How Real is Synesthesia?

Hearing Colours And Seeing Sounds:
How Real Is Synesthesia?

In the psychological phenomenon known as "synesthesia," individuals' sensory systems are a bit more intertwined than usual. Some people, for example, report seeing colours when musical notes are played.

One of the most common forms is grapheme-colour synesthesia, in which letters or numbers (collectively called "graphemes") are highlighted with particular colours. Although synesthesia has been well documented, it is unknown whether these experiences, reported as vivid and realistic, are actually being perceived or if they are a byproduct of some other psychological mechanism such as memory.

New research published in the June issue of Psychological Science, a journal of the Association for Psychological Science, sheds some light on the veracity of these perceptions.

When anyone views a particular colour, specific neurons in the visual cortex area of our brain are activated. These specific neurons will deactivate, however, if a colour from the opposite end of the spectrum is presented.

Any neuron activated when the colour blue is present will deactivate when it's exact opposite, yellow, comes into the visual field.

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Protein's Internal Motion

Researchers at the University of Pennsylvania School of Medicine are the first to observe and measure the internal motion inside proteins, or its “dark energy.” This research, appearing in the current issue of Nature, has revealed how the internal motion of proteins affects their function and overturns the standard view of protein structure-function relationships, suggesting why rational drug design has been so difficult.

“The situation is akin to the discussion in astrophysics in which theoreticians predict that there is dark matter, or energy, that no one has yet seen,” says senior author A. Joshua Wand, PhD, Benjamin Rush Professor of Biochemistry. “Biological theoreticians have been kicking around the idea that proteins have energy represented by internal motion, but no one can see it. We figured out how to see it and have begun to quantify the so-called ‘dark energy’ of proteins.”

Proteins are malleable in shape and internal structure, which enables them to twist and turn to bind with other proteins. “The motions that we are looking at are very small, but very fast, on the time scale of billions of movements per second,” explains Wand. “Proteins just twitch and shake.” The internal motion represents a type of energy called entropy.

Current models of protein structure and function used in research and drug design often do not account for their non-static nature. “The traditional model is almost a composite of all the different conformations a protein could take,” says Wand.

The researchers measured a protein called calmodulin and its interactions with six other proteins when bound to a protein partner one at a time. These binding partners included proteins important in smooth muscle contraction and a variety of brain functions.

Using nuclear magnetic resonance spectroscopy, the investigators were able to look at the changes in the internal motion of calmodulin itself in each of the six different protein binding situations. They found a direct correlation between a change in calmodulin’s entropy – a component of its stored energy – and the total entropy change leading to the formation of the calmodulin-protein complex.


Finding out the contribution from individual proteins versus the entropy, or movement, of the entire protein complex has been more difficult and has been overcome in this study. From this individual contribution they deduced that changes in the entropy of the protein are indeed important to the process of calmodulin binding its partners.

“Before these unexpected results, most researchers in our field would have predicted that entropy’s contribution to protein-protein interactions would be zero or negligible,” says Wand. “But now it’s clearly an important component of the total energy in protein binding.”

Because of this new information, the researchers suggest that the entropy component may explain why drug design fails more often than it works. Currently, drugs are designed generally based on the precise structures of their biological targets, active regions on proteins that are intended to inhibit key molecules. However, the number of designed molecules actually binding to their targets is low for many engineered molecules. “We think that this is because the design is based on a model of a static protein, not the moving, hyper protein that is constantly changing shape,” say Wand. “We need to figure out how this new information fits in and perhaps drug design could be significantly improved.”

Future directions include understanding whether the principles revealed by this study are universal and impact the thousands of protein-protein interactions that underlie biology and disease. As Wand explains, “Protein-protein interactions are central to ‘signalling’, which is often the molecular origin of diseases. Cancer, diabetes, and asthma are three important examples. We are currently looking at the role of protein entropy in the control of critical signaling events in all three.”

Artist rendering of calmodulin molecule depicting protein "dark energy."
Image Credit: Mary Leonard and Michael Marlow, UP School of Medicine.

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Unravelling the Physics of DNA

Researchers at Duke University's School of Engineering have uncovered a missing link in scientists' understanding of the physical forces that give DNA its famous double helix shape.

The stability of DNA is fundamental to life. To create accurate models of DNA to study its interaction with proteins or drugs, you need to understand the basic physics of the molecule. For that, you need solid measurements of the forces that stabilize DNA.

Each DNA strand includes a sugar and phosphate "backbone" attached to one of four bases, which encode genetic sequences. The strength of the interactions within individual strands comes largely from the chemical attraction between the stacked bases. But the integrity of double-stranded DNA depends on both the stacking forces between base units along the length of the double helix and on the pairing forces between complementary bases, which form the rungs of the twisted ladder.

Earlier studies have focused more attention on the chemical bonds between opposing bases, measuring their strength by "unzipping" the molecules' two strands. Studies of intact DNA make it difficult for researchers to separate the stacking from the pairing forces.

To get around that problem in the new study, the Duke team used an atomic force microscope (AFM) to capture the "mechanical fingerprint" of the attraction between bases within DNA strands. The bonds within the molecules' sugar and phosphate backbones remained intact and therefore had only a minor influence on the force measurements.

Researchers tugged on individual strands that were tethered at one end to gold and measured the changes in force as they pulled. The AFM technique allows precise measurements of forces within individual molecules down to one pico-Newton--a trillionth of a Newton. For a sense of scale, the force of gravity on a two-liter bottle of soda is about 20 Newtons.

They captured the range of stacking forces by measuring two types of synthetic DNA strands: some made up only of the base thymine, which is known to have the weakest attraction between stacked units, and some made up only of the base adenine, known to have the strongest stacking forces. Because of those differences in chemical forces, the two types of single-stranded DNA take on different structures. Single strands of adenine coil in a fairly regular fashion to form a helix of their own, while thymine chains take on a more random shape.

The pure adenine strands exhibited an even more complex form of elasticity than had been anticipated, the researchers reported. As they stretched the adenine chains with increasing force, the researchers noted two places--at 23 and 113 pico-Newtons--where their measurements leveled off.

"Those plateaus reflect the breaking and unfolding of the helix," professor of mechanical engineering and materials sciences at Duke, Marszalek explained. With no bonds between bases to break, the thymine chains' showed little resistance to extension and no plateau.

Based on the known structure of the single stranded DNA molecules, they had expected to see only one such plateau as the stacking forces severed. Exactly what happens at the molecular level at each of the two plateaus will be the subject of continued investigation.
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White Blood Cells Are Picky About Sugar

Biology textbooks are blunt--neutrophils are mindless killers. These white blood cells patrol the body and guard against infection by bacteria and fungi, identifying and destroying any invaders that cross their path.

But new evidence, which may lead to better drugs to fight deadly pathogens, indicates that neutrophils might actually distinguish among their targets.

A scientist in the lab of Whitehead Member Gerald Fink has discovered that neutrophils recognize and respond to a specific form of sugar called beta-1,6-glucan on the surface of fungi. This sugar comprises just a small fraction of the fungal cell wall, much less than another sugar with a slightly different chemical conformation called beta-1,3-glucan. Because the scarce form of the sugar elicits a much stronger reaction from immune cells than the abundant one, it appears that neutrophils can distinguish between two nearly identical chemicals.

"These results show that engulfment and killing by neutrophils varies, depending on cell wall properties of the microbe," explains Whitehead postdoctoral researcher Ifat Rubin-Bejerano, first author on the paper, which appears July 11 in the journal Cell Host & Microbe. "We showed that neutrophils respond in a completely different way to slight changes in sugar composition. If we are able to use this unique sugar to excite the immune system, it may help the human body fight infection."

"Previously, everyone thought that these key cells of the immune system weren't picky and would eat anything that looked foreign," adds Fink, who is also an MIT professor of biology. "Ifat's work has shown that the cells aren't little Pac-Men, but can discriminate one pathogen from another."

Rubin-Bejerano had evidence that neutrophils respond to beta-glucan. After coating tiny beads with a variety of substances (including beta-1,3-glucan and beta-1,6-glucan), she exposed them to the neutrophils and was surprised to see a striking difference in their response to the two sugars. The neutrophils quickly engulfed many of the beads coated with beta-1,6-glucan, but only a few of those covered in beta-1,3-glucan.

Previous studies indicated that blood serum (basically blood minus cells) helps neutrophils recognize their enemies, so Rubin-Bejerano decided to look for clues to their response in this mixture. She identified several proteins in serum that bind to beta-1,6-glucan, but not beta-1,3-glucan, and then pinpointed a molecule on the surface of the neutrophil that recognizes these proteins.

To link her experiments back to real fungi, Rubin-Bejerano worked with the pathogen Candida albicans, which is the most common fungus in blood stream infections. She used an enzyme to digest beta-1,6-glucan from the fungal cell wall, leaving the beta-1,3-glucan intact. She then unleashed the neutrophils on these altered cells and observed a 50 percent reduction in the immune response.

Our bodies maintain a fine balance between the immune system and microbes. Antibiotics and antifungals tilt the balance in favor of the immune system by targeting the microbes directly. A substance like beta-1,6-glucan could help tilt this balance further by stimulating immune cells.

Rubin-Bejerano's work offers hope for combating the growing problem of microbial infections, which can seriously threaten human health--particularly in patients with compromised immune systems. In fact, Rubin-Bejerano co-founded a company called ImmuneXcite to explore this possibility.

Source: Whitehead Institute for Biomedical Research
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How DNA strands separate

Cornell researchers have answered a fundamental question about how two strands of DNA, known as a double helix, separate to start a process called replication, in which genes copy themselves.

Credit: Chris Pelkie and Daniel Ripoll/Cornell Theory Center


This image shows a DNA double helix (green and purple strands) being separated by a helicase enzyme (green globule) at the junction where the two strands fork. To show that helicases actively separate the two strands of DNA, the researchers attached one end of a DNA strand to a microscope cover slip and attached the end of the other DNA strand to a micron-sized plastic bead. The bead was then trapped in a tightly focused laser beam (red), which allowed the researchers to measure the motion of the helicase as it unwound the DNA.

The research, published in the current issue of the journal Cell, examined the role of an enzyme called a helicase, which plays a major role in separating DNA strands so that replication of a single strand can occur.

Scientists have known that helicases bind to the area of a double helix where the two strands fork away from each other, like the free ends of two pieces of thread wound around each other. The forked area opens and closes very rapidly. But scientists have debated whether helicases actively separate the two strands at the fork or if they passively wait for the fork to widen on its own.

The research found that the helicase appears to actively exert a force onto the fork and separate the two strands.

"A simple passive unwinding mechanism does not explain our data," said Michelle Wang, associate professor of physics and the paper's senior author.

"Defects in helicases are associated with many human diseases, ranging from predisposition to cancer to premature aging," said co-author Smita Patel, a biochemistry professor at the Robert Wood Johnson Medical School in Piscataway, N.J. "Helicases are involved in practically all DNA and RNA metabolic processes."

The researchers made their discovery by anchoring one end of one of the strands in a double helix to the surface of a microscope cover slip. The end of the other strand was attached to a micron-sized plastic bead. They then focused a laser beam on the tiny bead and trapped the bead in place within the beam of light. This setup allowed the researchers to measure the position and force on the bead, creating a very precise sensor of the helicase motion. As the helicase moved toward the fork and the double helix unwound, the tension on the two strands lessened. Using statistical mechanics models, the researchers could then compare actual measurements of movement with predictions based on both active and passive scenarios.

"The unwinding has to have some active component to it, and based on our data, we can tell you exactly how active it is," said Wang. "Basically, it is an active unwinding motor."

While helicases unwind very rapidly in cells, in test tube experiments the unwinding is much slower. The researchers believe that helicases work with other enzymes, where "accessory proteins are helping the helicase out by destabilizing the fork junction," said Wang.

Original Source: Cornell University
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Prions key in Alzheimer's disease

Proteins which cause mad cow disease may also protect against Alzheimer's disease, UK researchers say. Prions naturally present in the brain appear to prevent the build up of a key protein associated with the condition.

In laboratory tests, beta amyloid, the building block of Alzheimer's "plaques", did not accumulate if high levels of the prions were present. The findings could lead to new treatments, the Proceedings of the National Academy of Sciences reported.

In variant Creutzfeldt-Jakob disease (vCJD), the human version of mad cow disease, the normal version of the prion protein present in brain cells is corrupted by infectious prions causing it to change shape, resulting in brain damage and death. But little is known about purpose of the normal prion proteins.

Due to the similarities between Alzheimer's and diseases such as variant CJD, researchers at the University of Leeds, looked for a link.

Plaque formation

They found that in cells in the laboratory, high levels of the prions reduced the build-up of beta-amyloid protein, which is found in the brains of people with Alzheimer's disease. In comparison, when the level of the prions was low or absent, beta amyloid formation was found to go back up again, suggesting they have a preventive effect on the development of the condition.

The researchers also looked at mice who had been genetically engineered to lack the prion proteins and again found that the harmful beta-amyloid proteins were able to form.

Study leader Professor Nigel Hooper said they now needed to look at whether ageing had an affect on the ability of the prion proteins to protect against Alzheimer's.

"Until now, the normal function of prion proteins has remained unclear, but our findings clearly identify a role for normal prion proteins in regulating the production of beta-amyloid and in doing so preventing formation of Alzheimer's plaques.

"Whether this function is lost as a result of the normal ageing process, or if some people are more susceptible to it than others we don't know yet."

He said although they needed to learn more, theoretically if a treatment could be designed to mimic the effect of the prions it could halt the progression of the disease.

Professor Clive Ballard, director of research at the Alzheimer's Society said this was the first time a link had been made between prions and Alzheimer's. "These are early findings, which suggest prion proteins may have a regulatory effect on the development of beta amyloid." He added: "This provides the foundations for a novel approach to finding new therapeutic targets in Alzheimer's disease."

Original Source BBC health news 19 June 2007
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