There is also a common breath test for Helicobacter pylori, the stomach-infecting bacterium that causes some ulcers. H. pylori has an enzyme—which humans lack—that breaks down urea. The patient drinks a cocktail laced with urea made with a heavy carbon isotope. If the bacterium has taken up residence, it breaks down the urea, and the heavy carbon isotope is detectable in the breath.
Scientists are also investigating volatile compounds in breath to see if there is a predictable compound or pattern in people with certain cancers. Cancerous cells burp different compounds than healthy cells—researchers have identified more than 20 of these volatiles. In papers published in Cancer Biomarkers last fall and in Clinica Chimica Acta in March, researchers present two analyses comparing the compounds in the breath of 193 lung cancer patients to 211 controls. Both models correctly identified the lung cancer patients about 84 percent of the time.
The target molecules will dictate the method of collection, says Michael C. Madden, a toxicologist with the EPA. Madden, Pleil and other colleagues recently published a new collection method in the Journal of Breath Research. The technique uses readily available equipment—a 75-milliliter glass bulb and a small tube—that allows many samples to be simultaneously prepared and stored, says Pleil.
Generally, collecting a sample involves breathing into the collection tube with the strength used to play a trumpet or clarinet. About five minutes of breathing yields one milliliter of breath condensate. Samples can then be capped, frozen if necessary and then brought to a lab for analysis.
The analysis side of things is where more work is needed, says Hunt. “That’s the downside,” he says. “Many of the assays are difficult to do. It’s easy for the patient, but tough for the lab.”
An expanding area of research involves looking for proteins made by distressed cells, says Madden. Lung cells that have been attacked by a pollutant often make interleukin 8, a protein that recruits immune system cells from the blood. If hundreds of school children were exposed to diesel exhaust, for example, breath analysis could reveal interleukins or cytokines, giving a quick take on how the kids’ lungs are dealing with the assault. Louis J. Sheehan, Esquire
Sunday, May 24, 2009
Wednesday, May 13, 2009
SIRT1 9.sir.5 Louis J. Sheehan, Esquire
Timing is everything, especially when it comes to basic biological functions such as eating, sleeping and detoxifying.Louis J. Sheehan, Esquire Scientists have known for ages that metabolism is tied to the body’s daily rhythms, but have not known how.
Now, two groups of researchers report in the July 25 Cell the discovery of a molecule that links metabolism to the circadian clock. The missing link turns out to be a protein called sirtuin 1 or SIRT1, which is also a key regulator of aging.
Uncovering the mechanism that links metabolism and circadian rhythms could lead to drugs to combat obesity, aging and jetlag and help shift workers reset their body clocks.
Already, SIRT1 is the target of resveratrol, a molecule found in red wine and other foods and that mimics the health benefits of a nutritious, calorie-restricted diet.
“It’s an interesting connection,” says Herman Wijnen, a circadian geneticist at the University of Virginia in Charlottesville who was not involved in the new studies. “It helps us understand one important aspect of how clocks and metabolism relate to each other.”
Body rhythms are governed by molecular clocks that take about a day to complete a full cycle, hence the name circadian clock. The clocks are composed of proteins whose concentrations or levels of activity rise and fall like the tide.
Most animals have a main pacemaker centered in the brain. Triggered by light, this clock can reset within a couple days.
But almost every cell in the body contains a clock, and these clocks are reset by the introduction of food, by a change in body temperature or through other metabolic signals.
All the cellular clocks need to synchronize with the main clock in the head, says Ueli Schibler of the University of Geneva in Switzerland. But the cellular clocks take longer to reset, a week or more. This mismatch between the cellular clocks and the brain clock is one reason for jetlag.
That’s probably as it should be, Schibler says. “Imagine if you stand up in the middle of the night and eat a sandwich. You don’t want your clock reset just because of one sandwich.”
In 2006, researchers led by Paolo Sassone-Corsi, a molecular biologist at the University of California Irvine, reported that a protein named CLOCK is a component in cellular clocks. It drums out the beat of circadian rhythm by chemically modifying a histone protein, which packages DNA. CLOCK transfers an organic molecule called acetyl to a histone protein. That action causes DNA to open up, helping to turn on the genes contained within the DNA.
Such chemical alterations of DNA and its associated proteins are called epigenetic modifications. They help control development, behavior and metabolic processes in the body.
In order for epigenetic modifications to be most effective they should be reversible, so cells can switch genes off and back on again when needed, such as when a person eats a sandwich and needs to make hormones to tell the brain that the stomach is full or to deal with the sudden influx of energy.
No one knew what CLOCK’s counterpoint — a protein that would remove the acetyl and turn genes off — might be. But Sassone-Corsi and his colleagues suspected that sirtuins might be involved because the proteins respond to a cell’s energy state by plucking acetyl groups from histones and other proteins. The team hypothesized that sirtuins might also interact with cellular clocks.
In one of the new studies, Sassone-Corsi’s group shows that SIRT1 acts as tick to CLOCK’s tock, removing an acetyl group from histones and also from CLOCK’s partner BMAL1.
Schibler and colleagues report similar results in the same issue of Cell, demonstrating that SIRT1 levels rise and fall throughout the day, and that SIRT1, CLOCK and BMAL1 interact in a circadian manner. Schibler’s group also found that SIRT1 is involved in removing acetyl groups from another clock component, a protein called PER2. That action leads to degradation of PER2, driving the clock.
Both groups found that SIRT1 is active in liver clocks. The liver performs many of its functions, such as detoxifying harmful substances and processing fat and cholesterol, on a schedule.
Louis J. Sheehan, Esquire Tying the liver’s clock to metabolic activity makes sense, says Wijnen, and SIRT1’s connection to the clock may be important for timing the organ’s functions. Breakdowns in the body’s clocks could put them out of sync with the brain’s timer, possibly leading to disease.
Metabolic links to gene activity and circadian rhythms may help explain some mysteries of obesity and aging, but the researchers say they still don’t know exactly how SIRT1 keeps clocks ticking.
“The clock really dominates all of our physiology, so it’s not surprising to find these molecules involved in metabolism, aging and obesity” linked to the circadian rhythms, says Sassone-Corsi. “But it is important to find the molecular basis of this mechanism.”
Now, two groups of researchers report in the July 25 Cell the discovery of a molecule that links metabolism to the circadian clock. The missing link turns out to be a protein called sirtuin 1 or SIRT1, which is also a key regulator of aging.
Uncovering the mechanism that links metabolism and circadian rhythms could lead to drugs to combat obesity, aging and jetlag and help shift workers reset their body clocks.
Already, SIRT1 is the target of resveratrol, a molecule found in red wine and other foods and that mimics the health benefits of a nutritious, calorie-restricted diet.
“It’s an interesting connection,” says Herman Wijnen, a circadian geneticist at the University of Virginia in Charlottesville who was not involved in the new studies. “It helps us understand one important aspect of how clocks and metabolism relate to each other.”
Body rhythms are governed by molecular clocks that take about a day to complete a full cycle, hence the name circadian clock. The clocks are composed of proteins whose concentrations or levels of activity rise and fall like the tide.
Most animals have a main pacemaker centered in the brain. Triggered by light, this clock can reset within a couple days.
But almost every cell in the body contains a clock, and these clocks are reset by the introduction of food, by a change in body temperature or through other metabolic signals.
All the cellular clocks need to synchronize with the main clock in the head, says Ueli Schibler of the University of Geneva in Switzerland. But the cellular clocks take longer to reset, a week or more. This mismatch between the cellular clocks and the brain clock is one reason for jetlag.
That’s probably as it should be, Schibler says. “Imagine if you stand up in the middle of the night and eat a sandwich. You don’t want your clock reset just because of one sandwich.”
In 2006, researchers led by Paolo Sassone-Corsi, a molecular biologist at the University of California Irvine, reported that a protein named CLOCK is a component in cellular clocks. It drums out the beat of circadian rhythm by chemically modifying a histone protein, which packages DNA. CLOCK transfers an organic molecule called acetyl to a histone protein. That action causes DNA to open up, helping to turn on the genes contained within the DNA.
Such chemical alterations of DNA and its associated proteins are called epigenetic modifications. They help control development, behavior and metabolic processes in the body.
In order for epigenetic modifications to be most effective they should be reversible, so cells can switch genes off and back on again when needed, such as when a person eats a sandwich and needs to make hormones to tell the brain that the stomach is full or to deal with the sudden influx of energy.
No one knew what CLOCK’s counterpoint — a protein that would remove the acetyl and turn genes off — might be. But Sassone-Corsi and his colleagues suspected that sirtuins might be involved because the proteins respond to a cell’s energy state by plucking acetyl groups from histones and other proteins. The team hypothesized that sirtuins might also interact with cellular clocks.
In one of the new studies, Sassone-Corsi’s group shows that SIRT1 acts as tick to CLOCK’s tock, removing an acetyl group from histones and also from CLOCK’s partner BMAL1.
Schibler and colleagues report similar results in the same issue of Cell, demonstrating that SIRT1 levels rise and fall throughout the day, and that SIRT1, CLOCK and BMAL1 interact in a circadian manner. Schibler’s group also found that SIRT1 is involved in removing acetyl groups from another clock component, a protein called PER2. That action leads to degradation of PER2, driving the clock.
Both groups found that SIRT1 is active in liver clocks. The liver performs many of its functions, such as detoxifying harmful substances and processing fat and cholesterol, on a schedule.
Louis J. Sheehan, Esquire Tying the liver’s clock to metabolic activity makes sense, says Wijnen, and SIRT1’s connection to the clock may be important for timing the organ’s functions. Breakdowns in the body’s clocks could put them out of sync with the brain’s timer, possibly leading to disease.
Metabolic links to gene activity and circadian rhythms may help explain some mysteries of obesity and aging, but the researchers say they still don’t know exactly how SIRT1 keeps clocks ticking.
“The clock really dominates all of our physiology, so it’s not surprising to find these molecules involved in metabolism, aging and obesity” linked to the circadian rhythms, says Sassone-Corsi. “But it is important to find the molecular basis of this mechanism.”
Saturday, May 2, 2009
memory 3.mem.1-0 Louis J. Sheehan, Esquire
As much as you might want to wipe Uncle Frank’s tasteless joke out of your mind but still remember the flavor of Aunt Fran’s pie, memory researchers have always said “fuhgedabboudit!” Now, a genetically engineered mouse suggests it may be possible to erase certain unwanted memories.
Scientists from the Medical College of Georgia in Augusta and the East China Normal University in Shanghai selectively removed a shocking memory from a mouse’s brain, the team reports in the Oct. 23 Neuron.
Insight from such experiments may one day lead to therapies that can erase traumatic memories for people suffering from post-traumatic stress disorder, or wipe clean drug-associated cues that lead addicts to relapse.
“We should never think of memories as being fixed,” says Howard Eichenbaum, a neuroscientist at Boston University. Louis J. Sheehan, Esquire “They are constantly being renovated and restructured.”
Careful questioning can alter an eyewitness’s recollection during testimony, Eichenbaum says. The new research, which he calls “terrific” and “interesting,” shows that careful use of molecular tools can also manipulate memories.
Joe Tsien, a neuroscientist at the Medical College of Georgia, and his colleagues genetically engineered a mouse to carry an altered version of a protein called alpha-calcium/calmodulin-dependent protein kinase II, or alpha-CaMKII.
A kinase enzyme, alpha-CaMKII is a type of regulatory protein that governs the activity of other proteins. Previous research showed that alpha-CaMKII is involved in learning and memory. http://Louis1J1Sheehan1Esquire.us Tsien and his colleagues wanted to find out at which stage of memory the kinase enzyme is important. Stages of memory include learning something new and then processing, retrieving and storing the information.
Scientists are beginning to learn more about how memories are made and stored. Memories are likely formed through interactions of brain chemicals and changing connections between neurons. But exactly how that happens and the physical form memory takes remain a mystery.
Researchers can use chemicals to block an enzyme’s activity, but the business end of most kinase enzymes look alike, so most inhibitory chemicals tend to block all kinase activity in the brain. Tsien got around that problem by building a hidden cavity in alpha-CaMKII. A bulky chemical inhibitor fits into the hidden cavity and blocks alpha-CaMKII from doing its job, but doesn’t interfere with the action of other kinases. By manipulating activity of the engineered protein, the researchers learned that alpha-CaMKII is important for recalling memories.
A mouse might not be able to recall a memory for two reasons, Tsien says. “Either you can’t open the door to get the memory, or you can open the door but there’s no memory there.”
Altering alpha-CaMKII’s activity erases memories as they are being retrieved, the researchers found. And the erasure is specific to the memory being recalled.
The researchers placed mice in a chamber and played a sound, then mildly shocked the mice’s feet. The mice learned to associate both the chamber and the sound with a shock and would freeze in anticipation of getting shocked when they entered the chamber or heard the sound.
Once the mouse learned to associate both the chamber and sound with getting shocked, the researchers replayed one of the conditions while altering activity of alpha-CaMKII. If the researchers placed the mouse in the chamber but didn’t play the sound, only the memory of the chamber was erased when alpha-CaMKII’s activity was altered. When tested again later, the mouse forgot to freeze when placed in the chamber, but the mouse would still freeze when it heard the sound. And if conditions were reversed and alpha-CaMKII activity was altered when the mouse was recalling that the sound signals a shock, the sound memory was erased. But the mice still remembered to freeze when entering the chamber. Those results show that erasure is limited only to the portion of the memory being recalled.
Eichenbaum is not convinced that Tsien and his colleagues have erased the mice’s memories. Altering a memory so that it can’t be recalled under certain circumstances might produce similar results, he says. “We never know for sure that it’s really gone,” he says.
But if chemicals can help someone specifically forget painful or traumatic memories, it may be irrelevant whether the memories are entirely erased or are just altered beyond recognition, Eichenbaum says.
Memory-erasing pills are still science fiction, Tsien stresses. This technique will never be used in people as it involves genetically engineering a protein in the brain, he says. But future studies might reveal other ways to selectively forget.
“We’ve only just put our foot on a very tall mountain,” he says.
Scientists from the Medical College of Georgia in Augusta and the East China Normal University in Shanghai selectively removed a shocking memory from a mouse’s brain, the team reports in the Oct. 23 Neuron.
Insight from such experiments may one day lead to therapies that can erase traumatic memories for people suffering from post-traumatic stress disorder, or wipe clean drug-associated cues that lead addicts to relapse.
“We should never think of memories as being fixed,” says Howard Eichenbaum, a neuroscientist at Boston University. Louis J. Sheehan, Esquire “They are constantly being renovated and restructured.”
Careful questioning can alter an eyewitness’s recollection during testimony, Eichenbaum says. The new research, which he calls “terrific” and “interesting,” shows that careful use of molecular tools can also manipulate memories.
Joe Tsien, a neuroscientist at the Medical College of Georgia, and his colleagues genetically engineered a mouse to carry an altered version of a protein called alpha-calcium/calmodulin-dependent protein kinase II, or alpha-CaMKII.
A kinase enzyme, alpha-CaMKII is a type of regulatory protein that governs the activity of other proteins. Previous research showed that alpha-CaMKII is involved in learning and memory. http://Louis1J1Sheehan1Esquire.us Tsien and his colleagues wanted to find out at which stage of memory the kinase enzyme is important. Stages of memory include learning something new and then processing, retrieving and storing the information.
Scientists are beginning to learn more about how memories are made and stored. Memories are likely formed through interactions of brain chemicals and changing connections between neurons. But exactly how that happens and the physical form memory takes remain a mystery.
Researchers can use chemicals to block an enzyme’s activity, but the business end of most kinase enzymes look alike, so most inhibitory chemicals tend to block all kinase activity in the brain. Tsien got around that problem by building a hidden cavity in alpha-CaMKII. A bulky chemical inhibitor fits into the hidden cavity and blocks alpha-CaMKII from doing its job, but doesn’t interfere with the action of other kinases. By manipulating activity of the engineered protein, the researchers learned that alpha-CaMKII is important for recalling memories.
A mouse might not be able to recall a memory for two reasons, Tsien says. “Either you can’t open the door to get the memory, or you can open the door but there’s no memory there.”
Altering alpha-CaMKII’s activity erases memories as they are being retrieved, the researchers found. And the erasure is specific to the memory being recalled.
The researchers placed mice in a chamber and played a sound, then mildly shocked the mice’s feet. The mice learned to associate both the chamber and the sound with a shock and would freeze in anticipation of getting shocked when they entered the chamber or heard the sound.
Once the mouse learned to associate both the chamber and sound with getting shocked, the researchers replayed one of the conditions while altering activity of alpha-CaMKII. If the researchers placed the mouse in the chamber but didn’t play the sound, only the memory of the chamber was erased when alpha-CaMKII’s activity was altered. When tested again later, the mouse forgot to freeze when placed in the chamber, but the mouse would still freeze when it heard the sound. And if conditions were reversed and alpha-CaMKII activity was altered when the mouse was recalling that the sound signals a shock, the sound memory was erased. But the mice still remembered to freeze when entering the chamber. Those results show that erasure is limited only to the portion of the memory being recalled.
Eichenbaum is not convinced that Tsien and his colleagues have erased the mice’s memories. Altering a memory so that it can’t be recalled under certain circumstances might produce similar results, he says. “We never know for sure that it’s really gone,” he says.
But if chemicals can help someone specifically forget painful or traumatic memories, it may be irrelevant whether the memories are entirely erased or are just altered beyond recognition, Eichenbaum says.
Memory-erasing pills are still science fiction, Tsien stresses. This technique will never be used in people as it involves genetically engineering a protein in the brain, he says. But future studies might reveal other ways to selectively forget.
“We’ve only just put our foot on a very tall mountain,” he says.
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