intellectual vanities… about close to everything

Researchers from Rome, Italy, describe a finding in the August 2007 print issue of The FASEB Journal that could lead to new drugs to fight the HIV/AIDS virus, as well as new vaccines to prevent infection. It has been known that HIV proteins disable the antibody-forming part of the immune system (the “homeland defense” or acquired immune system).

In this report, researchers demonstrate for the first time how the HIV-1 Nef viral protein delivers a one-two punch to the body’s innate immune system (our “early warning system” composed of dendritic and natural killer cells). First, Nef hijacks dendritic cells (DCs) to upset the function of natural killer (NK) cells. Second, after blocking this first line of defense against the immune system, Nef uses DCs and NK cells to create a microenvironment that actually makes it easier for HIV/AIDS to replicate.

According to Maria Giovanna Quaranta of Instituto Superiore de Sanità and first author of the article, “The findings described in this work may have several implications for AIDS treatment: the understanding of Nef function, mechanism of action, and cellular partners might aid the discovery of suitable drugs able to block the activity of this smart protein.” Quaranta added, “An exciting possibility is the design of a vaccine including a mutated Nef protein unable to assist the virus in the control of its host.”

The research findings also raise another intriguing possibility: Nef proteins may be able to boost or suppress DC and NK cell activity. If so, it may prove to be a valuable new therapeutic approach for people with diseases and disorders that involve overactive or underactive immune responses. DCs and NK cells play critical roles in the body’s initial defense against infection.

DCs are instrumental in identifying foreign invaders to the body and then orchestrating an immune response that ultimately removes them. NK cells are among the first cells summoned by DCs to help isolate and contain the infection until more potent reinforcements can be manufactured to eradicate the virus or bacteria. When DC cells can no longer adequately “manage” the immune response and when NK cells can no longer contain infections, the likelihood of survival without medical intervention is relatively low.

“HIV’s relatively rapid evolution has given it an ability to handle all our bodies can throw at it and more,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “Now that we know how the viral protein disables the innate as well as the acquired arm of our immune system, we can begin to design decoy proteins or to devise new vaccines. Millions of lives depend on our finding a way to restore both aspects of our immune defense against HIV/AIDS—this study should go a long way toward that goal.”

FASEB J. 2007 Apr 12; [Epub ahead of print]

HIV-1 Nef impairs the dynamic of DC/NK crosstalk: different outcome of CD56dim and CD56bright NK cell subsets.

Quaranta MG, Napolitano A, Sanchez M, Giordani L, Mattioli B, Viora M.

Carnegie Mellon University scientists have made an important discovery that aids the understanding of why HIV enters immune cells with ease. The researchers found that after HIV docks onto a host cell, it dramatically lowers the energy required for a cell membrane to bend, making it easier for the virus to infect immune cells. The finding, in press in Biophysical Journal, will provide vital data to conduct future computer simulations of HIV dynamics to help further drug discovery and prevent deadly infections.

“We found that HIV fusion peptide dramatically decreases the amount of energy needed to bend a cell-like membrane,” said Stephanie Tristram-Nagle, associate research professor of biological physics at Carnegie Mellon. “This helps membranes to curve, a necessary step for HIV to fuse with an immune cell as it infects it.”

The Carnegie Mellon scientists used X-rays to study how HIV fusion peptide (part of a larger protein) affected the energy of manufactured lipid bilayers made to mimic normal cell membranes. Lipid bilayers provide a protective barrier for the cell against intruders, yet also contain molecules to recognize and communicate with other cells or get nutrients. Cells also communicate with one another via small, membrane-bound vesicles that contain proteins or other molecular cargo. When delivering their goods, vesicles from one cell fuse with the outermost membrane of another cell to form a series of hybrid structures called fusion intermediates.

Through evolution, viruses have also become skilled at fusing with cells to unload their genetic contents, which turn host cells into virus-producing factories. In the case of HIV, a molecule called gp120 initially helps the virus lock onto its host T cell, a cell critical for maintaining immunity. Another protein — gp41 — then enables HIV to penetrate a T-cell membrane. Fusion takes place specifically through a short stretch of gp41 called fusion peptide 23, or FP-23 for short. Prior studies have shown that FP-23 fuses with, and can even break apart, blood cells and other man-made, cell-like structures called liposomes.

FP-23 likely plays several roles in viral fusion, according to the researchers. One role already suspected is that FP-23 attaches to its T cell victim to facilitate a change in the shape of gp41, which in turn drives uptake of HIV RNA and proteins by the T cell. But the Carnegie Mellon work suggests that FP-23 plays another, equally important function — reducing the free energy of curved fusion intermediates. These fleeting shapes arise and disappear as HIV enters a T cell.

Normally, a cell membrane resists bending. Scientists can quantify the energy needed to overcome this resistance. The Carnegie Mellon team found that FP-23 reduces the energy required to penetrate an artificial cell membrane by up to 13 fold, depending on the thickness of that membrane.

“Reducing this energy should help explain in part how HIV infection occurs so readily,” said Tristram-Nagle. “Our findings definitely will change how theoreticians think about virus-cell interactions. This same phenomenon could provide a general way that viruses use to infect cells, so it will be exciting to look at other viral systems with our experimental method,” she said.

Many different viruses could enter cells by efficiently lowering the energy required to penetrate a cell’s outer membrane, according to Tristram-Nagle and her collaborator, John Nagle, professor of physics and biological sciences at Carnegie Mellon.

The Carnegie Mellon scientists used X-rays to detect the effect of FP-23 on lipid bilayers that mimic cell membranes. Lipid bilayers form different phases that change with temperature, but the “fluid” phase is the most biologically relevant. Using X-ray diffuse scattering, the team quantified structural properties of different lipid bilayers seeded with FP-23 peptides. The lipid bilayers varied in their thicknesses, which affects the stiffness of cell membranes.

The research was conducted at Cornell University’s CHESS synchrotron, which provides a high-intensity source of X-rays for various studies. In their next trip to this facility, the team plans to study FP-23 together with cholesterol, a molecule known to modulate the stiffness of cell membranes.

Biophys J. 2007 May 25; [Epub ahead of print]

HIV-1 Fusion Peptide Decreases Bending Energy, Promotes Curved Fusion Intermediates.

Tristram-Nagle S, Nagle JF.

Carnegie Mellon University.

Guilt plays a vital role in the regulation of social behavior. That worried feeling in our gut often serves as the impetus for our stab at redemption. However, psychologists have trouble agreeing on the function of this complex emotion.

New research suggests that guilt is initially associated with withdrawal motivation, which then transforms into approach-motivated behavior when an opportunity for reparation presents itself. (Credit: iStockphoto/Angel Herrero de Frutos)

On one hand, the punitive feeling of guilt may keep you from repeating the same transgressive behavior in the future, which psychologists call “withdrawal motivation.” Conversely, some researchers view the function of guilt in a societal context, in that; it keeps people’s behavior in line with the moral standards of their community. This view emphasizes a more positive emotional experience and is associated with “approach motivation.”

In a new study, New York University psychologist, David M. Amodio, and his colleagues, Patricia G. Devine, and Eddie Harmon-Jones, sought to combine the two camps. The researchers believe that guilt is initially associated with withdrawal motivation, which then transforms into approach-motivated behavior when an opportunity for reparation presents itself. Furthermore, the researchers sought to test these questions about the functions guilt in the context of reducing racial prejudice.

To test their theory, the researchers showed participants pictures of White, Black, or Asian faces, while monitoring their brain activity using EEG. The researchers then relayed randomized scores to the participants, telling them whether they responded positively or negatively to the White, Black, and Asian faces.

After receiving feedback indicating that they had responded negatively toward Black faces, subjects reported significantly increased guilt, anxiety, and sadness. The increase in guilt was larger than the change in any other emotion. Their reports were confirmed by the EEG, which showed significant reduction in left-sided frontal asymmetry following feedback. A large body of literature contends that left-sided asymmetry corresponds to approach motivation. So, in this case, the participants were initially feeling the punitive effects of guilt, or withdrawal motivation.

The participants then completed another study in which they read a variety of magazine headlines. Interspersed among some filler headlines, were three titles pertaining to prejudice reduction (”Improving your interracial interactions,” 10 ways to reduce prejudice in everyday life,” and “Ways to eliminate your own racism in the new millennium”). The participants that were told they responded negatively toward black faces, revealed a large left-sided shift in frontal cortical activity while reading the prejudice-reduction titles, indicating approach motivation.

So, when subjects were given the opportunity for reparation, their feelings of guilt predicted their interest in prejudice-reducing behavior. Previously emotions have been considered relatively unchanging, basic, feeling states. Amodio’s research presents a new idea of emotions serving a dynamic motivational function for regulating behavior. These findings also suggest that although it feels bad, guilt plays a critical role in promoting prosocial changes in behavior, and Amodio’s research demonstrates these effects in context of reducing racial prejudice.

Psychol Sci. 2007 Jun;18(6):524-30.

A dynamic model of guilt: implications for motivation and self-regulation in the context of prejudice.

Amodio DM, Devine PG, Harmon-Jones E.

Department of Psychology, New York University, NY 10003, USA. david.amodio@nyu.edu

Think you haven’t got the aptitude to learn a foreign language? New research led by Northwestern University neuroscientists suggests that the problem, quite literally, could be in your head.
“Our study links brain anatomy to the ability to learn a second language in adulthood,” said neuroscientist Patrick Wong, assistant professor of communication sciences and disorders at Northwestern and lead author of a study appearing online July 25 in Cerebral Cortex.

Based on the size of Heschl’s Gyrus (HG), a brain structure that typically accounts for no more than 0.2 percent of entire brain volume, the researchers found they could predict — even before exposing study participants to an invented language — which participants would be more successful in learning 18 words in the “pseudo” language.

Wong and his colleagues measured the size of HG, a finger-shaped structure in both the right and left side of the brain, using a method developed by co-authors Virginia Penhune and Robert Zatorre (Montreal Neurological Institute). Zatorre and Penhune are well known for research on human speech and music processing and the brain.

“We found that the size of left HG, but not right HG, made the difference,” said Northwestern’s Catherine Warrier, a primary author of the article titled “Volume of Left Heschl’s Gyrus and Linguistic Pitch.” Anil K. Roy (Northwestern), Abdulmalek Sadehh (West Virginia University) and Todd Parish (Northwestern) also are co-authors.

The study is the first to consider the predictive value of a specific brain structure on linguistic learning even before training has begun. Specifically, the researchers measured the size of study participants’ right and left Heschl’s Gyrus on MRI brains scans, including calculations of the volume of gray and white matter.

Studies in the past have looked at the connection between brain structure and a participant’s ability to identify individual speech sounds in isolation rather than learning speech sounds in a linguistic context. Others have looked at the connection between existing language proficiency and brain structure.

“While our study demonstrates a link between biology and linguistics, we do not argue that biology is destiny when it comes to learning a second language,” Wong emphasized. Adults with smaller volumes of left HG gray matter need not despair that they can never learn another language.

“We are already testing different learning strategies for participants whom we predict will be less successful to see if altering the training paradigm results in more successful learning,” Wong added.

According to Warrier, Northwestern research professor of communication sciences and disorders, the researchers were surprised to find the HG important in second language learning. “The HG, which contains the primary region of the auditory cortex, is typically associated with handling the basic building blocks of sound — whether the pitch of a sound is going up or down, where sounds come from, and how loud a sound is — and not associated with speech per se,” she said.

The 17 research participants aged 18 to 26 who had their brain scans taken prior to participating in the pseudo second language training were previously participants in two related studies published by Wong and his research team.

The three studies have identified behavioral, neurophysiologic and, with the current study, neuroanatomic factors which, when combined, can better predict second language learning success than can each single factor alone.

In a behavioral study, Wong’s group found that musical training started at an early age contributed to more successful spoken foreign language learning. The study participants with musical experience also were found to be better at identifying pitch patterns before training.

In a neurophysiologic study — again with the same participants — Wong’s team used functional magnetic resonance imaging to observe what parts of brain were activated when participants listened to different pitch tones. They found that the more successful second language learners were those who showed activation in the auditory cortex (where HG resides).

The participants all were native American English speakers with no knowledge of tone languages. In tone languages (spoken by half the world’s population), the meaning of a word can change when delivered in a different pitch tone. In Mandarin, for example, the word “mi” in a level tone means “to squint,” in a rising tone means “to bewilder” and in a falling and then rising tone means “rice.”

For the study reported in “Cerebral Cortex,” Wong’s 17 participants entered a sound booth after having their brains were scanned. There they were trained to learn six one-syllable sounds (pesh, dree, ner, vece, nuck and fute). The sounds were originally produced by a speaker of American English and then re-synthesized at three different pitch tones, resulting in 18 different “pseudo” words.

The participants were repeatedly shown the 18 “pseudo” words and a black and white picture representing each word’s meaning. Pesh, for example, at one pitch meant “glass,” at another pitch meant “pencil,” and at a third meant “table.” Dree, depending upon pitch, meant “arm,” “cow,” or “telephone.”

As a group - and sometimes in fewer than two or three sessions — the nine participants predicted on the basis of left HG size to be “more successful learners” achieved an average of 97 percent accuracy in identifying the pseudo words. The “less successful” participants averaged 63 percent accuracy and sometimes required as many as 18 training sessions to correctly identify the words.

“What’s important is that we are looking at the brain in a new way that may allow us to understand brain functions more comprehensively and that could help us more effectively teach foreign languages and possibly other skills,” said Wong.

 Cereb Cortex. 2007 Jul 25; [Epub ahead of print]

Volume of Left Heschl’s Gyrus and Linguistic Pitch Learning.

Wong PC, Warrier CM, Penhune VB, Roy AK, Sadehh A, Parrish TB, Zatorre RJ.

An artificial big toe attached to the foot of an ancient Egyptian mummy could prove to be the world’s earliest functional prosthetic body part, say scientists.

The wood and leather artificial toe, from the Cairo Museum. (Credit: Image courtesy of University of Manchester)

Research at The University of Manchester is hoping to prove that the wood and leather artefact in the Cairo Museum not only looked the part but also helped its owner walk ‘like an Egyptian’.

If true, the toe will predate what is currently considered to be the earliest known practical prosthesis - an artificial leg from 300BC - by several hundred years.

Jacky Finch, who is carrying out the study at Manchester’s KNH Centre for Biomedical Egyptology, is recruiting volunteers whose right big toe has been lost in order to test an exact replica of the artificial toe.

A model of a second false Egyptian big toe on display in the British Museum, albeit without its mummy, will also be tested at the Human Performance Laboratory at nearby University of Salford.

“The toes date from between 1000 and 600BC, so if we can prove that one or both were functional then we will have pushed back prosthetic medicine by as much as 700 years,” said Jacky.

“The Cairo toe is the most likely of the two to be functional as it is articulated and shows signs of wear. It is still attached to the foot of the mummy of a female between 50 and 60 years of age. The amputation site is also well healed.”

The British Museum artefact - named the Greville Chester Great Toe after the collector who acquired it for the museum in 1881 - is made from cartonnage, a sort of papier maché made using linen, glue and plaster.

It too shows signs of wear, indicating that it may have been worn by its owner in life and not simply attached to the foot during mummification for religious or ritualistic reasons. However, unlike the Cairo specimen, the Greville Chester toe does not bend and so is likely to have been more cosmetic.

“The Human Performance Laboratory will use state-of-the-art technology to test whether the replicas of the artificial toes benefit the wearer and could therefore be deemed functional,” said Jacky.

“If either one is functional it may be interesting to manufacture it with modern materials and trial it for use on people with missing toes.”

Note: The oldest known functional prosthesis is the Roman Capua Leg, which was made of bronze and dates from about 300BC. The leg was held at the Royal College of Surgeons in London but was destroyed by Luftwaffe bombs during the Second World War.

Scholars believe that when the  Furies were originally referred to as the Eumenides (the “kindly ones”) it was not to reference their good sides but as a euphemism to avoid their wrath. I propose that it might be just for the fact that those meaning well usually do as desastrous damage as Erinyes would.

The capacity to resist peer pressure in early adolescence may depend on the strength of connections between certain areas of the brain, according to a study carried out by University of Nottingham researchers

New findings suggest that enhanced connections across brain regions involved in decision-making may underlie an individual’s ability to resist the influence of peers.

The study, published in the July 25 issue of The Journal of Neuroscience, suggests that brain regions which regulate different aspects of behaviour are more interconnected in children with high resistance to peer influence.

Professor Tomas Paus and colleagues at The University of Nottingham used functional neuroimaging to scan adolescents while they watched video clips of neutral or angry hand and face movements. Previous research has shown that anger is the most easily recognised emotion.

Professor Paus and his team observed 35 ten-year-olds with high and low resistance to peer influence, measured by a questionnaire. The researchers then showed the children video clips of angry hand movements and angry faces and measured their brain activity.

They found that the brains of all children showed activity in regions important for planning and extracting information about social cues from movement, but the connectivity within these regions was stronger in children who were marked as less vulnerable to peer influence.

Those children were also found to have more activity in the prefrontal cortex, an area important for decision-making and inhibition of unwanted behaviour.

Professor Paus said: “This is important if we are to understand how the adolescent brain attains the right balance between acknowledging the influences of others and maintaining one’s independence.”

Future research will involve follow-ups with the same children to determine whether their resistance to peer influence is related to the brain changes observed in this study.

J Neurosci. 2007 Jul 25;27(30):8040-5.

Neural mechanisms of resistance to peer influence in early adolescence.

Grosbras MH, Jansen M, Leonard G, McIntosh A, Osswald K, Poulsen C, Steinberg L, Toro R, Paus T.

Science Daily — Are your friends making you fat? Or keeping you slender? According to new research from Harvard and the University of California, San Diego, the short answer on both counts is “yes.”

A social network map of 2,200 people, the largest group of connected individuals in the Framingham Heart Study, in the year 2000. Each circle represents one person, and the size of each circle is proportional to that person’s body-mass index (BMI). Yellow circles indicate people who are considered medically obese and green circles indicate people who are not obese. Lines indicate family and friendship ties. (Credit: Figure courtesy of James Fowler, UC San Diego)

Appearing in the July 26 issue of the New England Journal of Medicine, a study coauthored by Nicholas Christakis of Harvard Medical School and James Fowler of UC San Diego suggests that obesity is “socially contagious,” spreading from person to person in a social network.

The study — the first to examine this phenomenon — finds that if one person becomes obese, those closely connected to them have a greater chance of becoming obese themselves. Surprisingly, the greatest effect is seen not among people sharing the same genes or the same household but among friends.

If a person you consider a friend becomes obese, the researchers found, your own chances of becoming obese go up 57 percent. Among mutual friends, the effect is even stronger, with chances increasing 171 percent.

Christakis and Fowler also looked at the influence of siblings, spouses and neighbors. Among siblings, if one becomes obese, the likelihood for the other to become obese increases 40 percent; among spouses, 37 percent. There was no effect among neighbors, unless they were also friends.

The researchers analyzed data over a period of 32 years for 12,067 adults, who underwent repeated medical assessments as part of the Framingham Heart Study. They were able to map a densely interconnected social network of the study’s subjects by using the tracking sheets (which had previously been archived in a basement) that recorded not only the subjects’ family members but also unrelated friends who could be expected to find them in a few years.

The network map took two years to assemble and includes information on the participants’ body-mass index. Among the first things the researchers noticed was that, consistent with other studies finding an obesity epidemic in the U.S., the whole network grew heavier over time.

Also immediately apparent were distinct clusters of thin and heavy individuals. Statistical analysis revealed that this clustering could not be attributed solely to the selective formation of ties among people of comparable weights.

“It’s not that obese or non-obese people simply find other similar people to hang out with,” said Christakis, a physician and a professor in Harvard Medical School’s department of health care policy. “Rather, there is a direct, causal relationship.”

Further analysis also suggested that people’s influence on each other’s obesity status could not be put down just to similarities in lifestyle and environment, to, for example, people eating the same foods together or engaging in the same physical activities. Not only do siblings and spouses have less influence than friends, but also geography doesn’t play a role. The striking impact of friends seems to be independent of whether or not the friends live in the same region.

“When we looked at the effect of distance, we found that your friend who’s 500 miles away has just as much impact on your obesity as [one] next door,” said Fowler, an associate professor of political science at UC San Diego and an expert in social networks.

In part because the study also identifies a larger effect among people of the same sex, the researchers believe that people affect not only each other’s behaviors but also, more subtly, norms.

“What appears to be happening is that a person becoming obese most likely causes a change of norms about what counts as an appropriate body size. People come to think that it is okay to be bigger since those around them are bigger, and this sensibility spreads,” said Christakis.

“This is about people’s ideas about their bodies and their health,” Fowler said. “Consciously or unconsciously, people look to others when they are deciding how much to eat, how much to exercise and how much weight is too much.”

“Social effects, I think, are much stronger than people before realized. There’s been an intensive effort to find genes that are responsible for obesity and physical processes that are responsible for obesity and what our paper suggests is that you really should spend time looking at the social side of life as well,” said Fowler.

The policy implications of the study, the researchers say, are profound. The social-network effects extend three degrees of separation — to your friends’ friends’ friends — so any public-health intervention aimed at reducing obesity should consider this in its cost-benefit analysis.

“When we help one person lose weight, we’re not just helping one person, we’re helping many,” Fowler said. “And that needs to be taken into account by policy analysts and also by politicians who are trying to decide what the best measures are for making society healthier.”

“It’s important to remember,” Fowler said, “that we’ve not only shown that obesity is contagious but that thinness is contagious.”

N Engl J Med. 2007 Jul 26;357(4):370-379. Epub 2007 Jul 25.

The Spread of Obesity in a Large Social Network over 32 Years.

Christakis NA, Fowler JH.

The active ingredient in Chinese medicinal sage could help alcoholics beat their addiction, Italian researchers said.

The National Research Council’s institute in Cagliari says the herb, Salvia Miltiorrhiza, has been used for centuries in China to treat blood diseases, heart disorders and insomnia, ANSA said Thursday.

Researcher Giancarlo Colombo said Chinese sage reduced alcohol consumption in mice and eliminated a “customary spike in drinking seen when mice go back on the bottle after being on the wagon for a while,” ANSA said.

Scientists said the herb may help turn alcoholics into moderate drinkers.

“It’s been working brilliantly in mice and we’re about to start on our human guinea pigs, once we’re sure it’s entirely safe,” Colombo said.

Alcohol Clin Exp Res. 2006 May;30(5):754-62.

Identification of miltirone as active ingredient of Salvia miltiorrhiza responsible for the reducing effect of root extracts on alcohol intake in rats.

Colombo G, Serra S, Vacca G, Orrù A, Maccioni P, Morazzoni P, Bombardelli E, Riva A, Gessa GL, Carai MA.

Dr Eugene Starostin and Dr Gert van der Heijden (both from UCL Civil & Environmental Engineering) recently published the solution to a 75-year-old mystery.

A Möbius strip made with a piece of paper and tape. (Credit: David Benbennick / Courtesy of Wikimedia Commons)

The two academics have discovered how to predict the shape of a Möbius strip, the ‘endless ribbon’ which is obtained by taking a rectangular strip of paper, twisting one end through 180 degrees, and then joining the ends.

The shape takes its name from August Möbius, the German mathematician who presented his discovery of a 3D-shape with only one ‘side’ to the Academy of Sciences in Paris in 1858. The shape was rediscovered by artists and famously depicted by Escher.

The first papers that attempted to work out how to predict the 3D shape of an inextensible Möbius strip were published in 1930, but the problem has remained unresolved until now.

Dr Starostin and Dr van der Heijden realised that the shape can be described by a set of 20-year-old equations that have only been published online. Their letter to ‘Nature Materials’ demonstrates that these differential equations govern the shapes of elastic strips when they are at rest, and enable researchers to calculate their geometry.

Möbius strips are not merely mathematical abstractions. Conveyor belts, recording tapes and rollercoasters are all manufactured in this shape, and chemists have now grown single crystals in the form of a Möbius strip.

The academics believe their methods can be used to model ‘crumpled’ shapes that are not based on rectangular strips, such as screwed-up paper, the drape of fabrics and leaves.

“This is the first non-trivial application of this mathematical theory,” said Dr Starostin. “It could prove to be useful to other research communities, such as mechanics and physics.”

Nat Mater. 2007 Jul 15; [Epub ahead of print]

The shape of a Möbius strip.

Starostin EL, van der Heijden GH.