine, learned that lentiviral carriers lack sufficient genetic material necessary for treatment.

HIV-1, when converted from virus to lentiviral vector, loses a specific RNA element required to pack its "container" with its own genetic material to be effective. After identifying the problem, researchers introduced the element into a lentiviral vector, successfully and significantly improving the quality and quantity of the gene therapy.

Arts and colleagues named the genetic element, Genomic RNA Packaging Enhancer element (or GRPE). During virus production, GRPE coordinates the production and filling of the container with the genetic material of HIV-1, or the desired human gene.

Delivery and success of gene therapy for human cells has the potential of increasing five to ten times with the introduction of the GRPE into the lentiviral vector.

"Using lentivirus for gene transfer appears to be a safe option," said Stanton L. Gerson, MD, director of the Case Comprehensive Cancer Center and the Asa and Patricia Shiverick- Jane Shiverick (Tripp) Professor of Hematological Oncology at Case Western Reserve School of Medicine and director of the Seidman Cancer Center at University Hospitals Case Medical Center, who is not involved in the study. "This discovery could greatly advance the recent successes ongoing in cancer and childhood congenital diseases. Improvements in the technology of gene delivery identified by Arts and his colleagues could lead to many more effective studies that help patients with many different diseases, including cancer. Its impact could be felt in a few short years."

Ultimately, introducing GRPE elements into viral vectors could enhance the ease and effectiveness of gene therapy, which typically uses transplanted human stem cells. Enhanced gene therapy and other improvements in targeted cell delivery might eliminate the need for stem cells and allow cells to be administered directly into patients.

Journal Reference:

1. Mastooreh Chamanian, Katarzyna J. Purzycka, Paul T. Wille, Janice S. Ha, David McDonald, Yong Gao, Stuart F.J. Le Grice, Eric J. Arts. A cis-Acting Element in Retroviral Genomic RNA Links Gag-Pol Ribosomal Frameshifting to Selective Viral RNA Encapsidation. Cell Host & Microbe, 2013; 13 (2): 181 DOI: 10.1016/j.chom.2013.01.007

Courtesy: ScienceDaily

Stem Cell-Based Bioartificial Tissues and Organs

Surgeon Paolo Macchiarini has made his name by successfully transplanting bioengineered stem cell-based trachea, composed of both artificial and biological material. He now plans to use the technique to recreate more complex tissues, such as the esophagus and diaphragm or organs such as the heart and lungs. He has also made an experimental attempt to regenerate brain in mice and rats. 

This is part of the news he will be presenting during his seminar at the scientific AAAS Annual Meeting in Boston.

In June 2011, media all over the world reported about a ground breaking transplant, where a patient received an artificial trachea covered in his own stem cells. The result was an artificial windpipe with biological functions. To date, five operations have been carried out using this technique.

"We learn something from each operation. This means we can develop and refine the technique. We are also evaluating how we can transfer our experiences to other fields, such as neurology. The aim is to make as much use of the body's own healing potential as we can," says Paolo Macchiarini, Professor of Regenerative Surgery at Karolinska Institutet, and responsible for the surgery.

At the AAAS Annual Meeting, he will talk about how he believes the technology can be used in the future. This will include:

• The plan to operate on a 2 year-old girl in the USA in March. The girl was born without a trachea and has lived her entire life in intensive care, where she breathes through a tube placed in the esophagus and connected directly to the lungs. Without a new trachea, she will never be able to leave the hospital. This will be the first time the procedure is conducted on a small child. It is also the first time the procedure will be conducted on an individual without a trachea -- as previously, diseased organs have been replaced.
• There are also plans to transplant the esophagus, an organ that is more complex than a trachea as it has muscles.
• In experimental trials on rats, the research team has investigated the possibility to replace brain matter that has been damaged by serious trauma sustained from events such as traffic accidents, gunshot wounds or surgery. The aim is to replace the lost brain matter with a cultivated stem cell based substance and in turn, avoid neurological damage. The experimental attempt that has been conducted on rats and mice has shown positive results.
• On two occasions, severely injured patients with acute refractory lung failure received stem cell based therapy showing immediate functional improvement. Although both patients died as a consequence of multi-organ failure, the result has provided the first evidence that stem cell therapy can be a promising alternative to restore function in certain damaged organs -- without the need for them to be removed and replaced with healthy donor organs.

Story Source:

The above story is reprinted from materials provided by Karolinska Institutet. 

Courtesy: ScienceDaily

'Snooze Button' On Biological Clocks Improves Cell Adaptability

The circadian clocks that control and influence dozens of basic biological processes have an unexpected "snooze button" that helps cells adapt to changes in their environment.

A study by Vanderbilt University researchers published online Feb. 17 by the journal Nature provides compelling new evidence that at least some species can alter the way that their biological clocks function by using different "synonyms" that exist in the genetic code.

"This provides organisms with a novel and previously unappreciated mechanism for responding to changes in their environment," said Professor of Biological Sciences Carl Johnson. He and Associate Professor of Biological Sciences Antonis Rokas collaborated on the study.

Like many written languages, the genetic code is filled with synonyms: differently spelled "words" that have the same or very similar meanings. For a long time, biologists thought that these synonyms, called synonymous codons, were in fact interchangeable. Recently, they have realized that this is not the case and that differences in synonymous codon usage have a significant impact on cellular processes, so scientists have advanced a wide variety of ideas about the role that these variations play.

The new insight is not only an important advance in understanding evolution at the molecular level, but it also has potential applications in biotechnology, such as biofuel production, and gene therapy.

"While biological clocks are vital to maintaining healthy patterns of sleep, metabolism, physiology and behavior, under certain environmental conditions strict adherence to these rhythms can be disadvantageous," said Michael Sesma of the National Institute of General Medical Sciences, which partially funded the work. "This work shows how organisms can ignore the clock under certain circumstances -- much like hitting a biological snooze button on the internal timepiece -- and enhance their survival in the face of ever-changing circumstances."

The basic letters of the genetic code are a quartet of molecules (nucleic acids) designated A, C, G and U. These are combined into 61 triplets called codons, which are analogous to words. The codons provide the blueprints that the cell's protein-building machinery uses to generate amino acids, which are the basic building blocks that make all the proteins found in living organisms. However, cells only use 20 amino acids. That means a number of amino acids are produced by several different codons. For example, CCA, CCG and CCC are synonymous codons because they all encode for the same amino acid, proline.

It turns out that there is a reason for this redundancy. Some codons are faster and easier for cells to process and assemble into proteins than others. Recognition of this difference led to the concept of optimal codons and the hypothesis that natural selection should drive organisms -- particularly fast growing ones -- to use genes that use optimal codons to make critical proteins that need to be highly abundant or synthesized rapidly in cells.

The problem with this hypothesis was shown by Johnson and Rokas' study of the effect of changing codon usage on the simple biological clock found in single-celled cyanobacteria (blue-green algae) and a similar study of the more complex biological clock found in bread mold performed by a team led by Yi Liu that were published together.

"What the Liu team found was that optimizing all the codons used by the fungal biological clock knocked the clock out, which was totally unexpected! Those researchers concluded that clock proteins in the fungus are not properly assembled if they are synthesized too rapidly; it's as if the speed of one's writing affected our ability to read the text," Johnson summarized.

In the cyanobacteria, however, the researchers observed a different phenomenon. At Vanderbilt, Research Associate Professor Yao Xu optimized the codons in the cyanobacteria's biological clock. This did not shut the clock down in the algae, but it did have a more subtle, but potentially as profound effect: It significantly reduced cell survival at certain temperatures.

"Xu figured that the biological clock with optimized codons might work better at lower temperatures and it did," Johnson said. However the substitution also modified the biological clock so it ran with a longer, 30-hour period. When forced to operate in a 24-hour daily light/dark cycles, the bacteria with the optimized clock grew significantly slower than "wild-type" cells. "In cyanobacteria, it's as if writing speed changes the meaning," said Rokas.

The potential importance of changes in synonymous codon usage in adapting to environmental factors is magnified by the fact that they can influence the operation of biological clocks, which function as a key adaptation to daily environmental rhythms. Biological clocks control and influence dozens of different basic biological processes, including sleeping and feeding patterns, core body temperature, brain activity, hormone production and cell regeneration.

"It is now clear that variations in codon usage is a fundamental and underappreciated form of gene regulation," said Rokas.

Recognition of the importance of this process has a number of potential applications in biotechnology. For example, "it should be possible to improve the ability of algae to robustly express biofuel-producing proteins from other organisms by optimizing the codons that they use," Johnson said.

Vanderbilt graduate student Peijun Ma, postdoctoral fellow Premal Shah from the University of Pennsylvania and Yi Liu, professor at the University of Texas Southwestern Medical Center also contributed to the study, which was funded by grants from the National Institute of General Medical Sciences (GM067152, GM088595, GM068496 & GM062591), the Welch Foundation (I-1560), the National Science Foundation (DEB-0844968), the Burroughs Wellcome Fund and a David and Lucille Packard Foundation Fellowship.

Journal Reference:

1. Yao Xu, Peijun Ma, Premal Shah, Antonis Rokas, Yi Liu, Carl Hirschie Johnson. Non-optimal codon usage is a mechanism to achieve circadian clock conditionality. Nature, 2013; DOI: 10.1038/nature11942

Courtesy: ScienceDaily

3-D Printing On the Micrometer Scale

At the Photonics West, the leading international fair for photonics taking place in San Francisco (USA) this week, Nanoscribe GmbH, a spin-off of Karlsruhe Institute of Technology (KIT), presents the world's fastest 3D printer of micro- and nanostructures. With this printer, smallest three-dimensional objects, often smaller than the diameter of a human hair, can be manufactured with minimum time consumption and maximum resolution. The printer is based on a novel laser lithography method.

The 3D laser litho-graphy systems developed by Nanoscribe -- the spin-off can still be found on KIT's Campus North -- are used for research by KIT and scientists worldwide. Work in the area of photonics concentrates on replacing conventional electronics by optical circuits of higher performance. For this purpose, Nanoscribe systems are used to print polymer waveguides reaching data transfer rates of more than 5 terabits per second.

Biosciences produce tailored scaffolds for cell growth studies among others. In materials research, functional materials of enhanced performance are developed for lightweight construction to reduce the consumption of resources.

Increased Speed: Hours Turn into Minutes

By means of the new laser lithography method, printing speed is increased by factor of about 100. This increase in speed results from the use of a galvo mirror system, a technology that is also applied in laser show devices or scanning units of CD and DVD drives. Reflecting a laser beam off the rotating galvo mirrors facilitates rapid and precise laser focus positioning. "We are revolutionizing 3D printing on the micrometer scale. Precision and speed are achieved by the industrially established galvo technology. Our product benefits from more than one decade of experience in photonics, the key technology of the 21st century," says Martin Hermatschweiler, the managing director of Nanoscribe GmbH.

Mechanism: Two-photon Polymerization

The direct laser writing technique underlying the 3D printing method is based on two-photon polymerization. Just as paper ignites when exposed to sunlight focused through a magnifying glass, ultra-short laser pulses polymerize photosensitive materials in the laser focus. Depending on the photosensitive material chosen, the exposed or unexposed volume only is dissolved. After a developer bath, these written areas remain as self-supporting micro- and nanostructures.

Removing Barriers

By means of the galvo technology, three-dimensional micro- and nanostructures can be printed rapidly and, hence, on large areas in principle. At highest resolution, however, the scanning field is limited physically to a few 100 µm due to the optical properties of the focusing objective. Just as floor tiles must be joined precisely, the respective scanning fields have to be connected seamlessly and accurately. By the so-called stitching, areas can be extended nearly arbitrarily.

Story Source:

The above story is reprinted from materials provided by Karlsruhe Institute of Technology. 

Courtesy: ScienceDaily

Paralyzed Man Uses Thoughts Alone to Control Robot Arm, Touch Friend's Hand, After Seven Years

Researchers at the University of Pittsburgh School of Medicine and UPMC describe in PLoS ONE how an electrode array sitting on top of the brain enabled a 30-year-old paralyzed man to control the movement of a character on a computer screen in three dimensions with just his thoughts. It also enabled him to move a robot arm to touch a friend's hand for the first time in the seven years since he was injured in a motorcycle accident.

With brain-computer interface (BCI) technology, the thoughts of Tim Hemmes, who sustained a spinal cord injury that left him unable to move his body below the shoulders, were interpreted by computer algorithms and translated into intended movement of a computer cursor and, later, a robot arm, explained lead investigator Wei Wang, Ph.D., assistant professor, Department of Physical Medicine and Rehabilitation, Pitt School of Medicine.

"When Tim reached out to high-five me with the robotic arm, we knew this technology had the potential to help people who cannot move their own arms achieve greater independence," said Dr. Wang, reflecting on a memorable scene from September 2011 that was re-told in stories around the world. "It's very important that we continue this effort to fulfill the promise we saw that day."

Six weeks before the implantation surgery, the team conducted functional magnetic resonance imaging (fMRI) of Mr. Hemmes' brain while he watched videos of arm movement. They used that information to place a postage stamp-size electrocortigraphy (ECoG) grid of 28 recording electrodes on the surface of the brain region that fMRI showed controlled right arm and hand movement. Wires from the device were tunneled under the skin of his neck to emerge from his chest where they could be connected to computer cables as necessary.

For 12 days at his home and nine days in the research lab, Mr. Hemmes began the testing protocol by watching a virtual arm move, which triggered neural signals that were sensed by the electrodes. Distinct signal patterns for particular observed movements were used to guide the up and down motion of a ball on a computer screen. Soon after mastering movement of the ball in two dimensions, namely up/down and right/left, he was able to also move it in/out with accuracy on a 3-dimensional display.

"During the learning process, the computer helped Tim hit his target smoothly by restricting how far off course the ball could wander," Dr. Wang said. "We gradually took off the 'training wheels,' as we called it, and he was soon doing the tasks by himself with 100 percent brain control."

The robot arm was developed by Johns Hopkins University's Applied Physics Laboratory. Currently, Jan Scheuermann, of Whitehall, Pa., is testing another BCI technology at Pitt/UPMC. 

Co-authors of the paper include Jennifer L. Collinger, Ph.D., Alan D. Degenhart, Andrew B. Schwartz, Ph.D., Douglas J. Weber, Ph.D., Brian Wodlinger, Ph.D., Ramana K. Vinjamuri, Ph.D., and Robin C. Ashmore, Ph.D., all of the University of Pittsburgh; Elizabeth C. Tyler-Kabara, M.D., Ph.D., and Michael L. Boninger, M.D., of the University of Pittsburgh and UPMC; Daniel W. Moran, Ph.D., of Washington University in St. Louis; and John W. Kelly, of Carnegie Mellon University.

The study was funded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, the University of Pittsburgh's Clinical and Translational Science Institute, and UPMC.

Journal Reference:

1. Wei Wang, Jennifer L. Collinger, Alan D. Degenhart, Elizabeth C. Tyler-Kabara, Andrew B. Schwartz, Daniel W. Moran, Douglas J. Weber, Brian Wodlinger, Ramana K. Vinjamuri, Robin C. Ashmore, John W. Kelly, Michael L. Boninger. An Electrocorticographic Brain Interface in an Individual with Tetraplegia. PLoS ONE, 2013; 8 (2): e55344 DOI: 10.1371/journal.pone.0055344

Courtesy: ScienceDaily

Old Drug May Point the Way to New Treatments for Diabetes and Obesity

Researchers at the University of Michigan's Life Sciences Institute have found that amlexanox, an off-patent drug currently prescribed for the treatment of asthma and other uses, also reverses obesity, diabetes and fatty liver in mice.

The findings from the lab of Alan Saltiel, the Mary Sue Coleman director of the Life Sciences Institute, are scheduled to be published online Feb. 10 in the journal Nature Medicine.

"One of the reasons that diets are so ineffective in producing weight loss for some people is that their bodies adjust to the reduced calories by also reducing their metabolism, so that they are 'defending' their body weight," Saltiel said. "Amlexanox seems to tweak the metabolic response to excessive calorie storage in mice."

Different formulations of amlexanox are currently prescribed to treat asthma in Japan and canker sores in the United States. Saltiel is teaming up with clinical-trial specialists at U-M to test whether amlexanox will be useful for treating obesity and diabetes in humans. He is also working with medicinal chemists at U-M to develop a new compound based on the drug that optimizes its formula.

The study appears to confirm and extend the notion that the genes IKKE and TBK1 play a crucial role for maintaining metabolic balance, a discovery published by the Saltiel lab in 2009 in the journal Cell.

"Amlexanox appears to work in mice by inhibiting two genes -- IKKE and TBK1 -- that we think together act as a sort of brake on metabolism," Saltiel said. "By releasing the brake, amlexanox seems to free the metabolic system to burn more, and possibly store less, energy."

Using high-throughput chemical screening at LSI's Center for Chemical Genomics to search for compounds that inhibit IKKE and TBK1, the researchers hit upon an approved off-patent drug: amlexanox. They then demonstrated that amlexanox had profound beneficial effects in both genetic and dietary-induced obese mice. The chemical lowered the weight of obese mice and reversed related metabolic problems such as diabetes and fatty liver.

"These studies tell us that, at least in mice, the IKKE/TBK1 pathway plays an important role in defending body weight by increasing storage and decreasing burning of calories, and that by inhibiting that pathway with a compound, we can increase metabolism and induce weight loss, reverse diabetes and reduce fatty liver," Saltiel said.

The drug has been on the market in Japan for more than 25 years.

However, the researchers don't yet know if humans respond with the same pathway, or if the discovery of amlexanox's effectiveness in mice can lead to a compound that is safe and effective for treating obesity and diabetes in humans.

"We will be working hard on that," Saltiel said.

Saltiel's search for a drug targeting the IKKE/TBK1 pathway was supported by the Life Science Institute's Innovation Partnership, which provides philanthropic funding and business mentorship to help move promising research toward commercialization.

The research was also supported by the National Institutes of Health, the Michigan Diabetes Research and Training Center, the Michigan Institute for Clinical and Health Research, and the Nathan Shock Center in the Basic Biology of Aging.

Journal Reference:

1. Shannon M Reilly, Shian-Huey Chiang, Stuart J Decker, Louise Chang, Maeran Uhm, Martha J Larsen, John R Rubin, Jonathan Mowers, Nicole M White, Irit Hochberg, Michael Downes, Ruth T Yu, Christopher Liddle, Ronald M Evans, Dayoung Oh, Pingping Li, Jerrold M Olefsky, Alan R Saltiel. An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice. Nature Medicine, 2013; DOI: 10.1038/nm.3082

 Courtesy: ScienceDaily

Nanomedicine: Controlled and Targeted Release of Drugs

Researchers have discovered a method that allows for the controlled release of an active agent on the basis of a magnetic nanovehicle. The research, conducted as part of the National Research Programme "Smart Materials" (NRP 62), opens up new possibilities for the development of targeted treatments, which are more efficient and trigger fewer side effects.

Certain drugs are toxic by nature. For example, anti-cancer drugs developed to kill diseased cells also harm healthy ones. To limit the side effects of chemotherapy, it would be a great step forward if it were possible to release a drug only in the affected area of the body. In the context of the National Research Programme "Smart Materials" (NRP 62) -- a cooperation between the SNSF and the Commission for Technology and Innovation (CTI) -- researchers of ETH Lausanne, the Adolphe Merkle Institute and the University Hospital of Geneva have discovered a method that might represent an important step towards the development of an intelligent drug of this kind. By combining their expert knowledge in the areas of material sciences, biological nanomaterials and medicine, they were able to prove the feasibility of using a nanovehicle to transport drugs and release them in a controlled manner.

This nanocontainer is a liposome, which takes the shape of a vesicle. It has a diameter of 100 to 200 nanometers and is 100 times smaller than a human cell. The membrane of the vesicle is composed of phospholipids and the inside of the vesicle offers room for the drug. On the surface of the liposome, specific molecules help to target malignant cells and to hide the nanocontainer from the immune system, which might otherwise consider it a foreign entity and seek to destroy it. Now the researchers only needed to discover a mechanism to open up the membrane at will.

Nano effect This is exactly what the researchers succeeded in doing (*). How they did it? By integrating into the liposome membrane superparamagnetic iron oxide nanoparticles (SPION), which only become magnetic in the presence of an external magnetic field. Once they are in the field, the SPION heat up. The heat makes the membrane permeable and the drug is released. Researchers proved the feasibility of such a nanovehicle by releasing in a controlled manner a coloured substance contained in the liposomes. "We can really talk of nanomedicine in this context because, by exploiting superparamagnetism, we are exploiting a quantum effect which only exists at the level of nanoparticles," explains Heinrich Hofmann of the Powder Technology Laboratory of EPFL. SPION are also an excellent contrast agent in magnetic resonance imaging (MRI). A simple MRI shows the location of the SPION and allows for the release of the drug once it has reached the targeted spot.

Designed for medical practice "To maximise the chances of discovering an effective treatment, we focused on nanocontainers, which would be readily accepted by doctors," adds Heinrich Hofmann. This strategy limits the range of possibilities. Liposomes, which are already used in a number of drugs on the market, are composed of natural phospholipids which can also be found in the membranes of human cells. To open them up, researchers focused on SPION, which had already been the subject of numerous toxicological studies. More efficient materials were ignored because little or nothing was known about their effects on humans. In terms of shape, another important parameter of magnetism, they chose to use only spherical nanoparticles, which are considered safer than fibrous shapes. The intensity and frequency of the magnetic field needed to release the active agent are compatible with human physiology.

The combination of these parameters presented the researchers with another challenge: to reach a temperature sufficiently high to open up the liposomes, they were forced to increase the size of the SPION from 6 to 15 nanometres. The membrane of the vesicles has a thickness of only 4-5 nanometres. Then the masterstroke: the research group of Alke Fink at the Adolphe Merkle Institute was able to regroup the SPION in one part of the membrane (*). This also made MRI detection easier. Before starting in-vivo tests, the researchers aim to study the integration of SPION into the liposome membrane in greater detail.

National Research Programme "Smart Materials" (NRP 62) NRP 62 is a cooperation programme between the Swiss National Science Foundation (SNSF) and the Commission for Technology and Innovation (CTI). It strives to promote scientific excellence and contribute to the successful industrial exploitation of smart materials and their applications. NRP 62 intends to combine the expertise and resources of various research institutions across Switzerland. The researchers will devise the technologies needed for the development of smart materials and for their application in intelligent systems and structures. NRP 62 consists of 21 projects of use-inspired fundamental research. It has a budget of CHF 11 million and ends in 2015.

Journal Reference:

1. Cécile Bonnaud, Dimitri Vanhecke, Davide Demurtas, Barbara Rothen-Rutishauser, Alke Petri-Fink. Spatial SPION Localization in Liposome Membranes. IEEE Transactions on Magnetics, 2013; 49 (1): 166 DOI: 10.1109/TMAG.2012.2219040

Courtesy: ScienceDaily