Climate warming will affect animals in many ways, including the sex of some species' offspring. For tuatara, unique and ancient reptiles from New Zealand, warmer nest temperatures produce male-biased clutches.
We predicted sex ratios and hatching times of tuatara clutches under future climate scenarios by linking egg development data with sophisticated models of soil microclimates.
Under extreme climate change only males would hatch from nests of the rarest tuatara species by the mid 2080s.
Our novel approach will help in assessing future translocation sites for tuatara, and for predicting climatic impacts on other species where sex is determined by temperature.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
publishing.royalsociety/proceedingsb
воскресенье, 8 мая 2011 г.
суббота, 7 мая 2011 г.
New Forecasting Tool Could Reduce Drug Development Costs
It now costs more than $800 million to develop a new drug. But what if pharmaceutical companies had a way to predict which experimental drugs will ultimately get FDA approval, giving them the confidence to invest money in them, and which drugs will ultimately fail, allowing them to cut their losses early?
In the February issue of Nature Reviews Drug Discovery, researchers from the Children's Hospital Boston Informatics Program (CHIP) present a forecasting model that may increase the efficiency of drug R&D and save hundreds of millions of dollars per new drug. They also argue that more data sharing by the drug industry - particularly of "negative" data - would greatly improve the accuracy of forecasting and benefit industry and patients alike, allowing more medical discoveries to be brought to the bedside.
Asher Schachter, MD, MMSc, MS, and Marco Ramoni, PhD, both of CHIP, constructed a Bayesian network model to calculate the probability that a given new drug would pass successfully through Phase III trials and receive New Drug Application (NDA) approval. Their approach differs from convention in modeling populations of drugs rather than populations of patients. They used publicly available safety and efficacy data for about 500 successful and failed new drugs, broken down by therapeutic category, then confirmed the validity of their model by testing it with a group of cancer drugs whose fates are already known.
To gauge the model's potential economic impact, Schachter and Ramoni then performed a pharmaco-economic analysis in collaboration with Stan Finkelstein, MD, Senior Research Scientist at the MIT Sloan School of Management. This analysis, using summary data on industry-reported expenditures and revenues, indicated that application of the model would reduce mean capitalized expenditures by an average of $283 million per successful new drug (from $727 to $444), and increase revenues by an average of $160 million per Phase III trial (from $347 to $507 million) during the drug's first seven years on the market.
Schachter, also a pediatric nephrologist at Children's Hospital Boston, believes that more data sharing by the pharmaceutical industry would enable the industry to learn more from its own failures. "There's a tendency in the industry to bury data on failed drugs and forget about them," Schachter says. "We hope our model will add fuel to efforts to show that data-sharing could be beneficial to everybody."
Such efforts include legislation introduced in the Senate last year (S3807) that would establish a clinical trial registry database that would report the results of later-stage clinical trials, both good and bad.
In their report in Nature Reviews Drug Discovery, Schachter and Ramoni also argue that more accurate clinical forecasting would eliminate unsafe investigational new drugs; avoid subjecting patients to unnecessary drug trials; reduce the cost of prescription drugs for consumers; and empower the industry to take risks on truly innovative new drugs, so that more get to market.
The need for pharmaceutical industry involvement in early trials is especially acute for pediatric drugs, Schachter adds. Companies are reluctant to conduct clinical trials in children, fearing a negative impact on marketability. Instead, doctors often resort to giving adult drugs to children off-label, outside the context of a controlled, safety-monitored study.
For more information on the model and related issues, visit: phorecaster/.
The Children's Hospital Informatics Program (CHIP) is a multidisciplinary applied research program at Children's Hospital Boston and the Harvard-MIT Division of Health, Sciences and Technology. CHIP focuses in three areas: bioinformatics, public health informatics (including biosurveillance), and clinical informatics. Its diverse faculty includes physicians trained in information science, computer scientists with expertise in the biomedical sciences, mathematicians, and epidemiologists. CHIP provides shared resources to develop innovative information technologies with the goal of both enhancing biomedical research and improving patient care. CHIP also serves as the bioinformatics core for several national genomics investigations. For more information, visit: chip/.
Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is the nation's leading pediatric medical center, the largest provider of health care to Massachusetts children, and the primary pediatric teaching hospital of Harvard Medical School. In addition to 347 pediatric and adolescent inpatient beds and comprehensive outpatient programs, Children's houses the world's largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. For more information about the hospital visit: childrenshospital/newsroom.
Contact: Anna Gonski
Children's Hospital Boston
In the February issue of Nature Reviews Drug Discovery, researchers from the Children's Hospital Boston Informatics Program (CHIP) present a forecasting model that may increase the efficiency of drug R&D and save hundreds of millions of dollars per new drug. They also argue that more data sharing by the drug industry - particularly of "negative" data - would greatly improve the accuracy of forecasting and benefit industry and patients alike, allowing more medical discoveries to be brought to the bedside.
Asher Schachter, MD, MMSc, MS, and Marco Ramoni, PhD, both of CHIP, constructed a Bayesian network model to calculate the probability that a given new drug would pass successfully through Phase III trials and receive New Drug Application (NDA) approval. Their approach differs from convention in modeling populations of drugs rather than populations of patients. They used publicly available safety and efficacy data for about 500 successful and failed new drugs, broken down by therapeutic category, then confirmed the validity of their model by testing it with a group of cancer drugs whose fates are already known.
To gauge the model's potential economic impact, Schachter and Ramoni then performed a pharmaco-economic analysis in collaboration with Stan Finkelstein, MD, Senior Research Scientist at the MIT Sloan School of Management. This analysis, using summary data on industry-reported expenditures and revenues, indicated that application of the model would reduce mean capitalized expenditures by an average of $283 million per successful new drug (from $727 to $444), and increase revenues by an average of $160 million per Phase III trial (from $347 to $507 million) during the drug's first seven years on the market.
Schachter, also a pediatric nephrologist at Children's Hospital Boston, believes that more data sharing by the pharmaceutical industry would enable the industry to learn more from its own failures. "There's a tendency in the industry to bury data on failed drugs and forget about them," Schachter says. "We hope our model will add fuel to efforts to show that data-sharing could be beneficial to everybody."
Such efforts include legislation introduced in the Senate last year (S3807) that would establish a clinical trial registry database that would report the results of later-stage clinical trials, both good and bad.
In their report in Nature Reviews Drug Discovery, Schachter and Ramoni also argue that more accurate clinical forecasting would eliminate unsafe investigational new drugs; avoid subjecting patients to unnecessary drug trials; reduce the cost of prescription drugs for consumers; and empower the industry to take risks on truly innovative new drugs, so that more get to market.
The need for pharmaceutical industry involvement in early trials is especially acute for pediatric drugs, Schachter adds. Companies are reluctant to conduct clinical trials in children, fearing a negative impact on marketability. Instead, doctors often resort to giving adult drugs to children off-label, outside the context of a controlled, safety-monitored study.
For more information on the model and related issues, visit: phorecaster/.
The Children's Hospital Informatics Program (CHIP) is a multidisciplinary applied research program at Children's Hospital Boston and the Harvard-MIT Division of Health, Sciences and Technology. CHIP focuses in three areas: bioinformatics, public health informatics (including biosurveillance), and clinical informatics. Its diverse faculty includes physicians trained in information science, computer scientists with expertise in the biomedical sciences, mathematicians, and epidemiologists. CHIP provides shared resources to develop innovative information technologies with the goal of both enhancing biomedical research and improving patient care. CHIP also serves as the bioinformatics core for several national genomics investigations. For more information, visit: chip/.
Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is the nation's leading pediatric medical center, the largest provider of health care to Massachusetts children, and the primary pediatric teaching hospital of Harvard Medical School. In addition to 347 pediatric and adolescent inpatient beds and comprehensive outpatient programs, Children's houses the world's largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. For more information about the hospital visit: childrenshospital/newsroom.
Contact: Anna Gonski
Children's Hospital Boston
пятница, 6 мая 2011 г.
Caltech Scientists Show Why Anti-HIV Antibodies Are Ineffective At Blocking Infection
-Some 25 years after the AIDS epidemic spawned a worldwide search for an effective vaccine against the human immunodeficiency virus (HIV), progress in the field seems to have effectively become stalled. The reason? According to new findings from a team of researchers from the California Institute of Technology (Caltech), it's at least partly due to the fact that our body's natural HIV antibodies simply don't have a long enough reach to effectively neutralize the viruses they are meant to target.
Their findings were published last week in the online early edition of the Proceedings of the National Academy of Sciences (PNAS).
"This study helps to clarify the obstacles that antibodies face in blocking infection," says Pamela Bjorkman, the Max DelbrГјck Professor of Biology at Caltech and a Howard Hughes Medical Institute Investigator, "and will hopefully shed more light on why developing an effective vaccine for HIV has proven so elusive."
Y-shaped antibodies are best at neutralizing viruses--i.e., blocking their entry into cells and preventing infection--when both arms of the Y are able to reach out and bind to their target proteins at more or less the same time. In the case of HIV, antibodies that can block infection target the proteins that stud the surface of the virus, which stick out like spikes from the viral membrane. But an antibody can only bind to two spikes at the same time if those spikes fall within its span--the distance the antibody's structure allows it to stretch its two arms.
"When both arms of an antibody are able to bind to a virus at the same time," says Joshua Klein, a Caltech graduate student in biochemistry and molecular biophysics and the PNAS paper's first author, "there can be a hundred- to thousandfold increase in the strength of the interaction, which can sometimes translate into an equally dramatic increase in its ability to neutralize a virus. Having antibodies with two arms is nature's way of ensuring a strong binding interaction."
As it turns out, this sort of double-armed binding is easier said than done--at least in the case of HIV.
In their PNAS paper, Bjorkman and Klein looked at the neutralization capabilities of two different monoclonal antibodies isolated from HIV-infected individuals. One, called b12, binds a protein known as gp120, which forms the upper portion of an HIV's protein spike. The other, 4E10, binds to gp41, which is found on a lower portion of the spike known as the stalk.
The researchers broke each of the antibodies down into their component parts and compared their abilities to bind and neutralize the virus. They found, as expected, that one-armed versions of the b12 antibody were less effective at neutralizing HIV than two-armed versions. When they looked at the 4E10 antibody, by comparison, they found that having two arms conferred almost no advantage over having only one arm. In addition, they found that larger versions of 4E10 were less effective than smaller ones. These results highlight potential obstacles that vaccines designed to elicit antibodies similar to 4E10 might face.
But b12 has its own obstacles to overcome as well. In fact, when the researchers looked more closely at their data, they realized that the benefits of having two arms--even for b12--were much smaller than those seen for antibodies against viruses like influenza. In other words, the body's natural anti-HIV antibodies are much less effective at neutralizing HIV than they should be.
But why?
"The story really starts to get interesting when we think about what the human immunodeficiency virus actually looks like," says Klein. Whereas a single influenza virus's surface is studded with approximately 450 spikes, he explains, the similarly sized HIV may have fewer than 15 spikes.
With spikes so few and far between, finding two that both fall within the reach of a b12 or 4E10 antibody--the spans of which generally measure between 12 and 15 nanometers--becomes much more of a challenge.
"HIV may have evolved a way to escape one of the main strategies our immune system uses to defeat infections," says Klein. "Based on these data, it seems that the virus is circumventing the bivalent effect that is so key to the potency of antibodies."
"I consider this a very important paper because it changes the focus of the discussion about why anti-HIV antibodies are so poor," adds virologist David Baltimore, the Robert Andrews Millikan Professor of Biology and a Nobel Prize winner. "It brings attention to a long-recognized but often forgotten aspect of antibody attack--that they attack with two heads. What this paper shows is that anti-HIV antibodies are restricted to using one head at a time and that makes them bind much less well. Responding to this newly recognized challenge will be difficult because it identifies an intrinsic limitation on the effectiveness of almost any natural anti-HIV antibodies."
In addition to Bjorkman and Klein, the authors on the PNAS paper, "Examination of the contributions of size and avidity to the neutralization mechanisms of the anti-HIV antibodies b12 and 4E10," are Caltech research technicians Priyanthi Gnanapragasam, Rachel Galimidi, and Christopher Foglesong, and senior research specialist Anthony West, Jr.
The work described in the paper was supported by a Bill and Melinda Gates Foundation Grant through the Grand Challenges in Global Health Initiative and the Collaboration for AIDS Vaccine Discovery.
Source:
Lori Oliwenstein
California Institute of Technology
Their findings were published last week in the online early edition of the Proceedings of the National Academy of Sciences (PNAS).
"This study helps to clarify the obstacles that antibodies face in blocking infection," says Pamela Bjorkman, the Max DelbrГјck Professor of Biology at Caltech and a Howard Hughes Medical Institute Investigator, "and will hopefully shed more light on why developing an effective vaccine for HIV has proven so elusive."
Y-shaped antibodies are best at neutralizing viruses--i.e., blocking their entry into cells and preventing infection--when both arms of the Y are able to reach out and bind to their target proteins at more or less the same time. In the case of HIV, antibodies that can block infection target the proteins that stud the surface of the virus, which stick out like spikes from the viral membrane. But an antibody can only bind to two spikes at the same time if those spikes fall within its span--the distance the antibody's structure allows it to stretch its two arms.
"When both arms of an antibody are able to bind to a virus at the same time," says Joshua Klein, a Caltech graduate student in biochemistry and molecular biophysics and the PNAS paper's first author, "there can be a hundred- to thousandfold increase in the strength of the interaction, which can sometimes translate into an equally dramatic increase in its ability to neutralize a virus. Having antibodies with two arms is nature's way of ensuring a strong binding interaction."
As it turns out, this sort of double-armed binding is easier said than done--at least in the case of HIV.
In their PNAS paper, Bjorkman and Klein looked at the neutralization capabilities of two different monoclonal antibodies isolated from HIV-infected individuals. One, called b12, binds a protein known as gp120, which forms the upper portion of an HIV's protein spike. The other, 4E10, binds to gp41, which is found on a lower portion of the spike known as the stalk.
The researchers broke each of the antibodies down into their component parts and compared their abilities to bind and neutralize the virus. They found, as expected, that one-armed versions of the b12 antibody were less effective at neutralizing HIV than two-armed versions. When they looked at the 4E10 antibody, by comparison, they found that having two arms conferred almost no advantage over having only one arm. In addition, they found that larger versions of 4E10 were less effective than smaller ones. These results highlight potential obstacles that vaccines designed to elicit antibodies similar to 4E10 might face.
But b12 has its own obstacles to overcome as well. In fact, when the researchers looked more closely at their data, they realized that the benefits of having two arms--even for b12--were much smaller than those seen for antibodies against viruses like influenza. In other words, the body's natural anti-HIV antibodies are much less effective at neutralizing HIV than they should be.
But why?
"The story really starts to get interesting when we think about what the human immunodeficiency virus actually looks like," says Klein. Whereas a single influenza virus's surface is studded with approximately 450 spikes, he explains, the similarly sized HIV may have fewer than 15 spikes.
With spikes so few and far between, finding two that both fall within the reach of a b12 or 4E10 antibody--the spans of which generally measure between 12 and 15 nanometers--becomes much more of a challenge.
"HIV may have evolved a way to escape one of the main strategies our immune system uses to defeat infections," says Klein. "Based on these data, it seems that the virus is circumventing the bivalent effect that is so key to the potency of antibodies."
"I consider this a very important paper because it changes the focus of the discussion about why anti-HIV antibodies are so poor," adds virologist David Baltimore, the Robert Andrews Millikan Professor of Biology and a Nobel Prize winner. "It brings attention to a long-recognized but often forgotten aspect of antibody attack--that they attack with two heads. What this paper shows is that anti-HIV antibodies are restricted to using one head at a time and that makes them bind much less well. Responding to this newly recognized challenge will be difficult because it identifies an intrinsic limitation on the effectiveness of almost any natural anti-HIV antibodies."
In addition to Bjorkman and Klein, the authors on the PNAS paper, "Examination of the contributions of size and avidity to the neutralization mechanisms of the anti-HIV antibodies b12 and 4E10," are Caltech research technicians Priyanthi Gnanapragasam, Rachel Galimidi, and Christopher Foglesong, and senior research specialist Anthony West, Jr.
The work described in the paper was supported by a Bill and Melinda Gates Foundation Grant through the Grand Challenges in Global Health Initiative and the Collaboration for AIDS Vaccine Discovery.
Source:
Lori Oliwenstein
California Institute of Technology
четверг, 5 мая 2011 г.
New Anti-Inflammatory Compound Discovered
Scientists have discovered that a lipid known to protect the heart from inflammation and to cause skin allergic reactions also reduces inflammation of the kidneys. The discovery could help devise new ways of treating inflammatory kidney diseases.
The lipid, called sphingosylphosphorylcholine (SPC), has been shown to cause an increase in urine production in the kidneys and an abnormal accumulation of salt in the urine. But how SPC works in the kidneys is not completely understood.
Andrea Huwiler and colleagues examined the various proteins activated by SPC in kidney cells and showed for the first time that SPC triggers proteins known to reduce inflammation. Although more details will be needed to understand how these proteins and how SPC may interact with other anti-inflammatory proteins - such as transforming growth factor beta - SPC may be useful in the treatment of chronic inflammatory and fibrotic diseases of the kidneys, the scientists concluded.
Article: "Sphingosylphosphorylcholine acts in an anti-inflammatory manner in renal mesangial cells by reducing interleukin-1b-induced prostaglandin E2 formation," by Cuiyan Xin, Shuyu Ren, Wolfgang Eberhardt, Josef Pfeilschifter, and Andrea Huwiler.
The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society's student members attend undergraduate or graduate institutions.
Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's purpose is to advance the science of biochemistry and molecular biology through publication of the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics, organization of scientific meetings, advocacy for funding of basic research and education, support of science education at all levels, and promoting the diversity of individuals entering the scientific work force.
For more information about ASBMB, see the Society's Web site at asbmb.
The lipid, called sphingosylphosphorylcholine (SPC), has been shown to cause an increase in urine production in the kidneys and an abnormal accumulation of salt in the urine. But how SPC works in the kidneys is not completely understood.
Andrea Huwiler and colleagues examined the various proteins activated by SPC in kidney cells and showed for the first time that SPC triggers proteins known to reduce inflammation. Although more details will be needed to understand how these proteins and how SPC may interact with other anti-inflammatory proteins - such as transforming growth factor beta - SPC may be useful in the treatment of chronic inflammatory and fibrotic diseases of the kidneys, the scientists concluded.
Article: "Sphingosylphosphorylcholine acts in an anti-inflammatory manner in renal mesangial cells by reducing interleukin-1b-induced prostaglandin E2 formation," by Cuiyan Xin, Shuyu Ren, Wolfgang Eberhardt, Josef Pfeilschifter, and Andrea Huwiler.
The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society's student members attend undergraduate or graduate institutions.
Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's purpose is to advance the science of biochemistry and molecular biology through publication of the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics, organization of scientific meetings, advocacy for funding of basic research and education, support of science education at all levels, and promoting the diversity of individuals entering the scientific work force.
For more information about ASBMB, see the Society's Web site at asbmb.
среда, 4 мая 2011 г.
Attention, Memory And Language Links In The Human Brain Mapped By Pioneering Study
A University of Arizona scientist who has specialized in studying how fireflies and other creatures communicate has won a million-dollar grant to conduct a pioneering 5-year study on the roles that attention and memory play when the human brain hears and processes spoken language.
"This is the chance to study the ultimate form of animal communication -- language," said Thomas A. Christensen of UA's department of speech, language and hearing sciences (SLHS). "Humans have evolved a very sophisticated symbolic form of communication. Language affects how we think, what we believe, how we interact with each other. I'd even go so far as to say that our future as a species depends on understanding how we communicate. But very little is known about what's going on in the brain when we're having a simple conversation."
Until recently, Christensen was a research scientist with the Arizona Research Laboratories' Division of Neurobiology, studying olfactory communication (the sense of smell) in insects. His research is grounded in the areas of learning and memory, systems physiology and animal communication. Encouraged by Elena Plante, head of the SLHS department, he applied for a $1 million career development award from the National Institute of Deafness and Other Communication Disorders. The grant was awarded in April.
The grant will take his career -- and biomedical science -- in new directions. Christensen will use UA's state-of-the-art magnetic resonance imaging (MRI) facilities to map the areas and networks within the brain linked to language, attention and memory. The UA's advanced MRI is a non-invasive imaging tool that is sensitive enough to show exactly what parts of the brain are involved when a person listens to another human voice.
"What you read in the text books is that if you're right handed, then language is localized to the left hemisphere of your brain," Christensen said. "I found out right away -- that's just not true. Analyzing a human voice also involves the right hemisphere and even parts of the cerebellum." The cerebellum is a large part of the brain that serves to coordinate voluntary movements, posture, and balance in humans.
"These MRI images destroy the myth that you're only using about 10 percent of your brain for any particular task," Christensen said. "The crux of this grant is to learn more about the language, attention and memory centers in the brain, and also about the complex interactions between them."
Inside the scanner, volunteer subjects don headphones and perform simple language discrimination tasks in Christensen's experiments. They're asked to respond by pressing a button when they hear words that fall into a certain semantic category -- the name of an animal, for example. Then, to make the task a bit harder, subjects are asked to respond only when they hear a woman's voice speak a word in the chosen category. The task taxes attention even more when subjects are asked to respond to a woman's voice speaking a 'target' word in one ear at the same time a man's voice is speaking words in the other.
The MRI scanner records activity throughout the 45-minute sessions, revealing multiple regions and networks, some deep within the brain, that scientists didn't suspect were involved when the brain listens.
"We're getting a snapshot of what that activity is across the population. What's so striking is how clearly we see that certain areas of the brain are strongly engaged in attentional control while other areas are not. As we scan more volunteers, we're definitely beginning to see a pattern here."
Christensen's research on the brain-governing system we called "attention" -- how the brain selects only some information from its environment and is able to focus awareness on objects and events relevant to immediate goals -- is profoundly relevant to such disorders as schizophrenia, ADHD and many other impairments that affect language abilities.
"ADHD (Attention Deficit Hyperactivity Disorder) is probably one of the most over-diagnosed disorders of our time," Christensen said. "The reason for that, I think, is that we really don't know very much about the biological basis of this syndrome. There's a lot of research on it, but there's still a lot of disagreement about what the root cause is, and about whether drugs like Ritalin that are being prescribed to children as young as 2 years old are doing any good, and if we have any business exposing our children to drugs at such a very early age," he added.
As Christensen collects more MRI data that show the connections among areas of the brain that are strongly engaged in language tasks, he plans to collaborate with computer modeling experts. "We could develop a mathematical model that would allow us to generate hypotheses about what we expect if we deliver a certain type of stimulus. We'd see what effect it would produce in our model."
Simulating brain activity in the mathematical model "would take the whole question of language processing beyond 'blobology' -- where you're just looking at blobs of activation in the brain. That's what I hope to do," Christensen said.
Contact: Lori Stiles
University of Arizona
View drug information on Ritalin LA.
"This is the chance to study the ultimate form of animal communication -- language," said Thomas A. Christensen of UA's department of speech, language and hearing sciences (SLHS). "Humans have evolved a very sophisticated symbolic form of communication. Language affects how we think, what we believe, how we interact with each other. I'd even go so far as to say that our future as a species depends on understanding how we communicate. But very little is known about what's going on in the brain when we're having a simple conversation."
Until recently, Christensen was a research scientist with the Arizona Research Laboratories' Division of Neurobiology, studying olfactory communication (the sense of smell) in insects. His research is grounded in the areas of learning and memory, systems physiology and animal communication. Encouraged by Elena Plante, head of the SLHS department, he applied for a $1 million career development award from the National Institute of Deafness and Other Communication Disorders. The grant was awarded in April.
The grant will take his career -- and biomedical science -- in new directions. Christensen will use UA's state-of-the-art magnetic resonance imaging (MRI) facilities to map the areas and networks within the brain linked to language, attention and memory. The UA's advanced MRI is a non-invasive imaging tool that is sensitive enough to show exactly what parts of the brain are involved when a person listens to another human voice.
"What you read in the text books is that if you're right handed, then language is localized to the left hemisphere of your brain," Christensen said. "I found out right away -- that's just not true. Analyzing a human voice also involves the right hemisphere and even parts of the cerebellum." The cerebellum is a large part of the brain that serves to coordinate voluntary movements, posture, and balance in humans.
"These MRI images destroy the myth that you're only using about 10 percent of your brain for any particular task," Christensen said. "The crux of this grant is to learn more about the language, attention and memory centers in the brain, and also about the complex interactions between them."
Inside the scanner, volunteer subjects don headphones and perform simple language discrimination tasks in Christensen's experiments. They're asked to respond by pressing a button when they hear words that fall into a certain semantic category -- the name of an animal, for example. Then, to make the task a bit harder, subjects are asked to respond only when they hear a woman's voice speak a word in the chosen category. The task taxes attention even more when subjects are asked to respond to a woman's voice speaking a 'target' word in one ear at the same time a man's voice is speaking words in the other.
The MRI scanner records activity throughout the 45-minute sessions, revealing multiple regions and networks, some deep within the brain, that scientists didn't suspect were involved when the brain listens.
"We're getting a snapshot of what that activity is across the population. What's so striking is how clearly we see that certain areas of the brain are strongly engaged in attentional control while other areas are not. As we scan more volunteers, we're definitely beginning to see a pattern here."
Christensen's research on the brain-governing system we called "attention" -- how the brain selects only some information from its environment and is able to focus awareness on objects and events relevant to immediate goals -- is profoundly relevant to such disorders as schizophrenia, ADHD and many other impairments that affect language abilities.
"ADHD (Attention Deficit Hyperactivity Disorder) is probably one of the most over-diagnosed disorders of our time," Christensen said. "The reason for that, I think, is that we really don't know very much about the biological basis of this syndrome. There's a lot of research on it, but there's still a lot of disagreement about what the root cause is, and about whether drugs like Ritalin that are being prescribed to children as young as 2 years old are doing any good, and if we have any business exposing our children to drugs at such a very early age," he added.
As Christensen collects more MRI data that show the connections among areas of the brain that are strongly engaged in language tasks, he plans to collaborate with computer modeling experts. "We could develop a mathematical model that would allow us to generate hypotheses about what we expect if we deliver a certain type of stimulus. We'd see what effect it would produce in our model."
Simulating brain activity in the mathematical model "would take the whole question of language processing beyond 'blobology' -- where you're just looking at blobs of activation in the brain. That's what I hope to do," Christensen said.
Contact: Lori Stiles
University of Arizona
View drug information on Ritalin LA.
вторник, 3 мая 2011 г.
Identification Of Potential New Drug Target For Depression
An acid-sensitive protein in the brain may represent a new target for the treatment of depression, according to animal research in the April 29 issue of The Journal of Neuroscience. The study shows that disrupting acid-sensitive ion channel-1a (ASIC1a) produces antidepressant-like effects in mice. The findings may one day benefit people who do not respond to traditional antidepressants or who cannot tolerate their side effects.
"Depression is one of the most devastating and difficult-to-treat disorders known to man," said John F. Cryan, PhD, at University College Cork in Ireland, who was not affiliated with the study. "Despite much research, all antidepressant medications that are currently prescribed work in much the same way and are of limited efficacy in more than a third of all patients. The development of antidepressants that act on other molecular targets in the brain would be a major breakthrough," Cryan said.
Although animal models cannot reproduce all of the symptoms of human depression, several behavioral tests in rodents are sensitive to antidepressant treatment, suggesting that they address important aspects of the disease. For example, chronically stressed mice lose their normal preference for sugary drinks, and mice repeatedly placed in a pool of water tend to give up and float rather than swim in the hopes of escaping. These mouse behaviors are thought to reflect loss of interest in pleasurable activities and hopelessness or despair. But traditional antidepressants are able to restore the mouse preference for sweet treats and reduce the amount of time that they float rather than swim.
The researchers, led by Matthew Coryell, PhD and senior researcher John Wemmie, MD, PhD, at the University of Iowa, found that mice lacking the ASIC1a gene and normal mice treated with drugs that inhibit ASIC1a showed reduced depression-like behaviors. These mice showed increased sweet taste preference and reduced immobility, consistent with antidepressant treatment.
Mice lacking the ASIC1a gene also failed to show a known biomarker for depression. Chronic stress normally decreases the amount of the BDNF gene in the brain, but mice lacking ASIC1a failed to show this change.
The researchers found that ASIC1a-based treatment works through a different biological pathway than traditional antidepressants, suggesting that it may benefit people who do not respond to traditional therapies.
ASIC1a is located in brain structures associated with mood, including the amygdala, which is critical for so-called negative emotions such as anger, anxiety, and fear. The researchers previously showed reduced amygdala activity in animals that lacked the ASIC1a gene. In the current study, they reversed the antidepressant effect of ASIC1a gene deletion by turning the ASIC1a gene back on only in the amygdala. These findings support the idea that depression could be caused, at least in part, by hyperactivity of the amygdala.
"ASIC1a inhibitors may combat depression by reducing amygdala activity. Because of the importance of the amygdala in negative emotions and fear, we speculate that ASIC1a inhibition increases the brain's resistance to the negative effects of stress, perhaps reducing the likelihood of developing depression," said study author Wemmie.
The research was supported by the National Institute of Mental Health, the National Alliance for Research on Schizophrenia and Depression, and the Department of Veteran Affairs.
Source:
Todd Bentsen
Society for Neuroscience
"Depression is one of the most devastating and difficult-to-treat disorders known to man," said John F. Cryan, PhD, at University College Cork in Ireland, who was not affiliated with the study. "Despite much research, all antidepressant medications that are currently prescribed work in much the same way and are of limited efficacy in more than a third of all patients. The development of antidepressants that act on other molecular targets in the brain would be a major breakthrough," Cryan said.
Although animal models cannot reproduce all of the symptoms of human depression, several behavioral tests in rodents are sensitive to antidepressant treatment, suggesting that they address important aspects of the disease. For example, chronically stressed mice lose their normal preference for sugary drinks, and mice repeatedly placed in a pool of water tend to give up and float rather than swim in the hopes of escaping. These mouse behaviors are thought to reflect loss of interest in pleasurable activities and hopelessness or despair. But traditional antidepressants are able to restore the mouse preference for sweet treats and reduce the amount of time that they float rather than swim.
The researchers, led by Matthew Coryell, PhD and senior researcher John Wemmie, MD, PhD, at the University of Iowa, found that mice lacking the ASIC1a gene and normal mice treated with drugs that inhibit ASIC1a showed reduced depression-like behaviors. These mice showed increased sweet taste preference and reduced immobility, consistent with antidepressant treatment.
Mice lacking the ASIC1a gene also failed to show a known biomarker for depression. Chronic stress normally decreases the amount of the BDNF gene in the brain, but mice lacking ASIC1a failed to show this change.
The researchers found that ASIC1a-based treatment works through a different biological pathway than traditional antidepressants, suggesting that it may benefit people who do not respond to traditional therapies.
ASIC1a is located in brain structures associated with mood, including the amygdala, which is critical for so-called negative emotions such as anger, anxiety, and fear. The researchers previously showed reduced amygdala activity in animals that lacked the ASIC1a gene. In the current study, they reversed the antidepressant effect of ASIC1a gene deletion by turning the ASIC1a gene back on only in the amygdala. These findings support the idea that depression could be caused, at least in part, by hyperactivity of the amygdala.
"ASIC1a inhibitors may combat depression by reducing amygdala activity. Because of the importance of the amygdala in negative emotions and fear, we speculate that ASIC1a inhibition increases the brain's resistance to the negative effects of stress, perhaps reducing the likelihood of developing depression," said study author Wemmie.
The research was supported by the National Institute of Mental Health, the National Alliance for Research on Schizophrenia and Depression, and the Department of Veteran Affairs.
Source:
Todd Bentsen
Society for Neuroscience
понедельник, 2 мая 2011 г.
Population Viscosity Can Promote The Evolution Of Altruistic Sterile Helpers And Eusociality
Over the last 10 years there has been controversy about whether limited dispersal can be an important factor favoring altruism.
To address this issue we investigated whether limited dispersal can favor the evolution of a caste of sterile workers as they occur in ants and other social insects.
We show that even under the simplest life-history conditions a sterile worker caste (i.e., an extreme case of reproductive altruism) may readily be selected for by limited dispersal and population viscosity.
This has relevant consequences for our understanding of the evolution of altruism, as many social organisms are characterized by limited dispersal and a significant genetic population structure.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
publishing.royalsociety/proceedingsb
To address this issue we investigated whether limited dispersal can favor the evolution of a caste of sterile workers as they occur in ants and other social insects.
We show that even under the simplest life-history conditions a sterile worker caste (i.e., an extreme case of reproductive altruism) may readily be selected for by limited dispersal and population viscosity.
This has relevant consequences for our understanding of the evolution of altruism, as many social organisms are characterized by limited dispersal and a significant genetic population structure.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
publishing.royalsociety/proceedingsb
Подписаться на:
Сообщения (Atom)