The activity of supposed 'dark matter' between the genes seems to be mostly noise from the genes themselves. NWO researcher Harm van Bakel researched RNA transcripts particles of copied DNA the function of which has been a mystery until now. He reached the conclusion that we need not assign any unexplained biological function to them. The results of his research were published by the open access journal PLoS BIOLOGY.
DNA provides instructions for the manufacture of proteins, which in turn make up our bodies. The DNA sends these instruction messages in the form of an RNA transcript. Over recent decades, however, researchers have discovered RNA transcripts that could not be traced back to the known genes and that had no demonstrable function. They compared this phenomenon with the 'dark matter' in the universe: widespread, but with nobody actually knowing its function. Many biologists suspect that the uprooted RNA transcripts have an important biological function, which has simply eluded people until now. Harm van Bakel has shown that this is unlikely.
Two percent of origins unknown
Harm van Bakel combined two measurement methods to find out where the odd RNA transcripts had come from. He used DNA chips and DNA sequence analysis. The latter method allowed Van Bakel to chart the origins of millions of fragments of transcripts. It turned out that 98% of the RNA transcripts actually came from known genes. The majority of the remaining 2% came from the vicinity of a known gene. The 'dark matter transcripts' are not, therefore, new signs of a hitherto hidden universe within the genome, but are probably simply the result of the noise associated with active genetic processes.
The fact that most of the 'dark matter transcripts' are the result of the activity of known genes also provides a new understanding of how the genome operates. It appears that the machinery responsible for gene expression is not as meticulous as it could be. Van Bakel's article can be consulted free of charge on the website of PLoS BIOLOGY.
Rubicon
The young researcher performed his research at the University of Toronto. The Netherlands Organisation for Scientific Research (NWO) financed his two-year residence at the Canadian university. Harm van Bakel was awarded a Rubicon Grant by NWO in 2006. Dutch researchers who have recently gained their doctorates can gain research experience in other countries using Rubicon.
Source: NWO (Netherlands Organization for Scientific Research)
вторник, 31 мая 2011 г.
понедельник, 30 мая 2011 г.
New Findings On Mercury Content In Salmon
A new study published in Environmental Toxicology
and Chemistry finds that although mercury levels in both wild
and farmed salmon from British Columbia are substantially below human
health consumption guidelines, the levels found in wild salmon were
three times higher than in farmed salmon.
A large proportion of the farmed salmon consumed in the United States
originates in British Columbia, Canada. Over the years, there have been
health concerns because high levels of methylmercury have been found in
long-lived fish species nearer to the top of the food chain - such as
tuna and salmon. High mercury levels have been associated with an
increase in the risk of cancer, and this has led many people to avoid
consuming certain fishes.
This most recent study has determined that levels of mercury and other
trace metals measured in both farmed and wild salmon were significantly
below
Health Canada's consumption guidelines. Compared to wild salmon, the
researchers found that farmed salmon did not
have significantly higher concentrations of metals such as arsenic,
cobalt, copper, or
cadmium. The threefold higher mercury concentration observed in the
flesh of wild salmon than in farmed salmon is potentially explained by
farmed salmon's low gastrointestinal absorption efficiency, its
negligible transfer of metals to muscle tissue, and its rapid growth
cycles (growth dilution). In farmed fish, there were no differences in
metal levels found between pre- and post-processing.
For comparison to other parts of the human diet, the researchers
indicate that total mercury levels were slightly
higher in wild or farmed salmon than in chicken, beef, or pork and
about the same as in fruit, vegetables, honey, and eggs. Compared to
other foods, salmon contains lower levels of other trace elements. The
average dietary intake of mercury and trace metals from salmon still
remains a paltry 0.05% to 32% compared to the 68% to 99% that is
absorbed from meat, poultry, fruit, and vegetables. Salmon
also contains its own protection against mercury in the form of the
element selenium. The moderate surplus of this metal can counteract
mercury's toxicity.
"Estimates of human dietary exposure indicate that human health risks
associated with trace metal exposure via consumption of farmed and wild
British Columbia salmon are negligible," conclude the authors. "The
current scientific evidence therefore supports the weekly consumption
of oily fish species (including all British Columbia salmon sources) as
recommended by the American Heart Association."
Mercury and Other Trace Elements in Farmed
and Wild Salmon from British Columbia, Canada
Barry C. Kelly, Michael
G. Ikonomou, David A. Higgs, Janice Oakes, and Cory Dubetz
Environmental Toxicology and Chemistry (2008). Vol.
27(6):1361-1370.
Click
here to view paper
Written by: Peter M Crosta
and Chemistry finds that although mercury levels in both wild
and farmed salmon from British Columbia are substantially below human
health consumption guidelines, the levels found in wild salmon were
three times higher than in farmed salmon.
A large proportion of the farmed salmon consumed in the United States
originates in British Columbia, Canada. Over the years, there have been
health concerns because high levels of methylmercury have been found in
long-lived fish species nearer to the top of the food chain - such as
tuna and salmon. High mercury levels have been associated with an
increase in the risk of cancer, and this has led many people to avoid
consuming certain fishes.
This most recent study has determined that levels of mercury and other
trace metals measured in both farmed and wild salmon were significantly
below
Health Canada's consumption guidelines. Compared to wild salmon, the
researchers found that farmed salmon did not
have significantly higher concentrations of metals such as arsenic,
cobalt, copper, or
cadmium. The threefold higher mercury concentration observed in the
flesh of wild salmon than in farmed salmon is potentially explained by
farmed salmon's low gastrointestinal absorption efficiency, its
negligible transfer of metals to muscle tissue, and its rapid growth
cycles (growth dilution). In farmed fish, there were no differences in
metal levels found between pre- and post-processing.
For comparison to other parts of the human diet, the researchers
indicate that total mercury levels were slightly
higher in wild or farmed salmon than in chicken, beef, or pork and
about the same as in fruit, vegetables, honey, and eggs. Compared to
other foods, salmon contains lower levels of other trace elements. The
average dietary intake of mercury and trace metals from salmon still
remains a paltry 0.05% to 32% compared to the 68% to 99% that is
absorbed from meat, poultry, fruit, and vegetables. Salmon
also contains its own protection against mercury in the form of the
element selenium. The moderate surplus of this metal can counteract
mercury's toxicity.
"Estimates of human dietary exposure indicate that human health risks
associated with trace metal exposure via consumption of farmed and wild
British Columbia salmon are negligible," conclude the authors. "The
current scientific evidence therefore supports the weekly consumption
of oily fish species (including all British Columbia salmon sources) as
recommended by the American Heart Association."
Mercury and Other Trace Elements in Farmed
and Wild Salmon from British Columbia, Canada
Barry C. Kelly, Michael
G. Ikonomou, David A. Higgs, Janice Oakes, and Cory Dubetz
Environmental Toxicology and Chemistry (2008). Vol.
27(6):1361-1370.
Click
here to view paper
Written by: Peter M Crosta
воскресенье, 29 мая 2011 г.
Team Finds A Better Way To Watch Bacteria Swim
Researchers have developed a new method for studying bacterial swimming, one that allows them to trap Escherichia coli bacteria and modify the microbes' environment without hindering the way they move.
The new approach, described this month in Nature Methods, uses optical traps, microfluidic chambers and fluorescence to get an improved picture of how E. coli get around.
The microfluidic chambers provide a controlled environment in which the bacteria swim, and allow the researchers to introduce specific stimuli - such as chemical attractants - to see if the microbes change direction in response to that stimulus.
Optical traps use lasers to confine individual cells without impeding their rotation or the movement of their flagella. University of Illinois physics professor Yann Chemla, who co-led the study with physics professor Ido Golding, calls the optical traps "bacterial treadmills."
Movement of the bacterial cell alters the light from the laser, allowing the researchers to track its behavior.
Fluorescent markers enhance visualization of the bacteria and their flagella under a microscope.
Three to six helical flagella emerge from various points along E. coli's rod-shaped body. When they rotate in a counterclockwise fashion (as seen from behind), they gather into what looks like a coordinated bundle that pushes the bacterium forward, causing it to corkscrew through its environment. But when one or more flagella rotate in the opposite direction, they splay apart, reorienting the bacterium.
This "run and tumble" behavior has long been of interest to scientists for two reasons, Golding said. First, the elaborate mechanics of bacterial swimming "tell you a lot about biomechanics," he said. And second, "it serves as a paradigm for the way living cells process information from their environment."
Earlier studies have been unable to follow individual bacterial cells moving in three dimensions for more than about 30 seconds, the researchers said. And it is nearly impossible to determine what cues are spurring a cell to move in a given direction. The new method addresses both of these problems without altering the normal behavior of the bacterium, they found.
"Because the cell is immobilized, what we do is change the environment around it," Chemla said. "We can set up a flow cell that has two different concentrations of some chemical, for example, and see how the bacterium responds. Technically we're moving the swimming pool relative to the swimmer," he said.
The new approach allows the researchers to track a single bacterium as it swims for up to an hour, "which is orders of magnitude above what people could do before," Golding said. This will offer a new look at questions that so far have been unanswerable, he said.
"For example, some people have asked whether E. coli has a nose. Does it have a front and back?" Golding said. The team's observations indicate that while the bacterium can travel in either direction, most E. coli have "a pronounced preference" for one over the other, he said.
The researchers found that after most tumbles, a bacterium usually continued swimming in the same general direction, but that about one in six tumbles caused it to change direction completely. They were also able to quantify other features of bacterial swimming, such as changes in velocity and the time spent running and tumbling. The new technique will allow researchers to address many more questions about this model organism, they said.
"That's the typical way biology moves forward," Golding said. "You develop a new measurement capability and then you can use that to go back and look at fundamental questions that people had been looking at but had no way of answering."
The study is a project of the National Science Foundation's Center for the Physics of Living Cells at the University of Illinois, which promotes collaboration across disciplines, the researchers said.
Source:
Diana Yates
University of Illinois at Urbana-Champaign
The new approach, described this month in Nature Methods, uses optical traps, microfluidic chambers and fluorescence to get an improved picture of how E. coli get around.
The microfluidic chambers provide a controlled environment in which the bacteria swim, and allow the researchers to introduce specific stimuli - such as chemical attractants - to see if the microbes change direction in response to that stimulus.
Optical traps use lasers to confine individual cells without impeding their rotation or the movement of their flagella. University of Illinois physics professor Yann Chemla, who co-led the study with physics professor Ido Golding, calls the optical traps "bacterial treadmills."
Movement of the bacterial cell alters the light from the laser, allowing the researchers to track its behavior.
Fluorescent markers enhance visualization of the bacteria and their flagella under a microscope.
Three to six helical flagella emerge from various points along E. coli's rod-shaped body. When they rotate in a counterclockwise fashion (as seen from behind), they gather into what looks like a coordinated bundle that pushes the bacterium forward, causing it to corkscrew through its environment. But when one or more flagella rotate in the opposite direction, they splay apart, reorienting the bacterium.
This "run and tumble" behavior has long been of interest to scientists for two reasons, Golding said. First, the elaborate mechanics of bacterial swimming "tell you a lot about biomechanics," he said. And second, "it serves as a paradigm for the way living cells process information from their environment."
Earlier studies have been unable to follow individual bacterial cells moving in three dimensions for more than about 30 seconds, the researchers said. And it is nearly impossible to determine what cues are spurring a cell to move in a given direction. The new method addresses both of these problems without altering the normal behavior of the bacterium, they found.
"Because the cell is immobilized, what we do is change the environment around it," Chemla said. "We can set up a flow cell that has two different concentrations of some chemical, for example, and see how the bacterium responds. Technically we're moving the swimming pool relative to the swimmer," he said.
The new approach allows the researchers to track a single bacterium as it swims for up to an hour, "which is orders of magnitude above what people could do before," Golding said. This will offer a new look at questions that so far have been unanswerable, he said.
"For example, some people have asked whether E. coli has a nose. Does it have a front and back?" Golding said. The team's observations indicate that while the bacterium can travel in either direction, most E. coli have "a pronounced preference" for one over the other, he said.
The researchers found that after most tumbles, a bacterium usually continued swimming in the same general direction, but that about one in six tumbles caused it to change direction completely. They were also able to quantify other features of bacterial swimming, such as changes in velocity and the time spent running and tumbling. The new technique will allow researchers to address many more questions about this model organism, they said.
"That's the typical way biology moves forward," Golding said. "You develop a new measurement capability and then you can use that to go back and look at fundamental questions that people had been looking at but had no way of answering."
The study is a project of the National Science Foundation's Center for the Physics of Living Cells at the University of Illinois, which promotes collaboration across disciplines, the researchers said.
Source:
Diana Yates
University of Illinois at Urbana-Champaign
суббота, 28 мая 2011 г.
Update On Jungle Yellow Fever (JYF) In Brazil, Paraguay, And Argentina
Yellow fever is a zoonosis of the tropical regions of South America and Africa, which occurs in two distinct epidemiologic cycles: jungle and urban. In the jungle cycle, the virus spreads among monkeys and humans, who may be infected when they enter the jungle and are bitten by mosquitoes infected with the yellow fever virus. Urban yellow fever has long been eradicated from the Americas, with the last cases occurring in Brazil in 1942.
Since the 1970s, the area where jungle yellow fever (JYF) cases have occurred has been restricted to the northern region of the South American continent. From 1985 to December 2007, 3,837 cases of JYF have been reported, with 2,229 deaths.
In 2007 and the beginning of 2008, Brazil reported an intense and extensive epizootic of Jungle Yellow Fever in an area encompassing 6 states (GoiГЎs, the Federal District, Mato Grosso do Sul, Minas Gerais, Tocantins, and SГЈo Paulo). The State Health Departments have confirmed the epizootic based on laboratory and clinical epidemiological criteria. In the past two months, 26 confirmed human cases were reported in 3 Federal States (GoiГЎs, Mato Grosso do Sul, and the Federal District); 13 of the patients died. The affected areas have high vaccination coverage. Nevertheless, as part of ongoing control measures, health authorities have intensified vaccination for people living in or traveling to affected areas.
On 15 January 2008, the national health authorities of Paraguay reported their first confirmed cases of Jungle Yellow Fever. One of the cases was confirmed using molecular techniques; the other four, by epidemiological nexus. As of 11 February 2008, 4 other suspected cases of JYF have been reported. All the confirmed cases reported by the national health authorities come from a rural area of San Pedro department in the northern part of the country. National health authorities have intensified epidemiological surveillance for the detection and investigation of suspected cases, and yellow fever vaccination for people living in or traveling to the affected area.
On 17 January 2008, the national health authorities of Argentina reported finding dead monkeys in PiГ±alito Park, San Pedro department, Misiones province. On 4 February 2008, yellow fever was confirmed in one of the primates using molecular techniques. Although there is high vaccination coverage in the area, national health authorities have intensified vaccination for people living in or traveling to the affected area with no previous vaccination history.
For many years, jungle yellow fever has caused numerous high-mortality epidemics. The clinical manifestations of infection from the yellow fever virus can vary greatly, from asymptomatic or subclinical forms with non-specific symptoms, to hemorrhagic fever, which develops in 15-25% of infected patients and which presents a case fatality of around 50%.
Currently, the recommended strategy for vaccination against yellow fever is to focus on protecting the population living in or traveling to areas with any risk of transmission, where epizootics or human cases were recently reported, thus avoiding massive vaccination and re-vaccination.
The Pan American Health Organization is providing technical support to these countries through advisors in its Country Offices and at Headquarters in Washington, DC, in accordance with requests from the countries.
The Pan American Health Organization, founded in 1902, works with all the countries of the Americas to improve the health and quality of life of their peoples. It serves as the Regional Office of the World Health Organization (WHO).
World Health Organization
Since the 1970s, the area where jungle yellow fever (JYF) cases have occurred has been restricted to the northern region of the South American continent. From 1985 to December 2007, 3,837 cases of JYF have been reported, with 2,229 deaths.
In 2007 and the beginning of 2008, Brazil reported an intense and extensive epizootic of Jungle Yellow Fever in an area encompassing 6 states (GoiГЎs, the Federal District, Mato Grosso do Sul, Minas Gerais, Tocantins, and SГЈo Paulo). The State Health Departments have confirmed the epizootic based on laboratory and clinical epidemiological criteria. In the past two months, 26 confirmed human cases were reported in 3 Federal States (GoiГЎs, Mato Grosso do Sul, and the Federal District); 13 of the patients died. The affected areas have high vaccination coverage. Nevertheless, as part of ongoing control measures, health authorities have intensified vaccination for people living in or traveling to affected areas.
On 15 January 2008, the national health authorities of Paraguay reported their first confirmed cases of Jungle Yellow Fever. One of the cases was confirmed using molecular techniques; the other four, by epidemiological nexus. As of 11 February 2008, 4 other suspected cases of JYF have been reported. All the confirmed cases reported by the national health authorities come from a rural area of San Pedro department in the northern part of the country. National health authorities have intensified epidemiological surveillance for the detection and investigation of suspected cases, and yellow fever vaccination for people living in or traveling to the affected area.
On 17 January 2008, the national health authorities of Argentina reported finding dead monkeys in PiГ±alito Park, San Pedro department, Misiones province. On 4 February 2008, yellow fever was confirmed in one of the primates using molecular techniques. Although there is high vaccination coverage in the area, national health authorities have intensified vaccination for people living in or traveling to the affected area with no previous vaccination history.
For many years, jungle yellow fever has caused numerous high-mortality epidemics. The clinical manifestations of infection from the yellow fever virus can vary greatly, from asymptomatic or subclinical forms with non-specific symptoms, to hemorrhagic fever, which develops in 15-25% of infected patients and which presents a case fatality of around 50%.
Currently, the recommended strategy for vaccination against yellow fever is to focus on protecting the population living in or traveling to areas with any risk of transmission, where epizootics or human cases were recently reported, thus avoiding massive vaccination and re-vaccination.
The Pan American Health Organization is providing technical support to these countries through advisors in its Country Offices and at Headquarters in Washington, DC, in accordance with requests from the countries.
The Pan American Health Organization, founded in 1902, works with all the countries of the Americas to improve the health and quality of life of their peoples. It serves as the Regional Office of the World Health Organization (WHO).
World Health Organization
пятница, 27 мая 2011 г.
Glycobiology: The Sheer Versatility Of Sugars - Glycobiology Is A Hot New Topic, A Science That Has Arrived And Blossomed In The Last Decade
The latest issue of The Biochemist puts glycobiology in perspective with an authoritative article on its origin by Professor Raymond Dwek and with reports from the cutting edge of this fascinating and vitally important new discipline. Read how it is making significant discoveries in the fields of molecular biology and in the fight against disease.
Also: the discovery of muscle biochemistry, how the structure of immunoglobin was found and what John Prescott is really like.
All this and much more in the latest issue of The Biochemist
Glycobiology at Oxford
By Raymond Dwek
How the study of oligosaccharides became glycobiology and became firmly established as part of mainstream biochemistry.
Recognizing glycans
By Kurt Drickamer and Maureen E. Taylor
Many well-understood examples of glycan-receptor interactions exist, but are there enough receptors to account for the number of glycans that are being identified?
Protein-carbohydrate interactions
By Nathan Sharon
Proteins that possess the ability to bind carbohydrates specifically and reversibly abound in nature, being present in all living organisms, from viruses to humans.
Glycobiology and medicine
By Pauline M. Rudd and Raymond A. Dwek
The bright future for high throughput glycan analysis and disease markers.
Glycobiology and viruses
By Nicole Zitzmann, Joanne M. O'Leary and Raymond Dwek
Most aspects of glycobiology play important roles in the 'life' of viruses, for example in the correct folding of their envelope glycoproteins as well as in immune representation and escape.
Raman optical activity
By Laurence D. Barron
A new light on proteins, carbohydrates and glycoproteins.
Q & A:
Interview with S. V. Perry
Flexing their muscles
By Michael P. Walsh
The Biochemical Journal classic papers of S. V. Perry and co-workers.
In the blood
By Michael A. Kerr
Rodney Porter and the structure of immunoglobulin.
The trap hypothesis
By Guy S. Salvesen
The classic Biochemical Journal paper of Alan Barrett and Phyllis Starkey.
48 Q & A:
Q. Is John Prescott a nice guy to work with?
A. Yes; the image of John given by the press and the media is very unfair.
Our exclusive interview with Phyllis Starkey, MP
Obituary
Helen Muir 1920-2005
By Tim Hardingham
biochemist/bio
Also: the discovery of muscle biochemistry, how the structure of immunoglobin was found and what John Prescott is really like.
All this and much more in the latest issue of The Biochemist
Glycobiology at Oxford
By Raymond Dwek
How the study of oligosaccharides became glycobiology and became firmly established as part of mainstream biochemistry.
Recognizing glycans
By Kurt Drickamer and Maureen E. Taylor
Many well-understood examples of glycan-receptor interactions exist, but are there enough receptors to account for the number of glycans that are being identified?
Protein-carbohydrate interactions
By Nathan Sharon
Proteins that possess the ability to bind carbohydrates specifically and reversibly abound in nature, being present in all living organisms, from viruses to humans.
Glycobiology and medicine
By Pauline M. Rudd and Raymond A. Dwek
The bright future for high throughput glycan analysis and disease markers.
Glycobiology and viruses
By Nicole Zitzmann, Joanne M. O'Leary and Raymond Dwek
Most aspects of glycobiology play important roles in the 'life' of viruses, for example in the correct folding of their envelope glycoproteins as well as in immune representation and escape.
Raman optical activity
By Laurence D. Barron
A new light on proteins, carbohydrates and glycoproteins.
Q & A:
Interview with S. V. Perry
Flexing their muscles
By Michael P. Walsh
The Biochemical Journal classic papers of S. V. Perry and co-workers.
In the blood
By Michael A. Kerr
Rodney Porter and the structure of immunoglobulin.
The trap hypothesis
By Guy S. Salvesen
The classic Biochemical Journal paper of Alan Barrett and Phyllis Starkey.
48 Q & A:
Q. Is John Prescott a nice guy to work with?
A. Yes; the image of John given by the press and the media is very unfair.
Our exclusive interview with Phyllis Starkey, MP
Obituary
Helen Muir 1920-2005
By Tim Hardingham
biochemist/bio
четверг, 26 мая 2011 г.
Treatment For Damaged Hearts Could Be Enhanced By Chymase Inhibitors
Millions of patients with high blood pressure and heart failure take a class of drugs known as ACE (angiotensin-converting enzyme) inhibitors. These drugs prevent the body from processing angiotensin II, a hormone that constricts blood vessels.
Scientists at Emory University, University of Alabama, Birmingham, and Fukuoka University in Japan have shown that another enzyme present in the heart called chymase is also capable of processing angiotensin II. Adding drugs that interfere with chymase to ACE inhibitors significantly boosted recovery of heart function in animals after heart attack, the researchers found.
The results, to be published in the April 2010 issue of the Journal of Clinical Investigation, could lead to improved treatments for people with high blood pressure, heart failure and other conditions.
"The development of ACE inhibitors was a major advance in the treatment of hypertension and heart failure, and they have become the standard of care," says senior author Ahsan Husain, PhD, professor of medicine (cardiology) at Emory University School of Medicine. "But ACE inhibitors don't work for everyone, and we think we have found a way to make them more effective."
Doctors have reported for years that taking an ACE inhibitor usually reduces a patient's blood pressure, but angiotensin II often returns to high levels over several months, a phenomenon called "ACE inhibitor escape." This is bad news because angiotensin II drives the release of other hormones, leading to fluid retention, and also has direct effects on the heart. For example, after a heart attack, it promotes scarring and enlargement of the heart. In addition, ACE inhibitors have been reported to be less effective for some population groups such as African Americans.
Sometimes an inadequate response to ACE inhibitors leads doctors to add drugs that can block some of angiotensin II's effects (angiotensin II receptor blockers), but the clinical evidence for an additional benefit from these drugs is still up for debate, Husain says.
Much of Husain's laboratory's research over the last 20 years has been aimed at understanding the production of angiotensin II in the heart. In 2008, Husain came to Emory from University of Alabama, Birmingham, where he had been working with the first author of the paper, assistant professor Chih-Chang (Kevin) Wei, PhD, and professor Louis Dell'Italia, MD. Naoki Hase at Teijin Pharma and Yukiko Inoue and Hidenori Urata, MD at Fukuoka University in Japan also contributed to the paper.
Wei, Husain and colleagues showed that chymase in the heart comes from mast cells, inflammatory cells that play a central role in allergies and asthma. Mast cells are missing in mice with mutations in the gene for the blood cell growth factor receptor c-kit. In these mice, angiotensin II almost disappears after treatment with ACE inhibitors. But giving normal mice ACE inhibitors induces mast cells to release chymase, restoring their ability to produce angiotensin II.
Previous research by Husain and Urata demonstrated that chymase activity is especially abundant in heart tissue from patients with heart failure. Inflammation arising from atherosclerosis or myocarditis may be attracting mast cells to the heart, Husain says.
To test whether chymase makes a difference in recovery after a heart attack, Wei, Husain and colleagues compared the effects of an experimental chymase inhibitor (provided by Teijin Pharma) to a standard ACE inhibitor on hamsters that had a simulated heart attack.
Combining the ACE inhibitor and the chymase inhibitor improved ejection fraction, a measure of heart function, and reduced the amount of dead tissue and scarring more than either drug by itself. The experiments on recovery after heart attack were performed on hamsters because mouse heart cells do not respond as much to angiotensin II as human or hamster heart cells do.
Chymase inhibitors are not available for clinical use, although pharmaceutical companies have begun investigations of their usefulness for conditions such as inflammatory bowel disease and asthma.
"Now, cardiovascular studies of chymase inhibitors in humans need to be done," Husain says. "Our hope is that pharmaceutical companies will see this as an opportunity to address a significant need."
The research was supported by the National Institutes of Health and the American Heart Association. Husain has received research funding from Teijin Pharma for a separate chymase-related project.
Reference: C.C. Wei et al Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme therapy in rodents J. Clin. Invest. 120, 1-11 (2010).
Source:
Jennifer Johnson
Emory University
Scientists at Emory University, University of Alabama, Birmingham, and Fukuoka University in Japan have shown that another enzyme present in the heart called chymase is also capable of processing angiotensin II. Adding drugs that interfere with chymase to ACE inhibitors significantly boosted recovery of heart function in animals after heart attack, the researchers found.
The results, to be published in the April 2010 issue of the Journal of Clinical Investigation, could lead to improved treatments for people with high blood pressure, heart failure and other conditions.
"The development of ACE inhibitors was a major advance in the treatment of hypertension and heart failure, and they have become the standard of care," says senior author Ahsan Husain, PhD, professor of medicine (cardiology) at Emory University School of Medicine. "But ACE inhibitors don't work for everyone, and we think we have found a way to make them more effective."
Doctors have reported for years that taking an ACE inhibitor usually reduces a patient's blood pressure, but angiotensin II often returns to high levels over several months, a phenomenon called "ACE inhibitor escape." This is bad news because angiotensin II drives the release of other hormones, leading to fluid retention, and also has direct effects on the heart. For example, after a heart attack, it promotes scarring and enlargement of the heart. In addition, ACE inhibitors have been reported to be less effective for some population groups such as African Americans.
Sometimes an inadequate response to ACE inhibitors leads doctors to add drugs that can block some of angiotensin II's effects (angiotensin II receptor blockers), but the clinical evidence for an additional benefit from these drugs is still up for debate, Husain says.
Much of Husain's laboratory's research over the last 20 years has been aimed at understanding the production of angiotensin II in the heart. In 2008, Husain came to Emory from University of Alabama, Birmingham, where he had been working with the first author of the paper, assistant professor Chih-Chang (Kevin) Wei, PhD, and professor Louis Dell'Italia, MD. Naoki Hase at Teijin Pharma and Yukiko Inoue and Hidenori Urata, MD at Fukuoka University in Japan also contributed to the paper.
Wei, Husain and colleagues showed that chymase in the heart comes from mast cells, inflammatory cells that play a central role in allergies and asthma. Mast cells are missing in mice with mutations in the gene for the blood cell growth factor receptor c-kit. In these mice, angiotensin II almost disappears after treatment with ACE inhibitors. But giving normal mice ACE inhibitors induces mast cells to release chymase, restoring their ability to produce angiotensin II.
Previous research by Husain and Urata demonstrated that chymase activity is especially abundant in heart tissue from patients with heart failure. Inflammation arising from atherosclerosis or myocarditis may be attracting mast cells to the heart, Husain says.
To test whether chymase makes a difference in recovery after a heart attack, Wei, Husain and colleagues compared the effects of an experimental chymase inhibitor (provided by Teijin Pharma) to a standard ACE inhibitor on hamsters that had a simulated heart attack.
Combining the ACE inhibitor and the chymase inhibitor improved ejection fraction, a measure of heart function, and reduced the amount of dead tissue and scarring more than either drug by itself. The experiments on recovery after heart attack were performed on hamsters because mouse heart cells do not respond as much to angiotensin II as human or hamster heart cells do.
Chymase inhibitors are not available for clinical use, although pharmaceutical companies have begun investigations of their usefulness for conditions such as inflammatory bowel disease and asthma.
"Now, cardiovascular studies of chymase inhibitors in humans need to be done," Husain says. "Our hope is that pharmaceutical companies will see this as an opportunity to address a significant need."
The research was supported by the National Institutes of Health and the American Heart Association. Husain has received research funding from Teijin Pharma for a separate chymase-related project.
Reference: C.C. Wei et al Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme therapy in rodents J. Clin. Invest. 120, 1-11 (2010).
Source:
Jennifer Johnson
Emory University
среда, 25 мая 2011 г.
Interstellar Chemical Created In The Lab
Chemists at the University of California, Riverside have created in the laboratory a type of molecules thought to exist only in interstellar space, which may have valuable applications in chemical industry.
The finding of their paper, titled Cyclopropenylidenes: From Interstellar Space to an Isolated Derivative in the Laboratory are being released today in Science Express a precursor to its publication in the journal Science. The co-authors are Vincent Lavallo, Yves Canac and Bruno Donnadieu who work in the laboratory of Distinguished Professor of Chemistry Guy Bertrand at UCR; and Chemistry Professor Wolfgang W. Schoeller of Germany's Universität Bielefeld.
"This is about a compound that is very abundant in deep space, which was supposed to not be able to exist in the laboratory, and we found a way to slightly modify it and make it stable," said Bertrand.
The new molecule belongs to a family of compounds known as carbenes, very few of which are stable. However, carbenes are now widely used to prepare catalysts that have many applications in industries such as pharmaceuticals, plastics and other petrochemicals. The cyclopropenylidene that exists naturally in space is made of three carbon atoms arranged in a triangle with two hydrogen atoms attached. The UCR researchers synthesized a more stable version by replacing the hydrogen with two nitrogen atoms. Because of its unique shape and size, the new carbene prepared at UCR might lead to even more powerful catalysts.
"We purposely targeted this molecule," said Lavallo, a first-year graduate student in Chemistry and the paper's lead author. "I was intrigued by some of the older literature regarding this class of molecules, which indicated that they were too reactive to be isolated, and decided to see if it was true."
"Everyday, scientists realize the usefulness of natural products, which exist on planet Earth, for pharmaceuticals, materials... Why not believe that molecules, which exist in space possess interesting and of course yet unknown properties?" Bertrand said.
Contact: Ricardo Duran
ricardo.duranucr
University of California - Riverside
The finding of their paper, titled Cyclopropenylidenes: From Interstellar Space to an Isolated Derivative in the Laboratory are being released today in Science Express a precursor to its publication in the journal Science. The co-authors are Vincent Lavallo, Yves Canac and Bruno Donnadieu who work in the laboratory of Distinguished Professor of Chemistry Guy Bertrand at UCR; and Chemistry Professor Wolfgang W. Schoeller of Germany's Universität Bielefeld.
"This is about a compound that is very abundant in deep space, which was supposed to not be able to exist in the laboratory, and we found a way to slightly modify it and make it stable," said Bertrand.
The new molecule belongs to a family of compounds known as carbenes, very few of which are stable. However, carbenes are now widely used to prepare catalysts that have many applications in industries such as pharmaceuticals, plastics and other petrochemicals. The cyclopropenylidene that exists naturally in space is made of three carbon atoms arranged in a triangle with two hydrogen atoms attached. The UCR researchers synthesized a more stable version by replacing the hydrogen with two nitrogen atoms. Because of its unique shape and size, the new carbene prepared at UCR might lead to even more powerful catalysts.
"We purposely targeted this molecule," said Lavallo, a first-year graduate student in Chemistry and the paper's lead author. "I was intrigued by some of the older literature regarding this class of molecules, which indicated that they were too reactive to be isolated, and decided to see if it was true."
"Everyday, scientists realize the usefulness of natural products, which exist on planet Earth, for pharmaceuticals, materials... Why not believe that molecules, which exist in space possess interesting and of course yet unknown properties?" Bertrand said.
Contact: Ricardo Duran
ricardo.duranucr
University of California - Riverside
вторник, 24 мая 2011 г.
Rensselaer researchers develop approach that predicts protein separation behavior
Applying math and computers to the drug-discovery process, researchers at Rensselaer Polytechnic Institute have developed a method to predict protein separation behavior directly from protein structure. This new multi-scale protein modeling approach may reduce the time it takes to bring pharmaceuticals to market and may have significant implications for an array of biotechnology applications, including bioprocessing, drug discovery, and proteomics, the study of protein structure and function.
"Predictive modeling is a new approach to drug discovery that takes information from lab analysis and concentrates it in predictive models that may be evaluated on a computer," said Curt M. Breneman, professor of chemistry and chemical biology at Rensselaer.
"The ability to predict the separation behavior of a particular protein directly from its structure has considerable implications for biotechnology processes," said Steven Cramer, professor of chemical and biological engineering at Rensselaer. "The research results thus far indicate that this modeling approach can be used to determine protein behavior for use in bioseparation applications, such as the protein purification methods used in drug discovery. This could potentially reduce the development time required to bring biopharmaceuticals to market."
The modeling technique is based on methods previously developed by Breneman's group for rapidly predicting the efficacy and side effects of small drug-like molecules. The newly developed model successfully predicted the amount of a protein that binds to a material under a range of conditions by using molecular information obtained from the protein structure. These predicted adsorption isotherm parameters then replicated experimental results by predicting the actual separation profile of proteins in chromatographic columns. Chromatography techniques are used to identify and purify molecules, in this case, particular proteins.
"We intend to test the model against more complicated protein structures as part of its further development," said Breneman. "The outcome of this work will yield fundamental information about the complex relationship between a protein's structural features and its chemical binding properties, and also aid in evaluating its potential biomedical applications."
The research findings are reported in the Aug. 16 issue of Proceedings of the National Academy of Sciences in a paper titled "A Priori Prediction of Adsorption Isotherm Parameters and Chromatographic Behavior in Ion-Exchange Systems."
In addition to Breneman and Cramer, the collaborative research team includes Asif Ladiwala and Kaushal Rege, who both recently earned doctorates in chemical and biological engineering at Rensselaer. The work was supported by the National Science Foundation and GE Healthcare.
The researchers' computational model uses a combination of molecular-level quantitative structure-property relationship models with macroscopic steric mass action isotherm models and support vector machine regression computations.
Biotechnology and Interdisciplinary Studies at Rensselaer
At Rensselaer, faculty and students in diverse academic and research disciplines are collaborating at the intersection of the life sciences and engineering to encourage discovery and innovation. Rensselaer's four biotechnology research constellations - biocatalysis and metabolic engineering, functional tissue engineering and regenerative medicine, biocomputation and bioinformatics, and integrative systems biology - engage a multidisciplinary mix of faculty and students focused on the application of engineering and physical and information sciences to the life sciences. Ranked among the world's most advanced research facilities, Rensselaer's Center for Biotechnology and Interdisciplinary Studies provides a state-of-the-art platform for collaborative research and world-class programs and symposia.
About Rensselaer
Rensselaer Polytechnic Institute, founded in 1824, is the nation's oldest technological university. The university offers bachelor's, master's, and doctoral degrees in engineering, the sciences, information technology, architecture, management, and the humanities and social sciences. Institute programs serve undergraduates, graduate students, and working professionals around the world. Rensselaer faculty are known for pre-eminence in research conducted in a wide range of fields, with particular emphasis in biotechnology, nanotechnology, information technology, and the media arts and technology. The Institute is well known for its success in the transfer of technology from the laboratory to the marketplace so that new discoveries and inventions benefit human life, protect the environment, and strengthen economic development.
Tiffany Lohwater
lohwatrpi
518-276-6542
Rensselaer Polytechnic Institute
rpi/dept/NewsComm
"Predictive modeling is a new approach to drug discovery that takes information from lab analysis and concentrates it in predictive models that may be evaluated on a computer," said Curt M. Breneman, professor of chemistry and chemical biology at Rensselaer.
"The ability to predict the separation behavior of a particular protein directly from its structure has considerable implications for biotechnology processes," said Steven Cramer, professor of chemical and biological engineering at Rensselaer. "The research results thus far indicate that this modeling approach can be used to determine protein behavior for use in bioseparation applications, such as the protein purification methods used in drug discovery. This could potentially reduce the development time required to bring biopharmaceuticals to market."
The modeling technique is based on methods previously developed by Breneman's group for rapidly predicting the efficacy and side effects of small drug-like molecules. The newly developed model successfully predicted the amount of a protein that binds to a material under a range of conditions by using molecular information obtained from the protein structure. These predicted adsorption isotherm parameters then replicated experimental results by predicting the actual separation profile of proteins in chromatographic columns. Chromatography techniques are used to identify and purify molecules, in this case, particular proteins.
"We intend to test the model against more complicated protein structures as part of its further development," said Breneman. "The outcome of this work will yield fundamental information about the complex relationship between a protein's structural features and its chemical binding properties, and also aid in evaluating its potential biomedical applications."
The research findings are reported in the Aug. 16 issue of Proceedings of the National Academy of Sciences in a paper titled "A Priori Prediction of Adsorption Isotherm Parameters and Chromatographic Behavior in Ion-Exchange Systems."
In addition to Breneman and Cramer, the collaborative research team includes Asif Ladiwala and Kaushal Rege, who both recently earned doctorates in chemical and biological engineering at Rensselaer. The work was supported by the National Science Foundation and GE Healthcare.
The researchers' computational model uses a combination of molecular-level quantitative structure-property relationship models with macroscopic steric mass action isotherm models and support vector machine regression computations.
Biotechnology and Interdisciplinary Studies at Rensselaer
At Rensselaer, faculty and students in diverse academic and research disciplines are collaborating at the intersection of the life sciences and engineering to encourage discovery and innovation. Rensselaer's four biotechnology research constellations - biocatalysis and metabolic engineering, functional tissue engineering and regenerative medicine, biocomputation and bioinformatics, and integrative systems biology - engage a multidisciplinary mix of faculty and students focused on the application of engineering and physical and information sciences to the life sciences. Ranked among the world's most advanced research facilities, Rensselaer's Center for Biotechnology and Interdisciplinary Studies provides a state-of-the-art platform for collaborative research and world-class programs and symposia.
About Rensselaer
Rensselaer Polytechnic Institute, founded in 1824, is the nation's oldest technological university. The university offers bachelor's, master's, and doctoral degrees in engineering, the sciences, information technology, architecture, management, and the humanities and social sciences. Institute programs serve undergraduates, graduate students, and working professionals around the world. Rensselaer faculty are known for pre-eminence in research conducted in a wide range of fields, with particular emphasis in biotechnology, nanotechnology, information technology, and the media arts and technology. The Institute is well known for its success in the transfer of technology from the laboratory to the marketplace so that new discoveries and inventions benefit human life, protect the environment, and strengthen economic development.
Tiffany Lohwater
lohwatrpi
518-276-6542
Rensselaer Polytechnic Institute
rpi/dept/NewsComm
понедельник, 23 мая 2011 г.
Sperm enzyme is essential for male fertility, study shows
A study led by scientists at the University of North Carolina at Chapel Hill has determined that a novel enzyme in sperm
is essential for sperm motility and male fertility.
The new study may offer a potential target for an effective, non-hormonal male contraceptive, the researchers said. The
findings will be published today (Nov. 15) in the online early edition of the journal Proceedings of the National Academy of
Sciences. A report also will appear Nov. 23 in the journal's print edition.
Collaborating with UNC were scientists from the U.S. National Institute of Environmental Health Sciences (NIEHS); Fudan
University in Shanghai, China; and the U.S. Environmental Protection Agency.
Sperm motility, produced by the coordinated movement of the extremely long sperm tail, requires substantial energy in the
form of adenosine triphosphate, or ATP, the major energy currency of the cell.
Specialized cellular structures known as mitochondria were thought to provide a substantial portion of the ATP needed for
sperm motility. In contrast, Dr. Deborah A. O'Brien, associate professor of cell and developmental biology at UNC's School of
Medicine, and her colleagues found that sperm motility and ATP production depend primarily on a metabolic pathway known as
glycolysis. This pathway uses sugar to produce energy, a common process in animal and plant cells.
The researchers focused on the enzyme glyceraldehyde 3-phosphate dehydrogenase-S, or GAPDS, a novel enzyme in the glycolytic
pathway that is expressed only in germ cells very late in the process of sperm production.
GAPDS is tightly bound to a structural element that extends along most of the length of the sperm tail. The study team used
gene targeting, or gene knockout technology, to produce mice that could not make this unique enzyme.
Without GAPDS, glycolysis is selectively blocked in sperm and this pathway produces no ATP. As expected, the females were
normal and the males had normal testes and sperm counts, but they were infertile, O'Brien said.
And when the researchers analyzed sperm movement under a microscope, they found a surprise.
"We expected that a type of motility known as 'hyperactivated motility' would be inhibited, but found that all progressive
movement was absent in sperm without GAPDS," O'Brien said.
"Glycolysis may not be as efficient as mitochondria for producing energy, but the enzymes are abundant and in the right place
for quick, localized energy production along the sperm tail. This paper provides proof of principle that GAPDS may be an
effective target for a contraceptive agent."
Co-authors with O'Brien are Dr. Kiyoshi Miki, research assistant professor in cell and developmental biology; Dr. Weidong Qu,
postdoctoral researcher at UNC and associate professor at Fudan University; Eugenia Goulding and William Willis, research
technicians at the NIEHS; Dr. Donna Bunch, assistant professor of medicine at UNC; Lillian Strader, research technician at
the EPA; Dr. Sally Perreault, chief, gamete and early embryo biology branch at the EPA; and Dr. Edward M. Eddy, who heads the
gamete biology section at the NIEHS.
By JAN MCCOLM
UNC School of Medicine
This research was supported by the Specialized Cooperative Centers Program in Reproductive Research at the National Institute
of Child Health and Human Development, the NIEHS, the National Institutes of Health's Fogarty International Center and the
EPA.
Note: Contact O'Brien at 919-962-8105 or daomed.unc.
School of Medicine contact: Les Lang, 919-843-9687 or llangmed.unc
Contact: Leslie H. Lang
llangmed.unc
919-843-9687
University of North Carolina School of Medicine
is essential for sperm motility and male fertility.
The new study may offer a potential target for an effective, non-hormonal male contraceptive, the researchers said. The
findings will be published today (Nov. 15) in the online early edition of the journal Proceedings of the National Academy of
Sciences. A report also will appear Nov. 23 in the journal's print edition.
Collaborating with UNC were scientists from the U.S. National Institute of Environmental Health Sciences (NIEHS); Fudan
University in Shanghai, China; and the U.S. Environmental Protection Agency.
Sperm motility, produced by the coordinated movement of the extremely long sperm tail, requires substantial energy in the
form of adenosine triphosphate, or ATP, the major energy currency of the cell.
Specialized cellular structures known as mitochondria were thought to provide a substantial portion of the ATP needed for
sperm motility. In contrast, Dr. Deborah A. O'Brien, associate professor of cell and developmental biology at UNC's School of
Medicine, and her colleagues found that sperm motility and ATP production depend primarily on a metabolic pathway known as
glycolysis. This pathway uses sugar to produce energy, a common process in animal and plant cells.
The researchers focused on the enzyme glyceraldehyde 3-phosphate dehydrogenase-S, or GAPDS, a novel enzyme in the glycolytic
pathway that is expressed only in germ cells very late in the process of sperm production.
GAPDS is tightly bound to a structural element that extends along most of the length of the sperm tail. The study team used
gene targeting, or gene knockout technology, to produce mice that could not make this unique enzyme.
Without GAPDS, glycolysis is selectively blocked in sperm and this pathway produces no ATP. As expected, the females were
normal and the males had normal testes and sperm counts, but they were infertile, O'Brien said.
And when the researchers analyzed sperm movement under a microscope, they found a surprise.
"We expected that a type of motility known as 'hyperactivated motility' would be inhibited, but found that all progressive
movement was absent in sperm without GAPDS," O'Brien said.
"Glycolysis may not be as efficient as mitochondria for producing energy, but the enzymes are abundant and in the right place
for quick, localized energy production along the sperm tail. This paper provides proof of principle that GAPDS may be an
effective target for a contraceptive agent."
Co-authors with O'Brien are Dr. Kiyoshi Miki, research assistant professor in cell and developmental biology; Dr. Weidong Qu,
postdoctoral researcher at UNC and associate professor at Fudan University; Eugenia Goulding and William Willis, research
technicians at the NIEHS; Dr. Donna Bunch, assistant professor of medicine at UNC; Lillian Strader, research technician at
the EPA; Dr. Sally Perreault, chief, gamete and early embryo biology branch at the EPA; and Dr. Edward M. Eddy, who heads the
gamete biology section at the NIEHS.
By JAN MCCOLM
UNC School of Medicine
This research was supported by the Specialized Cooperative Centers Program in Reproductive Research at the National Institute
of Child Health and Human Development, the NIEHS, the National Institutes of Health's Fogarty International Center and the
EPA.
Note: Contact O'Brien at 919-962-8105 or daomed.unc.
School of Medicine contact: Les Lang, 919-843-9687 or llangmed.unc
Contact: Leslie H. Lang
llangmed.unc
919-843-9687
University of North Carolina School of Medicine
воскресенье, 22 мая 2011 г.
Live Webcast Of HIV Vaccine Summit
What: On Tuesday, March 25, 2008, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, will host an HIV Vaccine Summit in Bethesda, Md. as an important step in the ongoing process to examine the current direction of HIV vaccine research. Through interactive panel discussions, NIAID and the scientific community will explore:
* The optimal balance between vaccine discovery research and development studies designed to advance promising vaccine candidates into clinical trials
* How to optimize and utilize non-human primate models to support vaccine research
* How best to integrate clinical research with vaccine discovery efforts
Based on the panel discussions, NIAID is seeking specific recommendations on the types of research to foster and how to attract novel vaccine research ideas.
When: Tuesday, March 25, 2008 8:30 a.m. to 4:45 p.m. EST
Where: To view the online NIAID HIV Vaccine Webcast, go to: hivsummit.dgimeetingsupport/. The "View Webcast" link will be live on March 25.
NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit nih/.
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at niaid.nih/.
Source: NIAID Office of Communications
NIH/National Institute of Allergy and Infectious Diseases
* The optimal balance between vaccine discovery research and development studies designed to advance promising vaccine candidates into clinical trials
* How to optimize and utilize non-human primate models to support vaccine research
* How best to integrate clinical research with vaccine discovery efforts
Based on the panel discussions, NIAID is seeking specific recommendations on the types of research to foster and how to attract novel vaccine research ideas.
When: Tuesday, March 25, 2008 8:30 a.m. to 4:45 p.m. EST
Where: To view the online NIAID HIV Vaccine Webcast, go to: hivsummit.dgimeetingsupport/. The "View Webcast" link will be live on March 25.
NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit nih/.
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at niaid.nih/.
Source: NIAID Office of Communications
NIH/National Institute of Allergy and Infectious Diseases
суббота, 21 мая 2011 г.
Improving Liver Cancer Diagnosis
Researchers report in the October 2007 issue of Molecular & Cellular Proteomics that they have identified proteins that could be used to improve the diagnosis of hepatocellular carcinoma, the most common type of liver cancer.
Hepatocellular carcinoma causes about one million deaths each year and is especially frequent in Asia, especially in China, where it is the second most frequent fatal cancer. But the diagnostic methods and therapies are limited, which has prompted scientists to look for proteins inside the body that indicate the presence of the disease.
Fuchu He and colleagues have used a state-of-the-art technique called two-dimensional difference gel electrophoresis to look for proteins whose copies are either increased or decreased in patients with hepatocellular carcinoma. Among the many proteins they found, two proteins were validated as novel potential markers of hepatocellular carcinoma.
Article: "Proteome Analysis of Hepatocellular Carcinoma by Two-dimensional Difference Gel Electrophoresis," by Wei Sun, Baocai Xing, Yi Sun, Xiaojuan Du, Min Lu, Chunyi Hao, Zhuang Lu, Wei Mi, Songfeng Wu, Handong Wei, Xue Gao, Yunping Zhu, Ying Jiang, Xiaohong Qian, and Fuchu He
The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society's student members attend undergraduate or graduate institutions.
Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's purpose is to advance the science of biochemistry and molecular biology through publication of the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics, organization of scientific meetings, advocacy for funding of basic research and education, support of science education at all levels, and promoting the diversity of individuals entering the scientific work force.
For more information about ASBMB, see the Society's Web site at asbmb.
American Society for Biochemistry and Molecular Biology (ASBMB)
9650 Rockville Pike
Bethesda, MD 20814-3996
United States
asbmb
Hepatocellular carcinoma causes about one million deaths each year and is especially frequent in Asia, especially in China, where it is the second most frequent fatal cancer. But the diagnostic methods and therapies are limited, which has prompted scientists to look for proteins inside the body that indicate the presence of the disease.
Fuchu He and colleagues have used a state-of-the-art technique called two-dimensional difference gel electrophoresis to look for proteins whose copies are either increased or decreased in patients with hepatocellular carcinoma. Among the many proteins they found, two proteins were validated as novel potential markers of hepatocellular carcinoma.
Article: "Proteome Analysis of Hepatocellular Carcinoma by Two-dimensional Difference Gel Electrophoresis," by Wei Sun, Baocai Xing, Yi Sun, Xiaojuan Du, Min Lu, Chunyi Hao, Zhuang Lu, Wei Mi, Songfeng Wu, Handong Wei, Xue Gao, Yunping Zhu, Ying Jiang, Xiaohong Qian, and Fuchu He
The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society's student members attend undergraduate or graduate institutions.
Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's purpose is to advance the science of biochemistry and molecular biology through publication of the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics, organization of scientific meetings, advocacy for funding of basic research and education, support of science education at all levels, and promoting the diversity of individuals entering the scientific work force.
For more information about ASBMB, see the Society's Web site at asbmb.
American Society for Biochemistry and Molecular Biology (ASBMB)
9650 Rockville Pike
Bethesda, MD 20814-3996
United States
asbmb
пятница, 20 мая 2011 г.
Carnegie's Doug Koshland Elected Fellow Of The American Academy Of Microbiology
Douglas E. Koshland, staff scientist at Carnegie's Department of Embryology, has been elected one of 72 Fellows by the American Academy of Microbiology. Fellows are annually elected "through a highly selective, peer-review process, based on their records of scientific achievement and original contributions that have advanced microbiology."
Using the simple, single-celled yeast Saccharomyces cerevisiae, Koshland has become a leader in studying the molecular processes that control the dynamics of chromosome structure and evolution - the foundations for understanding developmental problems and diseases such as cancer. He is interested in how genetic integrity is maintained during cell-division, particularly when duplicated chromosomes, known as sister chromatids, are produced, remain connected, and then separate to make two new cells.
"At a time when few believed it possible, Koshland showed how yeast could be used to reveal some of the most fundamental and important gene products and mechanisms governing animal (and human) chromosomes," remarked department director Allan Spradling. "If there was a way to measure a scientist's overall contribution of novel ideas and critical thought to his field, Doug Koshland would rank at the very top."
"All of us at Carnegie are proud of Doug's accomplishments. I know that this recognition by the American Academy of Microbiology is richly deserved," commented Carnegie president Richard A. Meserve.
Koshland has been a staff scientist at Carnegie since 1987 and a Howard Hughes Medical Institute investigator for about half that time. He is also an adjunct professor in the Department of Biology at the Johns Hopkins University. Among his many affiliations, Koshland is a member of the American Academy of Arts and Sciences and a fellow of the American Association for the Advancement of Science. He serves on numerous editorial boards. Koshland received his B.A. from Haverford College and his Ph.D. from the Massachusetts Institute of Technology.
The Carnegie Institution for Science (ciw/) has been a pioneering force in basic scientific research since 1902. It is a private, nonprofit organization with six research departments throughout the U.S. Carnegie scientists are leaders in plant biology, developmental biology, astronomy, materials science, global ecology, and Earth and planetary science.
For more information on the American Academy of Microbiology see academy.asm/
Source: Tina McDowell
Carnegie Institution
Using the simple, single-celled yeast Saccharomyces cerevisiae, Koshland has become a leader in studying the molecular processes that control the dynamics of chromosome structure and evolution - the foundations for understanding developmental problems and diseases such as cancer. He is interested in how genetic integrity is maintained during cell-division, particularly when duplicated chromosomes, known as sister chromatids, are produced, remain connected, and then separate to make two new cells.
"At a time when few believed it possible, Koshland showed how yeast could be used to reveal some of the most fundamental and important gene products and mechanisms governing animal (and human) chromosomes," remarked department director Allan Spradling. "If there was a way to measure a scientist's overall contribution of novel ideas and critical thought to his field, Doug Koshland would rank at the very top."
"All of us at Carnegie are proud of Doug's accomplishments. I know that this recognition by the American Academy of Microbiology is richly deserved," commented Carnegie president Richard A. Meserve.
Koshland has been a staff scientist at Carnegie since 1987 and a Howard Hughes Medical Institute investigator for about half that time. He is also an adjunct professor in the Department of Biology at the Johns Hopkins University. Among his many affiliations, Koshland is a member of the American Academy of Arts and Sciences and a fellow of the American Association for the Advancement of Science. He serves on numerous editorial boards. Koshland received his B.A. from Haverford College and his Ph.D. from the Massachusetts Institute of Technology.
The Carnegie Institution for Science (ciw/) has been a pioneering force in basic scientific research since 1902. It is a private, nonprofit organization with six research departments throughout the U.S. Carnegie scientists are leaders in plant biology, developmental biology, astronomy, materials science, global ecology, and Earth and planetary science.
For more information on the American Academy of Microbiology see academy.asm/
Source: Tina McDowell
Carnegie Institution
четверг, 19 мая 2011 г.
Why Certain Drug Combinations Backfire
Combination drug therapy has become a staple for treating many infections. For instance, doctors treat extensively drug resistant forms of tuberculosis with one drug that breaks down the pathogen's protective barriers and opens the door for another to deliver the deathblow.
Just as some drugs work better together, however, other pairings are counter-productive. "The question we asked was how can it be that two drugs in combination are less effective than one of them alone," said senior author and Harvard Medical School associate professor of systems biology Roy Kishony.
Kishony and his team have found that the answer lies in the way some antibiotic drugs influence a bacterial cell's gene expression levels. Combinations of these altered genetic behaviors can "put the cell in a better position for survival," said Kishony.
The work, which was done in collaboration with Stanford University research associate Selwyn Quan, is described in the November 13 Cell.
Kishony's work on drug combinations began in 2006 when his lab found that understanding why certain drugs work well or poorly together can help researchers identify the cellular functions they attack. For instance, drugs that block protein production work poorly with drugs that block DNA replication, but they work well with drugs that weaken the cell wall.
According to first author and research fellow in systems biology Tobias Bollenbach, clinical researchers are primarily interested in drugs that together work better than either alone, and so studies tend to focus on explaining some of the mechanisms behind synergistic drug pairings.
However, ever since the Kishony lab discovered in 2008 that antagonistic drug pairings slow down the evolution of antibiotic resistance, it has become increasingly clear that these drug combinations warrant further study.
To explore the dynamics of these antagonistic drug interactions, Kishony, Bollenbach, and doctoral candidate Remy Chait zeroed in on two classes of antibiotics that suppress one another. One class of drugs he investigated interrupts the replication of DNA and the other blocks the manufacture of proteins. They studied their combined effects on the bacteria Escherichia coli.
Drugs that impede DNA synthesis, such as Ciprofloxacin (a drug rarely used these days), interrupt cell division. As a result, E. coli enters a state of stress.
Normally, when a cell is in a stressful state it responds by trying to repair itself and by scaling back on its other activities, such as production of ribosomes, the molecular machines that manufacture proteins.
But with Ciprofloxacin, the cells try to repair DNA while still producing ribosomes. This is not in the cell's best interest, because making ribosomes uses up cellular resources and creates a surplus of proteins, which is even more costly.
When the team added the additional stress of a protein-synthesis inhibiting drug, such as Tetracycline, instead of causing the cells more trouble, the second drug counteracted the overproduction of ribosomes and proteins. "Since this other drug inhibits the ribosome, it corrects for the fact that the cell made too many in the first place," said Bollenbach.
The team hypothesized that the second drug restored the cellular equilibrium that the first drug distorted. This enabled the bacteria to flourish in the midst of this dual-antibiotic assault, though it isn't yet mechanistically clear why.
To corroborate these initial findings, the team conducted a second round of experiments in which they impaired the ability of E. coli to produce ribosomes. As a result, the cells could more easily withstand the assault of the first drug, yet succumbed to the second, completely removing the strong antagonism between the drugs.
This work "suggests that there are things about antibiotics and other inhibitors that we never suspected," said University of British Columbia microbiologist Julian Davies, "We are so naive about how drugs work. We are so naive about the activities of these compounds once they are actually in human beings. What I think will be important about this work is that people will be able to design model studies with animals. If one can reproduce these results in animal models, they could be adapted to a human situation."
The discovery has inspired Kishony and his team to ask a more general question about antibiotic interactions. Kishony recently received a federal stimulus grant to pursue a study that explores the genetic determinants of drug interactions more broadly and investigates whether cells can be synthetically manipulated to change the way drugs interact.
"Understanding how cells alter their genetic programs in the presence of antibiotic drugs could provide insights into new ways to discourage the growth of pathogens and encourage the growth of 'good' bacteria in the lab and in the clinic," said Kishony.
This research was funded by the National Institutes of Health. Bollenbach received support from an Alexander von Humboldt fellowship.
Citation:
Cell, Nov 13, 2009, Vol 139, No. 4
"Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions"
Tobias Bollenbach (1), Selwyn Quan (3), Remy Chait (1) and Roy Kishony (1,2)
(1) Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA
(2) School of Engineering and Applied Sciences, Harvard University, Cambridge, MA
(3) Department of Chemical and Systems Biology, Stanford University, 318 Campus Drive, Stanford, CA
Source: David Cameron
Harvard Medical School
Just as some drugs work better together, however, other pairings are counter-productive. "The question we asked was how can it be that two drugs in combination are less effective than one of them alone," said senior author and Harvard Medical School associate professor of systems biology Roy Kishony.
Kishony and his team have found that the answer lies in the way some antibiotic drugs influence a bacterial cell's gene expression levels. Combinations of these altered genetic behaviors can "put the cell in a better position for survival," said Kishony.
The work, which was done in collaboration with Stanford University research associate Selwyn Quan, is described in the November 13 Cell.
Kishony's work on drug combinations began in 2006 when his lab found that understanding why certain drugs work well or poorly together can help researchers identify the cellular functions they attack. For instance, drugs that block protein production work poorly with drugs that block DNA replication, but they work well with drugs that weaken the cell wall.
According to first author and research fellow in systems biology Tobias Bollenbach, clinical researchers are primarily interested in drugs that together work better than either alone, and so studies tend to focus on explaining some of the mechanisms behind synergistic drug pairings.
However, ever since the Kishony lab discovered in 2008 that antagonistic drug pairings slow down the evolution of antibiotic resistance, it has become increasingly clear that these drug combinations warrant further study.
To explore the dynamics of these antagonistic drug interactions, Kishony, Bollenbach, and doctoral candidate Remy Chait zeroed in on two classes of antibiotics that suppress one another. One class of drugs he investigated interrupts the replication of DNA and the other blocks the manufacture of proteins. They studied their combined effects on the bacteria Escherichia coli.
Drugs that impede DNA synthesis, such as Ciprofloxacin (a drug rarely used these days), interrupt cell division. As a result, E. coli enters a state of stress.
Normally, when a cell is in a stressful state it responds by trying to repair itself and by scaling back on its other activities, such as production of ribosomes, the molecular machines that manufacture proteins.
But with Ciprofloxacin, the cells try to repair DNA while still producing ribosomes. This is not in the cell's best interest, because making ribosomes uses up cellular resources and creates a surplus of proteins, which is even more costly.
When the team added the additional stress of a protein-synthesis inhibiting drug, such as Tetracycline, instead of causing the cells more trouble, the second drug counteracted the overproduction of ribosomes and proteins. "Since this other drug inhibits the ribosome, it corrects for the fact that the cell made too many in the first place," said Bollenbach.
The team hypothesized that the second drug restored the cellular equilibrium that the first drug distorted. This enabled the bacteria to flourish in the midst of this dual-antibiotic assault, though it isn't yet mechanistically clear why.
To corroborate these initial findings, the team conducted a second round of experiments in which they impaired the ability of E. coli to produce ribosomes. As a result, the cells could more easily withstand the assault of the first drug, yet succumbed to the second, completely removing the strong antagonism between the drugs.
This work "suggests that there are things about antibiotics and other inhibitors that we never suspected," said University of British Columbia microbiologist Julian Davies, "We are so naive about how drugs work. We are so naive about the activities of these compounds once they are actually in human beings. What I think will be important about this work is that people will be able to design model studies with animals. If one can reproduce these results in animal models, they could be adapted to a human situation."
The discovery has inspired Kishony and his team to ask a more general question about antibiotic interactions. Kishony recently received a federal stimulus grant to pursue a study that explores the genetic determinants of drug interactions more broadly and investigates whether cells can be synthetically manipulated to change the way drugs interact.
"Understanding how cells alter their genetic programs in the presence of antibiotic drugs could provide insights into new ways to discourage the growth of pathogens and encourage the growth of 'good' bacteria in the lab and in the clinic," said Kishony.
This research was funded by the National Institutes of Health. Bollenbach received support from an Alexander von Humboldt fellowship.
Citation:
Cell, Nov 13, 2009, Vol 139, No. 4
"Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions"
Tobias Bollenbach (1), Selwyn Quan (3), Remy Chait (1) and Roy Kishony (1,2)
(1) Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA
(2) School of Engineering and Applied Sciences, Harvard University, Cambridge, MA
(3) Department of Chemical and Systems Biology, Stanford University, 318 Campus Drive, Stanford, CA
Source: David Cameron
Harvard Medical School
среда, 18 мая 2011 г.
Boston University School Of Medicine's Vasculitis Center Receives $6m Grant From National Institutes Of Health
The Vasculitis Center at Boston University School of Medicine (BUSM) has received a five-year $6 million grant from the National Institutes of Health. The grant will be used to research new biomarkers for vasculitis disease activity and prognosis. The research will also develop and standardize outcome measures for the different types of vasculitis, and develop and standardize imaging techniques for the large vessel vasculitides. In addition, clinical trials of new therapeutic agents will be examined.
The VCRC, founded in 2003, is an integrated group of academic medical centers, patient support organizations, and clinical research resources dedicated to conducting clinical research in different forms of vasculitis and improving the care of patients with vasculitis. The operations of the VCRC are directed from Boston University and the VCRC Study Sites include Boston University, Cleveland Clinic Foundation, Johns Hopkins University, Mayo Clinic, University of Pittsburgh, University of Toronto, University of Utah, as well as several research partners in Europe. The VCRC is part of the NIH Rare Diseases Network.
Vasculitis is a rare disease that exists in several different forms. While some forms are due to infection or may be associated with other diseases, the causes of six kinds of vasculitis are unknown. Different forms of vasculitis cause inflammation in blood vessels, which may lead to the wall of the vessel weakening and possibly rupturing. The inflammation can also lead to thickening of the vessel wall, causing blockage of blood flow and tissue damage.
This new funding will be combined with other current NIH and Food and Drug Administration grants to the BU Vasculitis Center to support a series of clinical and translational research projects in vasculitis. The VCRC grant will specifically support clinical trials of new therapeutic agents for vasculitis, research into new biomarkers for vasculitis disease activity and prognosis, development and standardization of outcome measures for the different types of vasculitis, and training of new clinical investigators in vasculitis.
"We are extremely grateful for the ongoing generous support from the National Institutes of Health," said VCRC principal investigator Peter A. Merkel, M.D., M.P.H., director of the BU Vasculitis Center and professor of medicine at BUSM. "They have provided us with the resources necessary to create this ongoing clinical research infrastructure and continue our work to improve our understanding of the causes of vasculitis and find new treatments for our patients who suffer from these complex and serious diseases."
Source: Michelle Roberts
Boston University Medical Center
The VCRC, founded in 2003, is an integrated group of academic medical centers, patient support organizations, and clinical research resources dedicated to conducting clinical research in different forms of vasculitis and improving the care of patients with vasculitis. The operations of the VCRC are directed from Boston University and the VCRC Study Sites include Boston University, Cleveland Clinic Foundation, Johns Hopkins University, Mayo Clinic, University of Pittsburgh, University of Toronto, University of Utah, as well as several research partners in Europe. The VCRC is part of the NIH Rare Diseases Network.
Vasculitis is a rare disease that exists in several different forms. While some forms are due to infection or may be associated with other diseases, the causes of six kinds of vasculitis are unknown. Different forms of vasculitis cause inflammation in blood vessels, which may lead to the wall of the vessel weakening and possibly rupturing. The inflammation can also lead to thickening of the vessel wall, causing blockage of blood flow and tissue damage.
This new funding will be combined with other current NIH and Food and Drug Administration grants to the BU Vasculitis Center to support a series of clinical and translational research projects in vasculitis. The VCRC grant will specifically support clinical trials of new therapeutic agents for vasculitis, research into new biomarkers for vasculitis disease activity and prognosis, development and standardization of outcome measures for the different types of vasculitis, and training of new clinical investigators in vasculitis.
"We are extremely grateful for the ongoing generous support from the National Institutes of Health," said VCRC principal investigator Peter A. Merkel, M.D., M.P.H., director of the BU Vasculitis Center and professor of medicine at BUSM. "They have provided us with the resources necessary to create this ongoing clinical research infrastructure and continue our work to improve our understanding of the causes of vasculitis and find new treatments for our patients who suffer from these complex and serious diseases."
Source: Michelle Roberts
Boston University Medical Center
вторник, 17 мая 2011 г.
Parasite Evades Death By Promoting Host Cell Survival
The parasite Trypanosoma cruzi (or T. cruzi), which causes Chagas' disease, will go to great lengths to evade death once it has infected human host cells, researchers have discovered. In a study published in the November 17 online issue of Science Signaling, the researchers describe how a protein called parasite-derived neurotrophic factor (PDNF) prolongs the life of the T. cruzi parasite by activating anti-apoptotic (or anti-cell-death) molecules in the host cell. These protective mechanisms help to explain how host cells continue to survive despite being exploited by T. cruzi parasites.
"We asked ourselves, 'How is it possible that the host cells stay alive for so long with thousands of T. cruzi parasites consuming the host cell's vital resources?' We discovered that PDNF on the surface of the T. cruzi parasite essentially inhibits cell death signals and activates cell-protective mechanisms, ensuring T. cruzi sufficient time to develop and reproduce in the host cell," says senior author Mercio Perrin, MD, PhD, professor in the pathology department at Tufts University School of Medicine (TUSM) and member of the immunology program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.
Taking a multi-faceted approach, the researchers used bioinformatics, immunochemistry, intracellular colocalization microscopy, and in vitro enzymatic techniques to study T. cruzi's survival in the host. Perrin and co-author Marina Chuenkova, PhD, a research instructor in the pathology department at TUSM and the Sackler School, demonstrated that PDNF is a substrate and activator of Akt kinase, an enzyme that promotes cell survival by inhibiting "cell death" proteins.
"Further investigation showed that within T. cruzi-infected cells, PDNF also activates increased production of Akt, prolonging its protective effects," says Chuenkova. "Akt is a key regulator of diverse cellular processes, and supports cell survival not only by inhibiting apoptotic molecules, but additionally by increasing nutrient uptake and metabolism," she continued.
"In short, the T. cruzi parasite has a means of establishing life insurance once it has invaded the host. If we can fully understand the mechanisms behind this protection, we can begin to explore ways to undermine it with treatment," said Perrin.
Chagas' disease, typically transmitted to humans by blood-feeding insects, infects an estimated 8 to 11 million people throughout Mexico, and Central and South America. Although it is still rare in the United States, according to the Centers for Disease Control and Prevention (CDC), there are 300,000 people with Chagas' disease living in the United States, most of whom acquired the disease while living in other countries.
The acute phase of Chagas' disease can result in fever or swelling at the site of the insect bite, but many people do not experience symptoms at all. If left untreated, the disease enters an indeterminate phase in which no symptoms are present. During this phase, many people are not aware that they are infected, but approximately 30 percent will eventually develop life-threatening complications of the disease, including enlargement of the digestive tract and/or heart.
This study was funded by grants from the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health.
Chuenkova MV and PereiraPerrin M. Science Signaling. 2009. (November 17); 2(97), ra74. "Trypanosoma cruzi targets Akt in host cells as an intracellular antiapoptotic strategy." Published online November 17, 2009, doi: 10.1126/scisignal.2000374
About Tufts University School of Medicine
Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. The Sackler School undertakes research that is consistently rated among the highest in the nation for its impact on the advancement of medical science.
Source: Tufts University
"We asked ourselves, 'How is it possible that the host cells stay alive for so long with thousands of T. cruzi parasites consuming the host cell's vital resources?' We discovered that PDNF on the surface of the T. cruzi parasite essentially inhibits cell death signals and activates cell-protective mechanisms, ensuring T. cruzi sufficient time to develop and reproduce in the host cell," says senior author Mercio Perrin, MD, PhD, professor in the pathology department at Tufts University School of Medicine (TUSM) and member of the immunology program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.
Taking a multi-faceted approach, the researchers used bioinformatics, immunochemistry, intracellular colocalization microscopy, and in vitro enzymatic techniques to study T. cruzi's survival in the host. Perrin and co-author Marina Chuenkova, PhD, a research instructor in the pathology department at TUSM and the Sackler School, demonstrated that PDNF is a substrate and activator of Akt kinase, an enzyme that promotes cell survival by inhibiting "cell death" proteins.
"Further investigation showed that within T. cruzi-infected cells, PDNF also activates increased production of Akt, prolonging its protective effects," says Chuenkova. "Akt is a key regulator of diverse cellular processes, and supports cell survival not only by inhibiting apoptotic molecules, but additionally by increasing nutrient uptake and metabolism," she continued.
"In short, the T. cruzi parasite has a means of establishing life insurance once it has invaded the host. If we can fully understand the mechanisms behind this protection, we can begin to explore ways to undermine it with treatment," said Perrin.
Chagas' disease, typically transmitted to humans by blood-feeding insects, infects an estimated 8 to 11 million people throughout Mexico, and Central and South America. Although it is still rare in the United States, according to the Centers for Disease Control and Prevention (CDC), there are 300,000 people with Chagas' disease living in the United States, most of whom acquired the disease while living in other countries.
The acute phase of Chagas' disease can result in fever or swelling at the site of the insect bite, but many people do not experience symptoms at all. If left untreated, the disease enters an indeterminate phase in which no symptoms are present. During this phase, many people are not aware that they are infected, but approximately 30 percent will eventually develop life-threatening complications of the disease, including enlargement of the digestive tract and/or heart.
This study was funded by grants from the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health.
Chuenkova MV and PereiraPerrin M. Science Signaling. 2009. (November 17); 2(97), ra74. "Trypanosoma cruzi targets Akt in host cells as an intracellular antiapoptotic strategy." Published online November 17, 2009, doi: 10.1126/scisignal.2000374
About Tufts University School of Medicine
Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. The Sackler School undertakes research that is consistently rated among the highest in the nation for its impact on the advancement of medical science.
Source: Tufts University
понедельник, 16 мая 2011 г.
Humble Fast Food Meal Dissected In New Study Of Globalization And Diversity Of The Human Diet
A burger and fries may be the quintessential North American meal but it can also be viewed as the perfect example of humanity's increasingly varied diet, according to researchers who have conducted a unique study of the plants used around the world for food.
In the first-ever study of the "phylogenetic distribution" of the human diet, University of Calgary plant evolutionary ecologist Jana Vamosi, working with a team led by Serban Proches from Stellenbosch University in South Africa, found that humans likely stand alone when it comes to the spectrum of species we consume. Our ability to process food combined with an insatiable hunger for new tastes and international trade systems has also led to food becoming the ultimate product of a globalized society.
"Generally speaking, we eat very broadly from the tree of life," Vamosi said. "Others have looked at the sheer number of plant species we consume but nobody has ever examined whether the plants we eat are clustered in certain branches. It turns out that they are not."
In a paper published in the current issue of the scientific journal BioScience, the researchers examined more than 7,000 plant species commonly eaten by people to determine the origins and evolutionary relationships of the various plants that comprise humankind's menu. In addition to confirming the incredible number of species that are regularly eaten, they found that we chow down on members of a remarkably high number of plant families known to biology.
As a case study, the scientists analyzed the ingredients of a simple fast food meal - a McDonald's Big Mac, French fries and a cup of coffee - to illustrate how the average human diet in developed nations is more diverse than ever before. From potatoes that were first domesticated in South America to mustard that was developed in India, onions and wheat that originated in the Middle East and coffee from Ethiopia, they found the meal contained approximately 20 different species and ingredients that originated around the world (see attached Backgrounder). This leads to the conclusion that "a Big Mac is an apt symbol of globalization."
"That a single meal contains about 20 species is impressive, given that some human societies - those that are largely unaffected by current globalization trend - commonly include only 50 to 100 plant species in their entire diet," the paper states.
Vamosi says the study raises myriad questions about the diversity and nutritional aspects of the human diet that will be the subject of future investigations.
"Certainly, including many fruits and vegetables in your diet is something that has been encouraged by nutritionists for some time. However eating carrots and celery, for example, provides you with nutrients from the same plant family, as do apples, pears, apricots, peaches, raspberries and blackberries. Indeed broccoli, kale and cauliflower are actually a single species," Vamosi said.
"Eating lots of different produce might not actually provide you with a phylogenetically diverse diet, and whether that's important for providing maximum nutritional value remains to be seen."
The study also argues that steps to protect the diversity of human food plants may have to be taken as globalization and industrial-scale agriculture gradually leads to more uniform diets for the world's population overall.
"Individually we are probably eating a greater range of plant species than our ancestors, but the loss of indigenous knowledge and regional cuisines may mean that as a species our diet is becoming increasing focussed on a few plant species, and indeed a few varieties of those species" states coauthor John Wilson.
"The fact that we do eat so broadly indicates that we enjoy many different flavours and combinations of flavours and also indicates that many plants that we don't eat likely have some sort of culinary value that we just haven't discovered yet," Vamosi said. "Maintaining plant diversity ensures that we will continue to have the current flavours that we enjoy available to us and will also preserve other potential food sources into the future."
The paper "Plant Diversity in the Human Diet: Weak Phylogenetic Signal Indicates Breadth" by Serban Proches, John R. U. Wilson, Jana C. Vamosi and David M. Richardson is published in the February, 2008 issue of the journal BioScience. See the journal's website at: aibs/bioscience/index.html
Grady Semmens
Senior Communications Manager - Research
University of Calgary, External Relations
Source: Grady Semmens
University of Calgary
In the first-ever study of the "phylogenetic distribution" of the human diet, University of Calgary plant evolutionary ecologist Jana Vamosi, working with a team led by Serban Proches from Stellenbosch University in South Africa, found that humans likely stand alone when it comes to the spectrum of species we consume. Our ability to process food combined with an insatiable hunger for new tastes and international trade systems has also led to food becoming the ultimate product of a globalized society.
"Generally speaking, we eat very broadly from the tree of life," Vamosi said. "Others have looked at the sheer number of plant species we consume but nobody has ever examined whether the plants we eat are clustered in certain branches. It turns out that they are not."
In a paper published in the current issue of the scientific journal BioScience, the researchers examined more than 7,000 plant species commonly eaten by people to determine the origins and evolutionary relationships of the various plants that comprise humankind's menu. In addition to confirming the incredible number of species that are regularly eaten, they found that we chow down on members of a remarkably high number of plant families known to biology.
As a case study, the scientists analyzed the ingredients of a simple fast food meal - a McDonald's Big Mac, French fries and a cup of coffee - to illustrate how the average human diet in developed nations is more diverse than ever before. From potatoes that were first domesticated in South America to mustard that was developed in India, onions and wheat that originated in the Middle East and coffee from Ethiopia, they found the meal contained approximately 20 different species and ingredients that originated around the world (see attached Backgrounder). This leads to the conclusion that "a Big Mac is an apt symbol of globalization."
"That a single meal contains about 20 species is impressive, given that some human societies - those that are largely unaffected by current globalization trend - commonly include only 50 to 100 plant species in their entire diet," the paper states.
Vamosi says the study raises myriad questions about the diversity and nutritional aspects of the human diet that will be the subject of future investigations.
"Certainly, including many fruits and vegetables in your diet is something that has been encouraged by nutritionists for some time. However eating carrots and celery, for example, provides you with nutrients from the same plant family, as do apples, pears, apricots, peaches, raspberries and blackberries. Indeed broccoli, kale and cauliflower are actually a single species," Vamosi said.
"Eating lots of different produce might not actually provide you with a phylogenetically diverse diet, and whether that's important for providing maximum nutritional value remains to be seen."
The study also argues that steps to protect the diversity of human food plants may have to be taken as globalization and industrial-scale agriculture gradually leads to more uniform diets for the world's population overall.
"Individually we are probably eating a greater range of plant species than our ancestors, but the loss of indigenous knowledge and regional cuisines may mean that as a species our diet is becoming increasing focussed on a few plant species, and indeed a few varieties of those species" states coauthor John Wilson.
"The fact that we do eat so broadly indicates that we enjoy many different flavours and combinations of flavours and also indicates that many plants that we don't eat likely have some sort of culinary value that we just haven't discovered yet," Vamosi said. "Maintaining plant diversity ensures that we will continue to have the current flavours that we enjoy available to us and will also preserve other potential food sources into the future."
The paper "Plant Diversity in the Human Diet: Weak Phylogenetic Signal Indicates Breadth" by Serban Proches, John R. U. Wilson, Jana C. Vamosi and David M. Richardson is published in the February, 2008 issue of the journal BioScience. See the journal's website at: aibs/bioscience/index.html
Grady Semmens
Senior Communications Manager - Research
University of Calgary, External Relations
Source: Grady Semmens
University of Calgary
воскресенье, 15 мая 2011 г.
Innocuous Intestinal Bacteria May Be Reservoir For Resistance
"Harmless" bacteria in the digestive tracts of dairy cows, may not be so harmless after all. They may be a reservoir for antibiotic resistance genes that can be transferred to more harmful, disease-causing bacteria, according to research presented today at the 106th General Meeting of the American Society for Microbiology in Orlando, Florida.
"There is concern that veterinary therapeutic usage of antibiotics in animals is responsible for the emergence of drug-resistant Salmonella. For dairy farms recently surveyed in Georgia, there was no association found between antibiotic use and isolation of multi-drug resistant Salmonella. Where does the drug resistance in Salmonella originate?" says Susan Sanchez of the University of Georgia, who conducted the study with other researchers from the University of Georgia and the Universidad Complutense of Madrid.
Using DNA-based technology Sanchez and her colleagues discovered that a significant number of non-pathogenic, commensal bacteria isolated from cow manure contain the same antibiotic-resistance genes as those found in multi-drug resistant Salmonella strains found on the same farm. In addition, isolation of antibiotic-resistant Salmonella appears to be associated with whether or not commensal bacteria carry these resistance genes rather than antibiotic use on the farm.
"This work suggests that mobile DNA elements like plasmids are responsible for the rapid spread of drug resistance on farms. Ecology appears to play a more important role in the emergence of drug resistance in Salmonella than therapeutic antibiotic use," says Sanchez
Jim Sliwa
jsliwaasmusa
American Society for Microbiology
asm/
"There is concern that veterinary therapeutic usage of antibiotics in animals is responsible for the emergence of drug-resistant Salmonella. For dairy farms recently surveyed in Georgia, there was no association found between antibiotic use and isolation of multi-drug resistant Salmonella. Where does the drug resistance in Salmonella originate?" says Susan Sanchez of the University of Georgia, who conducted the study with other researchers from the University of Georgia and the Universidad Complutense of Madrid.
Using DNA-based technology Sanchez and her colleagues discovered that a significant number of non-pathogenic, commensal bacteria isolated from cow manure contain the same antibiotic-resistance genes as those found in multi-drug resistant Salmonella strains found on the same farm. In addition, isolation of antibiotic-resistant Salmonella appears to be associated with whether or not commensal bacteria carry these resistance genes rather than antibiotic use on the farm.
"This work suggests that mobile DNA elements like plasmids are responsible for the rapid spread of drug resistance on farms. Ecology appears to play a more important role in the emergence of drug resistance in Salmonella than therapeutic antibiotic use," says Sanchez
Jim Sliwa
jsliwaasmusa
American Society for Microbiology
asm/
суббота, 14 мая 2011 г.
Animal Studies Show Protection Against HIV In One-Third Of Subjects Vaccinated
New research at Oregon Health & Science University's Vaccine and Gene Therapy Institute suggests vaccines that specifically target HIV in the initial stages of infection before it becomes a rapidly replicating, system-wide infection - may be a successful approach in limiting the spread of the disease. The research is published in the early online edition of the journal Nature Medicine and will appear in a future printed edition.
The researchers used a vaccination method that involves creating and maintaining resistance by programming a portion of the body's immune system - effector memory T-cells - to look out for HIV at the site of infection.
"HIV appears to be vulnerable when it is first introduced into mucosal surfaces in the body," said Louis Picker, M.D., associate director of the OHSU VGTI and director of the VGTI's vaccine program. "However, once HIV spreads throughout the entire body, it replicates very rapidly and becomes difficult if not impossible to control. Our approach is to attack during this early period of vulnerability. The approach is similar to that of a homeowner who sprays their house with water before sparks land on the roof. This approach can prevent the roof from catching fire and, in the case of HIV, prevent the spread of the virus."
To determine whether they could proactively "educate" the immune system, scientists used a monkey model of AIDS - simian immunodeficiency virus (SIV) - the monkey counterpart to HIV. They introduced an altered monkey form of cytomegalovirus (CMV) programmed to express SIV proteins and trigger specialized effector memory T-cells to look for and attack SIV in its early stages.
In total, 12 rhesus macaque monkeys at the Oregon National Primate Research Center were vaccinated using this method. When the animals were later infected with SIV, one-third were protected.
The next step for the research team is to try to determine why only a portion of the monkeys who are vaccinated using this method are responding. The researchers also hope to expand the number of subjects to better determine the success rate of the therapy.
The research was funded by The National Institute of Allergy and Infectious Diseases and by the Bill and Melinda Gates Foundation.
Source: Jim Newman
Oregon Health & Science University
The researchers used a vaccination method that involves creating and maintaining resistance by programming a portion of the body's immune system - effector memory T-cells - to look out for HIV at the site of infection.
"HIV appears to be vulnerable when it is first introduced into mucosal surfaces in the body," said Louis Picker, M.D., associate director of the OHSU VGTI and director of the VGTI's vaccine program. "However, once HIV spreads throughout the entire body, it replicates very rapidly and becomes difficult if not impossible to control. Our approach is to attack during this early period of vulnerability. The approach is similar to that of a homeowner who sprays their house with water before sparks land on the roof. This approach can prevent the roof from catching fire and, in the case of HIV, prevent the spread of the virus."
To determine whether they could proactively "educate" the immune system, scientists used a monkey model of AIDS - simian immunodeficiency virus (SIV) - the monkey counterpart to HIV. They introduced an altered monkey form of cytomegalovirus (CMV) programmed to express SIV proteins and trigger specialized effector memory T-cells to look for and attack SIV in its early stages.
In total, 12 rhesus macaque monkeys at the Oregon National Primate Research Center were vaccinated using this method. When the animals were later infected with SIV, one-third were protected.
The next step for the research team is to try to determine why only a portion of the monkeys who are vaccinated using this method are responding. The researchers also hope to expand the number of subjects to better determine the success rate of the therapy.
The research was funded by The National Institute of Allergy and Infectious Diseases and by the Bill and Melinda Gates Foundation.
Source: Jim Newman
Oregon Health & Science University
пятница, 13 мая 2011 г.
Pattern Of Human Ebola Outbreaks Linked To Wildlife And Climate
A visiting biologist at the University of California, San Diego and her colleagues in Africa and Britain have shown that there are close linkages between outbreaks of Ebola hemorrhagic fever in human and wildlife populations, and that climate may influence the spread of the disease.
The decade-long study, published this month (with a cover date of January) in the journal Transactions of the Royal Society of Tropical Medicine and Hygiene, tracked animal disease outbreaks and human exposure to the Ebola virus in Gabon and adjoining northwestern Republic of the Congo (RoC). The researchers found that many additional wildlife and human populations within and outside of known epidemic zones have been exposed to the virus. When they considered disease outbreaks in all mammals, not just humans, the spread of Ebola no longer seemed erratic and inexplicable.
"Some researchers have hypothesized that outbreaks of Ebola are randomly-spaced periodic outbursts, while others have suggested that Ebola has spread like a wave surging over the Central African landscape," said Sally Lahm, a visiting scholar in UCSD's Division of Biological Sciences and the primary investigator of the study. "Our results are intermediate between these two views. There is a perceived pattern to the way the virus spreads, but it is not simply a wave affecting everything in its path, since apparently healthy mammal communities thrived in close proximity to Ebola epidemic sites."
Lahm has been a research associate at the Institute for Research in Tropical Ecology in Makokou, Gabon since 1982. She was conducting unrelated ecological studies when outbreaks of Ebola virus in humans prompted her to explore how the disease was affecting animal populations in the region. Between 1994 and 2003, she collected reports of animal illness and deaths from wildlife survey teams, villagers, hunters, fishers, loggers, miners, Ebola survivors and families of victims from across Gabon and into northwestern RoC.
Despite the low probability of finding dead animals in the humid forests that cover most of the region, due to the scavenging by animals and insects and rapid decomposition, Lahm received and verified reports of 397 dead animals. The carcasses, which were found at 35 different sites in Gabon and RoC, included gorillas, chimpanzees, mandrills, bush pigs, porcupines and four species of antelope. Tests on 14 samples from the decomposed carcasses did not detect the Ebola virus, but at 12 sites, observers also saw sick or dying animals with symptoms consistent with Ebola infection. In addition, 16 reported wildlife mortality incidents coincided with known Ebola epidemics.
"The transmission of Ebola within animal populations is much more widespread than previously believed," explained Lahm. "Ebola appears to spread both within species and between different species of animals."
To determine the extent of human exposure to Ebola within Gabon, Lahm collaborated with Maryvonne Kombila, the director of the Department of Tropical Medicine and Parasitology at the University of Health Sciences in Libreville, Gabon and with Robert Swanepoel, the director of the Special Pathogens Branch of the National Institute of Communicable Diseases in Sandringham, South Africa. Swanepoel tested for antibodies to the Ebola virus in more than one-thousand human blood samples that had been collected by Kombila and her colleagues for other research in Gabon between 1981 and 1997.
Fourteen of the blood samples tested positive for antibodies to Ebola. Some people had been exposed at least three years before the first known Ebola outbreak in Gabon, while others lived in regions where no known epidemics had occurred. In 2003, Lahm was able to track down six of the people whose blood samples indicated that they had been exposed to the Ebola virus. Life history interviews revealed that some of the antibody-positive people had never visited a region where known Ebola outbreaks occurred in humans. Therefore people have been exposed to the Ebola virus where it has not been recognized.
Based on their findings, the researchers were able to identify relationships among previously documented Ebola outbreaks in humans and wildlife in Gabon and RoC that initially seemed disparate and unrelated. They proposed that the virus first spread southwest across Gabon. It then looped back toward the northeast from sites in western or central Gabon and caused the most recent outbreaks in RoC.
"If the spread of the Ebola virus follows its current northeastward path, the next outbreak would be expected to occur in northern Republic of the Congo towards Cameroon and the Central African Republic," predicted Lahm.
However, according to the findings, the spread of Ebola also depends on climate factors. Illness and deaths among animals were most prevalent during periods of prolonged drought-like conditions in the rainforest, which indicates that severe environmental stress may facilitate disease transmission.
In the study, the researchers urge that public education is needed to decrease human contact with potentially infected wildlife by discouraging people from scavenging dead animals and by promoting safe hunting and trapping practices, especially because the results show that outbreaks in wildlife populations have been much more frequent than previously believed. They emphasize that monitoring wildlife in collaboration with rural African residents could provide information essential for protecting public health as well as comprehending the ecology of the disease.
Lahm points out that there remain many unanswered questions about Ebola including how the virus spreads within and between mammal species.
"Our study provides more pieces of the puzzle, but at the same time it is enlarging the puzzle," she noted.
Richard Barnes from the Environmental Sciences Research Center at Anglia Ruskin University, Cambridge, England, who is currently a visiting scholar in UCSD's Division of Biological Sciences, also contributed to the study.
Contact: Sherry Seethaler
University of California - San Diego
The decade-long study, published this month (with a cover date of January) in the journal Transactions of the Royal Society of Tropical Medicine and Hygiene, tracked animal disease outbreaks and human exposure to the Ebola virus in Gabon and adjoining northwestern Republic of the Congo (RoC). The researchers found that many additional wildlife and human populations within and outside of known epidemic zones have been exposed to the virus. When they considered disease outbreaks in all mammals, not just humans, the spread of Ebola no longer seemed erratic and inexplicable.
"Some researchers have hypothesized that outbreaks of Ebola are randomly-spaced periodic outbursts, while others have suggested that Ebola has spread like a wave surging over the Central African landscape," said Sally Lahm, a visiting scholar in UCSD's Division of Biological Sciences and the primary investigator of the study. "Our results are intermediate between these two views. There is a perceived pattern to the way the virus spreads, but it is not simply a wave affecting everything in its path, since apparently healthy mammal communities thrived in close proximity to Ebola epidemic sites."
Lahm has been a research associate at the Institute for Research in Tropical Ecology in Makokou, Gabon since 1982. She was conducting unrelated ecological studies when outbreaks of Ebola virus in humans prompted her to explore how the disease was affecting animal populations in the region. Between 1994 and 2003, she collected reports of animal illness and deaths from wildlife survey teams, villagers, hunters, fishers, loggers, miners, Ebola survivors and families of victims from across Gabon and into northwestern RoC.
Despite the low probability of finding dead animals in the humid forests that cover most of the region, due to the scavenging by animals and insects and rapid decomposition, Lahm received and verified reports of 397 dead animals. The carcasses, which were found at 35 different sites in Gabon and RoC, included gorillas, chimpanzees, mandrills, bush pigs, porcupines and four species of antelope. Tests on 14 samples from the decomposed carcasses did not detect the Ebola virus, but at 12 sites, observers also saw sick or dying animals with symptoms consistent with Ebola infection. In addition, 16 reported wildlife mortality incidents coincided with known Ebola epidemics.
"The transmission of Ebola within animal populations is much more widespread than previously believed," explained Lahm. "Ebola appears to spread both within species and between different species of animals."
To determine the extent of human exposure to Ebola within Gabon, Lahm collaborated with Maryvonne Kombila, the director of the Department of Tropical Medicine and Parasitology at the University of Health Sciences in Libreville, Gabon and with Robert Swanepoel, the director of the Special Pathogens Branch of the National Institute of Communicable Diseases in Sandringham, South Africa. Swanepoel tested for antibodies to the Ebola virus in more than one-thousand human blood samples that had been collected by Kombila and her colleagues for other research in Gabon between 1981 and 1997.
Fourteen of the blood samples tested positive for antibodies to Ebola. Some people had been exposed at least three years before the first known Ebola outbreak in Gabon, while others lived in regions where no known epidemics had occurred. In 2003, Lahm was able to track down six of the people whose blood samples indicated that they had been exposed to the Ebola virus. Life history interviews revealed that some of the antibody-positive people had never visited a region where known Ebola outbreaks occurred in humans. Therefore people have been exposed to the Ebola virus where it has not been recognized.
Based on their findings, the researchers were able to identify relationships among previously documented Ebola outbreaks in humans and wildlife in Gabon and RoC that initially seemed disparate and unrelated. They proposed that the virus first spread southwest across Gabon. It then looped back toward the northeast from sites in western or central Gabon and caused the most recent outbreaks in RoC.
"If the spread of the Ebola virus follows its current northeastward path, the next outbreak would be expected to occur in northern Republic of the Congo towards Cameroon and the Central African Republic," predicted Lahm.
However, according to the findings, the spread of Ebola also depends on climate factors. Illness and deaths among animals were most prevalent during periods of prolonged drought-like conditions in the rainforest, which indicates that severe environmental stress may facilitate disease transmission.
In the study, the researchers urge that public education is needed to decrease human contact with potentially infected wildlife by discouraging people from scavenging dead animals and by promoting safe hunting and trapping practices, especially because the results show that outbreaks in wildlife populations have been much more frequent than previously believed. They emphasize that monitoring wildlife in collaboration with rural African residents could provide information essential for protecting public health as well as comprehending the ecology of the disease.
Lahm points out that there remain many unanswered questions about Ebola including how the virus spreads within and between mammal species.
"Our study provides more pieces of the puzzle, but at the same time it is enlarging the puzzle," she noted.
Richard Barnes from the Environmental Sciences Research Center at Anglia Ruskin University, Cambridge, England, who is currently a visiting scholar in UCSD's Division of Biological Sciences, also contributed to the study.
Contact: Sherry Seethaler
University of California - San Diego
среда, 11 мая 2011 г.
New Small Molecule Could Act As Cancer Therapeutic
A small molecule derived from the spacer domain of the tumor-suppressor gene Rb2/p130 has demonstrated the ability to inhibit tumor growth in vivo and could be developed into an anti-cancer therapeutic, according to researchers at Temple University's Sbarro Institute for Cancer Research and Molecular Medicine.
The researchers reported their findings, "A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo," in the March 22 issue of the journal Oncogene (nature/onc).
Rb2/p130 was discovered in the early 1990s by Antonio Giordano, director of the Sbarro Institute (shro) and the Center for Biotechnology in Temple's College of Science and Technology, who headed the study.
The researchers discovered that within Rb2/p130's spacer domain--a sequence of 212 amino acids located in the pocket or middle section of the gene--was a small portion that resembled an amino-acidic sequence contained in the protein p21, which acts as a cdk (cyclin dependent kinase) inhibitor. Cdks play a critical role in cell cycle regulation.
"What we tested was the ability of the Rb2/p130 spacer region to inhibit the kinase activity of cdk2, which is the same kinase p21 inhibits," said Giordano, one of the study's lead authors. "And to our surprise, it happened."
The researchers then set about trying to reduce the spacer domain's 212 amino acids down to the smallest sequence that would still produce the same functionality as p21, explained Giordano.
"We thought we could narrow down the spacer region that contains the protein-like motif to a small portion that could be delivered as a small molecule or peptide," Giordano said.
They discovered a 39 amino-acid-long sequence, which they named Spa310. The molecule that was synthetically produced in the laboratory was introduced into mice that had been injected with tumor cells.
"Tumor growth was inhibited and the tumors began to reduce in size until they disappeared," Giordano said.
Giordano said because of the intrinsic nature of the compound, it can be easily reproduced as a biological drug in large quantities and does not require potentially dangerous means of delivery like viruses, as do most gene therapies; therefore Spa310 has a good chance to succeed as an anti-cancer therapy. For these reasons, he believes it may be easier to get approval for clinical trials.
"Fifteen years after discovering Rb2/p130, our research and hard work has led us to the discovery of this small molecule, which is a step forward in cancer research and a big step toward a cancer treatment," he said.
The study was carried out by Temple's Sbarro Institute in collaboration with Italy's University of Sassari, University of Siena, Regina Elena Cancer Institute and the Second University of Naples. It was funded by grants from the Sbarro Health Research Organization and the National Institutes of Health.
Temple University
301 University Services Bldg.1601 North Broad St.
Philadelphia, PA 19122
United States
temple/
The researchers reported their findings, "A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo," in the March 22 issue of the journal Oncogene (nature/onc).
Rb2/p130 was discovered in the early 1990s by Antonio Giordano, director of the Sbarro Institute (shro) and the Center for Biotechnology in Temple's College of Science and Technology, who headed the study.
The researchers discovered that within Rb2/p130's spacer domain--a sequence of 212 amino acids located in the pocket or middle section of the gene--was a small portion that resembled an amino-acidic sequence contained in the protein p21, which acts as a cdk (cyclin dependent kinase) inhibitor. Cdks play a critical role in cell cycle regulation.
"What we tested was the ability of the Rb2/p130 spacer region to inhibit the kinase activity of cdk2, which is the same kinase p21 inhibits," said Giordano, one of the study's lead authors. "And to our surprise, it happened."
The researchers then set about trying to reduce the spacer domain's 212 amino acids down to the smallest sequence that would still produce the same functionality as p21, explained Giordano.
"We thought we could narrow down the spacer region that contains the protein-like motif to a small portion that could be delivered as a small molecule or peptide," Giordano said.
They discovered a 39 amino-acid-long sequence, which they named Spa310. The molecule that was synthetically produced in the laboratory was introduced into mice that had been injected with tumor cells.
"Tumor growth was inhibited and the tumors began to reduce in size until they disappeared," Giordano said.
Giordano said because of the intrinsic nature of the compound, it can be easily reproduced as a biological drug in large quantities and does not require potentially dangerous means of delivery like viruses, as do most gene therapies; therefore Spa310 has a good chance to succeed as an anti-cancer therapy. For these reasons, he believes it may be easier to get approval for clinical trials.
"Fifteen years after discovering Rb2/p130, our research and hard work has led us to the discovery of this small molecule, which is a step forward in cancer research and a big step toward a cancer treatment," he said.
The study was carried out by Temple's Sbarro Institute in collaboration with Italy's University of Sassari, University of Siena, Regina Elena Cancer Institute and the Second University of Naples. It was funded by grants from the Sbarro Health Research Organization and the National Institutes of Health.
Temple University
301 University Services Bldg.1601 North Broad St.
Philadelphia, PA 19122
United States
temple/
вторник, 10 мая 2011 г.
Bacteria Manage Perfume Oil Production From Grass
Scientists in Italy have found bacteria in the root of a tropical grass whose oils have been used in the cosmetic and perfumery industries. These bacteria seem to promote the production of essential oils, but also they change the molecular structure of the oil, giving it different flavours and properties: termicidal, insecticidal, antimicrobial and antioxidant.
Studying the root of the tropical Vetiver grass through interdisciplinary research, the microbiologists Pietro Alifano and Luigi Del Giudice, the plant biologist Massimo Maffei and their colleagues found that Vetiver root cells produce a few oil precursors, which are then metabolised by the root bacteria to build up the complexity of the Vetiver oil. The bacteria were found in the oil-producing cells as well as in root locations that are closely associated with the essential oil.
The Vetiver grass is the only grass cultivated specifically for its root essential oil, which is made up of chemicals called sesquiterpenes. These are used in plants as pheromones and juvenile hormones. The essential oils also contain alcohols and hydrocarbons, which, together with the sesquiterpenes are primarily used in perfumery and cosmetics. The perfumery and flavouring industry could benefit from the increased variety that these bacteria provide to the smells and tastes of these oils.
The bacteria responsible for this transformation include alpha-, beta- and gamma-proteobacteria, high-G+C Gram-positive bacteria as well as microbes which belong to the Fibrobacteres / Acidobacteria group.
"This research opens new frontiers in the biotech arena of natural bioactive compounds" said Professor Alifano "Pharmaceutical, perfumery and flavouring industries may now exploit the selected microbial strains and widen their metabolic libraries".
"The ecological role of plant-microbial associations shows another fascinating aspect" said Professor Maffei "The metabolic interplay between a plant, which offers a few simple molecules, with root bacteria, that biotransform them into an array of bioactive compounds, increases fitness and reveals new cost-efficient survival strategies"
Source: Lucy Collister
Wiley-Blackwell
Studying the root of the tropical Vetiver grass through interdisciplinary research, the microbiologists Pietro Alifano and Luigi Del Giudice, the plant biologist Massimo Maffei and their colleagues found that Vetiver root cells produce a few oil precursors, which are then metabolised by the root bacteria to build up the complexity of the Vetiver oil. The bacteria were found in the oil-producing cells as well as in root locations that are closely associated with the essential oil.
The Vetiver grass is the only grass cultivated specifically for its root essential oil, which is made up of chemicals called sesquiterpenes. These are used in plants as pheromones and juvenile hormones. The essential oils also contain alcohols and hydrocarbons, which, together with the sesquiterpenes are primarily used in perfumery and cosmetics. The perfumery and flavouring industry could benefit from the increased variety that these bacteria provide to the smells and tastes of these oils.
The bacteria responsible for this transformation include alpha-, beta- and gamma-proteobacteria, high-G+C Gram-positive bacteria as well as microbes which belong to the Fibrobacteres / Acidobacteria group.
"This research opens new frontiers in the biotech arena of natural bioactive compounds" said Professor Alifano "Pharmaceutical, perfumery and flavouring industries may now exploit the selected microbial strains and widen their metabolic libraries".
"The ecological role of plant-microbial associations shows another fascinating aspect" said Professor Maffei "The metabolic interplay between a plant, which offers a few simple molecules, with root bacteria, that biotransform them into an array of bioactive compounds, increases fitness and reveals new cost-efficient survival strategies"
Source: Lucy Collister
Wiley-Blackwell
понедельник, 9 мая 2011 г.
Metabolon Identifies Preterm Labor Biomarkers
Metabolon, Inc., the leader in global metabolism, biomarker discovery and analysis, announces the publication of "Metabolomics in premature labor: a novel approach to identify patients at risk for preterm delivery", in The Journal of Maternal-Fetal and Neonatal Medicine.
The study, carried out in collaboration with co-authors Dr. Roberto Romero and colleagues of the NICHD, NIH, and DHHS, aimed to identify prognostic and diagnostic biomarkers of preterm delivery in women with spontaneous preterm labor (PTL) and intact membranes. Spontaneous preterm labor does not always lead to preterm delivery and the accurate and rapid identification of the risk of preterm delivery to pregnant women with PTL is needed for physicians to make immediate patient management decisions.
The report describes the identification of biomarkers for PTL and delivery and concludes that the risk of preterm delivery, in the presence or absence of infection and inflammation, can be assessed by metabolic profiling of amniotic fluid. In addition, the report presents a preliminary draft of the human amniotic fluid metabolome from women with PTL that shows biochemical intermediates of human metabolism as well as xenobiotics such as salicylamide and bacterial products can be measured in human amniotic fluid.
Source:
Metabolon, Inc.
The study, carried out in collaboration with co-authors Dr. Roberto Romero and colleagues of the NICHD, NIH, and DHHS, aimed to identify prognostic and diagnostic biomarkers of preterm delivery in women with spontaneous preterm labor (PTL) and intact membranes. Spontaneous preterm labor does not always lead to preterm delivery and the accurate and rapid identification of the risk of preterm delivery to pregnant women with PTL is needed for physicians to make immediate patient management decisions.
The report describes the identification of biomarkers for PTL and delivery and concludes that the risk of preterm delivery, in the presence or absence of infection and inflammation, can be assessed by metabolic profiling of amniotic fluid. In addition, the report presents a preliminary draft of the human amniotic fluid metabolome from women with PTL that shows biochemical intermediates of human metabolism as well as xenobiotics such as salicylamide and bacterial products can be measured in human amniotic fluid.
Source:
Metabolon, Inc.
воскресенье, 8 мая 2011 г.
Europe-Wide Investment In Lipid Research Will Help Tackle Disease, Says New Report
Leading scientists are calling for Europe to invest more funds into the study of lipids - the 'fatty' molecules that play a crucial role in the function of human cells and which are implicated in a range of diseases from obesity and diabetes to Alzheimer's.
Common lipids such as cholesterol are known to play an important part in the normal functioning of cells and tissues, but human cells contain thousands of different lipids which are also vital for functions that include storing energy, maintaining the structure of the cell and sending biochemical signals. Scientists are discovering that if the biochemical pathways that regulate the metabolism and transport of these lipids become disturbed, this can result in disease.
A report* published by the European Science Foundation (ESF) urges greater cooperation among researchers and more investment in the field of 'lipidomics' - the term given to the identification and analysis of the full complement of lipids in cells, tissues and body fluids, together with associated molecular structures such as enzymes and genes. The document is the output of a science policy activity led by the European Medical Research Councils (EMRC), the medical section within ESF.
The ESF science policy briefing document, drawn up by an international panel of experts led by Professor Gerrit van Meer of Utrecht University in The Netherlands and Professor Friedrich Spener of the University of Graz in Austria, says that the study of lipids has been largely neglected because until recently technology did not exist to analyse this complex class of molecules comprehensively. However, the application of an analytical technique called mass spectrometry now allows large numbers of lipids to be analysed rapidly. "This remarkable technological breakthrough will make it possible to better understand the cellular machineries that are responsible for producing and storing energy in cells, for the transport across and between cell membranes and for the signalling in and out of cells to name but a few examples," the report states.
A concerted research effort in lipidomics would help shed light on conditions ranging from obesity and heart disease to cancer and Alzheimer's, the report says, while pointing out that the number of European researchers with expertise in lipidomics is low and that increased funding is needed to help Europe to catch up with the level of research in countries such as Japan and the US.
The science policy briefing makes several key recommendations that would boost lipidomics research in Europe:
Investment in research programmes aimed at training biomedical scientists in lipid-related fields
Investment in further development of technologies for studying lipids, while establishing and maintaining strong links between technology developers and researchers
Development of a strong, coordinated and interdisciplinary research effort across Europe to understand lipid function and the roles of lipids in health and disease
Integration of European lipid databases and the facilitation of their communication with other databases worldwide. This would allow the 'holistic' interpretation of lipid data and provide a greater understanding of the role of lipids in health and disease.
Professor van Meer said, "Lipidomics not only involves the study of lipids, but it also involves enzymes, transporters, genes, proteins, and their biophysics. The challenge is to unite all these different datasets and bring them together with disease pathology in one concentrated database." Such an approach would provide invaluable new insights into diagnosing, monitoring and even curing disease, Professor van Meer added.
*Structural Medicine II: The Importance of Lipidomics for Health and Disease, European Science Foundation, Strasbourg. esf/spb31
Notes:
What is ESF?
The European Science Foundation (ESF) was established in 1974 to create a common European platform for cross-border cooperation in all aspects of scientific research.
With its emphasis on a multidisciplinary and pan-European approach, the Foundation provides the leadership necessary to open new frontiers in European science.
Its activities include providing science policy advice (Science Strategy); stimulating co-operation between researchers and organisations to explore new directions (Science Synergy); and the administration of externally funded programmes (Science Management). These take place in the following areas: Physical and engineering sciences; Medical sciences; Life, earth and environmental sciences; Humanities; Social sciences; Polar; Marine; Space; Radio astronomy frequencies; Nuclear physics.
Headquartered in Strasbourg with offices in Brussels and Ostend the ESF's membership comprises 77 national funding agencies, research performing agencies and academies from 30 European nations.
The Foundation's independence allows the ESF to objectively represent the priorities of all these members.
What is EMRC?
The European Medical Research Councils (EMRC) is the European Science Foundation's membership organisation for all medical research councils in Europe. The mission of the EMRC is to promote innovative medical research and its clinical application towards improved human health. EMRC offers authoritative strategic advice for science policy making, research management, ethics, and better health services. In its activities, EMRC serves as a voice of its Member Organisations and the European scientific community. EMRC disseminates knowledge and promotes the socio-economic value of medical research to the general public and the decision makers.
Source: Professor Gerrit van Meer
European Science Foundation
Common lipids such as cholesterol are known to play an important part in the normal functioning of cells and tissues, but human cells contain thousands of different lipids which are also vital for functions that include storing energy, maintaining the structure of the cell and sending biochemical signals. Scientists are discovering that if the biochemical pathways that regulate the metabolism and transport of these lipids become disturbed, this can result in disease.
A report* published by the European Science Foundation (ESF) urges greater cooperation among researchers and more investment in the field of 'lipidomics' - the term given to the identification and analysis of the full complement of lipids in cells, tissues and body fluids, together with associated molecular structures such as enzymes and genes. The document is the output of a science policy activity led by the European Medical Research Councils (EMRC), the medical section within ESF.
The ESF science policy briefing document, drawn up by an international panel of experts led by Professor Gerrit van Meer of Utrecht University in The Netherlands and Professor Friedrich Spener of the University of Graz in Austria, says that the study of lipids has been largely neglected because until recently technology did not exist to analyse this complex class of molecules comprehensively. However, the application of an analytical technique called mass spectrometry now allows large numbers of lipids to be analysed rapidly. "This remarkable technological breakthrough will make it possible to better understand the cellular machineries that are responsible for producing and storing energy in cells, for the transport across and between cell membranes and for the signalling in and out of cells to name but a few examples," the report states.
A concerted research effort in lipidomics would help shed light on conditions ranging from obesity and heart disease to cancer and Alzheimer's, the report says, while pointing out that the number of European researchers with expertise in lipidomics is low and that increased funding is needed to help Europe to catch up with the level of research in countries such as Japan and the US.
The science policy briefing makes several key recommendations that would boost lipidomics research in Europe:
Investment in research programmes aimed at training biomedical scientists in lipid-related fields
Investment in further development of technologies for studying lipids, while establishing and maintaining strong links between technology developers and researchers
Development of a strong, coordinated and interdisciplinary research effort across Europe to understand lipid function and the roles of lipids in health and disease
Integration of European lipid databases and the facilitation of their communication with other databases worldwide. This would allow the 'holistic' interpretation of lipid data and provide a greater understanding of the role of lipids in health and disease.
Professor van Meer said, "Lipidomics not only involves the study of lipids, but it also involves enzymes, transporters, genes, proteins, and their biophysics. The challenge is to unite all these different datasets and bring them together with disease pathology in one concentrated database." Such an approach would provide invaluable new insights into diagnosing, monitoring and even curing disease, Professor van Meer added.
*Structural Medicine II: The Importance of Lipidomics for Health and Disease, European Science Foundation, Strasbourg. esf/spb31
Notes:
What is ESF?
The European Science Foundation (ESF) was established in 1974 to create a common European platform for cross-border cooperation in all aspects of scientific research.
With its emphasis on a multidisciplinary and pan-European approach, the Foundation provides the leadership necessary to open new frontiers in European science.
Its activities include providing science policy advice (Science Strategy); stimulating co-operation between researchers and organisations to explore new directions (Science Synergy); and the administration of externally funded programmes (Science Management). These take place in the following areas: Physical and engineering sciences; Medical sciences; Life, earth and environmental sciences; Humanities; Social sciences; Polar; Marine; Space; Radio astronomy frequencies; Nuclear physics.
Headquartered in Strasbourg with offices in Brussels and Ostend the ESF's membership comprises 77 national funding agencies, research performing agencies and academies from 30 European nations.
The Foundation's independence allows the ESF to objectively represent the priorities of all these members.
What is EMRC?
The European Medical Research Councils (EMRC) is the European Science Foundation's membership organisation for all medical research councils in Europe. The mission of the EMRC is to promote innovative medical research and its clinical application towards improved human health. EMRC offers authoritative strategic advice for science policy making, research management, ethics, and better health services. In its activities, EMRC serves as a voice of its Member Organisations and the European scientific community. EMRC disseminates knowledge and promotes the socio-economic value of medical research to the general public and the decision makers.
Source: Professor Gerrit van Meer
European Science Foundation
суббота, 7 мая 2011 г.
Alternative Splicing Proteins Prompt Heart Development
Just as the emotions it represents are dynamic, the heart's development requires dynamic shifts in proteins that prompt alternative spicing, a mechanism that allows a given gene to program the cell to make several proteins, said a group of researchers at Baylor College of Medicine in a report that appears online in the journal Proceedings of the National Academy of Sciences.
Using a technique called splicing sensitive microarrays or gene chips that help identify genes, the researchers from BCM, Massachusetts Institute of Technology in Cambridge and Rosetta Inpharmatics, LLC in Seattle identified two proteins (CUGBP and ETR-3-like factors called CELF and muscleblind-like protein called MBNL1) that reprogram alternative splicing in the developing hearts of mice, affecting how the heart grows during the pre-birth, immediately post-birth periods.
There is a rapid decrease in the amount of CELF proteins (more than 10-fold) and a concomitant increase in MBNL1 proteins (nearly 4-fold) during the first two weeks after birth. The finding has implications for a muscle-wasting ailment called myotonic dystrophy as well as for normal heart development.
"These are physiologically important times," said Dr. Thomas Cooper, professor of pathology and molecular and cellular biology at BCM and the senior author of the report. "Before birth, the heart is getting ready for a complete change in function. After birth, it needs to work harder to accommodate the demands of moving about."
"It is now clear that there's a new level of regulation during development," he said. "It's not just turning genes on and off. It is changing the composition of the proteins expressed from this one set of genes."
In fact, half of the alternative splicing changes that occur during heart development are controlled by the CELF and muscleblind-like factors, said Cooper.
Most of the changes in alternative splicing found in mouse heart development were also found in chicken heart development strongly suggesting that the changes are very important for normal heart. It is very likely that the same changes are needed for normal human heart development as well.
Alternative splicing is a fairly common occurrence that is crucial to enabling an estimated 25,000 genes in humans to make the 100,000 or more proteins needed to carry out the functions of cells throughout the body. Genes, made up of DNA, have exons that carry the coding sequences for amino acids that make up proteins (the "genetic code"). However, before the proteins are made, messenger RNA (mRNA) must be made from the DNA. The mRNA then carries the code to the protein-building structures of the cell. The mRNA can contain all or just some of the exons or coding sequences of the gene. The protein that is made varies, depending on which exons are included in the mRNA. This variation in the mRNA is called alternative splicing because the mRNA splices in different coding sequences.
Now Cooper and his colleagues have identified two factors that are crucial in switching the alternative splicing, depending on the stage of heart development. "This work is the first to identify specific sets of exons that are regulated only by CUGBP1 or MBNL1", said Dr. Auinash Kalsotra, lead author of the paper and postdoctoral fellow in the department of pathology at BCM.
In myotonic dystrophy, the alternative splicing pattern is disrupted by the disease, switching from an adult to an embryonic pattern, said Cooper. The presence of embryonic rather than adult forms of proteins cause major symptoms of the disease. Myotonic dystrophy is the most common form of muscular dystrophy that begins in adulthood. Understanding normal modes of alternative splicing regulation will aid in identifying pathways that are disrupted in the disease which are considered to be potential targets for therapy.
Others who took part in this research include Amanda Ward of BCM, Xinshu Xiao and Christopher B. Burge of MIT, John C. Castle and Jason M. Johnson of Rosetta Inpharmatics LLC, Merck & Co., Inc., Seattle.
Funding for this work came from the National Institutes of Health.
This report is available at pnas/. For more science and health news from Baylor College of Medicine in Houston, go to bcm/fromthelab.
Source: Graciela Gutierrez
Baylor College of Medicine
Using a technique called splicing sensitive microarrays or gene chips that help identify genes, the researchers from BCM, Massachusetts Institute of Technology in Cambridge and Rosetta Inpharmatics, LLC in Seattle identified two proteins (CUGBP and ETR-3-like factors called CELF and muscleblind-like protein called MBNL1) that reprogram alternative splicing in the developing hearts of mice, affecting how the heart grows during the pre-birth, immediately post-birth periods.
There is a rapid decrease in the amount of CELF proteins (more than 10-fold) and a concomitant increase in MBNL1 proteins (nearly 4-fold) during the first two weeks after birth. The finding has implications for a muscle-wasting ailment called myotonic dystrophy as well as for normal heart development.
"These are physiologically important times," said Dr. Thomas Cooper, professor of pathology and molecular and cellular biology at BCM and the senior author of the report. "Before birth, the heart is getting ready for a complete change in function. After birth, it needs to work harder to accommodate the demands of moving about."
"It is now clear that there's a new level of regulation during development," he said. "It's not just turning genes on and off. It is changing the composition of the proteins expressed from this one set of genes."
In fact, half of the alternative splicing changes that occur during heart development are controlled by the CELF and muscleblind-like factors, said Cooper.
Most of the changes in alternative splicing found in mouse heart development were also found in chicken heart development strongly suggesting that the changes are very important for normal heart. It is very likely that the same changes are needed for normal human heart development as well.
Alternative splicing is a fairly common occurrence that is crucial to enabling an estimated 25,000 genes in humans to make the 100,000 or more proteins needed to carry out the functions of cells throughout the body. Genes, made up of DNA, have exons that carry the coding sequences for amino acids that make up proteins (the "genetic code"). However, before the proteins are made, messenger RNA (mRNA) must be made from the DNA. The mRNA then carries the code to the protein-building structures of the cell. The mRNA can contain all or just some of the exons or coding sequences of the gene. The protein that is made varies, depending on which exons are included in the mRNA. This variation in the mRNA is called alternative splicing because the mRNA splices in different coding sequences.
Now Cooper and his colleagues have identified two factors that are crucial in switching the alternative splicing, depending on the stage of heart development. "This work is the first to identify specific sets of exons that are regulated only by CUGBP1 or MBNL1", said Dr. Auinash Kalsotra, lead author of the paper and postdoctoral fellow in the department of pathology at BCM.
In myotonic dystrophy, the alternative splicing pattern is disrupted by the disease, switching from an adult to an embryonic pattern, said Cooper. The presence of embryonic rather than adult forms of proteins cause major symptoms of the disease. Myotonic dystrophy is the most common form of muscular dystrophy that begins in adulthood. Understanding normal modes of alternative splicing regulation will aid in identifying pathways that are disrupted in the disease which are considered to be potential targets for therapy.
Others who took part in this research include Amanda Ward of BCM, Xinshu Xiao and Christopher B. Burge of MIT, John C. Castle and Jason M. Johnson of Rosetta Inpharmatics LLC, Merck & Co., Inc., Seattle.
Funding for this work came from the National Institutes of Health.
This report is available at pnas/. For more science and health news from Baylor College of Medicine in Houston, go to bcm/fromthelab.
Source: Graciela Gutierrez
Baylor College of Medicine
пятница, 6 мая 2011 г.
Innovative View Of The Neurobiological Mechanisms Of Cognitive Control Opens Up New Lines Of Research
Psychologists and neurologists invest considerable effort in the study of working memory. In terms of information retention, there is a difference between long-term memory, which is affected in diseases such as Alzheimer, and short-term or working memory, which allows us to make immediate decisions or structure a discourse. This more ephemeral memory is affected in diseases such as schizophrenia and depression, although a cause-effect relationship has not been established.
People with a higher working-memory capacity score higher on intelligence tests and, for this reason, it is thought that it may be intimately linked to people's cognitive ability.
A study by IDIBAPS uses computational systems neurobiology models and functional magnetic resonance imaging scans to show that there are two parts of the cerebral cortex with highly differentiated roles implicated in this type of memory. The results of the study were published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS), in an article headed by Dr. Albert Compte of the Systems Neuroscience team of the Institut d'Investigacions BiomГЁdiques August Pi i Sunyer (IDIBAPS), and with Fredrik Edin as the first author. This study was carried out in collaboration with two other laboratories of the Karolinska Institute, Stockholm, led by professors Torkel Klingberg and Jesper TegnГ©r.
Thanks to complex computer algorithms, it is possible to simulate a virtual network in which a large number of neurons interact. These models can simulate the functioning of the structures in our brains. According to the computer model published in PNAS, when the working memory needs to be increased, the prefrontal cortex reinforces the activation of the parietal cortex, in which the information is temporarily stored. A brief stimulus that reaches the parietal cortex generates a reverberating activation that maintains a subpopulation active, while inhibitory interactions with neurons further away (lateral inhibition) prevents activation of the entire network. This lateral inhibition is also responsible for limiting the mnemonic capacity of the parietal network. The reinforcement of the parietal cortex by the prefrontal cortex prevents its inhibition, thereby temporarily improving working memory.
To verify this hypothesis, 25 healthy individuals carried out simple visual-memory tests while inside a functional magnetic resonance scanner. The differences in their ability to complete the exercises were linked to the intensity of activation of the prefrontal cortex and to their interconnection with the parietal cortex. The IDIBAPS and Karolinska researchers thus confirmed the hypothesis formulated based on the computer model. The more the prefrontal cortex is activated, the greater the capacity of the parietal cortex for retaining short-term visual information - an indicator of working-memory capacity.
This study explains many diverse results that have been obtained in recent years in psychology and neuroimaging studies on working memory. This is an innovative view of the neurobiological mechanisms of cognitive control and opens up new lines of research. Clinical studies will be needed to determine whether the stimulus of the prefrontal cortex, or its training by means of memory exercises and games, can have an effect on diseases in which working memory is damaged, such as depression or schizophrenia.
Source:
Alex Argemi
IDIBAPS - Institut d'Investigacions BiomГЁdiques August Pi i Sunyer
People with a higher working-memory capacity score higher on intelligence tests and, for this reason, it is thought that it may be intimately linked to people's cognitive ability.
A study by IDIBAPS uses computational systems neurobiology models and functional magnetic resonance imaging scans to show that there are two parts of the cerebral cortex with highly differentiated roles implicated in this type of memory. The results of the study were published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS), in an article headed by Dr. Albert Compte of the Systems Neuroscience team of the Institut d'Investigacions BiomГЁdiques August Pi i Sunyer (IDIBAPS), and with Fredrik Edin as the first author. This study was carried out in collaboration with two other laboratories of the Karolinska Institute, Stockholm, led by professors Torkel Klingberg and Jesper TegnГ©r.
Thanks to complex computer algorithms, it is possible to simulate a virtual network in which a large number of neurons interact. These models can simulate the functioning of the structures in our brains. According to the computer model published in PNAS, when the working memory needs to be increased, the prefrontal cortex reinforces the activation of the parietal cortex, in which the information is temporarily stored. A brief stimulus that reaches the parietal cortex generates a reverberating activation that maintains a subpopulation active, while inhibitory interactions with neurons further away (lateral inhibition) prevents activation of the entire network. This lateral inhibition is also responsible for limiting the mnemonic capacity of the parietal network. The reinforcement of the parietal cortex by the prefrontal cortex prevents its inhibition, thereby temporarily improving working memory.
To verify this hypothesis, 25 healthy individuals carried out simple visual-memory tests while inside a functional magnetic resonance scanner. The differences in their ability to complete the exercises were linked to the intensity of activation of the prefrontal cortex and to their interconnection with the parietal cortex. The IDIBAPS and Karolinska researchers thus confirmed the hypothesis formulated based on the computer model. The more the prefrontal cortex is activated, the greater the capacity of the parietal cortex for retaining short-term visual information - an indicator of working-memory capacity.
This study explains many diverse results that have been obtained in recent years in psychology and neuroimaging studies on working memory. This is an innovative view of the neurobiological mechanisms of cognitive control and opens up new lines of research. Clinical studies will be needed to determine whether the stimulus of the prefrontal cortex, or its training by means of memory exercises and games, can have an effect on diseases in which working memory is damaged, such as depression or schizophrenia.
Source:
Alex Argemi
IDIBAPS - Institut d'Investigacions BiomГЁdiques August Pi i Sunyer
четверг, 5 мая 2011 г.
To Escape Death By Hormonal Therapy Breast Cancer Cells Recycle
Many breast cancer cells facing potentially lethal antiestrogen therapy recycle to survive, researchers say.
About 70 percent of breast cancer cells have receptors for the hormone estrogen, which acts as a nutrient and stimulates their growth. Patients typically get an antiestrogen such as tamoxifen for five years to try to starve them to death, says Dr. Patricia V. Schoenlein, cancer researcher in the Medical College of Georgia Schools of Medicine and Graduate Studies.
"About 50 to 60 percent of these women really benefit from hormonal therapy," says Dr. Schoenlein. Why others don't has been asked for at least two decades.
One reason may be breast cancer cells switch into a survival mode that normal cells also use when faced with starvation, according to research published in the September issue of Molecular Cancer Therapeutics. Dr. Schoenlein also is reporting on the research during the 2nd World Conference on Magic Bullets (Ehrlich II) Oct. 3-5 in NГјrenberg, Germany.
It's called macroautophagy - autophagy means "self eating" - and within a week, breast cancer cells can reorganize component parts, degrade non-essentials and live in this state until antiestrogen therapy is stopped or the cells mutate and resume proliferation in the presence of tamoxifen. "It's like taking your foot off of the gas pedal of your car," says Dr. Schoenlein, corresponding author on the study. "The cancer cell is in idle, unable to grow or replicate. But the cell is smart enough to use component parts generated by macroautophagy for the most necessary things required for survival." She notes that macroautophagy can't be maintained indefinitely; cells can actually self-digest. "This is a time-buying strategy."
Chemotherapeutic drugs are more direct killers but also kill healthy cells and can be tolerated by patients only for relatively short periods. Antiestrogen therapy is more specific, targeting breast cancer cells that express estrogen receptors.
In the laboratory, 20-25 percent of breast cancer cells died when Dr. Schoenlein and colleagues gave antiestrogen continuously over time - similar to how patients get it. More typically, the cells expressed increasing levels of macroautophagy and survived. "They don't grow, but they survive the therapy. They will grow if you take away the therapy." Adding a macroautophagy inhibitor promoted robust cell death.
"We believe targeting the autophagosome function will significantly improve the efficacy of hormonal treatment for estrogen-positive breast cancer," says the researcher. She recently received a three-year, $1.1 million National Cancer Institute grant to pursue that strategy.
She'll now look for ways to block macroautophagy in an animal model, including using chloroquine, a drug used to treat malaria. "We know patients can take it with few side effects," she says. If it works in animals, the drug, in combination with an antiestrogen, could move relatively quickly into human testing.
During autophagy, the internal pH for the recycling center of the reorganized cell gets acidic and chloroquine increases pH. "If you add this particular inhibitor of the recycling center, you alter the pH and block its ability to do what it is supposed to do," says Dr. Schoenlein.
A University of Pennsylvania team led by Dr. Craig Thompson reported in 2007 in The Journal of Clinical Investigation that chloroquine increased death of suicide-resistant lymphoma cells being treated with chemotherapy. Dr. Schoenlein will give chloroquine along with an antiestrogen and measure cell death.
"Most cancers probably use autophagy as a survival mechanism. You can either block the autophagosome with your therapy or you can make the cell eat itself to the point of no return and the cell self-destructs. You have to push it either way," she says. Although there are no known compounds in clinical use to induce self-destruction by autophagy, there is some evidence arsenic trioxide, a compound used in China to treat some aggressive cancers, prompts cancer cells to die from self digestion, she says. That and other compounds will no doubt be studied further, she says.
Dr. Schoenlein believes breast cancer survival during macroautophagy requires high activity of the tumor suppressor protein Rb and low levels of the lipid ceramide. Ceramide is vital but causes cell death at high levels. MCG researcher Erhard Bieberich and colleague Dr. Brian G. Condie at the University of Georgia showed in 2003 that high levels of ceramide kill cells that are unnecessary to the developing brain. The new studies will further explore the roles of Rb and ceramide in breast cancer survival during macroautophagy and determine if chloroquine can change their balance.
MCG news categories related to this story:
Cancer
School of Medicine
School of Graduate Studies
Source: Toni Baker
Medical College of Georgia
About 70 percent of breast cancer cells have receptors for the hormone estrogen, which acts as a nutrient and stimulates their growth. Patients typically get an antiestrogen such as tamoxifen for five years to try to starve them to death, says Dr. Patricia V. Schoenlein, cancer researcher in the Medical College of Georgia Schools of Medicine and Graduate Studies.
"About 50 to 60 percent of these women really benefit from hormonal therapy," says Dr. Schoenlein. Why others don't has been asked for at least two decades.
One reason may be breast cancer cells switch into a survival mode that normal cells also use when faced with starvation, according to research published in the September issue of Molecular Cancer Therapeutics. Dr. Schoenlein also is reporting on the research during the 2nd World Conference on Magic Bullets (Ehrlich II) Oct. 3-5 in NГјrenberg, Germany.
It's called macroautophagy - autophagy means "self eating" - and within a week, breast cancer cells can reorganize component parts, degrade non-essentials and live in this state until antiestrogen therapy is stopped or the cells mutate and resume proliferation in the presence of tamoxifen. "It's like taking your foot off of the gas pedal of your car," says Dr. Schoenlein, corresponding author on the study. "The cancer cell is in idle, unable to grow or replicate. But the cell is smart enough to use component parts generated by macroautophagy for the most necessary things required for survival." She notes that macroautophagy can't be maintained indefinitely; cells can actually self-digest. "This is a time-buying strategy."
Chemotherapeutic drugs are more direct killers but also kill healthy cells and can be tolerated by patients only for relatively short periods. Antiestrogen therapy is more specific, targeting breast cancer cells that express estrogen receptors.
In the laboratory, 20-25 percent of breast cancer cells died when Dr. Schoenlein and colleagues gave antiestrogen continuously over time - similar to how patients get it. More typically, the cells expressed increasing levels of macroautophagy and survived. "They don't grow, but they survive the therapy. They will grow if you take away the therapy." Adding a macroautophagy inhibitor promoted robust cell death.
"We believe targeting the autophagosome function will significantly improve the efficacy of hormonal treatment for estrogen-positive breast cancer," says the researcher. She recently received a three-year, $1.1 million National Cancer Institute grant to pursue that strategy.
She'll now look for ways to block macroautophagy in an animal model, including using chloroquine, a drug used to treat malaria. "We know patients can take it with few side effects," she says. If it works in animals, the drug, in combination with an antiestrogen, could move relatively quickly into human testing.
During autophagy, the internal pH for the recycling center of the reorganized cell gets acidic and chloroquine increases pH. "If you add this particular inhibitor of the recycling center, you alter the pH and block its ability to do what it is supposed to do," says Dr. Schoenlein.
A University of Pennsylvania team led by Dr. Craig Thompson reported in 2007 in The Journal of Clinical Investigation that chloroquine increased death of suicide-resistant lymphoma cells being treated with chemotherapy. Dr. Schoenlein will give chloroquine along with an antiestrogen and measure cell death.
"Most cancers probably use autophagy as a survival mechanism. You can either block the autophagosome with your therapy or you can make the cell eat itself to the point of no return and the cell self-destructs. You have to push it either way," she says. Although there are no known compounds in clinical use to induce self-destruction by autophagy, there is some evidence arsenic trioxide, a compound used in China to treat some aggressive cancers, prompts cancer cells to die from self digestion, she says. That and other compounds will no doubt be studied further, she says.
Dr. Schoenlein believes breast cancer survival during macroautophagy requires high activity of the tumor suppressor protein Rb and low levels of the lipid ceramide. Ceramide is vital but causes cell death at high levels. MCG researcher Erhard Bieberich and colleague Dr. Brian G. Condie at the University of Georgia showed in 2003 that high levels of ceramide kill cells that are unnecessary to the developing brain. The new studies will further explore the roles of Rb and ceramide in breast cancer survival during macroautophagy and determine if chloroquine can change their balance.
MCG news categories related to this story:
Cancer
School of Medicine
School of Graduate Studies
Source: Toni Baker
Medical College of Georgia
среда, 4 мая 2011 г.
Sangamo BioSciences Announces Presentation Of Preliminary Data From Phase 1 Safety Trial Of SB-728-T For HIV/AIDS
Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced that preliminary data from the University of Pennsylvania investigator sponsored Phase 1 safety study of Sangamo's zinc finger nuclease (ZFN) based product, SB-728-T, for HIV/AIDS were presented on Friday, January 15, 2010 at the Keystone Symposium Session "HIV Biology and Pathogenesis." Sangamo's collaborator, Carl June, M.D., Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine, presented the data as an invited speaker in an NIAID Workshop entitled "The Next Challenge: Elimination of HIV Reservoirs."
"While only representative of a single individual in the trial, these data are very exciting," said Dr. June. "They demonstrate that the ZFN-modified T-cells were well tolerated by the body and persisted in the circulation at stable levels for the duration of our monitoring. In fact, we calculate that more ZFN-modified cells were present at 20 weeks than were initially infused. Total CD4+ T-cell counts were also stable during this time. Interestingly, we also observed ZFN-modified cells in the gut associated lymphoid tissue (GALT) which is a major reservoir of immune cells and a critical reservoir of HIV infection and suggests that the modified cells are functioning and trafficking normally in the body."
Dr. June described data from a single HIV- positive subject treated with SB-728-T who, as part of the study, began a structured treatment interruption (STI) from his antiviral drug therapy four weeks after SB-728-T treatment. Twelve weeks later, the STI ended and the subject resumed antiviral therapy. During the study, the subject's CD4+ T-cell count, the number of circulating ZFN-modified cells and viral loads were measured periodically. In addition, rectal biopsies were taken prior to treatment and at the end of the STI period to monitor levels of CD4+ and ZFN-modified T-cells in the GALT.
The subject entered the STI period with stable CD4+ and ZFN-modified T-cell levels and an undetectable viral load. Viral load was monitored with biweekly testing and it was observed that the subject experienced a delay in the return of virus, which was first detectable at six weeks post STI initiation. Previous studies have shown that in subjects undergoing an STI, the average time to detection of an increase in viral load is two to four weeks. At twelve weeks post STI, in accordance with the trial protocol, the subject resumed antiretroviral medication and his viral load decreased. During the monitoring period, the subject continued to demonstrate stable CD4+ T-cell counts and stable levels of ZFN-modified T-cells. In rectal biopsy samples taken at the end of the STI period, ZFN-modified cells were found in GALT suggesting that these cells circulate and traffic normally.
"These are the first human data from a ZFN-based therapeutic and, although preliminary, are very encouraging and recapitulate observations that we have made in preclinical studies," stated Dale Ando, Sangamo's vice president of therapeutic development and chief medical officer. "Importantly, ZFN-modified cells expanded over the period that we monitored the subject and were well tolerated. As expected, the subject's viral load increased during the STI. However, the kinetics of this subject's viral rebound was delayed. Presence of ZFN-modified cells in the GALT, an important HIV reservoir, demonstrates that we are achieving our pharmacologic biodistribution target. GALT HIV persistence in CD4+ T-cells is the reason that HIV is not eradicated in patients who are fully suppressed on highly active anti-retroviral treatment, or HAART. Ultimately, having a protected CD4+ T-cell population in the GALT may be extremely important in combating this disease.
"Our ZFN-based technology provides a totally new approach to HIV/AIDS with the aim of providing a reservoir of functional T-cells that are resistant to infection by HIV and available to fight opportunistic infections, and these data are an early indication that this may be possible."
About SB-728-T
SB-728-T is a cell product based on Sangamo's ZFN technology. CD4+ T-cells are removed from the subject's blood and treated with Sangamo's ZFNs designed to modify the DNA sequence encoding the CCR5 gene. This modification can occur directly in T-cells with only a brief exposure to the ZFNs. Once the CCR5 gene is modified, the gene is permanently disrupted in these cells.
CCR5 is a co-receptor that enables HIV to enter and infect cells of the immune system. About ten years ago, it was observed that individuals carrying a natural mutation of their CCR5 gene, CCR5-delta32, were highly resistant to infection by HIV. These individuals, lacking a functional CCR5 (approximately 1-2% of the general population), are immunologically "normal". A variety of small molecule and antibody antagonists of CCR5 have been tested and developed as potential therapeutic agents for the treatment of HIV infection. In addition, there is a recent report of a patient who had both HIV and leukemia and received a bone marrow transplant from a donor carrying the CCR5 mutation. After the successful bone marrow transplant, HIV treatment was discontinued and the virus could not be found in the circulating blood several months after the procedure.
About Sangamo
Sangamo BioSciences, Inc. is focused on the research and development of novel DNA-binding proteins for therapeutic gene regulation and modification. The most advanced ZFP Therapeutic(TM) development program is currently in a Phase 2b clinical trial for evaluation of safety and clinical effect in patients with diabetic neuropathy and a Phase 2 trial in ALS. Sangamo also has two Phase 1 clinical trials to evaluate safety and clinical effect of a treatment for HIV/AIDS and another Phase 1 trial to evaluate safety and clinical effect of a treatment for recurrent glioblastoma multiforme. Other therapeutic development programs are focused on neuropathic pain, nerve regeneration, Parkinson's disease and monogenic diseases. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TF) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFN) for gene modification. Sangamo has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation.
This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references to the clinical trials of SB-728-T, tolerability and efficacy of SB 509-728-T, research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the small size of the data set, completion of stages of the SB-728-T clinical trials, whether the SB-728-T clinical trials will validate and support tolerability and efficacy of SB-728-T, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. See Sangamo's SEC filings, and in particular, the risk factors described in the company's Annual Report on Form 10-K and most recent Quarterly Report on Form 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.
Source: Sangamo BioSciences, Inc
"While only representative of a single individual in the trial, these data are very exciting," said Dr. June. "They demonstrate that the ZFN-modified T-cells were well tolerated by the body and persisted in the circulation at stable levels for the duration of our monitoring. In fact, we calculate that more ZFN-modified cells were present at 20 weeks than were initially infused. Total CD4+ T-cell counts were also stable during this time. Interestingly, we also observed ZFN-modified cells in the gut associated lymphoid tissue (GALT) which is a major reservoir of immune cells and a critical reservoir of HIV infection and suggests that the modified cells are functioning and trafficking normally in the body."
Dr. June described data from a single HIV- positive subject treated with SB-728-T who, as part of the study, began a structured treatment interruption (STI) from his antiviral drug therapy four weeks after SB-728-T treatment. Twelve weeks later, the STI ended and the subject resumed antiviral therapy. During the study, the subject's CD4+ T-cell count, the number of circulating ZFN-modified cells and viral loads were measured periodically. In addition, rectal biopsies were taken prior to treatment and at the end of the STI period to monitor levels of CD4+ and ZFN-modified T-cells in the GALT.
The subject entered the STI period with stable CD4+ and ZFN-modified T-cell levels and an undetectable viral load. Viral load was monitored with biweekly testing and it was observed that the subject experienced a delay in the return of virus, which was first detectable at six weeks post STI initiation. Previous studies have shown that in subjects undergoing an STI, the average time to detection of an increase in viral load is two to four weeks. At twelve weeks post STI, in accordance with the trial protocol, the subject resumed antiretroviral medication and his viral load decreased. During the monitoring period, the subject continued to demonstrate stable CD4+ T-cell counts and stable levels of ZFN-modified T-cells. In rectal biopsy samples taken at the end of the STI period, ZFN-modified cells were found in GALT suggesting that these cells circulate and traffic normally.
"These are the first human data from a ZFN-based therapeutic and, although preliminary, are very encouraging and recapitulate observations that we have made in preclinical studies," stated Dale Ando, Sangamo's vice president of therapeutic development and chief medical officer. "Importantly, ZFN-modified cells expanded over the period that we monitored the subject and were well tolerated. As expected, the subject's viral load increased during the STI. However, the kinetics of this subject's viral rebound was delayed. Presence of ZFN-modified cells in the GALT, an important HIV reservoir, demonstrates that we are achieving our pharmacologic biodistribution target. GALT HIV persistence in CD4+ T-cells is the reason that HIV is not eradicated in patients who are fully suppressed on highly active anti-retroviral treatment, or HAART. Ultimately, having a protected CD4+ T-cell population in the GALT may be extremely important in combating this disease.
"Our ZFN-based technology provides a totally new approach to HIV/AIDS with the aim of providing a reservoir of functional T-cells that are resistant to infection by HIV and available to fight opportunistic infections, and these data are an early indication that this may be possible."
About SB-728-T
SB-728-T is a cell product based on Sangamo's ZFN technology. CD4+ T-cells are removed from the subject's blood and treated with Sangamo's ZFNs designed to modify the DNA sequence encoding the CCR5 gene. This modification can occur directly in T-cells with only a brief exposure to the ZFNs. Once the CCR5 gene is modified, the gene is permanently disrupted in these cells.
CCR5 is a co-receptor that enables HIV to enter and infect cells of the immune system. About ten years ago, it was observed that individuals carrying a natural mutation of their CCR5 gene, CCR5-delta32, were highly resistant to infection by HIV. These individuals, lacking a functional CCR5 (approximately 1-2% of the general population), are immunologically "normal". A variety of small molecule and antibody antagonists of CCR5 have been tested and developed as potential therapeutic agents for the treatment of HIV infection. In addition, there is a recent report of a patient who had both HIV and leukemia and received a bone marrow transplant from a donor carrying the CCR5 mutation. After the successful bone marrow transplant, HIV treatment was discontinued and the virus could not be found in the circulating blood several months after the procedure.
About Sangamo
Sangamo BioSciences, Inc. is focused on the research and development of novel DNA-binding proteins for therapeutic gene regulation and modification. The most advanced ZFP Therapeutic(TM) development program is currently in a Phase 2b clinical trial for evaluation of safety and clinical effect in patients with diabetic neuropathy and a Phase 2 trial in ALS. Sangamo also has two Phase 1 clinical trials to evaluate safety and clinical effect of a treatment for HIV/AIDS and another Phase 1 trial to evaluate safety and clinical effect of a treatment for recurrent glioblastoma multiforme. Other therapeutic development programs are focused on neuropathic pain, nerve regeneration, Parkinson's disease and monogenic diseases. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TF) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFN) for gene modification. Sangamo has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation.
This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references to the clinical trials of SB-728-T, tolerability and efficacy of SB 509-728-T, research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the small size of the data set, completion of stages of the SB-728-T clinical trials, whether the SB-728-T clinical trials will validate and support tolerability and efficacy of SB-728-T, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. See Sangamo's SEC filings, and in particular, the risk factors described in the company's Annual Report on Form 10-K and most recent Quarterly Report on Form 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.
Source: Sangamo BioSciences, Inc
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