Scientists studying biology and geography may seem worlds apart, but together they have answered a question that has defied explanation about the spread of the HIV-1 epidemic in Africa.
Writing in the September issue of AIDS, a research team led by scientists at the University of Florida explained why two subtypes of HIV-1 - the virus that causes acquired immunodeficiency syndrome, or AIDS - held steady at relatively low levels for more than 50 years in west central Africa before erupting as an epidemic in east Africa in the 1970s.
Essentially, the explanation for the HIV explosion - obscured until now - involves the relative ease with which people can travel from city to city in east Africa as opposed to the difficulties faced by people living in the population centers of the Democratic Republic of Congo, the point where HIV emerged from west central Africa in its spread to the east.
Later, as the epidemic raged in the east, cities in the Democratic Republic of Congo - a vast country almost as big as all of Western Europe - remained disconnected and isolated, explaining why the virus affected only about 5 percent of the country's population, a level that has not changed much since the 1950s.
"We live in a world that is more interconnected every day, and we have all seen how pathogens such as HIV or the swine flu virus can arise in a remote area of the planet and quickly become a global threat," said Marco Salemi, an assistant professor of pathology, immunology, and laboratory medicine at the UF College of Medicine and senior author of the study. "Understanding the factors that can lead to a full-scale pandemic is essential to protect our species from emerging dangers."
Investigators used databases, including GenBank from the National Center for Biotechnology Information, as well as actual DNA samples, including samples recently collected in Uganda - the vicinity where HIV entered east Africa - to follow the virus' molecular footprints since its emergence in the 1920s.
"HIV mutates rapidly," said Rebecca Gray, a postdoctoral associate in the department of pathology, immunology and laboratory medicine. "This is a successful strategy for the virus, because it evolves quickly and develops drug resistance. But we can use these changes in the genome to follow it over time and develop a history of its progress."
Researchers wanted to know why, the virus smoldered during the 1950s and `60s, before spreading like wildfire through east Africa in the 1970s.
A fateful piece of the puzzle came in the form of geographic information system data, which uses satellite imagery and painstakingly takes into account the availability and navigability of roads between population centers, transportation modes, elevation, climate, terrain and other factors that influence travel.
"We were able to use geographic data to interpret the genetic data," said Andrew J. Tatem, Ph.D., an assistant professor of geography in the College of Liberal Arts and Sciences and a member of UF's Emerging Pathogens Institute. "Genetic data showed once HIV moved out of the Democratic Republic of Congo, it expanded fast and moved rapidly across Uganda, Kenya and Tanzania, all while staying at low levels in the DRC. What was happening was the virus was circulating at stable levels in the urban centers of the DRC, but these centers were isolated. Once it hit east Africa, connectivity between population centers combined with better quality transportation networks, and higher rates of human movement caused HIV to spread exponentially."
HIV was prevalent in about 15 percent of the population in Kenya in 1997, although it has since dropped to about 7 percent, according to the Kaiser Family Foundation. As of 2007, an estimated 22 million people were living with HIV/AIDS in sub-Saharan Africa. About 1.1 million Americans have HIV or AIDS, and an estimated 5.1 million people in India are HIV-positive. In Eastern Europe, HIV infections more than doubled from 420,000 in 1998 to 1 million in 2001.
"If we can predict the specific routes of an epidemic, we can find the geographic regions more at risk and target these areas with medical intervention and strategies for prevention," Salemi said. "In terms of health-care applications, coupling genetic analysis with geographic information systems can give us a powerful tool to understand the spread of pathogens and contain emerging epidemics."
Working with Maureen M. Goodenow, Ph.D., the Stephany W. Holloway university chair for AIDS research at the UF College of Medicine, UF researchers collaborated with an array of scientists hailing from the National Institute of Allergy and Infectious Diseases, the Rakai Health Sciences Program and Makerere University of Uganda, and the Johns Hopkins University. They refer to the combination of techniques that led to the discovery as "landscape phylodynamics."
"It is the first study that has given us a clear picture of epidemic history of HIV in east Africa, including the geographic routes and the time scale that it occurred," said Oliver Pybus, Ph.D., a researcher in the department of zoology at Oxford University who did not participate in the study. "Genetic analysis of the HIV genome provides the family tree of the virus, combined with spatial analysis of high-resolution data of land use, topology and other factors. There is a huge potential in doing that kind of analysis, but it requires a rare combination of specialists in different fields to come together."
Source:
John Pastor
University of Florida
воскресенье, 13 ноября 2011 г.
четверг, 10 ноября 2011 г.
New Potential To Treat Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is defined by emphysema and/or chronic bronchitis. It destroys the normal architecture of the lung and inhibits the mechanical aspects of breathing, which prevents necessary gas exchange. Patients suffer from coughing fits, wheezing, and increased incidence of lung infections. These symptoms are associated with changes in the architecture of the lung. The air sacs, which usually inflate with air during breathing as they loose their elasticity, becoming rigid and unable to inflate. The lung becomes inflamed and increases its mucus production, which further inhibits gas exchange, and prevents the patient's ability to be physically active.
Although COPD is a leading cause of morbidity and mortality worldwide, there is currently no cure for the disease. Providing patients with concentrated oxygen therapy and instruction on breathing techniques increases survival rates.
In a new study published in Disease Models & Mechanisms (DMM), dmm.biologists, collaborative findings by European researchers demonstrate that an antioxidant protein, sestrin, triggers molecular pathways that induce some of the critical lung changes associated with COPD. By genetically inactivating this protein, they were able to improve the elastic features of the lung in a mouse model of emphysema. These authors believe that by inhibiting the antioxidant sestrin protein, they prevent the accelerated degradation of elastic fibers within the lung. This suggests that patients with COPD could benefit from treatment with drugs that block sestrin function.
Although sestrin is an antioxidant protein, the authors found that this characteristic of the protein is not likely to influence its effects on COPD progression in the lung. The negative effects of sestrin on lung elasticity results from its suppression of genes whose products maintain elastin. Elastin makes the lung flexible so that it can expand and contract. Without elastin fibers, the lung becomes rigid and increasingly unable to provide for gas exchange.
The report, titled 'Inactivation of sestrin 2 induces TGF-beta signalling and partially rescues pulmonary emphysema in a mouse model of COPD' was Frank Wempe, Silke De-Zolt, Thorsten Bangsow and Harald von Melchner at the University of Frankfurt Medical School, Nirmal Parajuli, Rio Dumitrascu and Norbert Weismann at the University of Giessen Lung Center, Anja Sterner-Kock at the Institute of Veterinary Pathology in Germany and Katri Koli and Jorma Keski-Oja at the University of Helsinki in Finland. The study will be published in the March/April issue of 2010 (Vol 3/Issue 3-4) of the research journal, Disease Models & Mechanisms (DMM), published by The Company of Biologists, a non-profit based in Cambridge, UK.
Source:
Kristy Kain
The Company of Biologists
Although COPD is a leading cause of morbidity and mortality worldwide, there is currently no cure for the disease. Providing patients with concentrated oxygen therapy and instruction on breathing techniques increases survival rates.
In a new study published in Disease Models & Mechanisms (DMM), dmm.biologists, collaborative findings by European researchers demonstrate that an antioxidant protein, sestrin, triggers molecular pathways that induce some of the critical lung changes associated with COPD. By genetically inactivating this protein, they were able to improve the elastic features of the lung in a mouse model of emphysema. These authors believe that by inhibiting the antioxidant sestrin protein, they prevent the accelerated degradation of elastic fibers within the lung. This suggests that patients with COPD could benefit from treatment with drugs that block sestrin function.
Although sestrin is an antioxidant protein, the authors found that this characteristic of the protein is not likely to influence its effects on COPD progression in the lung. The negative effects of sestrin on lung elasticity results from its suppression of genes whose products maintain elastin. Elastin makes the lung flexible so that it can expand and contract. Without elastin fibers, the lung becomes rigid and increasingly unable to provide for gas exchange.
The report, titled 'Inactivation of sestrin 2 induces TGF-beta signalling and partially rescues pulmonary emphysema in a mouse model of COPD' was Frank Wempe, Silke De-Zolt, Thorsten Bangsow and Harald von Melchner at the University of Frankfurt Medical School, Nirmal Parajuli, Rio Dumitrascu and Norbert Weismann at the University of Giessen Lung Center, Anja Sterner-Kock at the Institute of Veterinary Pathology in Germany and Katri Koli and Jorma Keski-Oja at the University of Helsinki in Finland. The study will be published in the March/April issue of 2010 (Vol 3/Issue 3-4) of the research journal, Disease Models & Mechanisms (DMM), published by The Company of Biologists, a non-profit based in Cambridge, UK.
Source:
Kristy Kain
The Company of Biologists
понедельник, 7 ноября 2011 г.
Transfer Of Biological Electron Captured In Real Time
Two research teams led by Dr. Michael Verkhovsky and Prof. Marten Wikstrom of the Institute of Biotechnology of the University of Helsinki have for the first time succeeded in monitoring electron transfer by Complex I in real time. In the future, this work might, for example, have medical relevance, because most of the maternally inherited so-called mitochondrial diseases are caused by dysfunction of Complex I.
This achievement required developing and building of a special device by which the enzyme-catalysed electron transfer could be captured at different time points by stopping the reaction at liquid nitrogen temperatures, on a microsecond (one millionth of a second) time scale. The electrons are very small elementary particles, which is why their transfer is very fast. This work is published this week in the prestigious journal of the American National Academy of Sciences (Proc. Natl. Acad. Sci.). The results give certain hints of the function of Complex I at the molecular level.
Electron transfer is central to many chemical reactions in the cell. It has particular functional importance in cell respiration, which in eukaryotes takes place in the inner mitochondrial membrane, and in the cell membrane of prokaryotes. In cellular respiration molecules stemming from food are oxidised to carbon dioxide, and the electrons liberated in the process are "fed" into the so-called respiratory chain, which consists of three successive membrane-bound enzyme complexes, finally to react with the oxygen we breathe, which is reduced to water using these electrons.
The purpose of electron transfer in cellular respiration is to release the major part of the energy of foodstuffs and to conserve it in a suitable form, ATP (adenosine triphosphate), which the cell may use in its energy-requiring reactions (e.g. biosynthesis, active transport, mechanical work), which are essential e.g. during fetal development and growth, in neural and kidney function, muscle contraction, etc. The energy captured in cellular respiration is transduced to ATP in two phases. The role of the respiratory chain is to couple electron transfer to the translocation of positively charged protons across the membrane, so that the mitochondrial membrane (or the cell membrane in bacteria) becomes electrically polarised, just like charging up a battery. In the second phase, the voltage difference of the battery is used to drive the protons back across the membrane, coupled to the synthesis of ATP by very special molecular machinery.
The first enzyme complex of the respiratory chain is called Complex I. High-energy electrons are fed into this complex in the form of a reduced coenzyme, NADH (nicotinamide adenine dinucleotide), which is oxidised to NAD+ having donated its two electrons. After this, the electrons are transferred along several protein-bound iron/sulphur centres in Complex I until they reach their destination, a molecule of ubiquinone, which is thus reduced to ubiquinol. This reaction, as catalysed by Complex I, is linked to proton translocation across the membrane and thus leads to "charging the battery". At a later stage ubiquinol donates its electrons further in the respiratory chain (ultimately to oxygen), by which it is oxidised back to ubiquinone to allow continuation of Complex I function.
Source: Marten Wikstrom
University of Helsinki
This achievement required developing and building of a special device by which the enzyme-catalysed electron transfer could be captured at different time points by stopping the reaction at liquid nitrogen temperatures, on a microsecond (one millionth of a second) time scale. The electrons are very small elementary particles, which is why their transfer is very fast. This work is published this week in the prestigious journal of the American National Academy of Sciences (Proc. Natl. Acad. Sci.). The results give certain hints of the function of Complex I at the molecular level.
Electron transfer is central to many chemical reactions in the cell. It has particular functional importance in cell respiration, which in eukaryotes takes place in the inner mitochondrial membrane, and in the cell membrane of prokaryotes. In cellular respiration molecules stemming from food are oxidised to carbon dioxide, and the electrons liberated in the process are "fed" into the so-called respiratory chain, which consists of three successive membrane-bound enzyme complexes, finally to react with the oxygen we breathe, which is reduced to water using these electrons.
The purpose of electron transfer in cellular respiration is to release the major part of the energy of foodstuffs and to conserve it in a suitable form, ATP (adenosine triphosphate), which the cell may use in its energy-requiring reactions (e.g. biosynthesis, active transport, mechanical work), which are essential e.g. during fetal development and growth, in neural and kidney function, muscle contraction, etc. The energy captured in cellular respiration is transduced to ATP in two phases. The role of the respiratory chain is to couple electron transfer to the translocation of positively charged protons across the membrane, so that the mitochondrial membrane (or the cell membrane in bacteria) becomes electrically polarised, just like charging up a battery. In the second phase, the voltage difference of the battery is used to drive the protons back across the membrane, coupled to the synthesis of ATP by very special molecular machinery.
The first enzyme complex of the respiratory chain is called Complex I. High-energy electrons are fed into this complex in the form of a reduced coenzyme, NADH (nicotinamide adenine dinucleotide), which is oxidised to NAD+ having donated its two electrons. After this, the electrons are transferred along several protein-bound iron/sulphur centres in Complex I until they reach their destination, a molecule of ubiquinone, which is thus reduced to ubiquinol. This reaction, as catalysed by Complex I, is linked to proton translocation across the membrane and thus leads to "charging the battery". At a later stage ubiquinol donates its electrons further in the respiratory chain (ultimately to oxygen), by which it is oxidised back to ubiquinone to allow continuation of Complex I function.
Source: Marten Wikstrom
University of Helsinki
пятница, 4 ноября 2011 г.
Novel Genomic Alterations Not Seen Before Revealed By Melanoma Transcriptome
Melanoma, the most deadly form of skin cancer, afflicts more than 50,000 people in the United States annually and the incidence rate continues to rise. In a study published online in Genome Research (genome), scientists have delved deeper than ever before into the RNA world of the melanoma tumor and identified genomic alterations that could play a role in the disease.
The latest high-throughput DNA sequencing technologies are ushering in a new era of discovery in cancer genomics that promises to reveal molecular mechanisms of the disease. Beyond cataloging the genetic mutations present in tumors, application of high-throughput sequencing to the RNA "transcriptome" can uncover other genomic alterations missed by DNA sequencing and identify potential targets for therapy.
For example, two adjacent genes can be transcribed together in a single "chimeric" RNA transcript. This RNA message is then translated into a protein with an altered or new function. In addition, rearrangements of the genome can cut and paste genes together, creating "gene fusions." These events occur in normal cells, but they also have the potential to cause disease. Recently these alterations have been detected a few tumor types, and it is very likely that more will be found in other cancers such as melanoma.
To capture the full spectrum of genomic alterations present in the expressed genes of melanoma, a team of researchers in the United States and Switzerland performed an integrative analysis of melanoma tumors using RNA sequencing and structural genomic data. The group identified 11 novel gene fusions involving several common cancer-related genes, and 12 cases of chimeric transcripts. "This is the first direct evidence for these types of genetic alterations in melanoma," said Michael Berger, a research scientist at the Broad Institute and first author of the report.
A particularly interesting finding was that a recurrent chimeric transcript was found involving the CDK2 gene, known to be required for melanoma cell proliferation. The authors suggest that the functional role of the aberrant CDK2 transcript is an attractive target of future investigation. In addition to novel gene fusions and chimeric transcripts, the research group also identified many other alterations in the melanoma tumors, including novel mutations, alternative splice variants, and expression changes.
Berger noted that this type of cancer transcriptome analysis is very appealing, as it complements common DNA-based genomic sequencing and characterization approaches to capture a more complete picture of the cancer genome. "Such studies should help reveal the cancer RNA world," added Levi Garraway, an Assistant Professor at Harvard Medical School/Dana-Farber Cancer Institute and the study's senior author, "thereby nominating many new genetic targets relevant to tumor biology and drug discovery."
Scientists from the Broad Institute of MIT and Harvard (Cambridge, MA), the Dana-Farber Cancer Institute (Boston, MA), the University of Zurich (Zurich, Switzerland), Massachusetts General Hospital (Boston, MA), the Massachusetts Institute of Technology (Cambridge, MA) and Harvard Medical School (Boston, MA) contributed to this study.
This work was supported by the Starr Cancer Consortium, the Melanoma Research Alliance, the Novartis Institutes of Biomedical Research, and the Adelson Medical Research Foundation.
Source:
Peggy Calicchia
Cold Spring Harbor Laboratory
The latest high-throughput DNA sequencing technologies are ushering in a new era of discovery in cancer genomics that promises to reveal molecular mechanisms of the disease. Beyond cataloging the genetic mutations present in tumors, application of high-throughput sequencing to the RNA "transcriptome" can uncover other genomic alterations missed by DNA sequencing and identify potential targets for therapy.
For example, two adjacent genes can be transcribed together in a single "chimeric" RNA transcript. This RNA message is then translated into a protein with an altered or new function. In addition, rearrangements of the genome can cut and paste genes together, creating "gene fusions." These events occur in normal cells, but they also have the potential to cause disease. Recently these alterations have been detected a few tumor types, and it is very likely that more will be found in other cancers such as melanoma.
To capture the full spectrum of genomic alterations present in the expressed genes of melanoma, a team of researchers in the United States and Switzerland performed an integrative analysis of melanoma tumors using RNA sequencing and structural genomic data. The group identified 11 novel gene fusions involving several common cancer-related genes, and 12 cases of chimeric transcripts. "This is the first direct evidence for these types of genetic alterations in melanoma," said Michael Berger, a research scientist at the Broad Institute and first author of the report.
A particularly interesting finding was that a recurrent chimeric transcript was found involving the CDK2 gene, known to be required for melanoma cell proliferation. The authors suggest that the functional role of the aberrant CDK2 transcript is an attractive target of future investigation. In addition to novel gene fusions and chimeric transcripts, the research group also identified many other alterations in the melanoma tumors, including novel mutations, alternative splice variants, and expression changes.
Berger noted that this type of cancer transcriptome analysis is very appealing, as it complements common DNA-based genomic sequencing and characterization approaches to capture a more complete picture of the cancer genome. "Such studies should help reveal the cancer RNA world," added Levi Garraway, an Assistant Professor at Harvard Medical School/Dana-Farber Cancer Institute and the study's senior author, "thereby nominating many new genetic targets relevant to tumor biology and drug discovery."
Scientists from the Broad Institute of MIT and Harvard (Cambridge, MA), the Dana-Farber Cancer Institute (Boston, MA), the University of Zurich (Zurich, Switzerland), Massachusetts General Hospital (Boston, MA), the Massachusetts Institute of Technology (Cambridge, MA) and Harvard Medical School (Boston, MA) contributed to this study.
This work was supported by the Starr Cancer Consortium, the Melanoma Research Alliance, the Novartis Institutes of Biomedical Research, and the Adelson Medical Research Foundation.
Source:
Peggy Calicchia
Cold Spring Harbor Laboratory
вторник, 1 ноября 2011 г.
CRi Oosight Imaging System A Key To Breakthrough Gene Replacement Method With Potential To Prevent Inherited Mitochondrial Diseases
U.S. researchers using CRi's Oosight(TM) imaging system have developed a gene transfer technique that has potential to prevent inherited diseases passed on from mothers to their children through mutated DNA in cell mitochondria. The research, which demonstrated the technique in rhesus monkeys, appears in the Aug. 26 issue of the journal Nature.
The group, headed by Dr. Shoukhrat Mitalipov of the Oregon National Primate Research Center and the Oregon Stem Cell Center, extracted the nuclear DNA from the mother's egg, guided by the Oosight system, and transplanted it into another egg that had the nucleus removed. The technique allowed the mother to pass along her nuclear genetic material to her offspring without her mitochondrial DNA. The eggs were fertilized and transplanted into surrogate mothers, resulting in the birth of four apparently healthy monkeys. Defects in DNA of mitochondria, the cell's "power plants," are associated with a wide range of human diseases.
The Oosight system solved a key problem in avoiding damage to the nuclear DNA during the transfer procedure by providing a non-invasive imaging technique for visualizing the genetic material. Traditional visualization methods employ a stain or involve exposure to ultraviolet light, either of which can damage DNA. The Oregon team had used the Oosight system in previous research, published in Nature in 2007, that provided a foundation for the current study. In that research, they cloned rhesus monkey embryos and used them to create embryonic stem cells.
The Oosight system uses polarized light to generate high-contrast, real-time images of biological features such as the spindle apparatus housing the chromosomes and other filamentous structures within the egg, such as the multi-layer zona pellucida, without the addition of toxic stains or labels, while simultaneously generating useful quantitative data of their structural composition. Two of the four offspring, Spindler and Spindy, were named after the spindle, which is what the Oosight system is used to visualize.
"This study underscores the potential of the Oosight system to advance reproductive medicine and highlights the enabling capabilities or our polarized light technology," said George Abe, president and CEO of CRi.
"With this advance, the Oosight imaging system, which is already widely used in fertility clinics, has offered new insights and possibilities into reproductive health and medicine," said Gary Borisy, director and CEO of the Marine Biological Laboratory (MBL) in Woods Hole, MA. The Oosight system is based on imaging technology originally developed by MBL scientists Rudolf Oldenbourg and Michael Shribek, working in collaboration with David Keefe, M.D., of the University of South Florida College of Medicine.
In in vitro fertilization (IVF) the Oosight system is used as an aid to intracytosplasmic sperm injection (ICSI). The system not only provides assurance that the genetic material is not damaged by the injection needle, but it can also be used as a measurement tool to assess egg viability in both fresh and frozen eggs. Data show that an egg with a weak or malformed spindle and inner layer zona as measured with the system is much less likely to result in pregnancy.
Other scientists have welcomed news of the advance. Mitochondria-expert Douglas Wallace of the University of California, Irvine, said "results were exciting" and the technique is "potentially very interesting." Although he did caution that "there are safety issues that are going to need to be addressed before one could think about it in humans."
The Nature article reported that 15 embryos were transplanted into nine surrogate mothers; three became pregnant, one with twins, and four offspring were born (only three of these offspring have been reported in the Nature paper) The success rate is similar to that of conventional in vitro fertilization.
Cambridge Research & Instrumentation, Inc. (CRi) is a leader in biomedical imaging, and is dedicated to providing comprehensive solutions that analyze disease-specific information from biological and clinical samples in the combined physiological, morphological, and biochemical context of intact tissues and organisms for a variety of applications. With over 80 patents pending and issued, CRi's award-winning innovations are being utilized around the world to enable our customers to perform leading research and provide better healthcare.
Source: Cambridge Research & Instrumentation, Inc
The group, headed by Dr. Shoukhrat Mitalipov of the Oregon National Primate Research Center and the Oregon Stem Cell Center, extracted the nuclear DNA from the mother's egg, guided by the Oosight system, and transplanted it into another egg that had the nucleus removed. The technique allowed the mother to pass along her nuclear genetic material to her offspring without her mitochondrial DNA. The eggs were fertilized and transplanted into surrogate mothers, resulting in the birth of four apparently healthy monkeys. Defects in DNA of mitochondria, the cell's "power plants," are associated with a wide range of human diseases.
The Oosight system solved a key problem in avoiding damage to the nuclear DNA during the transfer procedure by providing a non-invasive imaging technique for visualizing the genetic material. Traditional visualization methods employ a stain or involve exposure to ultraviolet light, either of which can damage DNA. The Oregon team had used the Oosight system in previous research, published in Nature in 2007, that provided a foundation for the current study. In that research, they cloned rhesus monkey embryos and used them to create embryonic stem cells.
The Oosight system uses polarized light to generate high-contrast, real-time images of biological features such as the spindle apparatus housing the chromosomes and other filamentous structures within the egg, such as the multi-layer zona pellucida, without the addition of toxic stains or labels, while simultaneously generating useful quantitative data of their structural composition. Two of the four offspring, Spindler and Spindy, were named after the spindle, which is what the Oosight system is used to visualize.
"This study underscores the potential of the Oosight system to advance reproductive medicine and highlights the enabling capabilities or our polarized light technology," said George Abe, president and CEO of CRi.
"With this advance, the Oosight imaging system, which is already widely used in fertility clinics, has offered new insights and possibilities into reproductive health and medicine," said Gary Borisy, director and CEO of the Marine Biological Laboratory (MBL) in Woods Hole, MA. The Oosight system is based on imaging technology originally developed by MBL scientists Rudolf Oldenbourg and Michael Shribek, working in collaboration with David Keefe, M.D., of the University of South Florida College of Medicine.
In in vitro fertilization (IVF) the Oosight system is used as an aid to intracytosplasmic sperm injection (ICSI). The system not only provides assurance that the genetic material is not damaged by the injection needle, but it can also be used as a measurement tool to assess egg viability in both fresh and frozen eggs. Data show that an egg with a weak or malformed spindle and inner layer zona as measured with the system is much less likely to result in pregnancy.
Other scientists have welcomed news of the advance. Mitochondria-expert Douglas Wallace of the University of California, Irvine, said "results were exciting" and the technique is "potentially very interesting." Although he did caution that "there are safety issues that are going to need to be addressed before one could think about it in humans."
The Nature article reported that 15 embryos were transplanted into nine surrogate mothers; three became pregnant, one with twins, and four offspring were born (only three of these offspring have been reported in the Nature paper) The success rate is similar to that of conventional in vitro fertilization.
Cambridge Research & Instrumentation, Inc. (CRi) is a leader in biomedical imaging, and is dedicated to providing comprehensive solutions that analyze disease-specific information from biological and clinical samples in the combined physiological, morphological, and biochemical context of intact tissues and organisms for a variety of applications. With over 80 patents pending and issued, CRi's award-winning innovations are being utilized around the world to enable our customers to perform leading research and provide better healthcare.
Source: Cambridge Research & Instrumentation, Inc
суббота, 29 октября 2011 г.
DNA Conclusive Yet Still Controversial, Carnegie Mellon Professor Says
Although the odds that DNA evidence found at a crime scene will match by chance the DNA of a person who was not there are infinitesimal, controversy continues about DNA identification and its use in criminal investigations, says Carnegie Mellon University Statistics Professor Kathryn Roeder. Roeder will present a historical overview of the use of DNA identification on Tuesday, April 25, during the Annual Symposia of the National Academy of Sciences in Washington, D.C.
Almost 28,000 cases nationwide have been prosecuted with help from the FBI's data bank of DNA profiles, while at least 170 people have seen their convictions overturned on appeal thanks to DNA evidence. Nonetheless, the use of DNA evidence in appeals has been impeded by political considerations and legal uncertainties, according to Roeder. "After all other legal avenues have been tried, the hope of any innocent person is that biological evidence from their cases still exists and can be subjected to DNA testing. But DNA's value to free the wrongfully convicted can be attained only if political leaders allow its full application," Roeder said. "Thousands currently await the evaluation of their cases."
In the early phases, technical disputes among scientists impeded the use of DNA evidence, Roeder said. One of the earliest controversies to erupt over DNA testing was the magnitude of genetic diversity among people of different ancestry.
Some controversy remains concerning the so-called "cold hit" technique, in which investigators search a DNA database to find a match of DNA found at a crime scene and then collect other evidence to build their case -- as opposed to first identifying a suspect through other evidence and then using DNA to confirm their case. Some critics claimed that this practice could snag an innocent person, but Roeder has demonstrated through her own research that the likelihood of a false hit are miniscule -- in one case, for example, it was about 1 in 26 quintillion, a probability so slight it needn't be shared with juries, Roeder said.
"The jury can't handle such small numbers. We would do them a service to simply tell them it matches or it doesn't match," Roeder said.
Roeder began her career as a biologist, and much of her current research is focused on using statistical tools to understand the workings of the human genome and the nature of inherited diseases. She is a member of the Bioinformatics and Statistics Genetics Group, which includes researchers in the departments of Statistics and Biological Sciences at Carnegie Mellon, and the departments of Psychiatry and Human Genetics at the University of Pittsburgh. The group's primary research goal is to develop statistical tools for finding associations between patterns of genetic variation and complex disease.
Contact: Jonathan Potts
Carnegie Mellon University
Almost 28,000 cases nationwide have been prosecuted with help from the FBI's data bank of DNA profiles, while at least 170 people have seen their convictions overturned on appeal thanks to DNA evidence. Nonetheless, the use of DNA evidence in appeals has been impeded by political considerations and legal uncertainties, according to Roeder. "After all other legal avenues have been tried, the hope of any innocent person is that biological evidence from their cases still exists and can be subjected to DNA testing. But DNA's value to free the wrongfully convicted can be attained only if political leaders allow its full application," Roeder said. "Thousands currently await the evaluation of their cases."
In the early phases, technical disputes among scientists impeded the use of DNA evidence, Roeder said. One of the earliest controversies to erupt over DNA testing was the magnitude of genetic diversity among people of different ancestry.
Some controversy remains concerning the so-called "cold hit" technique, in which investigators search a DNA database to find a match of DNA found at a crime scene and then collect other evidence to build their case -- as opposed to first identifying a suspect through other evidence and then using DNA to confirm their case. Some critics claimed that this practice could snag an innocent person, but Roeder has demonstrated through her own research that the likelihood of a false hit are miniscule -- in one case, for example, it was about 1 in 26 quintillion, a probability so slight it needn't be shared with juries, Roeder said.
"The jury can't handle such small numbers. We would do them a service to simply tell them it matches or it doesn't match," Roeder said.
Roeder began her career as a biologist, and much of her current research is focused on using statistical tools to understand the workings of the human genome and the nature of inherited diseases. She is a member of the Bioinformatics and Statistics Genetics Group, which includes researchers in the departments of Statistics and Biological Sciences at Carnegie Mellon, and the departments of Psychiatry and Human Genetics at the University of Pittsburgh. The group's primary research goal is to develop statistical tools for finding associations between patterns of genetic variation and complex disease.
Contact: Jonathan Potts
Carnegie Mellon University
среда, 26 октября 2011 г.
Genome Connects The Dots Between Amphimedon, Animal Descendants
The simple sponge can reveal much about life on Earth. Researchers who have sequenced the genome of one Down Under inhabitant are learning just how common those roots are.
In a paper published online this week in the journal Nature, Rice University's Nicholas Putnam is among a group of scientists who have established a draft genome sequence for Amphimedon queenslandica, a sponge found off the coast of Australia. The genome is helping evolutionary biologists connect the dots as they look for DNA sequences shared by metazoans, or multicelled animals.
Sponges are an ancient group, with fossils dating back at least 650 million years. They are thought to have been the first group of animals to branch from all the others. Therefore, genes shared by sponges and other animals must have been present in the common ancestor of all metazoans. This ancestor would have evolved mechanisms to coordinate cell division, growth, specialization, adhesion and death; this suggests that early sponges already had a developmental set of tools similar to those in metazoans today, said Putnam, an assistant professor of ecology and evolutionary biology.
"What's exciting is the new things we're learning about animal evolution," said Putnam, who got involved with the project while working at the Department of Energy's Joint Genome Institute in 2006. "For example, sponges have embryos, and having the genome helps us look at how they develop and make specific connections to developmental pathways in other animals.
"It's the kind of thing that will lead to a much clearer understanding of what the very first metazoans looked like," he said.
That distant ancestor may well have looked like a sponge. For the paper, Putnam helped compare Amphimedon's draft genome with 13 other complete animal genomes, including a selection of invertebrates, as well as a choanoflagellate. The researchers wrote of a "striking conservation of gene structure and genome organization" that is common to all. "We can now say that the large-scale patterns of genome organization we've seen conserved in other animal groups come from the very root of the animal tree," Putnam said.
The challenge ahead is learning what they do. "The focus of my research is to understand whether patterns that have been around for a billion years have some particular functions -- or if they're hanging around because not enough time has gone by to erase them."
What's missing is also interesting, he said. The ancestral patterns of genome organization common to other creatures is absent from certain arthropods -- invertebrates that include the likes of centipedes and lobsters -- and nematodes. "If the missing pattern is neutral, you'd say that somewhere along the history of those groups, the rate of (evolutionary) change sped up enough to break the connection," Putnam said. "If it's functional, then somehow those groups overcame whatever constraint is on it in other lineages."
Also puzzling is that while Amphimedon shares key developmental genes with a diverse set of metazoans, its basic structure hasn't changed in 600 million years. Given the same roots, researchers wonder why it didn't evolve more radically, and they are working to identify the differences that gave rise to, say, nerve cells in other creatures but not sponges.
Unlocking the basic mechanisms of multicellularity may also help researchers understand what happens when those mechanisms go wrong and lead to cancer and autoimmune disorders.
Notes:
The paper's senior authors are Daniel Rokhsar of the University of California, Berkeley, and Bernard Degnan of the University of Queensland in Australia.
The work was funded by the Australian Research Council, the Department of Energy Joint Genome Institute, Harvey Karp, the National Science Foundation, the National Institutes of Health/National Human Genome Research Institute, the University of Queensland Postdoctoral Fellowship, the Sars International Center for Marine Molecular Biology, Deutsche Forschungsgemeinschaft, Agricultural and Natural Resources/University of California, the French National Center for Scientific Research, the Gordon and Betty Moore Foundation and Richard Melmon.
Source:
David Ruth
Rice University
In a paper published online this week in the journal Nature, Rice University's Nicholas Putnam is among a group of scientists who have established a draft genome sequence for Amphimedon queenslandica, a sponge found off the coast of Australia. The genome is helping evolutionary biologists connect the dots as they look for DNA sequences shared by metazoans, or multicelled animals.
Sponges are an ancient group, with fossils dating back at least 650 million years. They are thought to have been the first group of animals to branch from all the others. Therefore, genes shared by sponges and other animals must have been present in the common ancestor of all metazoans. This ancestor would have evolved mechanisms to coordinate cell division, growth, specialization, adhesion and death; this suggests that early sponges already had a developmental set of tools similar to those in metazoans today, said Putnam, an assistant professor of ecology and evolutionary biology.
"What's exciting is the new things we're learning about animal evolution," said Putnam, who got involved with the project while working at the Department of Energy's Joint Genome Institute in 2006. "For example, sponges have embryos, and having the genome helps us look at how they develop and make specific connections to developmental pathways in other animals.
"It's the kind of thing that will lead to a much clearer understanding of what the very first metazoans looked like," he said.
That distant ancestor may well have looked like a sponge. For the paper, Putnam helped compare Amphimedon's draft genome with 13 other complete animal genomes, including a selection of invertebrates, as well as a choanoflagellate. The researchers wrote of a "striking conservation of gene structure and genome organization" that is common to all. "We can now say that the large-scale patterns of genome organization we've seen conserved in other animal groups come from the very root of the animal tree," Putnam said.
The challenge ahead is learning what they do. "The focus of my research is to understand whether patterns that have been around for a billion years have some particular functions -- or if they're hanging around because not enough time has gone by to erase them."
What's missing is also interesting, he said. The ancestral patterns of genome organization common to other creatures is absent from certain arthropods -- invertebrates that include the likes of centipedes and lobsters -- and nematodes. "If the missing pattern is neutral, you'd say that somewhere along the history of those groups, the rate of (evolutionary) change sped up enough to break the connection," Putnam said. "If it's functional, then somehow those groups overcame whatever constraint is on it in other lineages."
Also puzzling is that while Amphimedon shares key developmental genes with a diverse set of metazoans, its basic structure hasn't changed in 600 million years. Given the same roots, researchers wonder why it didn't evolve more radically, and they are working to identify the differences that gave rise to, say, nerve cells in other creatures but not sponges.
Unlocking the basic mechanisms of multicellularity may also help researchers understand what happens when those mechanisms go wrong and lead to cancer and autoimmune disorders.
Notes:
The paper's senior authors are Daniel Rokhsar of the University of California, Berkeley, and Bernard Degnan of the University of Queensland in Australia.
The work was funded by the Australian Research Council, the Department of Energy Joint Genome Institute, Harvey Karp, the National Science Foundation, the National Institutes of Health/National Human Genome Research Institute, the University of Queensland Postdoctoral Fellowship, the Sars International Center for Marine Molecular Biology, Deutsche Forschungsgemeinschaft, Agricultural and Natural Resources/University of California, the French National Center for Scientific Research, the Gordon and Betty Moore Foundation and Richard Melmon.
Source:
David Ruth
Rice University
воскресенье, 23 октября 2011 г.
Innovative Research Grant From Stand Up To Cancer Goes To UNC Lineberger Scientist
Angelique Whitehurst, PhD, assistant professor of pharmacology and a member of UNC Lineberger Comprehensive Cancer Center, has been awarded one of 13 Innovative Research Grants from Stand Up to Cancer, the scientific partner of the American Association of Cancer Research.
The grants were announced during an event at the American Association for Cancer Research (AACR) 102nd Annual Meeting 2011.
SU2C's Innovative Research Grants Program, which made its first round of 13 grants in December 2009, was designed specifically to support work that incorporates new ideas and new approaches to solve critical problems in cancer research.
These innovative projects are characterized as "high-risk" because they challenge existing paradigms, and because in order to receive a grant, the applicants were not required - as they would be by most conventional funding mechanisms - to have already conducted a portion of the research resulting in an established base of evidence. If successful, the projects have the potential for "high-reward" in terms of saving lives.
Whitehurst will use the grant to study how genes, otherwise required only for human reproduction, contribute to tumor cell survival. She will evaluate these genes to determine which are most critical for tumor survival and how they support growth of tumor cells. Ultimately her work will present new therapeutic targets that will selectively destroy tumor cells and leave normal tissue unharmed.
Whitehurst earned her bachelor's degree in biochemistry and chemistry from Virginia Polytechnic Institute and he doctorate in cell and molecular biology from the UT Southwestern Medical Center where she also completed her postdoctoral fellowship in cell biology before joining the UNC faculty in 2009.
Source:
Dianne Shaw
University of North Carolina School of Medicine
The grants were announced during an event at the American Association for Cancer Research (AACR) 102nd Annual Meeting 2011.
SU2C's Innovative Research Grants Program, which made its first round of 13 grants in December 2009, was designed specifically to support work that incorporates new ideas and new approaches to solve critical problems in cancer research.
These innovative projects are characterized as "high-risk" because they challenge existing paradigms, and because in order to receive a grant, the applicants were not required - as they would be by most conventional funding mechanisms - to have already conducted a portion of the research resulting in an established base of evidence. If successful, the projects have the potential for "high-reward" in terms of saving lives.
Whitehurst will use the grant to study how genes, otherwise required only for human reproduction, contribute to tumor cell survival. She will evaluate these genes to determine which are most critical for tumor survival and how they support growth of tumor cells. Ultimately her work will present new therapeutic targets that will selectively destroy tumor cells and leave normal tissue unharmed.
Whitehurst earned her bachelor's degree in biochemistry and chemistry from Virginia Polytechnic Institute and he doctorate in cell and molecular biology from the UT Southwestern Medical Center where she also completed her postdoctoral fellowship in cell biology before joining the UNC faculty in 2009.
Source:
Dianne Shaw
University of North Carolina School of Medicine
четверг, 20 октября 2011 г.
Einstein Researchers Take The Pulse Of A Gene In Living Cells
Scientists at the Albert Einstein College of Medicine of Yeshiva University have observed for the first time that gene expression can occur in the form of discrete "pulses" of gene activity. The researchers used pioneering microscopy techniques, developed by Dr. Robert Singer and colleagues at Einstein, that for the first time allow scientists to directly watch the behavior of a single gene in real time. Their findings appeared in the current issue of Current Biology.
When a gene is expressed or "turned on," genetic information is transferred from DNA into RNA. This process, known as transcription, is crucial for translating the gene's message into a functional protein. Diseases such as cancer can result when genes turn on at the improper time or in the wrong part of the body.
Researchers customarily use microarrays (also known as "gene chips") to assess gene expression in tumors and other tissues. But with millions of cells involved, microarrays reflect only "average" gene expression. Just how a gene is transcribed in a single cell--continuously, intermittently or some other way--has largely been a mystery.
Now, in observing a gene that plays a major role in how an organism develops, the Einstein researchers observed a phenomenon that until now has been indirectly observed and only in bacteria: pulses of transcription that turn on and off at irregular intervals. Dr. Singer and his co-workers used a fluorescent marker that sticks to the gene only when it is active. Under a microscope, this fluorescent marker appears when the gene turns on, then disappears (gene "off") and then appears again (gene "on").
The focus of the study was a gene important in the life cycle of the social amoeba Dictyostelium, thousands of which sometimes aggregate into a single slug-like mass. This developmental gene plays a major role in transforming the "slug" into a stalk-like structure called a fruiting body, which releases new amoebae.
"The pulsing we observed in this gene would allow it to very precisely regulate development," says Dr. Singer, the study's senior author and professor and co-chair of the Department of Anatomy & Structural Biology at Einstein. He likens a gene to a thermostat:
"Heating a home all the time would be wasteful and would overheat the house," he says. "The solution is a thermostat, which injects a little bit of heat when needed and then turns off. Similarly, a cell needs the gene to be turned on--but too much activity at the wrong time can be a problem, so the solution is to have small bursts of activity."
Still to be discovered, says Dr. Singer, is how the pulsing mechanism itself is controlled. In addition, these findings pertain to developmental genes, which are turned on selectively and only in certain tissues. "Other genes--so-called constitutive genes--are regularly expressed by all the cells of an organism," Dr. Singer notes. "We'd like to find out whether these genes pulse as well."
Also involved in this study were Jonathan R. Chubb (now at University of Dundee in the U.K.), Tatjana Trcek and Shailesh M. Shenoy.
Contact: Karen Gardner
Albert Einstein College of Medicine
When a gene is expressed or "turned on," genetic information is transferred from DNA into RNA. This process, known as transcription, is crucial for translating the gene's message into a functional protein. Diseases such as cancer can result when genes turn on at the improper time or in the wrong part of the body.
Researchers customarily use microarrays (also known as "gene chips") to assess gene expression in tumors and other tissues. But with millions of cells involved, microarrays reflect only "average" gene expression. Just how a gene is transcribed in a single cell--continuously, intermittently or some other way--has largely been a mystery.
Now, in observing a gene that plays a major role in how an organism develops, the Einstein researchers observed a phenomenon that until now has been indirectly observed and only in bacteria: pulses of transcription that turn on and off at irregular intervals. Dr. Singer and his co-workers used a fluorescent marker that sticks to the gene only when it is active. Under a microscope, this fluorescent marker appears when the gene turns on, then disappears (gene "off") and then appears again (gene "on").
The focus of the study was a gene important in the life cycle of the social amoeba Dictyostelium, thousands of which sometimes aggregate into a single slug-like mass. This developmental gene plays a major role in transforming the "slug" into a stalk-like structure called a fruiting body, which releases new amoebae.
"The pulsing we observed in this gene would allow it to very precisely regulate development," says Dr. Singer, the study's senior author and professor and co-chair of the Department of Anatomy & Structural Biology at Einstein. He likens a gene to a thermostat:
"Heating a home all the time would be wasteful and would overheat the house," he says. "The solution is a thermostat, which injects a little bit of heat when needed and then turns off. Similarly, a cell needs the gene to be turned on--but too much activity at the wrong time can be a problem, so the solution is to have small bursts of activity."
Still to be discovered, says Dr. Singer, is how the pulsing mechanism itself is controlled. In addition, these findings pertain to developmental genes, which are turned on selectively and only in certain tissues. "Other genes--so-called constitutive genes--are regularly expressed by all the cells of an organism," Dr. Singer notes. "We'd like to find out whether these genes pulse as well."
Also involved in this study were Jonathan R. Chubb (now at University of Dundee in the U.K.), Tatjana Trcek and Shailesh M. Shenoy.
Contact: Karen Gardner
Albert Einstein College of Medicine
понедельник, 17 октября 2011 г.
Detection Of DNA On Nanotubes Offers New Sensing, Sequencing Technologies
Researchers at the University of Illinois at Urbana-Champaign who recently reported that DNA-wrapped carbon nanotubes could serve as sensors in living cells now say the tiny tubes can be used to target specific DNA sequences. Potential applications for the new sensors range from rapid detection of hazardous biological agents to simpler and more efficient forensic identification.
In the Jan. 27 issue of the journal Science, chemical and biomolecular engineering professor Michael Strano and his students reported that single-walled carbon nanotubes coated with DNA could be placed in living cells and detect trace amounts of harmful contaminants. In a paper accepted for publication in the journal Nano Letters, and posted on its Web site, the researchers report they have taken the technique a significant step further.
"We have successfully demonstrated the optical detection of selective DNA hybridization on the surface of a nanotube," said Strano, who is also a researcher at the Beckman Institute for Advanced Science and Technology and at the university's Micro and Nanotechnology Laboratory. "This work opens possibilities for new types of nanotube-based sensing and sequencing technologies."
In its natural state, DNA is in the double stranded form, consisting of two complementary strands, each resembling the side of a ladder and having a specific sequence of nucleotide bases as rungs. Hybridization refers to the spontaneous binding of two complementary strands through base pair matching.
By wrapping one strand of DNA around the surface of a carbon nanotube, the researchers can create a sensor that is targeted for a particular piece of complementary DNA. When the complementary DNA then binds to the DNA probe, the nanotube's natural near-infrared fluorescence is shifted slightly, and can readily be detected.
"The optical detection of specific DNA sequences through hybridization with a complementary DNA probe has many potential applications in medicine, microbiology and environmental science," said Esther Jeng, a graduate student at Illinois and the paper's lead author. "For example, this system could be used in genomic screening to detect sequences that encode for genetic disorders, and that are precursors to diseases such as breast cancer."
"Optical detection allows for passive sensing of hybridization, meaning there is no need to pass voltage or current through the system," Jeng said. "Furthermore, optics yield high-resolution signals and require a relatively simple setup. And, because our detection setup is in solution, we can sense in a natural biological environment."
Co-authors of the paper with Strano and Jeng are undergraduate students Joseph Gastala, Anthonie Moll and Amanda Roy. The work was funded by the National Science Foundation.
Contact: James E. Kloeppel, Physical Sciences Editor
kloeppeluiuc.edu
University of Illinois at Urbana-Champaign
In the Jan. 27 issue of the journal Science, chemical and biomolecular engineering professor Michael Strano and his students reported that single-walled carbon nanotubes coated with DNA could be placed in living cells and detect trace amounts of harmful contaminants. In a paper accepted for publication in the journal Nano Letters, and posted on its Web site, the researchers report they have taken the technique a significant step further.
"We have successfully demonstrated the optical detection of selective DNA hybridization on the surface of a nanotube," said Strano, who is also a researcher at the Beckman Institute for Advanced Science and Technology and at the university's Micro and Nanotechnology Laboratory. "This work opens possibilities for new types of nanotube-based sensing and sequencing technologies."
In its natural state, DNA is in the double stranded form, consisting of two complementary strands, each resembling the side of a ladder and having a specific sequence of nucleotide bases as rungs. Hybridization refers to the spontaneous binding of two complementary strands through base pair matching.
By wrapping one strand of DNA around the surface of a carbon nanotube, the researchers can create a sensor that is targeted for a particular piece of complementary DNA. When the complementary DNA then binds to the DNA probe, the nanotube's natural near-infrared fluorescence is shifted slightly, and can readily be detected.
"The optical detection of specific DNA sequences through hybridization with a complementary DNA probe has many potential applications in medicine, microbiology and environmental science," said Esther Jeng, a graduate student at Illinois and the paper's lead author. "For example, this system could be used in genomic screening to detect sequences that encode for genetic disorders, and that are precursors to diseases such as breast cancer."
"Optical detection allows for passive sensing of hybridization, meaning there is no need to pass voltage or current through the system," Jeng said. "Furthermore, optics yield high-resolution signals and require a relatively simple setup. And, because our detection setup is in solution, we can sense in a natural biological environment."
Co-authors of the paper with Strano and Jeng are undergraduate students Joseph Gastala, Anthonie Moll and Amanda Roy. The work was funded by the National Science Foundation.
Contact: James E. Kloeppel, Physical Sciences Editor
kloeppeluiuc.edu
University of Illinois at Urbana-Champaign
пятница, 14 октября 2011 г.
Deciphering The Metabolism Of Sexual Assault Drug
It's a naturally occurring brain chemical with an unwieldy name: 4-hydroxybutyrate (4-HB). Taken by mouth, it can be abused or used as a date-rape drug.
Now, a team of Ohio and Michigan scientists have determined new routes by which 4-HB is metabolized by the body. "This is new and important information," said K. Michael Gibson, professor and chair of biological sciences at Michigan Technological University and a member of the research team. "It may provide new clues on how to counteract the drug's effects, or to enhance its metabolism and decrease toxicity for chronic abusers or victims of sexual assault."
Gibson is co-author with Guo-Fang Zhang and others in the laboratory of Prof. Henri Brunengraber from the Department of Nutrition at Case Western Reserve University School of Medicine of a paper published online by the Journal of Biological Chemistry. Their findings will appear in as "paper of the week" in the the print edition of the weekly journal on Nov. 27, 2009.
4-HB is a derivative of a major brain neurotransmitter in humans and other species. . It occurs naturally in small amounts in the brains of most animals and humans. In a rare genetic metabolic disorder, 4-HB accumulates in extremely high levels, causing significant developmental delays and seizures.
But 4-HB - also called gamma hydroxybutyrate or GHB - is best known and most feared when it is taken orally, because it is a drug that impairs the capacity to exercise judgment, like rohypnol and ketamine hydrochloride. For that reason, it can be used to facilitate acquaintance sexual assault, commonly called date rape.
Analyzing the chemicals produced by the breakdown of 4-HB in mice and rats, Zhang, Gibson and colleagues used very sophisticated mass spectrometry approaches to identify previously unknown enzymes and pathways that appear to act on 4-HB and other similarly structured compounds. They discovered that 4-HB is metabolized by two different chemical mechanisms or pathways. Their discovery of those pathways should open the door for future studies that can identify the enzymes involved in the following steps of the breakdown of 4-HB.
"This work may help to develop new antidotes and treatments for people who have ingested 4-HB, as well as treatment for children with the rare genetic disorder that causes the compound to accumulate in high levels," Gibson said. (For more information on genetic disorders of 4-HB, see pndassoc)
Source: Jennifer Donovan
Michigan Technological University
Now, a team of Ohio and Michigan scientists have determined new routes by which 4-HB is metabolized by the body. "This is new and important information," said K. Michael Gibson, professor and chair of biological sciences at Michigan Technological University and a member of the research team. "It may provide new clues on how to counteract the drug's effects, or to enhance its metabolism and decrease toxicity for chronic abusers or victims of sexual assault."
Gibson is co-author with Guo-Fang Zhang and others in the laboratory of Prof. Henri Brunengraber from the Department of Nutrition at Case Western Reserve University School of Medicine of a paper published online by the Journal of Biological Chemistry. Their findings will appear in as "paper of the week" in the the print edition of the weekly journal on Nov. 27, 2009.
4-HB is a derivative of a major brain neurotransmitter in humans and other species. . It occurs naturally in small amounts in the brains of most animals and humans. In a rare genetic metabolic disorder, 4-HB accumulates in extremely high levels, causing significant developmental delays and seizures.
But 4-HB - also called gamma hydroxybutyrate or GHB - is best known and most feared when it is taken orally, because it is a drug that impairs the capacity to exercise judgment, like rohypnol and ketamine hydrochloride. For that reason, it can be used to facilitate acquaintance sexual assault, commonly called date rape.
Analyzing the chemicals produced by the breakdown of 4-HB in mice and rats, Zhang, Gibson and colleagues used very sophisticated mass spectrometry approaches to identify previously unknown enzymes and pathways that appear to act on 4-HB and other similarly structured compounds. They discovered that 4-HB is metabolized by two different chemical mechanisms or pathways. Their discovery of those pathways should open the door for future studies that can identify the enzymes involved in the following steps of the breakdown of 4-HB.
"This work may help to develop new antidotes and treatments for people who have ingested 4-HB, as well as treatment for children with the rare genetic disorder that causes the compound to accumulate in high levels," Gibson said. (For more information on genetic disorders of 4-HB, see pndassoc)
Source: Jennifer Donovan
Michigan Technological University
вторник, 11 октября 2011 г.
Research To Examine Connection Between Cancer, Genetics Among American Indians
The Montana Cancer Institute Foundation and the Confederated Salish and Kootenai Tribal Health Department are collaborating on a new program to determine whether American Indians possess certain genetic traits that could fight cancer or make them respond less effectively to cancer treatments, the Lake County Leader & Advertiser reports.
American Indians coming to Tribal Health for regular appointments will be able to donate blood to the research. Participants each will be given $10 for donating. MCIF President Pat Beatty said that the goal is to collect blood from 1,000 local American Indians. Researchers at the University of Rochester will examine the blood samples to look for nine specific genetic markers. Beatty said similar testing has been conducted among other populations. According to Beatty, "Nobody has ever studied this systematically in Native Americans."
Research among American Indians has been difficult because of a lack of research institutions in areas with large American Indian populations. In addition, American Indians are often resistant to "outsiders performing research experiments," the Leader & Advertiser reports. Beatty said, "Many Native Americans, for good reason, don't have a lot of trust in the medical system. So that means that it's almost impossible for some unknown research project to come out and do something like this." The research project is being run through Tribal Health to help gain participants' trust, the Leader & Advertiser reports (McBride, Lake County Leader & Advertiser, 2/7).
Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation© 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
American Indians coming to Tribal Health for regular appointments will be able to donate blood to the research. Participants each will be given $10 for donating. MCIF President Pat Beatty said that the goal is to collect blood from 1,000 local American Indians. Researchers at the University of Rochester will examine the blood samples to look for nine specific genetic markers. Beatty said similar testing has been conducted among other populations. According to Beatty, "Nobody has ever studied this systematically in Native Americans."
Research among American Indians has been difficult because of a lack of research institutions in areas with large American Indian populations. In addition, American Indians are often resistant to "outsiders performing research experiments," the Leader & Advertiser reports. Beatty said, "Many Native Americans, for good reason, don't have a lot of trust in the medical system. So that means that it's almost impossible for some unknown research project to come out and do something like this." The research project is being run through Tribal Health to help gain participants' trust, the Leader & Advertiser reports (McBride, Lake County Leader & Advertiser, 2/7).
Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation© 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
суббота, 8 октября 2011 г.
New Test Helps Identify Hepatitis C Patients At High Risk Of Developing Cirrhosis
A researcher at the Stanford University School of Medicine has helped confirm the reliability of a new test for liver disease that is ushering in the long-promised era of personalized medicine based on each individual's genetic makeup.
The Stanford group was one of the five sites that helped determine that the genetic test can identify patients who are at high risk of developing cirrhosis from chronic hepatitis C infection. That means high-risk patients could be directed toward a long course of expensive, debilitating drug therapy, while low-risk patients might be better off delaying treatment.
"Management of cirrhosis patients is challenging," said Ramsey Cheung, MD, associate professor of medicine at the school and chief of hepatology at the Palo Alto Veterans Affairs Health Care System, who led the Stanford arm of the study. "This test is the first of its kind to use the genetic makeup of each patient to determine who is likely to develop cirrhosis. High-risk patients should be targeted for early treatment."
The test looks at variations of seven genes, and was developed by Celera, headquartered in Rockville, Md.
Cheung is the senior author of the study, which will be published in the advance online issue of the journal Hepatology. Cheung is a paid consultant for Celera, which also funded the study.
"Current therapy for hepatitis C unfortunately is very expensive, has multiple side effects and a suboptimal response rate for most patients," said Cheung. Treatment includes weekly injections of alpha interferon along with the drug ribavirin, which can cost more than $30,000 per year and can cause flu-like symptoms, nausea, depression and other side effects. And only half of patients undergoing this therapy will be cured of the infection.
Nearly 4 million Americans are infected with the hepatitis C virus, of which nearly 80 percent have a chronic infection, according to the American Liver Foundation. Chronic infection can lead to the severe scarring known as cirrhosis, which in turn may result in liver cancer or liver failure. Hepatitis C infection is the most common reason people need a liver transplant in the United States and is responsible for between 8,000 and 10,000 U.S. deaths annually.
But in the majority of people chronically infected with hepatitis C, the virus causes either no symptoms or vague, nonspecific ones. In around one-third of people chronically infected with the virus, the disease progression is slow and they may never develop cirrhosis, even after decades of infection.
The dilemma physicians face, explained Cheung, is deciding who to treat and who can wait for better therapies to come along. The key is being able to determine which patients are likely to see the infection progress to cirrhosis. Doctors consider such factors as age, gender and alcohol consumption to predict such risk, but because of individual variability, these factors don't yield a very accurate prediction. A liver biopsy can indicate the amount of damage to the liver up until the time of the biopsy, but can't reveal how much future damage will occur.
The new test assessed by Cheung and his colleagues is a way to hedge the bets.
The lead author of the paper is Hongjin Huang, PhD, associate director of liver diseases at Celera in Alameda, Calif. Huang and her Celera colleagues developed the test by initially scanning the DNA of more than 1,000 people who had hepatitis C. Out of 25,000 genetic variations tested, the researchers discovered seven that could be used together as a "signature" for predicting progression to cirrhosis in Caucasians.
The resulting gene signature - the Cirrhosis Risk Score - was then independently validated on 154 hepatitis C patients at Stanford, the University of Illinois-Chicago and California Pacific Medical Center. Among patients with early-stage liver disease, the researchers were able to divide them into a high-risk category based on their gene pattern, compared with those who had low-risk gene patterns. "The Cirrhosis Risk Score was superior to the known clinical factors, such as alcohol consumption, in predicting the risk of developing cirrhosis," said Cheung.
"This test allows both physicians and patients to make an intelligent decision about the urgency of beginning antiviral therapy," he said. "If a patient turns out to be low-risk, we might advise the patient to consider deferring treatment, avoiding unnecessary side effects and expense of current therapy."
Last June, Celera licensed Specialty Laboratories of Valencia, Calif., to perform the genetic test. The test currently costs about $500.
In addition to Cheung and Huang, the other 12 authors of the study are from Celera, Virginia Commonwealth University, Mount Sinai School of Medicine, California Pacific Medical Center, the University of Illinois-Chicago and the University of California-San Francisco.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford.edu/.
Contact: Mitzi Baker
Stanford University Medical Center
The Stanford group was one of the five sites that helped determine that the genetic test can identify patients who are at high risk of developing cirrhosis from chronic hepatitis C infection. That means high-risk patients could be directed toward a long course of expensive, debilitating drug therapy, while low-risk patients might be better off delaying treatment.
"Management of cirrhosis patients is challenging," said Ramsey Cheung, MD, associate professor of medicine at the school and chief of hepatology at the Palo Alto Veterans Affairs Health Care System, who led the Stanford arm of the study. "This test is the first of its kind to use the genetic makeup of each patient to determine who is likely to develop cirrhosis. High-risk patients should be targeted for early treatment."
The test looks at variations of seven genes, and was developed by Celera, headquartered in Rockville, Md.
Cheung is the senior author of the study, which will be published in the advance online issue of the journal Hepatology. Cheung is a paid consultant for Celera, which also funded the study.
"Current therapy for hepatitis C unfortunately is very expensive, has multiple side effects and a suboptimal response rate for most patients," said Cheung. Treatment includes weekly injections of alpha interferon along with the drug ribavirin, which can cost more than $30,000 per year and can cause flu-like symptoms, nausea, depression and other side effects. And only half of patients undergoing this therapy will be cured of the infection.
Nearly 4 million Americans are infected with the hepatitis C virus, of which nearly 80 percent have a chronic infection, according to the American Liver Foundation. Chronic infection can lead to the severe scarring known as cirrhosis, which in turn may result in liver cancer or liver failure. Hepatitis C infection is the most common reason people need a liver transplant in the United States and is responsible for between 8,000 and 10,000 U.S. deaths annually.
But in the majority of people chronically infected with hepatitis C, the virus causes either no symptoms or vague, nonspecific ones. In around one-third of people chronically infected with the virus, the disease progression is slow and they may never develop cirrhosis, even after decades of infection.
The dilemma physicians face, explained Cheung, is deciding who to treat and who can wait for better therapies to come along. The key is being able to determine which patients are likely to see the infection progress to cirrhosis. Doctors consider such factors as age, gender and alcohol consumption to predict such risk, but because of individual variability, these factors don't yield a very accurate prediction. A liver biopsy can indicate the amount of damage to the liver up until the time of the biopsy, but can't reveal how much future damage will occur.
The new test assessed by Cheung and his colleagues is a way to hedge the bets.
The lead author of the paper is Hongjin Huang, PhD, associate director of liver diseases at Celera in Alameda, Calif. Huang and her Celera colleagues developed the test by initially scanning the DNA of more than 1,000 people who had hepatitis C. Out of 25,000 genetic variations tested, the researchers discovered seven that could be used together as a "signature" for predicting progression to cirrhosis in Caucasians.
The resulting gene signature - the Cirrhosis Risk Score - was then independently validated on 154 hepatitis C patients at Stanford, the University of Illinois-Chicago and California Pacific Medical Center. Among patients with early-stage liver disease, the researchers were able to divide them into a high-risk category based on their gene pattern, compared with those who had low-risk gene patterns. "The Cirrhosis Risk Score was superior to the known clinical factors, such as alcohol consumption, in predicting the risk of developing cirrhosis," said Cheung.
"This test allows both physicians and patients to make an intelligent decision about the urgency of beginning antiviral therapy," he said. "If a patient turns out to be low-risk, we might advise the patient to consider deferring treatment, avoiding unnecessary side effects and expense of current therapy."
Last June, Celera licensed Specialty Laboratories of Valencia, Calif., to perform the genetic test. The test currently costs about $500.
In addition to Cheung and Huang, the other 12 authors of the study are from Celera, Virginia Commonwealth University, Mount Sinai School of Medicine, California Pacific Medical Center, the University of Illinois-Chicago and the University of California-San Francisco.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford.edu/.
Contact: Mitzi Baker
Stanford University Medical Center
среда, 5 октября 2011 г.
New Scenario For First Life On Earth
A team led by the University of Colorado at Boulder and the University of Milan has discovered some unexpected forms of liquid crystals of ultrashort DNA molecules immersed in water, providing a new scenario for a key step in the emergence of life on Earth.
CU-Boulder physics Professor Noel Clark said the team found that surprisingly short segments of DNA, life's molecular carrier of genetic information, could assemble into several distinct liquid crystal phases that "self-orient" parallel to one another and stack into columns when placed in a water solution. Life is widely believed to have emerged as segments of DNA- or RNA-like molecules in a prebiotic "soup" solution of ancient organic molecules.
A paper on the subject was published in the Nov. 23 issue of Science. The paper was authored by Clark, Michi Nakata and Christopher Jones from CU-Boulder, Giuliano Zanchetta and Tommaso Bellini of the University of Milan, Brandon Chapman and Ronald Pindak of Brookhaven National Laboratory and Julie Cross of Argonne National Laboratory. Nakata died in September 2006.
Since the formation of molecular chains as uniform as DNA by random chemistry is essentially impossible, Clark said, scientists have been seeking effective ways for simple molecules to spontaneously self-select, "chain-up" and self-replicate. The new study shows that in a mixture of tiny fragments of DNA, those molecules capable of forming liquid crystals selectively condense into droplets in which conditions are favorable for them to be chemically linked into longer molecules with enhanced liquid crystal-forming tendencies, he said.
"We found that even tiny fragments of double helix DNA can spontaneously self-assemble into columns that contain many molecules," Clark said. "Our vision is that from the collection of ancient molecules, short RNA pieces or some structurally related precursor emerged as the molecular fragments most capable of condensing into liquid crystal droplets, selectively developing into long molecules."
Liquid crystals -- organic materials related to soap that exhibit both solid and liquid properties -- are commonly used for information displays in computers, flat-panel televisions, cell phones, calculators and watches. Most liquid crystal phase molecules are rod-shaped and have the ability to spontaneously form large domains of a common orientation, which makes them particularly sensitive to stimuli like changes in temperature or applied voltage.
RNA and DNA are chain-like polymers with side groups known as nucleotides, or bases, that selectively adhere only to specific bases on a second chain. Matching, or complementary base sequences enable the chains to pair up and form the widely recognized double helix structure. Genetic information is encoded in sequences of thousands to millions of bases along the chains, which can be microns to millimeters in length.
Such DNA polynucleotides had previously been shown to organize into liquid crystal phases in which the chains spontaneously oriented parallel to each other, he said. Researchers understand the liquid crystal organization to be a result of DNA's elongated molecular shape, making parallel alignment easier, much like spaghetti thrown in a box and shaken would be prone to line up in parallel, Clark said.
The CU-Boulder and University of Milan team began a series of experiments to see how short the DNA segments could be and still show liquid crystal ordering, said Clark. The team found that even a DNA segment as short as six bases, when paired with a complementary segment that together measured just two nanometers long and two nanometers in diameter, could still assemble itself into the liquid crystal phases, in spite of having almost no elongation in shape.
Structural analysis of the liquid crystal phases showed that they appeared because such short DNA duplex pairs were able to stick together "end-to-end," forming rod-shaped aggregates that could then behave like much longer segments of DNA. The sticking was a result of small, oily patches found on the ends of the short DNA segments that help them adhere to each other in a reversible way -- much like magnetic buttons -- as they expelled water in between them, Clark said.
A key characterization technique employed was X-ray microbeam diffraction combined with in-situ optical microscopy, carried out with researchers from Argonne and Brookhaven National Laboratories. The team using a machine called the Argonne Advanced Photon Source synchrotron that enabled probing of the "nano DNA" molecular organization in single liquid crystal orientation domains only a few microns in size. The experiments provided direct evidence for the columnar stacking of the nano DNA pieces in a fluid liquid crystal phase.
"The key observation with respect to early life is that this aggregation of nano DNA strands is possible only if they form duplexes," Clark said. "In a sample of chains in which the bases don't match and the chains can't form helical duplexes, we did not observe liquid crystal ordering."
Subsequent tests by the team involved mixed solutions of complementary and noncomplementary DNA segments, said Clark. The results indicated that essentially all of the complementary DNA bits condensed out in the form of liquid crystal droplets, physically separating them from the noncomplementary DNA segments.
"We found this to be a remarkable result," Clark said. "It means that small molecules with the ability to pair up the right way can seek each other out and collect together into drops that are internally self-organized to facilitate the growth of larger pairable molecules.
"In essence, the liquid crystal phase condensation selects the appropriate molecular components, and with the right chemistry would evolve larger molecules tuned to stabilize the liquid crystal phase. If this is correct, the linear polymer shape of DNA itself is a vestige of formation by liquid crystal order."
Source: Noel Clark
University of Colorado at Boulder
CU-Boulder physics Professor Noel Clark said the team found that surprisingly short segments of DNA, life's molecular carrier of genetic information, could assemble into several distinct liquid crystal phases that "self-orient" parallel to one another and stack into columns when placed in a water solution. Life is widely believed to have emerged as segments of DNA- or RNA-like molecules in a prebiotic "soup" solution of ancient organic molecules.
A paper on the subject was published in the Nov. 23 issue of Science. The paper was authored by Clark, Michi Nakata and Christopher Jones from CU-Boulder, Giuliano Zanchetta and Tommaso Bellini of the University of Milan, Brandon Chapman and Ronald Pindak of Brookhaven National Laboratory and Julie Cross of Argonne National Laboratory. Nakata died in September 2006.
Since the formation of molecular chains as uniform as DNA by random chemistry is essentially impossible, Clark said, scientists have been seeking effective ways for simple molecules to spontaneously self-select, "chain-up" and self-replicate. The new study shows that in a mixture of tiny fragments of DNA, those molecules capable of forming liquid crystals selectively condense into droplets in which conditions are favorable for them to be chemically linked into longer molecules with enhanced liquid crystal-forming tendencies, he said.
"We found that even tiny fragments of double helix DNA can spontaneously self-assemble into columns that contain many molecules," Clark said. "Our vision is that from the collection of ancient molecules, short RNA pieces or some structurally related precursor emerged as the molecular fragments most capable of condensing into liquid crystal droplets, selectively developing into long molecules."
Liquid crystals -- organic materials related to soap that exhibit both solid and liquid properties -- are commonly used for information displays in computers, flat-panel televisions, cell phones, calculators and watches. Most liquid crystal phase molecules are rod-shaped and have the ability to spontaneously form large domains of a common orientation, which makes them particularly sensitive to stimuli like changes in temperature or applied voltage.
RNA and DNA are chain-like polymers with side groups known as nucleotides, or bases, that selectively adhere only to specific bases on a second chain. Matching, or complementary base sequences enable the chains to pair up and form the widely recognized double helix structure. Genetic information is encoded in sequences of thousands to millions of bases along the chains, which can be microns to millimeters in length.
Such DNA polynucleotides had previously been shown to organize into liquid crystal phases in which the chains spontaneously oriented parallel to each other, he said. Researchers understand the liquid crystal organization to be a result of DNA's elongated molecular shape, making parallel alignment easier, much like spaghetti thrown in a box and shaken would be prone to line up in parallel, Clark said.
The CU-Boulder and University of Milan team began a series of experiments to see how short the DNA segments could be and still show liquid crystal ordering, said Clark. The team found that even a DNA segment as short as six bases, when paired with a complementary segment that together measured just two nanometers long and two nanometers in diameter, could still assemble itself into the liquid crystal phases, in spite of having almost no elongation in shape.
Structural analysis of the liquid crystal phases showed that they appeared because such short DNA duplex pairs were able to stick together "end-to-end," forming rod-shaped aggregates that could then behave like much longer segments of DNA. The sticking was a result of small, oily patches found on the ends of the short DNA segments that help them adhere to each other in a reversible way -- much like magnetic buttons -- as they expelled water in between them, Clark said.
A key characterization technique employed was X-ray microbeam diffraction combined with in-situ optical microscopy, carried out with researchers from Argonne and Brookhaven National Laboratories. The team using a machine called the Argonne Advanced Photon Source synchrotron that enabled probing of the "nano DNA" molecular organization in single liquid crystal orientation domains only a few microns in size. The experiments provided direct evidence for the columnar stacking of the nano DNA pieces in a fluid liquid crystal phase.
"The key observation with respect to early life is that this aggregation of nano DNA strands is possible only if they form duplexes," Clark said. "In a sample of chains in which the bases don't match and the chains can't form helical duplexes, we did not observe liquid crystal ordering."
Subsequent tests by the team involved mixed solutions of complementary and noncomplementary DNA segments, said Clark. The results indicated that essentially all of the complementary DNA bits condensed out in the form of liquid crystal droplets, physically separating them from the noncomplementary DNA segments.
"We found this to be a remarkable result," Clark said. "It means that small molecules with the ability to pair up the right way can seek each other out and collect together into drops that are internally self-organized to facilitate the growth of larger pairable molecules.
"In essence, the liquid crystal phase condensation selects the appropriate molecular components, and with the right chemistry would evolve larger molecules tuned to stabilize the liquid crystal phase. If this is correct, the linear polymer shape of DNA itself is a vestige of formation by liquid crystal order."
Source: Noel Clark
University of Colorado at Boulder
воскресенье, 2 октября 2011 г.
Missing Evolutionary Link Found Using Tiny Fungus Crystal
The crystal structure of a molecule from a primitive fungus has served as a time machine to show researchers more about the evolution of life from the simple to the complex.
By studying the three-dimensional version of the fungus protein bound to an RNA molecule, scientists from Purdue University and the University of Texas at Austin have been able to visualize how life progressed from an early self-replicating molecule that also performed chemical reactions to one in which proteins assumed some of the work.
"Now we can see how RNA progressed to share functions with proteins," said Alan Lambowitz, director of the University of Texas Institute for Cellular and Molecular Biology. "This was a critical missing step."
Results of the study are published in today's (Jan. 3) issue of the journal Nature.
"It's thought that RNA, or a molecule like it, may have been among the first molecules of life, both carrying genetic code that can be transmitted from generation to generation and folding into structures so these molecules could work inside cells," said Purdue structural biologist Barbara Golden. "At some point, RNA evolved and became capable of making proteins. At that point, proteins started taking over roles that RNA played previously - acting as catalysts and building structures in cells."
In order to show this and learn more about the evolution from RNA to more complex life forms, Lambowitz and Paul Paukstelis, lead author and a research scientist at the Texas institute, needed to be able to see how the fungus' protein worked. That's where Golden's team joined the effort and crystallized the molecule at Purdue's macromolecular crystallization facility.
"Obviously, we can't see the process of moving from RNA to RNA and proteins and then to DNA, without a time machine," Golden said. "But by using this fungus protein, we can see this process occurring in modern life."
Looking at the crystal, the scientists saw two things, Golden said. One was that this protein uses two completely different molecular surfaces to perform its two roles. The second is that the protein seems to perform the same job that RNA performed in other simple organisms.
"The crystal structure provides a snapshot of how, during evolution, protein molecules came to assist RNA molecules in their biological functions and ultimately assumed roles previously played by RNA," Golden said.
Before the crystallization, Lambowitz, Paukstelis and their research team at The University of Texas at Austin were involved in a long-term project to study the function of the basic cellular workhorse protein and other evolutionary fossils from the fungus. In earlier work, the scientists studied a different protein that showed how biochemical processes could progress from a world with RNA and protein to DNA.
The protein, as found in the fungus, had adapted to take over some of the RNA molecule's chemical reaction jobs inside cells. The protein stabilizes the RNA molecule - called an intron - so that the RNA can cut out non-functional genetic material and splice together the ends of a functional gene, Paukstelis said.
"The RNA molecule in our study is capable of performing a specific chemical reaction on itself, but it requires a protein for this reaction to take place efficiently," he said.
This basic scientific information eventually could lead to clinical applications.
"This work has potential applications in the development of antifungal drugs to battle potentially deadly pathogens; that's one of the next steps," Lambowitz said. "Another is to produce more detailed structures so that we can understand the ancient chemical reactions."
Golden and Lambowitz are senior authors of the report. Golden is a member of the Markey Center for Structural Biology and Purdue Cancer Center. The Markey Center will be housed in the Hockmeyer Hall of Structural Biology when it's completed on the West Lafayette campus.
Other researchers involved in this study along with Paukstelis were Jui-Hui Chen, a Purdue biochemistry doctoral student, and Elaine Chase, a Purdue biochemistry research technician.
Source: Susan A. Steeves
Purdue University
By studying the three-dimensional version of the fungus protein bound to an RNA molecule, scientists from Purdue University and the University of Texas at Austin have been able to visualize how life progressed from an early self-replicating molecule that also performed chemical reactions to one in which proteins assumed some of the work.
"Now we can see how RNA progressed to share functions with proteins," said Alan Lambowitz, director of the University of Texas Institute for Cellular and Molecular Biology. "This was a critical missing step."
Results of the study are published in today's (Jan. 3) issue of the journal Nature.
"It's thought that RNA, or a molecule like it, may have been among the first molecules of life, both carrying genetic code that can be transmitted from generation to generation and folding into structures so these molecules could work inside cells," said Purdue structural biologist Barbara Golden. "At some point, RNA evolved and became capable of making proteins. At that point, proteins started taking over roles that RNA played previously - acting as catalysts and building structures in cells."
In order to show this and learn more about the evolution from RNA to more complex life forms, Lambowitz and Paul Paukstelis, lead author and a research scientist at the Texas institute, needed to be able to see how the fungus' protein worked. That's where Golden's team joined the effort and crystallized the molecule at Purdue's macromolecular crystallization facility.
"Obviously, we can't see the process of moving from RNA to RNA and proteins and then to DNA, without a time machine," Golden said. "But by using this fungus protein, we can see this process occurring in modern life."
Looking at the crystal, the scientists saw two things, Golden said. One was that this protein uses two completely different molecular surfaces to perform its two roles. The second is that the protein seems to perform the same job that RNA performed in other simple organisms.
"The crystal structure provides a snapshot of how, during evolution, protein molecules came to assist RNA molecules in their biological functions and ultimately assumed roles previously played by RNA," Golden said.
Before the crystallization, Lambowitz, Paukstelis and their research team at The University of Texas at Austin were involved in a long-term project to study the function of the basic cellular workhorse protein and other evolutionary fossils from the fungus. In earlier work, the scientists studied a different protein that showed how biochemical processes could progress from a world with RNA and protein to DNA.
The protein, as found in the fungus, had adapted to take over some of the RNA molecule's chemical reaction jobs inside cells. The protein stabilizes the RNA molecule - called an intron - so that the RNA can cut out non-functional genetic material and splice together the ends of a functional gene, Paukstelis said.
"The RNA molecule in our study is capable of performing a specific chemical reaction on itself, but it requires a protein for this reaction to take place efficiently," he said.
This basic scientific information eventually could lead to clinical applications.
"This work has potential applications in the development of antifungal drugs to battle potentially deadly pathogens; that's one of the next steps," Lambowitz said. "Another is to produce more detailed structures so that we can understand the ancient chemical reactions."
Golden and Lambowitz are senior authors of the report. Golden is a member of the Markey Center for Structural Biology and Purdue Cancer Center. The Markey Center will be housed in the Hockmeyer Hall of Structural Biology when it's completed on the West Lafayette campus.
Other researchers involved in this study along with Paukstelis were Jui-Hui Chen, a Purdue biochemistry doctoral student, and Elaine Chase, a Purdue biochemistry research technician.
Source: Susan A. Steeves
Purdue University
четверг, 29 сентября 2011 г.
Gut Microbes Promote Cell Turnover By A Well-Known Pathway
Microbes matter -- perhaps more than anyone realizes -- in basic biological development and, maybe, they could be a target for reducing cancer risks, according to University of Oregon researchers.
In a study of very basic biology of zebrafish, scientists in the UO Institute of Molecular Biology focused on the developing intestine during its early formation in the sterile environment of its eggshell through the exposure to natural colonizing bacteria after hatching.
What they found was eye opening, said Karen Guillemin, professor of biology: Resident microbes in the still-maturing intestine send messages that promote non-disease-related cell proliferation in the same Wnt [pronounced went] signaling pathway where genetic mutations have long been known to give rise to colorectal cancer. The findings appeared online ahead of regular publication in the Proceedings of the National Academy of Sciences.
The complex Wnt pathway in the gut already is considered the starting point for more than 70 percent of sporadic colorectal cancers. In the study, researchers used normal zebrafish and those harboring mutations in the Wnt pathway. They were reared under germ-free conditions and then exposed under laboratory conditions to specific microbes to define how microbial signals interact with the Wnt pathway to promote cell proliferation in the gut.
"We were able to show that microbial signals do feed into and enhance signaling in the Wnt pathway. They feed in at a point after the node where most cancer-promoting genetic mutations occur," Guillemin said. "What this says is that for anyone who is at risk for developing cancer because they have these mutations, it matters what microbes these mutations are associated with. These two pieces of information contribute in parallel and feed into the same pathway."
The findings, she said, add fodder in an emerging shift in cancer research to look at the impact of microbes and other infectious causes of the disease. "It may be that associated microbes play as significant a role in cancer risk as genetic mutations," she said. "We need to learn more about the contributions of microbe signaling to cell proliferation. Maybe you could intervene with a targeted therapy. Even if you can't fix a mutation you might manipulate the associated microbes to change the interaction and reduce unwanted cell proliferation."
Genetic research on zebrafish - a high-priority model organism for the National Institutes of Health, which supported the project - began at the UO in the early 1970s. Guillemin, who recently received an early career investigator-scholar award from the NIH Institute of Digestive and Kidney Diseases, is known for her studies in zebrafish on the role of good bacteria in the gastrointestinal tract.
Notes:
Co-authors on the paper were Sarah E. Cheesman, who was supported by an NIH Research Service Award fellowship, doctoral student James T. Neal and research technicians Erika Mittge and Barbara M. Seredick.
In addition to the NIH, the Burroughs Wellcome Fund supported the research.
Source:
Jim Barlow
University of Oregon
In a study of very basic biology of zebrafish, scientists in the UO Institute of Molecular Biology focused on the developing intestine during its early formation in the sterile environment of its eggshell through the exposure to natural colonizing bacteria after hatching.
What they found was eye opening, said Karen Guillemin, professor of biology: Resident microbes in the still-maturing intestine send messages that promote non-disease-related cell proliferation in the same Wnt [pronounced went] signaling pathway where genetic mutations have long been known to give rise to colorectal cancer. The findings appeared online ahead of regular publication in the Proceedings of the National Academy of Sciences.
The complex Wnt pathway in the gut already is considered the starting point for more than 70 percent of sporadic colorectal cancers. In the study, researchers used normal zebrafish and those harboring mutations in the Wnt pathway. They were reared under germ-free conditions and then exposed under laboratory conditions to specific microbes to define how microbial signals interact with the Wnt pathway to promote cell proliferation in the gut.
"We were able to show that microbial signals do feed into and enhance signaling in the Wnt pathway. They feed in at a point after the node where most cancer-promoting genetic mutations occur," Guillemin said. "What this says is that for anyone who is at risk for developing cancer because they have these mutations, it matters what microbes these mutations are associated with. These two pieces of information contribute in parallel and feed into the same pathway."
The findings, she said, add fodder in an emerging shift in cancer research to look at the impact of microbes and other infectious causes of the disease. "It may be that associated microbes play as significant a role in cancer risk as genetic mutations," she said. "We need to learn more about the contributions of microbe signaling to cell proliferation. Maybe you could intervene with a targeted therapy. Even if you can't fix a mutation you might manipulate the associated microbes to change the interaction and reduce unwanted cell proliferation."
Genetic research on zebrafish - a high-priority model organism for the National Institutes of Health, which supported the project - began at the UO in the early 1970s. Guillemin, who recently received an early career investigator-scholar award from the NIH Institute of Digestive and Kidney Diseases, is known for her studies in zebrafish on the role of good bacteria in the gastrointestinal tract.
Notes:
Co-authors on the paper were Sarah E. Cheesman, who was supported by an NIH Research Service Award fellowship, doctoral student James T. Neal and research technicians Erika Mittge and Barbara M. Seredick.
In addition to the NIH, the Burroughs Wellcome Fund supported the research.
Source:
Jim Barlow
University of Oregon
понедельник, 26 сентября 2011 г.
Drug That Switches On Genes Improves Myelodysplastic Syndrome Treatment
A potent member of a new class of drugs increases survival in some patients with myelodysplastic syndrome (MDS), and may become the new standard of therapy for this group of pre-cancer disorders, say researchers at The University of Texas M. D. Anderson Cancer Center who led a national study of the agent.
The drug, decitabine, is designed to turn on genes that cancer had switched off, and in this study, patients who were treated with it achieved a significantly higher overall response rate, compared to patients receiving supportive care, which includes transfusions of red blood cells and platelets.
Results of the randomized Phase III clinical trial, published March 13, 2006 in the online version of the journal Cancer, also concluded that in treated patients who responded to the drug, the median time to progression of the disease, or death, was 17.5 months, compared to 9.8 months in patients who did not.
"This is a very promising drug that we believe works even better when patients use it for a period that is longer than that tested in this trial," says lead author, Hagop Kantarjian, M.D., chair of the Department of Leukemia at M. D. Anderson.
For example, interim analysis of an ongoing study demonstrated a 40 percent complete response rate when the drug was given in lower doses over a longer period of time, said Kantarjian, who presented these results in December 2005, at the annual meeting of the American Society of Hematology. In contrast, the 83 patients treated with decitabine in this study received comparatively fewer rounds of therapy, and the response rate was 17 percent, he said.
"The data suggest to us that prolonged treatment is important for response but the optimal schedule for using decitabine is being studied," said Kantarjian.
Still, he says a significant response rate represents "a vast improvement" in the care of these pre-cancers, which are a group of diseases in which the bone marrow progenitor cells that normally morph into red and white blood cells and platelets, fail to respond to normal growth controls. That results in too many progenitor cells (also known as blasts) and too few mature blood cells, and in about 30 percent of patients, the disease progresses to acute myeloid leukemia (AML). About three-fourths of MDS patients succumb to either MDS or to AML within about 2-3 years from diagnosis.
MDS is difficult to treat, especially since it usually strikes the elderly. Ten years ago, there was little to offer patients other than blood transfusions and supportive care, Kantarjian says, and newer treatments, which include the use of stem cell transplants, are not for every patient.
Decitabine is a "biological disease modifier" that was given fast-track approval by the Food and Drug Administration in April 2003.
It is a DNA hypomethylating agent that fights cancer by reversing a chemical process (methylation) that turns off tumor-suppressor genes that protect cells from becoming cancerous. Methylation is the gradual addition of chemical units known as methyl groups to genes, and as these groups accumulate, the gene gradually shuts down. Decitabine prevents the methylation process, enabling the gene to become active again.
In addition to increased survival and time-to-progression in some patients, decitabine improved quality of life in patients who responded and eliminated the need for frequent transfusions, Kantarjian said.
Other institutions that participated in the study were The University of Rochester Medical Center, Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Roswell Park Cancer Institute, Duke University Medical Center, University of Illinois, Southwest Regional Cancer Center, Rush Medical Center, and H. Lee Moffitt Cancer Center.
The study was funded by Supergen Inc., which developed decitabine.
Contact: Julie A. Penne
jpennemdanderson
University of Texas M. D. Anderson Cancer Center
The drug, decitabine, is designed to turn on genes that cancer had switched off, and in this study, patients who were treated with it achieved a significantly higher overall response rate, compared to patients receiving supportive care, which includes transfusions of red blood cells and platelets.
Results of the randomized Phase III clinical trial, published March 13, 2006 in the online version of the journal Cancer, also concluded that in treated patients who responded to the drug, the median time to progression of the disease, or death, was 17.5 months, compared to 9.8 months in patients who did not.
"This is a very promising drug that we believe works even better when patients use it for a period that is longer than that tested in this trial," says lead author, Hagop Kantarjian, M.D., chair of the Department of Leukemia at M. D. Anderson.
For example, interim analysis of an ongoing study demonstrated a 40 percent complete response rate when the drug was given in lower doses over a longer period of time, said Kantarjian, who presented these results in December 2005, at the annual meeting of the American Society of Hematology. In contrast, the 83 patients treated with decitabine in this study received comparatively fewer rounds of therapy, and the response rate was 17 percent, he said.
"The data suggest to us that prolonged treatment is important for response but the optimal schedule for using decitabine is being studied," said Kantarjian.
Still, he says a significant response rate represents "a vast improvement" in the care of these pre-cancers, which are a group of diseases in which the bone marrow progenitor cells that normally morph into red and white blood cells and platelets, fail to respond to normal growth controls. That results in too many progenitor cells (also known as blasts) and too few mature blood cells, and in about 30 percent of patients, the disease progresses to acute myeloid leukemia (AML). About three-fourths of MDS patients succumb to either MDS or to AML within about 2-3 years from diagnosis.
MDS is difficult to treat, especially since it usually strikes the elderly. Ten years ago, there was little to offer patients other than blood transfusions and supportive care, Kantarjian says, and newer treatments, which include the use of stem cell transplants, are not for every patient.
Decitabine is a "biological disease modifier" that was given fast-track approval by the Food and Drug Administration in April 2003.
It is a DNA hypomethylating agent that fights cancer by reversing a chemical process (methylation) that turns off tumor-suppressor genes that protect cells from becoming cancerous. Methylation is the gradual addition of chemical units known as methyl groups to genes, and as these groups accumulate, the gene gradually shuts down. Decitabine prevents the methylation process, enabling the gene to become active again.
In addition to increased survival and time-to-progression in some patients, decitabine improved quality of life in patients who responded and eliminated the need for frequent transfusions, Kantarjian said.
Other institutions that participated in the study were The University of Rochester Medical Center, Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Roswell Park Cancer Institute, Duke University Medical Center, University of Illinois, Southwest Regional Cancer Center, Rush Medical Center, and H. Lee Moffitt Cancer Center.
The study was funded by Supergen Inc., which developed decitabine.
Contact: Julie A. Penne
jpennemdanderson
University of Texas M. D. Anderson Cancer Center
пятница, 23 сентября 2011 г.
Genetics Are Key To Age At Which Girls Start Their Periods
Genetic makeup explains more than half of the variation between UK women's ages at first period, according to a study of almost 26,000 UK women published today in the May edition of Paediatric and Perinatal Epidemiology.
Age at menarche (when periods begin) is known to run in families. However, the balance of genetic and environmental influences on this has been unclear.
Scientists at The Institute of Cancer Research (ICR) analysed data from women participating in the Breakthrough Generations Study - a major UK-wide investigation into the causes of breast cancer - who had at least one other female relative also taking part.
They found that a woman's age of menarche was significantly correlated with that of her relatives. For each 12 month delay in age at menarche of an older sister, mother or paternal aunt, there was a delay of around three months on average for the younger relative; and for a maternal grandmother or maternal aunt the delay in the younger relative was about 1.5 months. Age at menarche also strongly correlated between twins, particularly identical twins.
The researchers used mathematical modelling to find that genetic factors accounted for around 57 per cent of the variation in the age of menarche of women in the study. Environmental and behavioural factors from sharing an upbringing or family life did not appear to have any detectable effect; environmental factors not shared within families accounted for the other 43 per cent in variation.
The age at which menstruation begins is important because it has been linked to risk of a number of chronic diseases including breast cancer. Risk of breast cancer gradually increases with progressively younger age at menarche and older age at menopause, possibly because women are exposed to female sex hormones for a longer period of time. Each two year delay in menarche is associated with an estimated 10 per cent reduction in the relative risk of breast cancer.
"Our study findings suggest that genetic factors have a major influence on the age women in the UK begin menstruating, and these could have an impact on breast cancer risk," lead author Danielle Morris of the ICR says. "Although some genes associated with age at menarche have been found, considerable genetic variation remains to be explained."
The Breakthrough Generations Study is a comprehensive analysis of the causes of breast cancer. A partnership between Breakthrough Breast Cancer and the ICR, it began in 2003 and will follow more than 100,000 women participants for the next 40 years to unravel the lifestyle, environmental and genetic factors that cause the disease.
This arm of the study was funded by Breakthrough Breast Cancer, the ICR and the Sir John Fisher Foundation.
The Breakthrough Generations Study is led by Professor Anthony Swerdlow, Head of the Section of Epidemiology at the ICR, and Professor Alan Ashworth, Chief Executive of the ICR and formerly head of the Breakthrough Breast Cancer Research Centre at the ICR.
Familial concordance for age at menarche: analysis from the Breakthrough Generations Study publishes today in the journal Paediatric and Perinatal Epidemiology
About breast cancer
Breast cancer is the most commonly diagnosed cancer in the UK - nearly 46,000 women and around 300 men are diagnosed every year
Breast cancer accounts for nearly one in three of all female cancers
More than 1,000 women die of breast cancer every month in the UK
The good news is that more women than ever in the UK are surviving breast cancer thanks to better awareness, better treatments and better screening
Source:
The Institute of Cancer Research (ICR)
Age at menarche (when periods begin) is known to run in families. However, the balance of genetic and environmental influences on this has been unclear.
Scientists at The Institute of Cancer Research (ICR) analysed data from women participating in the Breakthrough Generations Study - a major UK-wide investigation into the causes of breast cancer - who had at least one other female relative also taking part.
They found that a woman's age of menarche was significantly correlated with that of her relatives. For each 12 month delay in age at menarche of an older sister, mother or paternal aunt, there was a delay of around three months on average for the younger relative; and for a maternal grandmother or maternal aunt the delay in the younger relative was about 1.5 months. Age at menarche also strongly correlated between twins, particularly identical twins.
The researchers used mathematical modelling to find that genetic factors accounted for around 57 per cent of the variation in the age of menarche of women in the study. Environmental and behavioural factors from sharing an upbringing or family life did not appear to have any detectable effect; environmental factors not shared within families accounted for the other 43 per cent in variation.
The age at which menstruation begins is important because it has been linked to risk of a number of chronic diseases including breast cancer. Risk of breast cancer gradually increases with progressively younger age at menarche and older age at menopause, possibly because women are exposed to female sex hormones for a longer period of time. Each two year delay in menarche is associated with an estimated 10 per cent reduction in the relative risk of breast cancer.
"Our study findings suggest that genetic factors have a major influence on the age women in the UK begin menstruating, and these could have an impact on breast cancer risk," lead author Danielle Morris of the ICR says. "Although some genes associated with age at menarche have been found, considerable genetic variation remains to be explained."
The Breakthrough Generations Study is a comprehensive analysis of the causes of breast cancer. A partnership between Breakthrough Breast Cancer and the ICR, it began in 2003 and will follow more than 100,000 women participants for the next 40 years to unravel the lifestyle, environmental and genetic factors that cause the disease.
This arm of the study was funded by Breakthrough Breast Cancer, the ICR and the Sir John Fisher Foundation.
The Breakthrough Generations Study is led by Professor Anthony Swerdlow, Head of the Section of Epidemiology at the ICR, and Professor Alan Ashworth, Chief Executive of the ICR and formerly head of the Breakthrough Breast Cancer Research Centre at the ICR.
Familial concordance for age at menarche: analysis from the Breakthrough Generations Study publishes today in the journal Paediatric and Perinatal Epidemiology
About breast cancer
Breast cancer is the most commonly diagnosed cancer in the UK - nearly 46,000 women and around 300 men are diagnosed every year
Breast cancer accounts for nearly one in three of all female cancers
More than 1,000 women die of breast cancer every month in the UK
The good news is that more women than ever in the UK are surviving breast cancer thanks to better awareness, better treatments and better screening
Source:
The Institute of Cancer Research (ICR)
вторник, 20 сентября 2011 г.
Parkinson's Disease: Blood-Related Genetic Mechanisms Important
What does the genetics of blood cells have to do with brain cells related to Parkinson's disease? From an unusual collaboration of neurologists and a pharmacologist comes the surprising answer: Genetic mechanisms at play in blood cells also control a gene and protein that cause Parkinson's disease.
The finding, by scientists from the University of Wisconsin School of Medicine and Public Health (SMPH), Harvard University-affiliated Brigham and Women's Hospital and the University of Ottawa, may lead to new treatments for the neurological disorder that affects as many as 1.5 million Americans.
The study is published in the Proceedings of the National Academy of Sciences Online Early Edition the week of July 21-25, 2008.
Patients with Parkinson's disease (PD) have elevated levels of the protein called alpha-synuclein in their brains. As the protein clumps, or aggregates, the resulting toxicity causes the death of neurons that produce the brain chemical dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.
The researchers discovered that the activity of three genes that control the synthesis of heme, the major component of hemoglobin that allows red blood cells to carry oxygen, precisely matched the activity of the alpha-synuclein gene, suggesting a common switch controlling both.
The scientists then found that a protein called GATA-1, which turns on the blood-related genes, was also a major switch for alpha-synuclein expression, and that it induced a significant increase in alpha-synuclein protein. Finally, they demonstrated that a related protein - GATA-2 - was expressed in PD-vulnerable brain cells and directly controlled alpha-synuclein production.
"Very little was known previously about what turns on alpha-synuclein in brain cells and causes variations in its expression," says Emery Bresnick, a UW-Madison professor of pharmacology who is an expert on GATA factors and their functions in blood. "Understanding how GATA factors work in the brain may provide fundamental insights into the biology of Parkinson's disease."
The new knowledge also may allow scientists to design therapies that keep alpha-synuclein levels within the normal range.
"Simply lowering alpha-synuclein levels by 40 percent may be enough to treat some forms of Parkinson's disease," says Dr. Clemens Scherzer of Harvard. "So far, researchers have focused on ways to get rid of too much 'bad' alpha-synuclein in Parkinson patients' brains. Now we will be able to tackle the problem from the production site, and search for new therapies that lower alpha-synuclein production up front."
Scherzer and Dr. Michael Schlossmacher, now at Ottawa, had independently analyzed the blood of PD patients and controls in a search for genes that were active in the disease. They both were surprised to notice large amounts of alpha-synuclein in the blood. To understand what it was doing there, Scherzer's group used gene chip data to see whether any of the thousands of genes active in blood were linked to alpha-synuclein. They found a gene expression pattern composed of alpha-synuclein and the heme genes, one of which Bresnick had previously shown to be a direct GATA-1 target gene.
The neurologists contacted Bresnick. The UW group rapidly determined that GATA-1 directly activated the alpha-synuclein gene, and that finding led the collaborators to discover that GATA-2 is expressed in regions of the brain that are relevant to PD.
"We all were excited because we realized that GATA-2 was active in the relevant brain regions, and so there could be a connection," says Bresnick. Together the researchers set out to examine whether common mechanisms activated alpha-synuclein transcription in both the blood and nerve cells.
The studies showed that GATA-1 and GATA-2 proteins find the alpha-synuclein gene, stick to it and then directly control it.
"This is not an indirect pathway; it is direct regulation of the gene," says Bresnick. "This directness provides the simplest scenario for creating a therapeutic strategy."
Bresnick, Schlossmacher and Scherzer are working with geneticists to see if possible abnormalities in the GATA-2 gene may exist in PD patients, stimulating more production of alpha-syinuclein.
"The discovery of the link between GATA proteins and the alpha-synuclein gene is like finding a long-sought-after molecular switch," says Schlossmacher. "We were very fortunate to find in Emery Bresnick's team the ideal partner in this endeavor."
The family of GATA factors consists of six members, and some of them, beyond GATA-2, may also be influencing alpha-synuclein expression in the brain, adds Schlossmacher.
"Identifying these would further add to the complexity of regulating the production of the 'bad player' in Parkinson's disease," he says.
Says Bresnick, "The $10 million question will be: Does deregulation of the GATA mechanism in humans lead to alpha-synuclein overproduction and Parkinson's disease?"
Source: Dian Land
University of Wisconsin-Madison
The finding, by scientists from the University of Wisconsin School of Medicine and Public Health (SMPH), Harvard University-affiliated Brigham and Women's Hospital and the University of Ottawa, may lead to new treatments for the neurological disorder that affects as many as 1.5 million Americans.
The study is published in the Proceedings of the National Academy of Sciences Online Early Edition the week of July 21-25, 2008.
Patients with Parkinson's disease (PD) have elevated levels of the protein called alpha-synuclein in their brains. As the protein clumps, or aggregates, the resulting toxicity causes the death of neurons that produce the brain chemical dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.
The researchers discovered that the activity of three genes that control the synthesis of heme, the major component of hemoglobin that allows red blood cells to carry oxygen, precisely matched the activity of the alpha-synuclein gene, suggesting a common switch controlling both.
The scientists then found that a protein called GATA-1, which turns on the blood-related genes, was also a major switch for alpha-synuclein expression, and that it induced a significant increase in alpha-synuclein protein. Finally, they demonstrated that a related protein - GATA-2 - was expressed in PD-vulnerable brain cells and directly controlled alpha-synuclein production.
"Very little was known previously about what turns on alpha-synuclein in brain cells and causes variations in its expression," says Emery Bresnick, a UW-Madison professor of pharmacology who is an expert on GATA factors and their functions in blood. "Understanding how GATA factors work in the brain may provide fundamental insights into the biology of Parkinson's disease."
The new knowledge also may allow scientists to design therapies that keep alpha-synuclein levels within the normal range.
"Simply lowering alpha-synuclein levels by 40 percent may be enough to treat some forms of Parkinson's disease," says Dr. Clemens Scherzer of Harvard. "So far, researchers have focused on ways to get rid of too much 'bad' alpha-synuclein in Parkinson patients' brains. Now we will be able to tackle the problem from the production site, and search for new therapies that lower alpha-synuclein production up front."
Scherzer and Dr. Michael Schlossmacher, now at Ottawa, had independently analyzed the blood of PD patients and controls in a search for genes that were active in the disease. They both were surprised to notice large amounts of alpha-synuclein in the blood. To understand what it was doing there, Scherzer's group used gene chip data to see whether any of the thousands of genes active in blood were linked to alpha-synuclein. They found a gene expression pattern composed of alpha-synuclein and the heme genes, one of which Bresnick had previously shown to be a direct GATA-1 target gene.
The neurologists contacted Bresnick. The UW group rapidly determined that GATA-1 directly activated the alpha-synuclein gene, and that finding led the collaborators to discover that GATA-2 is expressed in regions of the brain that are relevant to PD.
"We all were excited because we realized that GATA-2 was active in the relevant brain regions, and so there could be a connection," says Bresnick. Together the researchers set out to examine whether common mechanisms activated alpha-synuclein transcription in both the blood and nerve cells.
The studies showed that GATA-1 and GATA-2 proteins find the alpha-synuclein gene, stick to it and then directly control it.
"This is not an indirect pathway; it is direct regulation of the gene," says Bresnick. "This directness provides the simplest scenario for creating a therapeutic strategy."
Bresnick, Schlossmacher and Scherzer are working with geneticists to see if possible abnormalities in the GATA-2 gene may exist in PD patients, stimulating more production of alpha-syinuclein.
"The discovery of the link between GATA proteins and the alpha-synuclein gene is like finding a long-sought-after molecular switch," says Schlossmacher. "We were very fortunate to find in Emery Bresnick's team the ideal partner in this endeavor."
The family of GATA factors consists of six members, and some of them, beyond GATA-2, may also be influencing alpha-synuclein expression in the brain, adds Schlossmacher.
"Identifying these would further add to the complexity of regulating the production of the 'bad player' in Parkinson's disease," he says.
Says Bresnick, "The $10 million question will be: Does deregulation of the GATA mechanism in humans lead to alpha-synuclein overproduction and Parkinson's disease?"
Source: Dian Land
University of Wisconsin-Madison
суббота, 17 сентября 2011 г.
Particle Trap Paves Way For Personalized Medicine
Sequencing DNA base pairs - the individual molecules that make up DNA - is key for medical researchers working toward personalized medicine. Being able to isolate, study and sequence these DNA molecules would allow scientists to tailor diagnostic testing, therapies and treatments based on each patient's individual genetic makeup.
But being able to isolate individual molecules like DNA base pairs, which are just two nanometers across - or about 1/50,000th the diameter of a human hair - is incredibly expensive and difficult to control. In addition, devising a way to trap DNA molecules in their natural aqueous environment further complicates things. Scientists have spent the past decade struggling to isolate and trap individual DNA molecules in an aqueous solution by trying to thread it through a tiny hole the size of DNA, called a "nanopore," which is exceedingly difficult to make and control.
Now a team led by Yale University researchers has proven that isolating individual charged particles, like DNA molecules, is indeed possible using a method called "Paul trapping," which uses oscillating electric fields to confine the particles to a space only nanometers in size. (The technique is named for Wolfgang Paul, who won the Nobel Prize for the discovery.) Until now, scientists have only been able to use Paul traps for particles in a vacuum, but the Yale team was able to confine a charged test particle - in this case, a polystyrene bead - to an accuracy of just 10 nanometers in aqueous solutions between quadruple microelectrodes that supplied the electric field.
Their device can be contained on a single chip and is simple and inexpensive to manufacture. "The idea would be that doctors could take a tiny drop of blood from patients and be able to run diagnostic tests on it right there in their office, instead of sending it away to a lab where testing can take days and is expensive," said Weihua Guan, a Yale engineering graduate student who led the project.
In addition to diagnostics, this "lab-on-a-chip" would have a wide range of applications, Guan said, such as being able to analyze how individual cells respond to different stimulation. While there are several other techniques for cell-manipulation available now, such as optical tweezers, the Yale team's approach actually works better as the size of the targets gets smaller, contrary to other approaches.
The team, whose findings appear in the May 23 Early Edition of the Proceedings of the National Academy of Sciences, used charged polystyrene beads rather than actual DNA molecules, along with a two-dimensional trap to prove that the technique worked. Next, they will work toward creating a 3-D trap using DNA molecules, which, at two nanometers, are even smaller than the test beads. They hope to have a working, 3-D trap using DNA molecules in the next year or two. The project is funded by a National Institutes of Health program that aims to sequence a patient's entire genome for less than $1,000.
"This is the future of personalized medicine," Guan said.
Notes:
The project was directed by Mark Reed (Yale University) and Predrag Krstic (Oak Ridge National Laboratory). Other authors of the paper include Sony Joseph and Jae Hyun Park (Oak Ridge National Laboratory).
DOI: 10.1073/pnas.1100977108
Source:
Suzanne Taylor Muzzin
Yale University
But being able to isolate individual molecules like DNA base pairs, which are just two nanometers across - or about 1/50,000th the diameter of a human hair - is incredibly expensive and difficult to control. In addition, devising a way to trap DNA molecules in their natural aqueous environment further complicates things. Scientists have spent the past decade struggling to isolate and trap individual DNA molecules in an aqueous solution by trying to thread it through a tiny hole the size of DNA, called a "nanopore," which is exceedingly difficult to make and control.
Now a team led by Yale University researchers has proven that isolating individual charged particles, like DNA molecules, is indeed possible using a method called "Paul trapping," which uses oscillating electric fields to confine the particles to a space only nanometers in size. (The technique is named for Wolfgang Paul, who won the Nobel Prize for the discovery.) Until now, scientists have only been able to use Paul traps for particles in a vacuum, but the Yale team was able to confine a charged test particle - in this case, a polystyrene bead - to an accuracy of just 10 nanometers in aqueous solutions between quadruple microelectrodes that supplied the electric field.
Their device can be contained on a single chip and is simple and inexpensive to manufacture. "The idea would be that doctors could take a tiny drop of blood from patients and be able to run diagnostic tests on it right there in their office, instead of sending it away to a lab where testing can take days and is expensive," said Weihua Guan, a Yale engineering graduate student who led the project.
In addition to diagnostics, this "lab-on-a-chip" would have a wide range of applications, Guan said, such as being able to analyze how individual cells respond to different stimulation. While there are several other techniques for cell-manipulation available now, such as optical tweezers, the Yale team's approach actually works better as the size of the targets gets smaller, contrary to other approaches.
The team, whose findings appear in the May 23 Early Edition of the Proceedings of the National Academy of Sciences, used charged polystyrene beads rather than actual DNA molecules, along with a two-dimensional trap to prove that the technique worked. Next, they will work toward creating a 3-D trap using DNA molecules, which, at two nanometers, are even smaller than the test beads. They hope to have a working, 3-D trap using DNA molecules in the next year or two. The project is funded by a National Institutes of Health program that aims to sequence a patient's entire genome for less than $1,000.
"This is the future of personalized medicine," Guan said.
Notes:
The project was directed by Mark Reed (Yale University) and Predrag Krstic (Oak Ridge National Laboratory). Other authors of the paper include Sony Joseph and Jae Hyun Park (Oak Ridge National Laboratory).
DOI: 10.1073/pnas.1100977108
Source:
Suzanne Taylor Muzzin
Yale University
среда, 14 сентября 2011 г.
NIST, Army Researchers Pave The Way For Anthrax Spore Standards
Researchers from the National Institute of Standards and Technology (NIST) and the U.S. Army Dugway (Utah) Proving Ground have developed reliable methods based on DNA analysis to assess the concentration and viability of anthrax spores after prolonged storage. The techniques and data are essential steps in developing a reliable reference standard for anthrax detection and decontamination.
Bacillus anthracis, the bacterium that causes anthrax, has been a centuries-old threat to human health. In 2001, it was used as a letter-borne terrorist weapon that killed five Americans. Since the tenacious bacterium can survive for decades in a stable spore state, the Department of Homeland Security (DHS) has been working with NIST to develop anthrax spore reference materials. These materials could be used as controls in laboratory studies of anthrax, to calibrate spore detection equipment and to assess the efficiency of spore decontamination methods.
Because sample stability is a key requirement for reference materials, NIST and Army researchers recently compared different methods for measuring the concentration, biological activity and stability of laboratory-grade Bacillus anthracis spores under different storage conditions. Bacillus anthracis (Sterne), a harmless vaccine strain, was used in the study. The results of the research will be published in an upcoming issue of the Journal of Applied Microbiology.*
Working with samples that had been stored up to 2 1/2 years, the research team used two classic microbiological techniques to quantify the Bacillus anthracis concentrations: counting spores under a microscope and counting the bacterial colonies that grow after the spores are spread on a nutrient surface and germinate. The latter yields valuable data on the biological activity of the samples; however, only viable cells are counted and counts may be underestimated if cell clumping occurs. A better approach is to measure the amount of genetic material present in the sample. This method not only measures the DNA extracted from viable anthrax spores but also DNA in solution from damaged spores, cell debris and spore fragments - giving a truer measure of the source of DNA in the samples. Additionally, many of the new instruments available for rapid detection of anthrax spores are based on DNA markers, so it is important to accurately measure the DNA content of the reference samples that will be used to test and calibrate these devices.
Traditional methods for extracting DNA from Bacillus anthracis spores are too harsh to produce material suitable for reliable measurements. To overcome this obstacle, the team developed an extraction technique that used chemicals and enzymes to disrupt intact spores into releasing their DNA in a relatively pure state.
The NIST-Army study showed that laboratory-grade Bacillus anthracis spores in suspension maintained their viability and did not clump when stored for up to 900 days. The classical method for counting spores yielded comparable results to the DNA measurements used to determine spore concentrations. The results demonstrate that research quality spores can be stored for long periods of time and still maintain their important properties, proving that uniform and consistent reference materials are possible.
* J.L. Almeida, B. Harper and K.D. Cole. Bacillus anthracis spore suspensions: determination of stability and comparison of enumeration techniques. Journal of Applied Microbiology, 2008.
Source: Michael E. Newman
National Institute of Standards and Technology (NIST)
Bacillus anthracis, the bacterium that causes anthrax, has been a centuries-old threat to human health. In 2001, it was used as a letter-borne terrorist weapon that killed five Americans. Since the tenacious bacterium can survive for decades in a stable spore state, the Department of Homeland Security (DHS) has been working with NIST to develop anthrax spore reference materials. These materials could be used as controls in laboratory studies of anthrax, to calibrate spore detection equipment and to assess the efficiency of spore decontamination methods.
Because sample stability is a key requirement for reference materials, NIST and Army researchers recently compared different methods for measuring the concentration, biological activity and stability of laboratory-grade Bacillus anthracis spores under different storage conditions. Bacillus anthracis (Sterne), a harmless vaccine strain, was used in the study. The results of the research will be published in an upcoming issue of the Journal of Applied Microbiology.*
Working with samples that had been stored up to 2 1/2 years, the research team used two classic microbiological techniques to quantify the Bacillus anthracis concentrations: counting spores under a microscope and counting the bacterial colonies that grow after the spores are spread on a nutrient surface and germinate. The latter yields valuable data on the biological activity of the samples; however, only viable cells are counted and counts may be underestimated if cell clumping occurs. A better approach is to measure the amount of genetic material present in the sample. This method not only measures the DNA extracted from viable anthrax spores but also DNA in solution from damaged spores, cell debris and spore fragments - giving a truer measure of the source of DNA in the samples. Additionally, many of the new instruments available for rapid detection of anthrax spores are based on DNA markers, so it is important to accurately measure the DNA content of the reference samples that will be used to test and calibrate these devices.
Traditional methods for extracting DNA from Bacillus anthracis spores are too harsh to produce material suitable for reliable measurements. To overcome this obstacle, the team developed an extraction technique that used chemicals and enzymes to disrupt intact spores into releasing their DNA in a relatively pure state.
The NIST-Army study showed that laboratory-grade Bacillus anthracis spores in suspension maintained their viability and did not clump when stored for up to 900 days. The classical method for counting spores yielded comparable results to the DNA measurements used to determine spore concentrations. The results demonstrate that research quality spores can be stored for long periods of time and still maintain their important properties, proving that uniform and consistent reference materials are possible.
* J.L. Almeida, B. Harper and K.D. Cole. Bacillus anthracis spore suspensions: determination of stability and comparison of enumeration techniques. Journal of Applied Microbiology, 2008.
Source: Michael E. Newman
National Institute of Standards and Technology (NIST)
воскресенье, 11 сентября 2011 г.
Biologists Pinpoint A Genetic Change That Helps Tumors Move To Other Parts Of The Body
MIT cancer biologists have identified a genetic change that makes lung tumors more likely to spread to other parts of the body. The findings, to be published in the April 6 online issue of Nature, offers new insight into how lung cancers metastasize and could help identify drug targets to combat metastatic tumors, which account for 90 percent of cancer deaths.
The researchers, led by Tyler Jacks, director of the David H. Koch Institute for Integrative Cancer Research at MIT, found the alteration while studying a mouse model of lung cancer. They then compared their mouse data to genetic profiles of human lung tumors and found that reduced activity of the same gene, NKX2-1, is associated with higher death rates for lung-cancer patients.
This study represents an important step in understanding how changes that disable this gene would make tumors more aggressive, says Monte Winslow, a senior postdoctoral associate in Jacks' lab and lead author of a paper.
Understanding the role of NKX2-1 may help scientists pursue drugs that could counteract its loss. Right now, "the sad reality is that if you could tell a patient whether their cancer has turned down this gene, you would know they will have a worse outcome, but it wouldn't change the treatment," Winslow says.
Winslow and his colleagues at the Koch Institute studied mice that are genetically programmed to develop lung tumors. The mice's lung cells can be induced to express an activated form of the cancer-causing gene Kras, and the tumor suppressor gene p53 is deleted. While all of those mice develop lung tumors, only a subset of those tumors metastasizes, suggesting that additional changes are required for the cancer to spread.
The researchers analyzed the genomes of metastatic and non-metastatic tumors in hopes of finding some genetic differences that would account for the discrepancy. The absence of NKX2-1 activity in metastatic tumors was the most striking difference, Winslow says.
The NKX2-1 gene codes for a transcription factor a protein that controls expression of other genes. Its normal function is to control development of the lung, as well as the thyroid and some parts of the brain. When cancerous cells turn down the expression of the gene, they appear to revert to an immature state and gain the ability to detach from the lungs and spread through the body, seeding new tumors.
Once the researchers identified NKX2-1 as a gene important to metastasis, they started to look into the effects of the genes that it regulates. They zeroed in on a gene called HMGA2, which had been previously implicated in other types of cancer. It appears that NKX2-1 represses HMGA2 in adult tissues. When NKX2-1 is shut off in cancer cells, HMGA2 turns back on and helps the tumor to become more aggressive.
They also found that human tumors with NKX2-1 missing and HMGA turned on tended to be metastatic, though not all metastatic tumors fit that profile.
It would be difficult to target NKX2-1 with a drug because it's much harder to develop drugs that turn a gene back on than shut it off, Winslow noted. A more promising possibility is targeting HMGA2 or other genes that NKX2-1 represses.
Jacks' lab is now looking at other types of cancer, to see if NKX2-1 or HMGA2 have the same role in other metastatic cancers. "It's great to find something that's important in lung cancer metastasis, but it would be even better if it controlled metastasis in even a subset of other cancer types," Winslow says.
Source: Massachusetts Institute of Technology (MIT)
The researchers, led by Tyler Jacks, director of the David H. Koch Institute for Integrative Cancer Research at MIT, found the alteration while studying a mouse model of lung cancer. They then compared their mouse data to genetic profiles of human lung tumors and found that reduced activity of the same gene, NKX2-1, is associated with higher death rates for lung-cancer patients.
This study represents an important step in understanding how changes that disable this gene would make tumors more aggressive, says Monte Winslow, a senior postdoctoral associate in Jacks' lab and lead author of a paper.
Understanding the role of NKX2-1 may help scientists pursue drugs that could counteract its loss. Right now, "the sad reality is that if you could tell a patient whether their cancer has turned down this gene, you would know they will have a worse outcome, but it wouldn't change the treatment," Winslow says.
Winslow and his colleagues at the Koch Institute studied mice that are genetically programmed to develop lung tumors. The mice's lung cells can be induced to express an activated form of the cancer-causing gene Kras, and the tumor suppressor gene p53 is deleted. While all of those mice develop lung tumors, only a subset of those tumors metastasizes, suggesting that additional changes are required for the cancer to spread.
The researchers analyzed the genomes of metastatic and non-metastatic tumors in hopes of finding some genetic differences that would account for the discrepancy. The absence of NKX2-1 activity in metastatic tumors was the most striking difference, Winslow says.
The NKX2-1 gene codes for a transcription factor a protein that controls expression of other genes. Its normal function is to control development of the lung, as well as the thyroid and some parts of the brain. When cancerous cells turn down the expression of the gene, they appear to revert to an immature state and gain the ability to detach from the lungs and spread through the body, seeding new tumors.
Once the researchers identified NKX2-1 as a gene important to metastasis, they started to look into the effects of the genes that it regulates. They zeroed in on a gene called HMGA2, which had been previously implicated in other types of cancer. It appears that NKX2-1 represses HMGA2 in adult tissues. When NKX2-1 is shut off in cancer cells, HMGA2 turns back on and helps the tumor to become more aggressive.
They also found that human tumors with NKX2-1 missing and HMGA turned on tended to be metastatic, though not all metastatic tumors fit that profile.
It would be difficult to target NKX2-1 with a drug because it's much harder to develop drugs that turn a gene back on than shut it off, Winslow noted. A more promising possibility is targeting HMGA2 or other genes that NKX2-1 represses.
Jacks' lab is now looking at other types of cancer, to see if NKX2-1 or HMGA2 have the same role in other metastatic cancers. "It's great to find something that's important in lung cancer metastasis, but it would be even better if it controlled metastasis in even a subset of other cancer types," Winslow says.
Source: Massachusetts Institute of Technology (MIT)
четверг, 8 сентября 2011 г.
Gender And Genes Impact On Fat Storage - Belly Or Hip
The age-old question of why men store fat in their bellies and women store it in their hips may have finally been answered: Genetically speaking, the fat tissue is almost completely different.
"We found that out of about 40,000 mouse genes, only 138 are commonly found in both male and female fat cells," said Dr. Deborah Clegg, assistant professor of internal medicine at UT Southwestern Medical Center and senior author of the study appearing in the International Journal of Obesity. "This was completely unexpected. We expected the exact opposite - that 138 would be different and the rest would be the same between the sexes."
The study involved mice, which distribute their fat in a sexually dimorphic pattern similar to humans.
"Given the difference in gene expression profiles, a female fat tissue won't behave anything like a male fat tissue and vice versa," Dr. Clegg said. "The notion that fat cells between males and females are alike is inconsistent with our findings."
In humans, men are more likely to carry extra weight around their guts while pre-menopausal women store it in their butts, thighs and hips. The bad news for men is that belly, or visceral, fat has been associated with numerous obesity-related diseases including diabetes and heart disease. Women, on the other hand, are generally protected from these obesity-related disorders until menopause, when their ovarian hormone levels drop and fat storage tends to shift from their rear ends to their waists.
"Although our new findings don't explain why women begin storing fat in their bellies after menopause, the results do bring us a step closer to understanding the mechanisms behind the unwanted shift," Dr. Clegg said.
For this study, researchers used a microarray analysis to determine whether male fat cells and female fat cells were different between the waist and hips and if they were different based on gender at a genetic level.
Because the fat distribution patterns of male and female mice are similar to those of humans, the researchers used the animals to compare genes from the belly and hip fat pads of male mice, female mice and female mice whose ovaries had been removed - a condition that closely mimics human menopause. Waist and hip fat (subcutaneous fat) generally accumulates outside the muscle wall, whereas belly fat (visceral fat), a major health concern in men and postmenopausal women, develops around the internal organs.
In addition to the genetic differences among fat tissues, the researchers found that male mice that consumed a high-fat diet for 12 weeks gained more weight than female mice on the same diet. The males' fat tissue, particularly their belly fat, became highly inflamed, while the females had lower levels of genes associated with inflammation. The female mice whose ovaries had been removed, however, gained weight on the high-fat diet more like the males and deposited this fat in their bellies, also like the males.
"The fat of the female mice whose ovaries had been removed was inflamed and was starting to look like the unhealthy male fat," Dr. Clegg said. "However, estrogen replacement therapy in the mice reduced the inflammation and returned their fat distribution to that of mice with their ovaries intact."
Dr. Clegg said the results suggest that hormones made by the ovaries may be critical in determining where fat is deposited. Her overall goal is to determine how fat tissue is affected by sex hormones and whether it would be possible to develop a "designer" hormone replacement therapy that protected postmenopausal women from belly fat and related diseases such as metabolic syndrome.
Researchers from Oregon Health and Science University, Boston University School of Medicine and the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University also contributed to the study. The study was supported by the Society for Women's Health Research.
Source:
Kristen Holland Shear
UT Southwestern Medical Center
"We found that out of about 40,000 mouse genes, only 138 are commonly found in both male and female fat cells," said Dr. Deborah Clegg, assistant professor of internal medicine at UT Southwestern Medical Center and senior author of the study appearing in the International Journal of Obesity. "This was completely unexpected. We expected the exact opposite - that 138 would be different and the rest would be the same between the sexes."
The study involved mice, which distribute their fat in a sexually dimorphic pattern similar to humans.
"Given the difference in gene expression profiles, a female fat tissue won't behave anything like a male fat tissue and vice versa," Dr. Clegg said. "The notion that fat cells between males and females are alike is inconsistent with our findings."
In humans, men are more likely to carry extra weight around their guts while pre-menopausal women store it in their butts, thighs and hips. The bad news for men is that belly, or visceral, fat has been associated with numerous obesity-related diseases including diabetes and heart disease. Women, on the other hand, are generally protected from these obesity-related disorders until menopause, when their ovarian hormone levels drop and fat storage tends to shift from their rear ends to their waists.
"Although our new findings don't explain why women begin storing fat in their bellies after menopause, the results do bring us a step closer to understanding the mechanisms behind the unwanted shift," Dr. Clegg said.
For this study, researchers used a microarray analysis to determine whether male fat cells and female fat cells were different between the waist and hips and if they were different based on gender at a genetic level.
Because the fat distribution patterns of male and female mice are similar to those of humans, the researchers used the animals to compare genes from the belly and hip fat pads of male mice, female mice and female mice whose ovaries had been removed - a condition that closely mimics human menopause. Waist and hip fat (subcutaneous fat) generally accumulates outside the muscle wall, whereas belly fat (visceral fat), a major health concern in men and postmenopausal women, develops around the internal organs.
In addition to the genetic differences among fat tissues, the researchers found that male mice that consumed a high-fat diet for 12 weeks gained more weight than female mice on the same diet. The males' fat tissue, particularly their belly fat, became highly inflamed, while the females had lower levels of genes associated with inflammation. The female mice whose ovaries had been removed, however, gained weight on the high-fat diet more like the males and deposited this fat in their bellies, also like the males.
"The fat of the female mice whose ovaries had been removed was inflamed and was starting to look like the unhealthy male fat," Dr. Clegg said. "However, estrogen replacement therapy in the mice reduced the inflammation and returned their fat distribution to that of mice with their ovaries intact."
Dr. Clegg said the results suggest that hormones made by the ovaries may be critical in determining where fat is deposited. Her overall goal is to determine how fat tissue is affected by sex hormones and whether it would be possible to develop a "designer" hormone replacement therapy that protected postmenopausal women from belly fat and related diseases such as metabolic syndrome.
Researchers from Oregon Health and Science University, Boston University School of Medicine and the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University also contributed to the study. The study was supported by the Society for Women's Health Research.
Source:
Kristen Holland Shear
UT Southwestern Medical Center
понедельник, 5 сентября 2011 г.
NYIT Professor Discovers Next Generation Of DNA And RNA Microarrays
A novel invention developed
by a scientist from New York Institute of Technology (NYIT) could
revolutionize biological and clinical research and may lead to treatments
for cancer, AIDS, Alzheimer's, diabetes, and genetic and infectious
diseases.
Since the discovery of DNA, biologists have worked to unlock the
secrets of the human cell. Scientist Claude E. Gagna, Ph.D., an associate
professor at NYIT's School of Health Professions, Behavioral and Life
Sciences, discovered how to immobilize intact double-stranded (ds-),
multi-stranded or alternative DNA and RNA on one microarray. This
immobilization allows scientists to duplicate the environment of a cell,
and study, examine and experiment with human, bacterial and viral genes.
This invention provides the methodology to analyze more than 150,000
non-denatured genes.
"This patent represents a leap forward from conventional DNA
microarrays that use hybridization," says Gagna, a molecular
biologist-pathologist who performs research in the structure-function of
DNA in normal and diseased cells. "This will help pharmaceutical companies
produce new classes of drugs that target genes, with fewer side effects,"
he adds. "It will lower the cost and increase the speed of drug discovery,
saving millions of dollars."
The "Gagna/NYIT Multi-Stranded and Alternative DNA, RNA and Plasmid
Microarray," has been patented (#6,936,461) in the United States and is
pending in Europe and Asia. Gagna's discovery will help scientists
understand how transitions in DNA structure regulate gene expression (B-DNA
to Z-DNA), and how DNA-protein, and DNA-drug interactions regulate genes.
The breakthrough can aid in genetic screening, clinical diagnosis,
forensics, DNA synthesis-sequencing and biodefense.
In the near future, practical applications of the patent will include
enabling researchers to directly target and inhibit mutated genes and/or
proteins that are responsible for pathologies, making it easier to treat or
even cure disease. A discussion of the patent and two new applications --
known as transitional structural chemogenomics and transitional structural
chemoproteomics -- was published in the May 2006 issue of Medical
Hypotheses (67:1099-1114).
Additionally, Gagna has developed a novel surface that increases the
adherence of the DNA to the microarray so that any type of nucleic acid can
be anchored. Unlike conventional microarrays, which immobilize
single-stranded DNA, scientists will now be able to "secure intact,
non-denatured, unaltered ds-DNA, triplex-, quadruplex-, or pentaplex DNA
onto the microarray," says Gagna. "With this technology, one day we will
have tailor-made molecular medicine for patients."
Invented in 1991, DNA microarrays have become one of the most powerful
research tools. Scientists are able to perform thousands of experiments
with incredible accuracy and speed. According to MarketResearch, by
2009, sales of DNA microarrays are projected to be more than $5.3 billion a
year.
Gagna, a resident of Palisades Park, N.J., performs research in his lab
at New York College of Osteopathic Medicine of NYIT. He is an adjunct
assistant professor at the New Jersey Medical School: Department's of
Pathology and Medicine. Gagna earned a Doctor of Philosophy in anatomy and
biochemistry from New York University (NYU), Basic Medical Sciences. He
completed his postdoctoral work at NYU and at New Jersey Medical School,
researching DNA. Gagna received a Master of Science in anatomy from
Fairleigh Dickinson University, and a Bachelor of Science in biology from
St. Peters College.
For more information about Gagna's patent, please visit
nyit.edu/dnamicroarrays.
About NYIT
NYIT is the college of choice for more than 14,000 students enrolled in
more than 100 specialized courses of study leading to undergraduate,
graduate and professional degrees in academic areas such as architecture
and design; arts and sciences; education and professional services;
engineering and technology; extended education; health professions,
behavioral and life sciences; management; and osteopathic medicine. As a
private, nonprofit, independent institution of higher learning, NYIT
embraces an educational philosophy of career-oriented professional
education for all qualified students and supports applications-oriented
research to benefit the greater global community. Students attend classes
at NYIT's campuses in Manhattan and Long Island, as well as online and in a
number of programs throughout the world. To date, more than 69,000 alumni
have earned degrees at NYIT. For more information, visit
nyit.edu.
New York Institute of Technology
nyit.edu
by a scientist from New York Institute of Technology (NYIT) could
revolutionize biological and clinical research and may lead to treatments
for cancer, AIDS, Alzheimer's, diabetes, and genetic and infectious
diseases.
Since the discovery of DNA, biologists have worked to unlock the
secrets of the human cell. Scientist Claude E. Gagna, Ph.D., an associate
professor at NYIT's School of Health Professions, Behavioral and Life
Sciences, discovered how to immobilize intact double-stranded (ds-),
multi-stranded or alternative DNA and RNA on one microarray. This
immobilization allows scientists to duplicate the environment of a cell,
and study, examine and experiment with human, bacterial and viral genes.
This invention provides the methodology to analyze more than 150,000
non-denatured genes.
"This patent represents a leap forward from conventional DNA
microarrays that use hybridization," says Gagna, a molecular
biologist-pathologist who performs research in the structure-function of
DNA in normal and diseased cells. "This will help pharmaceutical companies
produce new classes of drugs that target genes, with fewer side effects,"
he adds. "It will lower the cost and increase the speed of drug discovery,
saving millions of dollars."
The "Gagna/NYIT Multi-Stranded and Alternative DNA, RNA and Plasmid
Microarray," has been patented (#6,936,461) in the United States and is
pending in Europe and Asia. Gagna's discovery will help scientists
understand how transitions in DNA structure regulate gene expression (B-DNA
to Z-DNA), and how DNA-protein, and DNA-drug interactions regulate genes.
The breakthrough can aid in genetic screening, clinical diagnosis,
forensics, DNA synthesis-sequencing and biodefense.
In the near future, practical applications of the patent will include
enabling researchers to directly target and inhibit mutated genes and/or
proteins that are responsible for pathologies, making it easier to treat or
even cure disease. A discussion of the patent and two new applications --
known as transitional structural chemogenomics and transitional structural
chemoproteomics -- was published in the May 2006 issue of Medical
Hypotheses (67:1099-1114).
Additionally, Gagna has developed a novel surface that increases the
adherence of the DNA to the microarray so that any type of nucleic acid can
be anchored. Unlike conventional microarrays, which immobilize
single-stranded DNA, scientists will now be able to "secure intact,
non-denatured, unaltered ds-DNA, triplex-, quadruplex-, or pentaplex DNA
onto the microarray," says Gagna. "With this technology, one day we will
have tailor-made molecular medicine for patients."
Invented in 1991, DNA microarrays have become one of the most powerful
research tools. Scientists are able to perform thousands of experiments
with incredible accuracy and speed. According to MarketResearch, by
2009, sales of DNA microarrays are projected to be more than $5.3 billion a
year.
Gagna, a resident of Palisades Park, N.J., performs research in his lab
at New York College of Osteopathic Medicine of NYIT. He is an adjunct
assistant professor at the New Jersey Medical School: Department's of
Pathology and Medicine. Gagna earned a Doctor of Philosophy in anatomy and
biochemistry from New York University (NYU), Basic Medical Sciences. He
completed his postdoctoral work at NYU and at New Jersey Medical School,
researching DNA. Gagna received a Master of Science in anatomy from
Fairleigh Dickinson University, and a Bachelor of Science in biology from
St. Peters College.
For more information about Gagna's patent, please visit
nyit.edu/dnamicroarrays.
About NYIT
NYIT is the college of choice for more than 14,000 students enrolled in
more than 100 specialized courses of study leading to undergraduate,
graduate and professional degrees in academic areas such as architecture
and design; arts and sciences; education and professional services;
engineering and technology; extended education; health professions,
behavioral and life sciences; management; and osteopathic medicine. As a
private, nonprofit, independent institution of higher learning, NYIT
embraces an educational philosophy of career-oriented professional
education for all qualified students and supports applications-oriented
research to benefit the greater global community. Students attend classes
at NYIT's campuses in Manhattan and Long Island, as well as online and in a
number of programs throughout the world. To date, more than 69,000 alumni
have earned degrees at NYIT. For more information, visit
nyit.edu.
New York Institute of Technology
nyit.edu
пятница, 2 сентября 2011 г.
Revealing The Unique Survival Mechanisms Of A Single-Cell Marine Predator
University of British Columbia researchers have uncovered the unique survival mechanisms of a marine organism that may be tiny, but in some ways has surpassed sharks in its predatory efficiency.
Published in the journal Nature Communications, the research team's portrait of the microscopic dinoflagellate Oxyrrhis marina reveals a predator so efficient that it has even acquired a gene from its prey.
"It's an interesting case of Lateral Gene Transfer, or the movement of genes between distantly related species," says Patrick Keeling, a UBC botany professor and one of the study's authors.
"Our study shows that Oxyrrhis marina has picked up a gene commonly used by marine bacteria for photosynthesis. Oxyrrhis probably got this gene by eating the bacteria, but the really interesting part is that the gene produces a protein called rhodopsin, which is a photoreceptor that can make energy from light."
Humans possess similar proteins in our eyes, called opsin, that enable vision in low-light conditions, but cannot produce energy.
"It is very much a case of 'you are what you eat,' because Oxyrrhis marina has so much rhodopsin in its system that it has assumed the protein's signature pink colour," says Keeling. "Our hypothesis is that it is using the rhodopsin to harvest energy from light - as bacteria often do - but we think that it also uses the energy to help digest its prey, some of which were the original supplier of the gene. It is a really neat mix of metabolic strategies."
Oxyrrhis marina is part of a family of marine plankton that also includes the organisms responsible for harmful red tides. It is common in shallow waters such as tide pools around the world, including along the British Columbia coast. It has evolved extreme survival mechanisms, including the ones described in the UBC study. Oxyrrhis marina can cannibalize its own species when no other prey is available.
"It definitely deserves to be called a predator - it can feed on cells almost as big as itself," says Keeling, director of the Centre for Microbial Diversity and Evolution and a member of Beaty Biodiversity Research Centre at UBC. "It is also extremely tough to kill it."
Source:
Brian Lin
University of British Columbia
Published in the journal Nature Communications, the research team's portrait of the microscopic dinoflagellate Oxyrrhis marina reveals a predator so efficient that it has even acquired a gene from its prey.
"It's an interesting case of Lateral Gene Transfer, or the movement of genes between distantly related species," says Patrick Keeling, a UBC botany professor and one of the study's authors.
"Our study shows that Oxyrrhis marina has picked up a gene commonly used by marine bacteria for photosynthesis. Oxyrrhis probably got this gene by eating the bacteria, but the really interesting part is that the gene produces a protein called rhodopsin, which is a photoreceptor that can make energy from light."
Humans possess similar proteins in our eyes, called opsin, that enable vision in low-light conditions, but cannot produce energy.
"It is very much a case of 'you are what you eat,' because Oxyrrhis marina has so much rhodopsin in its system that it has assumed the protein's signature pink colour," says Keeling. "Our hypothesis is that it is using the rhodopsin to harvest energy from light - as bacteria often do - but we think that it also uses the energy to help digest its prey, some of which were the original supplier of the gene. It is a really neat mix of metabolic strategies."
Oxyrrhis marina is part of a family of marine plankton that also includes the organisms responsible for harmful red tides. It is common in shallow waters such as tide pools around the world, including along the British Columbia coast. It has evolved extreme survival mechanisms, including the ones described in the UBC study. Oxyrrhis marina can cannibalize its own species when no other prey is available.
"It definitely deserves to be called a predator - it can feed on cells almost as big as itself," says Keeling, director of the Centre for Microbial Diversity and Evolution and a member of Beaty Biodiversity Research Centre at UBC. "It is also extremely tough to kill it."
Source:
Brian Lin
University of British Columbia
вторник, 30 августа 2011 г.
Further Investment For Genomics Announced
The Economic and Social Research Council (ESRC) announced on 23 Oct continued funding, from 2007 to 2012, for its three research centres, CESAGen, EGENIS and INNOGEN, that, along with the ESRC Genomics Policy and Research Forum, make up the ESRC Genomics Network. As part of the 2000 and 2002 Spending Review, the ESRC received 10 million pounds to fund initiatives looking at the social and economic context of genomics.
The Centre for Economic and Social Aspects of Genomics (CESAGen), which will receive around 8 million pounds of funding over five years, is a Cardiff-Lancaster collaboration led by Professor Ruth Chadwick, in which researchers from the social sciences and the humanities work closely with those in the natural and medical sciences to address the social, economic and policy aspects of development in genomics. Key challenges in the next few years will include addressing the social dimensions of the applications of genomics in health service delivery, with reference to both common and rare diseases; and in areas such as food and nutrition, behaviour and criminal responsibility, and human enhancement.
EGENIS, the ESRC Centre for Genomics in Society, based at Exeter will receive almost 4 million pounds over the five years. EGENIS, headed by Professor John Dupre, is an interdisciplinary research centre looking at the social implications of contemporary genetic science especially in areas such as nutrigenomics, systems biology and gene therapy which have the potential to become highly contentious in society.
Innogen, a collaboration between Edinburgh University and the Open University, is the ESRC Centre for Social and Economic Research on Innovation in Genomics and will receive further funding of around 5 million pounds over five years. Innogen's research programme brings together social, medical and natural scientists to work on evolution of the new life science economy and the governance of innovation in the life sciences, in partnership with industry and private interest groups; policy makers and regulators; citizens and public interest groups, in genomics innovation. Taking over from Professor Joyce Tait, Innogen will also welcome a new Centre Director, Professor David Wield, from October 2007.
Commenting on the announcements, Adrian Alsop, Director for Research, Training and Development for the ESRC, said, "We are delighted to announce this second phase of funding for our genomics research centres. The unique ESRC Genomics Network allows us to work in collaboration with medical and natural scientists in order to build understanding in this area. The Network has quickly established a world leading presence for the UK in this important area. Insights from social science explain how genomic technologies can benefit our health service and realise the potential benefits that they bring to developing countries."
FOR FURTHER INFORMATION, CONTACT: Alexandra Saxon at ESRC
1. The ESRC is the UK's largest funding agency for research and postgraduate training relating to social and economic issues. It provides independent, high quality, relevant research to business, the public sector and Government. The ESRC's planned total expenditure in 2006-07 is ?169 million. At any one time the ESRC supports over 4,000 researchers and postgraduate students in academic institutions and research policy institutes. More at esrcsocietytoday.ac/
2. ESRC Society Today offers free access to a broad range of social science research and presents it in a way that makes it easy to navigate and saves users valuable time. As well as bringing together all ESRC-funded research (formerly accessible via the Regard website) and key online resources such as the Social Science Information Gateway and the UK Data Archive, non-ESRC resources are included, for example the Office for National Statistics. The portal provides access to early findings and research summaries, as well as full texts and original datasets through integrated search facilities. More at esrcsocietytoday.ac/
3. CESAGen works with natural scientists while conducting multidisciplinary research into the economic and social factors that shape genomic science, as applied not only to humans but also to plants and animals. In the light of considerable national and international attention to these issues, and increased public debate, CESAGen aims to undertake a programme of public engagement as well as feeding its research into policy circles. For more information visit: cesagen.lancs.ac/
4. Egenis is the ESRC Centre for Genomics in Society charged with researching the impact of genetic technologies in society. Egenis is part of the University of Exeter. For more information visit: ex.ac/egenis
5. Innogen is the ESRC Centre for Social and Economic Research on Innovation in Genomics. Formed in October 2002, it is part of the ESRC Genomics Network and studies the evolution of genomics and life sciences and their far-reaching social and economic implications. Innogen's research provides a sound base for decision-making in science, industry, policy and public arenas and improves our understanding of each of these groups and their interactions. Innogen is based at the University of Edinburgh in collaboration with The Open University. Staff working at Innogen include interdisciplinary researchers, social scientists, economists, and lawyers. Innogen also engages with a wide range of stakeholders, nationally and internationally. For more information visit: innogen.ac/
Contact: Annika Howard
Economic & Social Research Council
The Centre for Economic and Social Aspects of Genomics (CESAGen), which will receive around 8 million pounds of funding over five years, is a Cardiff-Lancaster collaboration led by Professor Ruth Chadwick, in which researchers from the social sciences and the humanities work closely with those in the natural and medical sciences to address the social, economic and policy aspects of development in genomics. Key challenges in the next few years will include addressing the social dimensions of the applications of genomics in health service delivery, with reference to both common and rare diseases; and in areas such as food and nutrition, behaviour and criminal responsibility, and human enhancement.
EGENIS, the ESRC Centre for Genomics in Society, based at Exeter will receive almost 4 million pounds over the five years. EGENIS, headed by Professor John Dupre, is an interdisciplinary research centre looking at the social implications of contemporary genetic science especially in areas such as nutrigenomics, systems biology and gene therapy which have the potential to become highly contentious in society.
Innogen, a collaboration between Edinburgh University and the Open University, is the ESRC Centre for Social and Economic Research on Innovation in Genomics and will receive further funding of around 5 million pounds over five years. Innogen's research programme brings together social, medical and natural scientists to work on evolution of the new life science economy and the governance of innovation in the life sciences, in partnership with industry and private interest groups; policy makers and regulators; citizens and public interest groups, in genomics innovation. Taking over from Professor Joyce Tait, Innogen will also welcome a new Centre Director, Professor David Wield, from October 2007.
Commenting on the announcements, Adrian Alsop, Director for Research, Training and Development for the ESRC, said, "We are delighted to announce this second phase of funding for our genomics research centres. The unique ESRC Genomics Network allows us to work in collaboration with medical and natural scientists in order to build understanding in this area. The Network has quickly established a world leading presence for the UK in this important area. Insights from social science explain how genomic technologies can benefit our health service and realise the potential benefits that they bring to developing countries."
FOR FURTHER INFORMATION, CONTACT: Alexandra Saxon at ESRC
1. The ESRC is the UK's largest funding agency for research and postgraduate training relating to social and economic issues. It provides independent, high quality, relevant research to business, the public sector and Government. The ESRC's planned total expenditure in 2006-07 is ?169 million. At any one time the ESRC supports over 4,000 researchers and postgraduate students in academic institutions and research policy institutes. More at esrcsocietytoday.ac/
2. ESRC Society Today offers free access to a broad range of social science research and presents it in a way that makes it easy to navigate and saves users valuable time. As well as bringing together all ESRC-funded research (formerly accessible via the Regard website) and key online resources such as the Social Science Information Gateway and the UK Data Archive, non-ESRC resources are included, for example the Office for National Statistics. The portal provides access to early findings and research summaries, as well as full texts and original datasets through integrated search facilities. More at esrcsocietytoday.ac/
3. CESAGen works with natural scientists while conducting multidisciplinary research into the economic and social factors that shape genomic science, as applied not only to humans but also to plants and animals. In the light of considerable national and international attention to these issues, and increased public debate, CESAGen aims to undertake a programme of public engagement as well as feeding its research into policy circles. For more information visit: cesagen.lancs.ac/
4. Egenis is the ESRC Centre for Genomics in Society charged with researching the impact of genetic technologies in society. Egenis is part of the University of Exeter. For more information visit: ex.ac/egenis
5. Innogen is the ESRC Centre for Social and Economic Research on Innovation in Genomics. Formed in October 2002, it is part of the ESRC Genomics Network and studies the evolution of genomics and life sciences and their far-reaching social and economic implications. Innogen's research provides a sound base for decision-making in science, industry, policy and public arenas and improves our understanding of each of these groups and their interactions. Innogen is based at the University of Edinburgh in collaboration with The Open University. Staff working at Innogen include interdisciplinary researchers, social scientists, economists, and lawyers. Innogen also engages with a wide range of stakeholders, nationally and internationally. For more information visit: innogen.ac/
Contact: Annika Howard
Economic & Social Research Council
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