"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
Scientists Report Stem Cells' 'Suspended' State Preserved By Key Step
Scientists have identified a gene that is essential for embryonic stem cells to maintain their all-purpose, pluripotent state. Exploiting the finding may lead to a greater understanding of how cells acquire their specialized states and provide a strategy to efficiently reprogram mature cells back into the pluripotent state, an elusive step in stem cell research but one crucial to a range of potential clinical treatments.
The research was led by University of California, San Francisco scientists. It is reported in the advanced online edition of the journal Nature, and will be published in the journal's print edition at the end of July.
Embryonic stem cells are suspended in an "open" state, uniquely poised to become any one of many types of specialized cells, as genetic instructions dictate. Directing the specialization of embryonic stem cells to cells needed by patients is an area of enormous promise in stem cell research. Reversing the natural process - converting specialized cells back into the all-purpose stem cell stage - is another great promise of stem cell research.
Reprogramming specialized cells from Parkinson's patients, for example, would allow scientists to study the mechanisms that cause neurons in the brain to develop the disease. It also could lead to treatments by directing the restored stem cells to produce healthy neurons to introduce into patients.
The new research, conducted on mouse embryo cells, revealed that a gene known as Chd1 loosens the packaging that normally protects DNA in the cell nucleus. This step, known as chromatin remodeling, allows the cell's protein-making machinery to gain access to the DNA and transform progenitor cells into specialized cells and tissue, such as neurons, muscle and bone.
A number of genes are known to trigger chromatin remodeling, allowing small sections of DNA to become accessible in order to make specific proteins. Chd1 is the first gene found to regulate a "global" loosening of the DNA in embryonic stem cells, the scientists report. The global condition sets the stage for turning on many different genes to make a broad range of specialized cells.
"Embryonic stem cells are characterized by this open state, but, up to now, we didn't know the mechanisms that maintain this state, or even if it is necessary for the full stem cell potential," said Alexandre Gaspar-Maia, lead author of the paper.
"We found that Chd1 is critical for both, and for allowing an efficient reprogramming. Chd1 is important for allowing the normal differentiation process, and it is essential for playing the 'differentiation tape' backwards - bringing differentiated cells back to pluripotency."
Gaspar-Maia is a graduate student (from the PhD Program in Experimental Biology and Biomedicine, at the University of Coimbra, Portugal) in the lab of senior author Miguel Ramalho-Santos, PhD, of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.
The scientists discovered the pivotal role of Chd1 by using the powerful technique of RNA interference, or RNAi, to screen this gene and 40 other candidate genes. (RNAi is a naturally occurring process in which small RNAs bind to other RNAs to increase or decrease their activity.) In this case, the scientists used the technique to silence Chd1. When they did so, embryonic stem cells could not make the full range of specialized cells.
In a laboratory test used to simulate normal cell specialization, the scientists detected no differentiation of cardiac muscle, and also no formation of a tissue known as primitive endoderm, which is essential for the embryo to survive and develop.
Chd1 also was shown by the research team to be necessary for the reprogramming of specialized cells back to the pluripotent stem cell state. The team plans to study chromatin remodeling in still more detail to clarify what other molecules work in concert with the Chd1 gene to direct the process. This would aid efforts to increase the efficiency and safety of reprogramming cells. This research may also shed light on how cells transition from one type to another, a process that happens normally during embryonic development and goes astray in cancer.
"We now know that Chd1 is essential, and, so far, appears unique in its global effect, but we expect that there are major players yet to be discovered," said senior author Ramalho-Santos, UCSF assistant professor of obstetrics, gynecology and reproductive sciences, and pathology.
"If we can understand how Chd1 works, that will also tell us more about how the cells regulate their precise specialization during development, and turn on their pluripotency program during reprogramming."
The scientists conclude that embryonic stem cells exist in a dynamic state, poised between the open condition that may assure the cell's full potential, and the more constrained state that allows only certain kinds of cells to progress. Chd1, they say, is central to maintaining the open, pluripotent stem cell state.
Notes:
Other co-authors on the paper from UCSF are Fanny Polesso, research assistant in the Ramalho-Santos lab; Michael McManus, PhD, assistant professor in the UCSF Diabetes Center and Amy Heidershbach, at the time a research assistant in the McManus lab and now a UCSF graduate student.
This work was the result of an international collaboration between several young laboratories. Additional co-authors are graduate student Adi Alajem and Eran Meshorer, PhD, assistant professor of genetics, both at Hebrew University of Jerusalem; Kathrin Plath, PhD, assistant professor; Rupa Sridharan., PhD, postdoctoral fellow, and Michael Mason, graduate student, all of the Eli and Ely Broad Center of Regenerative Medicine and Stem Cell Research at UCLA; JoГЈo Ramalho-Santos, PhD, assistant professor at the Center for Neuroscience and Cell Biology at the University of Coimbra, Portugal.
The research is supported, in part, by the National Institutes of Health Director's New Innovator Award, the California Institute for Regenerative Medicine and the Juvenile Diabetes Foundation.
Source:
Jennifer O'Brien
University of California - San Francisco
The research was led by University of California, San Francisco scientists. It is reported in the advanced online edition of the journal Nature, and will be published in the journal's print edition at the end of July.
Embryonic stem cells are suspended in an "open" state, uniquely poised to become any one of many types of specialized cells, as genetic instructions dictate. Directing the specialization of embryonic stem cells to cells needed by patients is an area of enormous promise in stem cell research. Reversing the natural process - converting specialized cells back into the all-purpose stem cell stage - is another great promise of stem cell research.
Reprogramming specialized cells from Parkinson's patients, for example, would allow scientists to study the mechanisms that cause neurons in the brain to develop the disease. It also could lead to treatments by directing the restored stem cells to produce healthy neurons to introduce into patients.
The new research, conducted on mouse embryo cells, revealed that a gene known as Chd1 loosens the packaging that normally protects DNA in the cell nucleus. This step, known as chromatin remodeling, allows the cell's protein-making machinery to gain access to the DNA and transform progenitor cells into specialized cells and tissue, such as neurons, muscle and bone.
A number of genes are known to trigger chromatin remodeling, allowing small sections of DNA to become accessible in order to make specific proteins. Chd1 is the first gene found to regulate a "global" loosening of the DNA in embryonic stem cells, the scientists report. The global condition sets the stage for turning on many different genes to make a broad range of specialized cells.
"Embryonic stem cells are characterized by this open state, but, up to now, we didn't know the mechanisms that maintain this state, or even if it is necessary for the full stem cell potential," said Alexandre Gaspar-Maia, lead author of the paper.
"We found that Chd1 is critical for both, and for allowing an efficient reprogramming. Chd1 is important for allowing the normal differentiation process, and it is essential for playing the 'differentiation tape' backwards - bringing differentiated cells back to pluripotency."
Gaspar-Maia is a graduate student (from the PhD Program in Experimental Biology and Biomedicine, at the University of Coimbra, Portugal) in the lab of senior author Miguel Ramalho-Santos, PhD, of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.
The scientists discovered the pivotal role of Chd1 by using the powerful technique of RNA interference, or RNAi, to screen this gene and 40 other candidate genes. (RNAi is a naturally occurring process in which small RNAs bind to other RNAs to increase or decrease their activity.) In this case, the scientists used the technique to silence Chd1. When they did so, embryonic stem cells could not make the full range of specialized cells.
In a laboratory test used to simulate normal cell specialization, the scientists detected no differentiation of cardiac muscle, and also no formation of a tissue known as primitive endoderm, which is essential for the embryo to survive and develop.
Chd1 also was shown by the research team to be necessary for the reprogramming of specialized cells back to the pluripotent stem cell state. The team plans to study chromatin remodeling in still more detail to clarify what other molecules work in concert with the Chd1 gene to direct the process. This would aid efforts to increase the efficiency and safety of reprogramming cells. This research may also shed light on how cells transition from one type to another, a process that happens normally during embryonic development and goes astray in cancer.
"We now know that Chd1 is essential, and, so far, appears unique in its global effect, but we expect that there are major players yet to be discovered," said senior author Ramalho-Santos, UCSF assistant professor of obstetrics, gynecology and reproductive sciences, and pathology.
"If we can understand how Chd1 works, that will also tell us more about how the cells regulate their precise specialization during development, and turn on their pluripotency program during reprogramming."
The scientists conclude that embryonic stem cells exist in a dynamic state, poised between the open condition that may assure the cell's full potential, and the more constrained state that allows only certain kinds of cells to progress. Chd1, they say, is central to maintaining the open, pluripotent stem cell state.
Notes:
Other co-authors on the paper from UCSF are Fanny Polesso, research assistant in the Ramalho-Santos lab; Michael McManus, PhD, assistant professor in the UCSF Diabetes Center and Amy Heidershbach, at the time a research assistant in the McManus lab and now a UCSF graduate student.
This work was the result of an international collaboration between several young laboratories. Additional co-authors are graduate student Adi Alajem and Eran Meshorer, PhD, assistant professor of genetics, both at Hebrew University of Jerusalem; Kathrin Plath, PhD, assistant professor; Rupa Sridharan., PhD, postdoctoral fellow, and Michael Mason, graduate student, all of the Eli and Ely Broad Center of Regenerative Medicine and Stem Cell Research at UCLA; JoГЈo Ramalho-Santos, PhD, assistant professor at the Center for Neuroscience and Cell Biology at the University of Coimbra, Portugal.
The research is supported, in part, by the National Institutes of Health Director's New Innovator Award, the California Institute for Regenerative Medicine and the Juvenile Diabetes Foundation.
Source:
Jennifer O'Brien
University of California - San Francisco
Prostate Cancer: Measles Virus May Be Effective Treatment
A new study appearing in The Prostate has found that certain measles virus vaccine strain derivatives, including a strain known as MV-CEA, may prove to be an effective treatment for patients with advanced prostate cancer. The findings show that this type of treatment, called virotherapy, can effectively infect, replicate in and kill prostate cancer cells.
Prostate cancer is a leading cause death among males in the western world. It is currently the second most common cause of cancer-related deaths among American men with 186,320 new cases and 28,660 deaths expected to be recorded in 2008. A sizeable proportion of these patients ultimately relapse, with a 5-year failure rate for treatment ranging from 14 to 34 percent. No curative therapy is currently available for locally advanced or metastatic prostate cancer.
The median survival time of MV-CEA-treated mice in the study almost doubled compared to the controls, and complete tumor regression was observed in one-fifth of treated animals.
"Based on our preclinical results as well as the safety of measles derivatives in clinical trials against other tumor types, these viral strains could represent excellent candidates for clinical testing against advanced prostate cancer, including androgen resistant tumors," says Evanthia Galanis, M.D., of the Mayo Clinic, senior author of the study. The study was supported by the Mayo Clinic Specialized Program of Research Excellence (SPORE) in prostate cancer.
These oncolytic strains of measles virus, represent a novel class of therapeutic agents against cancer that demonstrates no cross-resistance with existing treatment approaches, and can therefore be combined with conventional treatment methods.
Because primary tumor sites are easily accessible in prostate cancer, locally recurrent disease represents a promising target for virotherapy approaches. The virotherapy agent can easily be applied directly to the prostate tumor via ultrasound-guided needle injections and close monitoring of therapy can be achieved by non-invasive techniques including ultrasound and MRI.
The measles vaccine strains also have an excellent safety record with millions of vaccine doses having been safely administered in over 40 years of use. Repeated measurements of the marker CEA (carcinoembryonic antigen, produced when the virus replicates) following MV-CEA treatment can be performed via a simple blood test, and can potentially allow for optimization of dosing as well as the tailoring of individualized treatment. To date, no significant toxicity from MV-CEA treatment of patients with other tumor types has been observed.
Prior studies have demonstrated the therapeutic potency of MV-Edm derivatives against a variety of preclinical animal models including ovarian cancer, glioblastoma multiforme, breast cancer, multiple myeloma, lymphoma and hepatocellular carcinoma.
The promising results prompted the rapid translation of engineered MV-Edm strains in three clinical trials that are currently active. In the ovarian cancer trial, the furthest advanced; evidence of biologic activity has been noted in refractory ovarian cancer patients.
The results set the foundation for additional studies in preparation for using engineered measles strains in a clinical trial for the treatment of patients with advanced prostate cancer.
This study is published in The Prostate.
Evanthia Galanis, M.D. is a Professor of Oncology at the Mayo Clinic College of Medicine.
The Prostate is a peer-reviewed journal dedicated to original studies of this organ and the male accessory glands. It serves as an international medium for these studies, presenting comprehensive coverage of clinical, anatomic, embryologic, physiologic, endocrinologic, and biochemical studies. For more information, please visit www3.interscience.wiley/journal/34304/home.
Source: Sean Wagner
Wiley-Blackwell
Prostate cancer is a leading cause death among males in the western world. It is currently the second most common cause of cancer-related deaths among American men with 186,320 new cases and 28,660 deaths expected to be recorded in 2008. A sizeable proportion of these patients ultimately relapse, with a 5-year failure rate for treatment ranging from 14 to 34 percent. No curative therapy is currently available for locally advanced or metastatic prostate cancer.
The median survival time of MV-CEA-treated mice in the study almost doubled compared to the controls, and complete tumor regression was observed in one-fifth of treated animals.
"Based on our preclinical results as well as the safety of measles derivatives in clinical trials against other tumor types, these viral strains could represent excellent candidates for clinical testing against advanced prostate cancer, including androgen resistant tumors," says Evanthia Galanis, M.D., of the Mayo Clinic, senior author of the study. The study was supported by the Mayo Clinic Specialized Program of Research Excellence (SPORE) in prostate cancer.
These oncolytic strains of measles virus, represent a novel class of therapeutic agents against cancer that demonstrates no cross-resistance with existing treatment approaches, and can therefore be combined with conventional treatment methods.
Because primary tumor sites are easily accessible in prostate cancer, locally recurrent disease represents a promising target for virotherapy approaches. The virotherapy agent can easily be applied directly to the prostate tumor via ultrasound-guided needle injections and close monitoring of therapy can be achieved by non-invasive techniques including ultrasound and MRI.
The measles vaccine strains also have an excellent safety record with millions of vaccine doses having been safely administered in over 40 years of use. Repeated measurements of the marker CEA (carcinoembryonic antigen, produced when the virus replicates) following MV-CEA treatment can be performed via a simple blood test, and can potentially allow for optimization of dosing as well as the tailoring of individualized treatment. To date, no significant toxicity from MV-CEA treatment of patients with other tumor types has been observed.
Prior studies have demonstrated the therapeutic potency of MV-Edm derivatives against a variety of preclinical animal models including ovarian cancer, glioblastoma multiforme, breast cancer, multiple myeloma, lymphoma and hepatocellular carcinoma.
The promising results prompted the rapid translation of engineered MV-Edm strains in three clinical trials that are currently active. In the ovarian cancer trial, the furthest advanced; evidence of biologic activity has been noted in refractory ovarian cancer patients.
The results set the foundation for additional studies in preparation for using engineered measles strains in a clinical trial for the treatment of patients with advanced prostate cancer.
This study is published in The Prostate.
Evanthia Galanis, M.D. is a Professor of Oncology at the Mayo Clinic College of Medicine.
The Prostate is a peer-reviewed journal dedicated to original studies of this organ and the male accessory glands. It serves as an international medium for these studies, presenting comprehensive coverage of clinical, anatomic, embryologic, physiologic, endocrinologic, and biochemical studies. For more information, please visit www3.interscience.wiley/journal/34304/home.
Source: Sean Wagner
Wiley-Blackwell
Architectural Code Of Caffeine's Main Target In The Body Finally Cracked
Many receptor models used in drug design may not be useful after all
It may very well be that models used for the design of new drugs have to be regarded as impractical. This is the sobering though important conclusion of the work of two Leiden University scientists published in Science this week. The editorial board of the renowned journal even decided to accelerate the publication on the crystal structure of the adenosine A2A receptor via Science Express. Together with an expert team at the Scripps Institute (La Jolla) led by crystallographer Ray Stevens, Ad IJzerman, head of the division of medicinal chemistry at the Leiden/Amsterdam Center for Drug Research, and postdoctoral fellow Rob Lane worked on the structure elucidation of this protein, which is one of caffeine's main targets in the human body, and a key player in Parkinson's disease.
Fatty
Obtaining a crystal structure of a receptor bound to a drug is by far the best way to learn and appreciate how drugs actually work. "For decades scientists from all over the world have struggled to get the crystal structure of this type of G protein-coupled receptor", IJzerman explains. "These arduous attempts are easily understood when one takes into account that the whole family of these proteins are the targets for almost half of the medicines that are available in the pharmacy shop. It seemed an impossible task, since these proteins are in the cell wall, which means they are in a fatty environment, and are fatty themselves. We all know that fat does not crystallize easily."
Fusion product
The scientists in California had found an elegant solution for this problem though. They coupled the receptor protein to another protein that, in contrast, crystallizes easily, and managed to obtain tiny crystals of the fusion product. That was sufficient to crack the architectural code of the protein, for which very advanced crystallization equipment was used. In fact, something similar had worked for yet another receptor, but this time it was an adenosine receptor's turn. These receptors are at the core of the research in the division of medicinal chemistry of the Leiden/Amsterdam Center for Drug Research, and that's exactly why the American colleagues turned to the Leiden group. Forces were joined, and that's how the receptor constructs were characterized biochemically and pharmacologically, while at the same time the crystallization trials were ongoing across the Atlantic.
Supercaffeine
By the end of June 2008 the first crystals of suitable quality had been obtained and analyzed. That led to a big surprise that will undoubtedly have tremendous implications for the pharmaceutical industry. "The binding site for drugs on this receptor is very different from the one that had been found on two other receptors that we currently know the crystal structure of", says Rob Lane, asked for comments. "In the adenosine A2A receptor a small molecule, prosaically called ZM241385, is co-crystallized. This compound has high affinity for the receptor, and therefore it is best described as some sort of 'supercaffeine', a type of molecule that we had worked on in Leiden before." With some degree of understatement, Lane continues: "The drug is in a very different position than was expected on the basis of the other crystal structures. And there's the rub; almost everybody in the world of drug design has so far used receptor models that may not be so useful at all. That is the sobering and at the same time important discovery we made."
This study was supported by the Dutch Top Institute Pharma
Source: Steven Hagers
Leiden University
It may very well be that models used for the design of new drugs have to be regarded as impractical. This is the sobering though important conclusion of the work of two Leiden University scientists published in Science this week. The editorial board of the renowned journal even decided to accelerate the publication on the crystal structure of the adenosine A2A receptor via Science Express. Together with an expert team at the Scripps Institute (La Jolla) led by crystallographer Ray Stevens, Ad IJzerman, head of the division of medicinal chemistry at the Leiden/Amsterdam Center for Drug Research, and postdoctoral fellow Rob Lane worked on the structure elucidation of this protein, which is one of caffeine's main targets in the human body, and a key player in Parkinson's disease.
Fatty
Obtaining a crystal structure of a receptor bound to a drug is by far the best way to learn and appreciate how drugs actually work. "For decades scientists from all over the world have struggled to get the crystal structure of this type of G protein-coupled receptor", IJzerman explains. "These arduous attempts are easily understood when one takes into account that the whole family of these proteins are the targets for almost half of the medicines that are available in the pharmacy shop. It seemed an impossible task, since these proteins are in the cell wall, which means they are in a fatty environment, and are fatty themselves. We all know that fat does not crystallize easily."
Fusion product
The scientists in California had found an elegant solution for this problem though. They coupled the receptor protein to another protein that, in contrast, crystallizes easily, and managed to obtain tiny crystals of the fusion product. That was sufficient to crack the architectural code of the protein, for which very advanced crystallization equipment was used. In fact, something similar had worked for yet another receptor, but this time it was an adenosine receptor's turn. These receptors are at the core of the research in the division of medicinal chemistry of the Leiden/Amsterdam Center for Drug Research, and that's exactly why the American colleagues turned to the Leiden group. Forces were joined, and that's how the receptor constructs were characterized biochemically and pharmacologically, while at the same time the crystallization trials were ongoing across the Atlantic.
Supercaffeine
By the end of June 2008 the first crystals of suitable quality had been obtained and analyzed. That led to a big surprise that will undoubtedly have tremendous implications for the pharmaceutical industry. "The binding site for drugs on this receptor is very different from the one that had been found on two other receptors that we currently know the crystal structure of", says Rob Lane, asked for comments. "In the adenosine A2A receptor a small molecule, prosaically called ZM241385, is co-crystallized. This compound has high affinity for the receptor, and therefore it is best described as some sort of 'supercaffeine', a type of molecule that we had worked on in Leiden before." With some degree of understatement, Lane continues: "The drug is in a very different position than was expected on the basis of the other crystal structures. And there's the rub; almost everybody in the world of drug design has so far used receptor models that may not be so useful at all. That is the sobering and at the same time important discovery we made."
This study was supported by the Dutch Top Institute Pharma
Source: Steven Hagers
Leiden University
What Is Bacteria? What Are Bacteria?
The word bacteria is the plural of bacterium. Grammatically the headline should just say "What are bacteria?" The incorrect usage has been included in the headline to remind readers that it is wrong - and hopefully help correct an increasingly common mistake in the English language. Bacteria are tiny living beings (microorganisms) - they are neither plants nor animals - they belong to a group all by themselves. Bacteria are tiny single-cell microorganisms, usually a few micrometers in length that normally exist together in millions.
A gram of soil typically contains about 40 million bacterial cells. A milliliter of fresh water usually holds about one million bacterial cells.
Planet Earth is estimated to hold at least 5 nonillion bacteria. Scientists say that much of Earth's biomass is made up of bacteria.
5 nonillion = 5,000,000,000,000,000,000,000,000,000,000 (or 5x1030)
(Nonillion = 30 zeros in USA English. In British English it equals 54 zeros. This text uses the American meaning)
Bacteria come in three main shapes:
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Spherical (like a ball)
These are usually the simplest ones. Bacteria shaped like this are called cocci (singular coccus).
Rod shaped
These are known as bacilli (singular bacillus).
Some of the rod-shaped bacteria are curved; these are known as vibrio.
Spiral
These known are as spirilla (singular spirillus).
If their coil is very tight they are known as spirochetes.
There are many variations within each shape group.
This is a file from Wikimedia Commons
Bacteria are found everywhere
Bacteria can be found in:
Soil
Radioactive waste
Water
Plants
Animals
Deep in the earth's crust
Organic material
Arctic ice
Glaciers
Hot springs
The stratosphere (between 6 to 30 miles up in the atmosphere)
Ocean depths - they have been found deep in ocean canyons and trenches over 32,800 feet (10,000 meters) deep. They live in total darkness by thermal vents at incredible pressure. They make their own food by oxidizing sulfur that oozes from deep inside the earth.
Scientists who specialize in bacteria - bacteriologists - say bacteria are found absolutely everywhere except for places that humans have sterilized. Even the most unlikely places where temperatures may be extreme, or where there may be a high concentration of toxic chemicals have bacteria - these are known as extremophiles (an extremophile is any organism adapted to living in conditions of extreme temperature, pressure, or/and chemical concentrations) - these bacteria can survive where no other organism can.
The cells of bacteria
A bacterial cell differs somewhat from the cell of a plant or animal. Bacterial cells have no nucleus and other organelles (sub-units within a cell with a specific function) bound by a membrane, except for ribosomes. Bacteria have pili, flagella, and a cell capsule (most of them), unlike animal or plant cells. An organism without a nucleus is called a prokaryote.
A bacterial cell includes:
Basal body - this anchors the base of the flagellum, allowing it to rotate.
Capsule - a layer on the outside of the cell wall. Some bacteria don't have a capsule.
Cell wall - a thin layer (membrane) outside the plasma membrane, and within the capsule.
DNA (Deoxyribonucleic acid) - contains all the genetic instructions used in the development and functioning of the bacterium. It is inside the cytoplasm.
Cytoplasm - a gelatinous substance inside the plasma membrane. Genetic material and ribosomes lie inside.
Flagellum - this is used for movement; to propel the cell. Some bacterial cells have more than one.
Pili (singular: pilus) - these spikes allow the cell to stick to surfaces and transfer genetic material to other cells. A study revealed that pili are involved in causing traveler's diarrhea.
Plasma membrane - it generates energy and transports chemicals. Substances can pass through the membrane (permeable). It is located within the cell wall.
Ribosomes - this is where protein is made (synthesized). Ribosomes are small organelles made up of RNA-rich granules.
This is a file from Wikimedia Commons
The origins and evolution of bacteria
Modern bacteria's ancestors - single-celled microorganisms - appeared on earth about 4 billion years ago. Scientists say they were the first life forms on Earth. For the following 3 billion years all life forms on Earth were microscopic in size, and included two dominant ones: 1. Bacteria, and 2. Archaea (classified as bacteria, but genetically and metabolically different from all other known bacteria).
There are fossils of bacteria. However, because their form and structure (morphology) are not distinctive it is virtually impossible to date them, making it extremely hard to study the process of bacterial evolution with any degree of accuracy. However, with the help of gene sequences, it is now possible to know that bacteria diverged from their original archaeal/eukaryotic ancestry (Eukaryotic = pertaining to an eukaryotice; a single-celled or multicellular organism whose cells contain a distinct membrane-bound nucleus).
Archaea is bacteria's most recent common ancestor - it was most likely hyperthermophile, an organism that thrived in extremely hot environments, approximately 2.5 - 3.2 billion years ago. Bacteria were also involved in the divergence of archaea and eukaryotes. Eukaryotes came from a very early bacteria which had an endosymbiotic association (when an organism lives within the body or cells of another organism) with the predecessors of eukaryotes cells, which were probably related to the Archaea. Biologists say that some algae probably originated from later endosymbiotic relationships.
Put simply - bacteria were the first organisms to appear on earth, about 4 billion years ago. Our oldest known fossils are of bacteria-like organisms.
A short history of bacteriology
Some people had suggested thousands of years ago that something too small for the naked eye to see may be the cause of disease. Over the hundreds of years that followed various theories were given. It was not until 1676 that bacteria were properly identified as microorganisms. Below is a short synopsis of some of the most famous scientists/microbiologists in history:
Marcus Terentius Varro (Roman - 116 BC-27 BC) - a prolific author. He suggested that disease may be caused by miniscule animals that floated in the air. He is admired by many scientists today for his anticipation of microbiology (the study of microorganisms and their effects on other living organisms) and epidemiology (the study of the causes, distribution, and control of disease in populations). He believed marshy places should be avoided during building work because they might contain insects too small for the eye to see that entered the body through the mouth and nostrils and cause diseases.
Interesting articles
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What are genes?
What is pneumonia?
What is food poisoning? What is gastroenteritis?
What is typhoid?
Hippocrates (c 460-377 BC) - a physician, considered one of the most outstanding figures in the history of medicine. He was the first physician to separate medicine from superstition. He said disease was not a punishment meted out by gods, but rather a result of lifestyle, diet and environmental factors. However, Hippocrates' theories on diseases being an imbalance of the four humors present in the human body, caused by miasmas - vapors from rotting vegetables or bodies, polluted rivers and marshy places - were slightly wider of the mark than we know about today.
Jacobo Forli and Alexandro Benedetti (Italian c. 14th/15th century) - they said it was not possible to get ill just by breathing in the air. They said particles that floated in the air may cause disease if they were breathed in.
Nevertheless, the Miasma Theory persevered for a long time, right from the first century through to about 1500, when the Germ Theory started to develop:
Antonie van Leeuwenhoek (Dutch 1632-1723) - he handcrafted single-lens microscopes himself, with which he saw what he called animalcules in 1676 (to be called bacteria 162 years later). In a series of letters to the Royal Society (England) he published his findings. He is commonly known as the father of microbiology and considered to be the first microbiologist.
Christian Gottfried Ehrenberg (German 1795-1876) - one of the most famous and prolific scientists during the nineteenth century, introduced the term bacterium in 1838.
Louis Pasteur (French - 1822 - 1895) - a remarkable chemist who became famous for many breakthroughs in the causes and preventions of disease. He created the first vaccine for rabies. Pasteur demonstrated in 1859 that the fermentation process is caused by the growth of microorganisms, and not spontaneous generation. He and Robert Kich, said that diseases were caused by germs (The Germ Theory).
Robert Koch (German - 1843-1910) - a brilliant physician/researcher who was awarded the Nobel Prize in 1905 after he proved The Germ Theory.
Paul Ehrlich (German - 1854-1915) - a scientist who became a world authority in immunology. He invented the term chemotherapy. He developed the first antibiotic (Salvarsan) and used it to cure syphilis. He was awarded the Nobel Prize in 1908 for his research on immunology. He pioneered the use of stains to detect bacteria.
Carl Woese (American - 1928-) - currently professor of microbiology at the University of Illinois at Urbana-Champaign. His work recognized that archaea evolved along a separate line from bacteria.
Metabolism - How do bacteria feed themselves?
Bacteria feed themselves in a variety of ways.
Heterotrophic bacteria (or just heterotrophs) - these eat other organisms.
Most of them are saprobes, they absorb dead organic material, such as decomposing flesh. Some of these parasitic bacteria kill their host, while others help them.
Autototrophic bacteria (or just autotrophs) - these make their own food.
This could be done by photosynthesis - they use sunlight, C02, and water to make their food. Bacteria that use sunlight to synthesize their food are called photoautotrophs. These include the cyanobacteria which probably played a vital role in creating the Earth's oxygen atmosphere. Other photoautotraphs do not produce oxygen, such as heliobacteria, purple non-sulfur bacteria, purple sulfur bacteria, and green sulfur bacteria.
Others do it by chemosynthesis - they use C02, water, and such chemicals as ammonia to synthesize their food. We call them nitrogen fixers. They are commonly in legume roots and ocean vents. Examples of legumes are alfalfa, clover, peas, beans, lentils, and peanuts. These bacteria are known as chemoautotrophs. Other chemicals used for nutrition are nitrogen, sulfur, phosphorous, vitamins, and such metallic elements as sodium, potassium, calcium, magnesium, manganese, iron, zinc, and cobalt.
What kinds of environments do bacteria inhabit?
Aerobes (aerobic bacteria) - these can grow only in the presence of oxygen. Some types may cause serious problems to people's infrastructure as they can cause corrosion, fouling, problems with water clarity, and bad smells.
Anaerobes (anaerobic bacteria) - these can only grow if there is no oxygen present. In humans, they are most commonly found in the gastrointestinal tract. They also cause gas gangrene, tetanus, and botulism. Most dental infections are caused by this type of bacterium.
Facultative anaerobes (facultative anaerobic bacteria) - these thrive in environments with or without oxygen. However, when given both options, they prefer to use oxygen for respiration. Most commonly found in soil, water, vegetation and some normal flora of humans and animals. An example of a facultative anaerobic bacterium is salmonella.
Mesophile (mesophilic bacteria) - these thrive in moderate temperatures. Examples include Listeria monocytogenes, Pesudomonas maltophilia, Thiobacillus novellus, Staphylococcus aureus, Streptococcus pyrogenes, Streptococcus pneumoniae, Escherichia coli, and Clostridium kluyveri. Human bacterial infections are mainly caused by mesophilic bacteria - this is because the body of a human is moderate (37 Celsius). The human intestinal flora contains many beneficial mesophilic bacteria, such as dietary Lactobacillus acidophilus.
Extremophiles (extremophilic bacteria) - these thrive in conditions considered too extreme for most life forms, including mankind. There are several different types of extremophilic bacteria, depending on what kind of extremes they can tolerate:
Thermophiles (thermophilic bacteria) - these thrive in temperatures above 55 Celsius, and can tolerate up to 75-80 Celsius. They take longer to destroy in boiling water than other bacteria. The bacteria Pyrolobus fumarii can tolerate temperatures up to 113 Celsius - it is classed as a hyperthermophile.
Halophiles (halophilic bacteria) - these only thrive in a salty environment, such as saltine lakes. An example is Halobacteriacea.
Acidophiles (acidophilic bacteria) - these only thrive in acidic environments. Cyanidium caldarium, and Ferroplasma sp can tolerate an environment with an acidity of pH 0.
Alkaliphiles (alkiliphilic bacteria) - these only thrive in alkaline environments. Natronobacterium, Bacillus firmus OF4, and Spirulina spp can all tolerate up to pH 10.5.
Psychrophiles (psychrophilic bacteria) - these thrive at very low temperatures, such as in glaciers. An example is Psychrobacter.
How do bacteria reproduce?
Binary fission
This is known as an asexual form of reproduction; it does not involve a male and female. The cell continues growing and growing, eventually a new cell wall grows through the center forming two daughter cells, which eventually separate. Each daughter cell has the same genetic material as the parent cell.
Bacterial recombination
The problem with binary fission is that every daughter cell is identical to the cell it came from, as well as all its sisters. This makes it harder for bacteria to prevail, especially if we attack them with antibiotics. To get around this, bacteria use a process called recombination. Bacterial recombination is achieved through:
Conjugation - this simply means passing pieces of genes from one bacterial cell to another one when they come in contact. A bacterium connects itself to another through a tube structure called pilus (there are lots of them, spiky things, plural: pilli), you can see them in the second illustration in this article (scroll up). Genes from one bacterial cell go through this tube into the other cell.
Transformation - some bacterial cells can grab DNA form the environment around them - often DNA from dead bacterial cells. The bacterial cell binds the DNA and carries it across the bacterial cell membrane. Put simply, it pulls the DNA in from outside through its cell wall.
Transduction - bacteria get infected by viruses called bacteriophages. The bacteriophage inserts its genome into the bacterium when it attaches itself to the bacterial cell. The genome of this virus, enzymes and components of the virus are replicated and assembled inside the host bacterium. The newly formed bacteriophages then cause the rupture or disintegration of the bacterial cell wall, resulting in the release of the replicated viruses. Sometimes, however, some of the bacterium's DNA can become encased in the viral capsid (protein shell that surrounds a virus particle) instead of the viral genome during the assembly process. When this bacteriophage goes and infects another bacterium it injects DNA fragments from its previous host (the first bacterium), which then becomes inserted into the DNA of the new bacterium. We call this generalized transduction.
Put simply - transduction is when a virus gets into the bacterium, picks up some of its DNA, and then places it in the next bacterium it gets into.
Researchers at Texas A&M University's Artie McFerrin Department of Chemical Engineering suggest that genetic material isn't really captured as much as it is simply utilized after it's injected into the bacteria by an invading virus.
Another form of transduction is specialized transduction. Fragments of the first bacterium's DNA become incorporated into the viral genome of the new bacteriophage. These DNA fragments are then transferred to the next bacterium the bacteriophage infects.
Resting stage - spores
This is more a form of hibernation than reproduction. When bacteria do not have enough resources they can reproduce by forming spores, which hold the organism's DNA material.
These spores are alive but not active. When conditions are appropriate the spores become new bacteria. Spores can remain dormant for centuries before becoming new bacteria. The main function of these spores is to survive through periods of environmental stress. They are resistant to ultraviolet and gamma radiation, desiccation, starvation, chemicals and extremes of temperature. Some bacteria produce endospores (internal spores) while others produce exospores (released outside) or cysts. The spore contains enzymes which are involved in germination.
An example of an endospore-forming bacterium is Clostridium, which consists of about 100 species that include common free-living bacteria as well as important human disease causing bacteria, such as botulism (C. botulinim) and pseudomembranous colitis (C. difficile).
A study found that bacterial spores "listen in" find out what their neighbors and doing.
The effects of bacteria
Most people tend to imagine negative things when asked about bacteria. It is important to remember that bacteria are so ubiquitous, and have been around so long - since the beginning of life on earth, in fact - that we would not have existed without them. The air we breathe - specifically the oxygen in the air we breathe - was most probably created millions of years ago by the activity of bacteria.
Nitrogen fixation
Bacteria assimilate atmospheric nitrogen and then release it for plant use when they die. Plants cannot extract nitrogen from the air and place it in the soil - but plants need nitrogen in soil to live - without the bacteria doing this would not be able to carry out a vital part of their metabolism. The relationship between plant and bacteria has become so close in this sense that many plant seeds have a small container of bacteria that will be used when the plant sprouts.
Humans need bacteria to survive
The human body contains huge amounts of friendly bacteria that are either neutral or help us somehow. Bacteria in the digestive system are crucial for the breakdown of certain types of nutrients, such as complex sugars, into forms the body can use. Friendly bacteria also protect us from dangerous ones by occupying places in the body the pathogenic (disease causing) bacteria want attach to. Some friendly bacteria actually come to the rescue and attack the pathogens.
Bacteria and the obesity epidemic
According to a study released by the International & American Association for Dental Research, bacteria may be a contributory factor in today's obesity explosion.
Effect of bacteria as pathogens to humans (causes of diseases)
Some of the most deadly diseases and devastating epidemics in human history have been caused by bacteria.
Smallpox and malaria - not caused by bacteria - have killed more humans than bacterial diseases. However, the following bacterial diseases have destroyed hundreds of millions of human lives:
Cholera
Diphtheria
Dysentery
Plague
Pneumonia
Tuberculosis
Typhoid
Typhus
In the year 1900 pneumonia, tuberculosis and diarrhea were the three biggest killers in the USA. As water purification improved, vaccines and immunization programs evolved, and antibiotic treatment became more advanced - the human death toll in the USA from bacterial diseases has dropped significantly (as well as in the rest of the developed world). In developing countries, success rates have depended on several factors, such as the strategies implemented by local health authorities, and whether countries enjoyed periods of peacetime (no wars). Countries such as Mexico, Argentina, and Uruguay, to mention but a few, have also seen significant falls in bacterial related deaths over the last 100 years.
Significance of bacteria in food technology
Lactic acid bacteria, such as Lactobacillus and Lactococcus together with yeast and molds (fungi) have been used for the preparation of such foods as cheese, soy sauce, vinegar, yoghurt and pickles. Humans have been using these bacteria for preparing fermented foods for thousands of years.
Significance of bacteria in other technologies
Bacteria can break down organic compounds at remarkable speed and help us in our waste processing and bioremediation activities. Bacteria are frequently used for cleaning up oil spills. They are useful in clearing up toxic waste.
The pharmaceutical and chemical industries use bacteria in the production of certain chemicals. They are used in the molecular biology, biochemistry and genetic research because they can grow quickly and are relative easy to manipulate. Scientists can use bacteria to study the functions of genes and enzymes, as well as bacterial metabolic pathways, and then test out their results on more complex organisms.
Such bacteria as Bacillus thuringiensis (BT) can be used in agriculture instead of pesticides, without the undesirable environmental consequences that pesticide use may cause.
Scientists from University College London created an arsenic biosensor from living bacteria.
Sources: National Health Service (NHS), UK, The Mayo Clinic, Wikipedia, HHS (Department of Health and Human Services USA), NIH (National Institutes of Health, USA).
Written by
A gram of soil typically contains about 40 million bacterial cells. A milliliter of fresh water usually holds about one million bacterial cells.
Planet Earth is estimated to hold at least 5 nonillion bacteria. Scientists say that much of Earth's biomass is made up of bacteria.
5 nonillion = 5,000,000,000,000,000,000,000,000,000,000 (or 5x1030)
(Nonillion = 30 zeros in USA English. In British English it equals 54 zeros. This text uses the American meaning)
Bacteria come in three main shapes:
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Spherical (like a ball)
These are usually the simplest ones. Bacteria shaped like this are called cocci (singular coccus).
Rod shaped
These are known as bacilli (singular bacillus).
Some of the rod-shaped bacteria are curved; these are known as vibrio.
Spiral
These known are as spirilla (singular spirillus).
If their coil is very tight they are known as spirochetes.
There are many variations within each shape group.
This is a file from Wikimedia Commons
Bacteria are found everywhere
Bacteria can be found in:
Soil
Radioactive waste
Water
Plants
Animals
Deep in the earth's crust
Organic material
Arctic ice
Glaciers
Hot springs
The stratosphere (between 6 to 30 miles up in the atmosphere)
Ocean depths - they have been found deep in ocean canyons and trenches over 32,800 feet (10,000 meters) deep. They live in total darkness by thermal vents at incredible pressure. They make their own food by oxidizing sulfur that oozes from deep inside the earth.
Scientists who specialize in bacteria - bacteriologists - say bacteria are found absolutely everywhere except for places that humans have sterilized. Even the most unlikely places where temperatures may be extreme, or where there may be a high concentration of toxic chemicals have bacteria - these are known as extremophiles (an extremophile is any organism adapted to living in conditions of extreme temperature, pressure, or/and chemical concentrations) - these bacteria can survive where no other organism can.
The cells of bacteria
A bacterial cell differs somewhat from the cell of a plant or animal. Bacterial cells have no nucleus and other organelles (sub-units within a cell with a specific function) bound by a membrane, except for ribosomes. Bacteria have pili, flagella, and a cell capsule (most of them), unlike animal or plant cells. An organism without a nucleus is called a prokaryote.
A bacterial cell includes:
Basal body - this anchors the base of the flagellum, allowing it to rotate.
Capsule - a layer on the outside of the cell wall. Some bacteria don't have a capsule.
Cell wall - a thin layer (membrane) outside the plasma membrane, and within the capsule.
DNA (Deoxyribonucleic acid) - contains all the genetic instructions used in the development and functioning of the bacterium. It is inside the cytoplasm.
Cytoplasm - a gelatinous substance inside the plasma membrane. Genetic material and ribosomes lie inside.
Flagellum - this is used for movement; to propel the cell. Some bacterial cells have more than one.
Pili (singular: pilus) - these spikes allow the cell to stick to surfaces and transfer genetic material to other cells. A study revealed that pili are involved in causing traveler's diarrhea.
Plasma membrane - it generates energy and transports chemicals. Substances can pass through the membrane (permeable). It is located within the cell wall.
Ribosomes - this is where protein is made (synthesized). Ribosomes are small organelles made up of RNA-rich granules.
This is a file from Wikimedia Commons
The origins and evolution of bacteria
Modern bacteria's ancestors - single-celled microorganisms - appeared on earth about 4 billion years ago. Scientists say they were the first life forms on Earth. For the following 3 billion years all life forms on Earth were microscopic in size, and included two dominant ones: 1. Bacteria, and 2. Archaea (classified as bacteria, but genetically and metabolically different from all other known bacteria).
There are fossils of bacteria. However, because their form and structure (morphology) are not distinctive it is virtually impossible to date them, making it extremely hard to study the process of bacterial evolution with any degree of accuracy. However, with the help of gene sequences, it is now possible to know that bacteria diverged from their original archaeal/eukaryotic ancestry (Eukaryotic = pertaining to an eukaryotice; a single-celled or multicellular organism whose cells contain a distinct membrane-bound nucleus).
Archaea is bacteria's most recent common ancestor - it was most likely hyperthermophile, an organism that thrived in extremely hot environments, approximately 2.5 - 3.2 billion years ago. Bacteria were also involved in the divergence of archaea and eukaryotes. Eukaryotes came from a very early bacteria which had an endosymbiotic association (when an organism lives within the body or cells of another organism) with the predecessors of eukaryotes cells, which were probably related to the Archaea. Biologists say that some algae probably originated from later endosymbiotic relationships.
Put simply - bacteria were the first organisms to appear on earth, about 4 billion years ago. Our oldest known fossils are of bacteria-like organisms.
A short history of bacteriology
Some people had suggested thousands of years ago that something too small for the naked eye to see may be the cause of disease. Over the hundreds of years that followed various theories were given. It was not until 1676 that bacteria were properly identified as microorganisms. Below is a short synopsis of some of the most famous scientists/microbiologists in history:
Marcus Terentius Varro (Roman - 116 BC-27 BC) - a prolific author. He suggested that disease may be caused by miniscule animals that floated in the air. He is admired by many scientists today for his anticipation of microbiology (the study of microorganisms and their effects on other living organisms) and epidemiology (the study of the causes, distribution, and control of disease in populations). He believed marshy places should be avoided during building work because they might contain insects too small for the eye to see that entered the body through the mouth and nostrils and cause diseases.
Interesting articles
What are antibiotics? How do antibiotics work?
What is MRSA? Why is MRSA a concern?
What are genes?
What is pneumonia?
What is food poisoning? What is gastroenteritis?
What is typhoid?
Hippocrates (c 460-377 BC) - a physician, considered one of the most outstanding figures in the history of medicine. He was the first physician to separate medicine from superstition. He said disease was not a punishment meted out by gods, but rather a result of lifestyle, diet and environmental factors. However, Hippocrates' theories on diseases being an imbalance of the four humors present in the human body, caused by miasmas - vapors from rotting vegetables or bodies, polluted rivers and marshy places - were slightly wider of the mark than we know about today.
Jacobo Forli and Alexandro Benedetti (Italian c. 14th/15th century) - they said it was not possible to get ill just by breathing in the air. They said particles that floated in the air may cause disease if they were breathed in.
Nevertheless, the Miasma Theory persevered for a long time, right from the first century through to about 1500, when the Germ Theory started to develop:
Antonie van Leeuwenhoek (Dutch 1632-1723) - he handcrafted single-lens microscopes himself, with which he saw what he called animalcules in 1676 (to be called bacteria 162 years later). In a series of letters to the Royal Society (England) he published his findings. He is commonly known as the father of microbiology and considered to be the first microbiologist.
Christian Gottfried Ehrenberg (German 1795-1876) - one of the most famous and prolific scientists during the nineteenth century, introduced the term bacterium in 1838.
Louis Pasteur (French - 1822 - 1895) - a remarkable chemist who became famous for many breakthroughs in the causes and preventions of disease. He created the first vaccine for rabies. Pasteur demonstrated in 1859 that the fermentation process is caused by the growth of microorganisms, and not spontaneous generation. He and Robert Kich, said that diseases were caused by germs (The Germ Theory).
Robert Koch (German - 1843-1910) - a brilliant physician/researcher who was awarded the Nobel Prize in 1905 after he proved The Germ Theory.
Paul Ehrlich (German - 1854-1915) - a scientist who became a world authority in immunology. He invented the term chemotherapy. He developed the first antibiotic (Salvarsan) and used it to cure syphilis. He was awarded the Nobel Prize in 1908 for his research on immunology. He pioneered the use of stains to detect bacteria.
Carl Woese (American - 1928-) - currently professor of microbiology at the University of Illinois at Urbana-Champaign. His work recognized that archaea evolved along a separate line from bacteria.
Metabolism - How do bacteria feed themselves?
Bacteria feed themselves in a variety of ways.
Heterotrophic bacteria (or just heterotrophs) - these eat other organisms.
Most of them are saprobes, they absorb dead organic material, such as decomposing flesh. Some of these parasitic bacteria kill their host, while others help them.
Autototrophic bacteria (or just autotrophs) - these make their own food.
This could be done by photosynthesis - they use sunlight, C02, and water to make their food. Bacteria that use sunlight to synthesize their food are called photoautotrophs. These include the cyanobacteria which probably played a vital role in creating the Earth's oxygen atmosphere. Other photoautotraphs do not produce oxygen, such as heliobacteria, purple non-sulfur bacteria, purple sulfur bacteria, and green sulfur bacteria.
Others do it by chemosynthesis - they use C02, water, and such chemicals as ammonia to synthesize their food. We call them nitrogen fixers. They are commonly in legume roots and ocean vents. Examples of legumes are alfalfa, clover, peas, beans, lentils, and peanuts. These bacteria are known as chemoautotrophs. Other chemicals used for nutrition are nitrogen, sulfur, phosphorous, vitamins, and such metallic elements as sodium, potassium, calcium, magnesium, manganese, iron, zinc, and cobalt.
What kinds of environments do bacteria inhabit?
Aerobes (aerobic bacteria) - these can grow only in the presence of oxygen. Some types may cause serious problems to people's infrastructure as they can cause corrosion, fouling, problems with water clarity, and bad smells.
Anaerobes (anaerobic bacteria) - these can only grow if there is no oxygen present. In humans, they are most commonly found in the gastrointestinal tract. They also cause gas gangrene, tetanus, and botulism. Most dental infections are caused by this type of bacterium.
Facultative anaerobes (facultative anaerobic bacteria) - these thrive in environments with or without oxygen. However, when given both options, they prefer to use oxygen for respiration. Most commonly found in soil, water, vegetation and some normal flora of humans and animals. An example of a facultative anaerobic bacterium is salmonella.
Mesophile (mesophilic bacteria) - these thrive in moderate temperatures. Examples include Listeria monocytogenes, Pesudomonas maltophilia, Thiobacillus novellus, Staphylococcus aureus, Streptococcus pyrogenes, Streptococcus pneumoniae, Escherichia coli, and Clostridium kluyveri. Human bacterial infections are mainly caused by mesophilic bacteria - this is because the body of a human is moderate (37 Celsius). The human intestinal flora contains many beneficial mesophilic bacteria, such as dietary Lactobacillus acidophilus.
Extremophiles (extremophilic bacteria) - these thrive in conditions considered too extreme for most life forms, including mankind. There are several different types of extremophilic bacteria, depending on what kind of extremes they can tolerate:
Thermophiles (thermophilic bacteria) - these thrive in temperatures above 55 Celsius, and can tolerate up to 75-80 Celsius. They take longer to destroy in boiling water than other bacteria. The bacteria Pyrolobus fumarii can tolerate temperatures up to 113 Celsius - it is classed as a hyperthermophile.
Halophiles (halophilic bacteria) - these only thrive in a salty environment, such as saltine lakes. An example is Halobacteriacea.
Acidophiles (acidophilic bacteria) - these only thrive in acidic environments. Cyanidium caldarium, and Ferroplasma sp can tolerate an environment with an acidity of pH 0.
Alkaliphiles (alkiliphilic bacteria) - these only thrive in alkaline environments. Natronobacterium, Bacillus firmus OF4, and Spirulina spp can all tolerate up to pH 10.5.
Psychrophiles (psychrophilic bacteria) - these thrive at very low temperatures, such as in glaciers. An example is Psychrobacter.
How do bacteria reproduce?
Binary fission
This is known as an asexual form of reproduction; it does not involve a male and female. The cell continues growing and growing, eventually a new cell wall grows through the center forming two daughter cells, which eventually separate. Each daughter cell has the same genetic material as the parent cell.
Bacterial recombination
The problem with binary fission is that every daughter cell is identical to the cell it came from, as well as all its sisters. This makes it harder for bacteria to prevail, especially if we attack them with antibiotics. To get around this, bacteria use a process called recombination. Bacterial recombination is achieved through:
Conjugation - this simply means passing pieces of genes from one bacterial cell to another one when they come in contact. A bacterium connects itself to another through a tube structure called pilus (there are lots of them, spiky things, plural: pilli), you can see them in the second illustration in this article (scroll up). Genes from one bacterial cell go through this tube into the other cell.
Transformation - some bacterial cells can grab DNA form the environment around them - often DNA from dead bacterial cells. The bacterial cell binds the DNA and carries it across the bacterial cell membrane. Put simply, it pulls the DNA in from outside through its cell wall.
Transduction - bacteria get infected by viruses called bacteriophages. The bacteriophage inserts its genome into the bacterium when it attaches itself to the bacterial cell. The genome of this virus, enzymes and components of the virus are replicated and assembled inside the host bacterium. The newly formed bacteriophages then cause the rupture or disintegration of the bacterial cell wall, resulting in the release of the replicated viruses. Sometimes, however, some of the bacterium's DNA can become encased in the viral capsid (protein shell that surrounds a virus particle) instead of the viral genome during the assembly process. When this bacteriophage goes and infects another bacterium it injects DNA fragments from its previous host (the first bacterium), which then becomes inserted into the DNA of the new bacterium. We call this generalized transduction.
Put simply - transduction is when a virus gets into the bacterium, picks up some of its DNA, and then places it in the next bacterium it gets into.
Researchers at Texas A&M University's Artie McFerrin Department of Chemical Engineering suggest that genetic material isn't really captured as much as it is simply utilized after it's injected into the bacteria by an invading virus.
Another form of transduction is specialized transduction. Fragments of the first bacterium's DNA become incorporated into the viral genome of the new bacteriophage. These DNA fragments are then transferred to the next bacterium the bacteriophage infects.
Resting stage - spores
This is more a form of hibernation than reproduction. When bacteria do not have enough resources they can reproduce by forming spores, which hold the organism's DNA material.
These spores are alive but not active. When conditions are appropriate the spores become new bacteria. Spores can remain dormant for centuries before becoming new bacteria. The main function of these spores is to survive through periods of environmental stress. They are resistant to ultraviolet and gamma radiation, desiccation, starvation, chemicals and extremes of temperature. Some bacteria produce endospores (internal spores) while others produce exospores (released outside) or cysts. The spore contains enzymes which are involved in germination.
An example of an endospore-forming bacterium is Clostridium, which consists of about 100 species that include common free-living bacteria as well as important human disease causing bacteria, such as botulism (C. botulinim) and pseudomembranous colitis (C. difficile).
A study found that bacterial spores "listen in" find out what their neighbors and doing.
The effects of bacteria
Most people tend to imagine negative things when asked about bacteria. It is important to remember that bacteria are so ubiquitous, and have been around so long - since the beginning of life on earth, in fact - that we would not have existed without them. The air we breathe - specifically the oxygen in the air we breathe - was most probably created millions of years ago by the activity of bacteria.
Nitrogen fixation
Bacteria assimilate atmospheric nitrogen and then release it for plant use when they die. Plants cannot extract nitrogen from the air and place it in the soil - but plants need nitrogen in soil to live - without the bacteria doing this would not be able to carry out a vital part of their metabolism. The relationship between plant and bacteria has become so close in this sense that many plant seeds have a small container of bacteria that will be used when the plant sprouts.
Humans need bacteria to survive
The human body contains huge amounts of friendly bacteria that are either neutral or help us somehow. Bacteria in the digestive system are crucial for the breakdown of certain types of nutrients, such as complex sugars, into forms the body can use. Friendly bacteria also protect us from dangerous ones by occupying places in the body the pathogenic (disease causing) bacteria want attach to. Some friendly bacteria actually come to the rescue and attack the pathogens.
Bacteria and the obesity epidemic
According to a study released by the International & American Association for Dental Research, bacteria may be a contributory factor in today's obesity explosion.
Effect of bacteria as pathogens to humans (causes of diseases)
Some of the most deadly diseases and devastating epidemics in human history have been caused by bacteria.
Smallpox and malaria - not caused by bacteria - have killed more humans than bacterial diseases. However, the following bacterial diseases have destroyed hundreds of millions of human lives:
Cholera
Diphtheria
Dysentery
Plague
Pneumonia
Tuberculosis
Typhoid
Typhus
In the year 1900 pneumonia, tuberculosis and diarrhea were the three biggest killers in the USA. As water purification improved, vaccines and immunization programs evolved, and antibiotic treatment became more advanced - the human death toll in the USA from bacterial diseases has dropped significantly (as well as in the rest of the developed world). In developing countries, success rates have depended on several factors, such as the strategies implemented by local health authorities, and whether countries enjoyed periods of peacetime (no wars). Countries such as Mexico, Argentina, and Uruguay, to mention but a few, have also seen significant falls in bacterial related deaths over the last 100 years.
Significance of bacteria in food technology
Lactic acid bacteria, such as Lactobacillus and Lactococcus together with yeast and molds (fungi) have been used for the preparation of such foods as cheese, soy sauce, vinegar, yoghurt and pickles. Humans have been using these bacteria for preparing fermented foods for thousands of years.
Significance of bacteria in other technologies
Bacteria can break down organic compounds at remarkable speed and help us in our waste processing and bioremediation activities. Bacteria are frequently used for cleaning up oil spills. They are useful in clearing up toxic waste.
The pharmaceutical and chemical industries use bacteria in the production of certain chemicals. They are used in the molecular biology, biochemistry and genetic research because they can grow quickly and are relative easy to manipulate. Scientists can use bacteria to study the functions of genes and enzymes, as well as bacterial metabolic pathways, and then test out their results on more complex organisms.
Such bacteria as Bacillus thuringiensis (BT) can be used in agriculture instead of pesticides, without the undesirable environmental consequences that pesticide use may cause.
Scientists from University College London created an arsenic biosensor from living bacteria.
Sources: National Health Service (NHS), UK, The Mayo Clinic, Wikipedia, HHS (Department of Health and Human Services USA), NIH (National Institutes of Health, USA).
Written by
Permission To Create Chimeras, Not Hybrids, For Stem Cell Research
A chimera is an organism which has two or more genetically different groups of cells that originate from different organisms. A hybrid is a being made from the egg of one species and the sperm of another. A mule is a hybrid of a donkey and a horse.
Scientists from Newcastle University, UK, and Kings College, London, UK, want to get cows' eggs and place human nuclei inside them. They say it is a route for creating stem cell lines. They say this research would help us better understand and cure diseases. It could eventually lead to the creation of organs for transplant. The application has been submitted to the Human Fertilisation and Embryology Authority (HFEA ) for a three-year licence.
This route would free scientists from using donated human eggs.
Chimeras of the same species can exist. However, the scientists seek permission to create non-human oocytes. The stem cells they would like to create would be 99.9% human and 0.1% animal. The animal's egg would have no nucleus, but would contain minute quantities of mitochondrial DNA. The animal's egg would mix with human nuclei, a chimera oocyte would be formed and the stem cells harvested after a few days. In other words, imagine using just the shell of, say, a cows' eggs to hold the human nuclei.
(Oocytes = Eggs whose nuclei have been removed)
As it is impossible to carry out experiments on humans, this procedure could be used for this, say the scientists.
Dr Stephen Minger, King's College London, said "What we are proposing to do is not really create chimeras but rather use non-human oocytes merely as a surrogate to generate human embryonic stem cell lines from individuals with genetic forms of neurodegenerative diseases." Minger and team aim to use this technology to research Alzheimer's and Parkinson's disease.
Dr Lyle Armstrong, University of Newscastle said "We are very hopeful that the HFEA will grant us permission for this work, which will help us to understand more about how cells behave after the nuclear transfer process. We need this information to enable us to take this area of stem cell research to the next stage. At the moment we don't know if the nuclear transfer process works well enough in humans to create useful embryonic stem cells. We need to carry out many tests to establish this and, as animal eggs are freely available, it makes sense to use these as a source of material for our laboratory work.... Stem cell research promises huge potential medical advantages and we believe we will be working towards our ultimate goal of developing new patient therapies."
"Researchers seek permission for stem cell work using animal eggs
Newcastle University"
Click here to read article online
Written by:
Scientists from Newcastle University, UK, and Kings College, London, UK, want to get cows' eggs and place human nuclei inside them. They say it is a route for creating stem cell lines. They say this research would help us better understand and cure diseases. It could eventually lead to the creation of organs for transplant. The application has been submitted to the Human Fertilisation and Embryology Authority (HFEA ) for a three-year licence.
This route would free scientists from using donated human eggs.
Chimeras of the same species can exist. However, the scientists seek permission to create non-human oocytes. The stem cells they would like to create would be 99.9% human and 0.1% animal. The animal's egg would have no nucleus, but would contain minute quantities of mitochondrial DNA. The animal's egg would mix with human nuclei, a chimera oocyte would be formed and the stem cells harvested after a few days. In other words, imagine using just the shell of, say, a cows' eggs to hold the human nuclei.
(Oocytes = Eggs whose nuclei have been removed)
As it is impossible to carry out experiments on humans, this procedure could be used for this, say the scientists.
Dr Stephen Minger, King's College London, said "What we are proposing to do is not really create chimeras but rather use non-human oocytes merely as a surrogate to generate human embryonic stem cell lines from individuals with genetic forms of neurodegenerative diseases." Minger and team aim to use this technology to research Alzheimer's and Parkinson's disease.
Dr Lyle Armstrong, University of Newscastle said "We are very hopeful that the HFEA will grant us permission for this work, which will help us to understand more about how cells behave after the nuclear transfer process. We need this information to enable us to take this area of stem cell research to the next stage. At the moment we don't know if the nuclear transfer process works well enough in humans to create useful embryonic stem cells. We need to carry out many tests to establish this and, as animal eggs are freely available, it makes sense to use these as a source of material for our laboratory work.... Stem cell research promises huge potential medical advantages and we believe we will be working towards our ultimate goal of developing new patient therapies."
"Researchers seek permission for stem cell work using animal eggs
Newcastle University"
Click here to read article online
Written by:
Human Evolution And Fly Genomics
New work on fruit fly genomics suggests new ways to look at the much larger human genome, and gives insights into the role of adaptation in evolution.
In two recent papers, researchers led by David Begun and Charles Langley, professors of evolution and ecology at the UC Davis Center for Population Biology, compared the whole genomes of several individuals of the fly Drosophila simulans to close relatives D. melanogaster and D. yakuba.
The same approach could be extended to the much larger genomes of humans and our close relatives, Begun said, showing which changes in the genome are uniquely human.
Stretches of DNA that showed a lot of variability within D. simulans did not match up with areas that were most divergent between species. That could be because when beneficial mutations occur, natural selection increases their frequency and reduces variation at nearby sites. The data provide a comprehensive view of adaptive protein evolution, Begun said.
"You can let the genome tell you what processes have experienced adaptive evolution," Begun said. "The organism is telling you what's been important in its history."
The researchers also found the first evidence that the fly's X chromosome is evolving faster than other parts of the genome. The work is published in the journal Public Library of Science (PLoS) Biology.
A second recent paper by postdoctoral researcher Alisha Holloway and colleagues explores the relationship between genomic variation in D. simulans, D. melanogaster and D. yakuba and gene expression, or the pattern in which genes are turned on or off. That work is published in PLoS Genetics.
Holloway found that genes relatively highly expressed in D. simulans have experienced adaptive evolution in the three-prime regions immediately downstream. Those regions can regulate how DNA is translated into RNA. Genes that evolved higher expression levels in one species when compared with the others were also decelerating in their rates of evolution at the protein level, Holloway said. That agrees with previous work showing that highly expressed genes evolve slowly.
Begun, co-author Langley and two other UC Davis researchers are also among about 100 authors on a paper in the Nov. 8 issue of Nature describing the genomes of 12 species of Drosophila flies, including D. simulans, D. yakuba and D. melanogaster.
The other authors on the PLoS Biology paper were Holloway and Kristian Stevens at UC Davis; Yu-Ping Poh at UC Davis and National Tsing Hua University, Taiwan; Mathew Hahn and Phillip Nista at Indiana University, Bloomington; Corbin Jones at the University of North Carolina Chapel Hill; Andrew Kern, UC Santa Cruz; Colin Dewey, University of Wisconsin, Madison; Lior Pachter and Eugene Myers, UC Berkeley. Authors on the PLoS Genetics paper in addition to Holloway were: Begun, Jones, Mara Lawniczak, University College London, England, and Jason Mezey, Cornell University.
Source: Andy Fell
University of California - Davis
In two recent papers, researchers led by David Begun and Charles Langley, professors of evolution and ecology at the UC Davis Center for Population Biology, compared the whole genomes of several individuals of the fly Drosophila simulans to close relatives D. melanogaster and D. yakuba.
The same approach could be extended to the much larger genomes of humans and our close relatives, Begun said, showing which changes in the genome are uniquely human.
Stretches of DNA that showed a lot of variability within D. simulans did not match up with areas that were most divergent between species. That could be because when beneficial mutations occur, natural selection increases their frequency and reduces variation at nearby sites. The data provide a comprehensive view of adaptive protein evolution, Begun said.
"You can let the genome tell you what processes have experienced adaptive evolution," Begun said. "The organism is telling you what's been important in its history."
The researchers also found the first evidence that the fly's X chromosome is evolving faster than other parts of the genome. The work is published in the journal Public Library of Science (PLoS) Biology.
A second recent paper by postdoctoral researcher Alisha Holloway and colleagues explores the relationship between genomic variation in D. simulans, D. melanogaster and D. yakuba and gene expression, or the pattern in which genes are turned on or off. That work is published in PLoS Genetics.
Holloway found that genes relatively highly expressed in D. simulans have experienced adaptive evolution in the three-prime regions immediately downstream. Those regions can regulate how DNA is translated into RNA. Genes that evolved higher expression levels in one species when compared with the others were also decelerating in their rates of evolution at the protein level, Holloway said. That agrees with previous work showing that highly expressed genes evolve slowly.
Begun, co-author Langley and two other UC Davis researchers are also among about 100 authors on a paper in the Nov. 8 issue of Nature describing the genomes of 12 species of Drosophila flies, including D. simulans, D. yakuba and D. melanogaster.
The other authors on the PLoS Biology paper were Holloway and Kristian Stevens at UC Davis; Yu-Ping Poh at UC Davis and National Tsing Hua University, Taiwan; Mathew Hahn and Phillip Nista at Indiana University, Bloomington; Corbin Jones at the University of North Carolina Chapel Hill; Andrew Kern, UC Santa Cruz; Colin Dewey, University of Wisconsin, Madison; Lior Pachter and Eugene Myers, UC Berkeley. Authors on the PLoS Genetics paper in addition to Holloway were: Begun, Jones, Mara Lawniczak, University College London, England, and Jason Mezey, Cornell University.
Source: Andy Fell
University of California - Davis
How Measles Virus Spreads In Its Host Discovered By Mayo Researchers
Measles, one of the most common contagious diseases, has been thought to enter the body through the surface of airways and lungs, like many other major viruses. Now, Mayo Clinic researchers and their collaborators say that's not the case, and some medical texts will have to be revised. The findings are reported in the online edition of The Journal of Clinical Investigation.
"It has long been assumed that measles virus infects the airway epithelium before infecting immune cells," says Roberto Cattaneo, Ph.D., Mayo Clinic virologist and senior author of the study. "But we've shown that replication in the airways is not required, and that a virus replicating only in immune cells causes measles in monkeys."
The research team generated a measles virus that cannot enter the airway epithelium and showed that it spread in lymphocytes, cells of the immune system, and remained virulent. Researchers also showed, as they predicted in a new model of infection, that the virus could not cross the respiratory epithelium on its way out of the lungs and was not shed from infected monkeys.
Significance of the Research
From a treatment standpoint, the findings help physician-researchers better understand how measles virus, which can be reprogrammed to eliminate cancer cells, spreads in its host. The research may help improve efficacy and safety of cancer therapy, and lead to a better understanding of how viruses similar to measles function. A result could be more effective vaccines for other diseases.
From a strictly scientific perspective, the study challenges a widely held assumption about this common contagion. In the introduction to their article, the researchers cite two recent medical texts on the measles virus that say it infects the upper respiratory epithelium before spreading to the rest of the body. In light of their findings, the investigators say those statements will have to be revised.
The team tested their hypothesis by developing a form of the measles virus that could not enter epithelia because it was made "blind" to the epithelial cell receptor, but could enter lymphatic cells through another receptor. The virus was tested on rhesus monkeys, inoculated via the nasal tract. They developed a rash and lost weight (both symptoms of measles in the species), but follow-up tests showed that the virus did not enter through the airway epithelium, though the lymph system was infected.
Co-authors include Vincent Leonard, Ph.D.; Tanner Miest; and Patricia Devaux, Ph.D., Mayo Clinic; Partrick Sinn, Ph.D., and Paul McCray, Jr., M.D., University of Iowa Carver College of Medicine; Gregory Hodge and Michael B. McChesney, Ph.D., University of California Davis; Numan Oezguen, Ph.D., and Werner Braun, Ph.D., University of Texas Medical Branch, Galveston. Support for the study came from the National Institutes of Health.
Source: Robert Nellis
Mayo Clinic
"It has long been assumed that measles virus infects the airway epithelium before infecting immune cells," says Roberto Cattaneo, Ph.D., Mayo Clinic virologist and senior author of the study. "But we've shown that replication in the airways is not required, and that a virus replicating only in immune cells causes measles in monkeys."
The research team generated a measles virus that cannot enter the airway epithelium and showed that it spread in lymphocytes, cells of the immune system, and remained virulent. Researchers also showed, as they predicted in a new model of infection, that the virus could not cross the respiratory epithelium on its way out of the lungs and was not shed from infected monkeys.
Significance of the Research
From a treatment standpoint, the findings help physician-researchers better understand how measles virus, which can be reprogrammed to eliminate cancer cells, spreads in its host. The research may help improve efficacy and safety of cancer therapy, and lead to a better understanding of how viruses similar to measles function. A result could be more effective vaccines for other diseases.
From a strictly scientific perspective, the study challenges a widely held assumption about this common contagion. In the introduction to their article, the researchers cite two recent medical texts on the measles virus that say it infects the upper respiratory epithelium before spreading to the rest of the body. In light of their findings, the investigators say those statements will have to be revised.
The team tested their hypothesis by developing a form of the measles virus that could not enter epithelia because it was made "blind" to the epithelial cell receptor, but could enter lymphatic cells through another receptor. The virus was tested on rhesus monkeys, inoculated via the nasal tract. They developed a rash and lost weight (both symptoms of measles in the species), but follow-up tests showed that the virus did not enter through the airway epithelium, though the lymph system was infected.
Co-authors include Vincent Leonard, Ph.D.; Tanner Miest; and Patricia Devaux, Ph.D., Mayo Clinic; Partrick Sinn, Ph.D., and Paul McCray, Jr., M.D., University of Iowa Carver College of Medicine; Gregory Hodge and Michael B. McChesney, Ph.D., University of California Davis; Numan Oezguen, Ph.D., and Werner Braun, Ph.D., University of Texas Medical Branch, Galveston. Support for the study came from the National Institutes of Health.
Source: Robert Nellis
Mayo Clinic
Quick And Easy Diagnosis For Mitochondrial Disorders
Soon you could be genetically screened for mitochondrial disorders quickly and comprehensively. Research published in BioMed Central's open access journal, Genome Medicine, outlines an innovative clinical diagnostic test for the early identification of a wide range of mitochondrial disorders. Mutations to one of the mitochondrial genes, or to a number of nuclear genes with roles in mitochondrial function, can cause diseases which have very similar symptoms, making them difficult to diagnose and treat.
Researchers from the Seattle Children's Research Institute teamed up with researchers from the Genome Sciences and Pediatrics Departments of the University of Washington to create a molecular diagnostic tool that uses targeted genetic sequencing to screen patient's DNA for variations in 362 genes which have been associated with mitochondrial disease or mitochondrial function. They tested this tool by using it to screen three DNA samples. Two of these samples were taken from patients with mitochondrial disorders, who had been previously diagnosed by traditional sequencing methods, while the third came from a healthy individual selected from the Coriell Repositories HapMap catalogue of human DNA samples. The researchers then assessed the potential impact of all the novel mutations they detected. They found that the new method was able to accurately identify the mutation underlying each patient's condition. The large number of candidate genes examined is likely to increase sensitivity for identifying previously unknown genes responsible for mitochondrial disorders.
"Early and effective diagnosis [of mitochondrial disorders] is crucial for permitting appropriate management and accurate counselling", say lead authors, Jay Shendure and Sihoun Hahn. "Mitochondrial diseases affect as many as 1 in 5000 children; however diagnosis is notoriously difficult due to the huge number of genes potentially responsible for these disorders. For these reasons, some patients may remain undiagnosed and even die of untreated disease" according to Dr Hahn. In addition to providing accurate diagnosis, the large number of genes used in this method allows a large number of potentially harmful mutations to be detected which might otherwise be missed. He adds, "Our study indicates that the use of next generation sequencing technology holds great promise as a tool for screening mitochondrial disorders."
Notes:
Next generation sequence analysis for mitochondrial disorders
Valeria Vasta, Sarah B Ng, Emily H Turner, Jay Shendure and Si Houn Hahn
Genome Medicine (in press)
genomemedicine/
Source:
Charlotte Webber
BioMed Central
Researchers from the Seattle Children's Research Institute teamed up with researchers from the Genome Sciences and Pediatrics Departments of the University of Washington to create a molecular diagnostic tool that uses targeted genetic sequencing to screen patient's DNA for variations in 362 genes which have been associated with mitochondrial disease or mitochondrial function. They tested this tool by using it to screen three DNA samples. Two of these samples were taken from patients with mitochondrial disorders, who had been previously diagnosed by traditional sequencing methods, while the third came from a healthy individual selected from the Coriell Repositories HapMap catalogue of human DNA samples. The researchers then assessed the potential impact of all the novel mutations they detected. They found that the new method was able to accurately identify the mutation underlying each patient's condition. The large number of candidate genes examined is likely to increase sensitivity for identifying previously unknown genes responsible for mitochondrial disorders.
"Early and effective diagnosis [of mitochondrial disorders] is crucial for permitting appropriate management and accurate counselling", say lead authors, Jay Shendure and Sihoun Hahn. "Mitochondrial diseases affect as many as 1 in 5000 children; however diagnosis is notoriously difficult due to the huge number of genes potentially responsible for these disorders. For these reasons, some patients may remain undiagnosed and even die of untreated disease" according to Dr Hahn. In addition to providing accurate diagnosis, the large number of genes used in this method allows a large number of potentially harmful mutations to be detected which might otherwise be missed. He adds, "Our study indicates that the use of next generation sequencing technology holds great promise as a tool for screening mitochondrial disorders."
Notes:
Next generation sequence analysis for mitochondrial disorders
Valeria Vasta, Sarah B Ng, Emily H Turner, Jay Shendure and Si Houn Hahn
Genome Medicine (in press)
genomemedicine/
Source:
Charlotte Webber
BioMed Central
Fruit Flies Can Shed Light On High Cholesterol, Obesity In Humans
How do fruit flies get high cholesterol and become obese? The same way as people do - by eating a diet that's too rich in fats.
More importantly, according to two new studies led by a University of Utah human geneticist, fruit flies use the same molecular mechanisms as humans to help maintain proper balances of cholesterol and a key form of stored fat that contributes to obesity. The findings mean that as researchers try to learn more about the genetic and biological processes through which people regulate cholesterol and fat metabolism, the humble fruit fly, also called Drosophila, can teach humans much about themselves.
"Not a lot is known about these regulatory mechanisms in people," says Carl S. Thummel, Ph.D., professor of human genetics at the U of U School of Medicine and senior author on the two studies. "But we can learn a lot by studying metabolic control in fruit flies and apply what we learn to humans."
High cholesterol and obesity, which affects an estimated 25 percent to 30 percent of the U.S. population, are linked to heart disease, diabetes, and other diseases that take huge tolls on health and add billions of dollars to the nation's medical bills. Understanding the processes that regulate cholesterol and fat in humans could be critical for addressing those health risks in people, Thummel believes.
The two studies identify a nuclear receptor, DHR96, which plays a critical role in regulating the balance or homeostasis of cholesterol and another fat molecule called triacylglycerol (TAG). Nuclear receptors are proteins that sense the presence of chemical compounds within cells. DHR96 corresponds closely to a nuclear receptor in humans, called LXR, that is known to regulate cholesterol levels.
In a study published Dec. 2 in Genes & Development, Thummel and colleagues at the U of U and two Canadian universities show that DHR96 helps regulate cholesterol in fruit flies by binding with this compound. When this binding occurs, it allows DNA to be read, which switches genes on and off that help maintain proper levels of cholesterol, according to Thummel, who also holds an H.A. and Edna Benning Presidential Endowed Chair in Human Genetics.
The researchers used a technique developed by University of Utah biologist Kent Golic, Ph.D., in which they silenced or disabled the DHR96 protein so it couldn't function in fruit flies. They then grew flies in which DHR96 was silenced. Depending on what the fruit flies were fed, lean or fat diets, they had either too little or too much cholesterol. Flies fed too little cholesterol died, while those with too much developed hypercholesterolemia or chronically excessive cholesterol levels. At the same time, flies in which DHR96 functioned normally maintained a proper level of cholesterol.
"When they lacked the DHR96 receptor, the flies were unable to maintain cholesterol homeostasis," Thummel says. "This is similar to what happens in humans who have high cholesterol levels."
Fruit flies are good for such research insights in large part because of the insects' short life span - about 30 days - meaning their development and biological processes are more easily observed than in other, longer-lived models, such as mice. Fruit flies also are easy to manipulate genetically and are less expensive to study compared to mice or other models, according to Thummel. In addition, the mechanisms by which metabolism is controlled in fruit flies are very similar to those in mice or humans.
"We can do a lot more mechanistic studies in a fly than are possible in a mouse," he says. "We can study metabolic pathways faster and more in-depth."
Along with its important role in helping to maintain proper levels of cholesterol, DHR96 also plays an integral part in regulating dietary fat metabolism, Thummel and another U of U researcher report in a Dec. 2 study in Cell Metabolism.
In flies in which DHR96 was silenced, TAG levels were markedly reduced in the intestine, making the insects resistant to diet-induced obesity. But when DHR96 was overexpressed, meaning there were higher levels of the protein, it led to increased TAG levels and made the flies more prone to being overweight. These findings show that DHR96 is required for breaking down dietary fat in the intestine of fruit flies and provide insight into how dietary fat metabolism is regulated in Drosophila.
"This nuclear receptor plays a major role in sensing and regulating cholesterol and TAG uptake in the intestine in fruit flies," Thummel says. "It functions similarly to the way LXR functions in humans, although we have a relatively poor understanding about how LXR controls these pathways."
In his future studies, Thummel intends to learn more about how DHR96 regulates metabolism by studying the functions of the genes that it controls.
Source: Phil Sahm
University of Utah Health Sciences
More importantly, according to two new studies led by a University of Utah human geneticist, fruit flies use the same molecular mechanisms as humans to help maintain proper balances of cholesterol and a key form of stored fat that contributes to obesity. The findings mean that as researchers try to learn more about the genetic and biological processes through which people regulate cholesterol and fat metabolism, the humble fruit fly, also called Drosophila, can teach humans much about themselves.
"Not a lot is known about these regulatory mechanisms in people," says Carl S. Thummel, Ph.D., professor of human genetics at the U of U School of Medicine and senior author on the two studies. "But we can learn a lot by studying metabolic control in fruit flies and apply what we learn to humans."
High cholesterol and obesity, which affects an estimated 25 percent to 30 percent of the U.S. population, are linked to heart disease, diabetes, and other diseases that take huge tolls on health and add billions of dollars to the nation's medical bills. Understanding the processes that regulate cholesterol and fat in humans could be critical for addressing those health risks in people, Thummel believes.
The two studies identify a nuclear receptor, DHR96, which plays a critical role in regulating the balance or homeostasis of cholesterol and another fat molecule called triacylglycerol (TAG). Nuclear receptors are proteins that sense the presence of chemical compounds within cells. DHR96 corresponds closely to a nuclear receptor in humans, called LXR, that is known to regulate cholesterol levels.
In a study published Dec. 2 in Genes & Development, Thummel and colleagues at the U of U and two Canadian universities show that DHR96 helps regulate cholesterol in fruit flies by binding with this compound. When this binding occurs, it allows DNA to be read, which switches genes on and off that help maintain proper levels of cholesterol, according to Thummel, who also holds an H.A. and Edna Benning Presidential Endowed Chair in Human Genetics.
The researchers used a technique developed by University of Utah biologist Kent Golic, Ph.D., in which they silenced or disabled the DHR96 protein so it couldn't function in fruit flies. They then grew flies in which DHR96 was silenced. Depending on what the fruit flies were fed, lean or fat diets, they had either too little or too much cholesterol. Flies fed too little cholesterol died, while those with too much developed hypercholesterolemia or chronically excessive cholesterol levels. At the same time, flies in which DHR96 functioned normally maintained a proper level of cholesterol.
"When they lacked the DHR96 receptor, the flies were unable to maintain cholesterol homeostasis," Thummel says. "This is similar to what happens in humans who have high cholesterol levels."
Fruit flies are good for such research insights in large part because of the insects' short life span - about 30 days - meaning their development and biological processes are more easily observed than in other, longer-lived models, such as mice. Fruit flies also are easy to manipulate genetically and are less expensive to study compared to mice or other models, according to Thummel. In addition, the mechanisms by which metabolism is controlled in fruit flies are very similar to those in mice or humans.
"We can do a lot more mechanistic studies in a fly than are possible in a mouse," he says. "We can study metabolic pathways faster and more in-depth."
Along with its important role in helping to maintain proper levels of cholesterol, DHR96 also plays an integral part in regulating dietary fat metabolism, Thummel and another U of U researcher report in a Dec. 2 study in Cell Metabolism.
In flies in which DHR96 was silenced, TAG levels were markedly reduced in the intestine, making the insects resistant to diet-induced obesity. But when DHR96 was overexpressed, meaning there were higher levels of the protein, it led to increased TAG levels and made the flies more prone to being overweight. These findings show that DHR96 is required for breaking down dietary fat in the intestine of fruit flies and provide insight into how dietary fat metabolism is regulated in Drosophila.
"This nuclear receptor plays a major role in sensing and regulating cholesterol and TAG uptake in the intestine in fruit flies," Thummel says. "It functions similarly to the way LXR functions in humans, although we have a relatively poor understanding about how LXR controls these pathways."
In his future studies, Thummel intends to learn more about how DHR96 regulates metabolism by studying the functions of the genes that it controls.
Source: Phil Sahm
University of Utah Health Sciences
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