Archive for July 2007
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.
*Department of Drug Research and Evaluation,Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
Dendritic cells (DCs) and natural killer (NK) cells are essential components of the innate immunity and play a critical role in the first phase of host defense against infection. Interactions between DCs and NK cells have been demonstrated in a variety of settings, with evidence emerging of complex bidirectional crosstalk between the two cell types. The accessory HIV-1 Nef protein is a crucial determinant for viral replication and pathogenesis. We previously demonstrated that Nef, hijacking DC functional activity, subverts the DC arm of immune response to escape the adaptive immune attack. Here, we monitor the effect of Nef on the outcome of the innate immune response, focusing on the impact of Nef on DC/NK crosstalk. We demonstrate that Nef up-regulates the ability of DCs to stimulate the immunoregulatory NK cells (CD56(bright)) as assessed by the activated phenotype, up-regulation of their proliferative response and INF-gamma release. On the other hand, Nef-pulsed DCs inhibit cytotoxic NK cells (CD56(dim)), as assessed by the reduced HLA-DR surface expression, reduced proliferation and cytotoxic activity. Moreover, in the presence of Nef-pulsed DCs, we found a significant up-regulation of TNF-alpha secretion and a significant reduction of IL-10, GM-CSF, MIP-1alpha and RANTES secretion. Our findings suggest that the Nef-induced dysregulation in the DC/NK cell crosstalk may represent a potential mechanism through which HIV escapes innate immune surveillance.–Quaranta, M.G., Napolitano, A., Sanchez, M., Giordani, L., Mattioli, B., Viora, M. HIV-1 Nef impairs the dynamic of DC/NK crosstalk: different outcome of CD56(dim) and CD56(bright) NK cell subsets.
PMID: 17431094 [PubMed – as supplied by publisher]
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.
A crucial step in HIV infection is fusion between the viral envelope and the T-cell membrane, which must involve intermediate membrane states with high curvature. Our main result from diffuse x-ray scattering is that the bending modulus KC is greatly reduced upon addition of the HIV fusion peptide FP-23 to lipid bilayers. A smaller bending modulus reduces the free energy barriers required to achieve and pass through the highly curved intermediate states and thereby facilitates fusion and HIV infection. The reduction in KC is by a factor of 13 for the thicker, stiffer diC22:1PC bilayers, and by a factor of 3 for DOPC bilayers. The reduction in KC decays exponentially with concentration of FP-23 and the 1/e concentration is less than 1 mole % peptide to lipid, which is well within the physiological range for a fusion site. A secondary result is, when FP-23 is added to the samples which consist of stacks of membranes, that the distance between membranes increases and eventually becomes infinite at full hydration (unbinding); we attribute this both to electrostatic repulsion of the positively charged arginine in the FP-23 and to an increase in the repulsive fluctuation interaction brought about by the smaller KC. While this latter interaction works against membrane fusion, our results show that the energy that it requires of the fusion protein machinery to bring the HIV envelope membrane and the target T-cell membrane into close contact is negligible.
PMID: 17526585 [PubMed – as supplied by publisher]
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. email@example.com
Guilt is widely recognized as an important self-regulatory emotion, yet alternative theoretical accounts view guilt primarily as either a punishment cue or a prosocial motivator. Integrating these views, we propose that guilt functions dynamically to first provide a negative reinforcement cue associated with reduced approach motivation, which transforms into approach-motivated behavior when an opportunity for reparation presents itself. We tested this hypothesis in the context of racial prejudice. White subjects viewed a multiracial series of faces while cortical activity was recorded using electroencephalography. Following bogus feedback indicating anti-Black responses, subjects reported elevated guilt, which was associated with changes in frontal cortical asymmetry indicating reduced approach motivation. When subjects were presented with an opportunity to engage in prejudice-reducing behavior, guilt predicted greater interest in prejudice reduction, which in turn was associated with an approach-related shift in frontal asymmetry. The results support a dynamic model in which guilt is associated with adaptive changes in motivation and behavior.
PMID: 17576266 [PubMed – in process]
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.
The Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60208, USA.
Research on the contributions of the human nervous system to language processing and learning has generally been focused on the association regions of the brain without considering the possible contribution of primary and adjacent sensory areas. We report a study examining the relationship between the anatomy of Heschl’s Gyrus (HG), which includes predominately primary auditory areas and is often found to be associated with nonlinguistic pitch processing and language learning. Unlike English, most languages of the world use pitch patterns to signal word meaning. In the present study, native English-speaking adult subjects learned to incorporate foreign pitch patterns in word identification. Subjects who were less successful in learning showed a smaller HG volume on the left (especially gray matter volume), but not on the right, relative to learners who were successful. These results suggest that HG, typically shown to be associated with the processing of acoustic cues in nonspeech processing, is also involved in speech learning. These results also suggest that primary auditory regions may be important for encoding basic acoustic cues during the course of spoken language learning.
PMID: 17652466 [PubMed – as supplied by publisher]
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.
Brain and Body Centre, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
During the shift from a parent-dependent child to a fully autonomous adult, peers take on a significant role in shaping the adolescent’s behavior. Peer-derived influences are not always positive, however. Here, we explore neural correlates of interindividual differences in the probability of resisting peer influence in early adolescence. Using functional magnetic resonance imaging, we found striking differences between 10-year-old children with high and low resistance to peer influence in their brain activity during observation of angry hand movements and angry facial expressions: compared with subjects with low resistance to peer influence, individuals with high resistance showed a highly coordinated brain activity in neural systems underlying perception of action and decision making. These findings suggest that the probability of resisting peer influence depends on neural interactions during observation of emotion-laden actions.
PMID: 17652594 [PubMed – in process]