"Dramatic" losses of a key biochemical substance in heart muscle tissue occur in the very earliest stages of diabetes induced in laboratory mice, scientists in Missouri are reporting ACS' Biochemistry, a weekly journal. Xianlin Han and colleagues did the study as part of a broader medical effort to understand diabetic cardiomyopathy. Heart abnormalities are the relatively common complication of diabetes and account for much of the increased mortality from heart disease in patients with diabetes.
The researchers used a powerful new technology termed "shotgun lipidomics" to show that hearts of diabetic mice lose large amounts of cardiolipin (CL), fatty materials essential for the heart's production of the energy needed for normal contraction. The changes, which involved a loss of CL followed by changes in the remaining CL, occurred as early as 5 days after rats became diabetic through administration of a compound that impairs insulin-producing cells in the pancreas.
Researchers observed the changes in two models of diabetes commonly used to study the two types of human diabetes. The changes happen before the appearance of toxic fatty materials regarded as a hallmark of diabetic cardiomyopathy and might be used as very sensitive biomarkers for the condition, the report indicates.
"Alterations in Myocardial Cardiolipin Content and Composition Occur at the Very Earliest Stages of Diabetes: A Shotgun Lipidomics Study"
CONTACT:
Xianlin Han, Ph.D.
Washington University School of Medicine
St. Louis, Missouri 63130
Green Goals for the Pharmaceutical Industry
The ACS Green Chemistry Institute Pharmaceutical Roundtable has developed a list of priority research areas where "green" alternatives to conventional reactions are needed to develop medications with minimal impact on the environment. Their review paper, describes and prioritizes research needs,. It can be a valuable resource for journalists writing about green chemistry. Although the paper focuses on pharmaceuticals, it includes reactions and processes used by the broader chemical enterprise.
rsc/Publishing/Journals/GC/article.asp?doi=b703488c
The 11th Annual Green Chemistry & Engineering Conference
This pioneering conference on one of the hottest topics in chemistry will be held June 26-29, 2007 at the Capital Hilton hotel in Washington, DC. gcande/
The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
Contact: Michael Woods
American Chemical Society
понедельник, 30 мая 2011 г.
How A Protein Binds To Genes And Regulates Human Genome
Out of chaos, control: Cornell University molecular biologists have discovered how a protein called PARP-1 binds to genes and regulates their expression across the human genome. Knowing where PARP-1 is located and how it works may allow scientists to target this protein while battling common human diseases.
Their research is in a study published today (Feb.8, 2008) in the journal Science.
"This finding was unexpected -- especially since it entails a broad distribution of PARP-1 across the human genome and a strong correlation of the protein binding with genes being turned on," said W. Lee Kraus, Cornell associate professor in molecular biology and the corresponding author in the published study. Kraus has a dual appointment at Cornell's Weill Medical College in New York City. "Our research won't necessarily find cures for human diseases, but it provides molecular insight into the regulation of gene expression that will gives us clues where to look next."
Kraus explains that PARP-1 and another genome-binding protein called histone H1 compete for binding to gene "promoters" (the on-off switches for genes) and, as such, act as part of a control panel for the human genome. H1 puts genes in an "off" position and PARP-1 turns them "on." The new study, said Kraus, shows that for a surprising number genes, the PARP-1 protein is present and histone H1 is not, helping to keep those genes turned on.
When human cells are exposed to physiological signals, such as hormones, or to stress signals, such as metabolic shock or DNA damage caused by agents like ultra-violet (UV) light, the cells take action. One of the cellular responses is the production of NAD (nicotinamide adenine dinucleotide), a metabolic communication signal. NAD promotes the removal of PARP from the genome and alters PARP-1's ability to keep genes on, the scientists have found.
Knowing where this component of the genome's control panel -- the PARP-1 protein -- is located, scientists can better understand the effects of synthetic chemical inhibitors of PARP-1 activity, which are being explored for the treatment of human diseases including stroke, heart disease and cancer. Thus, conceivably, when a patient is having stroke, it may one day be possible to use PARP-1 inhibitors as part of stroke therapy, or one day play a role in targeting cancer, says Kraus.
"Think of PARP-1 as a key regulator of gene expression in response to normal signals and harmful stresses," said Kraus. "If you could control most of the traffic lights in a city's street grid with one hand, this is analogous to controlling gene expression across the genome with PARP-1. Under really adverse conditions, you can set all the lights to stop."
The article, "Reciprocal Binding of PARP-1 and Histone H1 at Promoters Specifies Transciptional Outcomes," was authored by Raga Krishnakumar (co first-author), a graduate student in molecular biology and Matthew J. Gamble (co first-author), a post doctoral researcher at Cornell; and Kristine M. Frizzell, Jhoanna G. Berrocal and Miltiadis Kininis, all Cornell graduate students in molecular biology and genetics. Kraus is the corresponding author. The National Institutes of Health funded the research.
Source: Blaine Friedlander
Cornell University Communications
Their research is in a study published today (Feb.8, 2008) in the journal Science.
"This finding was unexpected -- especially since it entails a broad distribution of PARP-1 across the human genome and a strong correlation of the protein binding with genes being turned on," said W. Lee Kraus, Cornell associate professor in molecular biology and the corresponding author in the published study. Kraus has a dual appointment at Cornell's Weill Medical College in New York City. "Our research won't necessarily find cures for human diseases, but it provides molecular insight into the regulation of gene expression that will gives us clues where to look next."
Kraus explains that PARP-1 and another genome-binding protein called histone H1 compete for binding to gene "promoters" (the on-off switches for genes) and, as such, act as part of a control panel for the human genome. H1 puts genes in an "off" position and PARP-1 turns them "on." The new study, said Kraus, shows that for a surprising number genes, the PARP-1 protein is present and histone H1 is not, helping to keep those genes turned on.
When human cells are exposed to physiological signals, such as hormones, or to stress signals, such as metabolic shock or DNA damage caused by agents like ultra-violet (UV) light, the cells take action. One of the cellular responses is the production of NAD (nicotinamide adenine dinucleotide), a metabolic communication signal. NAD promotes the removal of PARP from the genome and alters PARP-1's ability to keep genes on, the scientists have found.
Knowing where this component of the genome's control panel -- the PARP-1 protein -- is located, scientists can better understand the effects of synthetic chemical inhibitors of PARP-1 activity, which are being explored for the treatment of human diseases including stroke, heart disease and cancer. Thus, conceivably, when a patient is having stroke, it may one day be possible to use PARP-1 inhibitors as part of stroke therapy, or one day play a role in targeting cancer, says Kraus.
"Think of PARP-1 as a key regulator of gene expression in response to normal signals and harmful stresses," said Kraus. "If you could control most of the traffic lights in a city's street grid with one hand, this is analogous to controlling gene expression across the genome with PARP-1. Under really adverse conditions, you can set all the lights to stop."
The article, "Reciprocal Binding of PARP-1 and Histone H1 at Promoters Specifies Transciptional Outcomes," was authored by Raga Krishnakumar (co first-author), a graduate student in molecular biology and Matthew J. Gamble (co first-author), a post doctoral researcher at Cornell; and Kristine M. Frizzell, Jhoanna G. Berrocal and Miltiadis Kininis, all Cornell graduate students in molecular biology and genetics. Kraus is the corresponding author. The National Institutes of Health funded the research.
Source: Blaine Friedlander
Cornell University Communications
Funding To Establish A Max Planck Institute In Palm Beach Florida
The Max Planck Society has received an offer to establish its first foreign institute in the US: Florida's Palm Beach County unanimously proposed the sum of $86.9 million for the next 10 years. In the coming weeks, it is expected that the State of Florida will contribute funds to complete the financing, and that specific negotiations on the establishment of an institute will take place.
The County's decision paved the way for the equally necessary approval by the State of Florida, which intends to boost the sum provided by the County to a total of $190 million. This would facilitate the creation of a Max Planck Institute in the life sciences on the Jupiter Campus of Florida Atlantic University (FAU), in the immediate vicinity of the Scripps Research Institute.
"Yesterday's decision is a great compliment for the Max Planck Society. We are very pleased that the County Commissioners have demonstrated such great faith in us," said MPS President Gruss after the vote. With the recent addition of Scripps, and now perhaps also the Max Planck Society, the State of Florida aims to quickly gain a place in the premier league of the world's biotechnology hubs. The state hopes to attract yet further internationally renowned research institutes and biotech companies to its emerging biotechnology center. This would allow Florida to expand its basis of wealth and thus ensure its long-term economic success.
The Scripps Research Institute, internationally renowned in the field of biomedicine, opened its doors on the Florida Atlantic University campus just three years ago. The prospect of close cooperation on a shared campus with Scripps is the primary reason for the Max Planck Society's interest in Palm Beach County. "Scripps and Max Planck are a dream team for innovative basic research in biomedicine," says Gruss. The offer extended to the Max Planck Society is also supported by the local Florida Atlantic University (FAU). The FAU, the fastest-growing university in the U.S., will be a key partner in educating junior researchers and will provide the land for the new construction.
First Institute on American Soil
"We met with incredible support and enthusiasm for our research in Florida, not only on the business and political front, but also in the private sector," says MPS President Peter Gruss. "Florida offers a particularly dynamic environment for outstanding basic research." If the State were to now follow the positive vote of the County and also agree to provide funding for the institute, specific contract negotiations could get under way and the institute could take up its work as early as 2008. The institute would eventually have three departments in which 135 employees from all over the world could carry out their research. At the same time, the Max Planck Society wants to offer a visiting scientist program and provide lab space for internationally renowned researchers to carry out their work.
"The Max Planck Florida institute would give us an independent foothold in the world's most important country for science," says Peter Gruss, who views the negotiations in the U.S. as part of a wider internationalization of the Max Planck Society. "We want to export the Max Planck success model and step up our international activities in Europe, the U.S. and Asia." In this context, forms of cooperation can range from partner institutes all the way to full-fledged Max Planck Institutes.
Of the currently 78 Max Planck Institutes, three are located outside of Germany: the Bibliotheca Hertziana in Rome, the Art History Institute in Florence and the Max Planck Institute for Psycholinguistics in Nijmegen, The Netherlands. In addition, the MPS co-founded a Max Planck Partner Institute in Shanghai in partnership with the Chinese Academy of Sciences.
Source: Dr. Bernd Wirsing
Max-Planck-Gesellschaft
The County's decision paved the way for the equally necessary approval by the State of Florida, which intends to boost the sum provided by the County to a total of $190 million. This would facilitate the creation of a Max Planck Institute in the life sciences on the Jupiter Campus of Florida Atlantic University (FAU), in the immediate vicinity of the Scripps Research Institute.
"Yesterday's decision is a great compliment for the Max Planck Society. We are very pleased that the County Commissioners have demonstrated such great faith in us," said MPS President Gruss after the vote. With the recent addition of Scripps, and now perhaps also the Max Planck Society, the State of Florida aims to quickly gain a place in the premier league of the world's biotechnology hubs. The state hopes to attract yet further internationally renowned research institutes and biotech companies to its emerging biotechnology center. This would allow Florida to expand its basis of wealth and thus ensure its long-term economic success.
The Scripps Research Institute, internationally renowned in the field of biomedicine, opened its doors on the Florida Atlantic University campus just three years ago. The prospect of close cooperation on a shared campus with Scripps is the primary reason for the Max Planck Society's interest in Palm Beach County. "Scripps and Max Planck are a dream team for innovative basic research in biomedicine," says Gruss. The offer extended to the Max Planck Society is also supported by the local Florida Atlantic University (FAU). The FAU, the fastest-growing university in the U.S., will be a key partner in educating junior researchers and will provide the land for the new construction.
First Institute on American Soil
"We met with incredible support and enthusiasm for our research in Florida, not only on the business and political front, but also in the private sector," says MPS President Peter Gruss. "Florida offers a particularly dynamic environment for outstanding basic research." If the State were to now follow the positive vote of the County and also agree to provide funding for the institute, specific contract negotiations could get under way and the institute could take up its work as early as 2008. The institute would eventually have three departments in which 135 employees from all over the world could carry out their research. At the same time, the Max Planck Society wants to offer a visiting scientist program and provide lab space for internationally renowned researchers to carry out their work.
"The Max Planck Florida institute would give us an independent foothold in the world's most important country for science," says Peter Gruss, who views the negotiations in the U.S. as part of a wider internationalization of the Max Planck Society. "We want to export the Max Planck success model and step up our international activities in Europe, the U.S. and Asia." In this context, forms of cooperation can range from partner institutes all the way to full-fledged Max Planck Institutes.
Of the currently 78 Max Planck Institutes, three are located outside of Germany: the Bibliotheca Hertziana in Rome, the Art History Institute in Florence and the Max Planck Institute for Psycholinguistics in Nijmegen, The Netherlands. In addition, the MPS co-founded a Max Planck Partner Institute in Shanghai in partnership with the Chinese Academy of Sciences.
Source: Dr. Bernd Wirsing
Max-Planck-Gesellschaft
Brain Scientists Offer Medical Educators Tips On The Neurobiology Of Learning
Everyone would like MDs to have the best education and to absorb what they are taught. The lead article in the April 4 issue of the journal Academic Medicine connects research on how the brain learns to how to incorporate this understanding into real world education, particularly the education of doctors.
"Repetition, reward, and visualization are tried and true teaching strategies. Now, knowing what is happening in the brain will enhance teaching and learning," said Michael J. Friedlander, executive director of the Virginia Tech Carilion Research Institute and professor of biological sciences and of biomedical engineering and science at Virginia Tech. He is the lead author on the article, "What can medical education learn from the neurobiology of learning?"
Friedlander collaborated on the article with Dr. Linda Andrews, senior associate dean for medical education, Baylor College of Medicine; Elizabeth G. Armstrong, director of Harvard Macy Institute, Harvard Medical School; Dr. Carol Aschenbrenner, executive vice president of the Association of American Medical Colleges; Dr. Joseph S. Kass, chief of neurology and director of the Stroke Center at Ben Taub Hospital and assistant professor of neurology, Center for Ethics and Health Policy, Baylor College of Medicine; Dr. Paul Ogden, associate dean for educational program development, Texas A&M Health Sciences Center and College of Medicine; Dr. Richard Schwartzstein, director of the Harvard Medical School Academy; and Dr. Tom Viggiano, the associate dean for faculty affairs, professor of medical education and medicine, and the Barbara Woodward Lips professor at Mayo Medical School.
The research
In the past 50 years, behavioral approaches combined with functional brain imaging and computational neuroscience have revealed strategies employed by mammals' brains to acquire, store, and retrieve information. In addition to molecular and cellular approaches to describe the workings of the underlying hardware changes that occur in the brain during learning and the formation of memories, there has also been progress in higher-order, human-based studies of cognition, including learning and memory. Scientists have used functional magnetic resonance imaging (fMRI) of the living brain combined with computational modeling to elucidate the strategies employed and the underlying biological processes.
The research has shown how learning leads to functional and structural changes in the cellular networks including the chemical communication points or synapses between neurons at a variety of sites throughout the central nervous system. The functional changes in the effectiveness of communication between individual neurons and within networks of neurons are accompanied by substantial changes in the structural circuitry of the brain, once thought to be hard-wired in adults.
"One of the most exciting advances, as a result of optical imaging of the living brain, is the demonstration that there is growth, retraction, and modifying connectivity between neurons," said Friedlander. "We have also seen that the mature brain can generate new neurons, although, this research is so new that the functional implications of these new neurons and their potential contribution to learning and memory formation remain to be determined," he said.
The recommendations
The most effective delivery of the best possible care requires identifying and assigning levels of importance to the biological components of learning. Here are 10 key aspects of learning based on decades of research by many scientists that the article's authors believe can be incorporated into effective teaching.
Repetition
Medical curricula often employ compressed coverage over limited time frames of a great amount of material. Learning theory and the neurobiology of learning and memory suggest that going deeper is more likely to result in better retention and depth of understanding. With repetition, many components of the neural processes become more efficient, requiring less energy and leaving higher-order pathways available for additional cognitive processing. However, repetitions must be appropriately spaced.
Reward and reinforcement
Reward is a key component of learning at all stages of life. "The brain's intrinsic reward system self-congratulations with the realization of success -- plays a major role in reinforcement of learned behaviors," Friedlander said. "An important factor is the realization that accomplishing an immediate goal and a successful step toward a future goal can be equally rewarding."
In the case of medical students, there are considerable rewards ahead of them in addition to the more immediate rewards of the satisfaction of understanding medicine. The students who derive joy from learning as they proceed through their medical education may have a greater chance of using the brain's capacity to provide reward signals on an ongoing basis, facilitating their learning process.
Visualization
Visualization and mental rehearsal are real biological processes with associated patterned activation of neural circuitry in sensory, motor, executive, and decision-making pathways in the brain. Internally generated activity in the brain from thoughts, visualization, memories, and emotions should be able to contribute to the learning process.
Active engagement
There is considerable neurobiological evidence that functional changes in neural circuitry that are associated with learning occur best when the learner is actively engaged.. Learners' having multiple opportunities to assume the role of teacher also invoke neural motivation and reward pathways -- and another major biological component of the learning process: stress.
Stress
Although the consequences of stress are generally considered undesirable, there is evidence that the molecular signals associated with stress can enhance synaptic activity involved in the formation of memory. However, particularly high levels of stress can have opposite effects. The small, interactive teaching format may be judiciously employed to moderately engage the stress system.
Fatigue
Patterns of neuronal activity during sleep reinforce the day's events. Research suggests that it is important to have appropriate downtime between intense problem-solving sessions. Downtime permits consolidation away from the formal teaching process.
Multitasking
Multitasking is a distraction from learning, unless all of the tasks are relevant to the material being taught. The challenge is to integrate information from multiple sources, such as a lecture and a hand-held device.
Individual learning styles
Neural responses of different individuals vary, which is the rationale for embracing multiple learning styles to provide opportunities for all learners to be most effectively reached.
Active involvement
Doing is learning. And success at doing and learning builds confidence.
Revisiting information and concepts using multimedia
Addressing the same information using different sensory processes, such as seeing and hearing, enhances the learning process, potentially bringing more neural hardware to bear to process and store information.
The researchers recommend that medical students be taught the underlying neurobiological principles that shape their learning experiences. "By appealing not only to students' capacity to derive pleasure from learning about medicine but also to their intellectual capacity for understanding the rationale for the educational process selected ... real motivation can be engendered. ... They become more effective communicators and enhance their patients' success at learning the information they need for managing their own health and treatments as well."
Friedlander is the founding chair of the Association of Medical School Neuroscience Department Chairs. He has served nationally at the Association of American Medical Colleges (AAMC) on their task forces on the scientific foundations of future physicians jointly sponsored by the Howard Hughes Medical Institute, on the interactions of industry and medical education, and on the medical college admission test (MCAT) comprehensive review panel. Friedlander conducts research in the area of neuroscience, including learning and synaptic plasticity, brain development and traumatic brain injury.
Sources: Virginia Tech, AlphaGalileo Foundation.
"Repetition, reward, and visualization are tried and true teaching strategies. Now, knowing what is happening in the brain will enhance teaching and learning," said Michael J. Friedlander, executive director of the Virginia Tech Carilion Research Institute and professor of biological sciences and of biomedical engineering and science at Virginia Tech. He is the lead author on the article, "What can medical education learn from the neurobiology of learning?"
Friedlander collaborated on the article with Dr. Linda Andrews, senior associate dean for medical education, Baylor College of Medicine; Elizabeth G. Armstrong, director of Harvard Macy Institute, Harvard Medical School; Dr. Carol Aschenbrenner, executive vice president of the Association of American Medical Colleges; Dr. Joseph S. Kass, chief of neurology and director of the Stroke Center at Ben Taub Hospital and assistant professor of neurology, Center for Ethics and Health Policy, Baylor College of Medicine; Dr. Paul Ogden, associate dean for educational program development, Texas A&M Health Sciences Center and College of Medicine; Dr. Richard Schwartzstein, director of the Harvard Medical School Academy; and Dr. Tom Viggiano, the associate dean for faculty affairs, professor of medical education and medicine, and the Barbara Woodward Lips professor at Mayo Medical School.
The research
In the past 50 years, behavioral approaches combined with functional brain imaging and computational neuroscience have revealed strategies employed by mammals' brains to acquire, store, and retrieve information. In addition to molecular and cellular approaches to describe the workings of the underlying hardware changes that occur in the brain during learning and the formation of memories, there has also been progress in higher-order, human-based studies of cognition, including learning and memory. Scientists have used functional magnetic resonance imaging (fMRI) of the living brain combined with computational modeling to elucidate the strategies employed and the underlying biological processes.
The research has shown how learning leads to functional and structural changes in the cellular networks including the chemical communication points or synapses between neurons at a variety of sites throughout the central nervous system. The functional changes in the effectiveness of communication between individual neurons and within networks of neurons are accompanied by substantial changes in the structural circuitry of the brain, once thought to be hard-wired in adults.
"One of the most exciting advances, as a result of optical imaging of the living brain, is the demonstration that there is growth, retraction, and modifying connectivity between neurons," said Friedlander. "We have also seen that the mature brain can generate new neurons, although, this research is so new that the functional implications of these new neurons and their potential contribution to learning and memory formation remain to be determined," he said.
The recommendations
The most effective delivery of the best possible care requires identifying and assigning levels of importance to the biological components of learning. Here are 10 key aspects of learning based on decades of research by many scientists that the article's authors believe can be incorporated into effective teaching.
Repetition
Medical curricula often employ compressed coverage over limited time frames of a great amount of material. Learning theory and the neurobiology of learning and memory suggest that going deeper is more likely to result in better retention and depth of understanding. With repetition, many components of the neural processes become more efficient, requiring less energy and leaving higher-order pathways available for additional cognitive processing. However, repetitions must be appropriately spaced.
Reward and reinforcement
Reward is a key component of learning at all stages of life. "The brain's intrinsic reward system self-congratulations with the realization of success -- plays a major role in reinforcement of learned behaviors," Friedlander said. "An important factor is the realization that accomplishing an immediate goal and a successful step toward a future goal can be equally rewarding."
In the case of medical students, there are considerable rewards ahead of them in addition to the more immediate rewards of the satisfaction of understanding medicine. The students who derive joy from learning as they proceed through their medical education may have a greater chance of using the brain's capacity to provide reward signals on an ongoing basis, facilitating their learning process.
Visualization
Visualization and mental rehearsal are real biological processes with associated patterned activation of neural circuitry in sensory, motor, executive, and decision-making pathways in the brain. Internally generated activity in the brain from thoughts, visualization, memories, and emotions should be able to contribute to the learning process.
Active engagement
There is considerable neurobiological evidence that functional changes in neural circuitry that are associated with learning occur best when the learner is actively engaged.. Learners' having multiple opportunities to assume the role of teacher also invoke neural motivation and reward pathways -- and another major biological component of the learning process: stress.
Stress
Although the consequences of stress are generally considered undesirable, there is evidence that the molecular signals associated with stress can enhance synaptic activity involved in the formation of memory. However, particularly high levels of stress can have opposite effects. The small, interactive teaching format may be judiciously employed to moderately engage the stress system.
Fatigue
Patterns of neuronal activity during sleep reinforce the day's events. Research suggests that it is important to have appropriate downtime between intense problem-solving sessions. Downtime permits consolidation away from the formal teaching process.
Multitasking
Multitasking is a distraction from learning, unless all of the tasks are relevant to the material being taught. The challenge is to integrate information from multiple sources, such as a lecture and a hand-held device.
Individual learning styles
Neural responses of different individuals vary, which is the rationale for embracing multiple learning styles to provide opportunities for all learners to be most effectively reached.
Active involvement
Doing is learning. And success at doing and learning builds confidence.
Revisiting information and concepts using multimedia
Addressing the same information using different sensory processes, such as seeing and hearing, enhances the learning process, potentially bringing more neural hardware to bear to process and store information.
The researchers recommend that medical students be taught the underlying neurobiological principles that shape their learning experiences. "By appealing not only to students' capacity to derive pleasure from learning about medicine but also to their intellectual capacity for understanding the rationale for the educational process selected ... real motivation can be engendered. ... They become more effective communicators and enhance their patients' success at learning the information they need for managing their own health and treatments as well."
Friedlander is the founding chair of the Association of Medical School Neuroscience Department Chairs. He has served nationally at the Association of American Medical Colleges (AAMC) on their task forces on the scientific foundations of future physicians jointly sponsored by the Howard Hughes Medical Institute, on the interactions of industry and medical education, and on the medical college admission test (MCAT) comprehensive review panel. Friedlander conducts research in the area of neuroscience, including learning and synaptic plasticity, brain development and traumatic brain injury.
Sources: Virginia Tech, AlphaGalileo Foundation.
Touch Sensitivity Can Be Result Of Moderate Prenatal Exposure To Alcohol And Stress In Monkeys
A new study on monkeys has found that moderate exposure to alcohol and stress during pregnancy can lead to sensitivity to touch in the monkeys' babies. In human children, sensitivity to touch is one of a number of characteristics of the approximately 5 percent of children who over-respond to sensory information. Since these characteristics can lead to behavioral or emotional problems, early identification and treatment are important. Children who are sensitive to touch have unpleasant and sometimes painful reactions to otherwise pleasant or neutral forms of touching.
The study, conducted by researchers at the University of Wisconsin-Madison, appears in the January/February 2008 issue of the journal Child Development.
"Our results with monkeys have important implications for preventing childhood disorders," according to Mary L Schneider, professor of occupational therapy and psychology at the University of Wisconsin-Madison and the study's lead author.
Researchers studied 38 5- to 7-year-old rhesus monkeys born to mothers who either drank a moderate dose of alcohol every day during their pregnancies, were exposed to a mild 10-minute stressor during their pregnancies, drank a moderate amount of alcohol and were exposed to the stressor during their pregnancies, or were undisturbed while they were pregnant. A moderate dose of alcohol for the monkeys was defined as the equivalent of two drinks a day for a human.
Without knowing which situation the mother monkeys had experienced, the researchers rated the monkeys' offspring according to how they responded to repeated touch with a feather, a cotton ball, and a stiff brush. They found that monkeys whose mothers had not been stressed or consumed alcohol got used to touch over time, while monkeys whose mothers had been stressed grew more disturbed by touch over time. Monkeys who had been exposed to alcohol prenatally were disturbed by touch more than monkeys who had not been exposed to alcohol prenatally.
Using a brain neuro-imaging technique known as positron emission tomography, or PET, the researchers found that the monkeys' sensitivities to touch were related to changes in a brain chemical called dopamine in one area of the brain, the striatum. Regulating dopamine plays a crucial role in mental and physical health. Particularly important for learning, dopamine plays a major role in addictions.
"Our findings with monkeys suggest that when mothers are under stress and/or drink alcohol while pregnant, their offspring are at risk for sensory sensitivities," notes Schneider.
Schneider called for further studies to determine whether reducing sensory sensitivities at an early age in children might help prevent the development of fetal alcohol-related behavioral problems.
"Our findings also have important implications for women of childbearing age," she added, "suggesting that sensory sensitivities might be reduced by decreasing stress levels and abstaining from alcohol during pregnancy or if planning pregnancy."
The study was funded in part by the National Institute of Health's National Institute of Alcohol Abuse and Alcoholism.
Summarized from Child Development, Vol. 79, Issue 1, Sensory Processing Disorder in a Primate Model: Evidence from a Longitudinal Study of Prenatal Alcohol and Prenatal Stress Effects by Schneider, ML, Moore, CF, Gajewski, LL, and Larson, JA (University of Wisconsin-Madison), Roberts, AD (Minnesota State University-Mankato, formerly with University of Wisconsin-Madison), and Converse, AK, and DeJesus, OT (University of Wisconsin-Madison). Copyright 2008 The Society for Research in Child Development, Inc. All rights reserved.
Source: Andrea Browning
Society for Research in Child Development
The study, conducted by researchers at the University of Wisconsin-Madison, appears in the January/February 2008 issue of the journal Child Development.
"Our results with monkeys have important implications for preventing childhood disorders," according to Mary L Schneider, professor of occupational therapy and psychology at the University of Wisconsin-Madison and the study's lead author.
Researchers studied 38 5- to 7-year-old rhesus monkeys born to mothers who either drank a moderate dose of alcohol every day during their pregnancies, were exposed to a mild 10-minute stressor during their pregnancies, drank a moderate amount of alcohol and were exposed to the stressor during their pregnancies, or were undisturbed while they were pregnant. A moderate dose of alcohol for the monkeys was defined as the equivalent of two drinks a day for a human.
Without knowing which situation the mother monkeys had experienced, the researchers rated the monkeys' offspring according to how they responded to repeated touch with a feather, a cotton ball, and a stiff brush. They found that monkeys whose mothers had not been stressed or consumed alcohol got used to touch over time, while monkeys whose mothers had been stressed grew more disturbed by touch over time. Monkeys who had been exposed to alcohol prenatally were disturbed by touch more than monkeys who had not been exposed to alcohol prenatally.
Using a brain neuro-imaging technique known as positron emission tomography, or PET, the researchers found that the monkeys' sensitivities to touch were related to changes in a brain chemical called dopamine in one area of the brain, the striatum. Regulating dopamine plays a crucial role in mental and physical health. Particularly important for learning, dopamine plays a major role in addictions.
"Our findings with monkeys suggest that when mothers are under stress and/or drink alcohol while pregnant, their offspring are at risk for sensory sensitivities," notes Schneider.
Schneider called for further studies to determine whether reducing sensory sensitivities at an early age in children might help prevent the development of fetal alcohol-related behavioral problems.
"Our findings also have important implications for women of childbearing age," she added, "suggesting that sensory sensitivities might be reduced by decreasing stress levels and abstaining from alcohol during pregnancy or if planning pregnancy."
The study was funded in part by the National Institute of Health's National Institute of Alcohol Abuse and Alcoholism.
Summarized from Child Development, Vol. 79, Issue 1, Sensory Processing Disorder in a Primate Model: Evidence from a Longitudinal Study of Prenatal Alcohol and Prenatal Stress Effects by Schneider, ML, Moore, CF, Gajewski, LL, and Larson, JA (University of Wisconsin-Madison), Roberts, AD (Minnesota State University-Mankato, formerly with University of Wisconsin-Madison), and Converse, AK, and DeJesus, OT (University of Wisconsin-Madison). Copyright 2008 The Society for Research in Child Development, Inc. All rights reserved.
Source: Andrea Browning
Society for Research in Child Development
Journal Of Clinical Investigation: Sept. 18, 2008
Maternal diet can increase development and severity of asthma in offspring
John Hollingsworth and colleagues, at Duke University Medical Center, Durham, have generated evidence in mice that a maternal diet rich in methyl donors, of which one source is the prenatal supplement folate, increases the chance that the developing fetus will suffer from asthma after birth.
In the study, the development and severity of allergic airway disease (the experimental equivalent of asthma) was found to be enhanced in mice born to mothers who had eaten a diet supplemented with methyl donors. In addition, enhanced development and severity of allergic airway disease was observed in mice born to those exposed to methyl donors in utero, i.e. the problems were inherited. Further analysis indicated that some genes in the mice exposed to methyl donors in utero were modified by methylation in a different way to mice not exposed to methyl donors in utero. This change in the pattern of methylation, altered the expression of the genes and is likely to be the underlying cause of the increased development and severity of allergic airway disease. Both the authors and, in an accompanying commentary, Rachel Miller, at Columbia University College of Physicians and Surgeons, New York, discuss the potential implications of this study in light of the fact that folate is a source of methyl donors and is an important prenatal supplement that helps prevent congential abnormalities. As they caution, it is important to determine if the same effects occur in humans before changing the current recommendations about prenatal supplementation.
TITLE: In utero supplementation with methyl donors enhances allergic airway disease in mice
AUTHOR CONTACT:
John W. Hollingsworth
Duke University Medical Center, Durham, North Carolina, USA.
William Allstetter
National Jewish Health, Denver, Colorado, USA.
ACCOMPANYING COMMENTARY TITLE: Prenatal maternal diet affects asthma risk in offspring
AUTHOR CONTACT:
Rachel L. Miller
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Statins block one cause of pregnancy loss in mice
In women, the inflammatory condition antiphospholipid syndrome (APS) often causes pregnancy-related complications, including miscarriage, intrauterine growth restriction, and fetal death. It is caused by molecules known as antiphospholipid antibodies, which are made by cells of the immune system. Using a mouse model of the pregnancy-related complications of APS, in which human antiphospholipid antibodies are infused into pregnant mice, Guillermina Girardi and colleagues, at Weill Medical College of Cornell University, New York, have delineated a central mechanism by which antiphospholipid antibodies induce fetal loss. As two distinct statins were found to affect the molecular pathway identified and prevent pregnancy loss, the authors suggest that statins may be a good treatment for women with pregnancy complications caused by APS.
In an accompanying commentary, Hartmut Weiler, at the BloodCenter of Wisconsin, Milwaukee, provides more insight into the mechanistic pathways uncovered, which are distinct from those many thought were likely to be involved.
TITLE: Neutrophil activation by tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome
AUTHOR CONTACT:
Guillermina Girardi
Weill Medical College, Cornell University, New York, New York, USA.
ACCOMPANYING COMMENTARY TITLE: Tracing the molecular pathogenesis of antiphospholipid syndrome
AUTHOR CONTACT:
Hartmut Weiler
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA.
New vaccine element could generate better protection from avian influenza
Current vaccines for influenza provide protection against specific seasonal influenza A strains and their close relatives, but not against more distant seasonal influenza A viruses and new avian influenza A viruses, such as H5N1, which still poses a real global health concern. However, a team of researchers led by Tao Dong and Andrew McMichael, at Oxford University, United Kingdom, has now generated data that suggest adding a new component to vaccines for influenza might enable them to confer protection against a broad range of avian and seasonal influenza A viruses. In an accompanying commentary, Peter Doherty and Anne Kelso discuss in more detail how the data generated in this paper might be translated into a new and improved vaccine.
In the study, subsets of immune cells known as memory CD4+ and memory CD8+ T cells from individuals from the United Kingdom and Viet Nam were found to respond to fragments of proteins from both a seasonal influenza A strain and a strain of H5N1. Nearly all people tested had cells that cross-reacted between the seasonal influenza A strain and H5N1. The authors therefore suggest that adding fragments of influenza proteins to current vaccines for influenza might boost memory CD4+ and memory CD8+ T cell responses towards both seasonal and avian influenza viruses, providing broad protection.
TITLE: Memory T cells established by seasonal influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals
AUTHOR CONTACT:
Tao Dong
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Andrew McMichael
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
AUTHOR CONTACT:
Peter C. Doherty
St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
AUTOIMMUNITY: Killers of pancreatic beta-cells identified in type I diabetics
Type 1 diabetes occurs when the immune system attacks and destroys the beta-cells in the pancreas, the cells that produce the hormone insulin. Although much is known about the mechanisms by which beta-cells are killed in mouse models of type 1 diabetes, little is known about how beta-cells are killed in humans with the disease. However, Mark Peakman and colleagues, at King's College London, United Kingdom, have now identified both immune cells capable of killing beta-cells in the pancreas and a mechanism by which killing is accelerated in the later stages of the development of clinical diabetes.
In the study, immune cells known as CD8+ T cells that recognized fragments of the precursor form of insulin (preproinsulin) were found in the blood of patients with type 1 diabetes. Furthermore, these preproinsulin fragments were detected on the surface of human beta-cells in a form that enabled the CD8+ T cells from the blood of patients with type 1 diabetes to recognize them and kill the beta cells. Importantly, if the human beta-cells were exposed to high concentrations of glucose (which is what happens in individuals as type 1 diabetes progresses, because the decrease in insulin production as beta-cells are killed causes the amount of glucose in the blood to increase) then the amount of these preproinsulin fragments on the surface of the remaining beta-cells increased, as did CD8+ T cell killing. These data indicate that CD8+ T cells that can kill beta-cells are present in individuals with type 1 diabetes and identify a self-propelling loop likely to result in increasing beta-cell death as the disease progresses. The authors and, in an accompanying commentary, Jeffrey Frelinger, from the University of North Carolina, Chapel Hill, therefore suggest that targeting CD8+ T cells that recognize preproinsulin fragments as soon after an individual is diagnosed with type 1 diabetes as possible would be beneficial.
TITLE: CTLs are targeted to kill beta-cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope
AUTHOR CONTACT:
Mark Peakman
King's College London, London, United Kingdom.
ACCOMPANYING COMMENTARY TITLE: Novel epitope begets a novel pathway in type 1 diabetes progression
AUTHOR CONTACT:
Jeffrey A. Frelinger
University of North Carolina, Chapel Hill, North Carolina, USA.
AUTOIMMUNITY: Brain protein expressed in the liver protects mice from multiple sclerosis-like disease
Autoimmune diseases occur when the immune system attacks and destroys cells of the body. It has been suggested that developing approaches to generate immune cells known as Tregs, which are able to dampen the destructive autoimmune response, might be of therapeutic benefit to individuals with autoimmune disease. Consistent with this, Johannes Herkel and colleagues, at the University Medical Centre Hamburg-Eppendorf, Germany, have now shown that mice are protected from disease in a model of multiple sclerosis if they express in their liver a brain protein targeted by immune cells that cause multiple sclerosis-like disease. Furthermore, protection was mediated by Tregs, which developed from naГЇve T cells. The authors therefore suggest that directing proteins that are targeted by destructive autoimmune responses to the liver might be a new approach to treating and preventing autoimmune disease. In an accompanying commentary, Brad Hoffman and Roland Herzog, at the University of Florida, Gainesville, discuss these therapeutic potentials as well as their limitations.
TITLE: Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs
AUTHOR CONTACT:
Johannes Herkel
University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
ACCOMPANYING COMMENTARY TITLE: Coaxing the liver into preventing autoimmune disease in the brain
AUTHOR CONTACT:
Roland W. Herzog
University of Florida, Gainesville, Florida, USA.
AUTOIMMUNITY: B cells have distinct roles at different stages of a multiple sclerosis-like disease
A recent clinical trial indicated that depletion of a subset of immune cells known as B cells using the drug rituximab has some benefit in individuals with the inflammatory disease multiple sclerosis. However, B cell depletion has been shown to worsen or trigger other inflammatory diseases, such as ulcerative colitis and psoriasis. As the most effective use of a B cell depleting drug requires knowledge of the role of B cells in disease processes, Thomas Tedder and colleagues, at Duke University Medical Center, Durham, set out to investigate the role of B cells at different stages of a mouse disease known as EAE, which is used to model multiple sclerosis.
In the study, rituximab-mediated B cell depletion before the induction of EAE markedly exacerbated the severity of the disease. By contrast, rituximab-mediated B cell depletion during EAE disease progression diminished the severity of the disease. Further analysis indicated that these opposing effects occurred because B cell depletion before disease onset eliminated a rare subset of regulatory B cells that were effective at dampening disease severity during early EAE disease initiation but were ineffective during disease progression. In addition, B cell depletion during EAE disease progression eliminated B cells essential for the disease process. These data indicate that B cells have different roles at different stages of EAE. As discussed by the authors and, in an accompanying commentary, Tomohiro Kurosaki, at RIKEN Research Center for Allergy and Immunology, Japan, this has important implications for developing effective approaches to using B cell depleting drugs such as rituximab.
TITLE: Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression
AUTHOR CONTACT:
Thomas F. Tedder
Duke University Medical Center, Durham, North Carolina, USA.
ACCOMPANYING COMMENTARY TITLE: Paradox of B cell-targeted therapies
AUTHOR CONTACT:
Tomohiro Kurosaki
RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
GASTROENTEROLOGY: A thorny issue: Hedgehog signaling involved in bile duct damage
Chronic injury to the small bile ducts in the liver can lead to scarring, fibrosis, cirrhosis, and ultimately liver failure. New data, generated by Anna Mae Diehl and colleagues, at Duke University Medical Center, Durham, using rodent models of biliary fibrosis as well as human and rodent cells, has provide new insight into the molecular pathways involved in the development of the condition. In an accompanying commentary, Linda Greenbaum, at the University of Pennsylvania School of Medicine, Philadelphia, discusses the importance of this work in furthering our understanding of a health problem that can have such deleterious consequences.
In the study, it was found that some adult bile ductular cells (which are known as cholangiocytes) in liver sections from patients with chronic biliary injury were undergoing a process known as EMT, which has been suggested to have a role in chronic biliary injury. Furthermore, this process only occurred in cells that exhibited high levels of signaling through the hedgehog (Hh) pathway. Similarly, in a rat model of biliary fibrosis only cholangiocytes exhibiting high levels of Hh signaling activity were undergoing EMT. Reversing biliary injury in the rats reduced Hh signaling activity, EMT, and biliary fibrosis. Additional analysis in vitro and in mice provided more evidence that molecules that stimulate Hh signaling promote EMT and contribute to the development of biliary fibrosis when bile ducts are obstructed and subjected to constant injury.
TITLE: Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans
AUTHOR CONTACT:
Anna Mae Diehl
Duke University Medical Center, Durham, North Carolina, USA.
ACCOMPANYING COMMENTARY TITLE: Hedgehog signaling in biliary fibrosis
AUTHOR CONTACT:
Linda E. Greenbaum
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
DERMATOLOGY: To heal or scar: a key role for the protein GSK-3beta
Although the two GSK-3 proteins GSK-3alpha and GSK-3beta are thought to be involved in the processes that occur after wounding, healing and scarring, the precise role of these proteins has not been determined. Now, Andrew Leask and colleagues, at the University of Western Ontario, London, have identified a mechanism by which GSK-3beta controls the progression of wound healing and scarring in mice.
In the study, mice lacking GSK-3beta only in cells known as fibroblasts (cells that have a crucial role in wound closure) were found to exhibit faster wound closure and increased scarring. This was associated with increased levels of the protein ET-1, due to increased production by the GSK-3beta-deficient fibroblasts. Antagonizing ET-1 restored the speed of wound closure to normal and dramatically diminished scarring. The authors therefore suggest that modulating the GSK-3beta pathway or ET-1 might be translated for the treatment of nonhealing or chronic skin wounds and of excessive scarring.
TITLE: GSK-3beta in mouse fibroblasts controls wound healing and fibrosis through an endothelin-1-dependent mechanism
AUTHOR CONTACT:
Andrew Leask
University of Western Ontario, London, Ontario, Canada.
Source: Karen Honey
Journal of Clinical Investigation
John Hollingsworth and colleagues, at Duke University Medical Center, Durham, have generated evidence in mice that a maternal diet rich in methyl donors, of which one source is the prenatal supplement folate, increases the chance that the developing fetus will suffer from asthma after birth.
In the study, the development and severity of allergic airway disease (the experimental equivalent of asthma) was found to be enhanced in mice born to mothers who had eaten a diet supplemented with methyl donors. In addition, enhanced development and severity of allergic airway disease was observed in mice born to those exposed to methyl donors in utero, i.e. the problems were inherited. Further analysis indicated that some genes in the mice exposed to methyl donors in utero were modified by methylation in a different way to mice not exposed to methyl donors in utero. This change in the pattern of methylation, altered the expression of the genes and is likely to be the underlying cause of the increased development and severity of allergic airway disease. Both the authors and, in an accompanying commentary, Rachel Miller, at Columbia University College of Physicians and Surgeons, New York, discuss the potential implications of this study in light of the fact that folate is a source of methyl donors and is an important prenatal supplement that helps prevent congential abnormalities. As they caution, it is important to determine if the same effects occur in humans before changing the current recommendations about prenatal supplementation.
TITLE: In utero supplementation with methyl donors enhances allergic airway disease in mice
AUTHOR CONTACT:
John W. Hollingsworth
Duke University Medical Center, Durham, North Carolina, USA.
William Allstetter
National Jewish Health, Denver, Colorado, USA.
ACCOMPANYING COMMENTARY TITLE: Prenatal maternal diet affects asthma risk in offspring
AUTHOR CONTACT:
Rachel L. Miller
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Statins block one cause of pregnancy loss in mice
In women, the inflammatory condition antiphospholipid syndrome (APS) often causes pregnancy-related complications, including miscarriage, intrauterine growth restriction, and fetal death. It is caused by molecules known as antiphospholipid antibodies, which are made by cells of the immune system. Using a mouse model of the pregnancy-related complications of APS, in which human antiphospholipid antibodies are infused into pregnant mice, Guillermina Girardi and colleagues, at Weill Medical College of Cornell University, New York, have delineated a central mechanism by which antiphospholipid antibodies induce fetal loss. As two distinct statins were found to affect the molecular pathway identified and prevent pregnancy loss, the authors suggest that statins may be a good treatment for women with pregnancy complications caused by APS.
In an accompanying commentary, Hartmut Weiler, at the BloodCenter of Wisconsin, Milwaukee, provides more insight into the mechanistic pathways uncovered, which are distinct from those many thought were likely to be involved.
TITLE: Neutrophil activation by tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome
AUTHOR CONTACT:
Guillermina Girardi
Weill Medical College, Cornell University, New York, New York, USA.
ACCOMPANYING COMMENTARY TITLE: Tracing the molecular pathogenesis of antiphospholipid syndrome
AUTHOR CONTACT:
Hartmut Weiler
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA.
New vaccine element could generate better protection from avian influenza
Current vaccines for influenza provide protection against specific seasonal influenza A strains and their close relatives, but not against more distant seasonal influenza A viruses and new avian influenza A viruses, such as H5N1, which still poses a real global health concern. However, a team of researchers led by Tao Dong and Andrew McMichael, at Oxford University, United Kingdom, has now generated data that suggest adding a new component to vaccines for influenza might enable them to confer protection against a broad range of avian and seasonal influenza A viruses. In an accompanying commentary, Peter Doherty and Anne Kelso discuss in more detail how the data generated in this paper might be translated into a new and improved vaccine.
In the study, subsets of immune cells known as memory CD4+ and memory CD8+ T cells from individuals from the United Kingdom and Viet Nam were found to respond to fragments of proteins from both a seasonal influenza A strain and a strain of H5N1. Nearly all people tested had cells that cross-reacted between the seasonal influenza A strain and H5N1. The authors therefore suggest that adding fragments of influenza proteins to current vaccines for influenza might boost memory CD4+ and memory CD8+ T cell responses towards both seasonal and avian influenza viruses, providing broad protection.
TITLE: Memory T cells established by seasonal influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals
AUTHOR CONTACT:
Tao Dong
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Andrew McMichael
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
AUTHOR CONTACT:
Peter C. Doherty
St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
AUTOIMMUNITY: Killers of pancreatic beta-cells identified in type I diabetics
Type 1 diabetes occurs when the immune system attacks and destroys the beta-cells in the pancreas, the cells that produce the hormone insulin. Although much is known about the mechanisms by which beta-cells are killed in mouse models of type 1 diabetes, little is known about how beta-cells are killed in humans with the disease. However, Mark Peakman and colleagues, at King's College London, United Kingdom, have now identified both immune cells capable of killing beta-cells in the pancreas and a mechanism by which killing is accelerated in the later stages of the development of clinical diabetes.
In the study, immune cells known as CD8+ T cells that recognized fragments of the precursor form of insulin (preproinsulin) were found in the blood of patients with type 1 diabetes. Furthermore, these preproinsulin fragments were detected on the surface of human beta-cells in a form that enabled the CD8+ T cells from the blood of patients with type 1 diabetes to recognize them and kill the beta cells. Importantly, if the human beta-cells were exposed to high concentrations of glucose (which is what happens in individuals as type 1 diabetes progresses, because the decrease in insulin production as beta-cells are killed causes the amount of glucose in the blood to increase) then the amount of these preproinsulin fragments on the surface of the remaining beta-cells increased, as did CD8+ T cell killing. These data indicate that CD8+ T cells that can kill beta-cells are present in individuals with type 1 diabetes and identify a self-propelling loop likely to result in increasing beta-cell death as the disease progresses. The authors and, in an accompanying commentary, Jeffrey Frelinger, from the University of North Carolina, Chapel Hill, therefore suggest that targeting CD8+ T cells that recognize preproinsulin fragments as soon after an individual is diagnosed with type 1 diabetes as possible would be beneficial.
TITLE: CTLs are targeted to kill beta-cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope
AUTHOR CONTACT:
Mark Peakman
King's College London, London, United Kingdom.
ACCOMPANYING COMMENTARY TITLE: Novel epitope begets a novel pathway in type 1 diabetes progression
AUTHOR CONTACT:
Jeffrey A. Frelinger
University of North Carolina, Chapel Hill, North Carolina, USA.
AUTOIMMUNITY: Brain protein expressed in the liver protects mice from multiple sclerosis-like disease
Autoimmune diseases occur when the immune system attacks and destroys cells of the body. It has been suggested that developing approaches to generate immune cells known as Tregs, which are able to dampen the destructive autoimmune response, might be of therapeutic benefit to individuals with autoimmune disease. Consistent with this, Johannes Herkel and colleagues, at the University Medical Centre Hamburg-Eppendorf, Germany, have now shown that mice are protected from disease in a model of multiple sclerosis if they express in their liver a brain protein targeted by immune cells that cause multiple sclerosis-like disease. Furthermore, protection was mediated by Tregs, which developed from naГЇve T cells. The authors therefore suggest that directing proteins that are targeted by destructive autoimmune responses to the liver might be a new approach to treating and preventing autoimmune disease. In an accompanying commentary, Brad Hoffman and Roland Herzog, at the University of Florida, Gainesville, discuss these therapeutic potentials as well as their limitations.
TITLE: Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs
AUTHOR CONTACT:
Johannes Herkel
University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
ACCOMPANYING COMMENTARY TITLE: Coaxing the liver into preventing autoimmune disease in the brain
AUTHOR CONTACT:
Roland W. Herzog
University of Florida, Gainesville, Florida, USA.
AUTOIMMUNITY: B cells have distinct roles at different stages of a multiple sclerosis-like disease
A recent clinical trial indicated that depletion of a subset of immune cells known as B cells using the drug rituximab has some benefit in individuals with the inflammatory disease multiple sclerosis. However, B cell depletion has been shown to worsen or trigger other inflammatory diseases, such as ulcerative colitis and psoriasis. As the most effective use of a B cell depleting drug requires knowledge of the role of B cells in disease processes, Thomas Tedder and colleagues, at Duke University Medical Center, Durham, set out to investigate the role of B cells at different stages of a mouse disease known as EAE, which is used to model multiple sclerosis.
In the study, rituximab-mediated B cell depletion before the induction of EAE markedly exacerbated the severity of the disease. By contrast, rituximab-mediated B cell depletion during EAE disease progression diminished the severity of the disease. Further analysis indicated that these opposing effects occurred because B cell depletion before disease onset eliminated a rare subset of regulatory B cells that were effective at dampening disease severity during early EAE disease initiation but were ineffective during disease progression. In addition, B cell depletion during EAE disease progression eliminated B cells essential for the disease process. These data indicate that B cells have different roles at different stages of EAE. As discussed by the authors and, in an accompanying commentary, Tomohiro Kurosaki, at RIKEN Research Center for Allergy and Immunology, Japan, this has important implications for developing effective approaches to using B cell depleting drugs such as rituximab.
TITLE: Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression
AUTHOR CONTACT:
Thomas F. Tedder
Duke University Medical Center, Durham, North Carolina, USA.
ACCOMPANYING COMMENTARY TITLE: Paradox of B cell-targeted therapies
AUTHOR CONTACT:
Tomohiro Kurosaki
RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
GASTROENTEROLOGY: A thorny issue: Hedgehog signaling involved in bile duct damage
Chronic injury to the small bile ducts in the liver can lead to scarring, fibrosis, cirrhosis, and ultimately liver failure. New data, generated by Anna Mae Diehl and colleagues, at Duke University Medical Center, Durham, using rodent models of biliary fibrosis as well as human and rodent cells, has provide new insight into the molecular pathways involved in the development of the condition. In an accompanying commentary, Linda Greenbaum, at the University of Pennsylvania School of Medicine, Philadelphia, discusses the importance of this work in furthering our understanding of a health problem that can have such deleterious consequences.
In the study, it was found that some adult bile ductular cells (which are known as cholangiocytes) in liver sections from patients with chronic biliary injury were undergoing a process known as EMT, which has been suggested to have a role in chronic biliary injury. Furthermore, this process only occurred in cells that exhibited high levels of signaling through the hedgehog (Hh) pathway. Similarly, in a rat model of biliary fibrosis only cholangiocytes exhibiting high levels of Hh signaling activity were undergoing EMT. Reversing biliary injury in the rats reduced Hh signaling activity, EMT, and biliary fibrosis. Additional analysis in vitro and in mice provided more evidence that molecules that stimulate Hh signaling promote EMT and contribute to the development of biliary fibrosis when bile ducts are obstructed and subjected to constant injury.
TITLE: Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans
AUTHOR CONTACT:
Anna Mae Diehl
Duke University Medical Center, Durham, North Carolina, USA.
ACCOMPANYING COMMENTARY TITLE: Hedgehog signaling in biliary fibrosis
AUTHOR CONTACT:
Linda E. Greenbaum
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
DERMATOLOGY: To heal or scar: a key role for the protein GSK-3beta
Although the two GSK-3 proteins GSK-3alpha and GSK-3beta are thought to be involved in the processes that occur after wounding, healing and scarring, the precise role of these proteins has not been determined. Now, Andrew Leask and colleagues, at the University of Western Ontario, London, have identified a mechanism by which GSK-3beta controls the progression of wound healing and scarring in mice.
In the study, mice lacking GSK-3beta only in cells known as fibroblasts (cells that have a crucial role in wound closure) were found to exhibit faster wound closure and increased scarring. This was associated with increased levels of the protein ET-1, due to increased production by the GSK-3beta-deficient fibroblasts. Antagonizing ET-1 restored the speed of wound closure to normal and dramatically diminished scarring. The authors therefore suggest that modulating the GSK-3beta pathway or ET-1 might be translated for the treatment of nonhealing or chronic skin wounds and of excessive scarring.
TITLE: GSK-3beta in mouse fibroblasts controls wound healing and fibrosis through an endothelin-1-dependent mechanism
AUTHOR CONTACT:
Andrew Leask
University of Western Ontario, London, Ontario, Canada.
Source: Karen Honey
Journal of Clinical Investigation
Potentially Widespread Cell-To-Cell Communication Discovered In Mechanism For Worm Defecation, With Human Therapeutic Implications
The focus of two recent Nobel prizes, a species of roundworm has made possible another advance in the understanding of how cells talk to one another, according to a study published online Feb. 21 in the journal Current Biology.
In 2002, researchers won the Nobel Prize for Medicine for work in the roundworm Caenorhabditis elegans (C. elegans) on the genetics of how cells "decide" to self-destruct, a topic now central to human cancer research. Another team won in 2006 for the discovery in C. elegans of an ancient defense mechanism against attempts by viruses to disrupt cells' genetic machinery.
In the latest worm-related news, today's publication provides evidence of a new mechanism through which cells in the worm's intestine signal for nearby muscle cells to flex by briefly making the area between them more acidic. Researchers believe that short-lived changes in acidity may have implications for cell signaling throughout the animal kingdom, from the sending of human nerve messages to worm defecation. The worm's influence proceeds from the fact that its cells resemble human cells in many ways, but are easier to study.
"I worked with mammals during my training, but my research is focused now exclusively in worms," said Keith Nehrke, Ph.D., assistant professor of Medicine within the Nephrology Division at the University of Rochester Medical Center, and corresponding author of the Current Biology study. "We don't restrain or anesthetize the worms during our experiments, which allows us to study complex interactions between organs that only occur in eating, moving animals. It remains to be seen whether pH signaling is commonly utilized in man, but the potential impact is fantastic, as almost all biologic processes are regulated by acidity."
Study Details
Theory holds that atoms are the building blocks of the universe. Atoms, in turn, are thought to be composed of energy bundles called electrons that orbit around protons and neutrons at the atom's center. Furthermore, atoms exhibit a property called charge that explains their behavior. Like charges repel each other; opposites attract, and cells have harnessed these forces to drive life processes.
Some cellular machines work by pumping positively charged particles (e.g. calcium, sodium and potassium ions) into or out of cells. In some cases particles of like charge build up outside the cell, and are eager to rush back in if given the chance. That chance comes, under careful regulation, when cells open channel proteins in their outer membranes, enabling say calcium ions to enter. The charge flow is used as an energy source in some instances, and in others, as a biological switch to kick on life processes. Past studies have shown that the rhythmic wave of muscle contractions that push waste along the worm intestine is carefully regulated by signals captured in rising and falling levels of positively charged calcium ions.
What the current study found is that intertwined with calcium signaling may be a second mechanism, where positively charged hydrogen ions, also called protons, are employed to send signals.
A substance that by nature donates protons to a solution or other molecules is called an acid, and pH is a measure of proton concentration in a fluid. Outside a certain pH range, the proteins that make up human cells and tissues break down and the body fails. One reason that the current work is so intriguing is proteins involved in worm muscle signaling are the same ones recognized for many years as those in charge of maintaining pH balance, a basic housekeeping function. The results of the current work suggest that cells may have usurped this housekeeping function to better communicate.
Nehrke's Current Biology publication dovetails on an article (Cell 2008, 132, 149) published in January by Eric Jorgensen, Ph.D., professor of Biology at the University of Utah. Jorgensen used a genetic approach to define a signaling link between two specific proteins, a sodium-proton exchanger that pushes protons out of the worm intestine and a proton receptor on adjacent muscle cells that responds to protons by causing muscular contractions that make possible defecation. The current study validated these conclusions, and demonstrated that protons move from the lumen of the intestine and across the cell prior to signaling adjacent muscles, resulting in pH oscillations inside as well as outside the cells. Sodium/proton exchangers enable the flow of protons across cell membranes while maintaining charge balance. Although this class of proteins has been recognized for many years as capable of helping cells regulate pH and fluid levels, this is the first example of sodium/proton exchangers being involved in communication.
The team used molecular biology techniques to genetically express in the nematode intestinal cells a fluorescent molecule whose brightness is sensitive to pH. Fluorescent imaging then showed proton levels to be carefully controlled during defecation, oscillating in tandem with calcium levels in the intestine. Many calcium regulatory processes are sensitive to pH, and the study suggests that crosstalk occurs between these two signaling mechanisms to regulate the frequency as well as the execution of the defecation muscle contractions.
If this is confirmed in humans, proton signaling could conceivably represent a new target for regulating cell communication, perhaps with therapeutic implications. Many regions in the human body are subject to an acidic environment, and in some cases, are already known to recognize pH changes in their surroundings. In addition, several of proteins that contribute to synaptic transmission, signaling between nerve cells, can be regulated by pH. Are there cellular proton depots near synaptic junctions, with proteins in place to export them as part of signaling mechanisms, and nearby proton receptors awaiting their call? Does abnormal proton signaling contribute to Parkinson's, Alzheimer's or other neurodegenerative diseases? Future studies will tell.
"In the next few years, I think we will see that protons act as a neurotransmitter in the human brain," said Jorgensen. "This is an enormous surprise. Protons are subatomic particles. Their effects are usually nonspecific. To imagine that they are communicating specific signals between cells is extraordinary. The current paper demonstrates that the intestinal cells themselves are experiencing these pulsatile fluctuations in protons. The cell seems to be using protons to communicate information internally as well as externally."
Source: Greg Williams
University of Rochester Medical Center
In 2002, researchers won the Nobel Prize for Medicine for work in the roundworm Caenorhabditis elegans (C. elegans) on the genetics of how cells "decide" to self-destruct, a topic now central to human cancer research. Another team won in 2006 for the discovery in C. elegans of an ancient defense mechanism against attempts by viruses to disrupt cells' genetic machinery.
In the latest worm-related news, today's publication provides evidence of a new mechanism through which cells in the worm's intestine signal for nearby muscle cells to flex by briefly making the area between them more acidic. Researchers believe that short-lived changes in acidity may have implications for cell signaling throughout the animal kingdom, from the sending of human nerve messages to worm defecation. The worm's influence proceeds from the fact that its cells resemble human cells in many ways, but are easier to study.
"I worked with mammals during my training, but my research is focused now exclusively in worms," said Keith Nehrke, Ph.D., assistant professor of Medicine within the Nephrology Division at the University of Rochester Medical Center, and corresponding author of the Current Biology study. "We don't restrain or anesthetize the worms during our experiments, which allows us to study complex interactions between organs that only occur in eating, moving animals. It remains to be seen whether pH signaling is commonly utilized in man, but the potential impact is fantastic, as almost all biologic processes are regulated by acidity."
Study Details
Theory holds that atoms are the building blocks of the universe. Atoms, in turn, are thought to be composed of energy bundles called electrons that orbit around protons and neutrons at the atom's center. Furthermore, atoms exhibit a property called charge that explains their behavior. Like charges repel each other; opposites attract, and cells have harnessed these forces to drive life processes.
Some cellular machines work by pumping positively charged particles (e.g. calcium, sodium and potassium ions) into or out of cells. In some cases particles of like charge build up outside the cell, and are eager to rush back in if given the chance. That chance comes, under careful regulation, when cells open channel proteins in their outer membranes, enabling say calcium ions to enter. The charge flow is used as an energy source in some instances, and in others, as a biological switch to kick on life processes. Past studies have shown that the rhythmic wave of muscle contractions that push waste along the worm intestine is carefully regulated by signals captured in rising and falling levels of positively charged calcium ions.
What the current study found is that intertwined with calcium signaling may be a second mechanism, where positively charged hydrogen ions, also called protons, are employed to send signals.
A substance that by nature donates protons to a solution or other molecules is called an acid, and pH is a measure of proton concentration in a fluid. Outside a certain pH range, the proteins that make up human cells and tissues break down and the body fails. One reason that the current work is so intriguing is proteins involved in worm muscle signaling are the same ones recognized for many years as those in charge of maintaining pH balance, a basic housekeeping function. The results of the current work suggest that cells may have usurped this housekeeping function to better communicate.
Nehrke's Current Biology publication dovetails on an article (Cell 2008, 132, 149) published in January by Eric Jorgensen, Ph.D., professor of Biology at the University of Utah. Jorgensen used a genetic approach to define a signaling link between two specific proteins, a sodium-proton exchanger that pushes protons out of the worm intestine and a proton receptor on adjacent muscle cells that responds to protons by causing muscular contractions that make possible defecation. The current study validated these conclusions, and demonstrated that protons move from the lumen of the intestine and across the cell prior to signaling adjacent muscles, resulting in pH oscillations inside as well as outside the cells. Sodium/proton exchangers enable the flow of protons across cell membranes while maintaining charge balance. Although this class of proteins has been recognized for many years as capable of helping cells regulate pH and fluid levels, this is the first example of sodium/proton exchangers being involved in communication.
The team used molecular biology techniques to genetically express in the nematode intestinal cells a fluorescent molecule whose brightness is sensitive to pH. Fluorescent imaging then showed proton levels to be carefully controlled during defecation, oscillating in tandem with calcium levels in the intestine. Many calcium regulatory processes are sensitive to pH, and the study suggests that crosstalk occurs between these two signaling mechanisms to regulate the frequency as well as the execution of the defecation muscle contractions.
If this is confirmed in humans, proton signaling could conceivably represent a new target for regulating cell communication, perhaps with therapeutic implications. Many regions in the human body are subject to an acidic environment, and in some cases, are already known to recognize pH changes in their surroundings. In addition, several of proteins that contribute to synaptic transmission, signaling between nerve cells, can be regulated by pH. Are there cellular proton depots near synaptic junctions, with proteins in place to export them as part of signaling mechanisms, and nearby proton receptors awaiting their call? Does abnormal proton signaling contribute to Parkinson's, Alzheimer's or other neurodegenerative diseases? Future studies will tell.
"In the next few years, I think we will see that protons act as a neurotransmitter in the human brain," said Jorgensen. "This is an enormous surprise. Protons are subatomic particles. Their effects are usually nonspecific. To imagine that they are communicating specific signals between cells is extraordinary. The current paper demonstrates that the intestinal cells themselves are experiencing these pulsatile fluctuations in protons. The cell seems to be using protons to communicate information internally as well as externally."
Source: Greg Williams
University of Rochester Medical Center
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