Metabolic Switch for Storing or Burning Fat

Metabolic Switch for Storing or Burning Fat

  9:50:00 AM    Science Lover

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From Feast to Famine: A Metabolic Switch That May Help Diabetes Treatment

Humans are built to hunger for fat, packing it on during times of feast
and burning it during periods of famine. But when deluged by foods rich
in fat and sugar, the modern waistline often far exceeds the need to
store energy for lean times, and the result has been an epidemic of
diabetes, heart disease and other obesity-related problems.

The Salk researchers discovered that mice lacking a
protein known as fibroblast growth factor 1 (FGF1)
were unable to store and use fat normally. When these
mice were switched from a high-fat diet to a normal diet,
they developed uneven lumps of fat (seen in white in the
above image) in their body tissues, suggesting that their
fat metabolism mechanisms had gone awry. (Credit:
Courtesy of Jae Myoung Suh, research associate, Gene
Expression Laboratory)

Now, scientists at the Salk Institute for Biological Studies have identified the linchpin of fat metabolism, a protein known as fibroblast growth factor 1 (FGF1), which may open new avenues in the treatment of diabetes.

In a paper published April 22 in Nature, the Evans lab reports that FGF1 activity is triggered by a high-fat diet and that mice lacking the protein swiftly develop diabetes. This suggests that FGF1 is crucial to maintaining the body's sensitivity to insulin and normal levels of sugar in the blood.

"Because humans are good at storing fat during times of plenty, we are also excellent at surviving times of famine," says Ronald M. Evans, a professor in Salk's Gene Expression Laboratory and lead author of the paper. "The fat tissues of our body are like batteries, providing us with a steady source of energy when food is scarce. FGF1 governs the expansion and contraction of fat and thus controls the ebb and flow of energy throughout our body."

Obesity rates have soared in the United States in recent decades, with more than one third of U.S. adults and 17 percent of children and adolescents now considered obese, according to the Centers for Disease Control and Prevention.

As the number of overweight people has grown, so too has the incidence of metabolic disease, with nearly 26 million Americans estimated to have obesity-related type 2 diabetes. With annual costs exceeding well over $200 billion, obesity is a chronic disease that is consuming a huge portion of our health care dollars.

Although exercise and calorie restriction are known to be effective at preventing and treating diabetes, the obesity epidemic continues to grow and new drugs to treat the problem are desperately needed. Against this backdrop, the Evans' lab discovery is an important breakthrough -- -- and a surprise.

"The discovery of FGF1 was unexpected -- -- and intriguing -- -- because it was believed to do nothing," says Jae Myoung Suh, a postdoctoral researcher in Evans' laboratory and co-first author on the paper. "If you deplete FGF1 from the body, nothing happens when the mice are fed a steady low fat diet. But when given a high-fat, "Western-style" diet the mice develop an aggressive form of diabetes and experience a system-wide breakdown of their metabolic health."

"These abnormalities cause abdominal or stomach fat to become inflamed," says Michael Downes, a senior staff scientist in Salk's Gene Expression Laboratory and co-lead author on the paper. "This is important because inflamed visceral fat has been linked to heightened risk for diabetes and other obesity-related diseases, such as heart disease and stroke."

The scientists also found that FGF1 is regulated by the antidiabetic drug Actos, which is used to increase the body's sensitivity to insulin. But Actos and related drugs, though helpful, have side effects that limit their use.

Thus, Evans and his colleagues plan to explore whether FGF1 might point to a new way to control diabetes by avoiding the drawbacks of Actos and providing a more natural means of increasing insulin sensitivity.

The research was supported by the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust and the Howard Hughes Medical Institute.

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Brain Cells Responsible for Keeping Us Awake

Brain Cells Responsible for Keeping Us Awake

  11:46:00 PM    Science Lover

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Bright light arouses us. Bright light makes it easier to stay awake. Very bright light not only arouses us but is known to have antidepressant effects. Conversely, dark rooms can make us sleepy. It's the reason some people use masks to make sure light doesn't wake them while they sleep.

Researchers have identified the group of neurons
that mediates whether light arouses us and keeps
us awake, or not. (Credit: iStockphoto/Osman Safi)

Now researchers at UCLA have identified the group of neurons that mediates whether light arouses us -- or not. Jerome Siegel, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA, and colleagues report in the current online edition of the Journal of Neuroscience that the cells necessary for a light-induced arousal response are located in the hypothalamus, an area at the base of the brain responsible for, among other things, control of the autonomic nervous system, body temperature, hunger, thirst, fatigue -- and sleep.

These cells release a neurotransmitter called hypocretin, Siegel said. The researchers compared mice with and without hypocretin and found that those who didn't have it were unable to stay awake in the light, while those who had it showed intense activation of these cells in the light but not while they were awake in the dark.

This same UCLA research group earlier determined that the loss of hypocretin was responsible for narcolepsy and the sleepiness associated with Parkinson's disease. But the neurotransmitter's role in normal behavior was, until now, unclear.

"This current finding explains prior work in humans that found that narcoleptics lack the arousing response to light, unlike other equally sleepy individuals, and that both narcoleptics and Parkinson's patients have an increased tendency to be depressed compared to others with chronic illnesses," said Siegel, who is also a member of the UCLA Brain Research Institute and chief of neurobiology research at the Sepulveda Veterans Affairs Medical Center in Mission Hills, Calif.



Prior studies of the behavioral role of hypocretin in rodents had examined the neurotransmitter's function during only light phases (normal sleep time for mice) or dark phases (their normal wake time), but not both. And the studies only examined the rodents when they were performing a single task.

In the current study, researchers examined the behavioral capabilities of mice that had their hypocretin genetically "knocked-out" (KO mice) and compared them with the activities of normal, wild-type mice (WT) that still had their hypocretin neurons. The researchers tested the two groups while they performed a variety of tasks during both light and dark phases.

Surprisingly, they found that the KO mice were only deficient at working for positive rewards during the light phase. During the dark phase, however, these mice learned at the same rate as their WT littermates and were completely unimpaired in working for the same rewards.

Consistent with the data in the KO mice, the activity of hypocretin neurons in their WT littermates was maximized when working for positive rewards during the light phase, but the cells were not activated when performing the same tasks in the dark phase.

"The findings suggest that administering hypocretin and boosting the function of hypocretin cells will increase the light-induced arousal response," Siegel said. "Conversely, blocking their function by administering hypocretin receptor blockers will reduce this response and thereby induce sleep."

Further, Siegel noted, "The administration of hypocretin may also have antidepressant properties, and blocking it may increase tendencies toward depression. So we feel this work has implications for treating sleep disorders as well as depression."

Other authors on the study included Ronald McGregor (first author), Ming-Fung Wu, Grace Barber and Lalini Ramanathan, all of UCLA, the Veterans Affairs Greater Los Angeles Healthcare System and the UCLA Brain Research Institute.

The research was supported by the National Institutes of Health and the Medical Research Service of the Department of Veterans Affairs. The authors report no conflict of interest.

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New Treatments for Baldness? Scientists Find Stem Cells That Tell Hair It's Time to Grow

New Treatments for Baldness? Scientists Find Stem Cells That Tell Hair It's Time to Grow

  12:41:00 AM    Science Lover

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Yale researchers have discovered the source of signals that trigger hair growth, an insight that may lead to new treatments for baldness.

Researchers have discovered the source of signalsthat 
trigger hair growth, an insight that may lead to new 
treatments for baldness. (Credit: © Tasosk / Fotolia)

The researchers identified stem cells within the skin's fatty layer and showed that molecular signals from these cells were necessary to spur hair growth in mice, according to research published in the Sept. 2 issue of the journal Cell.

"If we can get these fat cells in the skin to talk to the dormant stem cells at the base of hair follicles, we might be able to get hair to grow again," said Valerie Horsley, assistant professor of molecular, cellular and developmental biology and senior author of the paper.

Men with male pattern baldness still have stem cells in follicle roots but these stem cells lose the ability to jump-start hair regeneration. Scientists have known that these follicle stem cells need signals from within the skin to grow hair, but the source of those signals has been unclear.




Horsley's team observed that when hair dies, the layer of fat in the scalp that comprises most of the skin's thickness shrinks. When hair growth begins, the fat layer expands in a process called adipogenesis. Researchers found that a type of stem cell involved in creation of new fat cells -- adipose precursor cells -- was required for hair regeneration in mice. They also found these cells produce molecules called PDGF (platelet derived growth factors), which are necessary to produce hair growth.

Horsley's lab is trying to identify other signals produced by adipose precursor stem cells that may play a role in regulating hair growth. She also wants to know whether these same signals are required for human hair growth. Other authors from Yale are lead author Eric Festa, Jackie Fretz, Ryan Berry, Barbara Schmidt, Matthew Rodeheffer and Mark Horowitz.

The work was funded by the National Institutes of Health and the Connecticut Stem Cell Research Program.

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Glowing, Blinking Bacteria Reveal How Cells Synchronize Biological Clocks

Glowing, Blinking Bacteria Reveal How Cells Synchronize Biological Clocks

  5:17:00 PM    Science Lover

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Biologists have long known that organisms from bacteria to humans use the 24 hour cycle of light and darkness to set their biological clocks. But exactly how these clocks are synchronized at the molecular level to perform the interactions within a population of cells that depend on the precise timing of circadian rhythms is less well understood.

Green fluorescent protein causes the E. coli to glow 
when the cells' clock is activated. (Credit: UC San Diego)

To better understand that process, biologists and bioengineers at UC San Diego created a model biological system consisting of glowing, blinking E. coli bacteria. This simple circadian system, the researchers report in the September 2 issue of Science, allowed them to study in detail how a population of cells synchronizes their biological clocks and enabled the researchers for the first time to describe this process mathematically.

"The cells in our bodies are entrained, or synchronized, by light and would drift out of phase if not for sunlight," said Jeff Hasty, a professor of biology and bioengineering at UC San Diego who headed the research team. "But understanding the phenomenon of entrainment has been difficult because it's difficult to make measurements. The dynamics of the process involve many components and it's tricky to precisely characterize how it works. Synthetic biology provides an excellent tool for reducing the complexity of such systems in order to quantitatively understand them from the ground up. It's reductionism at its finest."

To study the process of entrainment at the genetic level, Hasty and his team of researchers at UC San Diego's Biocircuits Institute combined techniques from synthetic biology, microfluidic technology and computational modeling to build a microfluidic chip with a series of chambers containing populations of E. coli bacteria. Within each bacterium, the genetic machinery responsible for the biological clock oscillations was tied to green fluorescent protein, which caused the bacteria to periodically fluoresce.



To simulate day and night cycles, the researchers modified the bacteria to glow and blink whenever arabinose -- a chemical that triggered the oscillatory clock mechanisms of the bacteria -- was flushed through the microfluidic chip. In this way, the scientists were able to simulate periodic day-night cycles over a period of only minutes instead of days to better understand how a population of cells synchronizes its biological clocks.

Hasty said a similar microfluidic system in principal could be constructed with mammalian cells to study how human cells synchronize with light and darkness. Such genetic model systems would have important future applications since scientists have discovered that problems with the biological clock can result in many common medical problems from diabetes to sleep disorders.

Other members of Hasty's team included Lev Tsimring, associate director of the BioCircuits Institute, and bioengineering graduate students Octavio Mondragon, Tal Danino and Jangir Selimkhanov. Their research was supported by grants from the National Institutes of Health and General Medicine and the San Diego Center for Systems Biology.

Story Source: The above story is reprinted (with editorial adaptations) from materials provided by University of California - San Diego.

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Word Association: Study Matches Brain Scans With Complex Thought

Word Association: Study Matches Brain Scans With Complex Thought

  4:16:00 PM    Science Lover

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In an effort to understand what happens in the brain when a person reads or considers such abstract ideas as love or justice, Princeton researchers have for the first time matched images of brain activity with categories of words related to the concepts a person is thinking about. The results could lead to a better understanding of how people consider meaning and context when reading or thinking.

Princeton researchers developed a method to determine the
probability of various words being associated with the object a person
thought about during a brain scan. They produced color-coded figures
that illustrate the probability of words within the Wikipedia article
about the object the participant saw during the scan actually being
associated with the object. The more red a word is, the more likely a
person is to associate it, in this case, with "cow." On the other hand,
bright blue suggests a strong correlation with "carrot." Black and grey
"neutral" words had no specific association or were not considered at
all. (Credit: Illustration courtesy of Francisco Pereira)

The researchers report in the journal Frontiers in Human Neuroscience that they used functional magnetic resonance imaging (fMRI) to identify areas of the brain activated when study participants thought about physical objects such as a carrot, a horse or a house. The researchers then generated a list of topics related to those objects and used the fMRI images to determine the brain activity that words within each topic shared. For instance, thoughts about "eye" and "foot" produced similar neural stirrings as other words related to body parts.

Once the researchers knew the brain activity a topic sparked, they were able to use fMRI images alone to predict the subjects and words a person likely thought about during the scan. This capability to put people's brain activity into words provides an initial step toward further exploring themes the human brain touches upon during complex thought.

"The basic idea is that whatever subject matter is on someone's mind -- not just topics or concepts, but also, emotions, plans or socially oriented thoughts -- is ultimately reflected in the pattern of activity across all areas of his or her brain," said the team's senior researcher, Matthew Botvinick, an associate professor in Princeton's Department of Psychology and in the Princeton Neuroscience Institute.

"The long-term goal is to translate that brain-activity pattern into the words that likely describe the original mental 'subject matter,'" Botvinick said. "One can imagine doing this with any mental content that can be verbalized, not only about objects, but also about people, actions and abstract concepts and relationships. This study is a first step toward that more general goal.

"If we give way to unbridled speculation, one can imagine years from now being able to 'translate' brain activity into written output for people who are unable to communicate otherwise, which is an exciting thing to consider. In the short term, our technique could be used to learn more about the way that concepts are represented at the neural level -- how ideas relate to one another and how they are engaged or activated."

The research, which was published Aug. 23, was funded by a grant from the National Institute of Neurological Disease and Stroke, part of the National Institutes of Health.

Depicting a person's thoughts through text is a "promising and innovative method" that the Princeton project introduces to the larger goal of correlating brain activity with mental content, said Marcel Just, a professor of psychology at Carnegie Mellon University. The Princeton researchers worked from brain scans Just had previously collected in his lab, but he had no active role in the project.

"The general goal for the future is to understand the neural coding of any thought and any combination of concepts," Just said. "The significance of this work is that it points to a method for interpreting brain activation patterns that correspond to complex thoughts."

Tracking the brain's 'semantic threads'

Largely designed and conducted in Botvinick's lab by lead author and Princeton postdoctoral researcher Francisco Pereira, the study takes a currently popular approach to neuroscience research in a new direction, Botvinick said. He, Pereira and coauthor Greg Detre, who earned his Ph.D. from Princeton in 2010, based their work on various research endeavors during the past decade that used brain-activity patterns captured by fMRI to reconstruct pictures that participants viewed during the scan.

"This 'generative' approach -- actually synthesizing something, an artifact, from the brain-imaging data -- is what inspired us in our study, but we generated words rather than pictures," Botvinick said.

"The thought is that there are many things that can be expressed with language that are more difficult to capture in a picture. Our study dealt with concrete objects, things that are easy to put into a picture, but even then there was an interesting difference between generating a picture of a chair and generating a list of words that a person associates with 'chair.'"

Those word associations, lead author Pereira explained, can be thought of as "semantic threads" that can lead people to think of objects and concepts far from the original subject matter yet strangely related.

"Someone will start thinking of a chair and their mind wanders to the chair of a corporation then to Chairman Mao -- you'd be surprised," Pereira said. "The brain tends to drift, with multiple processes taking place at the same time. If a person thinks about a table, then a lot of related words will come to mind, too. And we thought that if we want to understand what is in a person's mind when they think about anything concrete, we can follow those words."

Pereira and his co-authors worked from fMRI images of brain activity that a team led by Just and fellow Carnegie Mellon researcher Tom Mitchell, a professor of computer science, published in the journal Science in 2008. For those scans, nine people were presented with the word and picture of five concrete objects from 12 categories. The drawing and word for the 60 total objects were displayed in random order until each had been shown six times. Each time an image and word appeared, participants were asked to visualize the object and its properties for three seconds as the fMRI scanner recorded their brain activity.

Matching words and brain activity with related topics

Separately, Pereira and Detre constructed a list of topics with which to categorize the fMRI data. They used a computer program developed by Princeton Associate Professor of Computer Science David Blei to condense 3,500 articles about concrete objects from the online encyclopedia Wikipedia into all the topics the articles covered. The articles included a broad array of subjects, such as an airplane, heroin, birds and manual transmission. The program came up with 40 possible topics -- such as aviation, drugs, animals or machinery -- with which the articles could relate. Each topic was defined by the words most associated with it.

The computer ultimately created a database of topics and associated words that were free from the researchers' biases, Pereira said.

"We let the software discern the factors that make up meaning rather than stipulating it ourselves," he said. "There is always a danger that we could impose our preconceived notions of the meaning words have. Plus, I can identify and describe, for instance, a bird, but I don't think I can list all the characteristics that make a bird a bird. So instead of postulating, we let the computer find semantic threads in an unsupervised manner."




The topic database let the researchers objectively arrange the fMRI images by subject matter, Pereira said. To do so, the team searched the brain scans of related objects for similar activity to determine common brain patterns for an entire subject, Pereira said. The neural response for thinking about "furniture," for example, was determined by the common patterns found in the fMRI images for "table," "chair," "bed," "desk" and "dresser." At the same time, the team established all the words associated with "furniture" by matching each fMRI image with related words from the Wikipedia-based list.

Based on the similar brain activity and related words, Pereira, Botvinick and Detre concluded that the same neural response would appear whenever a person thought of any of the words related to furniture, Pereira said. And a scientist analyzing that brain activity would know that person was thinking of furniture. The same would follow for any topic.

Using images to predict the words on a person's mind
Finally, to ensure their method was accurate, the researchers conducted a blind comparison of each of the 60 fMRI images against each of the others. Without knowing the objects the pair of scans pertained to, Pereira and his colleagues estimated the presence of certain topics on a participant's mind based solely on the fMRI data. Knowing the applicable Wikipedia topics for a given brain image, and the keywords for each topic, they could predict the most likely set of words associated with the brain image.

The researchers found that they could confidently determine from an fMRI image the general topic on a participant's mind, but that deciphering specific objects was trickier, Pereira said. For example, they could compare the fMRI scan for "carrot" against that for "cow" and safely say that at the time the participant had thought about vegetables in the first example instead of animals. In turn, they could say that the person most likely thought of other words related to vegetables, as opposed to words related to animals.

On the other hand, when the scan for "carrot" was compared to that for "celery," Pereira and his colleagues knew the participant had thought of vegetables, but they could not identify related words unique to either object.

One aim going forward, Pereira said, is to fine-tune the group's method to be more sensitive to such detail. In addition, he and Botvinick have begun performing fMRI scans on people as they read in an effort to observe the various topics the mind accesses.

"Essentially," Pereira said, "we have found a way to generally identify mental content through the text related to it. We can now expand that capability to even further open the door to describing thoughts that are not amenable to being depicted with pictures."

Story Source:
The above story is reprinted (with editorial adaptations) from materials provided by Princeton University.

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Biologists Discovery May Force Revision of Biology Textbooks: Novel Chromatin Particle Halfway Between DNA and a Nucleosome

Biologists Discovery May Force Revision of Biology Textbooks: Novel Chromatin Particle Halfway Between DNA and a Nucleosome

  10:16:00 AM    Science Lover

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Basic biology textbooks may need a bit of revising now that biologists at UC San Diego have discovered a never-before-noticed component of our basic genetic material.

Biologists have discovered a novel chromatin 
particle halfway between DNA and a nucleosome. 
While it looks like a nucleosome, it is in fact a 
distinct particle of its own, researchers say. 
(Credit: James Kadonaga, UC San Diego)

According to the textbooks, chromatin, the natural state of DNA in the cell, is made up of nucleosomes. And nucleosomes are the basic repeating unit of chromatin.

When viewed by a high powered microscope, nucleosomes look like beads on a string. But in the Aug. 19 issue of the journal Molecular Cell, UC San Diego biologists report their discovery of a novel chromatin particle halfway between DNA and a nucleosome. While it looks like a nucleosome, they say, it is in fact a distinct particle of its own.

"This novel particle was found as a precursor to a nucleosome," said James Kadonaga, a professor of biology at UC San Diego who headed the research team and calls the particle a "pre-nucleosome." "These findings suggest that it is necessary to reconsider what chromatin is. The pre-nucleosome is likely to be an important player in how our genetic material is duplicated and used."



The biologists say that while the pre-nucleosome may look something like a nucleosome under the microscope, biochemical tests have shown that it is in reality halfway between DNA and a nucleosome.

These pre-nucleosomes, the researchers say, are converted into nucleosomes by a motor protein that uses the energy molecule ATP.

"The discovery of pre-nucleosomes suggests that much of chromatin, which has been generally presumed to consist only of nucleosomes, may be a mixture of nucleosomes and pre-nucleosomes," said Kadonaga. "So, this discovery may be the beginning of a revolution in our understanding of what chromatin is."

"The packaging of DNA with histone proteins to form chromatin helps stabilize chromosomes and plays an important role in regulating gene activities and DNA replication," said Anthony Carter, who oversees chromatin grants at the National Institute of General Medical Sciences of the National Institutes of Health, which funded the research. "The discovery of a novel intermediate DNA-histone complex offers intriguing insights into the nature of chromatin and may help us better understand how it impacts these key cellular processes."

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Cellular Stress Can Induce Yeast to Promote Prion Formation

Cellular Stress Can Induce Yeast to Promote Prion Formation

  6:53:00 PM    Science Lover

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It's a chicken and egg question. Where do the infectious protein particles called prions come from? Essentially clumps of misfolded proteins, prions cause neurodegenerative disorders, such as mad cow/Creutzfeld-Jakob disease, in humans and animals. Prions trigger the misfolding and aggregation of their properly folded protein counterparts, but they usually need some kind of "seed" to get started.

Biochemists at Emory University School of Medicine have identified a yeast protein called Lsb2 that can promote spontaneous prion formation. This unstable, short-lived protein is strongly induced by cellular stresses such as heat. Lsb2's properties also illustrate how cells have developed ways to control and regulate prion formation. Research in yeast has shown that sometimes, prions can actually help cells adapt to different conditions.

The results are published in the July 22 issue of the journal Molecular Cell. The senior author is Keith Wilkinson, PhD, professor of biochemistry at Emory University School of Medicine The first author is senior associate Tatiana Chernova, PhD.

The aggregated form of proteins connected with several other neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's can, in some circumstances, act like prions. So the Emory team's finding provides insight into how the ways that cells deal with stress might lead to poisonous protein aggregation in human diseases.

"A direct human homolog of Lsb2 doesn't exist, but there may be a protein that performs the same function," Wilkinson says. "The mechanism may say more about other types of protein aggregates than about classical prions in humans, This mechanism of seeding and growth may be more important for aggregate formation in diseases such as Huntington's."



Lsb2 does not appear to form stable prions by itself. Rather, it seems to bind to and encourage the aggregation of another protein, Sup35, which does form prions.

"Our model is that stress induces high levels of Lsb2, which allows the accumulation of misfolded prion proteins," Wilkinson says. "Lsb2 protects enough of these newborn prion particles from the quality control machinery for a few of them to get out."

The research was supported by the National Institutes of Health.

More information: T.A. Chernova et al. Prion Induction by the Short-lived Stress Induced Protein Lsb2 Is Regulated by Ubiquitination and Association with the Actin Cytoskeleton Mol. Cell (2011).
Provided by Emory University

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Memories May Skew Visual Perception

Memories May Skew Visual Perception

  6:46:00 PM    Science Lover

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Taking a trip down memory lane while you are driving could land you in a roadside ditch, new research indicates. Vanderbilt University psychologists have found that our visual perception can be contaminated by memories of what we have recently seen, impairing our ability to properly understand and act on what we are currently seeing.

aking a trip down memory lane while you are driving could 
land you in a roadside ditch, new research indicates. 
(Credit: © yellowj / Fotolia)

"This study shows that holding the memory of a visual event in our mind for a short period of time can 'contaminate' visual perception during the time that we're remembering," Randolph Blake, study co-author and Centennial Professor of Psychology, said.

"Our study represents the first conclusive evidence for such contamination, and the results strongly suggest that remembering and perceiving engage at least some of the same brain areas."

The study, led by research associate Min-Suk Kang, was recently published in the journal Psychonomic Bulletin & Review.

"There are numerous instances where we engage in visually guided activities, such as driving, while rehashing visual events in our mind's eye. Common sense tells us that this mental replay is harmless in that it does not interfere with our ability to register and react to objects within our visual field," Kang and his co-authors wrote. "Evidently, however, that is not always true when the contents of our working memories overlap with the contents of our perceptual world."

Illusion offers clues

In this study, the researchers used a visual illusion called motion repulsion to learn whether information held in working memory affects perception. This illusion is produced when two sets of moving dots are superimposed, with dots in one set moving in a different direction from those in the other set. Under these conditions, people tend to misperceive the actual directions of motion, and perceive a larger difference between the two sets of motions than actually exists.



Ordinarily this illusion is produced by having people view both sets of motion at the same time. Kang and colleagues set out to determine if the illusion would occur when one set of motions, rather than being physically present, was held in working memory.

In the experiment, participants were shown a random pattern of dots and were asked to remember the direction in which the dots were moving. They were then were shown a second pattern of moving dots. They were asked to report on the direction of second dots' movement.

The research subjects' reports of the second dots' movement was exaggerated and influenced by what they had previously seen. If they were first shown dots moving in one direction and later shown dots moving in a slightly counterclockwise direction relative to the first presented dots, they reported the counterclockwise movement to be more dramatic than it had actually been.

"We find that observers misperceive the actual direction of motion of a single motion stimulus if, while viewing that stimulus, they are holding a different motion direction in visual working memory," the authors wrote.

The results provide further support for previous findings by Vanderbilt researchers Frank Tong and Stephanie Harrison that the contents of working memory may be represented in early visual areas in the brain, including the primary visual cortex, that were previously thought to play no role in higher cognitive functions such as memory.

"Our findings provide compelling evidence that visual working memory representations directly interact with the same neural mechanisms involved in processing basic sensory events," Kang and his colleagues wrote.

Kang and Blake's co-authors were research associate Sang Wook Hong and Assistant Professor of Psychology Geoffrey Woodman. Funding from the National Institutes of Health, the National Science Foundation and the World Class University Initiative of the National Research Foundation of Korea and the Ministry of Education, Science and Technology supported the research.

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It's Not an Apple a Day After All -- It's Strawberries: Flavonoids Could Represent Two-Fisted Assault On Diabetes and Nervous System Disorders

It's Not an Apple a Day After All -- It's Strawberries: Flavonoids Could Represent Two-Fisted Assault On Diabetes and Nervous System Disorders

  8:52:00 PM    Science Lover

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A recent study from scientists at the Salk Institute for Biological Studies suggests that a strawberry a day (or more accurately, 37 of them) could keep not just one doctor away, but an entire fleet of them, including the neurologist, the endocrinologist, and maybe even the oncologist.

Fisetin, a naturally-occurring flavonoid found most 
abundantly in strawberries, lessens complications of diabetes. 
(Credit: Courtesy of the Salk Institute for Biological Studies)

Investigations conducted in the Salk Institute's Cellular Neurobiology Laboratory (CNL) will appear in the June 27, 2011, issue of PLoS ONE. The report explains that fisetin, a naturally-occurring flavonoid found most abundantly in strawberries and to a lesser extent in other fruits and vegetables, lessens complications of diabetes. Previously, the lab showed that fisetin promoted survival of neurons grown in culture and enhanced memory in healthy mice. That fisetin can target multiple organs strongly suggests that a single drug could be used to mitigate numerous medical complications.

"This manuscript describes for the first time a drug that prevents both kidney and brain complications in a type 1 diabetes mouse model," says David Schubert, Ph.D., professor and head of the Cellular Neurobiology Laboratory and one of the manuscript's co-authors. "Moreover, it demonstrates the probable molecular basis of how the therapeutic is working."

Pam Maher, Ph.D., a senior staff scientist in the CNL, is the study's corresponding author. Maher initially identified fisetin as a neuroprotective flavonoid ten years ago. "In plants, flavonoids act as sunscreens and protect leaves and fruit from insects," she explains. "As foods they are implicated in the protective effect of the 'Mediterranean Diet.'"

Other celebrity flavonoids include polyphenolic compounds in blueberries and red wine.

Although her group's focus is neurobiology, Maher and colleagues reasoned that, like other flavonoids, fisetin might ameliorate a spectrum of disorders seen in diabetic patients. To test this, they evaluated effects of fisetin supplementation in Akita mice, a very robust model of type 1 diabetes, also called childhood onset diabetes.

Akita mice exhibit increased blood sugar typical of type 1 diabetes and display pathologies seen in serious human complications of both type 1 and 2 diabetes. Those include diabetic nephropathy or kidney disease, retinopathy, and neuropathies in which patients lose touch or heat sensations.

Mice fed a fisetin-enriched diet remained diabetic, but acute kidney enlargement-or hypertrophy-seen in untreated mice was reversed, and high urine protein levels, a sure sign of kidney disease, fell. Moreover, fisetin ingestion ameliorated anxiety-related behaviors seen in diabetic mice. "Most mice put in a large area become exploratory," says Maher. "But anxious mice tend not to move around. Akita mice showed enhanced anxiety behavior, but fisetin feeding restored their locomotion to more normal levels."



The study also defines a likely molecular mechanism underlying these effects. Researchers observed that blood and brain levels of sugars affixed to proteins known as advanced glycation end-products-or AGEs-were reduced in fisetin-treated compared to untreated Akita mice. These decreases were accompanied by increased activity of the enzyme glyoxalase 1, which promotes removal of toxic AGE precursors.

The discovery of an AGE-antagonizing enzyme upregulated by fisetin is very intriguing, because substantial evidence implicates high blood AGE levels with many if not most diabetic complications. "We know that fisetin increases activity of the glyoxalase enzyme and may increase its expression," says Maher. "But what is important is that ours is the first report that any compound can enhance glyoxalase 1 activity."

Interestingly, excessively high AGE levels also correlate with inflammatory activity thought to promote some cancers. In fact, studies published by others confirm that fisetin decreases tumorigenicity of prostate cancer cells both in culture and in animal models, which if supported would represent a major added incentive to eat your strawberries.

To ingest fisetin levels equivalent to those fed Akita mice, Maher estimates that humans would have to eat 37 strawberries a day, assuming that strawberry fisetin is as readily metabolizable by humans as fisetin-spiked lab chow is by mice. Rather than through diet, Maher envisions that fisetin-like drugs could be taken as a supplement.

Schubert notes that fisetin is also effective in mouse models of Alzheimer's disease. "We and others have shown that diabetes may be a risk factor for Alzheimer's disease, making identification of a safe prophylactic like fisetin highly significant," he says.

Maher acknowledges that the public may be suffering from flavonoid-fatigue, given media coverage of the promises of these compounds. "Polyphenolics like fisetin and those in blueberry extracts are found in fruits and vegetables and are related to each other chemically," she says. "There is increasing evidence that they all work in multiple diseases. Hopefully some combination of these compounds will eventually get to the clinic."

Schubert concurs that their findings only reinforce what common sense and our mothers told us was a healthy lifestyle. "Eat a balanced diet and as much freshly prepared organic food as possible, get some exercise, keep socially and mentally active and avoid sodas with sugar and highly processed foods since they can contain high levels of AGEs," he advises.

But he also worries that hoops that must be jumped through to bring a natural product like fisetin, as opposed to a totally synthetic drug, to clinical trials are daunting because it is difficult to protect patents on natural products. "We will never know if a compound like fisetin works in humans until someone is willing to support a clinical trial."

Also contributing to this study were Richard Dargusch and Jennifer L. Ehren, Ph.D.,of the Cellular Neurobiology Laboratory, and Kumar Sharma, M.D., and Shinichi Okada, M.D., Ph.D., of the Department of Medicine at University of California, San Diego.

Funding for the study came from the Fritz B. Burns Foundation, the Juvenile Diabetes Research Foundation, the Hewitt Foundation, and the National Institutes of Health.

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Prolonged TV Viewing Linked to Health Risks

Prolonged TV Viewing Linked to Health Risks

  11:08:00 PM    Science Lover

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Watching television is the most common daily activity apart from work and sleep in many parts of the world, but it is time for people to change their viewing habits. According to a new study from Harvard School of Public Health (HSPH) researchers, prolonged TV viewing was associated with increased risk of type 2 diabetes, cardiovascular disease, and premature death.

New research finds that prolonged TV viewing is 
associated with increased risk of type 2 diabetes, 
cardiovascular disease, and premature death. 
(Credit: © alessandrozocc / Fotolia)

The study appears in the June 15, 2011, edition of the Journal of the American Medical Association.

"The message is simple. Cutting back on TV watching can significantly reduce risk of type 2 diabetes, heart disease, and premature mortality," said senior author Frank Hu, professor of nutrition and epidemiology at HSPH. "We should not only promote increasing physical activity levels but also reduce sedentary behaviors, especially prolonged TV watching," said Hu.

Many people around the world divide their days largely between working, sleeping, and watching television, according to the researchers. Europeans spend an average of 40 percent of their daily free time in front of the television set; Australians, 50 percent. This corresponds to three to four hours of daily viewing -- still less than a reported average of five hours in the U.S. The negative health effects of TV viewing have been documented in prior studies, including associations with reduced physical activity levels and unhealthy diets.



Hu and first author Anders Grøntved, a doctoral student and visiting researcher in the HSPH Department of Nutrition, conducted a meta-analysis, a systematic assessment of all published studies from 1970 to 2011 that linked TV viewing with increased risk of type 2 diabetes, cardiovascular disease, and premature death. Eight large prospective cohort studies from the United States, Europe, and Australia met the researchers' criteria and were included in the meta-analysis.

The results showed that more than two hours of TV viewing per day increased risk of type 2 diabetes and cardiovascular disease, and more than three hours of daily viewing increased risk of premature death. For each additional two hours of TV viewing per day, the risk of type 2 diabetes, cardiovascular disease, and premature mortality increased by 20, 15, and 13 percent respectively. Based on disease incidence in the United States, Hu and Grøntved estimated that among 100,000 individuals per year, each 2-hour increment in TV viewing per day was associated with 176 new cases of type 2 diabetes, 38 new cases of fatal cardiovascular disease, and 104 new cases of all-cause mortality.

Hu and Grøntved found that the effect of prolonged television viewing on type 2 diabetes, which usually occurs in adults, was to some extent explained by the unfavorable influence of TV viewing on obesity. Obesity is related to unhealthy eating habits and low activity levels, major risk factors for both type 2 diabetes and cardiovascular disease.

Limitations to the meta-analysis included the relatively small number of studies and that the assessment of TV viewing was self-reported by participants. In addition, the majority of the studies did not assess the role of diet and physical activity in explaining the adverse effects of TV watching on chronic disease risk.

"Sedentary lifestyle, especially prolonged TV watching, is clearly an important and modifiable risk factor for type 2 diabetes and cardiovascular disease," said Grøntved. "Future research should also look into the effects of extensive use of new media devices on energy balance and chronic disease risk."

Support for the study was provided by the Danish Heart Foundation, Sygekassernes Helsefond (the Danish Health Fund), the Oticon Foundation, the Augustinus Foundation, and the National Institutes of Health.

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New Clues About Aging: Genetic Splicing Mechanism Triggers Both Premature Aging Syndrome and Normal Cellular Aging

New Clues About Aging: Genetic Splicing Mechanism Triggers Both Premature Aging Syndrome and Normal Cellular Aging

  12:36:00 AM    Science Lover

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National Institutes of Health researchers have identified a new pathway that sets the clock for programmed aging in normal cells. The study provides insights about the interaction between a toxic protein called progerin and telomeres, which cap the ends of chromosomes like aglets, the plastic tips that bind the ends of shoelaces.

The 46 human chromosomes are shown in blue, with 
the telomeres appearing as white pinpoints. The DNA 
has already been copied, so each chromosome is 
actually made up of two identical lengths of DNA, 
each with its own two telomeres. 
(Credit: Hesed Padilla-Nash and Thomas Ried)

The study by researchers from the National Human Genome Research Institute (NHGRI) appears online in the Journal of Clinical Investigation.

Telomeres wear away during cell division. When they degrade sufficiently, the cell stops dividing and dies. The researchers have found that short or dysfunctional telomeres activate production of progerin, which is associated with age-related cell damage. As the telomeres shorten, the cell produces more progerin.

Progerin is a mutated version of a normal cellular protein called lamin A, which is encoded by the normal LMNA gene. Lamin A helps to maintain the normal structure of a cell's nucleus, the cellular repository of genetic information.

In 2003, NHGRI researchers discovered that a mutation in LMNA causes the rare premature aging condition, progeria, formally known as known as Hutchinson-Gilford progeria syndrome. Progeria is an extremely rare disease in which children experience symptoms normally associated with advanced age, including hair loss, diminished subcutaneous fat, premature atherosclerosis and skeletal abnormalities. These children typically die from cardiovascular complications in their teens.

"Connecting this rare disease phenomenon and normal aging is bearing fruit in an important way," said NIH Director Francis S. Collins, M.D., Ph.D., a senior author of the current paper. "This study highlights that valuable biological insights are gained by studying rare genetic disorders such as progeria. Our sense from the start was that progeria had a lot to teach us about the normal aging process and clues about more general biochemical and molecular mechanisms."



Collins led the earlier discovery of the gene mutation responsible for progeria and subsequent advances at NIH in understanding the biochemical and molecular underpinnings of the disease.

In a 2007 study, NIH researchers showed that normal cells of healthy people can produce a small amount of progerin, the toxic protein, even when they do not carry the mutation. The more cell divisions the cell underwent, the shorter the telomeres and the greater the production of progerin. But a mystery remained: What was triggering the production of the toxic progerin protein?

The current study shows that the mutation that causes progeria strongly activates the splicing of lamin A to produce the toxic progerin protein, leading to all of the features of premature aging suffered by children with this disease. But modifications in the splicing of LMNA are also at play in the presence of the normal gene.

The research suggests that the shortening of telomeres during normal cell division in individuals with normal LMNA genes somehow alters the way a normal cell processes genetic information when turning it into a protein, a process called RNA splicing. To build proteins, RNA is transcribed from genetic instructions embedded in DNA. RNA does not carry all of the linear information embedded in the ribbon of DNA; rather, the cell splices together segments of genetic information called exons that contain the code for building proteins, and removes the intervening letters of unused genetic information called introns. This mechanism appears to be altered by telomere shortening, and affects protein production for multiple proteins that are important for cytoskeleton integrity. Most importantly, this alteration in RNA splicing affects the processing of the LMNA messenger RNA, leading to an accumulation of the toxic progerin protein.

Cells age as part of the normal cell cycle process called senescence, which progressively advances through a limited number of divisions in the cell lifetime. "Telomere shortening during cellular senescence plays a causative role in activating progerin production and leads to extensive change in alternative splicing in multiple other genes," said lead author Kan Cao, Ph.D., an assistant professor of cell biology and molecular genetics at the University of Maryland, College Park.

Telomerase is an enzyme that can extend the structure of telomeres so that cells continue to maintain the ability to divide. The study supplied support for the telomere-progerin link, showing that cells that have a perpetual supply of telomerase, known as immortalized cells, produce very little progerin RNA. Most cells of this kind are cancer cells, which do not reach a normal cell cycle end point, and instead replicate out of control.

The researchers also conducted laboratory tests on normal cells from healthy individuals using biochemical markers to indicate the occurrence of progerin-generating RNA splicing in cells. The cell donors ranged in age from 10 to 92 years. Regardless of age, cells that passed through many cell cycles had progressively higher progerin production. Normal cells that produce higher concentrations of progerin also displayed shortened and dysfunctional telomeres, the tell-tale indication of many cell divisions.

In addition to their focus on progerin, the researchers conducted the first systematic analysis across the genome of alternative splicing during cellular aging, considering which other protein products are affected by jumbled instructions as RNA molecules assemble proteins through splicing. Using laboratory techniques that analyze the order of chemical units of RNA, called nucleotides, the researchers found that splicing is altered by short telomeres, affecting lamin A and a number of other genes, including those that encode proteins that play a role in the structure of the cell.

The researchers suggest that the combination of telomere fraying and loss with progerin production together induces cell aging. This finding lends insights into how progerin may participate in the normal aging process.

For more about Hutchinson-Gilford progeria syndrome, see: http://www.genome.gov/11007255.

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Quitting Smoking Without Gaining Weight

Quitting Smoking Without Gaining Weight

  3:41:00 PM    Science Lover

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Smokers tend to die young, but they tend to die thinner than non-smokers. A team of scientists led by Yale School of Medicine has discovered exactly how nicotine suppresses appetite -- findings that suggest that it might be possible to develop a drug that would help smokers, and non-smokers, stay thin.

Scientists have discovered exactly how nicotine suppresses appetite -- findings that suggest that it might be possible to develop a drug that would help smokers, and non-smokers, stay thin.

Nicotine activates a small set of neurons in a section of the hypothalamus that signals the body has had enough to eat, the researchers report in the June 10 issue of the journal Science. Nicotine accomplishes this trick by activating a different set of receptors on the surface of neurons than those that trigger a craving for tobacco.

"Unfortunately, smoking does keep weight off," said Marina Picciotto, the Charles B.G. Murphy Professor of Psychiatry, professor of neurobiology and pharmacology and senior author of the paper. "Many people say they won't quit smoking because they'll gain weight. Ultimately, we would like to help people maintain their body weight when they kick the habit and perhaps help non-smokers who are struggling with obesity."

Picciotto is an expert on the function of nicotine receptors located on the surface of neurons. Nicotinic acetylcholine receptors have many functions, and in the brain are the primary targets of nicotine. Yann Mineur, an associate research scientist in her lab, was investigating a potential drug for depression that acts upon these receptors when he noticed that mice given the drug ate less than those not on the medication. With the help of researchers at Carleton University in Ottawa and the University of Hawaii, they decided to investigate why.

In a variety of experiments, the researchers found that the experimental drug activated a specific type of nicotine receptor, which in turn activated the subset of neurons in the hypothalamus, called pro-opiomelanocortin or POMC cells. The team also found that when subjected to nicotine, mice lacking the POMC pathway did not lose weight, unlike mice with the pathway intact. Intriguingly, they also showed that these receptors were of a different type than those known to trigger tobacco craving in smokers.

"This suggests it is possible to get the effect of appetite suppression without also triggering the brain's reward centers," Picciotto said. Baylor College of Medicine contributed to the study. Other Yale authors are Yan Rao, Ralph J. DiLeone, Sabrina Diano, Tamas L. Horvath and Xiao-Bing Gao.

The study was funded by the National Institutes of Health.

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Mechanism of Long-Term Memory Identified

Mechanism of Long-Term Memory Identified

  12:59:00 AM    Science Lover

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Using advanced imaging technology, scientists from the Florida campus of The Scripps Research Institute have identified a change in chemical influx into a specific set of neurons in the common fruit fly that is fundamental to long-term memory.

Researchers have identified a change in chemical influx 
into a specific set of neurons in the common fruit fly that 
is fundamental to long-term memory. 
(Credit: © Sebastian Kaulitzki / Fotolia)

The study was published in the April 13, 2011 issue of The Journal of Neuroscience.

"In studying fruit flies' learning and long-term memory storage, we observed an increase in calcium influx into a specific set of brain neurons in normal fruit flies that was absent in 26 different mutants known to impair long-term memory,," said Ron Davis, chair of the Scripps Research Department of Neuroscience, who led the study. "This logical conclusion is that this increase, which we call a memory trace, is a signature component of long-term memory."

The memory trace in question is an increased influx of calcium into a set of neurons after long-term memory forms in a part of the insect brain known as mushroom bodies, a pair of oversized lobes known to mediate learning and memory, particularly the memories of smell. They have been compared to the hippocampus, a site of memory formation in humans.

Increases in calcium influx also occur with learning in other animal models, Davis said, and it seems highly likely a similar correlation exists in humans.

Measuring Memory Traces


To measure the changes in the Drosophila neurons, Davis and his colleagues used functional optical imaging, an advanced technology that his laboratory helped pioneer for the study of learning and memory. Using protein sensors that become fluorescent when calcium levels are increased, the team was able to highlight changes in the levels of calcium influx into the mushroom body neurons in response to odor learning. These observed memory traces occur in parallel with behavioral changes.

Interestingly, these memory traces occur only with spaced conditioning -- where the insects receive multiple episodes of learning but with periods of rest between each episode. Spaced conditioning is required for long-term memories to form.

In an earlier study last December, also published in The Journal of Neuroscience, Davis found not only that fruit flies receiving spaced conditioning exhibited a long-term memory trace, but also that their memories lasted between four and seven days. In flies that were given a single episode of learning, memory formation lasted only a day and the long-term memory trace failed to form. These two studies are the newest in a series of six studies on the topic, including those published in the journal Neuron in 2004 and 2006, Cell in 2005, and Nature Neuroscience in 2008. Davis reviewed all of his studies of memory traces in the most recent issue of Neuron.

"The phenomenon of spaced conditioning is conserved across all species," Davis said. "No one really knows why it's important to long-term memory formation but there appears to be something magical about that rest period during learning."

The study was supported by the National Institutes of Health.

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How Neurons Decide How to Transmit Information

How Neurons Decide How to Transmit Information

  11:39:00 PM    Science Lover

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There are billions of neurons in the brain and at any given time tens of thousands of these neurons might be trying to send signals to one another. Much like a person trying to be heard by his friend across a crowded room, neurons must figure out the best way to get their message heard above the din.

Inhibitory circuits in the olfactory bulb use a novel, 
time-scale dependent strategy to mediate how neurons 
choose between encoding and propagating 
information. (Credit: Sonya Giridhar)

Researchers from the Center for the Neural Basis of Cognition, a joint program between Carnegie Mellon University and the University of Pittsburgh, have found two ways that neurons accomplish this, establishing a fundamental mechanism by which neurons communicate. The findings have been published in an online early edition of Proceedings of the National Academy of Sciences (PNAS).

"Neurons face a universal communications conundrum. They can speak together and be heard far and wide, or they can speak individually and say more. Both are important. We wanted to find out how neurons choose between these strategies," said Nathan Urban, the Dr. Frederick A. Schwertz Distinguish Professor of Life Sciences and head of the Department of Biological Sciences at CMU.

Neurons communicate by sending out electrical impulses called action potentials or "spikes." These spikes code information much like a version of Morse code with only dots and no dashes. Groups of neurons can choose to communicate information in one of two ways: by spiking simultaneously or by spiking separately.

To find out how the brain decided which method to use to process a sensory input, the researchers looked at mitral cell neurons in the brain's olfactory bulb -- the part of the brain that sorts out smells and a common model for studying global information processing. Using slice electrophysiology and computer simulations, the researchers found that the brain had a clever strategy for ensuring that the neurons' message was being heard.

Over the short time scale of a few milliseconds, the brain engaged its inhibitory circuitry to make the neurons fire in synchrony. This simultaneous, correlated firing creates a loud, but simple, signal. The effect was much like a crowd at a sporting event chanting, "Let's go team!" Over short time intervals, individual neurons produced the same short message, increasing the effectiveness with which activity was transmitted to other brain areas. The researchers say that in both human and neuronal communication alike, this collective communication works well for simple messages, but not for longer or more complex messages that contain more intricate information.

The neurons studied used longer timescales (around one second) to convey these more complex concepts. Over longer time intervals, the inhibitory circuitry generated a form of competition between neurons, so that the more strongly activated neurons silenced the activity of weakly activated neurons, enhancing the differences in their firing rates and making their activity less correlated. Each neuron was able to communicate a different piece of information about the stimulus without being drowned out by the chatter of competing neurons. It would be like being in a group where each person spoke in turn. The room would be much quieter than a sports arena and the immediate audience would be able to listen and learn much more complex information.

Researchers believe that the findings can be applied beyond the olfactory system to other neural systems, and perhaps even be used in other biological systems.

"Across biology, from genetics to ecology, systems must simultaneously complete multiple functions. The solution we found in neuroscience can be applied to other systems to try to understand how they manage competing demands," Urban said.

Co-authors of the study include Brent Doiron, assistant professor of mathematics at the University of Pittsburgh, and Sonya Giridhar, a doctoral student in the Center for Neuroscience at Pitt. Both are members of the Center for the Neural Basis of Cognition.

The study was funded by the National Institute on Deafness and Other Communications Disorders, the National Institutes of Health and the National Science Foundation.

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