Researchers Link Master Regulator of Innate Immunity to the Hypoxic Response

Wednesday, April 23, 2008

Survival of all animals depends on their ability to withstand microbial infections and adapt to fluctuations in oxygen concentrations. These abilities depend on two ancient, evolutionary gene expression responses called the innate immune response and the hypoxic response. In a new study published in the advanced online edition of the journal Nature on April 23, researchers at the University of California, San Diego School of Medicine reveal that a single protein is essential to both responses. This understanding may lead to new therapies to boost the body’s immune function or to limit inflammatory damage in tissues deprived of oxygen.

The research, led by Michael Karin, Ph.D., professor of pharmacology in UCSD’s Laboratory of Gene Regulation and Signal Transduction, and Jordi Rius, Ph.D, a postdoctoral fellow, shows that transcription factor NF kappa B (NF-κB) – previously known for its role as the master regulator of the innate immune response – is also a critical regulator of the hypoxic response.

More than ten years ago, the Karin lab identified an enzyme called IκB kinase beta (IKKβ) as the critical activator of NF-κB. In this study, the UCSD researchers interfered with activation of NF-κB by inactivating IKKβ in different cells and tissues of a laboratory mouse. When they examined how macrophages deficient in IKKβ responded to bacterial infections or oxygen deprivation, the researchers found that, in addition to the expected defect in activation of NF-κB, the macrophages also failed to accumulate HIF-1α, the master regulator of the hypoxic response. HIF-1α is normally accumulated in cells experiencing low ambient oxygen, or hypoxia; in turn, it activates several genes responsible for generating energy to allow cell survival.

Previous work by UCSD co-contributors Victor Nizet, MD, professor of pediatrics and pharmacy and Randall S. Johnson, Ph.D., professor of biology, showed that bacterial infections – which deplete infected cells and tissues of critical oxygen – lead to accumulation of HIF 1α and activation of the hypoxic response.

“The hypoxic response is important in order for macrophages and other immune cells to kill and eliminate bacteria. The surprising result of the new study is the discovery that HIF-1α accumulation is dependent on activation of NF-κB,” said Karin.

The NF-ΚΒ and HIF-1 pathways have been extensively investigated as targets for new drug therapies. “Our new understanding of the interrelationship of NF-kB and the hypoxic response provides clues toward new treatment strategies to boost the immune function of white blood cells in infected tissues.” said Nizet. “Inhibition of the hypoxic response in macrophages might also limit inflammatory damage to brain tissues following stroke or cardiac arrest”.

A unique series of mice with specific genetic alterations of HIF-1 or IKKβ in various cells and tissues have been developed in the Karin and Johnson laboratories to continue these promising lines of investigation.

Additional contributors to the paper, all at UCSD, include Gabriel G. Haddad, M.D., professor of pediatrics; Katerina Akassoglou, Ph.D., UCSD assistant professor of pharmacology; and postgraduate researchers; Monica Guma, Ph.D., Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology; Christian Schachtrup, Ph.D., Department of Pharmacology, and Annelies S. Zinkernagel, M.D., Department of Pediatrics.

The study was funded in part by grants from the National Institutes of Health, with additional support from the Spanish Ministry of Education and Science. Michael Karin is an American Cancer Society Research Professor.

Source: University of California, San Diego

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Time Stamp: 4/23/2008 at 5:06:40 PM UTC

Brain reacts to fairness as it does to money and chocolate, study shows

Tuesday, April 22, 2008

The human brain responds to being treated fairly the same way it responds to winning money and eating chocolate, UCLA scientists report. Being treated fairly turns on the brain's reward circuitry.

"We may be hard-wired to treat fairness as a reward," said study co-author Matthew D. Lieberman, UCLA associate professor of psychology and a founder of social cognitive neuroscience.

"Receiving a fair offer activates the same brain circuitry as when we eat craved food, win money or see a beautiful face," said Golnaz Tabibnia, a postdoctoral scholar at the Semel Institute for Neuroscience and Human Behavior at UCLA and lead author of the study, which appears in the April issue of the journal Psychological Science.

The activated brain regions include the ventral striatum and ventromedial prefrontal cortex. Humans share the ventral striatum with rats, mice and monkeys, Tabibnia said.

"Fairness is activating the same part of the brain that responds to food in rats," she said. This is consistent with the notion that being treated fairly satisfies a basic need, she added.

In the study, subjects were asked whether they would accept or decline another person's offer to divide money in a particular way. If they declined, neither they nor the person making the offer would receive anything. Some of the offers were fair, such as receiving $5 out of $10 or $12, while others were unfair, such as receiving $5 out of $23.

"In both cases, they were being offered the same amount of money, but in one case it's fair and in the other case it's not," Tabibnia said.

Almost half the time, people agreed to accept offers of just 20 to 30 percent of the total money, but when they accepted these unfair offers, most of the brain's reward circuitry was not activated; those brain regions were activated only for the fair offers. Less than 2 percent accepted offers of 10 percent of the total money.

The study group consisted of 12 UCLA students, nine of them female, with an average age of 21. They had their brains scanned at UCLA's Ahmanson–Lovelace Brain Mapping Center. The subjects saw photographs of various people who were said to be making the offers.

"The brain's reward regions were more active when people were given a $5 offer out of $10 than when they received a $5 offer out of $23," Lieberman said. "We call this finding the 'sunny side of fairness' because it shows the rewarding experience of being treated fairly."

A region of the brain called the insula, associated with disgust, is more active when people are given insulting offers, Lieberman said.

When people accepted the insulting offers, they tended to turn on a region of the prefrontal cortex that is associated with emotion regulation, while the insula was less active.

"We're showing what happens in the brain when people swallow their pride," Tabibnia said. "The region of the brain most associated with self-control gets activated and the disgust-related region shows less of a response."

"If we can regulate our sense of insult, we can say yes to the insulting offer and accept the cash," Lieberman said.

Image Caption: Matthew D. Lieberman, UCLA associate professor of psychology and a founder of social cognitive neuroscience

Image Credit: UCLA News Room

Source: University of California, Los Angeles

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Time Stamp: 4/22/2008 at 10:44:27 AM CST

Low Cortisol Levels Found in Kids Whose Mothers Show Signs of Depression

Monday, April 21, 2008

A new study of young children living in extreme poverty found that those whose mothers showed symptoms of depression had low levels of cortisol, a hormone activated during times of stress, compared with children whose mothers did not exhibit depressive symptoms.

The researchers say the blunted cortisol levels they found in some children may indicate an adaptive response to chronic stress on the hypothalamic-pituitary-adrenal (HPA) system, which is responsible for producing hormones that help our bodies respond to stressful situations.

Cortisol is a corticosteroid hormone pumped out by the adrenal glands as part of a body's fight-or-flight response to stress. It raises blood pressure and blood sugar levels to help with quick bursts of energy, and is naturally found at higher levels in the early morning, declining to its lowest point at bedtime.

"Many people assume that the only way the body responds to constant stress is to produce too much cortisol, but repeated stress can also cause the HPA system to shut down so that you are not producing cortisol when you normally should," said Lia Fernald, assistant professor of community health and human development at the University of California, Berkeley, and lead author of the study.

The findings, appearing in the Spring 2008 issue of the journal Development and Psychopathology, highlight a biological effect in children who are facing not only economic deprivation, but also an added risk of possible depression in a key caregiver, the researchers said.

"The unexpectedly low levels of cortisol we found are most likely an expression of chronic, intense, long-term stress on the HPA system," said Megan Gunnar, professor of child development at the University of Minnesota and co-author of the study. "Really high increases over a period of time end up driving the system to the ground."

Awareness of hypo-cortisol levels has grown in the past five to 10 years, said Gunnar, a developmental psychobiologist. The researchers said that depressed levels of cortisol have been seen a few times before in young children, including in studies of neglected children in Romanian orphanages and preschoolers who experienced repeated bouts of foster care beginning in infancy.

The few studies that have been done suggest a link between low cortisol levels in children and disruptive behavior disorders, including aggression.

This new study is part of a larger project studying social welfare interventions for low-income families in Mexico. Researchers focused on children in some of Mexico's poorest regions, areas identified through a baseline census of families across the country. The study's sample of 639 children, ages 2.5 to 5, live in a region where the median per capita income is $730 per year, more than 14 times lower than the national figure in Mexico of approximately $10,000 per year. Approximately 40 percent of the children come from homes without electricity or running water, and many are from isolated indigenous communities.

In 2003, a research team of health professionals paid unannounced visits to homes in the low-income regions, providing verbal explanations of the goals and risks of research to participants and obtaining informed consent from the mothers. The researchers conducted one-hour interviews with each mother that included a standard screening test used to assess symptoms of depression. Although the screening tool has not been extensively used in Mexico, it has been used in the United States, where a score of 16 or higher indicates that the respondent is at risk for clinical depression.

More than 60 percent of the mothers in the study scored above 16, with 10 percent scoring above 35.

At the same time the mother was being interviewed, the researchers selected one child, usually the eldest, to undergo cognitive tests. They also took three samples of saliva from the child throughout the hour to determine whether any significant changes in levels occurred during the visit, and they controlled for the time of day the sample was taken.

The initial saliva sample, collected approximately five minutes after arrival in the home, represented baseline cortisol levels, since it takes more than five minutes for stress activations of the HPA system to raise cortisol concentrations in saliva. It takes about 20 to 25 minutes for the hormone's secretion to reach peak levels.

The unexpected presence of strangers was used by researchers as a mild stressor for young children. The administration of standardized cognitive tasks to assess language and cognitive competence was a second mild stressor for the children.

These are situations in which it would be normal for cortisol levels to increase moderately, said Fernald.

The researchers found that for all children, higher maternal scores on the depression screening tool were linked to the youngsters' lower overall cortisol levels. The baseline values for salivary cortisol in the children averaged 2.78 nanomoles per liter; about two to 2.5 times lower than what a typical middle class child in the United States would be showing at the same time of day.

"This study speaks to the fact that maternal depression, particularly when it goes along with poverty, really needs to be addressed," said Fernald. "Public health interventions typically focus on physical health, such as promoting immunizations and preventing malnutrition. However, we are seeing that a mother's mental health could be a critical factor influencing the physiology of their kids."

Moreover, the researchers found a greater impact of maternal depression symptoms on girls than on boys. Girls whose mothers had a greater number of depressive symptoms had the lowest baseline levels of cortisol.

"It is unclear why a larger effect was seen among girls, but I would suspect that it would be necessary to go beyond biology for an explanation," said Gunnar. "It may be related to the unique relationship between mothers and daughters, and the possibility that daughters often spend more time in the home."

"Maternal depression is very tough on little kids because it interferes with the mother's capacity to be responsive and supportive," added Gunnar. "On the flip side of that is that a mother who can provide supportive care can buffer her children from a lot of adversity. Other studies have shown that. But of course, it's hard to be sensitive and supportive to the demands of young children when you are struggling emotionally and physically with trying to live in extremely impoverished conditions."

The study was also co-authored by Heather Burke, assistant adjunct professor of psychiatry at UC San Francisco. It was supported by the John D. and Catherine T. MacArthur Foundation Network on SES (Socioeconomic Status) and Health, the Fogarty International Center of the National Institutes of Health, and the National Institute of Mental Health.

Source: University of California, Berkeley / Sarah Yang

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Time Stamp: 4/21/2008 at 2:19:57 PM CST

Scientists Discover The Travel Patterns Of Seasonal Flu

Friday, April 18, 2008

Scientists discover the travel patterns of seasonal flu - findings may lead to improved flu vaccines.

Outbreaks of the most common type of influenza virus, A (H3N2), are seeded by viruses that originate in East and Southeast Asia and migrate around the world, new research has found. This discovery may help to further improve flu vaccines and make the evolution of the virus more predictable.

Scientists at the University of Cambridge, in collaboration with scientists from the World Health Organization (WHO) Global Influenza Surveillance Network, found that each year since 2002 influenza A (H3N2) viruses have migrated out of what the authors call the “East and Southeast Asian circulation network” (which includes tropical, subtropical, and temperate countries) and spread throughout the world. Their findings are reported in the current edition of Science.

Annual influenza epidemics are thought to infect 5-15% of the world population each year, cause 3 to 5 million cases of severe illness, and between 250,000 and 500,000 deaths, according to the World Health Organization. The flu vaccine protects the 300 million people vaccinated each year.

Because the flu virus evolves so quickly, there are a number of challenges involved in making the vaccine. In order to create an effective vaccine, each year in February and September a WHO committee meets to select the strains of flu to use in the influenza virus vaccine. These scientists (many of whom are co-authors on this study) decide which strains pose the greatest threat for the next flu season.

One of the serious challenges to creating flu vaccines is that the global migration pattern of influenza viruses has been a mystery. Several competing hypotheses have emerged including migration between the Northern and Southern hemispheres following the seasons, migration out of the tropics where influenza viruses were thought to circulate continuously, and migration out of China.

Colin Russell of the University of Cambridge and his colleagues analyzed 13,000 samples of influenza A (H3N2) virus, collected worldwide by the World Health Organization Global Influenza Surveillance Network between 2002 and 2007.

The analyses allowed the researchers to identify different strains of A (H3N2), the subtype of seasonal flu that causes the most disease, as they arrived at new locations around the world over the five-year period. The results revealed that new strains emerge in East and Southeast Asia and then about six to nine months later reach Europe and North America. Several months later still, the strains arrive in South America. Once viruses leave East and Southeast Asia they rarely return and thus regions outside of East and Southeast Asia are essentially the evolutionary graveyards of influenza viruses.

For reasons that aren’t well-understood, flu epidemics typically occur during the winter months in the temperate regions of the northern and southern hemisphere and in tropical countries, flu epidemics often coincide with the rainy season. Because there is variation in the timing of the rainy season in different parts of East and Southeast Asia, combined with the wintertime epidemics in the temperate parts of the region, the overlap in the timing of epidemics gives the opportunity for influenza viruses to circulate year round in East and Southeast Asia. The authors find that this year-round circulation allows East and Southeast Asia to serve as the source of influenza A (H3N2) viruses for epidemics in the rest of the world.

“Flu epidemics appear to be driven by seasonal factors such as winter, or rainy seasons. So there can be cities that are only 700 miles away from each other, such as Bangkok and Kuala Lumpur, which have epidemics six months apart. There is a lot of variability like this in East and Southeast Asia, so lots of opportunity for an epidemic in one country to seed an epidemic to another nearby country, like a baton passed by runners in a relay race,” said Derek Smith of the University of Cambridge, who is the corresponding author of the study.

The authors emphasized that the flu vaccine works very well, and protects the 300 million people vaccinated each year. But, from time to time, a new strain emerges after the vaccine strain selection has already been made.

“The ultimate goal of our collaboration is to increase our ability to predict the evolution of influenza viruses. This study is one step along that path and in particular highlights the importance of ongoing collaborations and surveillance in East and Southeast Asia, and expanding these collaborations in the future,” said Smith.

A fundamental component of the study is the integration of quantitative analyses of genetic and ‘antigenic’ data (data that can be used to infer the similarity of viruses from the perspective of the immune system) on the strains of flu. Combining these two types of data provides a comprehensive picture of virus evolution. The key innovation that enabled the quantitative analysis of the antigenic data is a computational technique called antigenic cartography, map-making that shows differences between viruses.

Antigenic cartography is a method developed by researchers at Erasmus Medical Center, Los Alamos National Laboratory and the University of Cambridge. Given measurements for multiple viruses, antigenic cartography can be used to create a map in which the distance between viruses in the map reflects their antigenic similarity and can be used to compare thousands of viruses at a time. From these antigenic maps it is then possible to trace the evolution of the viruses.

“By applying an innovative strategy to map differences in seasonal influenza strains worldwide, Smith and his colleagues have offered important insights into patterns of influenza virus spread that could greatly improve surveillance and vaccine strain selection,” said Elias A. Zerhouni, M.D., director of the U.S. National Institutes of Health. “This research, which was partially funded by our Pioneer Award program, shows the value of supporting exceptionally creative approaches to major challenges in biomedical and behavioral research.”

Another fundamental component of this work is its thoroughly collaborative and global nature. Many authors on this paper are scientists in WHO’s Global Influenza Surveillance Network, which comprises over 100 labs in 80 countries around the world. Influenza virus evolves continuously at such pace that the scientists in charge of its surveillance are essentially “tracking its evolution in real time,” said Smith.

“Because flu evolves so quickly, flu science and public health necessarily go hand in hand,” said Smith. “The World Health Organization’s Global Influenza Surveillance Network tracks the evolution of influenza viruses for the primary purpose of influenza vaccine strain selection, but this also enables the Network to improve strain selection through evolutionary studies as witnessed by this highly collaborative and thoroughly international study.”

Source: University of Cambridge

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Time Stamp: 4/18/2008 at 12:23:58 AM CST

Are Sacrificial Bacteria Altruistic or Just Unlucky?

Wednesday, April 16, 2008

Genetic study finds chance helps determine fate of B. subtilis bacteria

An investigation of the genes that govern spore formation in the bacteria B. subtilis shows that chance plays a significant role in determining which of the microbes sacrifice themselves for the colony and which go on to form spores.
 
B. subtilis, a common soil bacteria, is a well-known survivor. When running short of food, it can alternatively band together in colonies or encase itself in a tough, protective spore to wait for better times. In fact, B. subtilis is so good at making spores that it's often used as a model organism by biologists who study bacterial spore formation.
 
"It's too early to say whether B. subtilis is truly altruistic," said co-author Oleg Igoshin, assistant professor of bioengineering at Rice University. "What is clear from this is that not all bacteria are going to look and act the same, and that's something that can be overlooked when people either study or attempt to control bacteria with population-wide approaches."
 
For example, Igoshin said doctors and food safety engineers might need to amend general approaches aimed at controlling bacteria with more targeted methods that also account for the uncharacteristic individual.
 
The new results appear in the April 15 issue of Molecular Systems Biology. The experimental work, which was done by Jan-Willem Veening, currently at Newcastle University, and by other members of Oscar Kuipers' research group at the University of Groningen in the Netherlands, focused on the B. subtilis genes that regulate both spore formation and the production cycles of two proteins -- subtilisin and bacillopeptidase. These two proteins help break apart dead cells and convert them into food. They are produced and released into the surrounding environment by B. subtilis cells that are running low on food.
 
From previous studies, scientists know there is some overlap between genes that control the production of the two proteins and those that control spore formation.
 
"Only a portion of the bacteria in a colony will form spores and only portion of the bacteria produce subtilisin, and we were interested in probing the genetic basis for this," Igoshin said. "How is it decided which cells become spores and which don't?"
 
Igoshin, a computational biologist, used computer simulations to help decipher and interpret the team's experimental results. He said the team found that fewer than 30 percent of individuals in a colony produce large quantities of the food-converting proteins. Even though the proteins benefit all members of the colony and help some cells to become spores, the cells that produce the proteins in bulk do not form spores themselves.
 
"There's a feedback loop, so that cells that start producing the proteins early get a reinforced signal to keep making them," Igoshin said. "We found that it's probabilistic events -- chance, if you will -- that dictates who is early and who is late. The early ones start working for the benefit of everyone while the later ones save valuable resources to ensure successful completion of sporulation program. Many cells will end up committing to sporulation before they had a chance to contribute to protease production"
 
Igoshin said a key piece of evidence confirming modeling predictions came in experiments that tracked genetically identical sister cells, some of which became protein producers and some of which didn't.
 
The research was supported by the Netherlands Organization of Scientific Research, the Royal Netherlands Academy of Arts and Sciences, the Biotechnology and Biological Sciences Research Council, the Wellcome Trust and Rice University. Co-authors also include Robyn Eijlander and Reindert Nijland of the University of Groningen, and Leendert Hamoen of Newcastle University in Great Britain.

Source: Rice University / Jade Boyd

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Time Stamp: 4/16/2008 at 9:07:09 PM CST