Alzheimer's: Newly Identified Protein Pathology Impairs RNA Splicing

Researchers at Emory University School of Medicine's Alzheimer's Disease Research Center have identified a previously unrecognized type of pathology in the brains of patients with Alzheimer's disease.

These tangle-like structures appear at early stages of Alzheimer's and are not found in other neurodegenerative diseases such as Parkinson's disease.

 

In Alzheimer's disease, all that tangles is not tau. A protein pathology identified by Emory investigators could have major implications for understanding the disease mechanism. Tangled string-like structures involving aggregated U1 snRNP splicing proteins can be seen on the right side of this photo. The darker round structures are cell nuclei. (Credit: Woodruff Health Sciences Center)

What makes these tangles distinct is that they sequester proteins involved in RNA splicing, the process by which instructional messages from genes are cut and pasted together. The researchers show that the appearance of these tangles is linked to widespread changes in RNA splicing in Alzheimer's brains compared to healthy brains.

The finding could change scientists' understanding of how the disease develops and progresses, by explaining how genes that have been linked to Alzheimer's contribute their effects, and could lead to new biomarkers, diagnostic approaches, and therapies.

The results are published in the Proceedings of the National Academy of Sciences, Early Edition.

"We were very surprised to find alterations in proteins that are responsible for RNA splicing in Alzheimer's, which could have major implications for the disease mechanism," says Allan Levey, MD, PhD, chair of neurology at Emory University School of Medicine and director of the Emory ADRC.

"This is a brand new arena," says James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Many Alzheimer's investigators have looked at how the disease affects alternative splicing of individual genes. Our results suggest a global distortion of RNA processing is taking place."

This research was led by Drs. Levey, Lah, and Junmin Peng, PhD, who was previously associate professor of genetics at Emory and is now a faculty member at St Jude Children's Research Hospital. They were aided by collaborators at University of Kentucky, Rush University, and University of Washington as well as colleagues at Emory.

Accumulations of plaques and tangles in the brains of patients with Alzheimer's disease were first observed more than a century ago. Investigating the proteins in these pathological structures has been central to the study of the disease.

Most experimental treatments for Alzheimer's have aimed at curbing beta-amyloid, an apparently toxic protein fragment that is the dominant component of amyloid plaques. Other approaches target the abnormal accumulation of the protein tau in neurofibrillary tangles. Yet the development of Alzheimer's is not solely explained by amyloid and tau pathologies, Lah says.

"Two individuals may harbor similar amounts of amyloid plaques and tau tangles in their brains, but one may be completely healthy while the other may have severe memory loss and dementia," he says.

These discrepancies led Emory investigators to take a "back to basics" proteomics approach, cataloguing the proteins that make up insoluble deposits in the brains of Alzheimer's patients.

"The Alzheimer's field has been very focused on amyloid and tau, and we wanted to use today's proteomics technologies to take a comprehensive, unbiased approach," Levey says.

The team identified 36 proteins that were much more abundant in the detergent-resistant deposits in brain tissue from Alzheimer's patients. This list included the usual suspects: tau and beta-amyloid. Also on the list were several "U1 snRNP" proteins, which are involved in RNA splicing.

These U1 proteins are normally seen in the nucleus of normal cells, but in Alzheimer's brains they accumulated in tangle-like structures. Accumulation of insoluble U1 protein was seen in samples from patients with mild cognitive impairment (MCI), a precursor stage to Alzheimer's, but the U1 pathology was not seen in any other brain diseases that were examined.

According to Chad Hales, MD, PhD, one of the study's lead authors, "U1 aggregation is occurring early in the disease, and U1 tangles can be seen independently of tau pathology. In some cases, we see accumulation of insoluble U1 proteins before the appearance of insoluble tau, suggesting that it is a very early event."

For most genes, after RNA is read out from the DNA (transcription), some of the RNA must be spliced out. When brain cells accumulate clumps of U1 proteins, that could mean the process of splicing is impaired. To test this, the Emory team examined RNA from the brains of Alzheimer's patients. In comparison to RNA from healthy brains, more of the RNA from Alzheimer's brain samples was unspliced.

The finding could explain how many genes that have been linked to Alzheimer's are having their effects. In cells, U1 snRNP plays multiple roles in processing RNA including the process of alternative splicing, by which one gene can make instructions for two or more proteins.

"U1 dysfunction might produce changes in RNA processing affecting many genes or specific changes affecting a few key genes that are important in Alzheimer's," Lah says. "Understanding the disruption of such a fundamental process will almost certainly identify new ways to understand Alzheimer's and new approaches to treating patients."

 

Journal Reference:

1. B. Bai, C. M. Hales, P.-C. Chen, Y. Gozal, E. B. Dammer, J. J. Fritz, X. Wang, Q. Xia, D. M. Duong, C. Street, G. Cantero, D. Cheng, D. R. Jones, Z. Wu, Y. Li, I. Diner, C. J. Heilman, H. D. Rees, H. Wu, L. Lin, K. E. Szulwach, M. Gearing, E. J. Mufson, D. A. Bennett, T. J. Montine, N. T. Seyfried, T. S. Wingo, Y. E. Sun, P. Jin, J. Hanfelt, D. M. Willcock, A. Levey, J. J. Lah, J. Peng. U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1310249110

 

Study Establishes Human Model of Influenza Pathogenesis

A National Institutes of Health (NIH) clinical study of healthy adult volunteers who consented to be infected with the 2009 H1N1 influenza virus under carefully controlled conditions has provided researchers with concrete information about the minimum dose of virus needed to produce mild-to-moderate illness. The study also gives a clearer picture of how much time elapses between a known time of infection, the start of viral shedding (a signal of contagiousness), the development of an immune response, and the onset and duration of influenza symptoms. The data obtained from this study provide a basis for more rapid, cost-effective clinical trials to evaluate new influenza drugs or to determine the efficacy of candidate vaccines for both seasonal and pandemic influenza.

In the study, 46 volunteers were divided into five groups and exposed to influenza virus in escalating doses. The virus, synthesized in the lab under Good Manufacturing Practice conditions, was genetically identical to the virus that caused 2009 H1N1 pandemic influenza. The volunteers all gave informed consent and subsequently were admitted to an isolation unit at the NIH Clinical Center in Bethesda, Md., for a minimum of eight days following virus exposure. The volunteers' health was closely monitored throughout their stay in the clinic and for two months afterward. The researchers sought to determine the minimum dose of virus needed to produce both shedding of live virus in nasal secretions and mild or moderate flu symptoms in 60 percent or more of dosed volunteers. When the scientists administered an influenza virus dose of 107 TCID50 (a measure of the amount of virus required to produce cell death in 50 percent of cultured cells inoculated with virus) to 13 volunteers, 9 (or 69 percent) shed virus and developed symptoms. Lower dosages did not generate responses that met this threshold, thereby establishing the minimum dose of influenza virus needed to produce mild-to-moderate illness.
Researchers from NIH's National Institute of Allergy and Infectious Diseases (NIAID) presented the preliminary study results at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in Denver in September 2013.

Story Source:
The above story is based on materials provided by NIH/National Institute of Allergy and Infectious Diseases.

Courtesy: ScienceDaily

A Microbe's Trick for Staying Young

Researchers have discovered a microbe that stays forever young by rejuvenating every time it reproduces. The findings, published in Current Biology, provide fundamental insights into the mechanisms of aging.

 Three generations of yeast cells from the mother cell (green) via two daughters (red) to four granddaughter cells. (Credit: MPI f. Molecular Cell Biology and Genetics)

While aging remains an inevitable fact of life, an international team involving researchers from the University of Bristol and the Max-Planck Institute for Molecular Cell Biology and Genetics in Germany has found that this is not the case for a common species of yeast microbe which has evolved to stay young.
The team has shown that, unlike other species, the yeast microbe called S. pombe, is immune to aging when it is reproducing and under favourable growth conditions.
In general, even symmetrically diving microbes, do not split into two exactly identical halves. Detailed investigations revealed that there are mechanism in place that ensure that one half gets older, often defective, cell material, whereas the other half is equipped with new fully-functional material. So like humans microbes, in a sense, produce offspring that is younger than the parent.
But aging is not inevitable for the common yeast, S. pombe. The newly-published work shows that this microbe is immune to aging under certain conditions. When the yeast is treated well, it reproduces by splitting into two halves that both inherit their fair share of old cell material. "However," explains Iva Tolic, the lead investigator on the project "as both cells get only half of the damaged material, they are both younger than before." At least in a sense, the yeast is rejuvenated a bit, every time it reproduces.
Unlike other species S. pombe can escape aging as long as it keeps dividing fast enough, but what happens when it is treated badly? To test this, the researchers exposed the yeast to heat, ultraviolet radiation, and damaging chemicals, which slowed its growth to a point where the microbes could not divide fast enough to stay young. Once subjected to these negative influences the yeast cells started splitting into a younger and an older half just like other cells. While the older cells eventually died, their offspring survived long enough to reproduce even in the harsh environments.
So, although S. pombe can age just like other organisms when it has to, it can escape aging when times are good. "The cells manage this switch by cleverly exploiting the laws of physics" added Dr Thilo Gross, from the University of Bristol's Department of Engineering Mathematics, who supervised some of the modelling and data-analysis work on the project, "that microbes age is in itself surprising and it is amazing to see that even such simple organisms have evolved very powerful strategies to survive."
The findings highlight S. pombe, as an interesting organism that could potentially serve as a model of certain non-aging types of cells in humans.
 

Journal Reference:

1. Miguel Coelho, Aygül Dereli, Anett Haese, Sebastian Kühn, Liliana Malinovska, Morgan E. Desantis, James Shorter, Simon Alberti, Thilo Gross, Iva M. Tolić-Nørrelykke. Fission Yeast Does Not Age under Favorable Conditions, but Does So after Stress. Current Biology, September 2013 DOI: 10.1016/j.cub.2013.07.084

Courtesy: ScienceDaily
 

Human Urine Metabolome: What Scientists Can See in Your Urine

Researchers at the University of Alberta announced today that they have determined the chemical composition of human urine. The study, which took more than seven years and involved a team of nearly 20 researchers, has revealed that more than 3,000 chemicals or "metabolites" can be detected in urine. The results are expected to have significant implications for medical, nutritional, drug and environmental testing.

"Urine is an incredibly complex biofluid. We had no idea there could be so many different compounds going into our toilets," noted David Wishart, the senior scientist on the project.
Wishart's research team used state-of-the-art analytical chemistry techniques including nuclear magnetic resonance spectroscopy, gas chromatography, mass spectrometry and liquid chromatography to systematically identify and quantify hundreds of compounds from a wide range of human urine samples.
To help supplement their experimental results, they also used computer-based data mining techniques to scour more than 100 years of published scientific literature about human urine. This chemical inventory -- which includes chemical names, synonyms, descriptions, structures, concentrations and disease associations for thousands of urinary metabolites -- is housed in a freely available database called the Urine Metabolome Database, or UMDB. The UMDB is a worldwide reference resource to facilitate clinical, drug and environmental urinalysis. The UMDB is maintained by The Metabolomics Innovation Centre, Canada's national metabolomics core facility.
The chemical composition of urine is of particular interest to physicians, nutritionists and environmental scientists because it reveals key information not only about a person's health, but also about what they have eaten, what they are drinking, what drugs they are taking and what pollutants they may have been exposed to in their environment. Analysis of urine for medical purposes dates back more than 3,000 years. In fact, up until the late 1800s, urine analysis using colour, taste and smell (called uroscopy) was one of the primary methods early physicians used to diagnose disease. Even today, millions of chemically based urine tests are performed every day to identify newborn metabolic disorders, diagnose diabetes, monitor kidney function, confirm bladder infections and detect illicit drug use.
"Most medical textbooks only list 50 to 100 chemicals in urine, and most common clinical urine tests only measure six to seven compounds," said Wishart. "Expanding the list of known chemicals in urine by a factor of 30 and improving the technology so that we can detect hundreds of urine chemicals at a time could be a real game-changer for medical testing." Wishart says this study is particularly significant because it will allow a whole new generation of fast, cheap and painless medical tests to be performed using urine instead of blood or tissue biopsies. In particular, he notes that new urine-based diagnostic tests for colon cancer, prostate cancer, celiac disease, ulcerative colitis, pneumonia and organ transplant rejection are already being developed or are about to enter the marketplace, thanks in part to this work.
The Human Urine Metabolome paper appeared today in PLOS ONE. The word metabolome (which is derived from the words "metabolism" and "genome") is defined as the complete collection of metabolites or chemicals found in a particular organism or tissue. The human urine study is part of a series of studies by researchers at the University of Alberta aimed at systematically characterizing the entire human metabolome. In 2008 the same U of A team described the chemical composition of human cerebrospinal fluid and in 2011 they determined the chemical composition of human blood.
"This is certainly not the final word on the chemical composition of urine," Wishart said. "As new techniques are developed and as more sensitive instruments are produced, I am sure that hundreds more urinary compounds will be identified. In fact, new compounds are being added to the UMDB almost every day.
"While the human genome project certainly continues to capture most of the world's attention, I believe that these studies on the human metabolome are already having a far more significant and immediate impact on human health."
 

Journal Reference:

1. Souhaila Bouatra, Farid Aziat, Rupasri Mandal, An Chi Guo, Michael R. Wilson, Craig Knox, Trent C. Bjorndahl, Ramanarayan Krishnamurthy, Fozia Saleem, Philip Liu, Zerihun T. Dame, Jenna Poelzer, Jessica Huynh, Faizath S. Yallou, Nick Psychogios, Edison Dong, Ralf Bogumil, Cornelia Roehring, David S. Wishart. The Human Urine Metabolome. PLoS ONE, 2013; 8 (9): e73076 DOI: 10.1371/journal.pone.0073076

 

 Courtesy: ScienceDaily

Scientists Use DNA to Assemble a Transistor from Graphene

Graphene is a sheet of carbon atoms arrayed in a honeycomb pattern, just a single atom thick. It could be a better semiconductor than silicon -- if we could fashion it into ribbons 20 to 50 atoms wide. Could DNA help?

 

To the right is a honeycomb of graphene atoms. To the left is a double strand of DNA. The white spheres represent copper ions integral to the chemical assembly process. The fire represents the heat that is an essential ingredient in the technique. (Credit: Anatoliy Sokolov)
 
DNA is the blueprint for life. Could it also become the template for making a new generation of computer chips based not on silicon, but on an experimental material known as graphene?
That's the theory behind a process that Stanford chemical engineering professor Zhenan Bao reveals in Nature Communications.
Bao and her co-authors, former post-doctoral fellows Anatoliy Sokolov and Fung Ling Yap, hope to solve a problem clouding the future of electronics: consumers expect silicon chips to continue getting smaller, faster and cheaper, but engineers fear that this virtuous cycle could grind to a halt.
Why has to do with how silicon chips work.
Everything starts with the notion of the semiconductor, a type of material that can be induced to either conduct or stop the flow of electricity. Silicon has long been the most popular semiconductor material used to make chips.
The basic working unit on a chip is the transistor. Transistors are tiny gates that switch electricity on or off, creating the zeroes and ones that run software.
To build more powerful chips, designers have done two things at the same time: they've shrunk transistors in size and also swung those gates open and shut faster and faster.
The net result of these actions has been to concentrate more electricity in a diminishing space. So far that has produced small, faster, cheaper chips. But at a certain point, heat and other forms of interference could disrupt the inner workings of silicon chips.
"We need a material that will let us build smaller transistors that operate faster using less power," Bao said.
Graphene has the physical and electrical properties to become a next-generation semiconductor material -- if researchers can figure out how to mass-produce it.
Graphene is a single layer of carbon atoms arranged in a honeycomb pattern. Visually it resembles chicken wire. Electrically this lattice of carbon atoms is an extremely efficient conductor.
Bao and other researchers believe that ribbons of graphene, laid side-by-side, could create semiconductor circuits. Given the material's tiny dimensions and favorable electrical properties, graphene nano ribbons could create very fast chips that run on very low power, she said.
"However, as one might imagine, making something that is only one atom thick and 20 to 50 atoms wide is a significant challenge," said co-author Sokolov.
To handle this challenge, the Stanford team came up with the idea of using DNA as an assembly mechanism.
Physically, DNA strands are long and thin, and exist in roughly the same dimensions as the graphene ribbons that researchers wanted to assemble.
Chemically, DNA molecules contain carbon atoms, the material that forms graphene.
The real trick is how Bao and her team put DNA's physical and chemical properties to work.
The researchers started with a tiny platter of silicon to provide a support (substrate) for their experimental transistor. They dipped the silicon platter into a solution of DNA derived from bacteria and used a known technique to comb the DNA strands into relatively straight lines.
Next, the DNA on the platter was exposed to a copper salt solution. The chemical properties of the solution allowed the copper ions to be absorbed into the DNA.
Next the platter was heated and bathed in methane gas, which contains carbon atoms. Once again chemical forces came into play to aid in the assembly process. The heat sparked a chemical reaction that freed some of the carbon atoms in the DNA and methane. These free carbon atoms quickly joined together to form stable honeycombs of graphene.
"The loose carbon atoms stayed close to where they broke free from the DNA strands, and so they formed ribbons that followed the structure of the DNA," Yap said.
So part one of the invention involved using DNA to assemble ribbons of carbon. But the researchers also wanted to show that these carbon ribbons could perform electronic tasks. So they made transistors on the ribbons.
"We demonstrated for the first time that you can use DNA to grow narrow ribbons and then make working transistors," Sokolov said.
The paper drew praise from UC Berkeley associate professor Ali Javey, an expert in the use of advanced materials and next-generation electronics.
"This technique is very unique and takes advantage of the use of DNA as an effective template for controlled growth of electronic materials," Javey said. "In this regard the project addresses an important research need for the field."
Bao said the assembly process needs a lot of refinement. For instance, not all of the carbon atoms formed honeycombed ribbons a single atom thick. In some places they bunched up in irregular patterns, leading the researchers to label the material graphitic instead of graphene.
Even so, the process, about two years in the making, points toward a strategy for turning this carbon-based material from a curiosity into a serious contender to succeed silicon.
"Our DNA-based fabrication method is highly scalable, offers high resolution and low manufacturing cost," said co-author Yap. "All these advantages make the method very attractive for industrial adoption."
The experiment was supported in part by the National Science Foundation and the Stanford Global Climate and Energy Program.
 

Journal Reference:

1. Anatoliy N. Sokolov, Fung Ling Yap, Nan Liu, Kwanpyo Kim, Lijie Ci, Olasupo B. Johnson, Huiliang Wang, Michael Vosgueritchian, Ai Leen Koh, Jihua Chen, Jinseong Park, Zhenan Bao. Direct growth of aligned graphitic nanoribbons from a DNA template by chemical vapour deposition. Nature Communications, 2013; 4 DOI: 10.1038/ncomms3402

Courtesy: ScienceDaily
 

Children With Behavioral Problems More at Risk of Inflammation, Health Problems Later in Life

Children with behavioral problems may be at risk of many chronic diseases in adulthood including heart disease, obesity, diabetes, as well as inflammatory illnesses (conditions which are caused by cell damage).

Analyzing data on more than 4,000 participants in the Children of the 90s study at the University of Bristol, researchers from Harvard and Columbia's Mailman School of Public Health found that children with behavioral problems at the age of 8, had higher levels of two proteins (C-reactive protein -- CRP; and Interleukin 6 -- IL-6) in their blood when tested at the age of 10. This was the case even after a large number of other factors, including sex, race, background, and medication use, were taken into account.
Having raised levels of CRP and IL-6 can be an early warning sign that a person may be at risk of chronic or inflammatory conditions later in life.
Previous research has shown that children with behavioral problems can go on to develop health problems during adulthood, but this is the first time that a link has been found between mental health and inflammation in childhood.
The researchers believe the link may be due to the fact that many behavioral problems are associated with how the hypothalamic pituitary adrenal (HPA) axis works. The HPA axis plays a major role in controlling reactions to stress and the immune system and, if it malfunctions, it can stimulate the release of the two proteins that cause chronically elevated levels of inflammation, which is tissue's response to injury.
Speaking about the findings, Karestan Koenen, PhD, the report's senior author and associate professor of Epidemiology, said: "This new research shows for the first time that having behavioral problems in childhood can put children on the path to ill health much earlier than we previously realized. The important message for healthcare professionals is that they need to monitor the physical health as well as the mental health of children with behavioral problems in order to identify those at risk as early as possible."
Findings are published in the journal Psychoneuroendocrinology.
 

Journal Reference:

1. Natalie Slopen, Laura D. Kubzansky, Katie A. McLaughlin, Karestan C. Koenen. Childhood adversity and inflammatory processes in youth: A prospective study. Psychoneuroendocrinology, 2013; 38 (2): 188 DOI: 10.1016/j.psyneuen.2012.05.013

Courtesy: ScienceDaily
 

Important Mechanism Underlying Alzheimer's Disease Discovered

Alzheimer's disease affects more than 26 million people worldwide. It is predicted to skyrocket as boomers age -- nearly 106 million people are projected to have the disease by 2050. Fortunately, scientists are making progress towards therapies. A collaboration among several research entities, including the Salk Institute and the Sanford-Burnham Medical Research Institute, has defined a key mechanism behind the disease's progress, giving hope that a newly modified Alzheimer's drug will be effective.

In a previous study in 2009, Stephen F. Heinemann, a professor in Salk's Molecular Neurobiology Laboratory, found that a nicotinic receptor called Alpha7 may help trigger Alzheimer's disease. "Previous studies exposed a possible interaction between Alpha-7 nicotinic receptors (α7Rs) with amyloid beta, the toxic protein found in the disease's hallmark plaques," says Gustavo Dziewczapolski, a staff researcher in Heinemann's lab. "We showed for the first time, in vivo, that the binding of this two proteins, α7Rs and amyloid beta, provoke detrimental effects in mice similar to the symptoms observed in Alzheimer's disease ."
Their experiments, published in The Journal of Neuroscience, with Dziewczapolski as first author, consisted in testing Alzheimer's disease-induced mice with and without the gene for α7Rs. They found that while both types of mice developed plaques, only the ones with α7Rs showed the impairments associated with Alzheimer's.
But that still left a key question: Why was the pairing deleterious?
In a recent paper in the Proceedings of the National Academy of Sciences, Heinemann and Dziewczapolski here at Salk with Juan Piña-Crespo, Sara Sanz-Blasco, Stuart A. Lipton of the Sanford-Burnham Medical Research Institute and their collaborators announced they had found the answer in unexpected interactions among neurons and other brain cells.
Neurons communicate by sending electrical and chemical signals to each other across gaps called synapses. The biochemical mix at synapses resembles a major airport on a holiday weekend -- it's crowded, complicated and exquisitely sensitive to increases and decreases in traffic. One of these signaling chemicals is glutamate, an excitatory neurotransmitter, which is essential for learning and storing memories. In the right balance, glutamate is part of the normal functioning of neuronal synapses. But neurons are not the only cells in the brain capable of releasing glutamate. Astrocytes, once thought to be merely cellular glue between neurons, also release this neurotransmitter.
In this new understanding of Alzheimer's disease, there is a cellular signaling cascade, in which amyloid beta stimulates the alpha 7 nicotine receptors, which trigger astrocytes to release additional glutamate into the synapse, overwhelming it with excitatory ("go") signals.
This release in turn activates another set of receptors outside of the synapse, called extrasynaptic-N-methyl-D-aspartate receptors (eNMDARs) that depress synaptic activity. Unfortunately, the eNMDARs seem to overly depress synaptic function, leading to the memory loss and confusion associated with Alzheimer's.
Now that the team has finally determined the steps in this destructive pathway, the good news is that a drug developed by the Lipton's Laboratory called NitroMemantine, a modification of the earlier Alzheimer's medication, Memantine, may block the entry of eNMDARs into the cascade.
"Thanks to the joint effort of our colleagues and collaborators, we seem to finally have a clear mechanistic link between a key target of the amyloid beta in the brain, the Alpha7 nicotinic receptors, triggering downstream harmful effects associated with the initiation and progression of Alzheimer's disease," says Dziewczapolski. "This is a clear demonstration of the value of basic biomedical research. Drug development cannot proceed without knowing the details of interactions at the molecular and cellular level. Our research revealed two potential targets, α7Rs and eNMDARs, for future disease-modifying therapeutics, which Dr. Heinemann and I both hope will translate in a better treatment for Alzheimer's patients."
Other researchers on the study were Maria Talantova, Xiaofei Zhang, Peng Xia, Mohd Waseem Akhtar, Shu-ichi Okamoto, Tomohiro Nakamura, Gang Cao, Alexander E. Pratt, Yeon-Joo Kang, Shichun Tu, Elena Molokanova, Gary Tong, Scott R. McKercher, James Parker, Emily A. Holland, Traci Fang-Newmeyer, Dongxian Zhang, Nobuki Nakanishi, H.-S. Vincent Chen and Rajesh Ambasudhan of the Sanford-Burnham Medical Research Institute; Samuel Andrew Hires of the Howard Hughes Medical Research Institute; Herman Wolosker and Hagit Sason of the Technion-Israel Institute of Technology in Israel; Yuqiang Wang of Jinan University in China and Panorama Research Institute in California; Loren H. Parsons, David G. Stouffer, Matthew W. Buczynski, Amanda Roberts, James P. Solomon, Evan T. Powers and Jeffery W. Kelly of the Scripps Research Institute; Sarah Michael and Eliezer Masliah of UCSD School of Medicine.
This work was supported by the National Institutes of Health, Department of Defense, National Institute of Neurological Disorders and Stroke, American Heart Association and the Ministry of Education and Science of Spain.
 

Journal Reference:

1. M. Talantova, S. Sanz-Blasco, X. Zhang, P. Xia, M. W. Akhtar, S.-i. Okamoto, G. Dziewczapolski, T. Nakamura, G. Cao, A. E. Pratt, Y.-J. Kang, S. Tu, E. Molokanova, S. R. McKercher, S. A. Hires, H. Sason, D. G. Stouffer, M. W. Buczynski, J. P. Solomon, S. Michael, E. T. Powers, J. W. Kelly, A. Roberts, G. Tong, T. Fang-Newmeyer, J. Parker, E. A. Holland, D. Zhang, N. Nakanishi, H.- S. V. Chen, H. Wolosker, Y. Wang, L. H. Parsons, R. Ambasudhan, E. Masliah, S. F. Heinemann, J. C. Pina-Crespo, S. A. Lipton. A  induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proceedings of the National Academy of Sciences, 2013; 110 (27): E2518 DOI: 10.1073/pnas.1306832110

Courtesy: ScienceDaily
 

Frogs That Hear With Their Mouth: X-Rays Reveal a New Hearing Mechanism for Animals Without an Ear

Gardiner's frogs from the Seychelles islands, one of the smallest frogs in the world, do not possess a middle ear with an eardrum yet can croak themselves, and hear other frogs. An international team of scientists using X-rays has now solved this mystery and established that these frogs are using their mouth cavity and tissue to transmit sound to their inner ears.

The results are published in the Proceedings of the National Academy of Sciences on September 2, 2013.
The team led by Renaud Boistel from CNRS and University of Poitiers, comprised also scientists from Institut Langevin of ESPCI ParisTech, the Laboratoire de Mécanique et d'Acoustique in Marseilles, the Institute of Systems and Synthetic Biology at the University of Evry (France), the Nature Protection Trust of Seychelles, and the European Synchrotron ESRF in Grenoble.
The way sound is heard is common to many lineages of animals and appeared during the Triassic age (200-250 million years ago). Although the auditory systems of the four-legged animals have undergone many changes since, they have in common the middle ear with eardrum and ossicles, which emerged independently in the major lineages. On the other hand, some animals notably most frogs, do not possess an outer ear like humans, but a middle ear with an eardrum located directly on the surface of the head. Incoming sound waves make the eardrum vibrate, and the eardrum delivers these vibrations using the ossicles to the inner ear where hair cells translate them into electric signals sent to the brain. Is it possible to detect sound in the brain without a middle ear? The answer is no because 99.9% of a sound wave reaching an animal is reflected at the surface of its skin.
"However, we know of frog species that croak like other frogs but do no have tympanic middle ears to listen to each other. This seems to be a contradiction," says Renaud Boistel from the IPHEP of the University of Poitiers and CNRS. "These small animals, Gardiner's frogs, have been living isolated in the rainforest of the Seychelles for 47 to 65 million years, since these islands split away from the main continent. If they can hear, their auditory system must be a survivor of life forms on the ancient supercontinent Gondwana."
To establish whether these frogs actually use sound for communicate with each other, the scientists set up loudspeakers in their natural habitat and broadcast pre-recorded frog songs. This caused males present in the rainforest to answer, proving that they were able to hear the sound from the loudspeakers.
The next step was to identify the mechanism by which these seemingly deaf frogs were able to hear sound. Various mechanisms have been proposed: an extra-tympanic pathway through the lungs, muscles which in frogs connect the pectoral girdle to the region of the inner ear, or bone conduction. "Whether body tissue will transport sound or not depends on its biomechanical properties. With X-ray imaging techniques here at the ESRF, we could establish that neither the pulmonary system nor the muscles of these frogs contribute significantly to the transmission of sound to the inner ears," says Peter Cloetens, a scientist at the ESRF who took part in the study. "As these animals are tiny, just one centimetre long, we needed X-ray images of the soft tissue and the bony parts with micrometric resolution to determine which body parts contribute to sound propagation."
Numerical simulations helped to investigate the third hypothesis, that the sound was received through the frog's heads. These simulations confirmed that the mouth acts as a resonator, or amplifier, for the frequencies emitted by this species. Synchrotron X-ray imaging on different species showed that the transmission of the sound from the oral cavity to the inner ear has been optimized by two evolutionary adapt

ations: a reduced thickness of the tissue between the mouth and the inner ear and a smaller number of tissue layers between the mouth and the inner ear. "The combination of a mouth cavity and bone conduction allows Gardiner's frogs to perceive sound effectively without use of a tympanic middle ear," concludes Renaud Boistel.
 

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The above story is based on materials provided by European Synchrotron Radiation Facility.

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Toward an Early Diagnostic Tool for Alzheimer's Disease

Despite all the research done on Alzheimer's, there is still no early diagnostic tool for the disease. By looking at the brain wave components of individuals with the disease, Professor Tiago H. Falk of INRS's Centre Énergie Matériaux Télécommunications has identified a promising avenue of research that may not only help diagnose the disease, but also assess its severity. 

This non-invasive, objective method is the subject of an article in the journal PLOS ONE.
Patients with Alzheimer's disease currently undergo neuropsychological testing to detect signs of the disease. The test results are difficult to interpret and are insufficient for making a definitive diagnosis. But as scientists have already discovered, activity in certain areas of the cerebral cortex is affected even in the early stages of the disease. Professor Falk, who specialises in biological signal acquisition, examined this phenomenon and compared the electroencephalograms (EEGs) of healthy individuals (27), individuals with mild Alzheimer's (27), and individuals with moderate cases of the disease (22). He found statistically significant differences across the three groups.
In collaboration with neurologists and Francisco J. Fraga, an INRS visiting professor specializing in biological signals, Professor Falk used an algorithm that dissects brain waves of varying frequencies. "What makes this algorithm innovative is that it characterizes the changes in temporal dynamics of the patients' brain waves," explains Professor Falk. "The findings show that healthy individuals have different patterns than those with mild Alzheimer's disease. We also found a difference between patients with mild levels of the disease and those with moderate Alzheimer's."
To validate the model in order to eventually develop an early diagnostic tool for Alzheimer's disease, Professor Falk's team is sharing their algorithm on the NeuroAccelerator.org online data analysis portal. It is the first open source algorithm posted on the portal and may be used by researchers around the world to produce additional research findings.
Alzheimer's disease accounts for 60% to 80% of all dementia cases in North America and is skyrocketing. This step toward the development of an early diagnostic tool that is non-invasive, objective, and relatively inexpensive is therefore welcome news for the research community.
 

Journal Reference:

1. Francisco J. Fraga, Tiago H. Falk, Paulo A. M. Kanda, Renato Anghinah. Characterizing Alzheimer’s Disease Severity via Resting-Awake EEG Amplitude Modulation Analysis. PLoS ONE, 2013; 8 (8): e72240 DOI: 10.1371/journal.pone.0072240

Courtesy: ScienceDaily
 

Transparent Artificial Muscle Plays Music to Prove a Point

In a materials science laboratory at Harvard University, a transparent disk connected to a laptop fills the room with music -- it's the "Morning" prelude from Peer Gynt, played on an ionic speaker.

No ordinary speaker, it consists of a thin sheet of rubber sandwiched between two layers of a saltwater gel, and it's as clear as a window. A high-voltage signal that runs across the surfaces and through the layers forces the rubber to rapidly contract and vibrate, producing sounds that span the entire audible spectrum, 20 hertz to 20 kilohertz.
But this is not an electronic device, nor has it ever been seen before. Published in the August 30 issue of Science, it represents the first demonstration that electrical charges carried by ions, rather than electrons, can be put to meaningful use in fast-moving, high-voltage devices.
"Ionic conductors could replace certain electronic systems; they even offer several advantages," says co-lead author Jeong-Yun Sun, a postdoctoral fellow at the Harvard School of Engineering and Applied Sciences (SEAS).
For example, ionic conductors can be stretched to many times their normal area without an increase in resistivity -- a problem common in stretchable electronic devices. Secondly, they can be transparent, making them well suited for optical applications. Thirdly, the gels used as electrolytes are biocompatible, so it would be relatively easy to incorporate ionic devices -- such as artificial muscles or skin -- into biological systems.
After all, signals carried by charged ions are the electricity of the human body, allowing neurons to share knowledge and spurring the heart to beat. Bioengineers would dearly love to mesh artificial organs and limbs with that system.
"The big vision is soft machines," says co-lead author Christoph Keplinger, who worked on the project as a postdoctoral fellow at Harvard SEAS and in the Department of Chemistry and Chemical Biology. "Engineered ionic systems can achieve a lot of functions that our body has: they can sense, they can conduct a signal, and they can actuate movement. We're really approaching the type of soft machine that biology has to offer."
The audio speaker represents a robust proof of concept for ionic conductors because producing sounds across the entire audible spectrum requires both high voltage (to squeeze hard on the rubber layer) and high-speed actuation (to vibrate quickly) -- two criteria which are important for applications but which would have ruled out the use of ionic conductors in the past.
The traditional constraints are well known: high voltages can set off electrochemical reactions in ionic materials, producing gases and burning up the materials. Ions are also much larger and heavier than electrons, so physically moving them through a circuit is typically slow. The system invented at Harvard overcomes both of these problems, opening up a vast number of potential applications including not just biomedical devices, but also fast-moving robotics and adaptive optics.
"It must seem counterintuitive to many people, that ionic conductors could be used in a system that requires very fast actuation, like our speaker," says Sun. "Yet by exploiting the rubber layer as an insulator, we're able to control the voltage at the interfaces where the gel connects to the electrodes, so we don't have to worry about unwanted chemical reactions. The input signal is an alternating current (AC), and we use the rubber sheet as a capacitor, which blocks the flow of charge carriers through the circuit. As a result, we don't have to continuously move the ions in one direction, which would be slow; we simply redistribute them, which we can do thousands of times per second."
Sun works in a research group led by Zhigang Suo, the Allen E. and Marilyn M. Puckett Professor of Mechanics and Materials at Harvard SEAS. An expert in the mechanical behaviors of materials, Suo is also a Kavli Scholar at the Kavli Institute for Bionano Science & Technology, which is based at SEAS.
Suo teamed up with George M. Whitesides, a prominent chemist who specializes in soft machines, among many other topics. Whitesides is the Woodford L. and Ann A. Flowers University Professor in the Department of Chemistry and Chemical Biology, co-director of the Kavli Institute at Harvard, and a Core Faculty Member at the Wyss Institute for Biologically Inspired Engineering at Harvard.
"We'd like to change people's attitudes about where ionics can be used," says Keplinger, who now works in Whitesides' research group. "Our system doesn't need a lot of power, and you can integrate it anywhere you would need a soft, transparent layer that deforms in response to electrical stimuli -- for example, on the screen of a TV, laptop, or smartphone to generate sound or provide localized haptic feedback -- and people are even thinking about smart windows. You could potentially place this speaker on a window and achieve active noise cancellation, with complete silence inside."
Sam Liss, Director of Business Development in Harvard's Office of Technology Development, is working closely with the Suo and Whitesides labs to commercialize the technology. Their plan is to work with companies in a range of product categories, including tablet computing, smartphones, wearable electronics, consumer audio devices, and adaptive optics.
"With wearable computing devices becoming a reality, you could imagine eventually having a pair of glasses that toggles between wide-angle, telephoto, or reading modes based on voice commands or gestures," suggests Liss.
For now, there is much more engineering and chemistry work to be done. The Harvard team chose to make its audio speaker out of very simple materials -- the electrolyte is a polyacrylamide gel swollen with salt water -- but they emphasize that an entire class of ionically conductive materials is available for experimentation. Future work will focus on identifying the best combinations of materials for compatibility, long life, and adhesion between the layers.
In addition to Keplinger, Sun, Whitesides, and Suo, coauthors included Keith Choon Chiang Foo, a former postdoctoral fellow at Harvard SEAS, now at the Institute of High Performance Computing in Singapore; and Philipp Rothemund, a graduate student at Harvard SEAS.
This research was supported by the National Science Foundation through a grant to the Materials Research Science and Engineering Center at Harvard University (DMR-0820484) and by the Army Research Office (W911NF-09-1-0476). It was also enabled in part by the Department of Energy (ER45852) and the Agency for Science, Technology, and Research (A*STAR), Singapore.
 

Journal Reference:

1. C. Keplinger, J.-Y. Sun, C. C. Foo, P. Rothemund, G. M. Whitesides, Z. Suo. Stretchable, Transparent, Ionic Conductors. Science, 2013; 341 (6149): 984 DOI: 10.1126/science.1240228

Courtesy: ScienceDaily