Posts tagged science
Articles and news from the latest research reports.
The Unstable Repeats—Three Evolving Faces of Neurological Disease
Disorders characterized by expansion of an unstable nucleotide repeat account for a number of inherited neurological diseases. Here, we review examples of unstable repeat disorders that nicely illustrate three of the major pathogenic mechanisms associated with these diseases: loss of function typically by disrupting transcription of the mutated gene, RNA toxic gain of function, and protein toxic gain of function. In addition to providing insight into the mechanisms underlying these devastating neurological disorders, the study of these unstable microsatellite repeat disorders has provided insight into very basic aspects of neuroscience.
New structural insight into neurodegenerative disease
A research team from the Korea Advanced Institute of Science and Technology (KAIST) released their results on the structure and molecular details of the neurodegenerative disease-associated protein Ataxin-1. Mutations in Ataxin-1 cause the neurological disease, Spinocerebellar Ataxia Type 1 (SCA1), which is characterized by a loss of muscular coordination and balance (ataxia), as is seen in Parkinson’s, Alzheimer’s, and Huntington’s diseases.
SCA1-causing mutations in the ATAXIN1 gene alter the length of a glutamine stretch in the Ataxin-1 protein. The research team provides the first structural insight into the complex formation of ATAXIN-1 with its binding partner, Capicua (CIC). The team, led by Professor Ji-Joon Song from the Department of Biological Sciences at KAIST, solved the structure of Ataxin-1 and CIC complex in atomic level revealing molecular details of the interaction between Ataxin-1 and CIC.
Professor Song explained his recent research work, “We are able to see the intricate process of complex formation and reconfiguration of the two proteins when they interact with each other. Our work, we expect, will provide a new therapeutic target to modulate SCA1 neurodegenerative disease.”
Understanding structural and molecular details of proteins at the atomic level will help researchers to track the molecular pathogenesis of the disease and, ultimately, design targeted therapies or treatments for patients, rather than just relieving the symptoms of diseases.
Professor Song’s research paper, entitled “Structural Basis of Protein Complex Formation and Reconfiguration by Polyglutamine Disease Protein ATAXIN-1 and Capicua,” will be published in the March 15th issue of Genes & Development
Ten extraordinary Pentagon mind experiments
It’s been 30 years since the first message was sent over initial nodes of the Arpanet, the Pentagon-sponsored precursor to the internet. But this month, researchers announced something that could be equally historic: the passing of messages between two rat brains, the first step toward what they call the “brain net”.
Connecting the brains of two rats through implanted electrodes, scientists at Duke University demonstrated that in response to a visual cue, the trained response of one rat, called an encoder, could be mimicked without a visual cue in a second rat, called the decoder. In other words, the brain of one rat had communicated to the other.
"These experiments demonstrated the ability to establish a sophisticated, direct communication linkage between rat brains, and that the decoder brain is working as a pattern-recognition device,” said Miguel Nicolelis, a professor at Duke University School of Medicine. “So basically, we are creating an organic computer that solves a puzzle.”
Whether or not the Duke University experiments turn out to be historic (some skepticism has already been raised), the work reflects a growing Pentagon interest in neuroscience for applications that range from such far-off ideas as teleoperation of military devices (think mind-controlled drones), to more near-term and less controversial technology, like prosthetics controlled by the human brain. In fact, like the Arpanet, the experiment on the rat “brain net” was sponsored by the Defense Advanced Research Projects Agency (Darpa).
The Pentagon’s expanding work in neuroscience in recent years has focused heavily on medical applications, like research to understand traumatic brain injury, but a good portion of the past decade’s work has also been on concepts that are intended to help the military fight wars more effectively, such as studying ways to keep soldiers’ brains alert even after days without sleep. Under the rubric of “Augmented Cognition,” Darpa has also pursued a number of military technologies, like goggles that would monitor a soldier’s brain signals to pick up potential threats before the conscious mind is aware of them.
Now, such work may get an even bigger boost: President Barack Obama is set to announce an initiative that could funnel billions of dollars to the field of neuroscience. That could mean more money for the Pentagon’s forays into brain science.
While some of the applications might be a generation away, or may never arrive, like mind-controlled drones, others, like the brain-monitoring goggles, are already in testing (though probably not ready for use in the field). That’s raising questions from ethicists, who are pushing for the government to begin now to think about “neuro ethics.”
In a 2012 article published last year in the journal Plos Biology, Jonathan Moreno, a professor of medical ethics, and Michael Tennison, a professor of neurology, argued that many neuroscientists don’t think about the contribution of their work to warfare, or consider the ethical implication of such work.
The question they raise is what choice future soldiers might have in such cognitively enhanced warfare. “If a warfighter is allowed no autonomous freedom to accept or decline an enhancement intervention, and the intervention in question is as invasive as remote brain control,” they write, “then the ethical implications are immense.”
Whether this era will come to pass, remains to be seen. But, for now, expect many more advances in the world of neuroscience to come from the Pentagon.
Improved Detection of Frontotemporal Degeneration May Aid Clinical Trial Efforts
A series of studies demonstrate improved detection of the second most common form of dementia, providing diagnostic specificity that clears the way for refined clinical trials testing targeted treatments. The new research is being presented by experts from the Perelman School of Medicine at the University of Pennsylvania at the American Academy of Neurology’s 65th Annual Meeting in San Diego March 16-23, 2013.
Frontotemporal degeneration, the most common dementia in people under 60, can be hereditary or sporadic in nature and caused by one of two different mutated proteins (tau or TDP-43). The disease results in damage to the anterior temporal and/or frontal lobes of the brain. As the disease progresses, it becomes increasingly difficult for people to plan or organize activities, behave appropriately in social or work settings, interact with others, and care for oneself, resulting in increasing dependency.
In one study, the team confirmed that a novel multimodal imaging approach was more accurate (88 percent) than using either MRI (72 percent) or DTI (81 percent) alone to detect FTD versus Alzheimer’s disease. The two imaging techniques integrate measures of white matter and grey matter, providing a statistically powerful method for predicting underlying pathology in order to screen patients for clinical trials.
“We are moving forward on our biomarker work to optimize our ability to identify the specific cause of an individual’s difficulties during life, said senior author Murray Grossman, MD, EdD, professor of Neurology and director of the Penn FTLD Center. “We use a novel multi-modality approach involving behavioral, imaging and biofluid biomarker measures.”
In a second study, researchers found that a brief series of neuropsychological tests of memory, word generation and conceptual flexibility (needed for creative problem-solving) helped differentiate people with very mild behavioral variant FTD (bvFTD) and those with mild cognitive impairment (MCI). The combination of tests correctly classified 85.7 percent of bvFTD cases and 83.3 percent of MCI cases at early stages of disease.
“This is particularly important because treatment trials with disease-modifying agents are emerging, often based on animal studies, yet we still don’t have all the tools we need to identify who is most appropriate to participate in one of these trials. Moreover, we can use this information we ascertain to help determine who is responding to a treatment in a clinical trial.”
The third study being presented at the meeting showed that hereditary forms of FTD appear to have more rapid cognitive decline and differing tau profiles compared with sporadic forms of the disease. For clinical trials testing whether a drug can delay damage caused by tau, any known differences in the speed of disease progression could interfere with trial results.
(Image courtesy: University of Pennsylvania)
Tau Transmission Model Opens Doors for New Alzheimer’s, Parkinson’s Therapies
Injecting synthetic tau fibrils into animal models induces Alzheimer’s-like tau tangles and imitates the spread of tau pathology, according to research from the Perelman School of Medicine at the University of Pennsylvania being presented at the American Academy of Neurology’s 65th Annual Meeting in San Diego March 16-23, 2013.
This Alzheimer’s research, along with additional Parkinson’s research from Penn and beyond, further demonstrates the cell-to-cell transmission of neurodegenerative proteins. John Q. Trojanowski, MD, PhD, co-director of the Center for Neurodegenerative Disease Research (CNDR) and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, will present the research in the Hot Topics plenary session on Tuesday, March 19 starting at 5:15pm.
"The transmission model better explains the spread of disease within neurodegenerative disease, and has uncovered new therapeutic opportunities which we are exploring vigorously," said Dr. Trojanowski. “However, it is important to emphasize that the spread of Alzheimer’s and Parkinson’s pathology does not mean these diseases are infectious, like Mad Cow disease, based on data from another recent study from our group.”
For supplemental information on the transmission of tau pathology, the laboratory of senior author Virginia M.-Y. Lee, Ph.D., MBA, director of CNDR and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, published additional findings in the Journal of Neuroscience.
Dynamic new software improves care of aging brain
Innovative medical records software developed by geriatricians and informaticians from the Regenstrief Institute and the Indiana University Center for Aging Research will provide more personalized health care for older adult patients, a population at significant risk for mental health decline and disorders.
A new study published in eGEMs, a peer-reviewed online publication recently launched by the Electronic Data Methods Forum, unveils the enhanced Electronic Medical Record Aging Brain Care Software, an automated decision-support system that enables care coordinators to track the health of the aging brain and help meet the complex biopsychosocial needs of patients and their informal caregivers.
The eMR-ABC captures and monitors the cognitive, functional, behavioral and psychological symptoms of older adults suffering from dementia or depression. It also collects information on the burden placed on patients’ family caregivers.
Utilizing this information, the software application provides decision support to care coordinators, who, working with physicians, social workers and other members of the health care team, create a personalized care plan that includes evidence-based non-pharmacological protocols, self-management handouts and alerts of medications with potentially adverse cognitive effects. The software’s built-in engine tracks patient visits and can be used to generate population reports for specified indicators such as cognitive decline or caregiver burnout.
"The number of older adults is growing rapidly. Delivering personalized care to this population is difficult and requires the ability to track a large number of mental and physical indicators," said Regenstrief Institute investigator Malaz Boustani, M.D., MPH, associate director of the IU Center for Aging Research and associate professor of medicine at the IU School of Medicine. He is senior author of the new study. "The software we have developed will help care coordinators measure the many needs of patients and their loved ones and monitor the effectiveness of individualized care plans."
In clinical trials over the past decade, Regenstrief and the IU Center for Aging Research investigator-clinicians developed and demonstrated the efficacy of an Alzheimer’s disease collaborative care model called the Aging Brain Care Medical Home. A hallmark of the ABC-MedHome is the employment of care coordinators who help clinicians identify and manage processes and protocols for Alzheimer’s patients who receive care in local primary care physician offices. The ABC-MedHome has been shown to improve the quality of Alzheimer’s care and decrease its burden on the health care system.
Within the ABC-MedHome program, Dr. Boustani and colleagues have now developed, tested, implemented and improved software that is sensitive to the clinical needs of a multispecialty team of professionals who provide care to complex patients across a variety of settings. The new software allows tracking of individual patient health outcomes as well as the ability to follow the status of an entire patient population with key quality, health and cost metrics.
"Integration of the eMR-ABC program within Wishard-Eskenazi Health was pivotal to our receipt in 2012 of a Health Care Innovation Challenge award from the Centers for Medicare & Medicaid Services to expand from care of 250 patients to 2,000 patients plus caregivers," said Dr. Boustani, who is medical director of the Wishard Healthy Aging Brain Center and also an IU Health geriatrician. "New models of care, supported by population health management tools, are needed if we are to provide improved quality of care and encourage better health outcomes for our patients and be cost sensitive. We are using health information technology to manage high-risk populations while achieving the triple aim of better health and better care at lower cost."
(Source: eurekalert.org)
Discovery could yield treatment for cocaine addicts
Scientists have discovered a molecular process in the brain triggered by cocaine use that could provide a target for treatments to prevent or reverse addiction to the drug.
Reporting in the Journal of Neuroscience, Michigan State University (MSU) neuroscientist A.J. Robison and colleagues say cocaine alters the nucleus accumbens, the brain’s pleasure center that responds to stimuli such as food, sex and drugs.
“Understanding what happens molecularly to this brain region during long-term exposure to drugs might give us insight into how addiction occurs,” said Robison, assistant professor in the Department of Physiology and in the Neuroscience Program.
The researchers found that cocaine causes cells in the nucleus accumbens to boost production of two proteins, one associated with addiction and the other related to learning. The proteins have a reciprocal relationship – they increase each other’s production and stability in the cells – so the result is a snowball effect that Robison calls a feed-forward loop.
Robison and colleagues demonstrated that loop’s essential role in cocaine responses by manipulating the process in rodents. They found that raising production of the protein linked to addiction made animals behave as if they were exposed to cocaine even when they weren’t. They also were able to break the loop, disrupting rodents’ response to cocaine by preventing the function of the learning protein.
“At every level that we study, interrupting this loop disrupts the process that seems to occur with long-term exposure to drugs,” said Robison, who conducted the study as a postdoctoral fellow at Mount Sinai School of Medicine in New York City before joining the faculty at MSU.
Robison said the study was particularly compelling because it found signs of the same feed-forward loop in the brains of people who died while addicted to cocaine.
“The increased production of these proteins that we found in the animals exposed to drugs was exactly paralleled in a population of human cocaine addicts,” he said. “That makes us believe that the further experiments and manipulations we did in the animals are directly relevant to humans.”
Robison said the growing understanding of addiction at the molecular level could help pave the way for new treatments for addicts.
“This sort of molecular pathway could be interrupted using genetic medicine, which is what we did with the mice,” he said. “Many researchers think that is the future of medicine.”
(Image: UTHSC)
The Mysterious GRIN3A and the Cause of Schizophrenia
Since the 1960s, psychiatrists have been hunting for substances made by the body that might accumulate in abnormally high levels to produce the symptoms associated with schizophrenia. In particular, there was a search for chemicals that might be related to the hallucinogens phencyclidine (PCP) or lysergic acid diethylamide (LSD), which could explain the emergence of psychotic symptoms in schizophrenia. This “auto-intoxication” hypothesis led investigators on a wild goose chase where substances, including the “Pink Spot” and the “Frohman Factor”, were isolated from people with schizophrenia and implicated in their illness, but these findings were later discredited.
The mysterious GRIN3A is a new version of the hunt for an intrinsic mechanism that produces schizophrenia-like symptoms. GRIN3A is a gene that codes for the GluN3A subunit of the N-methyl-D-aspartate-type (NMDA) receptor, a target for the neurotransmitter glutamate in the brain. Functional NMDA receptors usually have two GluN1 subunits and two GluN2 subunits. The ability of glutamate to activate these receptors is blocked by PCP and the anesthetic/hallucinogen, ketamine. When the GluN3A subunit is incorporated, it prevents the NMDA receptor from being activated by glutamate, almost as if the receptor had been blocked by PCP.
It is unclear why the brain needs this mechanism for normal brain development and function, hence the mystery surrounding GRIN3A. One piece of evidence supporting a link between GluN3A and schizophrenia is the finding that GluN3A levels are elevated in the post-mortem brain tissue from people who had been diagnosed with schizophrenia.
In this issue of Biological Psychiatry, Japanese researchers led by Dr. Takeo Yoshikawa provide new support for this hypothesis by implicating variation in GRIN3A in the heritable risk for schizophrenia.
Schizophrenia is thought to have a substantial genetic background which is, to some extent, population-specific. Genome-wide searches have revealed many common genomic variants with weak effects, but the remaining “missing heritability” is largely unknown. Scientists theorize that it may be partly explained by rare variants with large effect.
To identify genetic variants with larger effect sizes, Yoshikawa and his colleagues examined genetic data from several Asian populations. They identified a rare variant in GRIN3A with study-wide significance.
"This discovery is important, because the ‘NMDA receptor hypothesis’ for schizophrenia is a common disease model," said Yoshikawa. "We propose a novel point of therapeutic intervention in the NMDA receptor signaling system for schizophrenia."
Dr. John Krystal, Editor of Biological Psychiatry, commented, “The notion that a genetic trait that acts like PCP in the brain produces schizophrenia is a very attractive but over-simplistic hypothesis. It is that the biology of schizophrenia is much more complicated than this single factor. Nonetheless, perhaps this study of GRIN3A brings us another step closer to understanding glutamate abnormalities in schizophrenia.”
(Source: alphagalileo.org)
Psychology Prof. Richard Russell reveals a new sign of aging in perception research
The contrasting nature of facial features is one of the signals that people unconsciously use to decipher how old someone looks, says Psychology Prof. Richard Russell, who has been collaborating with researchers from CE.R.I.E.S. (Epidermal and Sensory Research and Investigation Center), a department of Chanel Research and Technology dedicated to skin related issues and facial appearance.
“Unlike with wrinkles, none of us are consciously aware that we’re using this cue, even though it stares us in the face every day,” said Russell.
The discovery of this cue to facial age perception may partly explain why cosmetics are worn the way they are, and it lends more evidence to the idea that makeup use reflects our biological as well as our cultural heritage, according to Russell.
In one study, Russell and his team measured images of 289 faces ranging in age from 20 to 70 years old, and found that through the aging process, the color of the lips, eyes and eyebrows change, while the skin becomes darker. This results in less contrast between the features and the surrounding skin – leaving older faces to have less contrast than younger faces.
The difference in redness between the lips and the surrounding skin decreases, as does the luminance difference between the eyebrow and the forehead, as the face ages. Although not consciously aware of this sign of aging, the mind uses it as a cue for perceiving how old someone is.
In another study involving more than a hundred subjects in Gettysburg and Paris, the scientists artificially increased these facial contrasts and found that the faces were perceived as younger. When they artificially decreased the facial contrasts, the faces were perceived as older.
The image shows two identical images of the same face, except that the facial contrast has been increased in the left image and decreased in the right image. The face on the left appears younger than the one on the right.
Cosmetics are commonly used to increase aspects of facial contrast, such as the redness of lips. Scientists propose that this can partly explain why makeup is worn the way that it is – shades of lipstick that increase the redness of the lips are making the face appear younger, which is related to healthiness and beauty.
More on Russell’s study is available from PLOS ONE, an open-access publisher that makes the world’s scientific and medical literature a public resource.
How can we stlil raed words wehn teh lettres are jmbuled up?
Researchers in the UK have taken an important step towards understanding how the human brain ‘decodes’ letters on a page to read a word. The work, funded by the Economic and Social Research Council (ESRC), will help psychologists unravel the subtle thinking mechanisms involved in reading, and could provide solutions for helping people who find it difficult to read, for example in conditions such as dyslexia.
In order to read successfully, readers need not only to identify the letters in words, but also to accurately code the positions of those letters, so that they can distinguish words like CAT and ACT. At the same time, however, it’s clear that raeders can dael wtih wodrs in wihch not all teh leettrs aer in thier corerct psotiions.
"How the brain can make sense of some jumbled sequences of letters but not others is a key question that psychologists need to answer to understand the code that the brain uses when reading," says Professor Colin Davis of Royal Holloway, University of London, who led the research.
For many years researchers have used a standard psychological test to try to work out which sequences of letters in a word are important cues that the brain uses, where jumbled words are flashed momentarily on a screen to see if they help the brain to recognise the properly spelt word.
But, this technique had limitations that made it impossible to probe more extreme rearrangements of sequences of letters. Professor Davis’s team used computer simulations to work out that a simple modification to the test would allow it to question these more complex changes to words. This increases the test’s sensitivity significantly and makes it far more valuable for comparing different coding theories.
"For example, if we take the word VACATION and change it to AVACITNO, previously the test would not tell us if the brain recognises it as VACATION because other words such as AVOCADO or AVIATION might start popping into the person’s head,” says Professor Davis. "With our modification we can show that indeed the brain does relate AVACITNO to VACATION, and this starts to give us much more of an insight into the nature of the code that the brain is using – something that was not possible with the existing test."
The modified test should allow researchers not only to crack the code that the brain uses to make sense of strings of letters, but also to examine differences between individuals – how a ‘good’ reader decodes letter sequences compared with someone who finds reading difficult.
"These kinds of methods can be very sensitive to individual differences in reading ability and we are starting to get a better idea of some of the issues that underpin people’s difficulty in reading," says Professor Davis. Ultimately, this could lead to new approaches to helping people to overcome reading problems.
(Source: esrc.ac.uk)